Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH3:21])[C:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)=O.[NH:22]([C:24](OCC)=[O:25])[NH2:23].[Na]>Cl.C(O)C>[CH2:20]([CH:2]1[O:1][C:24](=[O:25])[NH:22][N:23]=[C:3]1[C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)[CH3:21]
Reactant: CCC(O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Reactant: CCOC(=O)NN
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCC1OC(=O)NN=C1c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (178 μmol) 2-hydroxy-1-(2-phenyl-benzoxazol-6-yl)-butan-1-one are refluxed together with 20.36 mg (196 μmol) ethyl hydrazinoformate, 1 drop of 0.1N hydrochloric acid and 500 μl ethanol for 10 min, then the solvent is completely removed i. V. The residue is dissolved in 2 ml dry ethanol. 40 mg (1740 μmol) sodium are dissolved in 1.2 ml dry ethanol and added dropwise to the first solution, the mixture is stirred overnight at RT, then separated by RP-HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:17]([NH:33][C:34]2[S:35][CH:36]=[N:37][N:38]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: O=C(NC1(C(=O)O)CCCC1)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)Nc2nncs2)CCCC1)OCc1ccccc1
Yield: 63.8 %

Procedure:
10 g of N-benzyloxycarbonylcycloleucine, 3.9 g of triethylamine, 150 ml of chloroform, 4.1 g of ethyl chlorocarbonate and 3.9 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example 1(i) to obtain 8.4 g (yield: 64%) of 2-(N-benzyloxycarbonyl-cycloleucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 229°-233° C.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]([NH2:15])=[C:8]([O:16][CH3:17])[C:7]=1[O:18][CH3:19].[O-:20][C:21]#[N:22].[K+].[OH-].[Na+]>O>[Cl:5][C:6]1[CH:14]=[C:10]2[C:9](=[C:8]([O:16][CH3:17])[C:7]=1[O:18][CH3:19])[NH:15][C:21](=[O:20])[NH:22][C:11]2=[O:13]
Reactant: N#C[O-]
Reactant: COc1c(Cl)cc(C(=O)O)c(N)c1OC
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(Cl)cc2c(=O)[nH]c(=O)[nH]c2c1OC
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Acetic acid (10.5 g., 0.175 mole) was added to a vigorously stirred suspension of 5-chloro-3,4-dimethoxyanthranilic acid (28.9 g., 0.125 mole) in 600 ml. water. Then 506 ml. 5% potassium cyanate (0.312 mole) solution was gradually added and stirred 1 hour at 40° C. After cooling the reaction mixture to 20° C., 175 g. (4.37 moles) of sodium hydroxide pellets were added while maintaining the temperature below 40° C. The reaction mixture was heated to 90° C. for 45 minutes. Upon cooling in an ice bath, the sodium salt of the product precipitated, was filtered, resuspended in 125 ml. water, acidified with concentrated hydrochloric acid, cooled and filtered to yield 25.8 g. (80%) of colorless, pure product, M.P. 272°-3° C.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[NH:67]1[CH2:72][CH2:71][CH:70]([O:73][C:74]2[CH:81]=[CH:80][C:77]([CH:78]=O)=[CH:76][CH:75]=2)[CH2:69][CH2:68]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:76]=[CH:75][C:74]([O:73][CH:70]4[CH2:71][CH2:72][NH:67][CH2:68][CH2:69]4)=[CH:81][CH:80]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: O=Cc1ccc(OC2CCNCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(OC4CCNCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 24 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-(piperidin-4-yloxy)benzaldehyde (1.2 eq, 0.091 mmol, 22 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (10 mg, 24%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.77-1.81 (m, 2H, 2× piperidine CHAHB), 2.09-2.11 (m, 2H, 2× piperidine CHAHB), 2.62 (s, br, 4H, piperazine N(CH2)2), 3.00-3.07 (m, 2H, 2× piperidine CHAHB), 3.20-3.24 (m, 2H, 2× piperidine CHAHB), 3.62 (s, 2H, NCH2), 3.66 (s, br, 4H, piperazine N(CH2)2), 4.70-4.76 (m, 1H, piperidine CH), 7.15 (d, J=8.9 Hz, 2H, phenyl H-3 & H-5), 7.39 (dd, J=7.6, 4.7 Hz, 1H, pyridine H-5), 7.78 (d, br, J=7.8 Hz, pyridine H-4), 8.13 (d, J=8.7 Hz, 2H, phenyl H-2 & H-6), 8.21 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.7, 1.4 Hz, 1H, pyridine H-6), 8.56 (s, br, 1H, pyridine H-2), 13.42 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH2:7][C:8]([S:10][C:5]=2[CH:4]=1)=[O:9].[CH:13](=O)[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]>C(O)C.C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]3[CH:13]([S:10][C:5]=2[CH:4]=1)[C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[O:16][C:8]3=[O:9]
Reactant: COc1ccc2c(c1)SC(=O)C2
Reactant: O=Cc1ccccc1O
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)SC1c3ccccc3OC(=O)C21
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a stirred solution of 6-methoxythianaphthen-2-one (52.6 g, 290 mmol) in a mixture of ethanol (260 mL) and methylene chloride (130 mL) was added triethylamine (2.0 mL, 14.8 mmol) followed by salicylaldehyde (32 mL, 300 mmol) at room temperature. After 1 h, a solid began to precipitate and stirring was continued for 3.5 h. The mixture was then diluted with cold hexane and filtered to yield 68.3 g (83%) of the title product as a powdery white solid, pure by 1H-NMR analysis: 1H NMR (300 MHz, CDCl3) δ 7.45 (d, J=7.5 Hz, 1H), 7.33 (m, 2H), 7.17 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.69 (dd, J=2.4, 8.5 Hz, 1H), 5.25 (d, J=7.4 Hz, 1H), 4.37 (d, J=7.3 Hz, 1H), 3.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.4, 160.7, 150.8, 141.4, 130.1, 129.0, 127.7, 127.0, 124.9, 119.5, 117.2, 111.2, 108.3, 55.5, 50.6, 49.6; IR (CHCl3) 1766 cm-1 ; MS (FD) m/e 284 (M+); Anal. calc'd. for C16H12O3S: C, 67.59; H, 4.26. Found: C, 67.77; H, 4.24.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][NH:13][CH2:14][CH3:15]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([CH2:14][CH3:15])[CH3:12])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CCNC
Product: CCN(C)C(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and N-methyl-ethanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@@H:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:15]([C:24]([O:26]C)=[O:25])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Li+].O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@@H:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:15]([C:24]([OH:26])=[O:25])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)C2(c3ccc(Cl)cc3)CC2)C[C@H]1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CN(C(=O)C2(c3ccc(Cl)cc3)CC2)C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl (3S,4R)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-4-phenylpyrrolidine-3-carboxylate (50 mg, 0.0001 mol, example 39) in tetrahydrofuran (2 mL, 0.02 mol) was added lithium hydroxide (9.4 mg, 0.00039 mol) and water (0.5 mL, 0.03 mol) and the solution was stirred at rt for 1 h. The reaction mixture was then acidified (pH ˜2) and was extracted with AcOEt. The organic layer was dried (over MgSO4), and concentrated to afford the product. LCMS: m/z 370.4 (M+H)+
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=1.[NH2:10][C:11]1[C:31]([Cl:32])=[CH:30][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][NH2:27])[CH2:20][C@H:19]2[O:28][CH3:29])=[O:16])=[C:13]([O:33][CH3:34])[CH:12]=1>C(#N)C>[OH2:9].[NH2:10][C:11]1[C:31]([Cl:32])=[CH:30][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][NH:27][C:3]3[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=3)[CH2:20][C@H:19]2[O:28][CH3:29])=[O:16])=[C:13]([O:33][CH3:34])[CH:12]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN)C[C@H]1OC
Reactant: CSc1nccc(O)n1
Solvent: CC#N
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCNc2nccc(O)n2)C[C@H]1OC
Product: O
Reaction time: 40 h
Yield: 39.5 %

Procedure:
A mixture of 1.56 parts of 2-(methylthio)-4-pyrimidinol, 3.7 parts of cis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide and 64 parts of acetonitrile was stirred for 40 hours at reflux temperature. Another portion of 0.7 parts of 2-(methylthio)-4-pyrimidinol was added and stirring was continued over weekend at reflux temperature. The reaction mixture was evaporated. The residue was taken up in trichloromethane. The whole was washed with water, saturated with ammonium hydroxide, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.82 parts (39.5%) of cis-4-amino-5-chloro-N-[1-[3-[(4-hydroxy-2-pyrimidinyl)amino]propyl]-3-methoxy-4-piperidinyl]- 2-methoxybenzamide monohydrate; mp. 134.2° C. (compound 42).
Reaction SMILES: [Cl:1][C:2]1C(O)=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.[C:21](=[O:24])([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([O:31][CH3:32])=[O:30].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[C:3]=1[O:24][CH3:21]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCl
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1F
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC#N
Product: COC(=O)c1cc(N2C(=O)C3=CCCCN3C2=O)c(F)c(OC)c1Cl
Yield: 86.8 %

Procedure:
An acetonitrile (10 mL) solution of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.59 g, 2.0 mmol), potassium carbonate (0.2 g, 2.2 mmol) and methyl chloroacetate (0.2 mL, 2.2 mmol) was stirred for 5 hours under reflux. A saturated ammonium chloride solution (10 mL) was added to the resulting mixture, and the organic layer was separated and then the aqueous layer was extracted with diethyl ether (10 mL×2 times). The organic layer combined was washed with a saturated sodium chloride solution (20 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane =1/2) to obtain 2-(4-chloro-2-fluoro-5-methoxycarbonyl-methoxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.64 g, yield:86.5%).
Reaction SMILES: [CH2:1]([N:7]([CH2:14][C:15]#[N:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:17]1([S:23]([O:26]C)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C>[C:17]1([S:23]([O-:26])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:15]([CH2:14][N+:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:17])#[N:16]
Reactant: COS(=O)(=O)c1ccccc1
Reactant: CCCCCCN(CC#N)CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC[N+](C)(CC#N)CCCCCC
Product: O=S(=O)([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
18.0 g (0.08 mol) of dihexylaminoacetonitrile were initially introduced into 50 ml of ethyl acetate. 13.8 g (0.08 mol) of methyl benzenesulfonate were added dropwise to this solution at room temperature over the course of 10 min. The mixture was stirred for 24 hours at room temperature, and the clear solution was concentrated by evaporation on a rotary evaporator. The residue was stirred out with diethyl ether and the precipitated solid was filtered off with suction. It was washed with diethyl ether and then dried at 50° C. in a vacuum drying cabinet. This gave 20.5 g (0.052 mol) of (cyanomethyl)-di-n-methylammonium benzenesulfonate of a white powder, corresponding to a yield of 65%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](C(OC(C)(C)C)=O)[CH:7]=[C:6]2[C:19]1[N:31]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:22]2=[N:23][CH:24]=[C:25]3[CH:29]=[N:28][N:27]([CH3:30])[C:26]3=[C:21]2[CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:19]1[N:31]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:22]2=[N:23][CH:24]=[C:25]3[CH:29]=[N:28][N:27]([CH3:30])[C:26]3=[C:21]2[CH:20]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2[nH]cc(-c3cc4c5c(cnc4n3S(=O)(=O)c3ccc(C)cc3)cnn5C)c2c1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
tert-Butyl 5-methoxy-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indole-1-carboxylate (1.75 g, 3.06 mmol; Preparation #D.1) in DCM (30 mL) was treated with TFA (5.9 mL, 77 mmol) and then stirred at rt. After about 3 h the mixture was concentrated and diluted with water (50 mL). The mixture was extracted with DCM (3×25 mL) then the combined organics were dried over anhydrous MgSO4, filtered then concentrated under reduced pressure. The material was purified by flash chromatography on 80 g of silica gel using 8:2 DCM/EtOAc as an eluent to give 7-(5-methoxy-1H-indol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (1.11 g, 77%): LC/MS (Table 2, Method a) Rt=2.34 min; MS m/z 472 (M+H)+.
Reaction SMILES: [CH:1]1C2C(COC(N[C@H](CO)CCC)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:25]([NH:42][C@H:43]([C:47]([OH:49])=[O:48])[CH2:44][CH2:45][CH3:46])([O:27][CH2:28][CH:29]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26].S(Cl)(Cl)=O>CO.C(OCC)(=O)C>[CH3:1][O:48][C:47](=[O:49])[C@H:43]([CH2:44][CH2:45][CH3:46])[NH:42][C:25]([O:27][CH2:28][CH:29]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=2[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:26]
Reactant: CCC[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC

Procedure:
FIG. 11 depicts a reaction scheme for the synthesis of 11-2b, 9-fluorenylmethoxy-carbonyl-norvalinol, a description of the synthesis of which follows. To a chilled solution of Fmoc-norvaline (25 g, 73.75 mmol) in anhydrous methanol (469 ml), was added thionyl chloride (53.76 ml, 737.5 mmol) over one hour. Thin layer chromatography in ethyl acetate after an hour confirmed the completion of the reaction (Rf=0.85). The reaction mixture was concentrated and the remaining residue was dissolved in ethyl acetate. The organic layer was washed with several 200 ml portions of saturated sodium bicarbonate followed by brine. The organic layer was dried and concentrated to afford the title compound 9-fluorenylmethoxy-carbonyl-norvaline methyl ester 11-2a as a white solid (26.03 g) in quantitative yield. NMR δ ppm (CD3OD): 7.7 (m, 2H), 7.6 (m, 2H), 7.4 (m, 2H), 7.3 (m, 2H), 4.3 (m, 2H), 4.1 (m, 2H), 3.7 (s, 3H), 1.7 (m, 1H), 1.6 (m, 1H), 1.4 (m, 2H), 0.95 (t, 3H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([NH:14][CH2:15][CH2:16][CH3:17])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])C.C([CH:20]([C:24](Cl)=[O:25])[C:21](Cl)=[O:22])C.[CH2:27]([O:29]CC)[CH3:28]>>[CH2:27]([O:29][C:24]([C:20]1[C:21](=[O:22])[N:14]([CH2:15][CH2:16][CH3:17])[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[C:4]=1[OH:5])=[O:25])[CH3:28]
Reactant: CCCNc1nc(SC)ncc1C(=O)OCC
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: CCOCC
Product: CCCn1c(=O)c(C(=O)OCC)c(O)c2cnc(SC)nc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 12.8 g. (0.05 mole) of 2-methylthio-4-propylamino-5-pyrimidine carboxylic acid ethyl ester in 100 ml. of anhydrous diethyl ether was added 0.75 g. (0.025 mole) of ethyl malonyl chloride. The mixture was stirred at room temperature for 4 hours and was filtered. The filtrate was evaporated in a rotary evaporator and the residue was dissolved in 15 ml. of ethanol and this solution was added to a solution of 1.15 g. (0.05 g atom) of sodium in 100 ml. of ethanol. After stirring at room temperature for 5 minutes, the mixture was diluted with water to the cloudy point and was acidified with conc. hydrochloric acid. The precipitate which formed was collected, air dried and was recrystallized from ethyl acetate to give 0.2 g. of title product--m.p. 130°-133° C.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][NH2:8])[CH2:2][CH2:3][CH3:4].Br[CH2:15][CH:16]1[O:20][CH:19]([CH3:21])[CH:18]([CH3:22])[O:17]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:10]([O:9][CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][NH:8][CH2:15][CH:16]1[O:20][CH:19]([CH3:21])[CH:18]([CH3:22])[O:17]1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOC(CN)OCCCC
Reactant: CC1OC(CBr)OC1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCOC(CNCC1OC(C)C(C)O1)OCCCC
Temperature: 25 °C

Procedure:
2,2-Dibutoxyethylamine (0.11 mole), 2-bromomethyl-4,5-dimethyl-1,3-dioxolane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2,2dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)amine.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])([CH3:23])[CH3:22]>ClCCl.N1C=CC=CC=1>[CH3:22][CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[CH:21]([CH3:23])[CH3:22])=[O:13])[CH3:23]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: CC(C)c1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1C(C)C
Yield: 14.3 %

Procedure:
This compound was prepared according to the general method of Example 90 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2-isopropylaniline (1.60 g, 11.6 mmol) in 13 mL of pyridine. The crude product was recrystallized twice from acetonitrile-DMF to yield 0.45 g of the title compound, mp 235°-237° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:26][C:27]([OH:29])=[O:28])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3ncccc3c2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1

Procedure:
prepared by reaction of 4-tert-butyl-N-quinolin-6-yl-benzenesulfonamide with tert-butyl bromoacetate
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7][CH3:8])=[N:5][N:6]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([C:2]3[S:3][C:4]([S:7][CH3:8])=[N:5][N:6]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: CSc1nnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSc1nnc(-c2ccc3[nH]ccc3c2)s1
Temperature: 110 °C
Yield: 47 %

Procedure:
To a solution of 2-bromo-5-(methylthio)-1,3,4-thiadiazole (18.5 g, 87 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (21 g, 86 mmol) in p-dioxane (5 mL)/H2O (5 mL) was added Pd(PPh3)4 (15.1 g, 13 mmol) followed by K2CO3 (48.2 g, 349 mmol). The reaction was heated under argon atmosphere at 110° C. for 4 h, then cooled to RT. The mixture was diluted with EtOAc and H2O, and the two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The crude material was recrystallized in EtOH to give 2-(1H-indol-5-yl)-5-(methylthio)-1,3,4-thiadiazole (10 g, 50%) as an off-white solid. MS (ESI, pos. ion) m/z: 247.8 (M+1). 1H-NMR (DMSO-d6, 300 MHz): 2.8 (s, 3H), 6.6 (d, 1H), 7.5 (t, 1H), 7.55 (dd, 1H), 8.1 (s, 1H), 11.5 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.7 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (43.4 mg, 36%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[NH2:13])=O.[NH2:14][C:15](N)=[O:16]>O>[OH:16][C:15]1[N:14]=[CH:1][C:3]2[C:4](=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=2)[N:13]=1
Reactant: NC(N)=O
Reactant: COC(=O)c1ccc(C=O)c(N)c1
Solvent: O
Product: COC(=O)c1ccc2cnc(O)nc2c1
Temperature: 145 °C

Procedure:
To methyl 4-formyl-3-aminobenzoate (1 eq) was added urea (5 eq) and the mixture was heated to 145° C. for 16 h. To the crude was added water and the precipitated solid was filtered to give methyl 2-hydroxyquinazolin-7-carboxylate in quantitative yield. ES/MS m/z 205 (MH+).