Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH3:8])[C:5]2[C:9]([N+:18]([O-])=O)=[C:10]([Cl:17])[C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:4]=2[N:3]=1>[Pt]=O>[NH2:18][C:9]1[C:5]2[N:6]([CH2:7][CH3:8])[C:2]([Cl:1])=[N:3][C:4]=2[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[C:10]=1[Cl:17]
Reactant: CCn1c(Cl)nc2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c21
Agent: O=[Pt]
Product: CCn1c(Cl)nc2cc(C(F)(F)F)c(Cl)c(N)c21
Yield: 42.2 %

Procedure:
6-Chloro-1-ethyl-5-trifluoromethylbenzimidazolone was prepared by reaction of N1 -ethyl-4-trifluoroethyl-5-chloro-1,2-phenylenediamine with phosgene. The resultant benzimidazolone was chlorinated with POCl3 --HCl to give the corresponding 2-chlorobenzimidazole which was then nitrated with HNO3 --H2SO4 to give the 7-nitro derivative. The 2,6-dichloro-1-ethyl-7-nitro-5-trifluoromethylbenzimidazole (5g.) was hydrogenated in the presence of platinum oxide catalyst according to the procedure of Example IV to give 1.91g. (42.2%) of the desired product, m.p. 134°-141.5°C.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.O1CCCC1>[Si:1]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:27])[CH3:26])=[CH:21][CH:20]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
5 g of the 1-(4-{[t-butyl(diphenyl)silyl]oxy}phenyl)-1-ethanone [79-1] was dissolved in a mixture solvent of 50 mL of methanol and 30 mL of tetrahydrofuran, 606 mg of sodium borohydride was added thereto, and stirred at room temperature for 3 hours. The reaction mixture was added with 30 mL of water, and concentrated under reduced pressure. The residue was added with 150 mL of ethyl acetate, washed with water and saturated brine in the subsequent order, and the obtained organic layer was dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to obtain 5.02 g of 1-(4-{[t-butyl(diphenyl)silyl]oxy}phenyl)-1-ethanol [79-2] as a colorless oily product.
Reaction SMILES: [N:1]([C@H:4]([C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]([CH:10]=[CH:11][N:12]=[N:13]2)=[C:8]([Cl:23])[CH:7]=1)[CH3:5])=[N+]=[N-].[I-].[Na+].Cl[Si](C)(C)C.S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>CO.O>[Cl:23][C:8]1[CH:7]=[C:6]([C@@H:4]([NH2:1])[CH3:5])[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[N:13]2
Reactant: C[C@H](N=[N+]=[N-])c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CO
Product: C[C@H](N)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A solution of 7-[(1S)-1-azidoethyl]-5-chloro-8-(3-fluorophenyl)cinnoline (48 g, 150 mmol) in methanol (430 mL) was treated with sodium iodide (130 g, 880 mmol) and stirred at room temperature for 10 minutes. The reaction mixture was cooled with a water bath. The reaction mixture was treated with chlorotrimethylsilane (110 mL, 880 mmol) dropwise over 20 minutes while maintaining the internal temperature at 28-35° C. The reaction mixture turned dark red and the stirring was continued for 26 min. After 42 min, the reaction mixture was treated with a solution of sodium sulfite (130 g, 1.0 mol) in water (430 mL). The dark red color of the solution faded and gave a yellow suspension. The reaction mixture was stirred for 30 minutes and then concentrated under reduced pressure to remove the methanol. The mixture was adjusted to pH>11 with 3 N NaOH solution and extracted with dichloromethane. The pH of the solution changed during the work-up, potentially due to the slow hydrolysis of TMSCl. The pH needed to be checked regularly and basified to pH>11 by addition of 3 N NaOH. The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to give the desired product (43 g, 96%) as a solid. LCMS for C16H14ClFN3 (M+H)+: m/z=302.1; Found: 302.0; 1H NMR (300 MHz, DMSO-d6): δ 9.47 (d, J=5.9 Hz, 1H), 8.41 (d, J=1.9 Hz, 1H), 8.29 (d, J=5.9 Hz, 1H), 7.59-7.49 (m, 1H), 7.34-7.14 (m, 3H), 4.04-3.95 (m, 1H), 2.22 (br s, 2H), 1.21-1.16 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6](=S)[NH:7][NH2:8])([CH3:4])[CH3:3].Cl[CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].[S]>Cl>[CH3:1][C:2]([NH:5][C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([CH3:19])[NH:8][N:7]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(C)(C)NC(=S)NN
Agent: Cl
Agent: [S]
Product: CCOC(=O)c1c(NC(C)(C)C)n[nH]c1C
Temperature: 25 °C
Yield: 101.8 %

Procedure:
A solution of 25 g (0.17 mole) of 4-(1,1-dimethylethyl)-3-thiosemicarbazide in 85 mL of 2N ethanolic hydrogen chloride was cooled to 0° C. with an ice bath and while stirring under nitrogen atmosphere, 28 g (0.17 mole) of ethyl 2-chloroacetoacetate was added dropwise. The reaction mixture was allowed to come to room temperature while stirring for 16 hr. The pale yellow solution was then refluxed for 2 hr during which a film of sulfur deposited on the sides of the flask. The reaction mixture was cooled to room temperature and the sulfur removed by filtration. The filtrate was concentrated in vacuo to give 39 g of pale yellow oil which was dissolved in ligroin and, after standing at ~7°-10° C. for ~60 hr, yielded 20.5 g of large crystals, mp 118°-119° C. An additional 6.1 g of crude material was obtained by reworking the residues.
Reaction SMILES: [F:1][C:2]1([F:35])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:32][CH3:33])=[C:27]([C:29](O)=[O:30])[CH:28]=5)[C:20]([CH3:34])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[CH3:36][NH:37][CH3:38].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[F:35][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:32][CH3:33])=[C:27]([C:29]([N:37]([CH3:38])[CH3:36])=[O:30])[CH:28]=5)[C:20]([CH3:34])=[CH:19][CH:18]=4)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CNC
Reactant: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1C(=O)N(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a solution of 6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6′-methoxy-3-methyl-2,3′-bipyridine-5′-carboxylic acid (72 mg, 0.15 mmol), dimethyl amine (10 mg, 0.23 mmol), and triethylamine (42 μL, 0.30 mmol) in N,N-dimethylformamide (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (68 mg, 0.18 mmol) and the reaction mixture was stirred at 80° C. overnight. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (51 mg, 67%). ESI-MS m/z calc. 510.49. found 511.5 (M+1)+. Retention time 1.81 minutes.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[N:4]=[CH:3]1.[NH2:10][C:11]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])=[CH:29][N:28]([S:39]([C:42]4[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=4)(=[O:41])=[O:40])[C:25]3=[N:26][CH:27]=2)=[CH:18][C:12]=1[C:13]([N:15]([CH3:17])[CH3:16])=[O:14].N1C=CC=CC=1.[Cl-].[NH4+]>ClCCl>[CH3:17][N:15]([CH3:16])[C:13]([C:12]1[CH:18]=[C:19]([C:22]2[CH:23]=[C:24]3[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])=[CH:29][N:28]([S:39]([C:42]4[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=4)(=[O:41])=[O:40])[C:25]3=[N:26][CH:27]=2)[CH:20]=[CH:21][C:11]=1[NH:10][C:7]([C:5]1[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=1)=[O:8])=[O:14]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Reactant: Cn1cnc(C(=O)Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(NC(=O)c4cn(C)cn4)c(C(=O)N(C)C)c3)cc12
Reaction time: 24 h

Procedure:
1-Methyl-1H-imidazole-4-carbonyl chloride (0.092 mmol) was suspended in dichloromethane (1 mL) and a solution of 2-amino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (50 mg, 0.092 mmol) in 20% v/v pyridine in dichloromethane (0.5 mL) was added. After 24 h, saturated ammonium chloride solution was added and the layers were separated. The organic layers were dried over sodium sulfate and taken to the next step. MS: m/z 649 (M+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].OO.O.O.O.O.O.S([O-])([O-])(=[O:33])=S.[Na+].[Na+].O>C(O)(=O)C>[CH2:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)=[O:33])=[CH:18][CH:17]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1ccc(Sc2ccc(OCCCC)cc2)cc1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1ccc(S(=O)c2ccc(OCCCC)cc2)cc1
Reaction time: 12 h
Yield: 90 %

Procedure:
In 200 g of acetic acid was dissolved 30 g of bis(4-butoxyphenyl) sulfide obtained in Synthesis Example 1-17. While the solution was maintained at an internal temperature of 30° C., 8.8 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 12 hours, after which under ice cooling, a mixture of 0.9 g sodium thiosulfate pentahydrate and 30 g water was added dropwise to quench the reaction. The solution was combined with 200 g of methylene chloride and 50 g of water for extraction. The organic layer was separated, washed with water, and concentrated in vacuum. On subsequent purification by silica gel chromatography, 28 g of the target compound, bis(4-butoxyphenyl) sulfoxide was obtained as amorphous solid. Yield 90%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[S:11]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(=[O:13])=[O:12].Cl[Sn]Cl>Cl.CCO>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[S:11]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(=[O:13])=[O:12]
Reactant: Cc1cccc([N+](=O)[O-])c1S(=O)(=O)Nc1cccc2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1cccc(N)c1S(=O)(=O)Nc1cccc2cccnc12
Yield: 39.3 %

Procedure:
In a similar fashion using route 1 general procedure 4, 2-methyl-6-nitro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 268) (1.5 g, 4.3 mmol), SnCl2 (3.3 g, 17.5 mmol), 6N HCl (5 drops) and EtOH (15 ml) gave the title compound (530 mg, 38%), after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH:15]([CH:17]=[O:18])[CH2:14][CH2:13][NH:12]3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35]Br)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH:15]([CH:17]=[O:18])[CH2:14][CH2:13][N:12]3[CH2:35][CH2:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: O=CC1CCNC(c2nc3c(Cl)cccc3s2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CCN2CCC(C=O)CC2c2nc3c(Cl)cccc3s2)cc1
Temperature: 25 °C

Procedure:
Mix [2-(4-chlorobenzothiazolyl)](4-piperidinyl)methanone.CF3CO2H (9.19 mmol), 2-(4methoxyphenyl)ethyl bromide (2.07 g, 9.64 mmol), potassium carbonate (3.33 g, 24.1 mmol) and dimethylformamide (35 mL) and heat at 90° C. overnight. Cool to room temperature and partition between a 2:1 mixture of ethyl acetate/toluene and water. Separate the aqueous phase and wash the organic phase with water and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([NH2:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CS(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: CS(C)=O
Product: Cc1ccc(Nc2ccccc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
A solution of 1-fluoro-4-methyl-2-nitrobenzene (1.0 g, 6.45 mmol) in DMSO (3 mL) was purged with a stream of nitrogen prior to addition of phenylamine (1.18 mL, 12.9 mmol) and then stirred in a sealed tube at 100° C. for 20 h. After cooling to RT, the reaction mixture was partitioned between EtOAc (200 mL) and water (150 mL). The organic layer was then washed with water (150 mL×3), followed by brine, then dried (Na2SO4) and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-40% DCM in cyclohexane) affording (4-Methyl-2-nitrophenyl)phenylamine as a red oil (1.41 g, 96%). 1H NMR (DMSO, 400 MHz): δ 9.21 (1H, s), 7.94-7.91 (1H, m), 7.43-7.26 (5H, m), 7.19-7.12 (2H, m), 2.27 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37]1([CH3:49])[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[C:38]=1[S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)[S:45]([C:38]2[C:39]([CH3:44])=[CH:40][C:41]([CH3:43])=[CH:42][C:37]=2[CH3:49])(=[O:47])=[O:46])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: c1ccc(COc2ccc(NCc3cccc(OC4CCCCO4)c3)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(OCc3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.3 %

Procedure:
To a solution of (4-benzyloxy-phenyl)-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (12.7 g, 32.6 mmol) in 25 mL methylene chloride at 0° C. was added triethylamine (14.0 mL, 97.8 mmol), DMAP (0.400 g, 3.27 mmol) and 2-mesitylenesulfonyl chloride (14.3 g, 65.2 mmol). The reaction mixture was stirred at room temperature for 17 hr. The reaction mixture was diluted to a volume of 800 mL with methylene chloride and was washed with water (3×200 mL) and saturated aqueous sodium chloride (1×200 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography (10% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) afforded 8.82 g of the title compound of Step C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:32])[C:4]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9][CH2:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:6][CH2:5]1.[Sn]>Br.O>[CH2:19]([C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH:7]1[CH2:6][CH2:5][C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([N:3]([CH3:2])[CH3:32])[CH2:9][CH2:8]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(C)C1(c2ccccc2)CC=C(c2[nH]c3ccccc3c2CC2CCCCC2)CC1
Agent: Br
Agent: Cl
Agent: [Sn]
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(c2[nH]c3ccccc3c2Cc2ccccc2)CC1
Reaction time: 0.33 h

Procedure:
Ex. 41 (768 mg, 1.733 mmol) was dissolved in hydrogen bromide/glacial acetic acid (33% HBr, 40 ml). Tin powder (2.060 g, 17.353 mmol) was then added to the mixture in portions at room temperature in the course of 40 min and the mixture was stirred for a further 20 min. The mixture was then diluted with water (100 ml). The mixture was stirred at 5° C. for 1 h. The product precipitated out as the hydrobromide. This was filtered off and washed with water (2×5 ml). 1 N NaOH (50 ml) was added to the beige-coloured moist solid (4.3 g). The mixture was extracted with methylene chloride (3×30 ml). The combined organic phases were dried with Na2SO4 and then filtered. The volatile constituents were removed completely in vacuo. An oil (619 mg) remained. After separation of this mixture by chromatography [silica gel 60 (80 g); ethyl acetate (500 ml), ethyl acetate/methanol 20:1 (525 ml), ethyl acetate/methanol 5:1 (600 ml), ethyl acetate/methanol 2:1 (600 ml)], 4-(3-benzyl-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine (less polar diastereoisomer) (186 mg, 26%, m.p.: 194-199° C.) and the more polar diastereoisomer (241 mg, 34%, m.p.: 205-209° C.) were obtained as beige-coloured solids.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH2:15][CH2:16][OH:17])[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][OH:14])[CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:17][CH2:16][CH2:15][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][OH:14])[CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccc(CCO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccc(CCO)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.67 mL) in DCM (2 mL) was added dropwise to a stirred solution at 0° C. of 2,2′-(1,3-phenylene)diethanol (1.30 g) and triethylamine (1.36 mL) in DCM (30 mL). The reaction mixture was stirred for 1 hour at 0° C. and then washed with water. The aqueous layer was re-extracted with DCM and the combined organic phases were dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 3% methanol in dichloromethane as solvent. Fractions containing the product were evaporated to dryness to afford the titled compound. Yield 0.52 g.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CS(C)=O>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH:31][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: NCCc1ccccc1Br
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCc3ccccc3Br)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (150 mg, 0.50 mmol, 1.00 equiv), 2-(2-bromophenyl)ethanamine (300.5 mg, 1.51 mmol, 3.00 equiv), potassium carbonate (347.3 mg, 2.52 mmol, 5.00 equiv), toluene/DMSO (5/1 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum and applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 110 mg (47%) of methyl 3-(2-bromophenethylamino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[S:12][C:8]=2[CH:7]=[C:6]([O:21]C)[CH:5]=1)([OH:3])=[O:2].B(Br)(Br)Br>>[C:1]([C:4]1[C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[S:12][C:8]=2[CH:7]=[C:6]([OH:21])[CH:5]=1)([OH:3])=[O:2]
Reactant: COc1ccc(-c2nc3c(C(=O)O)cc(OC)cc3s2)cc1
Agent: BrB(Br)Br
Product: O=C(O)c1cc(O)cc2sc(-c3ccc(O)cc3)nc12
Yield: 74.4 %

Procedure:
4-Carboxy-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole (50 mg, 0.159 mmol) was treated with boron tribromide under standard condition to give 4-carboxy-6-hydroxy-2-(4-hydroxy-phenyl)-benzothiazole (34 mg, 74% yield) as a yellow solid. Mass spec: MH+=288. 1H NMR (DMSO-d6): 10.24 (s, 1H), 10.16 (s, 1H), 7.91 (d, 2H), 7.67 (s, 1H), 7.48 (s, 1H), 6.95 (d, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[C:7]1[CH:8]=[C:9]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=O)[N:18]=2)[CH:10]=[CH:11][C:12]=1[CH3:13])[CH3:2].[N:29]1C2C(=NC=CC=2)N(O)N=1.CCN=C=NCCCN(C)C.N>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:22][C:23]([O:24][CH2:25][CH3:26])=[O:27])[C:7]1[CH:8]=[C:9]([C:14]2[S:15][CH:16]=[C:17]([C:19]([NH2:29])=[O:21])[N:18]=2)[CH:10]=[CH:11][C:12]=1[CH3:13])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(-c2nc(C(=O)O)cs2)ccc1C
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(-c2nc(C(N)=O)cs2)ccc1C
Reaction time: 1.17 h
Yield: 92.3 %

Procedure:
The compound (4.59 g, 11.3 mmol) of step A was dissolved in N,N-dimethylformamide (60 ml), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (1.97 g, 14.5 mmol) and WSC (2.80 g, 14.6 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 70 min. Then, to the reaction mixture was added 28% aqueous ammonia (10 ml), and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate and water, and the organic layer was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was washed with a diethyl ether-hexane=1:1 mixed solvent, and dried under reduced pressure to give the title compound (4.23 g, yield 92%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.BrC1C=CC(OC)=NC=1.O1C2(CCC(=O)CC2)OCC1.[NH:37]1[CH2:40][CH:39]([NH:41][C:42](=[O:59])[CH2:43][NH:44][C:45]2[C:54]3[C:49](=[CH:50][CH:51]=[C:52]([C:55]([F:58])([F:57])[F:56])[CH:53]=3)[N:48]=[CH:47][N:46]=2)[CH2:38]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:37]2[CH2:38][CH:39]([NH:41][C:42](=[O:59])[CH2:43][NH:44][C:45]3[C:54]4[C:49](=[CH:50][CH:51]=[C:52]([C:55]([F:56])([F:58])[F:57])[CH:53]=4)[N:48]=[CH:47][N:46]=3)[CH2:40]2)[CH2:4][CH2:3]1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: COc1ccc(Br)cn1
Agent: O=C1CCC2(CC1)OCCO2
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4ncnc5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
Reaction of 4-hydroxy-4-(6-methoxypyridin-3-yl)cyclohexanone (prepared by the reaction of 5-bromo-2-methoxypyridine with 1,4-dioxaspiro[4.5]decan-8-one using the sequence described in Example 24 Step A-B) with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH2:18][C:8]2[S:7][C:6]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH:9]=2)[CH:20]=1
Reactant: COc1ccc2sccc2c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: COc1ccc2sc(Cc3cc(Br)ccc3Cl)cc2c1

Procedure:
5-Methoxybenzo[b]thiophene (see WO 97/25033) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 367/369 (M+H).