Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]2[N:20]=[CH:19][C:18]([CH:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH2:22][NH2:23])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][CH:21]([C:18]1[CH:19]=[N:20][C:15]([CH:12]2[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:6]
Reactant: NCC(c1ccc(C2CC2)nc1)N1CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccc(C2CC2)nc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](OC(=O)C)(=O)[CH3:16].C(N(CC)CC)C>CC(C)=O.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C>[CH:15]1[C:4]2[CH:3]=[CH:2][C:1]([N:7]3[C:8](=[O:14])[CH:9]=[CH:10][C:11]3=[O:12])=[CH:6][C:5]=2[CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)/C=C\C(=O)Nc1ccccc1
Agent: [Ni+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: O=C1C=CC(=O)N1c1ccc2c(c1)C=C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-phenyl-maleamic acid (6.00 g, 27.62 mmol) was partially dissolved in about 100 ml of acetone in a 250 ml round-bottomed flask. To this stirred heterogeneous mixture was added solid nickel acetate tetrahydrate (0.25 g), followed by the mixture of acetic anhydride (6.27 g. 61.42 mmol) and triethylamine (1.82 g, 23.0 mmol). Gradually, almost all the solids dissolved and the resultant reaction mixture was stirred at room temperature for two days. After all the solvent had been removed by rotary evaporation, the residual oil (smell of acetic acid) was mixed with a small amount of methylene chloride. The solution was passed through a small column containing silica gel saturated with hexane. The column was eluted with hexane until the yellow band developed reached its bottom. Then, it was eluted with methylene chloride. The second yellow fraction collected was then subjected to rotary evaporation and hexane was then added slowly to the concentrated solution to precipitate the product as a yellow solid. The product was collected, washed with hexane and air-dried overnight. Yield: 4.34 g (78.9%). Anal Calc. for C12H9NO2 : C, 72.35; H, 4.55; N, 7.03. Found: C, 71.84; H, 4.54; N, 6.90. Mass Spectroscopy: M+ , 199 (100%). Proton NMR (CDCl3),δ(ppm): 3.23 (singlet, 4H, alicyclic protons); 6.87 (singlet, 2H, olefinic protons); 7.03-7.33 (complex, 3H, aromatic protons). IR (KBr): ν(maleimide): 1710 cm-1, vs; 1772 cm-1, W.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[Br:12][C:13]1[C:14]([C:22]2[N:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=2)=[CH:15][C:16]2[O:20][CH2:19][O:18][C:17]=2[CH:21]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl.O1CCCC1.CO.[OH-].[Li+]>[Br:12][C:13]1[C:14]([C:22]2[N:23]=[CH:24][C:25]([NH:28][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])=[N:26][CH:27]=2)=[CH:15][C:16]2[O:20][CH2:19][O:18][C:17]=2[CH:21]=1
Reactant: Nc1cnc(-c2cc3c(cc2Br)OCO3)cn1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cnc(-c2cc3c(cc2Br)OCO3)cn1)c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 0.42 h
Yield: 66.9 %

Procedure:
Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (8.6 mg, 48 μmol) was added to a stirred solution of 15 (9.5 mg, 32 μmol), Hünig's base (17 μL, 13 mg, 97 μmol), and DMAP (1 mg, 8 μmol) in dichloromethane (200 μL) at room temperature. The reaction was stirred for 25 min. The solution was diluted with tetrahydrofuran (750 μL), methanol (500 μL) and 1.2 M lithium hydroxide solution (250 μL). The mixture was stirred and heated to 60° C. for 10 min then cooled to room temperature and diluted with dichloromethane (5 mL) and dried with sodium sulfate. The mixture was concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 16 (9.3 mg, 66%) as a solid: LRESIMS m/z 434.0 [M+H]+, calcd. for C18H11Br1F2N3O3 434.0.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[C:5]2=[N:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[C:18](=[O:19])[N:4]2[CH:3]=1.C(=O)(O)[O-].[Na+:27]>CN(C)C=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[C:5]2=[N:15][CH:16]=[C:17]([C:20]([O-:22])=[O:21])[C:18](=[O:19])[N:4]2[CH:3]=1.[Na+:27]
Reactant: Cc1cn2c(=O)c(C(=O)O)cnc2c2cc([N+](=O)[O-])ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn2c(=O)c(C(=O)[O-])cnc2c2cc([N+](=O)[O-])ccc12
Reaction time: 1 h

Procedure:
A solution of 7-methyl-10-nitro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (300 mg) in N,N-dimethylformamide (40 ml) was added to an aqueous sodium bicarbonate solution (60 ml). After being stirred for 1 hour, the mixture was allowed to stand in a refrigerator and the resultant precipitate was collected by filtration. To the solid was added aqueous methanol, stirred at room temperature, and collected by suction to give sodium 7-methyl-10-nitro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (0.29 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C(Cl)(=O)C(Cl)=O.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>C(Cl)Cl>[CH3:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:25])=[CH:19][CH:20]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: C1CCNC1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)N4CCCC4)cc3)c(-c3ccccc3)c(C)cc2c1
Reaction time: 12 h
Yield: 95.4 %

Procedure:
To a solution of (2E)-3-(4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)-2-propenoic acid (10) (0.135 g, 0.33 mmol) in CH2Cl2 (2 mL) was added oxalyl chloride (0.043 mL, 0.49 mmol) under N2. The resultant mixture was stirred at room temperature for 2 h. Reaction mixture was concentrated under reduced pressure to afford the crude acid chloride. The acid chloride was dried (Na2SO4) and re-dissolved in CH2Cl2 (5 mL) at room temperature. To the above solution pyrrolidine (0.055 ml, 0.66 mmol) was introduced slowly and the mixture was stirred for 12 h. Reaction mixture was concentrated under reduced pressure to afford the crude amide. The product was purified by SiO2 column chromatography using hexanes:EtOAc (9:1 to 3:2) as an eluent to afford 0.146 g (96%) of the title compound (243) as a white foam. 1H NMR (400 MHz, CDCl3): δ 7.71 (d, J=9.2 Hz, 1H), 7.55 (s, 1H), 7.54 d, J=15.6 Hz, 1H), 7.27-7.20 (m, 5H), 7.13-7.11 (m, 3H), 7.03 and 7.01 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 6.57 (d, J=8.8 Hz, 2H), 6.51 (d, J=15.2 Hz, 1H), 3.91 (s, 3H), 3.55 (t, J=6.8 Hz, 4H), 2.22 (s, 3H), 1.94 (quintet, J=6.4 Hz, 2H), 1.85 (quintet, J=6.8 Hz, 2H), 2.26 (s, 3H). LCMS (ESI) m/z 464.15 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[NH:21]([N:22]1[C:5](=[O:13])[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([Cl:1])[C:3]1=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Reactant: NNc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.14 g (20 mmol) of 3-chloro-4-phenylfuran-2,5-dione were initially charged in 50 ml of chloroform and, at room temperature, admixed dropwise with stirring with 2.16 g (20 mmol) of phenyl hydrazine, and the mixture was stirred at room temperature overnight. The mixture was filtered, washed three times with sodium bicarbonate solution and once with water, dried over sodium sulfate and concentrated under reduced pressure. Yield: 5.4 g of a crystalline solid, m.p. 144-146° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[F:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:38]=[CH:39][C:40]([C:43](O)=[O:44])=[N:41][CH:42]=2)[CH:34]=[CH:35][CH:36]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:43]([C:40]3[CH:39]=[CH:38][C:37]([C:33]4[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=4)=[CH:42][N:41]=3)=[O:44])[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)cn1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3ccc(-c4cccc(F)c4)cn3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
62 mg (0.11 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 27 mg (0.12 mmol, 1.1 eq.) of 5-(3-fluorophenyl)pyridine-2-carboxylic acid were reacted according to General Method 1. Yield: 31 mg (56% of theory)
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[O:16])[CH3:15])=[CH:4]1)[CH3:2].[CH2:17]([N:19]1C2C(=CC=C(OC)C=2)C=C1)C.COC(OC)N(C)C.N1CCCC1.Cl.ON>O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[O:16][N:19]=[CH:17][CH:15]=2)=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(C)=O)c2ccc(OC)cc21
Reactant: CCn1ccc2ccc(OC)cc21
Agent: COC(OC)N(C)C
Agent: Cl
Agent: NO
Solvent: C1CCNC1
Solvent: O
Product: CCn1cc(-c2ccno2)c2ccc(OC)cc21
Temperature: 80 °C
Yield: 66 %

Procedure:
1-(1-Ethyl-6-methoxy-1H-indol-3-yl)ethanone (100 mg, 0.46 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, is heated with 1.5 mL of dimethylformamide dimethylacetal and 100 μL of pyrrolidine at 110° C. overnight. The dimethylformamide dimethylacetal is then concentrated in vacuo. The residue is redissolved in 1.25 mL of EtOH and 250 μL of H2O, and is treated with hydroxyamine hydrochloride (66 mg, 0.95 mmol) and heated at 80° C. for 2 h. Partitioning between H2O and EtOAc and drying and concentration of the organic phase followed by purification by silica gel chromatography (EtOAc/CH2Cl2, 5/95) gives 1-ethyl-3-isoxazol-5-yl-6-methoxy-1H-indole as a white solid (72 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=O)[C:3]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.[BH4-].[Na+]>C(O)C>[CH2:25]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:20][CH2:21]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-fluoro-6-formylphenylcarbamate (48.0 g, 201 mmol) in ethanol (100 mL) was added 4-amino-1-benzylpiperidine (41.0 mL, 201 mmol). The solution was concentrated in vacuo, and then water was removed by twice dissolving the residue in toluene and concentrating the solution in vacuo. The resulting oil was dissolved in tetrahydrofuran (250 mL), cooled to 0° C., and treated with sodium borohydride (3.80 g, 100 mmol). The ice bath was removed and stirring continued overnight. The reaction was treated with ethanol (250 mL), an additional portion of sodium borohydride (2.00 g, 53 mmol), and an additional portion of 4-amino-1-benzylpiperidine (2.0 mL, 9.8 mmol). The resulting solution was stirred for 4 h at room temperature. The reaction was cooled to 0° C., quenched by addition of saturated ammonium chloride, filtered to remove solids, and concentrated to remove most (but not all) of the tetrahydrofuran. The reaction was extracted with diethyl ether (2×). The ethereal layer was washed with water (3×), then brine, dried over magnesium sulfate, and concentrated to give 83 g (100%) as a viscous yellow oil which was pure enough to use in the following step. Mass spec.: 414.51 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:19][C:18]2[C:13](=[N:14][C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:16][CH:17]=2)[N:12]([C@:29](O[SiH3])([CH3:47])[C:30](C2C=CC=CC=2)(C2C=CC=CC=2)C(C)(C)C)[C:11]1=[O:50].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:69]1CCCC1>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:19][C:18]2[C:13](=[N:14][C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:16][CH:17]=2)[N:12]([C@@H:29]([CH3:47])[CH2:30][OH:69])[C:11]1=[O:50]
Reactant: COc1ccc(Nc2ncc3c(n2)N([C@@](C)(O[SiH3])C(c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)N(c2ccc(OC)cc2F)C3)cc1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1ccc(Nc2ncc3c(n2)N([C@@H](C)CO)C(=O)N(c2ccc(OC)cc2F)C3)cc1
Reaction time: 4 h

Procedure:
(S)-3-(2-Fluoro-4-methoxy-phenyl)-1-(2-tert-butyl-diphenyl-silanyloxy-1-methyl-ethyl)-7-(4-methoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.25 g, 0.35 mmol) was dissolved in anhydrous tetrahydrofuran (2.5 mL) and treated with tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 1.40 mL, 1.400 mmol). The reaction was stirred in a water bath that was maintained in the 30–40° C. range. The reaction was complete after 4 hours and was concentrated. This residue was redissolved in ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, concentrated and then purified by flash chromatography (Biotage 40S, 75:25 ethyl acetate-hexanes) to give (S)-(+)-3-(2-fluoro-4-methoxy-phenyl)-1-(2-hydroxy-1-methyl-ethyl)-7-(4-methoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a pale yellow foam. (Yield 0.14 g, 85.1%).
Reaction SMILES: O.[OH-].[Li+].[NH:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:5][C:6]([N:8]([CH2:10][C:11]([N:13]([CH3:22])[C@H:14]([C:18]([O:20]C)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:9])=[O:7].Cl>C1COCC1.CO.O>[NH:4]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:5][C:6]([N:8]([CH2:10][C:11]([N:13]([CH3:22])[C@H:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:9])=[O:7]
Reactant: COC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)[C@@H](C(=O)O)N(C)C(=O)CN(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
From 600; Lithium hydroxide monohydrate (249 mg, 5.9 mmol) was added to a solution of 600 (740 mg, 1.98 mmol) in 15 mL of THF—CH3OH—H2O (3:1:1) at 25° C. and the resulting reaction mixture was stirred for 3 h. The reaction mixture was poured onto 3M aqueous HCl (8 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to give 7 (638 mg, 712 mg theoretical, 90%) as a white solid which was employed directly in the next reaction without further purification: white foam, mp 57-60° C.; 1H NMR (CDCl3, 400 MHz) 5.67 and 5.58 (two s, 1H), 4.63 (d, 1H, J=10.4 Hz), CH), 4.10-3.82 (m, 4H), 3.05, 3.04, 3.01 and 2.88 (four s, 6H), 2.30-2.20 (m, 1H), 1.43 and 1.41 (two s, 9H), 1.04 and 0.88 (two d, 6H, J=6.7 Hz); IR (KBr)max 3421, 2974, 1706, 1656, 1495, 1419, 1367, 1292, 1250, 1171, 1053, 953, 870, 837, 670 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24](O)=[O:25])=[CH:14][CH:13]=1>>[NH2:10][CH2:9][C@H:4]1[C@@H:3]([O:2][CH3:1])[CH2:8][CH2:7][CH2:6][N:5]1[C:24]([C:19]1[N:20]=[C:21]([CH3:23])[S:22][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)=[O:25]
Reactant: COc1cccnc1C#N
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: CO[C@H]1CCCN(C(=O)c2nc(C)sc2-c2ccc(F)cc2)[C@H]1CN

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using 3-methoxypicolinonitrile and 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) 464.4 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13](C)[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Oc1ccccc1)N1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.8 g of 6-chloro-1-(2-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine], free base of Example 28, and 0.5 g of phenyl chloroformate in 20 ml of methylene chloride is stirred at ambient temperature for 16 hours. Thereafter, the mixture is successively washed with 10% sodium hydroxide, washed with water, dried and concentrated under vacuum leaving a brownish oil. The oil is passed through an alumina column, ether eluant, providing a colorless gum of 6-chloro-1-(2-chlorophenyl)-1'-phenoxycarbonylspiro[indoline-3,4'-piperidine]. IR and NMR spectra confirm the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[CH:7]=1.[CH3:22][C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])([CH3:26])[C:24]#[CH:25].O1CCCC1.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:23]([CH3:22])([CH3:26])[C:24]#[CH:25])[CH:28]=4)[CH:21]=[CH:20][CH:19]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: C#CC(C)(C)c1cccc(C(=O)O)c1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#CC(C)(C)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(C)=O)sc4c3)c2)c1
Yield: 22.3 %

Procedure:
Using N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x), 3-(1,1-dimethylprop-2-yn-1-yl)benzoic acid (201 mg, 1.07 mmol), tetrahydrofuran (4 mL), N,N-dimethylformamide (10 μL), oxalyl chloride (170 mg, 1.34 mmol) and N,N-dimethylformamide (4 mL), and in the same manner as in Example A40(xi), the title compound (56 mg, 22%) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH:6]([O:12][CH3:13])[CH2:5]2.[C:14]([S@:18]([NH2:20])=[O:19])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[N:20]\[S@@:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:19])/[C@@H:6]([O:12][CH3:13])[CH2:5]2
Reactant: CC(C)(C)[S@](N)=O
Reactant: COC1Cc2cc(Cl)ccc2C1=O
Solvent: C1CCOC1
Product: CO[C@H]1Cc2cc(Cl)ccc2/C1=N\[S@](=O)C(C)(C)C
Temperature: 68 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
A 22 L multi-neck reactor equipped with a condenser, a nitrogen inlet, a heating mantle and an overhead mechanical stirrer was charged with 5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-one (18) (622.88 g, 3.17 mol) and (R)-tert-butylsulfinamide (460.7 g, 3.8 mol). Tetrahydrofuran (3100 mL) was added to the mixture and the temperature dropped to 9° C. Ti(OEt)4 (985 mL, 4.76 mol) was added over 10 minutes. The mixture was heated to 68° C. and all solids dissolved at about 35° C. After 5 hours, the reaction achieved a 50% yield as determined by HPLC wt % assay. The reaction was stirred at 68° C. for an additional 5 hours until the undesired diastereomer decomposed to less than 5% (AUC). The reaction was cooled to ambient temperature over 2 hours and stirred for 16 hours. HPLC analysis indicated no obvious change in reaction profile during this period. This crude reaction mixture was taken in to the next step without further purification.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:15]([O:27][CH2:28]C3C=CC=CC=3)[CH:14]=2)=O)=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:43])=O.[BH4-].[Na+]>C(#N)C.Cl>[ClH:43].[CH2:28]([O:27][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][C:16]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:8]([CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:2][CH:3]=1)[NH:10][CH2:11][CH2:12]2)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccc(-c2ccccc2)cc1)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(COc2cc3c(cc2OCc2ccccc2)C(Cc2ccc(-c4ccccc4)cc2)NCC3)cc1
Reaction time: 8 h

Procedure:
6,7-bis-benzyloxy-1-biphenyl-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride (2) was prepared as follows: A stirred solution of 3 g (5.69 mmol) of 2-biphenyl-4-yl-N-[2-(3,4-bis-benzyloxy-phenyl)-ethyl]-acetamide and 5.6 ml (60 mmol) of phosphorus oxychloride in 25 ml of anhydrous acetonitrile was refluxed for 20 hours. The reaction solution was evaporated under reduced pressure and the residue was dissolved in 25 ml of methanol. To this stirred solution at 0° C., 2.27 g (60 mmol) of sodium borohydride was added portionwise. The stirred reaction mixture was allowed to reach room temperature overnight and then it was poured in 150 ml of 10% aqueous HCl solution. The precipitate was collected on a glass filter funnel, washed with water (3×50 ml), and air-dried overnight. The solid was recrystallized using ether/methanol mixture to provide 2.56 g (82%) of off-white crystals, mp 187-189° C.
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:21]3[N:20]=[C:19]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[N:29])[N:18]=[C:16]([NH2:17])[C:15]=3[N:14]=[CH:13]2)[C@H:9]([OH:30])[C@@H:8]1[OH:31])([O-:4])([O-:3])=[O:2].C([NH+](CC)CC)C.C([NH+](CC)CC)C.Cl>O>[P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:21]3[N:20]=[C:19]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[N:29])[N:18]=[C:16]([NH2:17])[C:15]=3[N:14]=[CH:13]2)[C@H:9]([OH:30])[C@@H:8]1[OH:31])([OH:3])([OH:4])=[O:2]
Reactant: N#CCCCCC#Cc1nc(N)c2ncn([C@@H]3O[C@H](COP(=O)([O-])[O-])[C@@H](O)[C@H]3O)c2n1
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: O
Product: N#CCCCCC#Cc1nc(N)c2ncn([C@@H]3O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]3O)c2n1
Reaction time: 0.17 h

Procedure:
A triethylammonium 2-(6-cyano-1-hexyn-1-yl)adenosine 5′-monophosphate (1.1 g) was dissolved in water (20 mL), and, under ice-cooling conditions, 1N HCl solution (2 mL) was added thereto, followed by standing for 10 minutes. After having been diluted with water (20 mL), the resultant mixture was filtered. The residue was washed with water (20 mL) and then with ethanol (20 mL×2), to thereby yield 617 mg of the above-titled compound as a colorless amorphous substance.