Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]3)[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)#[N:30]>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:35]3[CH:36]=[C:31]([CH:32]=[CH:33][CH:34]=3)[C:29]#[N:30])[C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:15][CH2:16][C:17]([F:21])([F:20])[CH2:18][CH2:19]3)[C:4]=2[N:3]=1
Reactant: C[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCC(F)(F)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1C(=O)N(c2cccc(C#N)c2)c2cnc(Cl)nc2N1C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51 %

Procedure:
To a stirred solution of (7R)-2-chloro-8-(4,4-difluorocyclohexyl)-7-methyl-7,8-dihydropteridin-6(5H)-one (1.80 g, 5.7 mmol) in dichloromethane (75 mL) was added triethylamine (8.07 ml, 57.8 mmol), cupric acetate (2.09 g, 11.56 mmol) and (3-cyanophenyl)boronic acid (1.69 g, 11.56 mmol) followed by 4 Å molecular sieves (2 g). The reaction mixture was stirred for 48 h at rt with an air balloon on the top. The reaction mixture was then filtered over celite to give a clear solution. The solution was washed with aqueous saturated sodium bicarbonate (50 mL×2), dried over anhydrous sodium sulfate and evaporated to give a crude material, which was then purified by silica gel column chromatography (eluent: 2% methanol in dichloromethane) to give the desired product (51%). 1HNMR (300 MHz, CDCl3): δ 1.50 (d, J=6.9 Hz, 3H), 1.80-2.24 (m, 8H), 4.40-4.61 (m, 2H), 7.20-7.26 (m, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.55 (s, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[C:30]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH2:42])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][N:42]2[CH2:23][CH2:22][C:6]3([CH2:7][CH2:8][N:9]([S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])(=[O:13])=[O:14])[CH2:10][CH2:11]3)[C:4]2=[O:3])=[CH:38][CH:39]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(CCN)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CCN2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(4-tert-Butyl-phenyl)-ethylamine. MS (ESI): 489.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[I:15]N1C(=O)CCC1=O.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[C:9]=1[I:15]
Reactant: O=C1CCC(=O)N1I
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c[nH]c(-c2ccccc2F)c1I
Reaction time: 12 h
Yield: 13.5 %

Procedure:
5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (2.0 g) was dissolved in N,N-dimethylformamide (60 mL), N-iodosuccinimide (2.38 g) was added and the mixture was stirred at for 12 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate solution, a 3% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:3→1:1) to give the title compound as a pale-brown powder (yield 450 mg, 14%).
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[CH3:14][Si:15](Cl)([CH3:17])[CH3:16].C(OC)(C)(C)C>O1CCCC1.O>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:15]([CH3:17])([CH3:16])[CH3:14])[C:8]=1[F:13]
Reactant: C[Si](C)(C)Cl
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
625 ml (1 mol) of 1.6 M BuLi are added dropwise at −78° C. to a solution of 114 g (1 mol) of 1,2-difluorobenzene in 1 l of dry tetrahydrofuran. After 1 hour, 140 ml (120 g, 1.1 mol) of trimethylsilyl chloride are slowly added dropwise at −78° C. The mixture is allowed to warm to room temperature overnight, and then 200 ml of methyl tert-butyl ether and 200 ml of water are added. The organic phase is washed with water (2×100 ml) and sat. NaCl (1×100 ml) and dried using magnesium sulfate, and the solvent is removed under reduced pressure. 170 g (91%) of 5 distil over from the residue at from 100 to 102° C./70 mbar.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CN(C)C=O>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:6]=1[C:7]#[N:8])([O-:12])=[O:11]
Reactant: C1CCNCC1
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
63.9 g of 5-chloro-2-nitrobenzonitrile was dissolved in 200 ml of dimethylformamide, and 95 ml of piperidine was added to the solution. The mixture was stirred at 50° C. for 30 minutes while externally cooling because of heat generation. The reaction mixture was poured into water, and the precipitate thus formed was collected, washed with water and then with methanol, and dried to obtain 80 g of 2-nitro-5-piperidinobenzonitrile (melting point: 126°-127° C.).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([Cl:13])=[O:12])[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][NH2:22])[CH3:15]>>[ClH:13].[CH2:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][NH:22][C:11]([C:10]1[C:5]2[O:4][CH2:3][CH2:2][O:1][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12])[CH3:15]
Reactant: CCN1CCCC1CN
Reactant: O=C(Cl)c1cccc2c1OCCO2
Product: CCN1CCCC1CNC(=O)c1cccc2c1OCCO2
Product: Cl

Procedure:
In the same manner as described in Example 17, by reaction of 1,4-benzodioxane-5-carbonyl chloride with the 1-ethyl-2-aminomethyl pyrrolidine, the N-(1-ethyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-carboxamide hydrochloride was obtained (M.P.: 149°-150° C.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CC(N(C)C)=O>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:22][CH2:21][CH2:20][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:10])[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: NCCN1CCOCC1
Reactant: Cc1nc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1nc(C(=O)NCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of 6-methyl-5-nitropyridine-2-carboxylic acid (0.500 g, 3.0 mmol) in DCM (7 mL) were added 2-morpholin-4-ylethanamine (1.0 mL, 7.7 mmol), TBTU (0.992 g, 3.1 mmol), and DMA (1.34 mL, 7.7 mmol). The reaction mixture was allowed to stir at rt overnight and then quenched with water. The organic solution was separated and the aqueous solution was extracted with DCM. The organic solutions were combined and concentrated. The residue was purified by column chromatography to give 6-methyl-N-(2-morpholin-4-ylethyl)-5-nitropyridine-2-carboxamide (0.27 g, 30%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:3]1[CH:17]=CC1C=CC=CC=1.I([O-])(=O)(=O)=[O:26].[Na+].O>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH:17]([C:3]1[CH:2]([OH:1])[CH2:6][C:5](=[O:7])[C:4]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:26]
Reactant: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=CC1=C(CCCCCCC(=O)O)C(=O)CC1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture consisting of 13 parts of dl- 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoic acid, 17.8 parts of sodium periodate, 55 parts of water, 160 parts of dioxane and 2 parts of a 2% osmium tetroxide in dioxane solution is stirred under nitrogen at room temperature for about 4 hours. That reaction mixture is then extracted with ether and the ether layer is separated and extracted several times with 0.5% aqueous sodium chloride. The salt extracts are saturated with sodium chloride, then extracted with ether. The ether layer is separated, dried over anhydrous sodium sulfate, concentrated and dried under reduced pressure to afford dl- 2-formyl-3-hydroxy-5-oxocyclopent-1-eneheptanoic acid, characterized by an ultraviolet absorption maximum at about 228 millimicrons with a molecular extinction coefficient of about 10,100.
Reaction SMILES: F[C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[S:11][C:10](=[NH:12])[N:9]([CH2:13][CH2:14][O:15][CH3:16])[CH:8]=2)=[CH:4][CH:3]=1.[CH2:19]1[CH:26]2[C:22]3([C:28]([OH:30])=O)[CH2:23][CH:24]([CH2:27][CH:20]1[CH2:21]3)[CH2:25]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:48][P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:48][C:17]1[CH:18]=[CH:2][CH:3]=[CH:4][C:5]=1[CH2:6][C:7]1[S:11]/[C:10](=[N:12]\[C:28]([C:22]23[CH2:23][CH:24]4[CH2:27][CH:20]([CH2:19][CH:26]2[CH2:25]4)[CH2:21]3)=[O:30])/[N:9]([CH2:13][CH2:14][O:15][CH3:16])[CH:8]=1
Reactant: COCCn1cc(Cc2ccc(F)cc2)sc1=N
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: F[P-](F)(F)(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCn1cc(Cc2ccccc2F)s/c1=N\C(=O)C12CC3CC(CC1C3)C2

Procedure:
A mixture of the product of Example 44A (342 mg, 1.29 mmol), hexahydro-2,5-methano-pentalene-3a-carboxylic acid (256 mg, 1.54 mmol), HATU (737 mg, 1.24 mmol) and triethylamine (1.08 mL, 7.74 mmol) in 20 mL of DMF was processed according to the method of Example 43B to afford the title compound: 1H NMR (500 MHz, DMSO-d6) δ 1.51-1.61 (m, 4H) 1.65-1.74 (m, 4H) 2.07 (d, J=9.2 Hz, 2H) 2.22-2.26 (m, 2H) 2.51-2.53 (m, 1H) 3.24 (s, 3H) 3.66 (t, J=5.3 Hz, 2H) 3.98 (s, 2H) 4.23 (t, J=5.3 Hz, 2H) 7.16-7.22 (m, 3H) 7.23 (s, 1H) 7.29-7.38 (m, 2H); MS (DCI/NH3) m/z 415 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH2:45]([O:52][C:53](=[O:74])[C@H:54]([CH2:70][CH2:71][S:72][CH3:73])[NH:55][C:56](=[O:69])[C@H:57]([CH2:59][C:60]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[NH:62][CH:61]=1)[NH2:58])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C=O.O>[CH2:45]([O:52][C:53](=[O:74])[C@H:54]([CH2:70][CH2:71][S:72][CH3:73])[NH:55][C:56](=[O:69])[C@H:57]([CH2:59][C:60]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[NH:62][CH:61]=1)[NH:58][C:26](=[O:27])[CH2:25][NH:24][C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CSCC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
10.0 Parts N-t-butoxycarbonyl-L-tyrosylglycylglycine and 2.4 parts N-methylmorpholine are dissolved in 125 parts dimethylformamide and cooled to -15° C. Then 3.8 parts isobutyl chloroformate is added dropwise over a 30 minute period while maintaining the temperature at -15° C. Then, a solution of 12.7 parts L-tryptophyl-L-methionine benzyl ester hydrochloride in 50 parts dimethylformamide is slowly added at -15° C. and the mixture is stirred at this temperature for 30 minutes. The cooling apparatus is removed and the mixture is stirred at ambient temperature for an additional 2 hours. The product is isolated by diluting the reaction mixture with 10 volumes water and extracting with ethyl acetate. The ethyl acetate extracts are combined, dried over anhydrous sodium sulfate and stripped to dryness under reduced pressure. Purification of the residue by low pressure column chromatography affords N-t-butoxycarbonyl-L-tyrosylglycylglycyl-L-tryptophyl-L-methionine benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[C:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)=[O:15])[C:5](F)=[CH:4][N:3]=1.CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:16]([CH:17]3[CH2:19][CH2:18]3)[C:14](=[O:15])[CH:9]3[CH2:10][O:11][CH2:12][CH2:13][N:8]3[C:6]=2[N:7]=1
Reactant: O=C(NC1CC1)C1COCCN1c1nc(Cl)ncc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
A scintillation vial equipped with a magnetic stirrer was added 4-(2-chloro-5-fluoropyrimidin-4-yl)-N-cyclopropylmorpholine-3-carboxamide (325 mg, 1.081 mmol), DMF (5 ml), Cs2CO3 (528 mg, 1.621 mmol). The reaction was stirred at 60° C. for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate three times and the combined organic layers washed with sat. NaCl. The organic layers were dried with Na2SO4, filtered and dried in-vacuo to give a yellow solid. The crude material was washed with diethyl ether and filtered to afford 2-chloro-5-cyclopropyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (121 mg, 0.431 mmol, 39.9% yield) as a white solid. MS [M+H] found 281.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:41][C:38]2[C:39]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]1)=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccccc3F)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]#[N:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>FC(F)(F)C(O)C(F)(F)F>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:13][CH2:14][N:15]([C:18]([NH:25][C:24]4[CH:26]=[CH:27][C:21]([F:20])=[CH:22][CH:23]=4)=[NH:19])[CH2:16][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#CN1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: Nc1ccc(F)cc1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: N=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(4-cyanopiperazin-1-yl)quinoline (150 mg, 0.55 mmol) and 4-fluoroaniline (66 μL, 0.7 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (5 mL) are heated at 150° C. in a sealed tube for 66 h. The reaction mixture is concentrated, and the residue is purified by column chromatography with CH2Cl2—NH3-MeOH to give the title product as a colorless foam.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:32])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21][C:22]4[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=4)=[C:17]([Cl:28])[CH:16]=3)=[C:12]([C:29]#[N:30])[CH:11]=[N:10][N:9]2[CH:31]=1)=[O:5])C.[OH-].[Na+].CCO.C1COCC1.Cl>CCOC(C)=O>[Cl:28][C:17]1[CH:16]=[C:15]([NH:14][C:13]2[C:8]3[N:9]([CH:31]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=3[CH3:32])[N:10]=[CH:11][C:12]=2[C:29]#[N:30])[CH:20]=[CH:19][C:18]=1[S:21][C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=1
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cn2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
A mixture of 426 (70 mg, 0.15 mmol) and 6N NaOH (2 ml, 1.0 mmol) in a mixed solvents of EtOH/THF (2/1) (3 ml) was stirred at rt for 2 days. Neutralized with concentrated HCl to PH=6, treated with EtOAc (50 ml), the mixture was washed with H2O (2×20 ml) and brine (20 ml), dried with Na2SO4. Removal of the solvent gave 428A (55 mg, 93%) as a yellow solid. The product was used in next step without further purification. It has a retention time of 4.73 min (standard LC1 method, 8 min run). MS Found: (M+H)+=439.1
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])(=[O:31])=[O:30]
Reactant: CC(CO)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 0.25 h

Procedure:
Triethylamine (10 cc) is added with stirring to a solution, cooled to a temperature in the region of 5° C., of 10-(1-hydroxy-2-propyl)-2-phenothiazinecarbonitrile, L series (12.6 g) in methylene chloride (126 cc), a solution of methanesulphonyl chloride (5.6 cc) in methylene chloride (56 cc) is then introduced dropwise during 25 minutes, and stirring is continued for 1 hour 15 minutes at a temperature in the region of 10°-15° C. The reaction mixture is washed successively with distilled water (2×100 cc) and with saturated aqueous sodium chloride solution (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 2-(2-Cyano-10-phenothiazinyl)-1-propyl methanesulphonate, L series (16.2 g) is thereby obtained in the form of an orange oil, which is used without further purification for the next stage of the syntheses.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([S:11][CH3:12])[S:10][C:3]=12.[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:23][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([S:11][CH3:12])[S:10][C:3]=12
Reactant: CSc1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CSc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 200 °C
Yield: 0.1 %

Procedure:
To a suspension of 229 (100 mg, 0.463 mmol) in diphenyl ether (4 mL), was added 2-fluoro-4-nitrophenol (109 mg, 0.695 mmol) and sodium carbonate (147 mg, 1.39 mmol). The reaction mixture was heated atr 200° C. overnight, cooled to room temperature, loaded onto a flash chromatography column and eluted with EtOAc/hexane (1:1) to afford title compound 230 (0.135 mg, 86% yield) as a yellow solid. MS (m/z): 337.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][CH2:30][CH2:31][OH:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:32][CH2:31][CH2:30][CH2:29][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C@H:7]([NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])=[CH:25][CH:24]=1
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCO)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.6 %

Procedure:
A mixture of N-(benzyloxycarbonyl)-L-tyrosine tert-butyl ester (0.37 g, 1.0 mmol), 3-bromo-1-propanol (0.09 mL, 1.0 mmol), and cesium carbonate (0.33 g, 1.0 mmol) in anhydrous N,N-dimethylformamide (5 mL) was stirred at room temperature for 24 h. The reaction mixture was evaporated to dryness under high vacuum and the residue was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The ethyl acetate extracts were combined and washed once with saturated sodium bicarbonate and brine. The ethyl acetate was dried and evaporated to dryness. The residue was purified on a silica gel column (10 g Waters Sep-Pak) by eluting with a gradient of ethyl acetate and hexane from 20:80 to 30:70. The pure fractions were combined and evaporated to dryness to give the title compound (0.269 g, 63% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ7.34 (m, 5H), 7.05 (d, J=8.6 Hz, 2H), 6.80 (m, 2H), 5.22 (d, J=8.1 Hz, 1H), 5.10 (d, J=2.8 Hz, 2H), 4.48 (q, J=8.1 Hz, 1H), 4.09 (t, J=6.0 Hz, 2H), 3.86 (t, J=6.0 Hz, 2H), 3.02 (m, 2H), 2.03 (p, J=6.0 Hz, 2H), 1.41 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:46])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[C:16]1[C:17]([C:37]2C(C)=CC(C)=CC=2C)=[N:18][N:19]2[C:24]3[NH:25][CH2:26][CH2:27][C:23]=3[C:22]([C:28]3C(C)=CC(C)=CC=3C)=[N:21][C:20]=12.[C:47](Cl)(=[O:51])[CH2:48][CH2:49][CH3:50].O>ClCCl>[C:10]1([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=[C:8]([CH3:46])[C:9]=1[C:16]1[C:17]([CH3:37])=[N:18][N:19]2[C:24]3[N:25]([C:47](=[O:51])[CH2:48][CH2:49][CH3:50])[CH2:26][CH2:27][C:23]=3[C:22]([CH3:28])=[N:21][C:20]=12
Reactant: Cc1cc(C)c(-c2nc3c(-c4c(C)cc(C)cc4C)c(-c4c(C)cc(C)cc4C)nn3c3c2CCN3)c(C)c1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Reaction time: 2 h
Yield: 42.4 %

Procedure:
Triethylamine (0.091 mL, 0.652 mmol) was added to a solution of 3-mesityl-2,5-dimesityl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (100 mg, 0.326 mmol) which was prepared in Example 71 in dichloromethane (4 mL), butyryl chloride (0.037 mL, 0.358 mmol) was added dropwise at room temperature, followed by stirring for two hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with brine, and then dried over MgSO4. The solvent was evaporated, and the residue was subjected to silica gel column cromatography (7 g), to give the title compound (52 mg, 42%) as a pale yellow oil from a fraction of ethyl acetate-hexane (1:4 v/v).
Reaction SMILES: N[C@H]([C:7]([OH:9])=[O:8])CC(=O)O.NCC(O)=O.N[C@H](C(O)=O)[CH2:17][CH:18]([CH3:20])[CH3:19].[NH2:24][C@H:25]([C:34]([OH:36])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1.N[C@H](C(O)=O)CC1C=CC=CC=1.N[C@H](C(O)=O)CCCCN>>[NH:24]([C:7]([O:9][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:8])[C@H:25]([C:34]([OH:36])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: NCC(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Yield: 213 mg Rf value: 0.50 (n-butanol:pyridine:acetic acid: water=5:5:1:4) Amino acid analysis: Asp 1.98; Gly 1.00; Leu 0.99; Tyr 0.97; Phe 1.00; Lys 0.98; Pro 2.10