Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(N(CC)CC)C>[CH3:2][C:3]1[C:4]([C:19]([F:20])([F:22])[F:21])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)[CH2:16][CH2:17]3)[C:7]=2[CH:18]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)n2C1CCNCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)n2C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Methyl-1-(4-piperidinyl)-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D60) (2.2 mmol), was dissolved in 1,2-dichloroethane (50 ml) and triethylamine (7 ml), tetrahydro-4H-pyran-4-one (7 eq., 15.4 mmol, 1.4 ml), sodium triacetoxyborohydride (7 eq., ˜3.2 g) were added in that order at room temperature and the mixture was stirred at room temperature for 2 hours. Reaction mixture was quenched with 10 ml of NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent was evaporated to afford the crude product. The crude obtained was dissolved again in 1,2-dichloroethane (50 ml) and triethylamine (7 ml), tetrahydro-4H-pyran-4-one (7 eq., 15.4 mmol, 1.4 ml), sodium triacetoxyborohydride (7 eq., ˜3.2 g) were added at room temperature and the mixture was stirred at room temperature for three hours. Reaction mixture was quenched with 10 ml of NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent was evaporated to afford the crude product that was purified by chromatography (methanol-NH3-dichloromethane) to afford 6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one, 240 mg, 30%, M++H=384, which was subsequently converted into the hydrochloride salt using HCl solution (1M in diethyl ether, 2 eq).
Reaction SMILES: [NH2:1][C:2]1[NH:3][S:4](=[O:13])(=[O:12])[N:5]=[C:6]([CH2:8][CH2:9][S:10][CH3:11])[N:7]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[NH:3][S:4](=[O:13])(=[O:12])[N:5]=[C:6]([CH2:8][CH2:9][S:10]([CH3:11])=[O:22])[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCC1=NS(=O)(=O)NC(N)=N1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CS(=O)CCC1=NS(=O)(=O)NC(N)=N1
Yield: 96.9 %

Procedure:
To a solution of 3-amino-5-[2-(methylthio)ethyl]-1,2,4,6-thiatriazine-1,1-dioxide (1.22 gm, 5.5 mmol) in warm methanol (20 ml) there was added dropwise a solution of 80% pure m-chloroperbenzoic acid (1.2 gm, 5.6 mmol) in chloroform (20 ml). The product crystallized from solution during the addition and was collected by filtration and washed with diethyl ether to give 1.27 gm of pure product, m.p. 180°-182° C.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 135 °C
Yield: 60 %

Procedure:
(S)-N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.6 g, 1.9 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.1 g, 5.7 mmol), and DIEA (0.99 mL, 5.7 mmol) were placed in n-BuOH (4 mL) and heated at 135° C. for 12 hours. The reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography (500:15 DCM:MeOH) to give tert-butyl (R)-1-(5-bromo-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.55 g, 60% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.Br[CH2:27][CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:29][CH2:28][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:23][CH:24]=2)=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCCOCc1ccccc1
Reactant: OCCC(=C(c1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Product: OCCC(=C(c1ccc(OCCOCc2ccccc2)cc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1

Procedure:
is prepared from 4,4-bis(4-hydroxyphenyl)-3-phenylbut-3-en-1-ol (example 1c) and benzyl 2-bromoethyl ether by PTC reaction according to the method described in the example 1 a.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:20])[C:3]=1[NH:21][C:22](=[O:24])[CH3:23].C=O.[C:27]([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:27])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:20])[C:3]=1[NH:21][C:22](=[O:24])[CH3:23]
Reactant: [BH3-]C#N
Reactant: CC(=O)Nc1c(C)cc(NCc2ccc(C(F)(F)F)cc2)cc1C
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)Nc1c(C)cc(N(C)Cc2ccc(C(F)(F)F)cc2)cc1C
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
To a stirred solution of N-[2,6-dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-acetamide (4a, 1.0 g) and formaldehyde (1 mL) in methanol (20 mL) and acetic acid (1 mL) was slowly added sodium cyanoborohydride (0.30 g). After 15 minutes, the reaction mixture was cooled to 5° C. for 16 hours to precipitate the product, which was collected by filtration and washed with water (100 mL) to furnish 0.63 g (60% yield) of the title compound as a pale yellow solid. LC-MS-TOF (m/z) 351 (MH+); tR=2.58, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.97 (s, 3H), 2.02 (s, 6H), 2.97 (s, 3H), 4.63 (s, 2H), 7.41 (d, 2H), 7.68 (d, 2H), 8.88 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][C@@H:24]([CH2:32][OH:33])[NH:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:12]2)=[C:6]([C:7]([N:23]2[C@H:24]([CH2:32][OH:33])[CH2:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22]2)=[O:9])[CH:10]=1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)O)n1
Reactant: OC[C@@H]1Cc2ccccc2CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
To an ice cooled solution of 5-bromo-2-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl)benzoic acid (45.0 g, 127.8 mmol) in DCM (450 mL) were added (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (20.8 g, 102.27 mmol), HATU (72.7 g, 191.2 mmol), DIPEA (55.7 mL, 319.6 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with DCM (750 mL), washed with water (500 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the the title compound as a liquid 50 g (79%). Rf=0.44 (55% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.00-7.40 (m, 3H), 7.30-7.00 (m, 4H), 6.80-6.40 (m, 1H), 5.10-3.80 (m, 7H), 3.50-2.40 (m, 3H), 2.40-2.10 (m, 3H), 1.30-1.00 (m, 3H); ES-MS: m/z 498.2 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]([F:47])([F:46])[C:6]1[CH:7]=[C:8]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[C:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27]([OH:29])=O)[CH2:13][C@H:12]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:10].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O1CCCC1>[F:43][C:42]([F:44])([F:45])[C:40]1[CH:39]=[C:8]([CH:7]=[C:6]([C:5]([F:4])([F:47])[F:46])[CH:41]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[C:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](=[O:29])[N:2]([CH3:3])[CH3:1])[CH2:13][C@H:12]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:10]
Reactant: CNC
Reactant: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOC[C@H]3C(=O)O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOC[C@H]3C(=O)N(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A tetrahydrofuran solution of dimethylamine (2 M, 0.32 ml) was added to a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-carboxymorpholino)-2-butynyl]piperazine (0.13 g), 1-hydroxybenzotriazole (85 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g) in N,N-dimethylformamide (5 ml), and the whole was stirred at room temperature for 5 hours. After the solvent was removed by evaporation, dichloromethane and sodium hydrogen carbonate solution were added to the residue. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with 3% of methanol in dichloromethane as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-dimethylcarbamoylmorpholino)-2-butynyl]piperazine. It was dissolved in ethyl acetate (10 ml) and the solution was added 4N hydrogen chloride in ethyl acetate (0.26 ml). The mixture was evaporated in vacuo and the residue was triturated with a mixture of ethyl acetate and isopropyl ether to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-dimethylcarbamoylmorpholino)-2-butynyl]piperazine dihydrochloride (0.12 g) as a solid.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.O.[NH2:18][NH2:19]>COCCO>[NH:18]([C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1)[NH2:19]
Reactant: Clc1nccc2[nH]c(-c3ccccc3)nc12
Reactant: NN
Solvent: O
Solvent: COCCO
Product: NNc1nccc2[nH]c(-c3ccccc3)nc12

Procedure:
A mixture of 130 mg (0.568 mmol) of 4-chloro-2-phenyl-1H-imidazo[4,5-c]pyridine, 0.110 mL (114 mg, 2.4 mmol) of hydrazine hydrate, and 3 mL of 2-methoxyethanol was stirred at reflux for 2 days. The cooled solution was concentrated, and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to yield the title compound. LC-MS 226 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1>CN(C=O)C>[C:36]([O:35][C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=3)[C:10]([CH3:11])=[C:2]2[CH3:1])=[CH:22][CH:23]=1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 2,3-dimethyl-1H-indole-5-carboxylate (1.493 g, 6.87 mmol) in dry DMF (10 mL) at 0° C. under argon was added NaH (0.3 g, 60% dispersion in mineral oil, 7.56 mmol) in portions. The reaction mixture was stirred at rt for 30 min and then re-cooled to 0° C. Tert-butyl 4′-(bromomethyl)biphenyl-2-carboxylate (2.62 g, 7.56 mmol) in DMF (2 mL) was slowly added. The reaction mixture was stirred at rt for another 1 h. The completion of the reaction was monitored by anal. HPLC. The reaction was quenched with MeOH, and then the solvent was removed in vacuo. The crude was dissolved in AcOEt, washed with saturated aqueous NaHCO3, brine and dried over Na2 SO4 and filtered. The filtrate was evaporated in vacuo to obtain the crude which was purified by flash chromatography (AcOEt/Hex 10→100%) to obtain the title compound. ESI-MS (m/z): 484 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:11]=[C:10]([O:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[C:9]=1[C:31]1[O:35][N:34]=[C:33]([C:36]([O-])=[O:37])[CH:32]=1.[K+].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:62][CH:63]1[CH2:68][CH2:67][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:65][CH2:64]1>CN(C=O)C.C(OCC)(=O)C>[C:72]([O:71][C:69]([N:66]1[CH2:67][CH2:68][CH:63]([NH:62][C:36]([C:33]2[CH:32]=[C:31]([C:9]3[C:10]([O:21][C:22]4[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=4)=[CH:11][C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:13][C:8]=3[O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[O:35][N:34]=2)=[O:37])[CH2:64][CH2:65]1)=[O:70])([CH3:75])([CH3:73])[CH3:74]
Reactant: COCCOCOc1cc(OCOCCOC)c(-c2cc(C(=O)[O-])no2)c(Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCOc1cc(OCOCCOC)c(-c2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)no2)c(Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 0.33 h
Yield: 54.1 %

Procedure:
To a stirred solution of potassium 5-{2,4-bis[(2-methoxyethoxy)methoxy]-6-(4-nitrophenoxy)phenyl}isoxazole-3-carboxylate (3.8 g, 6.6 mol) in DMF (50 mL) was added portion wise TBTU (2.34 g, 7.3 mmol, 1.1 eq.) at 0° C. After stirring for 20 minutes, a solution of tert-butyl 4-aminopiperidine-1-carboxylate (1.6 g, 8 mmol, 1.2 eq.) in DMF (25 mL) was added and the reaction was set-aside at room temperature overnight. The reaction mixture was taken up in ethyl acetate and thoroughly washed with water then with brine. After drying over Na2SO4, the solvent was removed and the residue was carefully chromatographed over silica gel eluting with a mixture of ethyl acetate/hexane 4/7 to provide the title compound (3.1 g, 65% yield).
Reaction SMILES: O.[C:2]([O-])(=[O:4])C.[NH4+].C=O.[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]=1[OH:23])([CH3:12])([CH3:11])[CH3:10]>C(O)(=O)C>[C:19]([C:15]1[CH:16]=[C:17]([CH:18]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:14]=1[OH:23])[CH:2]=[O:4])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A 500 ml reaction flask fitted with a mechanical stirrer, heating mantle, thermometer and water-cooled condenser was charged with 200 ml of glacial acetic acid, and 61.7 g (0.8 mole) of ammonium acetate. To the stirred mixture there were slowly added 97 g of 37% formalin (1.2 moles of formaldehyde) and 20.6 g (0.1 mole) of 2,6-ditert.-butylphenol. The reaction flask was equipped with a take-off head to remove the methanol which is present in commercially available formalin. The mixture was refluxed (107°-9°) for 6 hours. After cooling to ambient temperature, the mixture was poured on a vacuum filter and the product cake was washed with water. After drying, there was obtained 15.8 g of crystalline 3,5-ditert.butyl-4-hydroxybenzaldehyde, m.p. 184°-86° (67.5%).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)=[O:16].CO.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)=[O:16]
Reactant: COC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(N)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 13 h
Yield: 97 %

Procedure:
3-Amino-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.01 g) is suspended in tetrahydrofuran (20 ml)-methanol, thereto is added 4 N aqueous sodium hydroxide solution (5 ml) under ice-cooling and the reaction solution is stirred at room temperature for 13 hours. The reaction solution is concentrated under reduced pressure, the resulting residue is diluted with water, and the mixture is adjusted to around pH 3 by pouring 10% hydrochloric acid. The precipitates are collected by filtration, washed with water and ethanol successively and dried to give the title compound (1.87 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(O)cc1Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
245.0 g of 1A was mixed with 1.6 liters of glacial acetic acid, and the resulting solution was stirred at 8°-10° C. while 109.6 g of 90% aqueous nitric acid was added (two hours). The mixture was stirred at 10°-15° C. for five hours, poured over ice water and extracted with ether/hexane. The extract was washed with water, dried and stripped to dryness. The residue was stirred with 3 liters of hexane and the hexane solution was filtered through silica gel. The filtrate was held at -20° C. for 16 hours, filtered, and the filtrate was concentrated to one liter, charcoaled, then held at -30° to -35° C. for two hours and filtered, to give 3-chloro-4-methyl-6-nitrophenol (1B).
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:49][CH:50]([CH3:52])[CH3:51])=[N:40][C:41]([CH3:48])=[CH:42][C:43]=2[O:44][CH:45]([CH3:47])[CH3:46])=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:63][C:64]1[O:65][C:66]2[CH:72]=[CH:71][CH:70]=[CH:69][C:67]=2[N:68]=1>>[O:65]1[C:66]2[CH:72]=[CH:71][CH:70]=[CH:69][C:67]=2[N:68]=[C:64]1[S:63][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:49][CH:50]([CH3:51])[CH3:52])=[N:40][C:41]([CH3:48])=[CH:42][C:43]=2[O:44][CH:45]([CH3:46])[CH3:47])=[O:36])[CH2:30][CH2:29]1
Reactant: Sc1nc2ccccc2o1
Reactant: Cc1cc(OC(C)C)c(NC(=O)CN2CCN(CCO)CC2)c(OC(C)C)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(OC(C)C)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c(OC(C)C)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(1-methylethoxy)-6-methylpyridin-3-yl]acetamide and 2mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, to thereby yield the title compound as a pale yellow viscous oil.
Reaction SMILES: [CH2:1]([Li])CCC.[I-].C[S+](C)(C)=O.[CH2:12]([O:14][C:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[C:33]=4[CH:38]=[O:39])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]>CS(C)=O>[CH2:12]([O:14][C:15]([C:17]1([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[C:33]=4[CH:38]4[CH2:1][O:39]4)=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: [Li]CCCC
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CO4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
n-Butyllithium (1.6 M in hexanes, 2.3 mL, 3.69 mmol) was dissolved in DMSO (8 mL). Trimethylsulfoxonium iodide (0.963 g, 4.29 mmol) was added, followed by 1-[4′-(4-formyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.46 g, 1.23 mmol) in DMSO (8 mL). The reaction was stirred at room temperature for 40 minutes and then poured over ice. The mixture was extracted three times with EtOAc, and the combined organic layers were washed three times with H2O, dried, and concentrated. The crude material was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C@H:10]2[CH2:18][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH3:19][S:20]([NH:23][C:24]1[CH:39]=[CH:38][C:27]2[NH:28][C:29]([CH2:34][C:35](O)=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1)(=[O:22])=[O:21].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17]2)[C:35](=[O:36])[CH2:34][C:29]2[NH:28][C:27]3[CH:38]=[CH:39][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][C:26]=3[S:31](=[O:32])(=[O:33])[N:30]=2)[C@H:10]2[CH2:18][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC1CC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC1CC1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a stirred solution of (1S,2R,3S,4R)-3-(2-cyclopropyl-ethylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (338.2 mg, 1.35 mmol) in anhydrous N,N-dimethylformamide (10 mL) under a nitrogen atmosphere, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1 g, 493 mg, 1.48 mmol), N-methylmorpholine (0.33 mL, 2.96 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (284 mg, 1.48 mmol) were added sequentially. After shaking at 25° C. for 21 h, additional (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 150 mg, 0.45 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (85 mg, 0.44 mmol) were added. After another 26 h, a 1.0 M aqueous hydrochloric acid solution (12 mL) was added and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with saturated aqueous brine solution (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-{(2-cyclopropyl-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a red oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C25H34N4O7S2 566.19, found 567.4 [M+H+].