Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@:5]1([CH3:25])[C@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.[Li+].[B-](CC)(CC)CC>C1COCC1>[C:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C@:5]1([CH2:3][OH:2])[CH3:25])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@]1(C)[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@]1(C)CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
To a solution of (2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester-2-methyl ester (58A) (1.08 g, 2.90 mmol) in THF (12 mL) at −78° C. was added a 1 M solution of Super-Hydride® in THF (14.50 mL, 14.50 mmol) in three portions over 15 min. After 10 min, the cold bath was removed and the reaction was allowed to warm to rt and was stirred for 18 h. The reaction was cooled again to −78° C. and more Super-Hydride® (7 mL) was added. After stirring an additional 24 h, the reaction was poured into a 1-L Erlenmeyer flask containing ice water and was then diluted with EtOAc. The layers were separated and the organic layer washed with 1 M H3PO4 (2×), NaHCO3 and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was diluted with CH2Cl2, stirred with silica gel for 10 min, then concentrated under reduced pressure and purified via flash chromatography, eluting with 20% EtOAc/hexane to obtain the title compound (0.54 g) as a clear oil. MS m/z 346 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[OH:13]O>C(O)(=O)C>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([CH3:1])=[N+:3]([O-:13])[CH:4]=1)=[O:7])[CH3:10]
Reactant: OO
Reactant: CCOC(=O)c1ccc(C)nc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(C)[n+]([O-])c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 14.9 g of ethyl 6-methylnicotinate, 60 ml of acetic acid and 21.5 ml of 30% hydrogen peroxide was stirred at 80° C. for 16 hours, the reaction liquid was concentrated under a reduced pressure, water was added to the concentrate, and the mixture was extracted with chloroform. The chloroform layer was washed with an aqueous solution of potassium carbonate and dried over anhydrous potassium carbonate, and the solvent was removed under a reduced pressure to obtain 14.0 g of 5-ethoxycarbonyl-2-methyl pyridine-1-oxide. ##STR6##
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10](OCC)=[O:11])[C:3]1=[O:15].[NH2:16][C:17]1[N:21]=[CH:20][NH:19][N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[N:21]=[CH:20][NH:19][N:18]=2)=[O:11])[C:3]1=[O:15]
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Product: Cc1cc(O)c(C(=O)Nc2nc[nH]n2)c(=O)n1C
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 81.3 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxyl ate and 78 mg of 3-amino-1,2,4-triazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 7.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 188 mg of 1,6-dimethyl-4-hydroxy-2-oxo-N-(1,2,4-triazol-3-yl)-1,2-dih ydropyridine-3-carboxamide (hereinafter, referred to as present compound 23) represented by the formula:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:27])[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20](=O)[CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[CH2:23][C:18]([CH3:27])([CH3:17])[CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of zinc powder (23.4 g, 0.36 mol) in THF (300 mL) was slowly added TiCl4 (20 mL, 0.18 mol) via a syringe at room temperature under a nitrogen atmosphere. The reaction mixture was heated at reflux for 1 h. A solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (10.0 g, 0.036 mol) and 3,3,5,5-tetramethylcyclohexanone (16.7 g, 0.108 mol) in THF (100 mL) was added to the reaction mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for an additional 2 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was poured into a 10% aqueous K2CO3 (1 L). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous phase was further extracted with EtOAc (4×250 mL). The combined organic phase was washed with brine (2×100 mL), dried (Na2SO4), filtered, and then filtrate was concentrated under reduced pressure to give the crude product as a gold-yellow oil. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 1:1) as an eluent to afford 10.45 g (73%) of compound 14 as a white solid. 1H NMR (300 MHz, CDCl3): δ 0.91 (s, 6H), 0.95 (s, 6H), 1.31 (s, 2H), 1.96 (s, 2H), 1.99 (s, 2H), 4.67 (s, 1H), 6.76 (d, J=8.7 Hz, 2H), 7.03 (d, J=6.0 Hz, 2H), 7.05 (d, J=6.0 Hz, 2H), 7.41(d, J=8.4 Hz, 2H). HRMS (EI) Calcd for C23H27BrO: 398.1245 (M+.). Found: 398.1248.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[S:22]1[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23]1>>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:27]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)=[O:28])[N:8]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reactant: O=C(Cl)c1ccsc1
Product: CN1C(=O)C(NC(=O)c2ccsc2)N=C(c2ccccc2F)c2ccccc21

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 3-thiophenecarbonyl chloride. The product was purified by chromatography on silica gel (5% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo to give the title compound which was dried at 65° C.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([F:31])([F:30])[F:29])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[F:31][C:28]([F:29])([F:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:15]([S:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: FC(F)(F)c1ccccc1C(Cl)Cn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
374 mg of a 55% w/w suspension of sodium hydride in mineral oil were added to 1.44 g of methyl 4-mercaptobenzoate in 9.1 mg of dry dimethylformamide, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. 2.14 g of 1-[2-chloro-2-(2-trifluoromethylphenyl)ethyl]imidazole in 11.2 ml of dry dimethylformamide were added to this solution, and the resulting mixture were heated at 60°-70° C. for 6 hours. At the end of this time, the reaction mixture was treated and purified by the same method as described in Example 1, to give 2.34 g of the title compound as white cyrstals, melting at 121°-126° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C)C=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:8][N:9]1[C:13](=[O:14])[C:12]2[C:11](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]1=[O:19])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a solution of ethyl bromoacetate (2.05 g, 12.3 mmol) in dimethylformamide (15 ml), N-hydroxyphthalimide (3.04 g, 18.4 mmol) and Hunig base (N,N-diisopropylethylamine, 4.24 mL) were added at room temperature, and the mixture was stirred at 80° C. overnight. The reaction solution was poured into saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate (3×40 ml). The combined organic layer was washed with saturated brine (2×30 ml), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100 g, n-hexane/ethyl acetate=2:1) to give (1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-acetic acid ethyl ester (1.83 g, 60%) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[C:11]([CH3:29])=[CH:12][CH:13]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[NH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>O1CCCC1>[CH3:45][N:42]1[CH2:43][CH2:44][N:39]([NH:38][CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:15]=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:13]=[CH:12][C:11]=3[CH3:29])=[O:8])=[CH:5][CH:4]=2)[CH2:40][CH2:41]1
Reactant: CN1CCN(N)CC1
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CNN2CCN(C)CC2)cc1
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
N-(5-(4-chloromethylbenzoylamino)-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (1.5 g, 3.49 mmol) was dissolved in tetrahydrofuran (30 ml), pyridine (560 μl, 6.98 mmol) was added, and the mixture was stirred for 30 minutes. 1-Amino-4-methylpiperazine (580 μl, 5.23 mmol) was added thereto, and the resulting mixture was refluxed for 12 hours and then filtered. The filtrate was concentrated and crystallized from dimethylether to give 4-(4-methylpiperazin-1-ylaminomethyl)-N-[2-methyl-5-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (1.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Br:30])=[N:6][CH:7]=1
Reactant: OCc1ccc(Br)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
5-Bromo-2-hydroxymethylpyridine (1 g, 5.32 mmol) was dissolved in dichloromethane (26.6 ml) and cooled to 0° C. Triphenylphosphine (1.604 g, 6.12 mmol) was added followed by carbon tetrabromide (2.028 g, 6.12 mmol) which caused the reaction to become yellow and heterogeneous. After 48 h, the mixture was concentrated by half and directly purified by silica gel column chromatography (0-37%, EtOAc-hexanes) to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 8.64 (t, J 2.7 Hz, 1H), 7.82 (m, 1H), 7.35 (dd, J 7.8 & 3.1 Hz, 1H), 4.51 (s, 2H).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:5]([CH:23]([CH3:25])[CH3:24])=[N:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[Li]CCCC>C1COCC1>[C:3]([C:4]1[C:5]([CH:23]([CH3:25])[CH3:24])=[N:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)#[CH:2]
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=C(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C
Temperature: -78 °C
Reaction time: 1.25 h

Procedure:
A solution of 3-(2,2-dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine (2.105 gm, 4.43 mmol) in dry THF (23 ml) was cooled to -78° C. and treated with n-BuLi (1.5M in hexane, 5.95 ml, 8.93 mmol) over a 4 minute period. After stirring at -78° C. for 1.25 hours, the deep purple solution was quenched with saturated NH4Cl, warmed to room temperature, diluted with H2O, and extracted 2× with Et2 O. The combined Et2O extracts were washed with brine, dried (Na2SO4), filtered and stripped to give a yellow solid. The solid was recrystallized from a minimum amount of hot hexane to afford analytically 3-ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine as white needles. The mother liquor was stripped and recrystallized again from hot hexane to give additional product (total yield 1.199 gm, 86%)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[N:4](C2CCCCO2)[N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:31]1[C:32]([N:51]2[CH2:55][CH2:54][C@@H:53]([OH:56])[CH2:52]2)=[N:33][CH:34]=[C:35]([CH:50]=1)[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]([Cl:49])([F:48])[F:47])=[CH:41][CH:40]=1)=[O:37].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:49][C:46]([F:47])([F:48])[O:45][C:42]1[CH:43]=[CH:44][C:39]([NH:38][C:36](=[O:37])[C:35]2[CH:50]=[C:31]([C:5]3[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=3)[C:32]([N:51]3[CH2:55][CH2:54][C@@H:53]([OH:56])[CH2:52]3)=[N:33][CH:34]=2)=[CH:40][CH:41]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C2CCCCO2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)[nH]n1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Stage 23.1, 150 mg, 0.359 mmol), K3PO4 (147 mg, 0.692 mmol) and Pd(PPh3)4 (15.98 mg, 0.014 mmol) were added to a solution of (R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2, 80 mg, 0.173 mmol) in toluene (1.5 mL) under an argon atmosphere and the RM was stirred at 110° C. for 2 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (1.5 mL), treated with TFA (0.533 mL, 6.92 mmol) and stirred at RT for 2 h. The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried over Na2SO4, and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel column, 12 g, DCM/MeOH from 99:1 to 92:8) and crystallized from DCM/n-hexane to give the title product as a white solid. HPLC (Condition 5) tR=5.92 min, UPLC-MS (Condition 3) tR=0.94 min, m/z=464.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.89 (m, 2H) 2.19-2.31 (m, 3H) 2.98 (d, J=10.95 Hz, 1H) 3.24-3.35 (m, 2H) 3.39-3.52 (m, 1H) 4.16-4.25 (m, 1H) 4.80-4.90 (m, 1H) 6.11-6.17 (m, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.87 (d, J=8.99 Hz, 2H) 7.97-8.06 (m, 1H) 8.66-8.78 (m, 1H) 10.16 (s, 1H) 12.51-12.70 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[OH:23]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: OO
Reactant: O=C1CC2CSc3ccccc3C2=NN1c1ccc(Cl)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2CS(=O)c3ccccc3C2=NN1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a mixture of 11.5 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one in 200 ml of acetic acid is added 66 ml of 35% hydrogen peroxide dropwise with stirring at room temperature. After the completion of addition, the mixture is stirred at room temperature for 3 hours, poured into an excess amount of water and extracted with chloroform. The extract is washed with water, dried over magnesium sulfate anhydride and the chloroform is distilled off under reduced pressure. To the precipitated crystals is added diisopropyl ether. The crystals are collected by filtration and recrystallized from isopropyl alcohol to give 7.7 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one 6-oxide, melting at 181°-183° C., as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([OH:18])=O)[CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([NH:34][CH:31]3[CH2:33][CH2:32]3)=[O:18])[CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Oc1ncn(-c2cccc(Br)c2)n1)C(=O)O
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(Oc1ncn(-c2cccc(Br)c2)n1)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Three g of the compound of Example 38 was dissolved in 20 ml of dimethylformamide, 2.4 g of carbonyldiimidazole was added, and the solution was stirred at room temperature for 20 minutes. To it was added 1.1 g of cyclopropylamine, and the mixture was stirred for 16 hours more. It was then poured over ice-water, and the product was collected, dried and recrystallized from ethanol to obtain 2.1 g of the desired product, m.p. 134°-135°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=[CH:15][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:19]=1.C1C2CCC3C=CC=CC=3SC=2C=C(C(O)=O)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1CC2
Agent: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2
Product: OCc1ccc2c(c1)Sc1ccc(F)cc1CC2

Procedure:
Repeat the process of Example 1, substituting an equivalent quantity of 8-fluoro-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid for the 10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid, to obtain the title product (m.p., 80°-81° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.CO.[Li+].[OH-]>CCOC(C)=O.C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1)=[O:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-({[2-[(tert-butoxycarbonyl)amino]-5-(2-thienyl)phenyl]amino}carbonyl)benzoate (3.20 g, 7.07 mmol) in 1:1:2 H2O:MeOH:THF (80 mL) was added LiOH (1.20 g, 50.1 mmol). The reaction was stirred at room temperature for 18 h, diluted with EtOAc, washed with 2 N HCl, dried (Na2SO4), and evaporated to give the desired product as a red solid. MS: cal'd 461 (MNa+), exp 461 (MNa+).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:13]([O-])=O>[Ni].O1CCOCC1>[NH2:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[Cl:1])[O:6][CH2:7][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1COCCO1
Product: CC(=O)COc1ccc(Cl)c(N)c1

Procedure:
A mixture of 23.8 g (0.104 mole) of 1-(4-chloro-3-nitrophenoxy)-2-propanone, 2 g of Raney nickel and 240 ml of dioxane is hydrogenated at normal pressure and room temperature. After 20 hours (hydrogen absorption: 103%), the whole is filtered with suction over Celite, then washed with dioxane and concentrated by evaporation in vacuo. Purification of the crude product by chromatographed with petroleum ether/ether over silica gel and subsequent recrystallisation from ether/petroleum ether yields 1-(3-amino-4-chlorophenoxy)-2-propanone having a melting point of 49°-51°.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].N#N.[CH2:17]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][NH2:22])[CH3:18].[OH:30][P:31]([OH:34])([OH:33])=[O:32].C>C1COCC1.CCO>[P:31]([OH:34])([OH:33])([OH:32])=[O:30].[CH2:17]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][NH:22][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=1)[CH3:18]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCN(CC)CCN
Agent: N#N
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCN(CC)CCNC(=O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
Dissolve 5.66 g (0.024 moles) 4-[(methylsulfonyl)amino]benzoyl chloride in 40 ml THF. Chill the solution on an ice/MeOH bath under a stream of N2. Add dropwise 4.5 g (0.024 moles) N-ethyl-N-heptyl-1,2-ethanediamine to the room temperature for about 24 hours. Follow the progress of the reaction by thin layer chromatography on silica gel (Acetonitrile:MeOH:Ammonia, 85:10:5). At the completion of the reaction, remove the solvents in vacuo. Dissolve the resulting oil in 10% K2CO3 solution and extract with 5×100 ml Et2O. Dry the organics over Na2SO4. Evaporate the solvents to provide an oil. Crude wt: 3.38 g. Dissolve the oil in 25 ml EtOH and acidify with 1.02 g 85% H3PO4. Treat the solution with activated charcoal, filter and evaporate the solvents to provide the title compound. Recrystallize the product from EtOH/Et2O.
Reaction SMILES: FC1C=CC=C2C=1[O:10]CCC2N.O1C2C(=CC=CC=2)C(N)CC1.FC1C=C2C(=CC=1)OCCC2N.ClC1C=C2C(=CC=1)OCCC2N.CC1C=C2C(=CC=1)OCCC2N.COC1C=C2C(=CC=1)OCCC2N.[F:73][C:74]1[CH:83]=[CH:82][CH:81]=[C:80]2[C:75]=1[CH:76](N)[CH2:77][CH2:78][O:79]2>>[F:73][C:74]1[CH:83]=[CH:82][CH:81]=[C:80]2[C:75]=1[C:76](=[O:10])[CH2:77][CH2:78][O:79]2
Reactant: NC1CCOc2c(F)cccc21
Reactant: NC1CCOc2cccc(F)c21
Agent: COc1ccc2c(c1)C(N)CCO2
Agent: Cc1ccc2c(c1)C(N)CCO2
Agent: NC1CCOc2ccc(Cl)cc21
Product: O=C1CCOc2cccc(F)c21

Procedure:
These amines were prepared via procedures described in Example 29 for the synthesis of 8-fluorochroman-4-amine. The corresponding chroman-4-ones were commercially available as advanced intermediates for the synthesis of chroman-4-amine, 6-fluorochroman-4-amine, 6-chlorochroman-4-amine, 6-methylchroman-4-amine, and 6-methoxychroman-4-amine. For the synthesis of 5-fluorochroman-4-amine, the intermediate 5-fluorochroman-4-one was obtained using procedures from GB 2355264, which also provided 7-fluorochroman-4-one. 7-Fluorochroman-4-one could be used in the synthesis of 7-fluorochroman-4-amine. Chroman-4-amine, 5-fluorochroman-4-amine, 6-fluorochroman-4-amine, 7-fluorochroman-4-amine, 5,8-difluorochroman-4-amine, and 6,8-difluorochroman-4-amine were resolved via the procedure described in Example 29 for the resolution of 8-fluorochroman-4-amine.