Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:37]([CH2:38][CH3:39])=[CH:36][N:35]=[C:34]([CH3:40])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:38]([C:37]1[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:41])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:18])([F:20])[F:19])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)=[CH:33][C:34]([CH3:40])=[N:35][CH:36]=1)[CH3:39]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)ncc3CC)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)ncc3CC)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(5-ethyl-2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M135) (0.30 g, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (220 mg, 92%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc([N+](=O)[O-])cc1
Yield: 79.9 %

Procedure:
Using 3-trifluoromethylaniline (1.77 g, 11.0 mmol) and 4-nitrobenzoic acid (1.67 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 2.48 g (80.0%) of the title compound in the form of colorless powder.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH2:10][C:11]([OH:15])(O)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.O=P(Cl)(Cl)Cl.CN([CH:24]=[O:25])C>>[F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:24]=[O:25])=[C:11]([OH:15])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: CN(C)C=O
Reactant: OC1(O)C=C2C(=CC1)CCCN2CCF
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2c(cc1O)N(CCF)CCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
290 mg (1.48 mmol) 1-(2-Fluoro-ethyl)-7-hydroxy-1,2,3,4-tetrahydro-quinolin-7-ol are dissolved in 5 mL DMF. 0.15 mL POCl3 are added dropwise at 0° C. The reaction mixture is slowly heated to 50° C., stirred an additional 3 h at this temperature, then cooled to RT and extracted with ethyl acetate and an aqueous saturated solution of sodium bicarbonate. The combined organic phases are washed with brine, dried over sodium sulphate and evaporated. The residue is column chromatographed (silica gel, ethyl acetate/petroleum ether 1:2) to yield 200 mg (60%) desired product as a brown solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1C(=O)C2=CC=CC=C2C1=O.O.NN>CO>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CO)c1
Agent: NN
Solvent: CO
Solvent: O
Product: NCCCOc1cccc(CO)c1
Yield: 52.1 %

Procedure:
N-[3-(3-hydroxymethylphenoxy)propyl]phthalimide (16 g) was dissolved in 300 ml of methanol, and 5 g of hydrazine hydrate was added. The mixture was refluxed for 5 hours, and after cooling, the insoluble matter was removed by filtration. The filtrate was concentrated to give 4.85 g (yield 52.1%) of 3-(3-hydroxymethylphenoxy)propylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O.C([BH3-])#N.[Na+].Cl>CO.O>[O:19]=[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: NCCCCC(=O)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CCCCN1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.4 g (42 mmol) of 4-nitrobenzaldehyde are dissolved in 150 ml of methanol and combined with 4.9 g (42 mmol) of 5-aminovaleric acid and 1.8 g (29 mmol) of sodium cyanoborohydride. The mixture is stirred for 18 hours at ambient temperature and then carefully mixed with 20 ml of conc. hydrochloric acid. The solvent is eliminated in vacuo, the residue is taken up in water and extracted with dichloromethane. The residue obtained after evaporation is chromatographed on silica gel (dichloromethane/methanol, 4:1). A mixture of methyl 5-(4-nitrobenzylamino)-pentanoate and 4-(2-oxopiperidinomethyl)-nitrobenzene is obtained which is dissolved in 100 methanol and combined with 50 ml of 1 N sodium hydroxide solution. The mixture is stirred for one hour at ambient temperature, 50 ml of 1 N hydrochloric acid are added and the reaction solution is evaporated down to 100 ml. The aqueous phase thus obtained is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and evaporated to dryness.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=1.I[CH3:21].O>CN(C)C=O>[CH3:21][O:3][C:4]1[CH:5]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=1
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OC)cc(C(=O)OCC)n1
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To a suspension of 60% sodium hydride (0.351 g, 8.77 mmol) in dimethylformamide (7.5 mL), a solution of diethyl 4-hydroxy-2,6-pyridinedicarboxylate (1.4 g, 5.85 mmol) in dimethylformamide (9 mL) was added dropwise under argon at room temperature and the reaction mixture was stirred for 5 minutes. Iodomethane (1.245 g, 8.77 mmol) was added and the reaction was stirred at room temperature for 20 hours. The mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was dried, concentrated to give 1.45 g (97.8%) diethyl 4-methoxy-2,6-pyridinedicarboxylate.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>C1COCC1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cccc2)cc1
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a suspension of 60% NaH (3.13 g) in THF (20 mL) was added dropwise a solution of pyrrole (5.00 g) in THF (20 mL). The mixture was stirred for 30 minutes, and thereto was added a solution of p-toluene sulfonylchloride (14.2 g) in THF (20 mL), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the organic layer was separated, dried, filtered, and concentrated. The residue was recrystallized from a mixed solvent of methanol and water (each 35 mL), and the resulting crystals were collected by filtration, and dried to give 1-p-toluenesulfonyl-1H-pyrrole (16.3 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]2[CH:13]=O.[CH3:15][N:16]1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]2[CH2:13][NH:16][CH3:15]
Reactant: Cc1c(C=O)n(C)c2ccccc12
Reactant: COc1cccc2c(C=O)cn(C)c12
Product: CNCc1cn(C)c2c(OC)cccc12
Yield: 94 %

Procedure:
According to the procedure of Preparation 13(c), except substituting 7-methoxy-1-methyl-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (1.6 g, 94%) was obtained as an amber oil: MS (ES) m/e 205.2 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][C:11]=1[N+]([O-])=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CO.ClCCl>[CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@H](C)Oc1ccc(O)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: CCCCCC[C@H](C)Oc1ccc(-c2ccc(O)cc2)cc1

Procedure:
The same procedure as that used for saponification of (S)-4-(1-methylheptyloxy)-3-nitro-phenol was used except the reaction was carried out in a methanol/dichloromethane [4:1]mixture at 60° C. Flash chromatography with hexanes/ethyl acetate [93/7] afforded (S)-4'-(1-methylheptyloxy)-4-hydroxybiphenyl (Compound 40, Scheme VIII, R2 =(S)--OCH(CH3)C6H13) as a white solid (mp 100.5° C.); Rf [hexanes/ethyl acetate 90/10]: 0.2; 1H NMR (300 MHz, CDCl3): δ0.88(t, 3H, J=6.6 Hz), 1.20-1.64(m, 9H), 1.33(d, 3H, J=6.1 Hz), 1.74(m, 1H), 4.38(m, 1H), 5.07(s, 1H), 6.87(d,2H, J=8.5 Hz), 6.93(d, 2H, J=8.5 Hz), 7.42(d, 2H, J =8.5 Hz), 7.44(d, 2H, J=8.5 Hz); 13C NMR (300 MHz, CDCl3): δ14.02, 19.73, 22.54, 25.51, 29.22, 31.74, 36.45, 74.17, 115.59, 116.16, 127.74, 127.94, 133.22, 133.77, 154.55, 157.31; IR (CHCl3): 3560, 3350(broad), 3020, 2920, 2840, 1610, 1500, 1250, 1220, 1175, 825 cm-1. Mass spectrum, m/z(rel.intensity): 298(M+ 11), 186(100), 185(4), 157(4).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14]>>[CH3:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: COCCCCCl
Product: COCCCCN1CCC(=O)CC1

Procedure:
1-(4-Methoxybutyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-4-methoxybutane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[CH:12]=[C:13]([Br:16])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)(=O)=O.[CH3:19][O:20][CH2:21][C:22]#[CH:23]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH:8]=[C:7]([C:23]#[C:22][CH2:21][O:20][CH3:19])[C:11]=2[CH:12]=1
Reactant: C#CCOC
Reactant: O=S(=O)(Oc1coc2ccc(Br)cc12)C(F)(F)F
Product: COCC#Cc1coc2ccc(Br)cc12

Procedure:
Analogously to residue 9a, 9.31 g of 5-bromobenzofuran-3-yl trifluoromethanesulphonate [440083-74-9] and 3.52 ml of 3-methoxypropyne are reacted. The title compound is obtained as a yellowish oil. Rf=0.43 (1:10 EtOAc-heptane). Rt=5.14 (gradient I).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:7])[CH:4]([CH3:6])[CH3:5].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[NH:18][C:19]1[NH:23][C:22]2[C:24]3[CH2:25][C:26]([CH3:36])([CH3:35])[O:27][C:28]=3[C:29]([C:31](OC)=O)=[CH:30][C:21]=2[N:20]=1>C1COCC1.O>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[NH:18][C:19]1[NH:23][C:22]2[C:24]3[CH2:25][C:26]([CH3:36])([CH3:35])[O:27][C:28]=3[C:29]([C:31]3[O:1][N:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:7]=3)=[CH:30][C:21]=2[N:20]=1
Reactant: CC(C)C(N)=NO
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1noc(-c2cc3nc(Nc4c(F)cccc4Cl)[nH]c3c3c2OC(C)(C)C3)n1
Yield: 17.7 %

Procedure:
Under nitrogen atmosphere, to a solution of N′-hydroxyisobutyrimidamide (0.028 g, 0.268 mmol) in THF was added sodium hydride (0.021 g, 0.51 mmol). The reaction mass was refluxed for 15-20 minutes. Then added methyl 2-((2-chloro-6-fluorophenyl)amino)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Step-1 of Intermediate-15, 0.100 g, 0.255 mmol) and continued reflux for 4-5 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified column chromatography to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 1.28 (d, 6H), 1.48 (s, 6H), 3.09 (m, 3H), 7.24 (m, 1H), 7.39 (m, 1H), 7.54 (d, J=7.2 Hz, 1H), 9-10 (s, 1H), 10.5 (s, 1H); MS [M]+: 458.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:23])[CH:12]=[CH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18].S(=O)(=O)(O)O.[CH3:29]O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:23])[CH:12]=[CH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([O:19][CH3:29])=[O:18]
Reactant: CO
Reactant: COc1ccc(OC)c(C(=O)C=Cc2cccc(C(=O)O)c2)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C=CC(=O)c2cc(OC)ccc2OC)c1
Reaction time: 12 h

Procedure:
A solution of 3-[3-(2,5-dimethoxyphenyl)-3-oxo-1-propenyl]-benzoic acid (2.86 g, 9.15 mmol) in methanol (200 mL) is treated with sulfuric acid (0.5 mL) and heated under reflux for 6 hours. After standing at room temperature 12 hours, the resulting solid is collected by filtration and washed with methanol to provide 2.2 g of the title compound; mp 108°-110° C. Additional material (0.7 g) is obtained by concentrating the filtrate and washings under vacuum, partitioning the residue between saturated sodium bicarbonate solution and dichloromethane, and concentrating the dried (MgSO4) organic layer to dryness.
Reaction SMILES: [CH3:1][CH:2]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([NH2:19])[CH:15]=[CH:14]2)[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].CCN(CC)CC.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>C1COCC1>[CH3:27][C:28]([CH3:33])([CH3:32])[C:29]([NH:19][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[C:9]([O:8][CH:2]([CH3:1])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:10]=[CH:11][CH:12]=2)[N:17]=1)=[O:30]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(CC(C)(C)C)Oc1cccc2ccc(N)nc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CC(C)(C)C)Oc1cccc2ccc(NC(=O)C(C)(C)C)nc12
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial was added a stir bar, the title compound from Example 16 (161 mg, 0.624 mmol) and 1.5 mL of THF. To the resultant solution was added Et3N (0.174 mL, 2 equiv) and trimethylacetylchloride (93 μL, 1.2 equiv). The solution was allowed to stir overnight, after which time the mixture placed directly on a silica column and eluted with EtOAc/hexanes to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.27 (m, 1H), 7.96–8.18 (m, 1H), 7.42 (m, 2H), 7.21 (m, 1H), 4.64–4.90 (m, 1H), 1.90 (m, 1H), 1.53 (m, 1H), 1.31 (m, 12H), 0.83–1.05 (m, 9H); MS (DCI/NH3) m/z 343 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]1[CH:30]=[C:29]([NH:31][C:32](OC2C=CC=CC=2)=[O:33])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:32](=[O:33])[NH:31][C:29]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([F:20])[CH:30]=3)=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1F
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Reaction time: 16 h
Yield: 61.9 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (321 mg, 1.03 mmol, 1.0 eq) in DCM (10 mL) was added TEA (0.28 mL, 0.26 mmol, 2.0 eq) followed by methyl 2-fluoro-4-(phenoxycarbonylamino)benzoate (300 mg, 1.03 mmol, 1.0 eq) at RT and stirred for 16 h. Then the reaction mixture was evaporated, diluted with water (50 mL) and extracted with ethyl acetate (2×70 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude product was purified CC using EtOAc/PE (2:3) as eluent to obtain methyl 4-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)-2-fluorobenzoate (300 mg; 63%) as a white solid (TLC: EtOAc/PE (1:1); Rf: 0.3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[SH:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.CN(C)C=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Sc1ncccn1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Sc2ncccn2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 3.5 g. of 2-amino-4-chloro-1-nitrobenzene, 5.5 g. of potassium carbonate, and 4.5 g. of 2-mercaptopyrimidine in 25 ml. dimethylformamide is heated overnight under nitrogen at 105°-110° C. The mixture is cooled, diluted with water and the product filtered off. Recrystallization from methanol yields 2-amino-1-nitro-4-(pyrimidin-2-ylthio)benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30].O.Cl>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH:20][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:6]([Cl:19])[CH:5]=1)(=[O:31])=[O:30]
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1)c1ccc(Cl)cc1Cl
Yield: 46.4 %

Procedure:
A solution of 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (102) (2.0 g, 5.79 mmol) and 2,4-dichloro benzenesulfonylchloride (1.5 g, 6.08 mmol) in pyridine (10 mL) was stirred at room temperature for 12 h. Water was added to the reaction mixture, which was then acidified by 2N HCl. Reaction mixture was extracted twice with AcOEt. Organic layer was washed by brine, dried over MgSO4 and concentrated. Crude residue was purified by column chromatography (H/A=4/1, 80 g of silica gel) to afford title compound (104) (1.49 g, 46%) as a white solid. Mp 73-75° C. 1H NMR (300 MHz, DMSO-d6) δ 7.29 (2H, s), 7.46 (1H, dd, J=2.2, 8.8 Hz), 7.69 (1H, d, J=8.8 Hz), 7.71 (1H, dd, J=2.2, 8.4 Hz), 7.95 (1H, d, J=2.2 Hz), 8.14 (1H, d, J=2.2 Hz), 8.18 (1H, d, J=8.4 Hz), 11.5 (1H, br s). MS (M+H) 553.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[BH3-]C#[N:15].[Na+]>C(O)(C)C>[F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:15])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(F)c(F)c21
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: NC1CCc2ccc(F)c(F)c21
Yield: 49.7 %

Procedure:
A solution of 6,7-difluoro-1-indanone (6.00 g, 35.70 mmol), NaBH3CN (15.70 g, 0.25 mol) and NH4OAc (82.60 g, 1.07 mol) in isopropanol was reacted according to the protocols as outlined in general procedure B to give 3.00 g of the crude title compound, which was used in the next step without further purification. Spectroscopic data: 1H NMR (300 MHz, CDCl3) □ 1.7 (br s, 2H), 1.78-1.90 (m, 1H), 2.44-2.57 (m, 1H), 2.72-2.87 (m, 1H), 2.95-3.09 (m, 1H), 4.7 (t, 1H, J=6.7 Hz), 6.86-7.00 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1.Cl[C:14]1[C:19]2[O:20][CH2:21][CH2:22][N:23]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:18]=2[N:17]=[CH:16][N:15]=1>>[CH3:1][C:2]1[C:7]([NH:8][C:14]2[C:19]3[O:20][CH2:21][CH2:22][N:23]([CH:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[C:18]=3[N:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1
Reactant: Cc1nc(S(C)(=O)=O)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Product: Cc1nc(S(C)(=O)=O)ccc1Nc1ncnc2c1OCCN2C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
By the procedure described in Example 3, with the exception that 2-methyl-6-(methylsulfonyl)pyridin-3-amine was used instead of 2-fluoro-4-(methylsulfonyl)-aniline, tert-butyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 3C was converted into Example 123. 1H NMR (500 MHz, CDCl3) δ ppm 1.45 (s, 9 H) 1.55-1.65 (m, 2 H) 1.66-1.72 (m, 2 H) 2.61 (s, 3 H) 2.82-2.90 (m, 2 H) 3.15 (s, 3 H) 3.45-3.48 (m, 2 H) 4.25-4.28 (m, 4 H) 4.79-4.88 (m, 1 H) 6.86-7.00 (m, 1 H) 7.91 (d, J=8.25 Hz, 1 H) 8.06 (s, 1 H) 8.91 (m, 1 H) LRMS (ESI): 505.3 [M+H]+.
Reaction SMILES: O.Cl.Cl[CH2:4][CH2:5][N:6]([CH3:8])[CH3:7].[Cl:9][C:10]1[CH:18]=[CH:17][C:16]2[N:15]3[CH:19]=[CH:20][CH:21]=[C:14]3[C:13](=[N:22][OH:23])[C:12]=2[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:9][C:10]1[CH:18]=[CH:17][C:16]2[N:15]3[CH:19]=[CH:20][CH:21]=[C:14]3[C:13](=[N:22][O:23][CH2:4][CH2:5][N:6]([CH3:8])[CH3:7])[C:12]=2[CH:11]=1
Reactant: ON=C1c2cc(Cl)ccc2-n2cccc21
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)CCON=C1c2cc(Cl)ccc2-n2cccc21

Procedure:
Add 5 ml of water, 0.94 g (6.5 mmol) of 1-chloro-2-(N,N-dimethylamino)ethane hydrochloride and 1.19 g (5.44 mmol) of 7-chloro-9-hydroxyiminopyrrolo[1,2-a]indole (Preparation 46) in succession to a solution of 1.56 g (14.7 mmol) of sodium carbonate in 100 ml of acetone, then heat the reaction mixture at reflux for 36 hours. The acetone is removed under reduced pressure and the residue is taken up in 50 ml of water and extracted with diethyl ether. The ethereal phase is washed with water, dried over magnesium sulfate, rendered colourless with animal charcoal, and then concentrated to dryness to yield the title product in the form of an oil (base).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:18]=2I)=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:28]([O-])([O-])=[O:29].[K+].[K+]>C(#N)C.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.[Cu]I>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:28](=[O:29])[C:18]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(S(C)(=O)=O)cc2I)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2nc3ccc(S(C)(=O)=O)cc3c(=O)o2)CC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a stirring solution of 2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-methylsulfonyliodobenzene (1.89 g, 3.72 mmol) in acetonitrile (50 mL) was added K2CO3 (2.53 g, 18.6 mmol) followed by Pd(PPh3)4 (0.22 g, 0.19 mmol) and CuI (0.036 g, 0.19 mmol). The mixture was placed under an atmosphere of CO and heated to 75° C. After 2 h, the heat was removed and the mixture was diluted with ethyl acetate and washed with water, then brine The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a gradient of 10% to 20% ethyl acetate in dichloromethane The product containing fractions were combined and concentrated in vacuo to give 0.485 g (32%) of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH2:22][OH:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/CO
Agent: [Mn+4]
Agent: [O-2]
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Yield: 75.2 %

Procedure:
From (E)-3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenol (0.301 g) and manganese (IV) oxide (2.101 g) by the process as described for the preparation of Intermediate (9a) to afford a yellow solid which was purified by FCC eluting with System A (2:3) to afford the title compound (0.225 g) as a white solid, λmax (EtOH) 260.0 (20,050) and 289.2 (inf) nm (ε10,890).