Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23]([NH:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:24])[CH:18]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Solvent: ClCCl
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (247 g, 1.20 mol), and TEA (250 g, 2.5 mol) in DCM (3500 mL) was added 6-chloropyrimidine-4-carbonyl chloride (190 g in 100 mL of DCM) slowly at −60° C. over 1 h. After addition, the mixture was then allowed to warm to 10° C. Stirring was continued for 1 h, at which time TLC showed the reaction was completed. The reaction was quenched by addition of water (1.5 L). The organic phase was collected, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (EtOAc˜DCM:MeOH=10:1) to give the desired product as a pale yellow solid. Four batches were run in parallel and produced a combined crude product weight of 800 g, 49% yield. 1H NMR (400 MHz, MeOD-d4) δ 8.73 (d, J=1.0 Hz, 1H), 8.07 (d, J=1.0 Hz, 1H), 7.17-7.06 (m, 3H), 7.00 (d, J=7.0 Hz, 1H), 4.12 (q, J=6.0 Hz, 1H), 3.74 (s, 2H), 3.64-3.53 (m, 2H), 2.94 (q, J=5.5 Hz, 2H), 2.92-2.81 (m, 2H), 2.78-2.64 (m, 2H); LCMS (m/z): 347.2 [M+H]+
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[N:13]=[C:12]([N:14]2[CH2:22][CH2:21][CH2:20][C@@H:15]2[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:10][CH:9]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=1[CH:34]1[C:47]2[C:46](=[O:48])[CH2:45][C:44]([CH3:50])([CH3:49])[CH2:43][C:42]=2[O:41][C:40]2[CH2:39][C:38]([CH3:52])([CH3:51])[CH2:37][C:36](=[O:53])[C:35]1=2.O>C(COC)OC.O.C(OCC)(=O)C>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:8]2[N:13]=[C:12]([N:14]3[CH2:22][CH2:21][CH2:20][C@@H:15]3[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:10][CH:9]=2)=[CH:27][C:26]=1[CH:34]1[C:35]2[C:36](=[O:53])[CH2:37][C:38]([CH3:51])([CH3:52])[CH2:39][C:40]=2[O:41][C:42]2[CH2:43][C:44]([CH3:50])([CH3:49])[CH2:45][C:46](=[O:48])[C:47]1=2
Reactant: COC(=O)[C@H]1CCCN1c1cccc(Br)n1
Reactant: COc1ccc(B(O)O)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)[C@H]1CCCN1c1cccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
Sodium carbonate (238 mg, 2.24 mmol) and tetrakistriphenylphosphine palladium(0) (86.3 mg, 74.7μμmol) were added to a solution of the methyl 1-(6-bromopyridin-2-yl)-D-prolinate (213 mg, 747 μmol) obtained in Example 15-1 and the [4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]boronic acid (317 mg, 747 μmol) obtained in Example 1-1 in dimethoxyethane/water (3:1, v/v) (4 mL) at room temperature. The mixture thus obtained was stirred at 80° C. for 4 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate three times. The organic layer thus obtained was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=8:2 to 1:3, v/v) to obtain the title compound (190 mg, yield: 44%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:29])(=[O:28])[N:26]([CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44](Cl)(=[O:46])[CH3:45]>C(Cl)Cl.CCOC(C)=O>[C:44]([N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1/[CH:16]=[CH:15]/[C:13]1[CH:12]=[CH:11][C:10]([N:23]2[S:27](=[O:28])(=[O:29])[N:26]([CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:25](=[O:36])[CH2:24]2)=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=1)(=[O:46])[CH3:45]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCCN3)cc2OCc2ccccc2)S1(=O)=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCCC1/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Reaction time: 18 h

Procedure:
To a solution of 5-[2-benzyloxy-4-((E)-2-piperidin-2-yl-vinyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (101 mg, 0.192 mmol) in methylene chloride (4 mL) is added triethylamine (0.134 mL, 0.956 mmol). The solution is stirred at RT for 5 min the acetyl chloride (0.0163 mL, 0.23 mmol) is added and stirring is continued for 18 h. The mixture is diluted with EtOAc and is washed with 1N HCl and brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure to give the title compound.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([N:13]([CH2:22][CH3:23])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH3:12]>>[CH2:11]([N:13]([CH2:22][CH3:23])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]([NH:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[NH:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCCCCCCC(N)=O
Reactant: CCN(CC)c1ccc(C=O)cc1
Product: CCCCCCCC(=O)NC(NC(=O)CCCCCCC)c1ccc(N(CC)CC)cc1
Yield: 68 %

Procedure:
Compound 54 was prepared from octanamide and 4-(diethylamino)benzaldehyde using method 1. Yield: 68%. 1H NMR (400 MHz, DMSO). δ 8.21 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 6.61 (d, J=8.8 Hz, 2H), 6.42 (t, J=8.0 Hz, 1H), 3.29-3.31 (m, 4H), 2.06-2.14 (m, 4H), 1.47-1.50 (m, 4H), 1.08-1.24 (m, 16H), 1.06 (t, J=7.2 Hz, 6H), 0.94 (t, J=7.2 Hz, 6H). LC-MS (ESI): m/z 446.3 (M+H)+. HRMS (ESI) for C27H48N3O2 (MH+): calcd, 446.3741. found 446.3734.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C@H:9]([N:17](C)[C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]3[N:32]4[CH2:33][CH2:34][NH:35][CH2:36][C:31]4=[N:30][N:29]=3)(=[O:26])=[O:25])=[CH:20][C:19]=2[S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])SC2C=CC=CC=2)CCO[CH2:3][CH2:2]1.[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][C:55](=O)[CH2:54][CH:53]1[CH3:59])=[O:51])([CH3:48])([CH3:47])[CH3:46].[C:60]([OH:63])(=O)[CH3:61].C([BH3-])#N.[Na+]>CO>[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([N:35]2[CH2:34][CH2:33][N:32]3[C:28]([NH:27][S:24]([C:21]4[CH:22]=[CH:23][C:18]([NH:17][C@@H:9]([CH2:40][S:37][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]=5)[CH2:8][CH2:7][N:1]5[CH2:61][CH2:60][O:63][CH2:3][CH2:2]5)=[C:19]([S:37]([C:40]([F:42])([F:41])[F:43])(=[O:39])=[O:38])[CH:20]=4)(=[O:25])=[O:26])=[N:29][N:30]=[C:31]3[CH2:36]2)[CH2:54][CH:53]1[CH3:59])=[O:51])([CH3:48])([CH3:47])[CH3:46]
Reactant: CN(c1ccc(S(=O)(=O)Nc2nnc3n2CCNC3)cc1S(=O)(=O)C(F)(F)F)[C@@H](CCN1CCOCC1)Sc1ccccc1
Reactant: CC(=O)O
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC1CC(N2CCn3c(nnc3NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)C2)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.1 %

Procedure:
To a vial containing 4-((R)-3-morpholin-4-yl-1-phenylsulfanyl-methyl-propylamino)-N-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-trifluoromethanesulfonyl-benzenesulfonamide (60 mg, 0.089 mmol) and 2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (47.3 mg, 0.222 mmol) was added methanol (3 mL) under nitrogen. The reaction mixture was stirred in an ice bath for 10 minutes and then acetic acid (6.104, 0.107 mmol) was added. After stirring in the ice bath for an additional 15 minutes, sodium cyanoborohydride (44.6 mg, 0.710 mmol) was then added, and the reaction was stirred at ambient temperature for 15 hours. The reaction mixture was concentrated, filtered, and purified via flash chromatography on silica gel (10-50% 7N NH3 in methanol in CH2Cl2) to afford 2-methyl-4-{3-[4-((R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonylamino]-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl}-piperidine-1-carboxylic acid tert-butyl ester (42 mg, 53% yield). MS [m/z; (M+1)+]: 873.8
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([OH:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[H-].[Na+].[CH3:26]I>C1COCC1>[CH3:26][O:21][C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:2]([F:1])([F:22])[F:23])=[N:4][N:5]=3)[CH:8]=2)=[CH:13][CH:14]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(O)c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 10-mL cone-shaped flask equipped with a magnetic stir bar 2-(4-(3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)propan-2-ol (28 mg) was dissolved in dry THF (1 mL) and NaH (60% suspension in mineral oil, 20 eq.) and MeI (50 eq.) were added. The reaction mixture was stirred overnight at room temperature. Extracted with water and EtOAc, organic layer dried over MgSO4, concentrated, and purified by chromatography (3% MeOH in methylene chloride). The desired 6-(4-(2-methoxypropan-2-yl)phenyl)-3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine was isolated.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[N:11]1>>[CH2:8]([C:5]1[CH:4]=[CH:3][C:2]([N:11]2[N:12]=[CH:13][CH:14]=[N:10]2)=[CH:7][N:6]=1)[CH3:9]
Reactant: c1c[nH]nn1
Reactant: CCc1ccc(Br)cn1
Product: CCc1ccc(-n2nccn2)cn1

Procedure:
The title compound was prepared from 5-bromo-2-ethylpyridine (Preparation 65) and 1,2,3-triazole by a similar method to Preparation 1. The regioisomeric product were separated by column chromatography on silica by gradient elution with ethyl acetate/hexane (1:1→1:0). Fractions containing the title compound eluted first, these were combined and evaporated under reduced pressure to yield an oil, which was distilled b.p.135° C. @ 0.05 mmHg (Kugelrohr).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][N:3]1[C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].IC.[H-].[Na+].[C:26](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:26][C@:5]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][C:2](=[O:1])[N:3]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:4]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C[C@H](c1ccccc1)N1CC(C(=O)OC(C)(C)C)CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)CC1=O
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-4-carboxylate (30.05 g, 0.104 mol) in N,N′-dimethylformamide (210 mL), iodomethane 26.0 mL (59.28 g, 0.418 mol), and then sodium hydride (55%, in oil, 11.35 g, 0.260 mol) was added at room temperature in nitrogen atmosphere while stirring the mixture. When inner temperature increased to about 50° C., the reaction mixture was cooled to 30° C. by adding ice water to the outer bath. After changing the bath to a water bath at an outer temperature of 17° C., the mixture was stirred for 23 hours. The reaction mixture was poured into cold aqueous solution of citric acid (1 L of 10% citric acid and 500 g of ice), and after stirring the mixture for 30 minutes, the mixture was extracted with ethyl acetate (800 mL, 500 mL). The organic layers were combined, and washed with saturated aqueous solution of sodium chloride. After drying with anhydrous sodium sulfate, the mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was purified by flash silica gel column chromatography (elution was started at hexane ethyl acetate of 5:1, and after elution of the low polarity isomer, hexane:ethyl acetate was changed to 4:1) to obtain 10.63 g (33.7%) of high polarity isomer the title compound as a white solid. 14.91 g (47.3%) of low polarity isomer of tert-butyl(4R)-4-methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-4-carboxylate was also obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:35][OH:36]>C(Cl)(=O)C1C=CC=CC=1>[OH:1][CH2:2][C@@H:3]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH2:30][CH2:31][N:32]([C:35]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:36])[CH2:33][CH2:34]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(N2CCNCC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Reactant: CO
Solvent: O=C(Cl)c1ccccc1
Product: Cc1cc(N2CCN(C(=O)c3ccccc3)CC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Reaction time: 0.08 h
Yield: 33 %

Procedure:
To a solution of (S)-4-(1-hydroxymethyl-2-phenyl-ethylamino)-3-(4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one (30 mg, 0.063 mmol) in methanol (2 mL) was added benzoyl chloride (1 drop). The reaction mixture was stirred for 5 min. and concentrated. The residue was purified by prep. HPLC to yield the title compound (11 mg, 33%). 1H NMR (400 MHz, CD3OD) δ 7.48–7.54 (5H, m), 7.37 (1H, s), 7.13–7.26 (7H, m), 6.08 (1H, d, J=7.7 Hz), 3.79–4.02 (5H, m), 3.76 (1H, dd, J=4.7, 11.2 Hz), 3.67 (1H, dd, J=5.7, 11.2 Hz), 3.54 (4H, m), 3.03 (1H, dd, J=5.7, 13.7 Hz), 2.89 (1H, dd, J=8.0, 13.7 Hz), 2.62 (3H, s). LCMS (M+H)+ m/z 563 (t=2.19 min.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.N12CCCN=C1CCCCC2.P(Cl)(Cl)(OC1C=CC=CC=1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(N)=O
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(Br)ccc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
A solution of 4-bromo-2-methoxybenzamide (508 mg, 2.21 mmol) in anhydrous DCM (10 mL) was cooled to 0° C. and then treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (0.991 mL, 6.62 mmol). The mixture was stirred at 0° C. for 15 min, and then treated with phenyl dichlorophosphate (0.660 mL, 4.42 mmol) over 2 min. The reaction was stirred at 0° C. for 10 min, and then warmed to RT where it stirred for 1 h. After this time, the mixture was partitioned between DCM (10 mL) and saturated NH4Cl (20 mL). The aqueous phase was extracted with DCM. The combined extracts were dried (MgSO4) and concentrated to give the crude product, which was purified by flash chromatography (12 g SiO2 column; 0-30% EtOAc/Hex gradient) to give 4-bromo-2-methoxybenzonitrile (250 mg, 1.18 mmol, 53% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.40 (1H, s), 7.16 (1H, s), 7.12 (1H, s), 3.91 (3H, s).
Reaction SMILES: Cl.N[N:3]=[CH:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][C:17]=2[O:31][CH3:32])=[CH:7][CH:6]=1.C([N:37](CC)CC)C.Cl[C:43]([O:45][CH3:46])=[O:44]>C(Cl)Cl>[NH2:3][C:4](=[N:37][C:43]([O:45][CH3:46])=[O:44])[C:5]1[CH:34]=[CH:33][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][C:17]=2[O:31][CH3:32])=[CH:7][CH:6]=1
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(C=NN)cc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)N=C(N)c1ccc(OCCCCCOc2ccc(C(=O)N(C(C)C)C(C)C)cc2OC)cc1
Reaction time: 0.5 h

Procedure:
A stirred, 0° C. solution of 4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide monohydrochloride (200 mg) in 4.0 mL anhydrous methylene chloride is treated sequentially with triethylamine (0.068 mL, 0.48 mmol) and methyl chloroformate (39 mg). The solution is stirred 30 minutes, concentrated in vacuo and the resulting solids are partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried over sodium sulfate and concentrated. The resulting material is purified by chromatography on silica gel (15 g) with 70-100% ethyl acetate/hexanes as the eluent to afford 4-[5-[4-[amino(methoxycarbonylimino)methyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide ##STR16## (i-Prop=isopropyl) as a colorless foam:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[O:8][C:9]([NH:11][C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:3][CH:2]=1.[Cl:25][C:26]1[O:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=1>>[ClH:25].[Cl:25][C:26]1[O:30][C:29]([C:31]([NH:18][C:13]2[C:12]([NH:11][C:9]([O:8][CH:7]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:10])=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:32])=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc(Cl)o1
Reactant: Nc1ccccc1NC(=O)OC(c1ccncc1)C1CCNCC1
Product: Cl
Product: O=C(Nc1ccccc1NC(=O)c1ccc(Cl)o1)OC(c1ccncc1)C1CCNCC1
Yield: 19.3 %

Procedure:
Using the procedure described in Example 168, N1-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl]-1,2-benzenediamine (0.61 mmol) and 5-chloro-2-furancarboxylic acid (1.2 mmol), purifying with RPHPLC Method A, yielded 57 mg (22%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:9].[CH2:10]=[C:11]1O[C:13](=[O:14])[CH2:12]1>C1(C)C=CC=CC=1>[CH3:10][C:11]1[C:6]2[C:5](=[CH:4][C:3]([NH2:9])=[C:2]([Cl:1])[CH:7]=2)[NH:8][C:13](=[O:14])[CH:12]=1
Reactant: Nc1ccc(Cl)c(N)c1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: Cc1cc(=O)[nH]c2cc(N)c(Cl)cc12
Temperature: 30 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
28.6 g of 4-chloro-1,3-phenylendiamine are suspended at 22° C. in 400 ml of toluene. 17.6 g of diketene in 100 ml of toluene are added to the grey suspension in the course of 30 minutes at 25±2° C., the suspension briefly passing into solution before the mono-diketenisation product is precipitated in the form of a beige solid. Stirring is then carried out for 6 h at 22° C. Then 5 g of pyridinium para-toluenesulfonate (PPTS) are added and the mixture is boiled under reflux for 16 h. The yellow suspension is cooled to 30° C., with stirring, and then at 30° C. 30 ml of 1 N NaOH are added. A further 100 ml of water are then added. The crude product is filtered at 22° C., washed neutral with H2O and dried overnight at 60° C. in vacuo. 38.5 g (yield: 92%, isomeric ratio of 4-methyl-6-chloro-7-aminoquinolone to 4-methyl-5-amino-6-chloroquinolone>95:5) of a beige solid having a melting point of 350° C. are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)[CH:12]=[C:11]([O:23][CH3:24])[N:10]=2)[CH2:5][CH2:4]1.[F:25][C:26]1[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=1>>[F:25][C:26]1[N:31]=[C:30]([CH2:32][NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]3[N:14]=[C:13](/[CH:15]=[C:16]4/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/4)[CH:12]=[C:11]([O:23][CH3:24])[N:10]=3)[CH2:5][CH2:4]2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCC(CN)CC2)n1
Reactant: O=Cc1cccc(F)n1
Product: COc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCC(CNCc3cccc(F)n3)CC2)n1

Procedure:
(Z)-5-((2-(4-((((6-fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Example 153), the general reductive amination procedure and 6-fluoropicolinaldehyde (26.1 mg, 59 mg theoretical, 43.9%). LC-MS m/z 459 (M+1).
Reaction SMILES: [S-2:1].[Na+].[Na+].[OH-].[Na+].[CH:6](O)([CH3:8])[CH3:7].[CH:10]([N:13]=[N:14][C:15]1(Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])[CH3:11]>O>[CH:6]([N:13]=[N:14][C:15]1([S:1][C:15]2([N:14]=[N:13][CH:10]([CH3:12])[CH3:11])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:8])[CH3:7]
Reactant: CC(C)O
Reactant: CC(C)N=NC1(Cl)CCCCC1
Reactant: [S-2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)N=NC1(SC2(N=NC(C)C)CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6.5 grams (.05 moles) of 60% sodium sulfide in 11 ml of water in a 250 ml 4-neck flask equipped with a magnetic stirrer, thermometer, and addition funnel was added 0.2 grams of 50% sodium hydroxide and 33 ml of isopropanol, the solution stirred for 15 minutes at room temperature and 18.85 grams (0.1 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) was added dropwise from the addition funnel over 30 minutes while holding the temperature at 20° C. to 25° C. After the addition was complete, the reaction was stirred an additional 60 minutes at room temperature, poured into 200 ml cold water and the product extracted into 100 ml of pentane. The pentane solution was washed successively with 50 ml portions of water, saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 13.4 grams (79% crude yield). The infrared spectrum of the product was in agreement with the structure of di[ 1-(isopropylazo)cyclohexyl]sulfide.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na].[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O>[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]2)=[CH:4][CH:3]=1)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc2ccc(S(=O)(=O)O)cc2c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc2ccc(S(=O)(=O)O)cc2c1)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of 7-aminonaphthalene-2-sulfonic acid, sodium salt (3.0 g, 12.2 mmol) in 70 mL of water is added solid NaOH (0.98 g, 24.0 mmol) at room temperature. The mixture is stirred for 30 minutes, and benzyl chloroformate (3.43 mL, 24.0 mmol) is then added. The resulting mixture is stirred over a period of 16 hours. The crude product is treated as in EXAMPLE 9, Part A, to give 4.18 g of crude N-CBz-7-aminonaphthalene-2-sulfonic acid, sodium salt. A mixture of the sulfonic acid, sodium salt (4.18 g, 11.0 mmol) in 12 mL of thionyl chloride is heated at 80° C. for 3 hours. The mixture is allowed to cool to room temperature and concentrated in vacuo. The residue is diluted with EtOAc and washed successively with water (2×), saturated NaHCO3 solution and saturated NaCl. The organic layer is dried over anhydrous MgSO4, filtered and concentrated to give a brown oil. The crude product is purified by column chromatography in a gradient of 10% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (1.76 g, 4.68. mmol) as a beige solid.