Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1OC(C(F)(F)F)=CC=1.[F:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][C:25]2[C:30]3([CH2:40][O:41][C:24]=2[CH:23]=1)[C:38]1[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:32][C:31]3=[O:39].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][C:25]2[C:30]3([CH2:40][O:41][C:24]=2[CH:23]=1)[C:38]1[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=1)[N:32]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[C:31]3=[O:39]
Reactant: BrCc1ccccn1
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)Nc2ccccc21
Agent: Br
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 6-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (55%): mp 108-109° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.71-7.66 (m, 1H), 7.29-7.20 (m, 3H), 7.15-7.03 (m, 3H), 6.93-6.90 (m, 1H), 6.79-6.76 (m, 1H), 5.26-4.85 (m, 4H); MS (ES+) m/z 371.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[CH2:34]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)[CH3:35]>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:41]([C:40]1[CH:44]=[CH:45][C:37]([O:36][CH2:34][CH3:35])=[CH:38][CH:39]=1)=[O:42])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOc1ccc(C(=O)Cl)cc1
Product: CCOc1ccc(C(=O)c2cn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c3cccc(F)c23)cc1

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 2-(3) and 4-ethoxybenzoyl chloride were treated in a manner similar to Example 2-(4) to give 4-ethoxyphenyl 4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indol-3-yl ketone as a colorless powder. APCI-Mass m/Z 614 (M+H). 1H-NMR (DMSO-d6) δ 1.38 (t, J=6.9 Hz, 3H), 1.68 (s, 3H), 1.97 (s, 3H), 1.98 (s, 3H), 2.04 (s, 3H), 4.11 (d, J=4.0 Hz, 2H), 4.16 (q, J=7.0 Hz, 2H), 4.28-4.31 (m, 1H), 5.30 (t, J=9.8 Hz, 1H), 5.54 (t, J=9.6 Hz, 1H), 5.76 (t, J=9.3 Hz, 1H), 6.34 (d, J=9.0 Hz, 1H), 7.01 (dd, J=10.6, 8.0 Hz, 1H), 7.07 (d, J=8.7 Hz, 2H), 7.36 (td, J=8.1, 4.9 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 8.14 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]([CH2:10][C:11]3[CH:22]=[CH:21][C:14]4[N:15]=[C:16](S(C)=O)[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]([CH2:10][C:11]3[CH:22]=[CH:21][C:14]4[N:15]=[C:16]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)ncn2Cc1ccc2nc(S(C)=O)oc2c1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)oc2c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 29.9 %

Procedure:
A mixture of 6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (450 mg, 1.32 mmol), (1R,2R)-2-aminocyclohexanol (228 mg, 1.98 mmol) and DIEA (341 mg, 2.64 mmol) in DMA (10 mL) was stirred at 120° C. for 1.5 h. The reaction mixture was cooled to rt and poured into water (30 mL) and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give (1R,2R)-2-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol as a white solid (155 mg, 29.9%). 1H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.33 (s, 1H), 7.16-7.08 (m, 3H), 6.82 (dd, J=2.4, 8.7 Hz, 1H), 5.42 (s, 2H), 4.68 (d, J=4.5 Hz, 1H), 3.75 (s, 3H), 3.35 (br s, 2H), 1.90 (m, 2H), 1.62 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/z 393 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:4]=1[SH:12].[C:13]([CH2:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])#N>ClC1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:9][C:8]1[C:3]2[N:2]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:12][C:4]=2[C:5]([F:11])=[CH:6][C:7]=1[F:10]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: CCOC(=O)c1cccc(CCC#N)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CCOC(=O)c1cccc(CCc2nc3c(F)c(F)cc(F)c3s2)c1
Yield: 30.3 %

Procedure:
To a solution of zinc chloride (26 mg, 0.19 mmol) in chlorobenzene (3 ml) was added a solution of 2-amino-3,4,6-trifluorothiophenol hydrochloride (269 mg, 1.2 mmol) in chlorobenzene (1 ml) and a solution of ethyl 3-(2-cyanoethyl)benzoate (254 mg, 1.2 mmol) in chlorobenzene (1 ml) and the mixture was heated to reflux for 40 hours. The reaction mixture was evaporated followed by addition of methylene chloride. The resulting mixture was washed with water, dried and evaporated to yield a residue, which was purified on a silica gel column to give ethyl 3-[2-(4,5,7-trifluorobenzothiazol-2-yl)ethyl]benzoate (133 mg, 30%) as an oil.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[Zn](CC)CC.Cl[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1>C1COCC1.CN1C(=O)CCC1.[O-]S([O-])(=O)=O.[Zn+2]>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([CH2:2][CH3:1])=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: CC[Mg+]
Agent: CC[Zn]CC
Agent: O=S(=O)([O-])[O-]
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)OC)cc1
Reaction time: 0.25 h
Yield: 93 %

Procedure:
A solution of EtMgBr (3 M in Et2O, 0.9 mL) is added to a solution of Et2Zn (3 M in toluene, 1 mL) at −78° C. After stirring for 15 min, the resulting cold solution of the zincate is added dropwise to a solution of methyl 4-chlorobenzoate (354 mg, 2.10 mmol) and Fe(acac)3 (36 mg, 0.1 mmol) in THF (6 mL) and NMP (0.5 mL) at 0° C. causing a spontaneous color change from yellow to brown-black. Standard extractive work up followed by flash chromatography affords 4-ethylbenzoic acid methyl ester (93%) the analytical and spectroscopic data of which are identical to those of a commercial sample.
Reaction SMILES: Br[C:2]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]4[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38]>>[F:31][C:32]1[CH:33]=[C:34]([C:2]2[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:5]3[NH:6][C:7]([N:9]4[CH2:10][CH2:11][N:12]([C:15]5[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:18]=[CH:17][N:16]=5)[CH2:13][CH2:14]4)=[N:8][C:4]=3[CH:3]=2)[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: FC(F)(F)c1cc2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2cc1Br
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Fc1ccc(-c2cc3nc(N4CCN(c5ncccc5C(F)(F)F)CC4)[nH]c3cc2C(F)(F)F)cc1F

Procedure:
The reaction of 5-bromo-6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (250 mg, 0.5 mmol, Example 89g) with 3,4-difluorophenylboronic acid (95 mg, 0.60 mmol, Aldrich) under the conditions of Example 88 afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 528.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][Br:38])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)c1oc2cccc(CO)c2c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cccc(CBr)c2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 0.200 g (0.855 mmol) 4-hydroxymethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester (Example 92, Step 2) in 5 mL of THF was added 0.336 g (1.28 mmol) of triphenylphosphine and 0.355 g (1.07 mmol) of carbon tetrabromide. The reaction was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was diluted ith 20 mL of ether and filtered. The filtrate was concentrated in vacuo and chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.196 g of 4-bromomethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[C:10](Br)[CH:11]=1)[CH3:2].[CH2:15]([N:17]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1)[C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>COCCOC.[Cl-].[Na+].O.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.O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[C:10]([C:25]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:24]=2[CH2:23][N:17]([C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[CH2:15][CH3:16])[CH:11]=1)[CH3:2]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)C1CC1
Reactant: CCOC(=O)Cc1cnc(Cl)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1cnc(Cl)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
(5-Bromo-6-chloro-pyridin-3-yl)-acetic acid ethyl ester (0.549 g, 1.97 mmol), cyclopropanecarboxylic acid ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amide (0.787 g, 1.97 mmol), and potassium carbonate (0.824 g, 5.91 mmol) were combined in DME (6 mL) and H2O (3 mL), and the solution was purged with N2 for 40 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.338 g, 0.20 mmol) was added, and the reaction was stirred at 85° C. for 2 hours. After cooling to room temperature, the mixture was worked-up with EtOAc, H2O, and brine, and the organic layer was separated, dried, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give (6-chloro-5-{2-[(N-cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F-].[K+].[CH3:13][C@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1>CS(C)=O>[CH3:13][C@H:14]1[N:19]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:15]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1c([N+](=O)[O-])cnn1C
Temperature: 100 °C
Yield: 87.6 %

Procedure:
To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (355 mg, 2.2 mmol) and potassium fluoride (511 mg, 8.8 mmol) in dry DMSO (20 mL) was added (R)-tert-butyl 3-methylpiperazine-1-carboxylate (507 mg, 2.53 mmol) and the mixture was heated in the microwave at 100° C. for 10 hr. The mixture was partitioned between water (40 mL) and EtOAc (100 mL) and the organic layer passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (R)-tert-butyl 3-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazine-1-carboxylate as an orange gum (627 mg). To a solution of this gum (179 mg, 0.55 mmol) and ammonium formate (256 mg, 4.4 mmol) in MeOH (10 mL) under nitrogen was added 10% palladium on carbon (59 mg, 0.55 mmol). The mixture was heated at 70° C. for 4 hr before being cooled, filtered and concentrated under reduced pressure. The residue was partitioned between water (20 mL) and DCM (60 mL) and the organic layer separated, passed through a phase separation cartridge and concentrated under reduced pressure to give (R)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate as a brown gum (150 mg, 80% over two steps). LCMS (ES+) m/z 296 (M+1).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[F:6][C:7]([F:22])([F:21])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C@H:15]([CH2:19][CH3:20])[CH2:16][C:17]#[N:18])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[F:6][C:7]([F:21])([F:22])[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C@H:15]([CH2:19][CH3:20])[CH2:16][C:17]([NH2:18])=[O:2])=[CH:12][CH:13]=1
Reactant: CC[C@H](CC#N)Nc1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC[C@H](CC(N)=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 35 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
Aqueous sulfuric acid (8.2 L sulfuric acid and 1.1 L water premixed and cooled to 35° C. or less) was added to the crude toluene solution of (3R)-3-(4-trifluoromethyl-phenylamino)-pentanenitrile from Example 1. The resulting bilayer was stirred well and heated to 35° C. for 17 hours. The lower aqueous layer was collected and quenched with aqueous sodium hydroxide (95 L water and 10.7 kg sodium hydroxide) and diisopropyl ether (IPE) (40 L). After extraction and removal of the aqueous layer, the organic layer was combined and extracted with saturated aqueous NaHCO3 (10 L). The organic phase from the resulting bilayer was concentrated by distillation to a volume of 19 L. The solution was then cooled to room temperature and seeded with (3R)-3-(4-trifluoromethyl-phenylamino)-pentanoic acid amide and allowed to granulate for 3 hours while stirring. To the heterogenous mixture was added cyclohexane (38 L) and the mixture was granulated for an additional 11 hours. The solids were filtered, rinsed with cyclohexane (4 L), dried under vacuum at 40° C. to afford 3021 g (75%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=1)=[O:4].[CH3:17][O:18][C:19]1[CH:34]=[CH:33][C:22]([CH:23]([NH2:32])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH:23]([NH:32][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=2)[OH:4])[C:22]2[CH:33]=[CH:34][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1F
Product: COc1ccc(C(NCC(O)c2ccc(F)c(NS(C)(=O)=O)c2)c2ccc(OC)cc2)cc1

Procedure:
The title compound was prepared by coupling of 2-bromo-1-[4-fluoro-3-[(methylsulfonyl)amino]phenyl]ethanone with 4,4'-dimethoxybenzhydrylamine (preparation described in Example 14) following the procedure described in step D of Example 1, except for the following modification: the crude product after coupling and reduction was chromatographed on silica gel using 75% EtOAc/hexane to elute pure title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl.[N:32]1([CH2:39][CH2:40][O:41][C:42]2[CH:50]=[CH:49][C:45]([C:46](O)=O)=[CH:44][N:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:39][CH2:40][O:41][C:42]2[N:43]=[CH:44][C:45]([CH2:46][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[C@@H:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:49][CH:50]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)nc1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)nc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 63.7 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 6-(2-azepan-1-ylethoxy)nicotinic acid hydrochloride (60 mg) according to an analogous synthetic method to Example 337 described below and purified by LC-MS, the title compound (26 mg) was obtained.
Reaction SMILES: [F:1][CH:2]([F:48])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)[N:11]=[C:10]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:9]=2)[C:6]2[CH:34]=[C:35]([NH:40]C(=O)OC(C)(C)C)[CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1.N>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:40][C:35]1[CH:36]=[C:37]([O:38][CH3:39])[C:5]2[N:4]=[C:3]([CH:2]([F:48])[F:1])[N:7]([C:8]3[N:9]=[C:10]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])(=[O:22])=[O:21])[CH2:16][CH2:15]4)[N:13]=3)[C:6]=2[CH:34]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN(C)C)CC2)n1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N)cc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the above carbamate (0.244 g, 0.035 mmol) in a mixture of 10 mL CH2Cl2 and 5 mL TFA was stirred at room temperature for 2 hrs. The mixture was diluted with CH2Cl2 and then made basic with dil. aq. NH3. The organic layer was dried and concentrated to give a quantitative yield of N-[2-({4-[4-[6-amino-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine: 1H NMR (CDCl3) δ 7.35 (t, JHF=53.8 Hz, 1H), 7.15 (d, J=1.9 Hz, 1H), 6.22 (d, J=1.9 Hz, 1H), 3.98 (m, 7H), 3.90-3.75 (m, 10H), 3.38 (m, 4H), 3.11 (dd, J=8.1, 6.5 Hz, 2H), 2.78 (dd, J=8.1, 6.4 Hz, 2H), 2.26 (s, 6H).
Reaction SMILES: [C:1]1([C:7]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>C1COCC1>[C:1]1([C:7]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH2:43][C:42]3[CH:45]=[CH:46][C:39]([C:31]4[O:30][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=5[N:32]=4)=[CH:40][CH:41]=3)[CH2:23][CH2:22]2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O[C@H]1CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(C(N[C@H]2CC[C@H](OCc3ccc(-c4nc5ccccc5o4)cc3)CC2)(c2ccccc2)c2ccccc2)cc1

Procedure:
To a mixture of trans-4-triphenylmethylaminocyclohexanol (3.18 g; 8.90 mmol) is 100 ml THF is added sodium hydride (60%; 0.320 g; 13.35 mmol) and this is followed by the addition of 4-(benzoxazol-2-yl)benzyl bromide after about 1 hr. The mixture is heated at reflux for 1 week, cooled, concentrated in vacuo and dissolved in about 40 ml CH2Cl2 ; hexane:ethylacetate (9:1 ). The solid material is filtered off and the residue flash chromatographed using hexane:ethylacetate; 7:1 to obtain trans-4-triphenylmethylamino-[4-(benzoxazol-2-yl)benzyloxy]cyclohexane as a white solid which is used directly in the next step.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[C:27]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C1CCCC1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1NC1CCCC1

Procedure:
The title compound, off-white foam, MS: m/e=453.2 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and cyclopentanone.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]2=[O:18])([O-])=O.C1(O)CCCCC1.[H][H]>[Ni]>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Ni]
Solvent: OC1CCCCC1
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 100 °C
Yield: 82.8 %

Procedure:
To a mixture of 12.8 grams of 5-nitrotetrahydroanthraquinone and 170 grams of cyclohexanol was added 0.3 gram of a Raney-nickel catalyst. Then, hydrogen was fed into the mixture while agitating at 100° C. for hydrogenation. After hydrogen was absorbed in an amount of 2 mols per mol of the nitro compound, the catalyst was separated by filtration. To the resultant filtrate was added 10 grams of a 20% aqueous sodium hydroxide solution, followed by agitating at 100° C. for 1 hour. Then, the reaction solution was cooled to 10° C. to precipitate crystals which were separated by filtration, washed with water and dried to obtain 9.2 grams of 1-aminoanthraquinone having a purity of 98%.
Reaction SMILES: C(OC(=O)[N:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:8]1[CH2:11][N:10]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:26]([NH:7][CH:8]1[CH2:11][N:10]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH2:9]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCNc1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)C(=O)OC(C)(C)C)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCNc1ccc(S(=O)(=O)N2CC(NCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a solution of Benzyl-[1-(4-butylamino-benzenesulfonyl)-azetidin-3-yl]-carbamicacid tert-butyl ester (0.19 g, 0.4 mmol) in dichloromethane (4 ml) was added trifluoroacetic acid (0.31 ml, 4 mmol). The mixture was stirred at room temperature for 2 h, and then quenched with saturated sodium carbonate solution, and extracted with dichloromethane. The organic solution was washed with brine, dried over sodium sufate, and evaporated. The crude product was chromatographed on silica gel (ethyl acetate-hexanes/3:2) to give 0.09 g of a colorless foam; MS (ES) m/z 374.1 (MH+); HRMS (EI) Calcd. for C20H27N3O2S (M+): 373.1824, Found: 373.1822.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[NH:4][CH2:3]1.[Br:12][CH2:13][CH2:14][CH2:15]Br>>[CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]([CH2:15][CH2:14][CH2:13][Br:12])[CH2:3]1
Reactant: BrCCCBr
Reactant: CC1CNc2ccccc2O1
Product: CC1CN(CCCBr)c2ccccc2O1
Yield: 42.9 %

Procedure:
From 2-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.5 g, 1 eq, 30.2 mmol) obtained in step (iii) above, and 1,3-dibromo propane (30 ml, 10 eq, 300 mmol) and following the procedure of step (iv), preparation 17 title compound (3.5 g, yield 48%) was obtained as viscous oil.