Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH:18]=[N:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([OH:23])[CH3:22])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[H][H]>C1COCC1.[Ni]>[F:1][C:2]1[C:3]([CH2:18][NH:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([OH:23])[CH3:22])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](N=Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1F)C(C)O
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)[C@@H](NCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1F)C(C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.5 %

Procedure:
Example 17A (767 mg, 2.85 mmol) and Example 107B (460 mg, 2.99 mmol) were dissolve in methanol (20 mL) and triethylamine (0.434 mL, 3.13 mmol). The orange solution was stirred at ambient temperature for 2 hours and 20 minutes, followed by the addition of sodium borohydride (237 mg, 6.27 mmol). After 4 hours, additional sodium borohydride (237 mg, 6.27 mmol) was added. The reaction was stirred overnight at ambient temperature, quenched with 100 mL 1.0 N NaOH, and extracted twice with 100 mL dichloromethane. The combined organic phase was dried over Na2SO4, filtered, and concentrated to provide (3R)-3-[({3-fluoro-6-[4-(trifluoromethyl)phenyl]pyridin-2-yl}methylene)amino]-4-methylpentan-2-ol (1.009 g, 2.74 mmol) as an orange oil. The imine (1.009 g, 2.74 mmol) in THF (40 mL) was added to Raney Nickel (1.009 g) in a 250 mL stainless steel pressure bottle. The mixture was pressurized with hydrogen (30 psi), and stirred for 20 hours at ambient temperature. The mixture was filtered through a nylon membrane, concentrated, and chromatographed on a Grace Reveleris 40 g column, eluted with 0-30% EtOAc in dichloromethane (30 mL/min) to provide the title compound (0.533 g, 1.439 mmol, 52.5% yield) as a yellow oil, a 3:1 mix of diastereomers by proton NMR. MS (ESI+) m/z 371.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J=8.3, 2H), 8.05 (dd, J=8.6, 3.7, 1H), 7.89-7.77 (m, 3H), 4.43 (d, J=4.8, 0.75H), 4.38 (d, J=5.2, 0.25H), 4.14-3.95 (m, 2H), 3.71-3.58 (m, 1H), 2.40-2.29 (m, 0.75H), 2.25-2.17 (m, 0.25H), 2.15-2.06 (m, 1H), 1.93-1.73 (m, 1H), 1.11-1.04 (m, 3H), 0.96-0.79 (m, 6H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([NH2:22])[CH:17]1[O:21][CH2:20][CH2:19][CH2:18]1>O>[C:10]1([CH:8]([OH:9])[CH:7]([NH:22][CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][O:21]2)[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCC1CCCO1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: O
Product: OC(c1ccccc1)C(NCC1CCCO1)c1ccccc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mole) and tetrahydrofurfurylamine (3.03 g, 0.030 mole) was heated at 140° C. for 2 hrs. After standing at ambient temperature for 18 hrs, the mixture was diluted with water (150 ml). An oil separated from the solution which solidified on standing for an hour. NMR and mass spectral analyses showed stilbene oxide remaining. The solid was treated with another 3.03 g of tetrahydrofurfurylamine and the mixture heated at 140° C. for another 3 hours. The reaction mixture was treated with water (150 ml) as before to obtain 2.28 g (77%) of an off-white solid after drying under ambient conditions for 18 hours. The solid was recrystallized from toluene, m.p. 167°-168° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])(=[O:17])[CH:14]([CH3:16])[CH3:15].Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>O1CCCC1.CCCCCC>[CH3:23][N:21]([CH3:22])[CH2:20][CH2:19][O:18][C:13]([O:17][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:14]([CH3:16])[CH3:15]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)C(=O)OCCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)=C(OCCN(C)C)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
To a solution of 31.78 g (44 mL, 0.314 mol) of diisopropylamine (Aldrich gold label) in 300 mL of tetrahydrofuran at -5° to 0° C. was added over a period of about 30 min. 0.314 mol of 1.6N n-butyl lithium in hexane (196 mL). After 30 min at 0° C., the solution was cooled to -78° C. and 50 g (0.314 mol) of 2-dimethylaminoethyl isobutyrate, prepared as above, was added keeping the temperature below -70° C. Then 34.11 g (39.9 mL, 0.314 mol) of chlorotrimethylsilane was added below -70° C. After warming to room temperature, the mixture was concentrated on a rotary evaporator, and the residue was treated with hexane and filtered under argon. The filtrate was concentrated on a rotary evaporator and distilled in a spinning band column to give 45.4 g of 1-(2-dimethylaminoethoxy)-1-trimethylsiloxy-2-methyl-1-propene, b.p. 39°-42.5° C. (0.5 mm). 1H-NMR (360 MHz, benzene-d6): 0.22 (s, 9 H, SiMe), 1.67 (s, 3 H, =CCH3), 1.77 (s, 3 H, =CCH3), 2.12 (s, 6 H, NCH3), 2.46 (t, J=6 Hz, 2 H, CH2N), 3.85 (t, J=6 Hz, 2 H, CH2O). Anal Calcd for C11H25O2SiN: C 57.09, H 10.89, N 6.05, Si 12.14. Found: C 57.27, H 11.11, N 6.17, Si 11.37. IR (neat): 1705 cm-1 (C=C), no C=O absorption.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[F:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1SC)[C:14]([C@@H:26]([N:28]1[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]1=[O:38])[CH3:27])=[CH:13]2.[CH2:39](Cl)Cl>>[F:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:3]([CH3:39])(=[O:5])=[O:2])[C:14]([C@@H:26]([N:28]1[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]1=[O:38])[CH3:27])=[CH:13]2
Reactant: O=S([O-])OO
Reactant: ClCCl
Reactant: CSc1ccccc1-c1nc2c(F)cccc2cc1[C@H](C)N1C(=O)c2ccccc2C1=O
Agent: [K+]
Product: C[C@@H](c1cc2cccc(F)c2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
To 70 mL of DCM was added 13.56 g (1.2 g/1 mmol of substrate) of wet Montmorillonite (˜0.2 g H2O/1 g of clay), and oxone (17.37 g, 28.2 mmol)1. To this suspension was added a solution of 2-((1S)-1-(8-fluoro-2-(2-(methylthio)-phenyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (5.0 g, 11.3 mmol) dissolved in DCM (10 mL). The slurry was stirred at rt for 72 h and then filtered through a fritted funnel. The solids were washed with DCM (˜600 mL) and the filtrates were concentrated under vacuum to give 2-((1S)-1-(8-fluoro-2-(2-(methylsulfonyl)phenyl)-3-quinolinyl)ethyl)-1H-isoindole-1,3(2H)-dione 7.11 g (97%) as a light yellow solid. The proton NMR reflects a 59/41 ratio of atropisomers at 25° C. 1H-NMR (500 MHz, CDCl3) δ ppm 8.86 (s, 0.59H), 8.79 (s, 0.41H), 8.26 (d, J=7.8 Hz, 0.41H), 8.04 (d, J=7.8 Hz, 0.59H), 7.89-7.36 (series of m, 9.6H), 7.20 (d, J=7.6 Hz, 0.41H), 5.70 (q, J=7.1 Hz, 0.59H), 5.54 (q, J=7.3 Hz, 0.41H), 3.19 (s, 1.75H), 3.15 (s, 1.25H), 1.98 (d, J=7.3 Hz, 1.75H), 1.85 (d, J=7.1 Hz, 1.25H). Mass Spectrum (ESI) m/e=475.0 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](Cl)(=[O:30])[C:27](Cl)=[O:28].[CH2:32]([OH:34])[CH3:33]>>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=[C:10]3[C:26](=[O:30])[C:27]([O:34][CH2:32][CH3:33])=[O:28])=[CH:22][CH:21]=1)(=[O:25])[CH3:24]
Reactant: CCO
Reactant: CC(=O)c1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1
Reactant: O=C(Cl)C(=O)Cl
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(C(C)=O)cc3)cc12

Procedure:
Ethyl 2-[5-(4-acetylphenyl)-1-benzyl-1H-indol-3-yl]-2-oxoacetate was prepared from 1-[4-(1-benzyl-1H-indol-5-yl)phenyl]-1-ethanone (0.255 g, 0.784 mmol), oxalyl chloride (0.14 mL, 1.6 mmol), and ethanol (2 mL), following the procedure described in Step 3 of Example 1. Purification by flash chromatography using 30-50% chloroform in hexane as an eluant and drying at 55° C. yielded a brownish solid (0.243 g, 73%). 1HNMR (300 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.5 (s, 1H), 8.05 (d, 2H, J=9.2 Hz), 7.8 (d, 2H, J=7.7 Hz), 7.7 (q, 2H, J=8.5 Hz), 7.25-7.4 (m, 5H), 5.65 (s, 2H), 4.35 (q, 2H, J=7.2 Hz), 2.6 (s, 3H), and 1.35 ppm (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and dodecanoic acid to yield (3aR,4S,7aR)-4-dodecanoyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=1.80 min; UPLC Method I
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][C:7]1[S:11][N:10]=[N:9][C:8]=1[C:12]([O:14]C)=O)([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26].C(Cl)Cl.C[Al](C)C>CCCCCC>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:12]([C:8]2[N:9]=[N:10][S:11][C:7]=2[CH2:6][O:5][Si:4]([CH:16]([CH3:17])[CH3:18])([CH:19]([CH3:20])[CH3:21])[CH:1]([CH3:2])[CH3:3])=[O:14])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: COC(=O)c1nnsc1CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: Nc1ccc(F)c(Cl)c1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)[Si](OCc1snnc1C(=O)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
To a cooled solution (0° C.) of methyl 5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carboxylate (2.2 g, 0.0066 mol) and 3-chloro-4-fluoroaniline (1.5 g, 0.010 mol) in DCM (20 mL, 0.4 mol) was added 2.0 M of trimethylaluminum in hexane (12 mL) under nitrogen and stirred for 15 minutes. The volatiles were removed in vacuo and the crude was purified by flash chromatography to give the desired product (2.3 g, 78%). MF═C19H27ClFN3O2SSi; LCMS calculated for C19H28ClFN3O2SSi (M+H)+: m/z=444.1.
Reaction SMILES: [N-]=C=O.[O:4]=[C:5]1[CH:10]=[N:9][C:8]2[N:11]=[CH:12][CH:13]=[C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])OC(C)(C)C)=[CH:18][CH:17]=3)[C:7]=2[NH:6]1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=C=O)=[CH:33][C:32]=1[C:40]([F:43])([F:42])[F:41]>FC(F)(F)C(O)=O>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]3[C:7]4[NH:6][C:5](=[O:4])[CH:10]=[N:9][C:8]=4[N:11]=[CH:12][CH:13]=3)=[CH:17][CH:18]=2)=[O:29])=[CH:33][C:32]=1[C:40]([F:41])([F:42])[F:43]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)cc1
Agent: [N-]=C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.7 %

Procedure:
Method F1 (one pot deprotection of Boc and coupling with isocyanate): Tert-butyl 4-(2-oxo-1,2-dihydropyrido[2,3-b]pyrazin-8-yloxy)phenylcarbamate (0.240 g, 0.67 mmol) is dissolved in trifluoroacetic acid (2 ml) and the solution is stirred at room temperature under Argon atmosphere for 2 h. The solvent is evaporated under reduced pressure and the resulting dark oil is dissolved in THF (3 ml) and triethylamine (1 ml). 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (0.180 g, 0.80 mmol) is added in one portion, and the solution was stirred overnight at 45 C under Ar atmosphere. The solution is then cooled and evaporated and the crude was crystallised from dichloromethane and diethyl ether to afford the title compound (15 mg, 5% yield) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH2:11])[CH2:5]2>CCCCCC.C(O)(C)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH2:11])[CH2:5]2
Reactant: NC1Cc2ccc(Br)cc2C1
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: N[C@H]1Cc2ccc(Br)cc2C1

Procedure:
2.93 g of (S)-5-bromo-indan-2-ylamine were prepared as described for the (R)enantiomer starting from 12.5 of racemic 5-bromo-indan-2-ylamine and the corresponding (1R)-(−)-campher-sulfonic acid. The enantiomeric purity was checked via chiral HPLC on a DAICEL Chiralcel OJ column (4.6×250 mm) using n-hexane:isopropanol:triethylamine (90:10:0.1) as eluent: 99% (S)-1% (R).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[N:16]([CH2:17][C:5]2=1)[CH2:15][CH2:14][CH2:13]3.ClC1C=CC2NC3CCN4C(C=3C=2C=1)CCC4.Br[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1.C(N(CC)CC)C>CCO.CCOC(C)=O>[F:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][CH2:36][N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[C:5]3[CH2:17][N:16]4[CH:12]([CH2:11][C:6]2=3)[CH2:13][CH2:14][CH2:15]4)=[CH:39][CH:40]=1
Reactant: Clc1ccc2[nH]c3c(c2c1)CN1CCCC1C3
Reactant: Fc1ccc(CCBr)cc1
Agent: Clc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN2CCCC2C3)cc1

Procedure:
A mixture of 7-chloro-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole and 10-chloro-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (non-separable regioisomers, 500 mg, 2.03 mmol, 1 equiv) and 1-(2-bromoethyl)-4-fluorobenzene (577 mg, 2.84 mmol, 1.4 equiv) were heated to 95° C. with triethyl amine (0.85 mL, 6.09 mmol, 3 equiv) in 6 mL of EtOH for 18 h. The mixture was brought to RT followed by dilution with EtOAc (40 mL), washed with water (2×10 mL), then with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography over 230-400-mesh silica gel using a gradient of MeOH in EtOAc (0 to 50%). The product was further purified by reverse phase HPLC. Column: ZORBAX SB C18, 4.6×250 mm, 5 μm, retention time (min): 9.47, purity: 80.24%;
Reaction SMILES: C1([C:7]2[C:15]3[C:10](=[CH:11][C:12](C(NS(N(C)C)(=O)=O)=O)=[CH:13][CH:14]=3)[N:9]3[CH:25](O)[C:26]4[C:31]([C:8]=23)=[CH:30][CH:29]=[C:28](OC)[CH:27]=4)CCCCC1.COP([C:41](=[CH2:46])[C:42](OC)=O)(OC)=O.[C:47](=[O:50])([O-])[O-:48].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH3:42][C:41]1[C:46]2[C:8]3=[CH:7][C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]3[CH2:25][C:26]([C:47]([OH:48])=[O:50])=[CH:27][C:28]=2[CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc2c(c1)C(O)n1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Reactant: C=C(C(=O)OC)P(=O)(OC)OC
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2c1-c1cc3ccccc3n1CC(C(=O)O)=C2
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxamide (cyclic hemiaminal) (63.0 g, 130 mmol), methyl 2-(dimethoxyphosphoryl)acrylate (60 g, 261 mmol), cesium carbonate (106 g, 326 mmol) in DMF (400 mL) was heated at 60° C. (bath temp) for 4.5 h. Additional methyl 2-(dimethoxyphosphoryl)acrylate (15 g, 65 mmol) and cesium carbonate (21.2 g, 65 mmol) were added and the reaction was heated at 60° C. overnight then and cooled to rt. The stirring reaction mixture was diluted with H2O (1 L), slowly neutralized with 1N aqueous HCl (800 mL), stirred 3 h, and then the precipitates were collected by filtration. The solids were triturated with Et2O (800 mL) and dried to yield methyl 7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid, 13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-, methyl ester (70.2 g, 127 mmol, 98%) as a yellow solid which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.09 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.08 (dd, J=2.6, 8.8 Hz, 1H), 6.98 (d, J=2.6 Hz, 1H), 5.75-5.51 (m, 1H), 4.29-4.01 (m, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.05 (s, 6H), 2.87-2.73 (m, 1H), 2.11-1.12 (m, 10H). LCMS: m/e 550 (M−H)−, ret time 3.21 min, column A, 4 minute gradient.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].Br.BrC[C:33]1[CH:38]=[CH:37][CH:36]=C[N:34]=1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][C:2]2[CH:36]=[CH:37][CH:38]=[CH:33][N:34]=2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: BrCc1ccccn1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Agent: Br
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCc2ccccn2)c1OCCC(C)c1ccc(F)cc1
Yield: 49 %

Procedure:
Example 8a (91 mg, 0.24 mmol) was reacted with 2-(bromomethyl)-pyridine hydrobromide (1.6 eq.) as described under General Procedure F and the crude mixture was purified by flash chromatography (silica gel, Et2O/hexane 1:1) to afford the title compound (55 mg, 49%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.57 (m, 1H), 7.71 (dt, J=Hz, 1.8, 7.7 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.24 (m, 1H), 7.11-7.06 (m, 2H), 6.94-6.88 (m, 2H), 5.17 (s, 2H), 3.95 (t, J=6.8 Hz, 2H) 3.86 (s, 3H), 2.93 (m, 1H), 2.45 (s, 3H), 2.20 (s, 3H), 1.97-1.91 (m, 2H), 1.20 (d, J=7.2 Hz, 3H). MS (ES+) m/z 472.2 (M+H+).
Reaction SMILES: Br[CH:2]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].N1C=CN=N1.O>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]([S:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:5])=[O:6])=[CH:2][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:15]=1
Reactant: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1
Agent: c1c[nH]nn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)C=C(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1
Yield: 73 %

Procedure:
2-Bromo-1-(4-chlorophenyl)-4,4-dimethyl-1-phenylsulfonylpentan-3-one (4.44 g) and triazole (2.76 g) were dissolved in dimethylformamide (30 ml), and the solution was refluxed for 2 hours. After cooling, it was poured into 100 ml of water and extracted with 100 ml of chloroform. The chloroform layer was washed for three times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized in n-hexane, and the crystals were collected by filtration and dried to give 2.65 g of 1-(4-chlorophenyl)-4,4-dimethyl-1-phenylsulfonyl-1-penten-3-one. m.p. 135°-136° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I.[H-].[Na+].Cl>O.O1CCCC1>[CH2:1]([O:8][C:9]([N:11]([CH3:24])[CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CCNC(=O)OCc2ccccc2)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCc1ccc(C(=O)O)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Methyl 4-(2-(benzyloxycarbonylamino)ethyl)benzoate ((3.2 g, 10.2 mmol) was added to tetrahydrofuran (34 mL) and reacted with methyl iodide (3.8 mL, 61.2 mmol), then sodium hydride (2.0 g, 51 mmol) was added batch-wise and the reaction mixture was stirred for 3 h at room temperature, and then water (1 mL) was added. The mixture was stirred at room temperature for 1 h, adjusted to pH=3 with 1N hydrochloric acid and the mixture was extracted by ethyl acetate (50 mL×3), washed by water and evaporated the solvent. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 10:1 to 2:1, acetic acid was added) to obtain 4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)benzoic acid (2.3 g, yield 72%) as yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.79-2.85 (m, 5H), 3.49 (m, 2H), 4.95-5.04 (t, J=19 Hz, 2H), 7.24-7.37 (m, 7H), 7.83-7.86 (m, 2H), 12.8 (s, 1H); LC-MS (ESI) m/z: 314 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][NH:10][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=1
Reactant: NCCc1cccc(F)c1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1cccc(F)c1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 250-mL, round-bottomed flask containing a solution of 2-(3-fluorophenyl)ethanamine (1.3 mL, 9.6 mmol) and diisopropylethylamine (1.7 mL, 9.6 mmol) in dichloromethane (32 mL) was cooled to 0° C. and treated dropwise with 4-(trifluoromethyl)benzoyl chloride (2.0 mL, 9.6 mmol) over 5 min. The ice-bath was removed after 2 h and the reaction mixture was stirred overnight. The precipitate formed was collected by filtration. The filtrate was diluted with dichloromethane (100 mL) and transferred to a separatory funnel and extracted with water (35 mL). The dichloromethane layer was separated and formation of precipitate was observed which was collected by filtration. The filtrate was concentrated to yield more solid and the combined solids were dried under vacuum to yield N-(3-fluorophenethyl)-4-(trifluoromethyl)benzamide as a white solid. MS (ESI pos. ion) m/z: 312 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[CH:8]=[C:9](I)[CH:10]=1)=[O:4].[CH:20]([N:23]1[C:27](B(O)O)=[CH:26][CH:25]=[N:24]1)([CH3:22])[CH3:21].CC([O-])=O.[K+].COCCOC>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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[CH:8]=[C:9]([C:27]2[N:23]([CH:20]([CH3:22])[CH3:21])[N:24]=[CH:25][CH:26]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cc2F)c1
Reactant: CC(C)n1nccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(C)cc2F)cc(-c2ccnn2C(C)C)c1
Temperature: 130 °C
Yield: 52.5 %

Procedure:
To a microwave vessel was added 2′-fluoro-5-iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester (1.91 g, 5.4 mmol), 2-isopropyl-2H-pyrazole-3-boronic acid (1.08 g, 7.02 mmol), KOAc (1.59 g, 16.2 mmol), Pd(PPh3)4 (0.187 g, 0.16 mmol), dimethylglycol (15 mL) and water (3 mL). The mixture was flushed with N2 before submitting to microwave heating at 130° C. for 1 hour. After cooling down to room temperature, the reaction mixture was extracted with EtOAc and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column to afford 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester as a viscous oil (1.0 g, 55.2%).