Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:22]=[CH:21][C:10]2[C@:11]3([CH3:20])[C@@H:16]([CH2:17][CH2:18][C:9]=2[CH:8]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3.[C:23](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:23][N:15]1[C@H:16]2[C@@:11]([CH3:20])([C:10]3[CH:21]=[CH:22][C:7]([C:6]4[CH:5]=[CH:4][S:3][C:2]=4[CH3:1])=[CH:8][C:9]=3[CH2:18][CH2:17]2)[CH2:12][CH2:13][C:14]1=[O:19]
Reactant: Cc1sccc1-c1ccc2c(c1)CC[C@H]1NC(=O)CC[C@]21C
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: Cc1sccc1-c1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C
Temperature: 25 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-methylthiophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (55 mg, 0.16 mmol), 0.4 mL of t-butanol, and potassium t-butoxide (55 mg, 0.48 mmol). Methyl iodide (0.031 mL, 0.48 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 15 mg (26%) of the title compound as an oil. FDMS: m/e=351.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Na].[SH:11][C:12]1[N:13]=[N:14][NH:15][CH:16]=1>CN(C)C=O>[NH:15]1[CH:16]=[C:12]([S:11][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[N:13]=[N:14]1
Reactant: Sc1c[nH]nn1
Reactant: N#Cc1ccc(F)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2c[nH]nn2)cc1
Temperature: 125 °C
Yield: 83.2 %

Procedure:
To 4-fluorobenzonitrile (6.1 g) in dry N,N-dimethylformamide (50 mL), under nitrogen, was added 4-mercapto-1,2,3-triazole sodium salt (6.2 g), and the stirred mixture heated in an oil bath at 125° C. for 18 h. The mixture was cooled to room temperature, and most of the solvent stripped at reduced pressure. The residue was partitioned between ethyl acetate and water, the organic phase washed with water, brine, then dried (sodium sulphate), and solvent stripped at reduced pressure. The residue was azeotroped with toluene, and the resulting solid triturated with isohexane, collected by filtration, washed with cold toluene, then isohexane, and dried in vacuo to give the title compound as a yellow solid (8.4 g). 1H NMR (360 MHz, CDCl3) δ 12.45 (1H, br s), 7.92 (1H, s), 7.51 (2H, d, J=8.5 Hz), 7.22 (2H, d, J=8.5 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COc1ccnc(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccnc(-c2ccc(Cl)cc2)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 72.9 %

Procedure:
To a suspension of 2-bromo-4-methoxypyridine (1.21 g), 4-chlorophenylboronic acid (1.21 g) and tetrakis(triphenylphosphine)-palladium (372 mg) in 1,2-dimethoxyethane (20 ml) was added 2M aqueous solution of sodium carbonate (7.74 ml). The mixture was stirred at 80° C. for 12 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. 2-Propanol was added to the residue. The precipitate was collected by filtration and dried under reduced pressure to give 4-(4-methoxypyridin-2-yl)-chlorobenzene (1.03 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:18]=[C:17](Br)[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[C:7]=1[OH:26])=[O:5])[CH3:2].[C:27]([Cu])#[N:28]>>[CH2:1]([O:3][C:4]([C:6]1[N:18]=[C:17]([C:27]#[N:28])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[C:7]=1[OH:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c3ccccc3n(-c3ccccc3)c2c1O
Reactant: N#C[Cu]
Product: CCOC(=O)c1nc(C#N)c2c3ccccc3n(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to that of Example 105(a) from 1-bromo-4-hydroxy-5-phenyl-5H-pyrido[4,3-b]indole-3-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 358 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([C:14]([N:35]1[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]1)=[O:16])([CH3:17])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: CN1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCN(C)CC1)O2
Yield: 83.4 %

Procedure:
Following the amide coupling procedure described in protocol A, 502 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.01 mmol), 354 mg CDI (2.18 mmol) and 220 mg N-methylpiprazine (2.2 mmol) produced 557 mg of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-methylpiperazin-1-yl)methanone as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]([CH2:17][CH3:18])[S:15][C:14](=[O:19])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(C(=O)C(Br)CC)C=CC=1OC.[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1)([O-:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43][N:13]2[N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:16]([CH2:17][CH3:18])[S:15][C:14]2=[O:19])=[CH:41][CH:40]=1)([O-:38])=[O:37]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CCC1SC(=O)NN=C1c1ccc(OC)c(OC)c1
Agent: CCC(Br)C(=O)c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1SC(=O)N(Cc2ccc([N+](=O)[O-])cc2)N=C1c1ccc(OC)c(OC)c1

Procedure:
A solution of 2.8 g of 5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one ("A") [obtainable by reacting 1-(3,4-dimethoxyphenyl)-2-bromobutan-1-one with methyl hydrazinethioformate] in 150 ml of acetone is boiled with 3 g of 4-nitrobenzyl chloride in the presence of 4 g of potassium carbonate for eight hours. The insoluble residue is filtered off and the solution is concentrated. The residue is worked up in the conventional manner to give 3-(4-nitrobenzyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[C:11]([N:13]([CH3:15])[CH3:14])[NH:12][C:4]=2[CH:3]=1.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:14][N:13]([CH3:15])[C:11]1[NH:12][C:4]2[CH:3]=[C:2]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:16][CH3:17])=[C:20]([C:28]([F:29])([F:31])[F:30])[CH:21]=3)[N:7]=[C:6]([C:8]#[N:9])[C:5]=2[N:10]=1
Reactant: CCOc1ccc(B(O)O)cc1C(F)(F)F
Reactant: CN(C)c1nc2c(C#N)nc(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1ccc(-c2cc3[nH]c(N(C)C)nc3c(C#N)n2)cc1C(F)(F)F
Temperature: 130 °C
Yield: 3 %

Procedure:
A suspension of 6-chloro-2-dimethylamino-1H-imidazo[4,5-c]pyridine-4-carbonitrile (100 mg, 0.45 mmol), 4-ethoxy-3-trifluoromethyl-phenyl boronic acid (198 mg, 0.88 mmol) tetrakis(triphenylphosphine)palladium(0) (50 mg, ˜10 mol %) and potassium carbonate (193.0 mg, 1.39 mmol) in THF (3 ml) was heated to 130° C. for 6 minutes in the “Smith” microwave. The crude mixture was concentrated under reduced pressure to remove THF before partitioning between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The material was then dissolved in DMSO and purified in aliquots by preparative HPLC. The desired fractions were collected and concentrated to give a white solid which was washed with ether to afford 2-dimethylamino-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (5.0 mg)
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([CH2:13][C:14]1[C:15]([C:24]2(Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:16][O:17][C:18]=1[C:19](OCC)=[O:20])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].COC1C=C(OC)C=CC=1CN(CC1C(C2CCCCC=2)=NOC=1C(OCC)=O)CC(OCC)=O.CC(C)([O-])C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[CH2:11]([O:10][C:8]([C:7]1[N:6]=[CH:13][C:14]2[C:15]([C:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=3)=[N:16][O:17][C:18]=2[C:19]=1[OH:20])=[O:9])[CH3:12]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(C2(Br)CCCCC2)noc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(C2=CCCCC2)noc1C(=O)OCC
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2c(C3=CCCCC3)noc2c1O
Temperature: -78 °C
Reaction time: 14 h

Procedure:
The above mixture of ethyl 4-(((2,4-dimethoxybenzyl)(2-ethoxy-2-oxoethyl)amino)-methyl)-3-(1-bromo-cyclohexyl)-isoxazole-5-carboxylate and ethyl 4-(((2,4-dimethoxybenzyl)(2-ethoxy-2-oxoethyl)amino)methyl)-3-(1-cyclohexenyl)-isoxazole-5-carboxylate was dissolved in 40 mL of THF and cooled to −78° C. Potassium tert-butoxide solution (6.9 mL, 6.9 mmol, 1M in THF) was added dropwise, and the mixture was stirred for 14 hours, the cold bath allowed to evaporate spontaneously. The reaction mixture was cooled in an ice bath and quenched with 20 mL of 1M HCl. The product was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated to give 0.8 g of crude oil. The crude intermediate was dissolved in 12 mL of CH2Cl2. Thionyl chloride (0.2 mL, 2.73 mmol) was added and the reaction mixture was stirred for 5 h at ambient temperature. The volatiles were evaporated and the residue was partitioned between CH2Cl2 (50 mL) and saturated sodium bicarbonate solution (50 mL). To the vigorously stirring biphasic mixture was added 4M hydrochloric acid until pH was 2. The aqueous layer was extracted with additional CH2Cl2 and the combined organic layer was dried over MgSO4 and concentrated. The crude residue was purified by chromatography (0-100% CH2Cl2/hexanes) to give 210 mg of the title compound. MS: (+) m/z 289.30 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[CH2:37]CC[N:34]([CH2:38]C(O)=O)[C:33]2=O)=[CH:28][CH:27]=1.FC1C=CC(C2(C3C=CC(F)=CC=3)CCNC2)=CC=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[F:49][C:46]1[CH:47]=[CH:48][C:43]([C:32]2([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[CH2:37][CH2:38][N:34]([C:14](=[O:16])[CH2:13][N:10]3[CH2:11][CH2:12][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[C:9]3=[O:17])[CH2:33]2)=[CH:44][CH:45]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: Fc1ccc(C2(c3ccc(F)cc3)CCNC2)cc1
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 58D for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 3,3-bis(4-fluorophenyl)pyrrolidine from Example 203A for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.38-7.28 (m, 4H), 7.18-7.09 (m, 4H), 7.03-6.93 (m, 8H), 4.11 (dd, J=5.1, 9.1, 4H), 3.61-3.48 (m, 3H), 3.42 (t, J=6.7, 1H), 2.77 (dd, J=6.4, 11.7, 2H), 2.57 (t, J=6.7, 1H), 2.47 (t, J=6.9, 1H); MS (DCI) m/z 573.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[N:5][CH:4]=1.CS(O[CH2:18][C:19]1[O:20][C:21]2[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=2[C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)=O>CN(C=O)C>[C:24]1([C:23]2[C:22]3[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=3[O:20][C:19]=2[CH2:18][N:7]2[CH:8]=[N:9][C:10]3[C:6]2=[N:5][CH:4]=[N:3][C:11]=3[NH2:12])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ncnc2[nH]cnc12
Reactant: CS(=O)(=O)OCc1oc2ccccc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1oc2ccccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of NaH (60% in mineral oil, 18 mg, 0.43 mmol) in DMF (5 mL) at 0° C. was added 9H-purin-6-ylamine (54 mg, 0.397 mmol). After 5 min stirring at 0° C., a solution of methanesulfonic acid 3-phenylbenzofuran-2-ylmethyl ester from Example 25 (100 mg, 0.331 mmol) in DMF (1 mL) was added dropwise and the mixture was slowly warmed to RT and stirred at RT for 2.5 h. The reaction mixture was then quenched by addition of water and diluted with DCM. The organic layer was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) and triturated form EtOAc with cyclohexane affording 163 as an off-white solid (33 mg, 29%). LCMS: RT 3.85 min [M+H]+ 342.1. 1H NMR (DMSO, 400 MHz): δ 8.21 (1H, s), 8.11 (1H, s), 7.79-7.74 (2H, m), 7.63-7.53 (4H, m), 7.50-7.44 (1H, m), 7.38-7.27 (2H, m), 7.23 (2H, s), 5.65 (2H, s)
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][CH:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1C.Cl[S:43]([OH:46])(=[O:45])=[O:44]>ClCCl>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][N:11]1[S:43]([OH:46])(=[O:45])=[O:44])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCC2CC(SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: Cc1ccccn1
Solvent: ClCCl
Product: O=S(=O)(O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine (0.435 g) in dichloromethane (30.0 ml) was treated with 2-picoline (2.11 ml) and chlorosulphonic acid (0.186 ml). The reaction mixture was stirred for 5 h at room temperature and evaporated to dryness. The residue was quenched with ice/water and extracted with EtOAc. The aqueous layer was saturated with sodium chloride and acidified with 1 molar HCl to pH 3.4 and extracted again with EtOAc. The organic phase was washed with brine, dried over magnesium sulphate and concentrated to obtain (2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-sulfonic acid (0.26 g) as an oil, MS: 544 (M−H)−.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C([O-])([O-])=O.[Na+].[Na+].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:6][C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
To a stirring solution of L-leucine methyl ester hydrochloride (2.0 g, 11.0 mmol) in 1,4-dioxane (20 mL) was added Na2CO3 (12.1 ml, 2M in water) followed by benzylchloroformate (1.96 g, 11.5 mmol). The mixture was stirred at room temperature for 4 h then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a colorless oil (3.1 g, 100%). 1H NMR (400 MHz, CDCl3) δ7.34 (m, 5H), 5.27 (d, 1H), 5.12 (s, 2H), 4.41 (s, 2H), 3.75 (s, 3H), 1.65 (m, 3H), 0.96 (m, 6H).
Reaction SMILES: Cl.[CH2:2]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][NH:3]1.[N:18]1[N:19]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[C:28](=O)[CH2:27][CH2:26]3)[N:20]=[CH:21][CH:22]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[N:18]1[N:19]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[C@H:28]([N:3]2[CH2:4][C:5]4([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]4)[CH2:2]2)[CH2:27][CH2:26]3)[N:20]=[CH:21][CH:22]=1
Reactant: O=C1CCc2cc(-n3nccn3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-n4nccn4)ccc31)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
To a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (4.35 g. 16.6 mmol) and 5-(2H-1,2,3-triazol-2-yl)indan-1-one (SM-1h, 3.3 g, 16.6 mmol) in dichloromethane (50 mL) was added triethylamine (6.94 mL, 49.7 mmol) followed by titanium(IV) isopropoxide (9.81 mL, 33.1 mmol). The reaction was stirred at room temperature overnight and sodium triacetoxyborohydride (4.21 g, 19.8 mmol) was added. After stirring for 4 days, the reaction was quenched with saturated ammonium chloride. The mixture was diluted with 50 mL of dichloromethane and 50 mL water and filtered through a Celite® pad. The aqueous layer was extracted with dichloromethane (30 mL×2). The combined organic layers were washed with brine and dried over MgSO4. The solvent was concentrated and the crude material was chromatographed on a Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) using an EtOAc/heptanes gradient. The enantiomers were separated via preparative chiral HPLC (Chiralcel OD-H, 250 mm×30 mm, flow-rate—100 g/min, 65/35 CO2/MeOH, with 0.1% IPA) to afford tert-butyl 2-((R)-5-(2H-1,2,3-triazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (6-1a, 1.58 g, 23%) as a white solid. MS (ES+) 410.5 (M+H)+. 1H NMR (CD3OD) δ 1.42 (s, 9H), 1.70-1.73 (m, 4H), 1.92-2.02 (m, 1H), 2.23-2.27 (m, 1H), 2.89-2.92 (m, 2H), 3.09-3.14 (m, 2H), 3.23-3.30 (m, 3H), 3.32-3.36 (m, 3H), 4.02-4.05 (m, 1H), 7.45 (d, 1H), 7.87 (s, 2H), 7.89-7.93 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.C1N2CCN(CC2)C1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[S:27]>CN(C=O)C>[CH3:24][N:25]([CH3:29])[C:26]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2)=[S:27]
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(OC(=S)N(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of methyl 6-hydroxy-2-naphthoate [J. Med. Chem., 2001, 44, 2869-2878] (156) (5.95 g, 29.4 mmol), DABCO (6.61 g, 58.9 mmol) and dimethylthiocarbamoyl chloride (5.46 g, 44.2 mmol) in dry DMF (40 mL) was stirred at room temperature for 8 h. The precipitated solid was collected, washed with water and dissolved in CH2Cl2. The solution was filtered through a column of silica gel and the product was triturated with i-Pr2O and recrystallised from CH2Cl2/hexane to give methyl 6-{[(dimethylamino)carbothioyl]oxy}-2-naphthoate (157) (7.47 g, 88%) as a white solid: mp 144-147° C.; 1H NMR [(CD3)2SO] δ 8.66 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 8.00 (dd, J=−8.6, 1.5 Hz, 1H), 7.70 (d, J=−2.3 Hz, 1H), 7.389 (dd, J=8.9, 2.3 Hz, 1H), 3.93 (s, 3H), 3.40 (s, 3H), 3.38 (s, 3H). Anal. (C15H15NO3S) C, H, N.
Reaction SMILES: [CH3:1][NH2:2].Cl.C[Al](C)C.CO[C:10](=[O:30])[CH2:11][CH:12]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C1C=CC=CC=1>[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([CH:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[CH2:11][C:10]([NH:2][CH3:1])=[O:30])[CH:29]=2)[CH:25]=[CH:26]1
Reactant: CN
Reactant: COC(=O)CC(c1ccc(OC)cc1)c1ccc2cc[nH]c2c1
Agent: C[Al](C)C
Agent: Cl
Solvent: c1ccccc1
Product: CNC(=O)CC(c1ccc(OC)cc1)c1ccc2cc[nH]c2c1
Temperature: 5 °C
Yield: 79 %

Procedure:
To a 5° C. stirring suspension of MeNH2.HCl (220 mg, 3.2 mmol) in benzene (3 ml) was added dropwise Me3Al (2 M in toluene, 1.6 ml, 3.2 mmol). The mixture was stirred at room temperature for 45 minutes. A solution of 3-(1H-indol-6-yl)-3-(4-methoxy-phenyl)-propionic acid methyl ester XXXIV (480 mg, 1.6 mmol) in benzene (15 ml) was added and the resulting mixture was stirred at reflux for 3 hours. The reaction mixture was cooled to room temperature and additional mixture of MeNH2.HCl (110 mg, 1.6 mmol) in benzene (1.5 ml) and Me3Al (2M in toluene, 0.8 ml, 1.6 mmol) was added. The resulting mixture was stirred at reflux for 1.5 hours, cooled to room temperature, and the reaction was quenched by slow addition of HCl (1M, 35 ml). The mixture was stirred vigorously for 5 minutes and extracted with EtOAc (50 ml). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, concentrated and purified via flash chromatography (hexane/EtOAc) to provide 3-(1H-indol-6-yl)-3-(4-methoxy-phenyl)-N-methyl-propionamide XXXV (390 mg, 81% yield) as a white solid.
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(Cl)Cl.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:30]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)[N:29]([C:44](Cl)=[O:45])[CH2:28][CH2:27]2>O>[CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH:7][C:44]([N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=2)[CH:30]1[C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)=[O:45])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2c3cc(OC)c(OC)cc3CCN2C(=O)Cl)cc1
Reactant: CC(C)N(CCN)C(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2c3cc(OC)c(OC)cc3CCN2C(=O)NCCN(C(C)C)C(C)C)cc1
Reaction time: 4 h

Procedure:
To a mixture of 2.5 parts of 2-diisopropylaminoethylamine and 12 parts of triethylamine in approximately 225 parts of chloroform is added portionwise, at room temperature, a solution of 5.0 parts of 6,7-dimethoxy-1-(4-methoxyphenyl)-3,4-dihydro-2(1H)-isoquinolinecarbonyl chloride in about 75 parts of chloroform. The reaction mixture is stirred for 3 to 5 hours, allowed to stand overnight and then poured into water. The chloroform layer is separated, dried over anhydrous calcium sulfate and stripped of solvent under reduced pressure. The resultant oil is triturated with n-hexane to give a solid. Crystallization of that solid from ethyl ether affords N-(2-diisopropylaminoethyl)-6,7-dimethoxy-1-(4-methoxyphenyl)-3,4-dihydro-2(1H)-isoquinolinecarboxamide as a low melting solid. That compound is characterized by infrared absorption maxima in chloroform at about 1640 and 3400 cm-1.