Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:35]CCl>C(O)C>[ClH:35].[CH3:31][O:30][C:26]1[CH:25]=[C:24](/[C:16](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:15]/[O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(/c2cccc(OC)c2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(/C(=C/OCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
E or Z-(R)-1-[2-[[2-(3-Methoxyphenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (0.50 g, 0.0012 mol) (prepared as described in Method D) was dissolved in ethanol (15 ml) and 12N sodium hydroxide solution (0.2 ml) was introduced. After stirring the solution at room temperature for 6 h, ice (100 g) was added, and the pH of the reaction mixture was adjusted to ca. 7 with 37% hydrochloric acid solution. Dichloromethane (200 ml) was added, and the pH was further adjusted to <2 with 37% hydrochloric acid solution. The dichloromethane phase was dried (Na2SO4) and evaporated to a solid (0.3 g, 60%), m.p. 188°-192°.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(Br)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cccc(C2(O)CCN(Cc3ccccc3)CC2)c1

Procedure:
This compound is prepared by the procedure described in step A of preparation 1.7, from 1.55 g of magnesium in 25 ml of THF, a solution of 11 g of 3-bromotoluene in 15 ml of THF and a solution of 10 g of 1-benzyl-4-piperidone in 30 ml of THF. The product obtained is chromatographed on silica gel, eluting with a DCM/MeOH (97/3; v/v) mixture. This gives 14.5 g of the expected product.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH:7]([NH:8][C:44]([C:40]1[CH:39]=[C:38]2[C:43](=[CH:42][CH:41]=1)[N:35]([CH2:34][C:31]1[CH:30]=[CH:29][C:28]([C:23]3[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:33][CH:32]=1)[C:36]([CH3:48])=[C:37]2[CH3:47])=[O:45])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NC(c1ccccc1)c1ccccc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC(c3ccccc3)c3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using diphenylmethanamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C@H:13]1[CH2:19][N:18]2[C:20]([CH2:23][CH:24]=O)=[CH:21][N:22]=[C:17]2[C@H:16]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:15][CH2:14]1.[CH3:34][NH:35][CH3:36].C(O)(=O)C>CO>[F:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C@H:13]1[CH2:19][N:18]2[C:20]([CH2:23][CH2:24][N:35]([CH3:36])[CH3:34])=[CH:21][N:22]=[C:17]2[C@H:16]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[CH2:15][CH2:14]1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC=O)cnc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
Sodium cyanoborohydride (12 mg, 0.185 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2-oxoethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (50 mg, 0.123 mmol) and dimethylamine (2.0 M in tetrahydrofuran; 0.185 mL, 0.370 mmol) in methanol (5 mL) adjusted to pH 5 with acetic acid. After 2 h, the solution was concentrated. Purification by silica gel chromatography (100% dichloromethane→92% dichloromethane/methanol) gave the title compound (45 mg). MS 435.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:4]=1[CH2:5][NH:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].[B].CSC.Cl.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: COc1cccc(OC)c1CNC(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [B]
Solvent: C1CCOC1
Solvent: O
Solvent: CSC
Product: COc1cccc(OC)c1CNCc1ccccc1[N+](=O)[O-]

Procedure:
7.5 g (23.71 mmol) N-(2,6-dimethoxybenzyl)-2-nitrobenzamide was dissolved in 130 mL THF, then 9.06 g boron-dimethyl sulfide-complex (2M solution in THF) was added by drops and the mixture was refluxed for 5 hours. Next 50 mL 2N HCl was added and the mixture was heated again at reflux for 30 minutes. For workup, the mixture was poured into water after cooling, a pH of approx. 10 was adjusted by adding 2N NaOH, further extraction was performed with ethyl acetate and the combined organic phases were dried with MgSO4. The crude product obtained by chromatography on silica gel (dichloromethane, 0-5% methanol) after filtration and evaporation yielded the desired amine; 3.58 g as a light yellow oil. ESI-MS [M+H+]=302.15.
Reaction SMILES: [C-]#N.[K+].[C:4]([NH2:7])(=O)C.[Cl-].C[N+](C)(C)[C:11]1[N:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([O:19][CH3:20])[N:12]=1>O>[C:4]([C:11]1[N:12]=[C:13]([O:19][CH3:20])[N:14]=[C:15]([O:17][CH3:18])[N:16]=1)#[N:7]
Reactant: COc1nc(OC)nc([N+](C)(C)C)n1
Reactant: CC(N)=O
Agent: [C-]#N
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: COc1nc(C#N)nc(OC)n1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
A mixture of 26 g of potassium cyanide and 60 g of oven-dried acetamide was heated to 85°-90° C. To this melt was added 24 g of the product from Example 2 in portions over a period of 15-20 minutes. The resulting brown reaction solution was heated to 90°-100° C. for an additional one hour. When the solution had cooled to room temperature, water was added and the aqueous layer was extracted with ether and methylene chloride. The combined organic extracts were backwashed with several small portions of water, brine, and were then dried over magnesium sulfate and concentrated in vacuo to afford 6.5 g of 2-cyano-4,6-dimethoxy-1,3,5-triazine as a light yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[CH:20]=[CH:21][C:22](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53]>C(OCC)(=O)C>[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)/[CH:20]=[CH:21]/[C:22]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: COc1cccc(C=CC(=O)Cl)c1
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1cccc(/C=C/c2nc3ccccc3n2-c2ccccn2)c1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and 3-methoxycinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull., 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound. MW: 417.42; mp: 163.0-164.0° C.; 1H-NMR (DMSO) δ: 8.78 (1H, dd, J=4.9, 1.3 Hz), 8.19 (1H, td, J=7.9, 2.0 Hz), 7.87 (1H, d, J=15.8 Hz), 7.77-7.72 (2H, m), 7.67-7.61 (1H, m), 7.48-7.44 (1H, m), 7.36-7.24 (3H, m), 7.22-7.15 (3H, m), 6.96-6.92 (1H, m), 3.78 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH3:22]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:22])[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCc1c(-c2ccccc2)[nH]c2ccc(Br)cc12
Reactant: CI
Solvent: CN(C)C=O
Product: CCCCCc1c(-c2ccccc2)n(C)c2ccc(Br)cc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 5-bromo-3-pentyl-2-phenyl-1H-indole (1.711 g, 5.000 mmol) was reacted with k-t-butoxide (0.589 g, 5.250 mmol) and methyl iodide (0.745 g, 5.250 mmol) in DMF (15 ml) to give the product (1.113 g, 3.124 mmol, 62%) as a colorless oil. 1H DMSO-d6) δ 0.76 (t, J=7.0 Hz, 3H), 1.13-1.18 (m, 4H), 1.44-1.50 (m, 2H), 2.58 (t, J=7.6 Hz, 2H), 3.53 (s, 3H), 7.27 (dd, J=2.0, 8.7 Hz, 1H), 7.41-7.44 (m, 3H), 7.48 (t, J=7.5 Hz, 1H), 7.54 (t, J=7.0 Hz, 2H), 7.71 (d, J=1.7 Hz, 1H); [ESI(+)], m/z 356/358 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:12][C@H:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1])[CH3:11]
Reactant: [H][H]
Reactant: C[C@H](N)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)c1cccc(N)c1
Yield: 99.9 %

Procedure:
A mixture of (1S)-1-(3-nitrophenyl)ethanamine (13.1 g, 79.4 mmol) and 10% palladium on carbon (0.75 g) in methanol (250 mL) was stirred vigorously under an atmoshphere of hydrogen for 19 hours. After this time the mixture was filtered through a pad of Celite and the pad was washed with methanol (800 mL). The combined filtrates were concentrated under reduced pressure to give 3-[(1S)-1-aminoethyl]aniline as a brown solid (10.8 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:21]2[CH2:23][CH2:22]2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:35])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:21]2[CH2:23][CH2:22]2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:35])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 130.1 %

Procedure:
100 mg (0.29 mmol) of the compound from Example 227 were introduced into 15 ml of dichloromethane at 0° C., 72 mg (0.29 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 135 mg of the title compound as mixture of diastereomers.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:30])=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: Cc1ccc(CCN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCc2ccc(C)cc2)ccc1Oc1ccc(C(N)=O)cn1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.100 g, 0.367 mmol), 2-p-tolylethylamine (0.0546 g, 0.404 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with (2.0 M NH3 in methanol) in ethyl acetate to give 6-{2-methoxy-4-[(2-p-tolylethylamino)methyl]phenoxy}nicotinamide (0.143 g, 97.8%). Dissolve the compound in dichloromethane (2.5 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to give the title compound (0.168 g, ˜100%): TOF MS ES+ 392.1 (M+H)+, HRMS calcd for C23H26N3O3 392.1974 (M+H)+, found 392.1966, time 0.39 min; HPLC [Waters XTerra™ MS C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 15 min], tR=8.4 min, 100% purity.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O.O>[CH3:9][S:8][C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(S)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC(C)=O
Product: CSc1cccc(O)c1
Reaction time: 0.75 h

Procedure:
3-Hydroxythiophenol (5.0 g, 39.7 mmol) and potassium carbonate (6.03 g, 43.6 mmol) were stirred in acetone (80 mL) at 0° C. Iodomethane (2.5 mL, 40 mmol) was added dropwise, and the reaction stirred for 45 min. The solution was diluted with H2O (150 mL) and extracted with EtOAc (2×100 mL). Organics were washed with brine (100 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (25% EtOAc/hexanes) 5.08 g (91%) of 3-methylsulfanyl-phenol as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.15 (t, 1H, J=8.1 Hz), 6.82 (d, 1H, J=8.1 Hz), 6.74 (t, 1H, J=1.8 Hz), 6.60 (dd, 1H, J=8.1, 1.8 Hz), 4.86 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: C1C2C(=CC(S[C:11]3[C:12]4[CH:20]=[CH:19][CH:18]=[N:17][C:13]=4[N:14]=[CH:15][N:16]=3)=CC=2)CC1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][CH2:26][CH2:25]2>O>[CH2:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:11]3[C:12]4[CH:20]=[CH:19][CH:18]=[N:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:30][CH:29]=2)[CH2:25][CH2:26]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: c1cnc2ncnc(Sc3ccc4c(c3)CCC4)c2c1
Solvent: O
Product: c1cnc2ncnc(Nc3ccc4c(c3)CCC4)c2c1
Temperature: 130 °C
Yield: 40 %

Procedure:
A suspension of 4-(5-indanylthio)-pyrido[2,3-d]pyrimidine (2.79 g, 10 mM) and 5-aminoindan (3.996 g, 30 mM) in water (100 ml) is heated in a sealed tube at 130° C. for 20 h. Then the water is evaporated under vacuum and the residue chromatographed on silica gel by using dichloromethane/methanol mixtures as eluant. Thus almost pure title compound is obtained in about 40% yield.
Reaction SMILES: BrC1C=CC(C2CCC2)=CC=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2(O)[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C([SiH](CC)CC)C>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: OC1(c2ccc(Br)cc2)CCCC1
Agent: Brc1ccc(C2CCC2)cc1
Agent: CC[SiH](CC)CC
Product: Brc1ccc(C2CCCC2)cc1

Procedure:
The title compound was synthesized in analogy to bromo-4-cyclobutyl-benzene (described in example S113) using 823 mg of 1-(4-bromo-phenyl)-cyclopentanol (3.41 mmol), 652 μl of triethylsilane (4.10 mmol) and 649 μl of boron trifluoride diethyl etherate complex (5.12 mmol). The isolated residue was purified by flash column chromatography (1:9 EtOAc/-cyclohexane) to give 727 mg of a mixture of the desired 4-cyclopentyl-benzene and 1-bromo-4-cyclopent-1-enyl-benzene as a white semi-solid. This mixture was used in the following step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)(c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reaction time: 16 h

Procedure:
Combine 1-(t-butoxycarbonyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (30 mmol) and triethylamine (8.2 mL, 59.2 mmol) in dichloromethane (150 mL). Cool in an ice-bath. Add methanesulfonyl chloride (2.5 mL, 32.6 mmol). After 16 hours, dilute the reaction mixture with dichloromethane and extract with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel to give 1-(t-butoxycarbonyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH2:14].[CH:15]([NH:18][C:19]([C:21]1[S:25][C:24](Cl)=[N:23][CH:22]=1)=[O:20])([CH3:17])[CH3:16]>CN(C=O)C>[CH:15]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:23][CH:22]=1)=[O:20])([CH3:17])[CH3:16]
Reactant: Cc1onc(-c2ccccc2)c1CN
Reactant: CC(C)NC(=O)c1cnc(Cl)s1
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1CNc1ncc(C(=O)NC(C)C)s1
Yield: 13.2 %

Procedure:
A stirred solution of (5-methyl-3-phenyl-4-isoxazolyl)methylamine (100 mg, 0.53 mmol) and 2-chloro-thiazole-5-carboxylic acid isopropylamide (100 mg, 0.49 mmol) in DMF (5 mL) was heated at 100° C. for 7 days, then at 150° C. under microwave irradiation for 15 min. The reaction mixture was cooled and concentrated in vacuo, then diluted with water and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated, then purified by chromatography (silica, 0 to 3% methanol in dichloromethane) to give the title compound (23 mg, 12%) as a white solid. MS: m/e=357.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[C:12]([CH:18]([CH3:20])[CH3:19])[CH-:13]3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Li+]>C1COCC1>[CH3:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[C:12]([CH:18]([CH3:20])[CH3:19])[CH2:13]3)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2cccc3[cH-]c(C(C)C)cc23)c1
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cccc3c2C=C(C(C)C)C3)c1
Yield: 72.8 %

Procedure:
SiMe2 Cl2(0.69 g, 5.4 mmol) was dissolved in 80 mL of THF. While stirring, lithium 4-(3′,5′-dimethylphenyl)-2-isopropylindenide (2.9 g, 11 mmol) was added as a dry powder and the contents allowed to stir overnight at room temperature. The solvent was removed in vacuo and the residue was taken up in pentane and filtered to removed LiCl salts. The pentane was removed in vacuo to yield a flaky white solid (2.1 g, 67%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][C:54]2[S:55][C:56]([Cl:59])=[CH:57][CH:58]=2)=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:59][C:56]1[S:55][C:54]([CH2:53][O:52][C:49]2[CH:48]=[CH:47][C:46]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]5[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)=[CH:21][CH:22]=5)=[O:15])=[CH:7][C:6]=4[CH:32]=3)=[CH:51][CH:50]=2)=[CH:58][CH:57]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: [O-]B([O-])Oc1ccc(OCc2ccc(Cl)s2)cc1
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: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCc5ccc(Cl)s5)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (10/1/1, 19.2 ml) and then were added 4-[(5-chloro-2-thienyl)methoxy]phenyl borate (186 mg) and potassium carbonate (175 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed at 100° C. for 8 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/2) and recrystallized from ethanol to give 7-[4-[(5-chloro-2-thienyl)methoxy]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 104) (137 mg).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[C:12]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([F:30])[CH:23]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C1(S(N2C3C(=CC=C([N+]([O-])=O)C=3)C(Br)=C2)(=O)=O)C=CC=CC=1.FC1C=C(B(O)O)C=CC=1C#N.C([O-])([O-])=O.[K+].[K+]>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.C1COCC1>[F:30][C:24]1[CH:23]=[C:22]([C:12]2[C:13]3[C:18](=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[NH:10][CH:11]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: N#Cc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3cc([N+](=O)[O-])ccc23)cc1F
Agent: [Pd]
Agent: N#Cc1ccc(B(O)O)cc1F
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2c[nH]c3cc([N+](=O)[O-])ccc23)cc1F

Procedure:
4-(1-Benzenesulfonyl-6-nitro-1H-indol-3-yl)-2-fluoro-benzonitrile from 1-benzenesulfonyl-3-bromo-6-nitro-1H-indole, 7, and 3-fluoro-4-cyanophenylboronic acid using Method AA: Pd2(dba)3, [(t-Bu3)PH]BF4, K2CO3, THF, H2O. Purify by precipitation from EtOAc/hexanes. Remove the benzenesulfonyl protecting group using TBAF and THF as described for 4-(6-nitro-1H-indol-3-yl)-benzonitrile (9) above. LRMS (API ES−)=280.0 (M−1).
Reaction SMILES: C#CC(N1CCCC1C)C.[CH2:11]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH3:20])[CH2:12][C:13]#[CH:14].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[C:24](I)[CH:23]=1.C(NC(C)C)(C)C>[Cu]I.BrC1C=CC2SC(CCO)=NC=2C=1>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([C:14]#[C:13][CH2:12][CH2:11][N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH3:20])[CH:23]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: C#CCCN1CCC[C@H]1C
Agent: [Cu]I
Agent: C#CC(C)N1CCCC1C
Agent: OCCc1nc2cc(Br)ccc2s1
Solvent: CC(C)NC(C)C
Product: C[C@@H]1CCCN1CCC#Cc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a solution of 1-butyn-3-yl-2-methyl-pyrrolidine in CH3CN (prepared in Example 65A assuming 100% conversion, 89 mmol) was added 4-bromo-2-iodo-phenylamine (12.0 g, 40 mmol) under nitrogen followed by addition of CuI (0.38 g, 2.0 mmol), PdCl2(PPh3) 2 (0.70 mg, 1.0 mmol) and diisopropylamine (33.6 mL, 240 mmol). The resulting solution was stirred at room temperature for 2 hours, at which time analytical HPLC analysis indicated that all 4-bromo-2-iodo-phenylamine was consumed. The solvent CH3CN was removed under vacuo and the residue was extracted with IPAC (500 mL) and 5% NaHCO3 (2×300 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound as a thick oil (11.96 g), which was used in the next step without further purification.