Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>CN(C)C=O>[CH3:3][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]([NH:34][C:35]4[NH:39][N:38]=[N:37][N:36]=4)=[O:18])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:1]
Reactant: CC(C)c1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1
Temperature: 105 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
2.88 g (0.01 mol) of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-7-carboxylic acid (Example 18) and 3.31 g (0.02 mol) of 1,1' carbonyldiimidazole (Aldrich Chemical Company) in 100 ml of dimethylformamide are stirred and heated in a wax bath at 105° C. for ninety minutes under nitrogen. The mixture is cooled and stirred at room temperature for thirty minutes and 1.03 g (0.01 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) is added and the resulting mixture is stirred and heated at 105° C. for one hundred thirty-five minutes under nitrogen. The mixture is allowed to stand overnight at room temperature, the precipitate is filtered and the filtrate is evaporated in vacuo. The residue is slurried in boiling methanol, the mixture cooled and filtered. This precipitate is combined with the previous precipitate to give 1.8 g of 2-(1-methylethyl)-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7 -carboxamide; mp 307° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[Li]CCCC.[O:28]1[CH2:31][C:30](=[O:32])[CH2:29]1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:30]3([OH:32])[CH2:31][O:28][CH2:29]3)[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: O=C1COC1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2nc3c(N4CCOCC4)nc(Cl)nc3n2C2CCCCO2)COC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a mixture of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (2.9 g, 9 mmol) in THF (50 mL) at −78° C. was added 2.5 M of n-BuLi (9 mL, 22 mmol) dropwise. The reaction was stirred at −78° C. for 30 minutes and then 3-oxetanone (1.3 mL, 18 mmol) was added, continue stirred for 2 hours at −78° C. The reaction was quenched with water and extracted with EtOAc. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The crude material was purified by Isco chromatography with 0-100% EtOAc/hexane to give pure 3-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)oxetan-3-ol as a white solid (2.5 g, 70% yield). LC/MS (ESI+): m/z 397 (M+H)
Reaction SMILES: [O:1]=[C:2]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)([OH:10])[CH2:6][CH2:5]1.[BH4-].[Na+].CO>O>[OH:1][CH:2]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)([OH:10])[CH2:6][CH2:5]1
Reactant: O=C(COc1ccc(F)cc1)CN1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(COc1ccc(F)cc1)CN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.9 g of 1-[2-oxo-3-(p-fluorophenoxy)propyl]-4-(p-chlorophenyl)-4-hydroxypiperidine, 0.38 g of sodium borohydride and 20 ml of methanol is stirred at room temperature for 3 hours. The resulting mixture is diluted with water and extracted with chloroform. The organic layer is dried over sodium sulfate and evaporated under reduced pressure to give 1-[2-hydroxy-3-(p-fluorophenoxy)propyl]-4-(p-chlorophenyl)-4-hydroxypiperidine, M.P. 103° to 105°C. Recrystallization from benzene-cyclohexane gives white crystals, M.P. 107° to 108°C.
Reaction SMILES: C1(NC(N)=S)C=CC=CC=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([S:30]([NH:33][CH:34]2[CH2:38][CH2:37][O:36][NH:35]2)(=[O:32])=[O:31])[C:24]=1[OH:39])=[S:21].[Si:40](Cl)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41].N1C=CN=C1>>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([S:30]([NH:33][CH:34]2[CH2:38][CH2:37][O:36][NH:35]2)(=[O:31])=[O:32])[C:24]=1[O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])=[S:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=S(=O)(NC1CCON1)c1c(Cl)ccc(NC(=S)Nc2cccc(Cl)c2Cl)c1O
Agent: NC(=S)Nc1ccccc1
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1c(NC(=S)Nc2cccc(Cl)c2Cl)ccc(Cl)c1S(=O)(=O)NC1CCON1
Yield: 49.3 %

Procedure:
Following the general procedure for protected phenyl thiourea formation outlined in example 1, N-(2,3-dichlorophenyl)-N′-[4-chloro-2-hydroxy-3-(N″-tetrahydroisoxazylaminosulfonyl)phenyl]thiourea (898 mg, 1.81 mmol), tert-butyldimethylsilyl chloride (1.4 g, 9.05 mmol) and imidazole (246 mg, 3.62 mmol) were reacted to form the desired product (546 mg, 49%). EI-MS m/z 611.81 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=1[O-:17].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=1[O-:17])=[O:26]
Reactant: [O-][n+]1ccccc1SCc1ccc(Cl)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(Cc1ccc(Cl)cc1Cl)c1cccc[n+]1[O-]

Procedure:
The procedure employed is identical to that of Example 68 using 5.8 gm (0.02 mol) 2-(2,4-Dichlorophenylmethylthio)pyridine N-oxide in 50 ml of chloroform and 4 gm (0.02 mol) MCPBA in 100 ml of chloroform.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br>CN(C=O)C.O>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: c1ccc2[nH]nnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Cn2nnc3ccccc32)c1
Reaction time: 0.42 h

Procedure:
To a solution of benzotriazole (3 g) in DMF (38 mL) at r.t. was added a solution of 10N NaOH (2.75 mL). After stirring for 25 min., 3-trifluoromethylbenzyl bromide (4.39 mL) was added. The mixture was further stirred for 30 min., diluted with H2O, and extracted with EtOAc. The EtOAc extract was washed brine (2×), water, brine, dried (MgSO4) and concentrated. The residue was stirred in diethyl ether/hexane to afford 3.96 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=[C:17]([Cl:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:21]([C:20]2[C:2]([Cl:1])=[C:3]([C:17]([Cl:24])=[CH:18][CH:19]=2)[CH2:4][O:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]3)=[O:22])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)O)c3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A suspension of 8-(2,6-dichloro-3-carboxybenzyloxy)-2-methylquinoline (200 mg), 1-(tert-butoxycarbonyl)piperazine (109 mg), 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (127 mg) and 1-hydroxybenzotriazole (104 mg) in N,N-dimethylformamide (2 ml) was stirred for 2 hours at ambient temperature. To the reaction mixture was added saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (n-hexane-ethyl acetate) to give 8-[3-[4-(tert-butoxycarbonyl)piperazine-1-carbonyl]-2,6-dichlorobenzyloxy]-2-methylquinoline (270 mg) as colorless amorphous.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][N:8]1[CH2:13][C:12]2[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=O)[CH:16]=[N:17][C:11]=2[NH:10][C:9]1=[O:23])=[O:6])[CH3:3].Cl.[CH3:25][N:26]1[CH2:32][C:31]2[CH:33]=[C:34](/[CH:37]=[CH:38]/[C:39](O)=O)C=N[C:30]=2[NH:29][C:28](=O)[CH2:27]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[CH2:2]([O:4][C:5](=[O:6])[CH2:7][N:8]1[CH2:13][C:12]2[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20](=[O:22])[N:29]([CH3:30])[CH2:28][C:27]3[N:26]([CH3:25])[C:32]4[C:38]([CH:39]=3)=[CH:37][CH:34]=[CH:33][CH:31]=4)[CH:16]=[N:17][C:11]=2[NH:10][C:9]1=[O:23])[CH3:3]
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CCOC(=O)CN1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CCOC(=O)CN1Cc2cc(/C=C/C(=O)N(C)Cc3cc4ccccc4n3C)cnc2NC1=O
Yield: 89 %

Procedure:
According to the procedure of Example 1 (a), except substituting (E)-3-(3-ethoxycarbonylmethyl-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (1.20 g, 89%) was prepared as a tan solid and as a mixture of amide rotomers: 1H NMR (300 MHz, CDCl3) δ 8.34-8.28 (m, 1H), 7.66-7.34 (m, 2H), 7.60-7.53 (m, 2H), 7.33-7.21 (m, 2H), 7.11 (t, J=7.5 Hz, 1H), 6.83 (d, J=15.0 Hz, 1H), 6.50-6.40 (m, 1H), 4.93-4.30 (m, 2H), 4.59-4.52 (m, 2H), 4.27-4.19 (m, 4H), 3.71 (s, 3H), 3.13-3.06 (m, 3H), 1.30 (t, J=7.2 Hz, 3H); MS (ESI) m/e 462 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][O:29][CH2:30][CH2:31][N:32]([CH3:37])[CH:33]([CH3:36])[C:34]#[CH:35]>>[CH3:28][O:29][CH2:30][CH2:31][N:32]([CH3:37])[CH:33]([CH3:36])[C:34]#[C:35][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:27])[F:26])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Reactant: C#CC(C)N(C)CCOC
Product: COCCN(C)C(C)C#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and (2-Methoxy-ethyl)-methyl-(1-methyl-prop-2-ynyl)-amine were converted to yield (2-Methoxy-ethyl)-methyl-{1-methyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amine as brown oil, MS: 419 (MH+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([CH2:10][I:11])[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2].C[C:22](OC(C)=O)=[O:23].N1C=CC=C[CH:29]=1>>[CH3:19][C:18]1[C:16](=[O:17])[NH:15][C:13](=[O:14])[N:12]([C@@H:7]2[O:8][C@:9]([C:10]#[CH:29])([CH2:22][OH:23])[CH:5]=[CH:6]2)[CH:20]=1.[C:1]([O:4][C@H:5]1[C@@H:9]([CH2:10][I:11])[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)O[C@@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CI
Product: C#C[C@@]1(CO)C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
TKD-4-114 (2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine, 4′-ethynyl-d4T) was synthesized by a series of reactions shown in Scheme B, starting from compound 6 which was prepared according to the published procedure: B. V. Joshi and C. B. Reese, Tetrahedron Lett., 32, 2371-2374 (1992). 1-(3-O-Acetyl-2,5-dideoxy-5-iodo-β-D-threo-pentofuranosyl)-thymine (7) A mixture of 6 (5.3 g, 15.05 mmol) and Ac2O (4.3 mL, 45.15 mmol) in pyridine (30 mL) was stirred at room temperature for 13 h. The reaction mixture was partitioned between CHCl3/saturated aqueous NaHCO3 (250 mL×3/50 mL). Silica gel column chromatography (hexane/EtOAc=1/1-1/2) of the organic layer gave 7 (5.53 g, 93%) as a foam: 1H NMR (CDCl3) δ 1.96 (3H, s, Me), 2.11 (3H, s, Ac), 2.11-2.16 (1H, m, H-2′a), 2.82 (1H, ddd, Jgem=15.8 Hz, J1′,2′b=8.0 Hz and J2′b,3′=5.7 Hz, H-2′b), 3.32-3.39 (2H, m, H-5′), 4.28 (1H, dt, J3′,4′=3.3 Hz and J4′,5′=7.1 Hz, H-4′), 5.48 (1H, dd, J2′b,3′=5.7 Hz and J3′,4′=3.3 Hz H-3′), 6.30 (1H, dd, J1′,2′a=2.8 Hz and J1′,2′b=8.0 Hz, H-1′), 7.38 (1H, d, J6,Me=0.7 Hz, H-6), 8.59 (1H, br, NH); FAB-MS m/z 395 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:10])=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1>C(O)C.C(Cl)Cl>[Cl:11][C:12]1[N:17]=[C:16]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=2[CH3:10])[CH:15]=[CH:14][N:13]=1
Reactant: COc1cccc(N)c1C
Reactant: Clc1ccnc(Cl)n1
Solvent: ClCCl
Solvent: CCO
Product: COc1cccc(Nc2ccnc(Cl)n2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 6.8 %

Procedure:
A mixture of 3-methoxy-2-methyl-phenylamine (0.68 g, 5 mmol) and 2,4-dichloro-pyrimidine (0.74 g, 5 mmol) were suspended in ethyl alcohol (10 mL) and stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (50 mL), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.085 g, 7%) as yellow solids.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+:13]>CCO.O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O-:6])=[O:5].[Na+:13]
Reactant: O=C(O)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 2,6-difluorobenzoic acid (1.00 g, 6.3 mmol) in EtOH and water (5:1, 60 mL) was added 1N aqueous sodium hydroxide solution (6.33 mL, 6.3 mmol). The reaction mixture was stirred for 10 minutes at room temperature and then solvents were removed in vacuo to yield sodium 2,6-difluorobenzoate (1.22 g, 6.3 mmol, quantitative) as an off white solid. 1H NMR (DMSO) δ 6.89 (2H, m), 7.15 (1H, m).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:6][CH2:5]1.[H-].[Na+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C=O)C>[O:18]=[C:10]1[C:7]2([CH2:8][CH2:9][N:4]([CH2:3][C:2]([F:1])([F:19])[F:20])[CH2:5][CH2:6]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]1[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: O=C1Nc2ccccc2C12CCN(CC(F)(F)F)CC2
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C2(CCN(CC(F)(F)F)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidin]-2-one from Step A (3.30 g, 11.6 mmol) in DMF (10 mL) was added sodium hydride (697 mg of a 60% dispersion in mineral oil, 17.4 mmol) at 0° C. The mixture was stirred at 0° C. for 45 min, then tert-butyl bromoacetate (1.88 mL, 12.8 mmol) was added and stirring was continued at room temperature for 72 h. The reaction mixture was quenched with H2O. The aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined CH2Cl2 layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 80:20, to provide the title compound. MS: m/z=399 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:12])[CH:10]=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:22][C:23]1([C:29]([O:31][CH3:32])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[C:16]([O:15][C:14]([NH:13][C:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)([CH3:12])[CH2:10][NH:22][C:23]1([C:29]([O:31][CH3:32])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1cc(F)cc(F)c1
Reactant: COC(=O)C1(N)CCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1(NCC(C)(NC(=O)OC(C)(C)C)c2cc(F)cc(F)c2)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl [1-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate from Step C (500 mg, 1.75 mmol), methyl 1-aminocyclohexanecarboxylate hydrochloride from Step D (1.38 g, 8.76 mmol), and AcOH (0.301 mL, 5.26 mmol) in MeOH (15 mL) was stirred at ambient temperature for 30 min. NaCNBH3 (165 mg, 2.63 mmol) was added and the pH of the mixture was checked and adjusted to pH ˜5 as necessary by addition of AcOH. The reaction mixture was stirred at ambient temperature for 1 h, then quenched with saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=427 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1.C([Li])CCC.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>CCOCC.CCCCCC>[CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21])=[N:3]1
Reactant: CC1(C)COC(c2cccs2)=N1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccsc1C1=NC(C)(C)CO1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4.5 g of 4,5-dihydro-4,4-dimethyl-2-(2-thienyl)-oxazole in 200 ml of anhydrous ether at -70° C. is added 11 ml of a 2.5M solution of n-butyl lithium in hexane, dropwise under a nitrogen atmosphere. The reaction mixture is stirred at -78° C. for 45 minutes and 8.3 g of tri-n-butyltin chloride in dry ether added dropwise. The reaction mixture is stirred at room temperature for 1 hour and quenched with water. The reaction mixture is extracted with ether, washed with water, dried over sodium sulfate and concentrated in vacuo to an oily residue.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]=[C:7]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1.[OH-].[Na+]>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC1=CCCc2c(F)cccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCOC(=O)Cc1cccc2c(F)cccc12
Yield: 34.8 %

Procedure:
To a solution of ethyl (5-fluoro-3,4-dihydronaphthalen-1-yl)acetate (16.4 g) in benzene (500 mL) was DDQ (2,3-dichloro-5,6-dicyanobenzoquinone)(21.5 g), and the mixture was stirred with heating for 3 hr. After cooling, the precipitated solid was dissolved in 1N sodium hydroxide, and the mixture was extracted with toluene. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give ethyl (5-fluoronaphthalen-1-yl)acetate (5.66 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:23][CH2:22][CH2:21][CH2:20][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)c1cc2ccccc2n1CCCCl
Temperature: 60 °C
Reaction time: 16 h
Yield: 104.7 %

Procedure:
To a cold solution of tert-butyl 1H-indole-2-carboxylate (1.15 g, 4.94 mmol, 1 equiv) in dimthylformamide sodium hydride (60% dispersion) (237 mg, 5.92 mmol, 1.2 equiv) was added and the reaction stirred until all the sodium hydride has been consumed. 1-bromo-3-chloropropane (1.46 ml, 14.88 mmol, 3 equiv) was added and the reaction stirred at 60° C. for 16 h. The reaction was partitioned between ethyl acetate and water. The organic layer was further washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP, 50 g cartridge, Rf=0.5, gradient—5%-25% ethyl acetate in hexanes) to afford the title compound as an oil (1.52 g, quant); MS for C16H20ClNO2 m/z 293.12 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:3]=1.[CH3:28][O:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].C(NC(C)C)(C)C>O1CCOCC1>[CH3:28][O:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=[N+]([O-])c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1Cl
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: COc1ccc(CNc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2[N+](=O)[O-])c(OC)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
15.00 g (38.99 mmol) of the compound from example 79A were dissolved in 200 ml of dioxane, 6.98 g (40.94 mmol) of 2,4-dimethoxybenzylamine and 5.54 g (42.88 mmol) of N,N-diisopropylamine were added and the mixture was stirred at 85° C. for 1 h. After cooling, the mixture was filtered and the filtrate was concentrated on a rotary evaporator and the residue was dried under high vacuum. The residue was crushed with a mortar and pestle, stirred with 250 ml of water, filtered off with suction and dried under high vacuum. 19.96 g (89% of theory) of the title compound were obtained.
Reaction SMILES: C([N:8]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:15]2[C:10](=[C:11]([Cl:30])[C:12]([O:28][CH3:29])=[CH:13][CH:14]=2)[CH2:9]1)C1C=CC=CC=1.Cl>C(O)C.[C].[Pd]>[Cl:30][C:11]1[C:12]([O:28][CH3:29])=[CH:13][CH:14]=[C:15]2[C:10]=1[CH2:9][NH:8][CH2:17][CH:16]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1
Reactant: COc1ccc(C2CN(Cc3ccccc3)Cc3c2ccc(OC)c3Cl)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(C2CNCc3c2ccc(OC)c3Cl)cc1OC
Yield: 65.2 %

Procedure:
1.13 g of 2-benzyl-8-chloro-7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 28 ml of ethanol, and after adding thereto 0.22 ml of 12N hydrochloric acid, hydrogenation reaction was performed by addition of 0.1 g of 10% palladium-carbon. After the hydrogenation reaction was over, the reaction solution was filtered, and concentrated. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 580 mg of 8-chloro-7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (m.p. 130°-132° C.). ##STR59##