Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[N:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1/[CH:21]=[C:31]1\[C:32](=[O:38])[NH:33][C:34]2[C:30]\1=[C:29]([C:26]1[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=1)[CH:37]=[CH:36][CH:35]=2
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4ccncc4)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 54 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 4-pyridin-4-yl-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-3-methyl-2-(2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-piperidin -1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 54 (40 mg, yield 54%) as a yellow solid.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:21](/B(O)O)=[CH:22]\[CH2:23][CH2:24][CH2:25][CH3:26]>>[CH:21](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:22]\[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCC/C=C/B(O)O
Reactant: Brc1cnc2ccc(NCCCN3CCOCC3)nn12
Product: CCCC/C=C/c1cnc2ccc(NCCCN3CCOCC3)nn12

Procedure:
Prepared from the product of step A (example 16) and (E)-1-hexeneboronic acid according to general procedure 2 providing the alkene (100 mg, 90%) as a brown oil; 1H NMR (500 MHz, CD3OD) δ 7.51 (d, J=9.6 Hz, 1H), 7.41 (s, 1H), 6.75 (dt, J=7.0, 16.1 Hz, 1H), 6.62-6.58 (m, 2H), 3.70 (t, J=4.8 Hz, 4H), 3.41 (t, J=6.9 Hz, 2H), 2.52 (m, 6H), 2.30-2.26 (m, 2H), 1.94-1.88 (m, 2H), 1.52-1.41 (m, 4H), 0.96 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:27]3[C@H:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:27]3[C@H:23]([CH2:24][N:25]([C:8](=[O:10])[C@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH3:11])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Reaction time: 0.67 h
Yield: 57.3 %

Procedure:
N,N'-Carbonyldiimidazole (0.66 g) is added to a solution of (S)-2-phenylpropionic acid (0.62 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 40 minutes at +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.35 g) and triethylamine (0.57 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 1.8 cm, height 15 cm), eluting with ethyl acetate and collecting 15 cc fractions. The first fraction is concentrated to dryness under reduced pressure (2.7 kPa). (3aR,7aR)-7,7-diphenyl-2-[(S)-2-phenylpropionyl]-4-perhydroisoindolone (1 g) is obtained in the form of a white meringue. [α]D20 =-231° (c=1, methanol).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][CH:8]=[C:7]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[CH:6]=1)[CH3:3].[NH2:15][C:16]1[C:19](=[O:20])[C:18](=[O:21])[C:17]=1OC>CO>[NH2:15][C:16]1[C:19](=[O:20])[C:18](=[O:21])[C:17]=1[NH:14][CH2:13][CH2:12][S:11][CH2:10][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:9][CH:8]=1
Reactant: COc1c(N)c(=O)c1=O
Reactant: CN(C)Cc1cc(CSCCN)cs1
Solvent: CO
Product: CN(C)Cc1cc(CSCCNc2c(N)c(=O)c2=O)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
A mixture of 2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamine (2.11 g, 8.68 mmoles) [prepared according to the procedure described in published European Patent Application 27,744] and 1-amino-2-methoxycyclobutene-3,4-dione (1.10 g, 8.68 mmoles) in methanol was stirred at ambient temperature for 18 hours and filtered. The crude product was recrystallized from 2-methoxyethanol to yield 1.30 g of the title compound as a colorless solid, m.p. 234°-236°.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=C2CCCCN2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].CO>C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:10]3[CH2:37][CH2:36][C:7](=[C:22]([C:19]4[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=4)[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH2:8][CH2:9]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Fc1ccc(C(=C2CCCCN2)c2ccc(F)cc2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(bis(4-fluorophenyl)methylenepiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 88% overall yield. FDMS m/e=474 (M+ of free base). α[D]589 =-8.49 (c=0.71, methanol).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1)[CH3:2].[N+:21]([O-])([OH:23])=[O:22].S(=O)(=O)(O)O>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:21]([O-:23])=[O:22])=[C:10]([O:13][CH3:14])[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cn(CC)c2nc(OC)ccc2c1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cn(CC)c2nc(OC)c([N+](=O)[O-])cc2c1=O
Temperature: 0 °C

Procedure:
Ethyl 1-ethyl-7-methoxy-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (82 g) was added to a mixture of fuming nitric acid (200 ml) and concd. sulfuric acid (330 ml), then the mixture was heated at 80° C. for 2 hours with stirring. The mixture was poured into 500 ml of ice-water. The precipitate was collected, washed with water, and dried. Recrystallization from ethanol gave 93.5 g of ethyl 1-ethyl-1,4-dihydro-7-methoxy-6-nitro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 223.5°-227° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.COCCOC.C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)=[CH:9][N:10]=3)[N:7]=2)[CH:33]=[N:32]1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Clc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: c1cnc2ccc(Cc3cnc4ccc(-c5cnn(CCOC6CCCCO6)c5)nn34)cc2c1
Temperature: 90 °C
Reaction time: 5.5 h
Yield: 80 %

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Example 14, 500 mg, 1.679 mmol) was introduced in a microwave reactor together with 1-[2-(tetrahydro-pyran-2-yloxy)ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 812 mg, 2.52 mmol) and DME (10 mL). The solution was degassed with argon before adding Pd(PPh3)2Cl2 (36 mg, 0.051 mmol) and 2 M K2CO3 (2.267 mL, 4.53 mmol). The mixture was stirred at 90° C. for 5.5 h. The RM was taken up with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford a first batch of the desired product as a brownish oil (80% pure). 10% of the residue was dissolved in DCM and purified by flash chromatography (DCM/MeOH=100:0→93.5:6.5) to afford the title compound as a brownish oil (tR 2.30 min (8), MH+=455.1).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:13][CH2:12]C[C:10]2[CH:9]=[C:8]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:7]=[CH:6][C:5]1=2)=[N+:2]=[N-:3].N([C@H]1C2C(=CC(C=O)=CC=2)[O:27]CC1)=[N+]=[N-]>>[N:1]([C@H:4]1[C:5]2[C:10](=[CH:9][C:8]([CH2:14][NH:15][CH:20]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[O:27][CH2:12][CH2:13]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Reactant: [N-]=[N+]=N[C@@H]1CCOc2cc(C=O)ccc21
Product: [N-]=[N+]=N[C@@H]1CCOc2cc(CNC3CCCC3)ccc21

Procedure:
Using the same procedure described for (20), and using (R)-4-azido-3,4-dihydro-2H-chromene-7-carbaldehyde afforded (R)-N-((4-Azido-3,4-dihydro-2H-chromen-7-yl)methyl)-cyclopentylamine (27) MS (m/z): 273.3 (M+H) (Calc'd for C15H20N4O−272.35).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:17])=[N:11][CH:12]=[CH:13][C:14]=1[OH:15])C1C=CC=CC=1>C(OCC)(=O)C.C(O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:10]2[C:9]([OH:8])=[C:14]([OH:15])[CH:13]=[CH:12][N:11]=2)=[O:17])=[CH:19][CH:20]=1
Reactant: O=C(c1ccc(F)cc1)c1nccc(O)c1OCc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)c1nccc(O)c1O

Procedure:
(3-Benzyloxy-4-hydroxy-pyridin-2-yl)-(4-fluorophenyl)-methanone: From 1.62 g of 3-benzyloxy-2-[hydroxy-(4-fluorophenyl)-methyl]-pyridin-4-ol there is obtained analogously to Example 70a, after chromatography, (3-benzyloxy-4-hydroxy-pyridin-2-yl)-(4-fluorophenyl)-methanone in the form of a greenish resin, Rf value: 0.53 (silica gel 60, ethyl acetate/ethanol 6/1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](O)=[O:11])[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:19][O:18][N:17]([CH3:16])[C:10](=[O:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1
Reactant: CNOC
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.6 %

Procedure:
To a solution of 3-(trifluoromethyl)phenylacetic acid (2.04 g, 10 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.07 g, 11 mmol) in DMF was added HATU (3.8 g, 10 mmol) and DIEA (6.99 ml, 40 mmol) and the resulting yellow solution was stirred at RT for overnight. The crude solution was then extracted with EtOAc and wash with NaHCO3 solution (5%), HCl solution (1:9 v/v) and brine, dried with sodium sulfate and concentrate to afford 2.66 gram of colorless oil as desired compound (4.1) used in the next step without further purification. Rf 0.5 (EtOAc/Hexane 1:1) MS (m/z): 248.1 (M+H), 1H NMR (CDCl3) δ 3.2 (s, 3H), 3.65 (s, 3H), 3.80 (s, 2H), 7.40-7.55 (m, 4H).
Reaction SMILES: C(OC([N:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)=[CH:12][CH:11]=1)[NH2:9])=O)(C)(C)C.O1CCOCC1.[ClH:27]>C(Cl)Cl>[ClH:27].[N:16]1([C:13]2[CH:14]=[CH:15][C:10]([NH:8][NH2:9])=[CH:11][CH:12]=2)[CH:20]=[CH:19][CH:18]=[N:17]1
Reactant: CC(C)(C)OC(=O)N(N)c1ccc(-n2cccn2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NNc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Title compound 51A, N-(4-Pyrazol-1-yl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (0.42 g, 1.0 eq, 1.53 mmol) was suspended in a mixture of 4M HCl in Dioxane (6.5 ml, 17.0 eq, 26 mmol) and DCM (5 ml). The mixture was then stirred at room temperature for 24 hours solvent was then removed in vacuo to yield impure title compound. (0.31 g). LCMS: [M+H]+=158/175, 65% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC3(CC2)COc2ccccc23)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 49.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.07 g, 0.14 mmol) obtained in step 2 and ethanesulfonamide (0.076 g, 0.72 mmol), the title compound (0.04 g, 50%) was obtained.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[O:35])[CH:32]=4)[C:27]([S:41][CH3:42])=[CH:26]3)=[N:23][CH:24]=2)[CH:14]=1>ClCCl>[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[N:23][C:22]([N:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[O:35])[CH:32]=4)[C:27]([S:41]([CH3:42])=[O:6])=[CH:26]3)=[N:21][CH:20]=2)[CH:14]=1
Reactant: CSc1cn(-c2ncc(-c3cc(C)ccn3)cn2)c2cc(C(=O)N3CCCC3)ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccnc(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCCC5)cc43)nc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
m-Chloroperoxybenzoic acid (77%, 0.14 g, 0.62 mmol) in dichloromethane (10 mL) was added at 0° C. to a solution of 269c) (0.33 g, 0.77 mmol) in dichloromethane (40 mL) and the reaction mixture was stirred at room temperature for 3 h. The mixture was then washed successively with saturated sodium hydrogen carbonate solution (2×20 mL) and brine (1×30 mL), dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography [silica gel; dichloromethane with 2% methanol]. White solid. Yield: 0.215 g (63% of theory)
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]([NH:24][C:25]([CH:27]([NH:32][C:33]([N:35]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[C:1]([NH:5][C:6]([CH:8]([NH:24][C:25]([CH:27]([NH:32][C:33]([N:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(C#Cc2ccccc2)cc1)C(=O)NC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(CCc2ccccc2)cc1)C(=O)NC(C)(C)C
Reaction time: 20.5 h
Yield: 64.6 %

Procedure:
To a solution of the product from Example 134 (0.187 g, 0.33 mmol) in 16 mL of 1:1 THF/methanol mixture was added 20% Pd/C (0.1 g). The resulting solution was hydrogenated for 20.5 hours at 20 psi. The crude mixture was evaporated to dryness and was purified by chromatography (silica gel, 30% ethyl acetate/hexane). It was further purified by crystallizing from petroleum ether and toluene to give the title compound (0.12 g, 65%) as a white solid, mp 155-156° C. Anal. Calc'd for C34H50N4O3: C, 72.56; H, 8.95; N, 9.95. Found: C, 72.2; H, 9.03; N, 9.80
Reaction SMILES: CO[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([C:14](=[O:30])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:23]=[N:24][C:25]([Cl:29])=[CH:26][C:27]=2[CH3:28])[CH:16]=1)[CH3:13].[NH3:32]>CO>[C:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([CH3:13])[C:14](=[O:30])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:23]=[N:24][C:25]([Cl:29])=[CH:26][C:27]=2[CH3:28])[CH:16]=1)(=[O:31])[NH2:32]
Reactant: N
Reactant: COC(=O)COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2cnc(Cl)cc2C)c1
Solvent: CO
Product: Cc1cc(Cl)ncc1-c1cc(C(=O)N(C)c2ccccc2OCC(N)=O)ccc1Cl
Temperature: 25 °C

Procedure:
(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-acetic acid methyl ester (28 mg, 0.06 mmol) was dissolved in 7N ammonia in MeOH (1 mL) and stirred at room temperature until starting material was consumed. The mixture was concentrated and taken up in MeOH, filtered and washed with methanol to yield N-(2-carbamoylmethoxy-phenyl)-4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-methyl-benzamide 6-1. MS [M+H]+: 444.0; tR=6.25 min; (method 2)
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:43](=[O:44])[C:35]3([CH2:37][CH:36]3[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:34](=O)[NH:33][C:32]3[CH:46]=[CH:47][CH:48]=[CH:49][C:31]2=3)=[CH:26][CH:25]=1>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:43](=[O:44])[C:35]3([CH2:37][CH:36]3[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:34](=[S:10])[NH:33][C:32]3[CH:46]=[CH:47][CH:48]=[CH:49][C:31]2=3)=[CH:26][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C1CC12C(=O)Nc1ccccc1N(c1ccc(Cl)cc1)C2=O
Solvent: C1CCOC1
Product: CCOC(=O)C1CC12C(=O)N(c1ccc(Cl)cc1)c1ccccc1NC2=S
Temperature: 80 °C
Yield: 44.8 %

Procedure:
Lawesson's Reagent (237 mg, 0.58 mmol) was added to a solution of ethyl 1-(4-chlorophenyl)-2,4-dioxo-1,2,4,5-tetrahydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropane]-2′-carboxylate (150 mg, 0.39 mmol) in THF (20 mL). The resulting mixture was heated at 80° C. overnight. The solution was evaporated and purified by CombiFlash (PE:EA=1:1) to get ethyl 1-(4-chlorophenyl)-2-oxo-4-thioxo-1,2,4,5-tetrahydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropane]-2′-carboxylate (70 mg, 45%) as brown solid. LRMS (M+H)+: 400 m/z. 1H NMR (300 MHz, CDCl3): δ 0.96-1.04 (t, J=7.2 Hz, 3H), 1.19-1.25 (m, 1H), 1.70-1.76 (m, 1H), 2.17-2.19 (m, 1H), 3.73-3.96 (m, 2H), 6.68-6.71 (d, 1H, J=8.1 Hz), 7.11-7.12 (m, 1H), 7.14-7.24 (m, 4H), 7.24-7.26 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H][H]>CO.O1CCCC1.[Ni]>[NH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(N)cc1F

Procedure:
Methyl 2-fluoro-4-nitrobenzoate (141 mg) was dissolved in methanol (1000 ml) and tetrahydrofuran (400 ml), and Raney nickel (20 g) was added to it, and stirred overnight in a hydrogen atmosphere. The catalyst was removed through filtration, and the solvent was evaporated away under reduced pressure to obtain methyl 4-amino-2-fluorobenzoate.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1>>[CH:32]1([NH:36][C:24]([C:7]2[C:6](=[O:29])[N:5]([CH2:4][C:3]([N:2]([CH3:31])[CH3:1])=[O:30])[C:14]3[C:9]([C:8]=2[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:13]=3)=[O:25])[CH2:35][CH2:34][CH2:33]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: NC1CCC1
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NC2CCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 245. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.34 (1H, br), 8.49 (1H, br), 7.77 (1H, br), 7.30 (2H, m), 7.12 (2H, t, J=8.8 Hz), 5.10 (2H, br s), 4.39 (1H, m), 4.09 (2H, br s), 3.11 (3H, s), 2.81 (3H, s), 2.27 (2H, m), 1.99 (2H, m), 1.70 (2H, m); HRMS calcd for C24H25FN4O4+H+: 453.1938. Found: 453.1937.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:19](O)=[O:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)Cl.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:38][NH:39][O:40][CH3:41]>CCOC(C)=O>[CH:13]1([C@H:11]2[CH2:12][N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[C@H:9]([C:19](=[O:20])[N:39]([O:40][CH3:41])[CH3:38])[CH2:10]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@@H]1C[C@@H](C2CCCCC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
(2S,4S)-Boc-4-cyclohexyl-pyrrolidine-2-carboxylic acid (Chem Impex Int'l, Wood Dale, Ill., 997 mg, 3.35 mmol) was treated with DCM (25 mL) followed by 1,1′-carbonyldiimidazole (598 mg, 3.69 mmol). The solution was allowed to stir at room temperature for 1.5 h then the reaction mixture was then treated with N,O-dimethyl hydroxylamine hydrochloride (360 mg, 3.69 mmol) and allowed to stir over the weekend at room temperature. The reaction mixture was diluted with EtOAc (50 mL), washed with a saturated solution of NaHCO3 (30 mL) and brine (30 mL), dried over MgSO4, filtered and concentrated affording crude (2S,4S)-tert-butyl 4-cyclohexyl-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1.14 g, 3.35 mmol, 99% yield) as a clear, colorless viscous oil. MS (ESI) 363.2 [M+Na]+. The crude material was used in the next step without further purification.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(=O)([O-])[O-].[Ca+2:9]>O>[N+:1]([O-:4])([O-:3])=[O:2].[Ca+2:9].[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=[N+]([O-])[O-]

Procedure:
90 ml of Nitric acid was primarily mixed with 62.33 g calcium carbonate in a 100 ml beaker. The slow addition of nitric acid to the calcium carbonate resulted in the formation of calcium nitrate and water. To this mixture 87 g of urea, 12.82 g of aluminum nitrate, and 12.7 g of silica fume were added at their appropriate amounts based on the final percentage of individual components required for cement formation. All the raw materials were bought from Fischer Scientific.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:2][CH2:3][CH3:4].[SH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]>>[CH2:1]([O:5][CH2:6][CH2:7][S:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[CH2:2][CH2:3][CH3:4]
Reactant: OCC(O)CS
Reactant: CCCCOCCOS(=O)(=O)c1ccc(C)cc1
Product: CCCCOCCSCC(O)CO

Procedure:
Following the procedure of Example 10, 2-butoxyethyltosylate (26.85 g, 98.7 mmol) and 3-mercapto-1,2-propanediol (10.68 g, 98.7 mmol) are reacted together to give 3-(2-butoxyethylthio)-1,2-propanediol, which diol (10.0 g, 52.5 mmol) is reacted with tosyl chloride (10.0 g) in pyridine. The tosylate (9.27 g, 25.6 mmol) is reacted with NaOH (1.02 g, 25.6 mmol) to give 2-(2-butoxyethylthiomethyl)oxirane. The oxirane (1.0 g, 5.26 mmol) and potassium t-butoxide (0.18 g, 1.58 mmol) are reacted together to give 3-(2-butoxyethylthio)-2-propenol, which propenol (4.72 g, 25.0 mmol) is reacted with acetic anhydride to give 3-(2-butoxyethylthio)-2-propenyl acetate.