Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH3:21][C:22]([CH3:37])([CH3:36])[CH2:23][N:24]([CH3:35])[CH2:25][C:26]([N:29]1[CH:33]=[C:32]([NH2:34])[N:31]=[CH:30]1)([CH3:28])[CH3:27]>>[CH3:21][C:22]([CH3:37])([CH3:36])[CH2:23][N:24]([CH3:35])[CH2:25][C:26]([N:29]1[CH:33]=[C:32]([NH:34][C:15](=[O:17])[CH:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])[N:31]=[CH:30]1)([CH3:27])[CH3:28]
Reactant: CN(CC(C)(C)C)CC(C)(C)n1cnc(N)c1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN(C)CC(C)(C)C)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 2) was reacted with 1-{2-[(2,2-Dimethyl-propyl)-methyl-amino]-1,1-dimethyl-ethyl}-1H-imidazol-4-ylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 26.8, 28.2, 28.8, 28.9, 29.8, 33.4, 36.6, 46.6, 52.8, 59.4, 59.5, 60.9, 72.4, 74.2, 101.1, 104.8, 106.9, 110.7, 110.9, 118.0, 131.1, 137.4, 139.3, 139.8, 162.2, 172.4, 194.6; MS m/z 504.4 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19](=[O:22])(=[O:21])[NH2:20])[CH:17]=2)[C:12]([Cl:23])=[CH:11][N:10]=1>CS(C)=O>[Cl:23][C:12]1[C:13]2[C:18](=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:9]([NH:4][C:3]([NH2:5])=[NH:2])=[N:10][CH:11]=1
Reactant: NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(N)(=O)=O)cc12
Temperature: 50 °C
Yield: 66.8 %

Procedure:
Guanidine hydrochloride (70 mg, 0.73 mmol) was added in one portion to a suspension of NaH (21 mg, 80% dispersion by wt in mineral oil, 0.66 mmol) in DMSO (2.0 mL) and the mixture was heated at 50° C. under N2 for 30 min. 1,4-Dichloro-7-sulphamoylisoquinoline (70 mg, 0.25 mmol) was added and the mixture heated at 90° C. for 18 h. The cooled mixture was partitioned between ethyl acetate (EtOAc) and water, and the organic phase was washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2—MeOH-0.880NH3 (95:5:0.5 to 90:10:1) as eluant to give 4-chloro-1-guanidino-7-sulphamoylisoquinoline (50 mg, 0.167 mmol) as a white solid.
Reaction SMILES: [O:1]=[C:2]([NH:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[S:23][CH:24]=1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([NH:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[S:23][CH:24]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1csc(-c2ccncc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1csc(-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a rt solution of 4.B (163 mg, 384 μmol) in dioxane (2.5 mL) was added 6.0 N HCl (1 mL). After stirring at rt for 30 min, the reaction mixture was poured into saturated aqueous NaHCO3 (5 m L), diluted with water (5 mL) and extracted by 30% iPrOH/CHCl3 (3×10 mL). The combined solution was washed with brine and dried over MgSO4. After removal of organic solvent under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-20% MeOH/CH2Cl2 for elution provided 4.C as a colorless solid (105 mg, 85%)
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:4]1([S:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[NH:14][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Nc1ccccc1Sc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1Sc1ccccc1)Oc1ccccc1
Temperature: 5 °C

Procedure:
2-Amino diphenylsulfide (0.4 mole) was dissolved in toluene (500 ml) and cooled to 5° C. Phenyl chloroformate (0.24 mole) in toluene (50 ml) was added slowly to the stirred solution over 1 hour. When addition was complete a simultaneous addition of phenyl chloroformate (0.24 mole) in toluene (50 ml) and an aqueous solution of sodium hydroxide (0.3 mole) and sodium carbonate (0.35 mole) (200 ml) was started.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][O:5][C:6]1[CH:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:8][C:7]=1[NH:18][C:19]1[N:24]=[C:23]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][C:34]([NH2:36])=[O:35])[C:22]([C:37]([F:40])([F:39])[F:38])=[CH:21][N:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO.C(Cl)Cl>CO.C(OCC)(=O)C>[CH2:1]([N:15]1[CH2:16][CH2:17][CH:12]([C:10]2[CH:9]=[CH:8][C:7]([NH:18][C:19]3[N:24]=[C:23]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH2:33][C:34]([NH2:36])=[O:35])[C:22]([C:37]([F:38])([F:39])[F:40])=[CH:21][N:20]=3)=[C:6]([O:5][CH3:4])[CH:11]=2)[CH2:13][CH2:14]1)[CH3:2]
Reactant: CC=O
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
Acetaldehyde (18 mg, 0.39 mmol) was added to a stirred solution of 2-(2-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (2) (40 mg, 78 μmol) in dry MeOH (2 mL). Sodium triacetoxyborohydride (83 mg, 0.39 mmol) was added under nitrogen and the resulting mixture was stirred at room temperature for 2 hours. The crude mixture was diluted with ethyl acetate and adsorbed onto silica gel. Chromatography (SiO2, 0-20% MeOH/DCM) gave the title compound (4) (10 mg, 24%) as a light coloured solid; 1H NMR (400 MHz, CD2Cl2) δ 8.52 (s, 1H), 8.34 (d, J=8.3 Hz, 1H), 7.92 (s, 7.28-7.14 (m, 4H), 6.92 (d, J=8.3 Hz, 1H), 6.82 (d, J=1.7 Hz, 1H), 5.91 (bs, 1H), 5.87 (bs, 1H), 3.91 (s, 3H), 3.66 (s, 2H), 3.63 (m, 2H), 3.20-3.01 (m, 6H), 2.73 (d, J=11.7 Hz, 2H), 2.42-2.21 (m, 3H), 2.02 (d, J=18.0 Hz, 4H), 1.37 (t, J=7.3 Hz, 3H). LCMS Method C: rt 4.96 min; m/z 542.2 [M+1]+, 540.1 [M−1]−.
Reaction SMILES: O=C(NN[C:13]([N:15]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][C:17]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]1=2)=[O:14])CCC1C=CC=CN=1.[F:31][C:32]([F:45])([CH:37]([OH:44])[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)[C:33]([NH:35][NH2:36])=[O:34].ClC1C=CC2OC3C=CC=CC=3CN(C(Cl)=O)C=2C=1.Cl>C(O)(=O)C>[F:45][C:32]([F:31])([CH:37]([OH:44])[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)[C:33]([NH:35][NH:36][C:13]([N:15]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][C:17]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]1=2)=[O:14])=[O:34]
Reactant: O=C(CCc1ccccn1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: NNC(=O)C(F)(F)C(O)c1ccncc1
Agent: Cl
Agent: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CC(=O)O
Product: O=C(NNC(=O)C(F)(F)C(O)c1ccncc1)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
The free base of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)carboxylic acid, 2-[2,2-difluoro-3-hydroxy-1-oxo-3-(4-pyridinyl)propyl]hydrazide (51) was prepared in the same manner as 8-chlorodibenz[b,f][1,41oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(2-pyridinyl)propyl]hydrazide (6), as described above in Example 6, on a 1.75 mmol scale from α,α-difluoro-β-hydroxy-3-(4-pyridinyl)-propanoic acid, hydrazide (50), prepared in the manner described above in Example 50, and 8-chlorodibenz[b,f]8 1,4]-oxazepine-10(11H)-carbonyl chloride (2), prepared in the manner described above in Example 2, for a yield of 0.098 g (12%) of product. The free base was taken up in acetic acid 1.5 mL) and 1M HCl (1.5 mL). The material was lyophilized to yield 0.049 mg of the hydrochloride salt. Analysis calculated for C22H17N4O4F2Cl.HCl.0.25 H2O (M.W. 514.83): C, 51.23; H, 3.62; N, 10.86. Found: C, 50.85; H, 3.67; N, 10.94.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2.C(C(O)=O)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:1]1[CH:5]=[C:4]([C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:34][CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[CH2:12][CH2:13]2)=[O:7])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2
Reactant: COc1ccc(CCBr)cc1
Reactant: O=C(c1csc2ccccc12)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCN2CCC(C(=O)c3csc4ccccc34)CC2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Mix (benzo[b]thiophene-3-yl)(4-piperidinyl)methanone. CF3CO2H (2.0 g, 5.56 mmol), 2-(4-methoxyphenyl)ethyl bromide (1.27 g, 5.93 mmol), potassium carbonate (1.95 g, 1.41 mmol) and anhydrous dimethylformamide (20 mL). Warm to approximately 90° C. and stir overnight. Allow to cool to room temperature and partition between a 2:1 mixture of ethyl acetate:toluene and water. Separate the aqueous phase and wash the organic phase with water and saturated sodium chloride. Dry (Na2SO4) and evaporate the solvent in vacuo. Purify by chromatography (40% ethyl acetate/hexane) and recrystallize (cyclohexane) to give the title compound as pale yellow plates; mp 114°-116° C.
Reaction SMILES: [CH:1]([C:4]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:5]=1[O:6][C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])=[O:8])([CH3:3])[CH3:2].Cl.C([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])(C)(C)C.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[CH:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:6][C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:34][CH2:33][CH2:32][C:31]([OH:35])=[O:30])=[O:12])=[O:8])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(C)c1cccc(C(C)C)c1OC(=O)c1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1OC(=O)c1ccccc1C(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 38 %

Procedure:
To a solution containing (102) (2.1 g, 6.4 mmol) and beta-alanine tert-butyl ester hydrochloride (1.16 g, 6.4 mmol) in DMF (20 mL) was added diisopropylethylamine (2.4 mL, 13.7 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.5 g, 6.5 mmol). The resulting reaction mixture was stirred at room temperature for 14 h, diluted with ethyl acetate (100 mL), washed with 10% aqueous citric acid solution (50 mL), followed by saturated aqueous NaHCO3 solution (50 mL) and brine (2×50 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The crude residue was dissolved in anhydrous dichloromethane (30 mL) and cooled to 0° C. before a solution of hydrochloric acid (10 mL, 4 N in dioxane) was added. The reaction was stirred for 1 h at 0° C. and 1 h at room temperature. The solvent was removed in vacuo and the crude residue was purified by preparative LC/MS to afford 0.85 g (38% yield over three steps) of the title compound (101). 1H NMR (400 MHz, CD3OD): δ 8.20 (dd, J=7.6, 0.8 Hz, 1H), 7.70–7.68 (m, 1H), 7.63–7.59 (m, 1H), 7.49 (dd, J=7.6, 0.8 Hz, 1H), 7.22–7.17 (m, 3H), 3.54 (t, J=7.2 Hz, 2H), 3.06–3.00 (m, 2H), 2.57 (t, J=6.8 Hz, 2H), 1.19 (d, J=6.8 Hz, 12H). MS (ESI) m/z 398.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=C[CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1[N:32]=C(CC)C(NC2C3C(=NC=CC=3)CC2)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[C:25](=[N:32][CH:19]=[CH:20][CH:21]=3)[CH2:24][CH2:23]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2CCc3ncccc32)c(CC)nc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCc2ncccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting N-(5-bromo-3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.50, 7.73, 7.51, 7.36-7.28, 7.17, 5.88, 4.67, 3.26-3.08, 2.86, 2.70, 2.51, 2.05-1.96, 1.29, 1.12; HRMS (FAB) calcd for C22H22Cl2N4+H 413.1299, found 413.1286.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+].S(=O)(=O)(O)O>O.CO.C1(C)C(C)=CC=CC=1>[C:1]([CH2:2][C:12](=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 130 °C

Procedure:
Acetophenone (30 grams; 0.25 mol), methylbenzoate (130 grams, 1.0 mol), sodium methoxide (17.3 grams; 0.32 mol) and xylene (350 ml) were placed into a four necked round bottom one liter flask, equipped with stirrer, nitrogen addition adapter, thermometer and Oldershaw column connected with a distillation head and a trap. The solution was heated under a blanket of nitrogen to a temperature of about 130° C. At about 130° C., the mixture of xylene and methanol begins to come off the reaction mixture. Upon cooling the reaction mixture is acidified by adding sulfuric acid (21 ml) in water (100 ml). Once the material goes into solution it is transferred to a separatory funnel and the aqueous layer is removed. The xylene layer is washed with water (100 ml of a 10% solution). Then it is stirred at 120° C. and 15 mm Hg. The yield of dibenzoyl methane was 94 weight percent having a purity of 97%.
Reaction SMILES: Cl.C[C@H]1CN[C@H]([C:8](O)=[S:9])C1.S(Cl)([Cl:13])=[O:12].Cl.C[N:17]1[CH2:25][CH2:24][CH2:23][C@H:18]1[C:19]([O:21][CH3:22])=S>CO>[ClH:13].[CH3:8][S:9][C@H:24]1[CH2:25][NH:17][C@H:18]([C:19]([O:21][CH3:22])=[O:12])[CH2:23]1
Reactant: C[C@H]1CN[C@H](C(O)=S)C1
Reactant: O=S(Cl)Cl
Reactant: COC(=S)[C@@H]1CCCN1C
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](SC)CN1

Procedure:
To a stirred solution of (trans)-4- methylthio-L-proline, hydrochloride (1.5 g., 7.59 mmole) [Patchett et al., "Studies on Hydroxyproline", JACS, Vol. 79, p. 185-192 (1957)] in 40 ml. of methanol at -30° under argon is added 3.32 ml. (6 eq.) of thionyl chloride dropwise over 5 minutes. The reaction mixture is worked up according to the procedure of Example 95(e). Recrystallization from acetonitrile/ether gives 630 mg. of (trans)-4- (methylthio-L-proline, methyl ester, hydrochloride as a colorless, crystalline material; m.p. 155-156°; [α]D20 =-11.3° (c=1.71, methanol).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[C:12]([CH3:36])=[C:13]2[C:18]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)=[C:17]([C:33]#[N:34])[CH:16]=[N:15][N:14]2[CH:35]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C(Cl)(Cl)Cl>[CH2:1]([NH:8][CH2:9][C:11]1[C:12]([CH3:36])=[C:13]2[C:18]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:24][CH:25]=3)=[C:17]([C:33]#[N:34])[CH:16]=[N:15][N:14]2[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1c(CNCc2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h
Yield: 70 %

Procedure:
Benzylamine (10 μl, 0.09 mmol) was added to a solution of 6-formyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile (Example 8) (32 mg, 0.087 mmol) in CH2Cl2/DMF (10/1) (2.2 ml). The mixture was stirred overnight, then treated with NaBH(OAc)3 (55 mg, 0.26 mmol) and stirred overnight again. Diluted with CHCl3, washed with saturated NaHCO3 and H2O, dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give the title compound (28 mg, 70%) as yellow-green oil (10% MeOH—CHCl3). It has a retention time of 6.46 min (standard LCl method, 8 min run). LCMS Found: (M+H)+=460.20
Reaction SMILES: [I-].[Na+].Cl[CH2:4][C:5]([NH2:7])=[O:6].C1(C)C=CC=CC=1.[CH2:15]([O:22][C:23]([NH:25][CH:26]([C:32]([O:34]CC)=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]CC.[Na+]>C(O)C>[CH2:15]([O:22][C:23]([NH:25][C:26]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:4][C:5](=[O:6])[NH:7][C:32]1=[O:34])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: NC(=O)CCl
Agent: CC[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To 123 kg of ethanol, 25.0 kg (167 mol) of sodium iodide and 14.2 kg (152 mol) of α-chloroacetamide were added and the resultant mixture was heated to 77° C. and was stirred for 3 hours. To the resultant suspension, 58.2 kg (130 mol) of 69% toluene solution of diethyl 2-benzyloxycarbonylaminomalonate was added, followed by cooling the resultant mixture to 0° C. Thereto, 89.1 kg (262 mol) of 20% ethanol solution of sodium ethoxide was dropped for 3 hours while maintaining the temperature at 0° C. After the reaction mixture was stirred for 3 hours at 0° C., the reaction was quenched by adding 7.9 kg of acetic acid and 15.1 kg of 85% phosphoric acid to the reaction mixture and the solvent was distilled off under reduced pressure. To the reaction mixture, 200 kg of toluene and 80 kg of water were added and the phase separation of the reaction mixture was performed. After the organic phase was washed with water 3 times, it was quantitatively analyzed and the yield of 2-benzyloxycarbonylamino-2-ethoxycarbonyl succinimide was found to be 87.5%. This solution was concentrated and then was recrystallized with toluene and ethanol to thereby obtaining 30 kg (yield: 72%) of 2-benzyloxycarbonylamino-2-ethoxycarbonyl succinimide as a white crystal.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5C(C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45].[OH-:46].[K+].C[CH2:49][O:50]CC>N1C=CC=CC=1.C(O)CC>[CH3:1][CH2:2][C:3]1[C:21]2[NH:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[NH:14][C:15]([C:16]5[C:49](=[O:50])[O:26][C:25](=[O:46])[C:24]6=[C:23]([CH3:32])[C:19]([CH:20]=2)=[N:18][C:17]=56)=[C:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C@@H:34]4[CH3:35])=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Reactant: CCOCC
Reactant: [OH-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCCO
Product: C=Cc1c(C)c2cc3[nH]c(c4c(=O)oc(=O)c5c(C)c(cc6[nH]c(cc1[nH]2)c(C)c6CC)nc5=4)=C(CCC(=O)OC)[C@@H]3C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Methyl pheophorbide-a 1 (700 mg) was dissolved in warm pyridine (10 ml) and the solution was diluted with ether (500 ml). The solution was stirred with a stream of air passing through it, and a solution of KOH (8.0 g) in propanol (20 ml) was added. The bright green mixture was stirred and aerated for 30 min and then extracted with water until the ethereal layer was no longer green. The ethereal solution layer was discarded, the aqueous extracts were combined, adjusted to pH 4 with cone sulfuric acid (8 ml) in water (40 ml), and extracted with dichloromethane until the aqueous layer was no longer green-brown. The combined dichloromethane extract containing unstable chlorin was subjected to repeated evaporation and redissolution in THF (freshly distilled) until no further increase in visible absorption at 700 nm was observed. The product was esterified with ethereal diazomethane and then washed with water, dried and evaporated to dryness. The product was purified by silica column, eluting with 2% methanol in dichloromethane. The appropriate eluates were combined, and the residue obtained evaporating the solvents was crystallized from dichloromethane/methanol to give the title compound in 50% yield (290 mg). m.p. >260° C. (decomp.) (lit., 260-280° C.). max 698 (), 642 (), 592 (), 546 (), 508 (), 478 () and 410 (). NMR ppm 9.55, 9.35, 8.57 (meso H), 7.88 (dd, 11.7, 2-a H), 6.29 (d, 2b-H), 6.18 (d, 2b'H), 5.17 (d, 7-H), 4.38 (q, 8-H), 3.76 (s, 3H), 2.73 (m, 7b-H), 2.47 (m, 7b'H), 2.43 (m, 7a-H), 1.99 (m, 7a'H), 1.74 (d, 8 Me), 1.65 (t, 4b-Me) and 2.01 and -0.09 (each br s, NH); (HRMS 78.2509. C34H34N4O5 requires 578.2529.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH3:29])=[N:24]2>CCCCCC.C(OCC)(=O)C>[CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]([C:7]([F:10])([F:9])[F:8])([OH:5])[CH2:6][NH:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH3:29])=[N:24]2
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc2c(NCC(O)(CC(C)(C)c3ccccc3)C(F)(F)F)cccc2n1
Yield: 58.8 %

Procedure:
Analogously to Example 1, 500 mg (2.05 mmol) of 2-(2-methyl-2-phenylpropyl)-2-(trifluoromethyl)oxirane and 650 mg (4.10 mmol) of 5-amino-2-methylquinoline are reacted. After chromatography on silica gel with hexane-ethyl acetate (0-70%), 485 mg of product is obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:13]Br>Br>[BrH:13].[Br:13][C:10]1[CH:9]=[N:8][C:7]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)=[CH:12][CH:11]=1
Reactant: BrBr
Reactant: c1ccc(N2CCNCC2)nc1
Agent: Br
Product: Brc1ccc(N2CCNCC2)nc1
Temperature: 115 °C

Procedure:
A solution of 81.5 g of 2-piperazinylpyridine [J. Org. Chem., 18, 1484 (1953)] in 250 g of 48% hydrobromic acid is heated at 70° C. With stirring, 80 g of liquid bromine is added dropwise. The mixture is heated at 115° C. for 1 hour. The mixture is cooled and the product 3-bromo-6-piperazinylpyridine hydrobromide is isolated by filtration. The salt is treated with excess dilute sodium hydroxide and extracted into toluene. The 3-bromo-6-piperazinylpyridine crystallizes as the solvent is removed in vacuo and is recrystallized from toluene-petroleum ether; mp 70°-73° C.