Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:13]=2[CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(Cl)cc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To a solution of [(S)-1-(6-chloro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (1.20 g, 3.23 mmol) in DCM (5 mL) was added TFA (5 mL) and the mixture stirred at RT for 3 h. The crude mixture was loaded into an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford (S)-1-(6-chloro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a yellow oil (796 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([C:27]#[N:28])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:34]1([NH2:40])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1.C(N(CC)CC)C>CN(C)C=O>[C:34]1([NH:40][C:21]([C:20]2[C:15]([NH:14][C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:29]([F:31])([F:30])[F:32])[CH:11]=3)=[O:22])=[C:16]([C:27]#[N:28])[CH:17]=[C:18]3[C:19]=2[NH:24][N:25]=[CH:26]3)=[O:23])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1
Reactant: NC1(C2CC2)CC1
Reactant: N#Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cc2cn[nH]c2c(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 500 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-9-oxo-1,9-dihydro-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalene-5-carbonitrile in 8 mL of N,N-dimethylformamide is added 218 mg (1.63 mmol) of bicyclopropyl-1-ylamine hydrochloride and 303 μL (2.18 mmol) of triethylamine. The reaction is stirred at 60° C. for 24 hours and then concentrated in vacuo. The residue is taken-up with water and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed several times with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 3:9) affords 76 mg (12% over two steps) of the product as white solid; LC/MS: 555/557 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CI.[C:18]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:18][O:13][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=1
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)phenol (47, 1.0 g, 4.35 mmol), methyl iodide (0.7 mL, 10.8 mmol) and K2CO3 (3 g, 21.75 mmol) in acetone (10 mL) was heated to reflux while stirring overnight. Solid residue was filtered off and the filtrate was concentrated on warm water bath at atmospheric pressure (Caution: product was volatile) to afford 1-methoxy-3,5-bis(trifluoromethyl)benzene (48, 0.6 g, 56%) as clear oil: 1H NMR (300 MHz, CDCl3) δ 7.46 (s, 1H), 7.30 (s, 1H), 3.90 (s, 1H).
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=O)[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>>[O:9]=[C:7]1[CH:2]2[CH:1]([CH2:6][CH2:5][CH2:4][CH2:3]2)[C:10](=[O:11])[N:12]1[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C1OC(=O)C2CCCCC12
Product: O=C(O)Cc1ccc(N2C(=O)C3CCCCC3C2=O)cc1

Procedure:
Equimolar amounts of cyclohexane-1,2-dicarboxylic acid anhydride and p-aminophenylacetic acid were reacted as described in step (a) of Example 1, yielding quantitatively 4-(1,3-dioxo-hexahydro-2-isoindolinyl)phenylacetic acid (melting point 219°-221° C.).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][O:7][CH2:8][C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=[CH:20][O:21]C)(O)[CH:10]=[CH2:11].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[F:28][C:26]([F:29])([F:27])[C:24]1[CH:23]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:25]=1)[CH2:6][O:7][CH2:8][C:9]1([CH:10]=[CH2:11])[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:19][CH2:20][O:21]1
Reactant: C=CC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1C=COC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C=CC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3,5-bis(trifluoromethyl)benzyloxy)-2-(2-(2-methoxyvinyl)phenyl)but-3-en-2-ol (190 mg, 0.426 mmol) and triethylsilane (0.27 mL, 1.7 mmol) in dichloromethane (4 mL) at −78° C. was added boron trifluoride etherate (0.11 mL, 0.85 mmol) dropwise. The ice bath was removed after 10 min, stirred at room temperature for 30 min, recooled to −78° C., and quenched by addition of saturated sodium bicarbonate. The mixture was extracted with diethyl ether (2×) which was washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (3%-->10% EtOAc/Hex) gave 125 mg (71%). 1H-NMR (CDCl3, 300 MHz) δ 7.74 (s, 1H), 7.64 (s, 2H), 7.20 (m, 2H), 7.13 (m, 2H), 6.04 (dd, J=17.1, 10.7 Hz, 1H), 5.31 (dd, J=10.7, 1.2 Hz, 1H), 5.20 (dd, J=17.4, 1.5 Hz, 1H), 4.67 (qAB, JAB=13.4 Hz, 2H), 4.04 (ddd, J=11.3, 5.5, 2.4 Hz, 1H), 3.87 (ddd, J=11.0, 11.0, 3.4 Hz, 1H), 3.79 (qAB, JAB=10.4 Hz, 2H), 3.04 (ddd, J=16.5, 11.0, 5.8 Hz, 1H), 2.64 (ddd, J=16.2, 2.7, 2.7 Hz, 1H); 13C-NMR (CDCl3, 126 MHz) δ 141.4, 139.1, 135.9, 135.2, 131.6 (q, J=33.6 Hz), 129.2, 127.3, 126.9, 126.4, 126.0, 123.5 (q, J=273 Hz), 121.4, 117.4, 80.0, 77.6, 72.2, 60.3, 29.4. Mass spec.: 439.25 (MNa)+.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15]Br.O>CO>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15][O:11][C:10]1[C:5]([NH2:4])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ncccc1O
Reactant: Fc1cccc(F)c1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ncccc1OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
At RT, 51 g of sodium methoxide (953 mmol, 1.05 equivalents) were initially charged in 1000 ml of methanol, 100 g of 2-amino-3-hydroxypyridine (908 mmol, 1 equivalent) were added and the mixture was stirred at RT for 15 min. The reaction mixture was concentrated under reduced pressure, the residue was taken up in 2500 ml of DMSO and 197 g of 2,6-difluorobenzyl bromide (953 mmol, 1.05 equivalents) were added. After 4 h at RT, the reaction mixture was poured into 20 l of water and stirred for 15 min, and the solid was filtered off. The solid was washed with 1 l of water, 100 ml of isopropanol and 500 ml of petroleum ether and dried under high vacuum. This gave 171 g of the title compound (78% of theory).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[C:18]([Br:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:9])([CH3:6])[CH3:5].Cl>C1COCC1.[OH-].[Na+].CO>[Br:20][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)=[C:10]([C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:33])=[O:2])=[O:9])[CH:19]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1cc(Br)c2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(NC(=O)c1cc(Br)c2ccccc2c1OCc1ccc(C(F)(F)F)cc1)C(=O)O

Procedure:
96 mg 2-{[4-bromo-1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester in 0.5 ml THF, 0.56 ml of 2 M sodium hydroxide and 1.4 ml methanol were reacted in a microwave at 120° C. for 6 min. The reaction was then acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, and concentrated. After purification of the residue by RP-HPLC 11 mg of 2-{[4-Bromo-1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([C@@H:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[C:19]([F:22])([F:21])[F:20])[CH3:11])[C:6]=2[CH:23]=1.C(O[C:29]([N:31]1[CH2:36][CH:35]=[C:34](B(O)O)[CH2:33][CH2:32]1)=[O:30])(C)(C)C.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.C1(C)C=CC=CC=1.C(O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:10]([N:7]2[C:6]3[CH:23]=[C:2]([C:34]4[CH2:33][CH2:32][N:31]([C:29]([C@H:32]5[CH2:33][CH2:34][CH2:35][CH2:36][NH:31]5)=[O:30])[CH2:36][CH:35]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[N:8]2)[CH3:11])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=1
Reactant: C[C@H](c1ccc(Cl)cc1C(F)(F)F)n1nnc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B(O)O)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: Cc1ccccc1
Solvent: CCO
Product: C[C@H](c1ccc(Cl)cc1C(F)(F)F)n1nnc2ccc(C3=CCN(C(=O)[C@H]4CCCCN4)CC3)cc21
Temperature: 100 °C
Yield: 162.5 %

Procedure:
A mixture of (R)-6-bromo-1-(1-(4-chloro-2-(trifluoromethyl)phenyl)ethyl)-1H-benzo[d][1,2,3]triazole (0.32 g, 0.8 mmol), (N-t-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pincol ester (0.27 g, 0.8 mmol), Pd(PPh3)4 (0.046 g, 0.039 mmol), and 2 M aqueous potassium carbonate (1.2 mL, 2.4 mmol) in 2:1 toluene/ethanol (3.6 mL) was purged with nitrogen for 5 min, and then heated at 100° C. for 2 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (15 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The resulting crude material was purified by flash chromatography (SiO2, 0-100% ethyl acetate in hexanes) to afford the desired product (0.33 g, 0.65 mmol, 83%).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([O:10][CH3:11])[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].N1CCCCC1>C(O)C>[C:13]([C:15]1[C:16](=[O:17])[NH:18][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([O:10][CH3:11])[CH2:9]2)#[N:14]
Reactant: N#CCC(N)=O
Reactant: COC1CCC(=O)C(C(C)=O)C1
Solvent: C1CCNCC1
Solvent: CCO
Product: COC1CCc2c(c(C)[nH]c(=O)c2C#N)C1
Yield: 35 %

Procedure:
1.02 g of 2-acetyl-4-methoxycyclohexanone and 0.462 g of cyanoacetamide were mixed with 5 ml of ethanol and a small amount of piperidine was added thereto. The obtained reaction mixture was heated under reflux for two hours. The crystals thus precipitated were filtered and recrystallized from methanol to give 0.42 g of 4-cyano-2,3,5,6,7,8-hexahydro-7-methoxy-1-methyl-3-oxoisoquinoline. m.p. 257°-259° C. NMRTMSCF3COOH : 2.25 (2H, m), 2.57 (3H, s), 2.97 (2H, m), 3.20 (2H, m), 3.66 (3H, s) and 4.16 (1H, m).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:23]([C:19]1[CH:18]=[C:17]([N:13]2[CH2:12][CH2:11][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:15][CH2:14]2)[CH:22]=[CH:21][N:20]=1)#[N:24]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: N#Cc1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccnc(C#N)c2)CC1
Temperature: 100 °C
Yield: 44 %

Procedure:
A mixture of tert-butyl methyl(piperidin-4-yl)carbamate (465 mg, 2.173 mmol, 1.0 eq.), 4-chloropyridine-2-carbonitrile (300 mg, 2.173 mmol, 1.0 eq.) and K2CO3 (600 mg, 4.34 mmol, 2.0 eq.) in THF (4 ml) was heated for 48 hours at 100° C. in a pressure vessel. The mixture was filtered and washed with THF (10 ml). The filtrate was concentrated and purified by column chromatography (silica gel, 1% MeOH in DCM). Yield: 44% (300 mg, 0.949 mmol)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[NH2:13][C:14]1[C:15]([CH:20]=O)=[N:16][CH:17]=[CH:18][CH:19]=1.C(OCC)(=O)C.N1CCCCC1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:10]#[N:11])=[CH:20][C:15]3[C:14](=[CH:19][CH:18]=[CH:17][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1C=O
Reactant: N#CCC(=O)c1cccc(F)c1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: N#Cc1cc2ncccc2nc1-c1cccc(F)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(3-fluorophenyl)-3-oxopropanenitrile (0.8991 g, 5.511 mmol) and 3-amino-2-pyridinecarbaldehyde (0.6730 g, 5.511 mmol) in ethyl acetate (16.70 mL, 5.511 mmol) was added piperidine (0.04360 mL, 0.4409 mmol) and the mixture was heated under reflux (bath temp. 85° C.) with stirring. After 1 h, the mixture was cooled to room temperature and concentrated under reduced pressure to give a dark brown solid. The dark brown solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc in hexane for 25 min as eluent to give 2-(3-fluorophenyl)-1,5-naphthyridine-3-carbonitrile as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.27 (1H, d, J=0.8 Hz), 9.18 (1H, dd, J=4.1, 1.8 Hz), 8.56-8.62 (1H, m), 8.01 (1H, dd, J=8.6, 3.9 Hz), 7.76-7.85 (2H, m), 7.63-7.71 (1H, m), 7.44-7.52 (1H, m); LC-MS (ESI) m/z 249.9 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]3=[C:11](I)[C:10]=2[CH:9]=1)#[N:2].[CH3:36][S:37]([O-:39])=[O:38].[Na+]>CN1C(=O)CCC1.[Cu]I>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]3=[C:11]([S:37]([CH3:36])(=[O:39])=[O:38])[C:10]=2[CH:9]=1)#[N:2]
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)c(I)c2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(S(C)(=O)=O)c2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Temperature: 125 °C
Yield: 39.1 %

Procedure:
tert-Butyl 2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (100 mg, 0.171 mmol) in NMP (2 mL) was added copper(I) iodide (162 mg, 0.853 mmol) and sodium methanesulfinate (102 mg, 0.853 mmol). The reaction mixture was heated at 125° C. under nitrogen protection for 8 h. The solid was filtered and washed with ethyl acetate. The filtrate was washed with water and dried over anhydrous Na2SO4. The solvent was evaporated and the residue was purified by column chromatography to give the title compound (36 mg). LCMS m/z=539.6 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.36 (s, 9H), 1.40 (d, J=6.0 Hz, 6H), 2.46-2.55 (m, 1H), 2.74 (dd, J=16.0, 9.0 Hz, 1H), 2.88-2.98 (m, 1H), 3.12 (s, 3H), 3.08-3.14 (dd, J=16.0, 3.6 Hz, 1H), 3.95-4.02 (m, 1H), 4.05-4.20 (m, 2H), 4.62-4.69 (m, 1H), 5.03 (s, 2H), 6.95 (dd, J=8.8, 2.4 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.59 (dd, J=8.7, 2.2 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([F:23])[C:16]=2[CH3:24])[C@H:10]1[CH3:25])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[F:23][C:17]1[C:16]([CH3:24])=[C:15]([N:11]2[C:12](=[O:14])[CH2:13][C@H:9]([OH:8])[C@@H:10]2[CH3:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: Cc1c(N2C(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2C)ccc(C#N)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)C[C@H](O)[C@@H]2C)ccc(C#N)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.5 %

Procedure:
To a solution of 4-[(2S,3S)-3-(tert-butyldimethylsilyloxy)-2-methyl-5-oxopyrrolidin-1-yl]-2-fluoro-3-methylbenzonitrile (330 mg) in THF (10 mL) was added tetrabutylammonium fluoride-THF solution (1.18 mL, 1 mol/L), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (yield: 139 mg, 62%).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1.O[Li].O.Cl>C1COCC1.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([S:5][CH2:4][C:3]([OH:13])=[O:2])=[N:7][CH:8]=1
Reactant: COC(=O)CSc1ccc(Cl)cn1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CSc1ccc(Cl)cn1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To the solution of the ester 14 (0.43 g, 2.0 mmol) in THF (18 mL) was added LiOH.H2O (0.17 g, 4 mmol) as a solution in 5 mL of H2O. The reaction mixture was stirred at room temperature and monitored by TLC. When no staring material was observed, the reaction mixture was acidified with 1N HCl, (˜4.5 mL) and concentrated under reduce pressure to remove the organic solvent. The mixture was diluted with 15 mL of H2O and extracted with EtOAc (2×120 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and dried under high vacuum over P2O5 to give 0.40 g (98% yield) of compound 15 which was used in subsequent reaction without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][C@H:13]([N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:18])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:28][N:29]1[C:33]([CH3:34])=[C:32](B2OC(C)(C)C(C)(C)O2)[C:31]([CH3:44])=[N:30]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH2:19]([N:17]([CH3:18])[C@H:13]1[CH2:14][CH2:15][C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:32]2[C:31]([CH3:44])=[N:30][N:29]([CH3:28])[C:33]=2[CH3:34])[CH2:12]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(Cc1ccccc1)[C@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
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: O
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N(C)Cc1ccccc1)C2
Reaction time: 3 h

Procedure:
(6S)-6-[Benzyl(methyl)amino]-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (5.0 g, 12.517 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (3.60 g, 15.246 mmol) and Pd(PPh3)4 (1.70 g, 1.471 mmol) were added to a solution of K2CO3 (3.31 g, 23.95 mmol) in a mixture of 1,2,-dimethoxyethane (120 mL) and H2O (15 mL). The reaction mixture was purged with N2 (g) for 10 min, and warmed up to reflux. The reaction was completed in 3 h (TLC analysis). It was allowed to reach room temperature, diluted with H2O (150 mL) and extracted with AcOEt (300 mL). The organic layer was filtered through Celite (washing with AcOEt), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-10-20% Et3N/AcOEt) to afford the desired product as a brown-colored oil. The material was dissolved in CH2Cl2 (100 mL) and acidified with HCl aqueous solution (6 N). The organic layer was discarded, and the aqueous layer was taken to pH>13 with NaOH aqueous solution (6 N). It was extracted with CH2Cl2 (3×200 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated, to give 3.67 g of the coupling product (Rf=0.3 (AcOEt), pale yellow oil, 81% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:14]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>C(Cl)Cl>[CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:14]2[CH2:20][CH2:19][CH2:18][N:17]([S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CCS(=O)(=O)Cl
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCCC2)C(C)(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Compound 314 (20 mg) and TEA (15 μL) in DCM was added ethanesulfonyl chloride (10 μL). After stirring at room temperature for 1 hour, the reaction was quenched with saturated aqueous NaHCO3. The organic phase was separated and dried over anhydrous Na2SO4. Evaporation under reduced pressure gave Compound 461. LC/MS (+ESI) m/z 476.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:5]=1.[Br:26]N1C(=O)CCC1=O.O>O1CCCC1>[Br:26][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(Br)(CCCCCc1ccc(Cl)cc1)C(=O)OCC
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
8.1 g (0.186 mol) of 55% sodium hydride in a mineral oil suspension is added in portions to a solution of 63.4 g (0.186 mol) of ethyl 7-(4-chlorophenyl)-2-ethoxycarbonylheptanoate (BM 13.861) in 500 ml of absolute tetrahydrofuran, and stirred for another 15 minutes to complete the salt formation. Then 33.1 g (0.186 mol) of N-bromosuccinimide is added and the mixture is stirred for 8 h at room temperature. Then it is poured into water, acidified, and extracted with ether. The combined extracts are washed, dried and concentrated by evaporation. The concentrate is chromatograhied with toluene on silica gel. 61.3 g (78% of theory) of ethyl 2-bromo-7-(4-chlorophenyl)-2-ethoxycarbonylheptanoate, a colorless oil, is obtained.
Reaction SMILES: [C:1]1([C:7]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd].C(O)C>[C:1]1([C:7]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)C(O)(C=Cc1ccccc1)c1ccccc1

Procedure:
Ethyl α-phenyl-α-phenylethynylglycolate (5.6 g., 0.02 mole) in 50 ml. of absolute ethanol, 0.2 g. of palladium on barium sulfate and a drop of quinoline were placed in a Parr shaker under 40 psi of hydrogen at room temperature. The required amount of hydrogen was taken up in 13 minutes. The catalyst was filtered and the filtrate stripped of ethanol in vacuo to yield 5.7 g. (100%) of crude product. Both n.m.r. and infrared spectroscopy confirmed the structure. The material was distilled to yield 4.1 g. of liquid, b.p. 130°-43° (0.16 mm.). N.m.r. analysis of the distilled material indicated that about 5 mole % of the fully saturated derivative was present as an impurity.