Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.8 %

Procedure:
A suspension of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.018 mole), 1,1'-carbonyldiimidazole (2.9 g, 0.018 mole), and anhydrous tetrahydrofuran (200 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 4 hours. The nitrogen flow was stopped and a solution of methylamine in tetrahydrofuran (36 ml of 1M) was added. The solution was stirred at room temperature under nitrogen for 1/2 hour. The reaction mixture was filtered and concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake was recrystallized from tetrahydrofuran-isopropyl ether, giving 4.6 g (74%). Recrystallization from isopropyl alcohol-isopropyl ether gave 4.4 g of off-white needles, mp 199°-201° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][S:15]([O:18][CH2:19][C:20]([CH3:34])([CH3:33])[C@@H:21]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([OH:24])=[O:23])(=[O:17])=[O:16].[C:35](Cl)(=O)[C:36](Cl)=O.C(O)C.N1C=CC=CC=1>ClCCl>[O:11]=[C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][CH2:14][S:15]([O:18][CH2:19][C:20]([CH3:34])([CH3:33])[C@@H:21]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:22]([O:24][CH2:35][CH3:36])=[O:23])(=[O:16])=[O:17]
Reactant: CC(C)(COS(=O)(=O)CCCN1C(=O)c2ccccc2C1=O)[C@@H](OCc1ccccc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN1C(=O)c2ccccc2C1=O
Yield: 84.5 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-{[3-(1,3-dioxobenzo[c]azolin-2-yl)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (20) (0.8 g, 1.6 mmol) was dissolved in 20 mL of anhydrous dichloromethane (DCM) and reacted with 0.96 mL (1.92 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 2.0 mL (1.58 g, 34.3 mmol) of ethanol (EtOH) and 0.14 mL (0.127 g, 1.6 mmol) of pyridine in 10 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.7 g (83% yield) of the title compound (22a) as a colorless oil. Rf=0.64 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.04 (s, 3H), 1.05 (s, 3H), 1.31 (t, J=6.8 Hz, 3H), 2.18-2.25 (m, 2H), 3.12-3.17 (m, 2H), 3.80 (t, J=6.8 Hz, 2H), 3.83 (s, 1H), 3.96 (d, J=8.8 Hz, 1H), 4.18-4.24 (m, 3H), 4.36 (d, J=11.2 Hz, 1H), 4.60 (d, J=11.6 Hz, 1H), 7.32-7.33 (m, 5H), 7.72-7.75 (m, 2H), 7.84-7.86 (m, 2H) ppm. MS (ESI) m/z 518.16 (M+H)+, 540.11 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:19]1[C:23]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)=[CH:22][N:21]=[CH:20]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([C:23]3[O:19][CH:20]=[N:21][CH:22]=3)=[N:25][CH:26]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=1.08 min; Mass spectrum (ESI+): m/z=423 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=2[NH:11][C:10](=[O:21])[CH2:9]1)C1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=2[NH:11][C:10](=[O:21])[CH2:9]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc2c(c1)CN(Cc1ccccc1)CC(=O)N2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC(=O)N2
Temperature: 25 °C
Yield: 92.9 %

Procedure:
To a solution of 4-benzyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (4.67 g, 16.5 mmol) in dichloromethane (150 mL) was added benzyl chloroformate (6.2 g, 36.0 mmol). The mixture was heated to reflux for four hours whereupon LCMS showed completion of the reaction. The mixture was cooled to room temperature, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography over silica gel (0-5% MeOH/DCM) to afford 5.0 g (93%) of 7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester; NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.35 (m, 5H), 7.04 (d, J=9 Hz, 1H), 6.84 (d, J=9 Hz, 1H), 5.08 (s, 2H), 4.54 (s, 2H), 4.20 (2s, 2H), 3.70 (2s, 3H);); MS (m/e) 327 (M+1); mp 138° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[N:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29]([O-])=[O:30])=[CH:28][C:23]=2[NH:22][CH:21]=1>>[CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:29]([C:27]3[CH:26]=[CH:25][C:24]4[NH:20][CH:21]=[N:22][C:23]=4[CH:28]=3)=[O:30])=[CH:12][CH:11]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc(N)cc2)cc1
Reactant: O=C([O-])c1ccc2nc[nH]c2c1
Product: CN(C)c1ccc(C(=O)Nc2ccc(NC(=O)c3ccc4[nH]cnc4c3)cc2)cc1

Procedure:
Compound 445 was prepared from 4-(4-dimethylaminobenzamido)aniline and benzimidazole-5-carboxylate by standard conditions. [M+H]+ calcd for C23H21N5O2: 400.17; found: 400.01.
Reaction SMILES: [CH:1](=[C:8]1[C:12]2=[N:13][C:14]3[CH:15]=[C:16]([NH:22][C:23](/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28])=[O:24])[CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.[CH3:34]COCC>CO>[CH:1](=[C:8]1[C:12]2=[N:13][C:14]3[CH:15]=[C:16]([NH:22][C:23](/[CH:25]=[CH:26]\[C:27]([O:29][CH3:34])=[O:28])=[O:24])[CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: O=C(O)/C=C\C(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Agent: FB(F)F
Solvent: CO
Product: COC(=O)/C=C\C(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3

Procedure:
(Z)-3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-2-propenoic acid (1.22 g) was heated in anhydrous methanol (190 ml) containing boron trifluoride etherate (1.58 ml) at reflux temperature for 8 hours. The reaction mixture was concentrated to a small volume in vacuo and the precipitate was filtered and washed with water until neutral to give 1.1 g of (Z)-3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-2-propenoic acid, methyl ester, m.p. 233°-235° C.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:27][C:28]1[CH:29]=[C:30]([NH:34][NH2:35])[CH:31]=[CH:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OCC(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: O=c1ccn(-c2ccc(OCC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-pyridazin-4-one (A-32) and 3-chloro-phenylhydrazine according to the method described for example 43. MS: M=447.1 (M+H)+
Reaction SMILES: [Cl-].[NH4+:2].[Al](C)(C)C.C[O:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([Cl:17])=[CH:13][N:12]=1)=O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:17][C:14]1[N:15]=[CH:16][C:11]([C:9]([NH2:2])=[O:8])=[N:12][CH:13]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1cnc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
Suspend ammonium chloride (0.465 g, 8.69 mmol) in toluene (14 mL). Cool to 0° C. and slowly add 2.0 M Al(CH3)3 in toluene (4.3 mL, 8.69 mmol). After the gas stops evolving, add 5-chloropyrazine-2-carboxylic acid methyl ester (0.500 g, 2.89 mmol). Heat at 50° C. overnight. Cool the reaction mixture to room temperature, then slowly pour into a slurry of silica gel (10 g) in CHCl3 (50 mL). Stir for 10 minutes before filtering. Wash the silica plug with methanol (2×100 mL) before concentrating. Take the resulting solid up in dichloromethane and wash with water (30 mL) and brine (40 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 50% ethyl acetate in hexanes to give the title compound (0.155 g, 34.0%): TOF MS EI+ 157.0 (M+), HRMS calcd for C5H4N3OCl 157.0043 (M+H)+, found 157.0047, time 4.19 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min. 5-95% over 19 min], tR=7.1 min, 100% purity.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:57])[N:32]([CH2:41][C:42]1[C:47]([F:48])=[CH:46][CH:45]=[C:44]([NH:49][S:50]([CH2:53][CH2:54][CH3:55])(=[O:52])=[O:51])[C:43]=1[F:56])[C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[O:40])=[CH:35][N:34]=1)([CH3:29])([CH3:28])[CH3:27].[Cl-].[NH4+]>O1CCCC1>[C:26]([O:30][C:31](=[O:57])[N:32]([CH2:41][C:42]1[C:47]([F:48])=[CH:46][CH:45]=[C:44]([NH:49][S:50]([CH2:53][CH2:54][CH3:55])(=[O:52])=[O:51])[C:43]=1[F:56])[C:33]1[CH:38]=[CH:37][C:36]([CH:39]([OH:40])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[CH:35][N:34]=1)([CH3:28])([CH3:27])[CH3:29]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(CN(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)c1F
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncccc34)cn2)c1F
Temperature: 15 °C

Procedure:
To a solution of 3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.644 g, 1.61 mmol) in tetrahydrofuran (10.0 mL) at −40° C. under nitrogen, isopropylmagnesium chloride (2.0M in tetrahydrofuran, 0.80 mL) was added slowly. The reaction was allowed to warm to 15° C. over 100 minutes, then cooled to −40° C., followed by adding [2,6-difluoro-3-(propane-1-sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (560, 0.100 g, 0.21 mmol, prepared as described in Example 60, Scheme 175) in tetrahydrofuran (2.0 mL). The reaction was allowed to warm to 5° C. over 2 hours, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a yellow solid (574, 75 mg, 47%). MS (ESI) [M+H+]+=744.7.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH2:12].C(N(CC)CC)C.Cl[C:27]1[S:31][N:30]=[C:29]([O:32][CH3:33])[N:28]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:12][C:27]1[S:31][N:30]=[C:29]([O:32][CH3:33])[N:28]=1
Reactant: COc1nsc(Cl)n1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)Nc1nc(OC)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
A solution of N-L-leucyl-L-proline methyl ester hydrochloride (5.6 g, 20 mmol, prepared according to the procedure by Jones, J. B. et al. in J. Med. Chem. 1995, 38, 3078) and triethylamine (5.6 mL, 40 mmol) in DMF (60 mL) was stirred at room temperature for 15 min. Then, a solution of 5-chloro-3-methoxy-[1,2,4]thiadiazole (1.51 g, 10 mmol) in DMF (10 mL) and tetrabutylammonium bromide (150 mg) were added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water and extracted into ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate, brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a mixture of hexane and ethyl acetate (7/3 and 6/4) afforded N-(3-methoxy-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester (1.92 g, 53.9%) as as an off-white foam. 1H-NMR (CDCl3) δ 7.10 (d, J=8.5 Hz, 1H, NHCH), 4.74 (m, 1H, NHCH), 4.57 (dd, J=8.6, 4.6 Hz, 1H, CHCO2), 3.92 (s, 3H, OMe), 3.85 (m, 1H), 3.69 (s, 3H, OMe), 3.62 (m, 1H), 2.17-2.23 (m, 1H), 1.95-2.07 (m, 4H), 1.77-1.82 (m, 1H), 1.59-1.66 (m, 1H), 0.97 (d, J=6.5 Hz 3H, Me), 0.94 (d, J=6.7 Hz, 3H, Me); MS (m/z) 357 (M++1), 228, 200, 130, 101, 70.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[S:24]([CH3:23])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccccc1CNCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccncc1)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 4.2 g. portion of 4-(2-fluorobenzylaminomethyl)pyridine was dissolved in 50 ml. of dichloromethane, and to it was added 3 g. of potassium carbonate and 2.5 g. of methanesulfonyl chloride. The mixture was stirred at ambient temperature for 4 days, and was then diluted with 50 ml. of water and extracted with 150 ml. of dichloromethane. The organic phase was dried over magnesium sulfate, and concentrated under vacuum. The oily residue was chromatographed on silica gel, eluting with 3:2 toluene:acetone. The product-containing fractions were evaporated to obtain an oil which solidified upon standing, and was triturated with petroleum ether to obtain 3.25 g. of the desired product, m.p. 69°-70°.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].N([O-])=O.[Na+].[ClH:21]>O.Cl[Cu]>[Cl:21][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
Reactant: Cl
Reactant: Nc1ccc2ccc(S(=O)(=O)[O-])cc2c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1ccc2ccc(Cl)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of sodium 7-aminonaphthalene-2-sulfonate (Pfaltz and Bauer, 1.00 g, 4.08 mmol) in water (6.0 mL) and conc. HCl (6.0 mL) was cooled to 0° C. A premixed solution of NaNO2 (295 mg, 4.28 mmol) in water (3.0 mL) was added slowly, maintaining the temperature close to 0° C. The resulting reaction mixture was stirred at room temperature for 30 min. A solution of CuCl (807 mg, 8.16 mmol) in water (1.0 mL) and conc. HCl (4.0 mL) was then added dropwise over 30 min, maintaining the temperature close to 0° C. The reaction mixture was stirred at room temperature for 2 h, then concentrated in vacuo and dissolved in a small amount of water. The solids were filtered off and retained. The filtrate was concentrated in vacuo, purified by preparative HPLC and combined with the filtered solids to give the title compound (843 mg, 85%) as a dark grey solid. MS(ESI−) m/z 241.2 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[C@H:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3]1.[H][H].[ClH:26]>C(O)C.[Pd].CCOCC>[ClH:26].[ClH:26].[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C@H:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C@H:4]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:11]=1
Reactant: CN1CC[C@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CN1CC[C@H](Oc2ccc(N)cc2)[C@H](c2ccccc2)C1
Reaction time: 48 h

Procedure:
A solution of 3.7 g of the free base of cis-1-methyl-4-(4-nitrophenoxy)-3-phenylpiperidine, of Example 7, in 100 ml of absolute ethanol is hydrogenated over 0.37 g of 10% Pd on carbon catalyst at 45 psi of hydrogen and room temperature. Uptake stops after 48 hours. The catalyst is filtered off and the filtrate is concentrated in vacuo to a gum. This material is chromatographed on silica gel using acetone and then 25% methanol/acetone as solvent. A purified free base is obtained and a portion of this material is dissolved in ether and is then added dropwise to a solution of dry HCl in ether. The resulting precipitate is filtered, washed with ether, and is then immediately suspended in boiling ether. Absolute ethanol is added until the mixture grows clear. Scratching of the cold solution causes crystallization to occur. The recrystallized solid is filtered, washed with cold acetone, then ether, and dried to afford a solid (m.p. 226°-227° C. dec.) of cis-4-(4-aminophenoxy)-1-methyl-3-phenylpiperidine dihydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]([NH:10][C:11]2[N:12]=[C:13]([CH3:35])[C:14]3[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]4[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29](C)(C)C)=[O:27])=[CH:24][CH:23]=4)[C:15]=3[N:16]=2)=[CH:8][CH:7]=1)=[O:5])C.OS(O)(=O)=O>CO>[CH3:29][O:28][C:26]([C:25]1[CH:33]=[CH:34][C:22]([N:17]2[C:15]3[N:16]=[C:11]([NH:10][C:9]4[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:1])=[O:5])=[CH:37][CH:36]=4)[N:12]=[C:13]([CH3:35])[C:14]=3[CH:20]=[CH:19][C:18]2=[O:21])=[CH:23][CH:24]=1)=[O:27]
Reactant: CCOC(=O)c1ccc(Nc2nc(C)c3ccc(=O)n(-c4ccc(C(=O)OC(C)(C)C)cc4)c3n2)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(Nc2nc(C)c3ccc(=O)n(-c4ccc(C(=O)OC)cc4)c3n2)cc1
Yield: 56.3 %

Procedure:
A solution of compound 3 (0.100 g; 0.200 mmol) and 96% H2SO4 (1 mL) in 100 mL of methanol was stirred under reflux for 24 h. The reaction mixture was concentrated, diluted with methylene chloride, and washed with aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulphate, concentrated and purified by silica gel column chromatography (eluant: CH2Cl2/CH3OH=190/10) to yield compound 41 (0.05 g; 56%).
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][NH:8][C:9]([C:11]1[C:16](=[O:17])[N:15]([CH3:18])[C:14]2[C:19]([CH3:25])=[C:20]([C:22]([OH:24])=[O:23])[S:21][C:13]=2[C:12]=1[OH:26])=[O:10])(C)(C)C.BrC1SC2C(O)=C(C(NCC(OC(C)(C)C)=O)=O)C(=O)N(C)C=2C=1C.[C]=O>CO.[Pd]>[C:6]([CH2:7][NH:8][C:9]([C:11]1[C:16](=[O:17])[N:15]([CH3:18])[C:14]2[C:19]([CH3:25])=[C:20]([C:22]([OH:24])=[O:23])[S:21][C:13]=2[C:12]=1[OH:26])=[O:10])([OH:27])=[O:5]
Reactant: Cc1c(C(=O)O)sc2c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n(C)c12
Agent: [Pd]
Agent: Cc1c(Br)sc2c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n(C)c12
Agent: [C]=O
Solvent: CO
Product: Cc1c(C(=O)O)sc2c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c12

Procedure:
6-((2-tert-Butoxy-2-oxoethyl)carbamoyl)-7-hydroxy-3,4-dimethyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-2-carboxylic acid. The title compound is prepared by palladium catalyzed carbonylation of tert-butyl 2-(2-bromo-7-hydroxy-3,4-dimethyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxamido)acetate with carbon monoxide in MeOH according to the procedure set forth in Tsuji, J. Palladium Reagents and catalysts: Innovations in Organic Synthesis Publisher: (Wiley, Chichester, UK), 340-5 (1995).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH2:9][CH3:10].[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.O>C(Cl)Cl>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:8](=[O:11])[CH2:9][CH3:10])=[CH:26][CH:25]=1
Reactant: Nc1ccc(OCc2nc3ccccc3s2)cc1
Reactant: CCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 3 h
Yield: 91 %

Procedure:
0.09 ml of triethylamine and 0.06 ml of propionyl chloride were added to a solution of 149.1 mg of 4-(benzothiazol-2-ylmethoxy)aniline [prepared as described in step (a) above] in 6 ml of methylene chloride cooled in an ice-water bath, and the resulting mixture was stirred at the same temperature for 3 hours. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was then removed under reduced pressure. The resulting residue was purified by column chromatography through silica gel using a 1:2 by volume mixture of hexane and ethyl acetate to give 165.5 mg of the title compound (yield 91%) as a solid having a melting point of 182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([O:34][C:35](=[O:45])[NH:36][C:37]1([CH2:43]O)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:45])[NH:36][C:37]1([CH2:43][N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)[S:21][C:20]2=[O:22])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC1(CO)CCOCC1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)NC1(CN2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CCOCC1

Procedure:
(4-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-ylmethyl}tetrahydro-2H-pyran-4-yl)carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione and (4-hydroxymethyltetrahydro-2H-pyran-4-yl)carbamic acid tert-butyl ester following General Procedure J.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@@H:9]2[O:10][C@@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][C:32]1[NH:33][CH:34]=[CH:35][N:36]=1)([CH3:23])[CH3:22]>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@H:9]([OH:10])[C@@H:8]([N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:21]([CH3:23])[CH3:22])[CH2:31][C:32]2[NH:36][CH:35]=[CH:34][N:33]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: CC(C)c1ccccc1NCc1ncc[nH]1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2ncc[nH]2)c2ccccc2C(C)C)[C@H]1O
Yield: 41.4 %

Procedure:
The title compound (72 mg, 42%) was prepared using (2R,3R,4R)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (100 mg, 0.35 mmol) and 2-isopropylphenyl-1H-imidazol-2-ylmethylamine (75 mg, 0.35 mmol), according to the same procedure used for the preparation of example 1 above.