Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([C:41]2[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=2)=[O:40])=[CH:35][CH:34]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:36]3[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=3)([C:41]3[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 2.67 mL, 6.66 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (3.00 g, 7.00 mmol, Intermediate 16) in dry THF (80 mL) at −78° C. After 3 minutes, a solution of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (1.65 g, 7.48 mmol, Intermediate 1: step b) in dry THF (80 mL) was added dropwise over the course of 3 minutes. The reaction mixture was stirred for 10 minutes at −78° C., then the reaction flask was removed from the cooling bath. After 10 minutes, the reaction flask was placed into an ice-water bath. After 30 minutes, saturated aqueous ammonium chloride solution (10 mL) was added. The biphasic mixture was warmed to room temperature then partitioned between half-saturated aqueous ammonium chloride solution (300 mL) and ethyl acetate (300 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (150 mL). The organic layers were combined. The combined solution was dried with sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 20% acetone-dichloromethane initially, grading to 100% acetone) to provide the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.11 (d, J=2.1 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.58-7.54 (m, 2H), 7.54-7.51 (m, 1H), 7.40-7.34 (m, 3H), 7.33-7.27 (m, 4H), 6.43 (t, J=2.1 Hz, 1H), 6.41-6.38 (m, 1H), 4.31 (s, 2H), 4.08 (s, 3H), 3.72 (s, 1H), 3.38 (s, 3H). MS (ESI): mass calcd. C31H25Cl2N5O2, 569.1; m/z found, 570.1 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)nc3)CC2)c(C)c1
Yield: 66.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (584 mg) described in Preparation Example 115 and oxazolidin-2-one (197 mg), the title compound (392 mg) was obtained.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:19]4[C:14](=[CH:15][C:16]5[O:22][CH2:21][O:20][C:17]=5[CH:18]=4)[C:13](=[O:23])[NH:12][N:11]=3)=[CH:4][C:3]=2[O:2]1.Br.Br[CH2:26][CH2:27][N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.CCOC(C)=O>[N:28]1([CH2:27][CH2:26][N:12]2[N:11]=[C:10]([C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)[C:19]3[C:14](=[CH:15][C:16]4[O:22][CH2:21][O:20][C:17]=4[CH:18]=3)[C:13]2=[O:23])[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: O=c1[nH]nc(-c2ccc3c(c2)OCO3)c2cc3c(cc12)OCO3
Reactant: BrCCn1ccnc1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c2cc3c(cc2c(-c2ccc4c(c2)OCO4)nn1CCn1ccnc1)OCO3
Temperature: 70 °C
Reaction time: 5 h
Yield: 15.5 %

Procedure:
A mixture of 4-(3,4-methylenedioxyphenyl)-6,7-methylenedioxy-1(2H)-phthalazinone (133 mg, 0.43 mmol), 1-(2-bromoethyl)imidazole hydrogen bromide (439 mg, 1.72 mmol), and K2CO3 (415 mg, 3.0 mmol) in DMF (10 mL) was stirred for 5 h at 70° C. The mixture was cooled, and 2N HCl and EtOAc were added to the mixture. The acidic aqueous layer was separated, made alkaline with 5% K2CO3 solution, and extracted with EtOAc. The extract was washed with brine, dried and concentrated under reduced pressure. The residual solid were purified by chromatography on silica gel with CHCl3-MeOH (20:1) to afford the product as a white solid (27 mg, 16%). 300 MHz 1H-NMR (CDCl3): δ 7.78 (s, 1H), 7.37 (s, 1H), 7.04-6.86 (m, 5H), 6.13 (s, 2H), 6.03 (s, 2H), 4.58 (m, 2H), 4.45 (m, 2H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][C:30]2[S:34][CH:33]=[N:32][C:31]=2[Cl:35])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH:36](=O)[CH:37]([CH3:39])[CH3:38].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([N:28]([CH2:29][C:30]2[S:34][CH:33]=[N:32][C:31]=2[Cl:35])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2scnc2Cl)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CN(Cc1scnc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 96.9 %

Procedure:
Add sodium triacetoxyborohydride (24.00 g, 113 mmol) to a stirred solution of 4-{[(4-chloro-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (21.78 g, 65.6 mmol), isobutyraldehyde (9.0 mL, 99.1 mmol), acetic acid (4.0 mL, 69.9 mmol), and 1,2-dichloroethane (260 mL). Stir the reaction for 18 hours at room temperature under nitrogen. Pour the reaction into 2N NaOH (300 mL) and extract with ethyl acetate (3×150 mL). Wash the ethyl acetate with brine (2×150 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 25% ethyl acetate/hexanes to yield 24.67 g (97%) of 4-{[(4-chloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=388.2 (M+1); 1H NMR (CDCl3): δ=8.65 (s, 1H), 4.21 (br s, 2H), 3.80 (s, 2H), 2.63-2.56 (m, 3H), 2.29 (d, 2H), 1.77-1.65 (m, 3H), 1.50-1.41 (m, 11H), 0.92 (d, 6H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:13]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH3:12])[CH:6]=1.CO.Cl>O1CCOCC1>[NH2:13][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[CH2:2][OH:1]
Reactant: COc1cc(C[C@@H](CO)NC(=O)OC(C)(C)C)ccn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C[C@H](N)CO)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vial was added tert-butyl {(1S)-2-hydroxy-1-[(2-methoxypyridin-4-yl)methyl]ethyl}carbamate (0.50 g, 1.8 mmol) and methanol (2.0 mL) and 4.0 M hydrogen chloride in dioxane (5.0 mL, 20. mmol). The reaction was stirred at room temperature overnight. Direct evaporation under reduced pressure afforded the final compound. LC-MS found: 183.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)([CH3:20])[CH3:19])=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]2[C:27]3[CH:26]=[C:25]([C:28]#[N:29])[CH:24]=[CH:23][C:22]=3[O:21][C:18]([CH3:20])([CH3:19])[CH2:17]2)=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C=Cc1ccc(OCc2ccccc2)c[n+]1[O-])Oc1ccc(C#N)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CC(c2ccc(OCc3ccccc3)c[n+]2[O-])c2cc(C#N)ccc2O1
Yield: 20.1 %

Procedure:
2.24 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-1-butenyl]pyridine N-oxide in 45 ml of toluene were heated to 80° C. for 12 hours. The solvent was removed by evaporation and the residue was chromatographed on silica gel using diethyl ether/methanol (97.5:2.5) for the elution to give 0.45 g of 5-benzyloxy-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide in the form of a white soli of melting point 224° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([Sn](C)(C)C)[CH:19]=2)=[CH:2]1.Br[C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42](=[O:43])[NH:41][C:39](=[O:40])[C:38]=12.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:40]=[C:39]1[C:38]2[C:37](=[CH:36][C:35]([C:18]3[CH:19]=[C:14]([O:13][CH2:12][C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:10][C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)[CH:15]=[N:16][CH:17]=3)=[CH:34][CH:33]=2)[C:42](=[O:43])[NH:41]1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc([Sn](C)(C)C)c1)Cc1c[nH]c2ccccc12
Reactant: O=C1NC(=O)c2c(Br)cccc21
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2ccc3c(c2)C(=O)NC3=O)c1)Cc1c[nH]c2ccccc12
Temperature: 75 °C
Yield: 73 %

Procedure:
A solution of Example 32A (0.2 g, 0.31 mmol) and 6-bromophthalimide (0.084 g, 0.4 mmol) in DMF (2 mL) was treated with Pd2dba3 (0.04 g, 0.02 mmol), tri-o-tolylphosphine (0.02 g, 0.01 mmol), and triethylamine (0.06 mL, 0.4 mmol). The reaction was heated to 75° C. for 6 hours in a sealed tube and concentrated. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide the desired product (0.116 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH:13]([C:18]([O:20][CH3:21])=[O:19])[C:14](OC)=[O:15])[CH2:9][N+:10]([O-])=O)=[CH:4][CH:3]=1>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][NH:10][C:14](=[O:15])[C@H:13]2[C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C(=O)OC)[C@@H](C[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [Ni]
Solvent: CO
Product: COC(=O)[C@@H]1C(=O)NC[C@H]1c1ccc(Cl)cc1
Yield: 85.7 %

Procedure:
To 210 ml of methanol was added 42.0 g (133 mmol) of dimethyl (R)-2-(1-(4-chlorophenyl)-2-nitroethyl)malonate and developed nickel (21 g), and the mixture was reacted at 35° C. for 8 hours under a hydrogen pressure of 0.5 Mpa (gauge pressure). After completion of the reaction, the nickel catalyst was filtrated, and the filtrate was concentrated under reduced pressure. Ethyl acetate and water were added to cause liquid-separation, the organic layer was concentrate under reduced pressure, and crystallized from heptanes/ethyl acetate. The resultant crystal was filtrated, and dried under reduced pressure, to obtain 28.8 g (114 mmol) of a title compound.
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[C:8]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][S:2]1.[OH2:22]>CO.[Cl-].[Na+].O>[O:22]=[S:2]1[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])=[CH:7][C:6]=2[CH2:1]1
Reactant: O
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CSCC3)C(=O)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CS(=O)CC3)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A solution of NaIO4 (220 mg, 1.03 mmol) in H2O (4.1 mL) is treated with a solution of (−)-N-[[(5S)-3-(3,4-dihydro-1H-2-benzothiopyran-7-yl)-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 14, 300 mg, 0.979 mmol) in MeOH (20 mL) over approximately 1 min, and the resulting mixture is stirred at ambient temperature for 18 hrs. The mixture is then diluted with brine (25 mL) and extracted with 10% MeOH/CH2Cl2 (4×25 mL), and the combined organic phase is dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (2/98-8/92), and those fractions with an Rf=0.20 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated to give 293 mg (93%) of the title compound (mixture of diastereomers) as an amorphous, white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][OH:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:12](O)=O.[K+].[Br-]>O>[OH:11][N:10]1[C:8](=[O:9])[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[CH:12]1
Reactant: Nc1cccnc1C(=O)NO
Reactant: O=CO
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: O=c1c2ncccc2ncn1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.224 g (8 mmol) of the product produced in Step D of Example 3 and 3 ml of 98% formic acid were heated under reflux for 15 minutes after which 8 ml of water was added, and the whole was boiled for 15 minutes and cooled to room temperature. The precipitate that separated was collected by filtration and washed with water (2×5 ml). After being boiled with ethanol twice, there was obtained 0.71 g (55%) of HODhad, which was obtained in an analytically pure form as a yellow solid: mp 318.5-320° C. (dec.); 1H NMR (DMSO-d6): δ12.15 (br, 1H, OH), 8.85 (dd, 1H), 8.69 (s, 1H, CH), 8.17 (dd, 1H), 7.84 (dd, 1H); IR (KBr): 2625 (broad, OH), 1683 (sh, vs, CON), 1600 (w), 1446 (m), 1410 (s), 1359 (s), 1223 (s), 990 (s), 902 (m), 791 (s) cm−1.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][S:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[O:31][CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1SCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1SCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 65 h
Yield: 113 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 1-[4-[(3-chloropropyl)-thio]-3-methoxyphenyl]ethanone (3.5 g, 13.6 mmol), KC2CO3 (2.3 g, 16.6 mmol), KI (200 mg) and CH3CN (100 ml) was stirred at reflux under nitrogen for 7.5 hours and then was left at ambient temperature for 65 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed twice with water, once with brine and dried over MgSO4. The solvent was removed in vacuo to afford 6.8 g of a light brown oil. The sample was purified by flash chromatography. Concentration of appropriate fractions yielded 3.0 g. Recrystallization from ethanol provided 2.4 g (41%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]thio]-3-methoxyphenyl]-ethanone as a beige solid, m.p.=93-95° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:26]([O-])=O)[CH:3]=1>[Ni].C1COCC1>[Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([CH:3]=1)[NH2:26]
Reactant: CNc1cc(N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CNc1cc(N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-chloro-N-methyl-2-nitro-5-(4-(4-trifluoromethylphenyl)-piperazin-1-yl)aniline (200 mg, 0.48 mmol), Ra—Ni (20 mg; 0.34 mmol) and THF (8 mL) was shaken under H2 atmosphere (1 atm) at rt for 4 h. The mixture was filtered through celite and the resulting solution was used immediately used in the next step.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2([CH3:23])OCC[O:19]2)[CH2:14][CH2:13]1.Cl.[OH-].[Na+]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([C:18](=[O:19])[CH3:23])[CH2:16][CH2:17]1
Reactant: CC1(C2CCN(CC3COc4ccccc4O3)CC2)OCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C1CCN(CC2COc3ccccc3O2)CC1
Yield: 55.8 %

Procedure:
A mixture of 20.6 parts of 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-(2-methyl-1,3-dioxolan-2-yl)piperidine and 200 parts of a hydrochloric acid solution 2N was stirred and refluxed for 15 hours. After cooling, crushed ice was added. The whole was treated with a sodium hydroxide solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 10 parts (55.8%) of 1-[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]ethanone as an oily residue (intermediate 87).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:21](=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of 2.73 g of L-phenylalanine methyl ester hydrochloride (12.7 mmol) in 5.00 g of pyridine (63.2 mmol) is dropwise added 12.90 g of acetic anhydride (126.0 mmol) under ice cooling. The mixture is allowed to stand for 2 hours and concentrated in vacuo. The residue is extracted with ethyl acetate. The extract is washed with 5% hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine in order, dried over sodium sulfate, filtered and concentrated in vacuo to give 2.34 g of the objective N-acetylphenylalanine methyl ester 4. Yield, 83.6%.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].C(=O)([O-])[O-].[K+].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:33])[C:20]([N:30]([CH3:32])[CH3:31])([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH3:22])=[CH:15][CH:14]=1>CC(N(C)C)=O>[SH:4][CH2:3][CH2:2][CH2:1][S:5][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:33])[C:20]([N:30]([CH3:32])[CH3:31])([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][CH3:22])=[CH:17][CH:18]=1
Reactant: SCCCS
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(F)cc1)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(SCCCS)cc1)N(C)C
Temperature: 50 °C
Reaction time: 12 h

Procedure:
32.5 g (0.3 mol) of 1,3-propanedithiol are dissolved in 50 ml of dry dimethylacetamide, and the solution is heated to about 50° C. together with 13.8 g (0.1 mol) of potassium carbonate. 15.0 g (0.05 mol) of 1-(4-fluorophenyl)-2-dimethylamino-2-benzyl-butan-1-one in 30 ml of dry dimethylacetamide are added dropwise. The suspension is stirred at 50° C. overnight (about 12 hours), then the solid is filtered off. The excess 1,3-propanedithiol and dimethylacetamide are distilled off. To the residue is added toluene, then the precipitate is filtered off. After distilling off the toluene, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:7) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 0.68 (t, 3H), 1.39 (t, 1H), 1.79-1.88 (m, 1H), 1.97-2.11 (m, 3H), 2.36 (s, 6H), 2.69 (q, 2H), 3.12 (t, 2H), 3.19 (s, 2H), 7.15-7.27 (m, 7H), 8.28 (d, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[NH:7][S:8]([C:11]3=[CH:12][CH:13]=[CH:14][C:3](=[C:4]23)[CH:2]=1)(=O)=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-].C1(C)C=CC=CC=1.S(=O)(=O)(O)O>C(COC)OC.O>[NH2:7][C:5]1[CH:6]=[CH:1][CH:2]=[C:3]2[C:4]=1[C:11]([SH:8])=[CH:12][CH:13]=[CH:14]2
Reactant: O=S1(=O)Nc2cccc3cccc1c23
Agent: COCCO[Al+]OCCOC
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: Nc1cccc2cccc(S)c12
Yield: 87.8 %

Procedure:
To a solution of 2.0 g of 1,8-naphthosultam in 7 mL of dimethoxyethane was added dropwise under gentle reflux a solution of 11.5 mL of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (3.4 mol solution in toluene) over a period of 15 minutes, then stirred at reflux for 17 hours. The mixture was cooled in an ice-bath, 5 mL of water were added dropwise then the solution was neutralized with 4N sulfuric acid (pH~7) and extracted with ether (3×75 mL). The combined ether solutions were washed with water (75 mL) then dried (magnesium sulfate) and removal of the solvent gave 1.5 g of 8 -amino-1-napthalenethiol. The thiol was recrystallized from ether--petroleum ether to afford 1.3 g of 8-amino-1-naphthalenethiol, mp. 69°-72°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29]([O:33][C:34](=[O:43])[N:35]([CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH2:42])[CH3:36])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:29]([O:33][C:34](=[O:43])[N:35]([CH3:36])[CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])([CH3:32])([CH3:30])[CH3:31]
Reactant: CN(CCOCCN)C(=O)OC(C)(C)C
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C)C(=O)OC(C)(C)C
Yield: 56.5 %

Procedure:
Methyl-[2-(2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethoxy)-ethyl]-carbamic acid tert-butyl ester (69 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (82 mg), [2-(2-amino-ethoxy)-ethyl]-methyl-carbamic acid tert-butyl ester (87 mg), HBTU (91 mg), and DIEA (52 uL).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[C:16]([F:22])[C:17](OCC)=[O:18])[C:7]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=3[O:9][CH2:10][C:4]=2[CH:3]=1.CO.[NH3:27]>C1COCC1>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[C:16]([F:22])[C:17]([NH2:27])=[O:18])[C:7]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=3[O:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(F)=C1c2ccc(Br)cc2COc2cc(F)ccc21
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)C(F)=C1c2ccc(Br)cc2COc2cc(F)ccc21
Temperature: 55 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
[step 2] Ethyl 2-(8-bromo-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)-2-fluoroacetate (1.6 g, 4.05 mmol) obtained in step 1 was dissolved in THF (14 mL), 2 mol/L ammonia methanol solution (20 mL, 40.5 mmol) was added, and the mixture was stirred at 55° C. overnight. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1 v/v) to give 2-(8-bromo-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)-2-fluoroacetamide (910 mg, 61%).