Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]([CH3:34])([CH2:21][CH2:22][C:23]1[C:24](=[O:33])[C:25]([CH3:32])=[C:26]([CH3:31])[C:27](=[O:30])[C:28]=1[CH3:29])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1.Cl>C(O)C>[OH:33][C:24]1[C:25]([CH3:32])=[C:26]([CH3:31])[C:27]([OH:30])=[C:28]([CH3:29])[C:23]=1[CH2:22][CH2:21][C:4]([OH:3])([CH3:34])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1
Reactant: CC1=C(C)C(=O)C(CCC(C)(O)COc2ccc(CC3SC(=O)NC3=O)cc2)=C(C)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(C)c(O)c(CCC(C)(O)COc2ccc(CC3SC(=O)NC3=O)cc2)c(C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
165 mg of sodium borohydride were added, whilst ice-cooling and stirring, to a solution of 1 g of 5-{4-[2-hydroxy-2-methyl-4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)butoxy]benzyl}-2,4-dioxothiazolidine (prepared as described in Example 1) dissolved in 10 ml of ethanol, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was poured into a mixture of 100 ml of ice-water and 0.6 ml of 35% v/v aqueous hydrochloric acid to precipitate white crystals. The crystals were collected by filtration and dried in vacuo over phosphorous pentoxide to afford 0.9 g of the title compound as a yellow powder melting at 84°-88° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].O>CN(C=O)C>[CH:18]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1)([CH3:20])[CH3:19]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=C1CCOc2cc(O)ccc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](Oc1ccc2c(c1)OCCC2=O)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
7-Hydroxy-4-chromanone (1.2 g, 7.3 mmol; Dann et al., Ann. 587, 16, 1954) and imidazole (1.0 g, 14.7 mmol) were dissolved in DMF (10 ml). Triisopropylsilyl chloride (1.8 ml, 8.2 mmol) in DMF (2 ml) was added dropwise at ambient temperature over 10 minutes. After stirring for 3 hours, the mixture was poured onto 100 ml ice and water, and extracted with ether (2×100 ml). The combined ether extracts were washed with 1M LiCl and then brine, dried over CaSO4, and concentrated to a brown oil which was purified by Kugelrohr distillation (0.5 torr, 70°-90° C). This removed a colorless, viscous oil impurity and left the brown oil product in the distillation pot (2.0 g, 85%). IR (KBr) 2945, 2867, 1685, 1605, 1268, 1163. HRMS Calcd. for MH+, 320.1807; observed, 320.1842.
Reaction SMILES: [CH2:1]([N:8]1[CH2:28][CH2:27][C:11]2[N:12]=[C:13](Cl)[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][C@H:17]3[CH3:25])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2B2OC(C)(C)C(C)(C)O2)[N:32]([S:48]([C:51]2[CH:57]=[CH:56][C:54]([CH3:55])=[CH:53][CH:52]=2)(=[O:50])=[O:49])[CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:1]([N:8]1[CH2:28][CH2:27][C:11]2[N:12]=[C:13]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]4[C:38]=3[C:30]([CH3:29])=[CH:31][N:32]4[S:48]([C:51]3[CH:57]=[CH:56][C:54]([CH3:55])=[CH:53][CH:52]=3)(=[O:50])=[O:49])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][C@H:17]3[CH3:25])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCN(c2nc(Cl)nc3c2CN(Cc2ccccc2)CC3)[C@H](C)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(B4OC(C)(C)C(C)(C)O4)cccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)N1CCN(c2nc(-c3cccc4c3c(C)cn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(Cc2ccccc2)CC3)[C@H](C)C1
Temperature: 140 °C

Procedure:
A mixture of (R)-1-(4-(6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)ethanone (0.27 g, 0.675 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (0.305 g, 0.743 mmol) and 2 M aq Na2CO3 (1.1 mL, 2.19 mmol) in DME (3 mL) was degassed by sparging with argon. Pd(PPh3P)4 (0.117 g, 0.101 mmol) was then added and the mixture was heated in a microwave reactor at 140° C. for 1.5 h. The reaction was filtered and diluted with EtOAc, washed successively with sat aq Na2CO3 and, brine, and then dried over Na2SO4. After concentration the residue was purified by FCC (5-70% EtOAc/heptane) to provide (R)-1-(4-(6-benzyl-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)ethanone. MS (ESI+) m/z 649.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(COc2cccc(Br)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(COc2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of methyl 4-((3-bromophenoxy)methyl)benzoate (1 g, 3.1 mmol) in tetrahydrofuran (30 mL) and methanol (10 mL) was added lithium hydroxide monohydrate (1.3 g, 31 mmol) in water (10 mL). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuo and acidified with concentrated hydrochloride acid (12 N, 15 mL). Then the mixture was extracted with ethyl acetate (20 mL). The organic phase was separated and concentrated to give the product 4-((3-bromophenoxy)methyl)benzoic acid as a white solid (0.6 g, 63%). LRMS (M+H+) m/z: calcd 305.99. found 305. 1H NMR (300 MHz, d6-DMSO): δ 12.95 (s, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.27-7.22 (m, 2H), 7.15-7.12 (m, 1H), 7.05-7.01 (m, 1H), 5.21 (s, 2H).
Reaction SMILES: [CH3:1][C@@H:2]([NH2:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37]([N:45]1[C@H:49]([C:50](O)=[O:51])[CH2:48][S@@:47](=[O:53])[CH2:46]1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[C:37]([N:45]1[C@H:49]([C:50](=[O:51])[NH:10][C@H:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=2)[CH2:48][S@@:47](=[O:53])[CH2:46]1)(=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(O)[C@@H]1C[S@@](=O)CN1C(=O)c1ccccc1
Reactant: C[C@@H](N)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)[C@@H]1C[S@@](=O)CN1C(=O)c1ccccc1)c1ccc(O)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
9.47 g (69.11 mmole) of (R)-α-methyl-p-hydroxybenzylamine (prepared as described in Preparation 13), 10.58 g (69.11 mmole) of N-hydroxybenzotriazole monohydrate and 14.26 g (69.11 mmole) of dicyclohexylcarbodiimide were added in that order to a solution of 17.50 g (69.11 mmole) of (1R,4R)-3-benzoyl-1-oxo-thiazolidine-4-carboxylic acid (prepared as described in Preparation 10) in 100 ml of dimethylformamide cooled at 5° C., and the mixture was stirred at a temperature between 3° and 6° C. for 30 minutes and then at room temperature for a further 4 hours. At the end of this time, the reaction mixture was filtered and the insolubles were washed with 100 ml of hot dimethylformamide. The filtrate and the washings were combined and concentrated by evaporation under reduced pressure to leave crystals. These crystals were recrystallized from methanol to give 19.21 g (74.6%) of the title compound in the form of colorless needles melting at 233°-234° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:18]([C:19](O)=[O:20])[CH2:17][CH:16]3[CH2:22][CH2:23][CH2:24][CH:15]23)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].ClC(OCC)=O.C(N1CCOCC1)C.C[Si]([NH:43][OH:44])(C)C>CN(C=O)C>[OH:44][NH:43][C:19]([CH:18]1[N:14]([S:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[CH:15]2[CH2:24][CH2:23][CH2:22][CH:16]2[CH2:17]1)=[O:20]
Reactant: C[Si](C)(C)NO
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)N2C(C(=O)O)CC3CCCC32)cc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(S(=O)(=O)N2C(C(=O)NO)CC3CCCC32)cc1
Temperature: 80 °C

Procedure:
200 mg (0.55 mmol) of 1-(4-methanesulfonylbenzenesulfonyl)octahydrocyclopenta-[b]pyrrole-2-carboxylic acid were dissolved in 10 ml of DMF, after which 0.60 mmol of ethyl chloroformate, 1.22 mmol of N-ethylmorpholine and 1.67 mmol of trimethylsilylhydroxylamine were added. After the mixture had been heated at 80° C. for 4 h, the solvent was removed under reduced pressure and the crude product was purified using chromatographic methods.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:16]2[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccc(Cl)cc1
Yield: 50 %

Procedure:
4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.036 g (50%) of 4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:27]=[CH:26][O:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:27]=[CH:26][O:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1ccon1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccon2)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 64.3 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 3-aminoisoxazol (70 mg, 0.834 mmol) was added. The resulting mixture was stirred at room temperature for four days and the final product was collected by filtration and washed with diethylether to yield the title compound (58 mg, 63.7% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](O)(=[O:24])[CH2:20][C:21](O)=[O:22].C(OC(=O)C)(=O)C>>[CH2:1]([N:8]1[C:19](=[O:24])[CH2:20][C:21](=[O:22])[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)NCc1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(=O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Yield: 95.4 %

Procedure:
Heated was a mixture of N,N′-dibenzylurea 12.02 g (50.0 mmol) and malonic acid 5.20 g (50.0 mmol) in acetic anhydride 50.0 mL (530 mmol, 10.6 equivalents) at 70° C.-75° C. for 14 hours under a nitrogen atmosphere. Then, removed were the volatile materials under the reduced pressure and distributed the residue between layers of 2 M sodium hydroxide 250 mL and ether 200 mL. Separated was the alkaline aqueous layer and after washing with ether, neutralized with concentrated hydrochloric acid under cooling in ice-water bath (pH 2-3). Extracted was the neutrallized aqueous solution with chloroform, washed with water, and dried over sodium sulfate. Removal of the solvent under reduced pressure gave 1,3-dibenzylbarbituric acid 14.7 g as pale yellow crystalline powder (95.6% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH:9]([CH3:11])[CH3:10].FC(F)(F)C(O)=O.[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:38])[F:39])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:42][CH2:43][N:44]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[CH:9]([CH3:11])[CH3:10])[CH2:45][CH2:46]2)[CH2:20][CH2:21][CH2:22]1
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Reactant: CC(C)c1c(N)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 96 h
Yield: 34.3 %

Procedure:
A reaction mixture of 6-Chloro-5-isopropyl-pyrimidin-4-ylamine (30.00 mg; 0.17 mmol; 1.00 eq.), 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (2) (109.16 mg; 0.17 mmol; 1.00 eq.), and Cs2CO3 (227.81 mg; 0.70 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for 4 days, purified by prep HPLC, collected title compound 31 mg, yield 27.7%. LC-MS: (M+1=532, obsd.=532).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH:8]2[CH2:10][O:9]2)=[CH:5][CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.O>[N:13]([CH2:10][CH:8]([OH:9])[CH2:7][C:6]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N+:14]=[N-:15]
Reactant: COc1ccc(CC2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CC(O)CN=[N+]=[N-])cc1
Temperature: 90 °C

Procedure:
To a stirring solution of 2-(4-methoxy-benzyl)-oxirane (2.0 g, 12.2 mmol) in 10 mL DMF was added a solution of sodium azide (0.87 g, 13.4 mmol) in 2 mL water. The solution was heated to 90° C. for 90 min. The solvents were removed under reduced pressure and the resulting solid residue partitioned between ethyl acetate and water. The aqueous phase was washed three times with 10 mL ethyl acetate. The combined organic layers were dried over magnesium sulfate, then purified on 40 g silica eluting with 5-50% ethyl acetate/hexanes to give the product as a clear oil. NMR (CDCl3) d (1H, 1.82 ppm), m (2H, 2.7-2.8 ppm), dd (1H, 3.25 ppm), dd (1H, 3.35 ppm), s (3H, 3.75 ppm), m (1H, 3.9-4.0 ppm), d (2H, 6.85 ppm), d (2H, 7.10 ppm).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:21])[CH3:20])#[CH:11]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]2[N:18]([C:19](=[O:21])[CH3:20])[C:13]3[C:12]([CH:10]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][CH:4]=1
Reactant: C#Cc1ccccc1NC(C)=O
Reactant: COc1ccc(I)cc1
Product: COc1ccc(-c2cc3ccccc3n2C(C)=O)cc1
Yield: 60 %

Procedure:
The general procedure was used to convert 1-iodo-4-methoxybenzene and N-(2-ethynylphenyl)acetamide to the title product. Purification by flash chromatography gave the analytically pure product as a slightly yellow solid, 60% yield. 1H NMR (300 MHz, DMSO) δ 8.23-8.21 (d, J=8.1, 1H), 7.56-7.54 (d, J=7.5, 1H), 7.43-7.40 (d, J=8.8, 2H), 7.31-7.21 (m, 2H), 7.02-7.00 (d, J=8.8, 2H) 6.64 (s, 1H), 3.78 (s, 3H), 2.03 (s, 3H). 13C NMR (75 MHz, DMSO) δ 171.96, 160.37, 140.53, 137.75, 131.13, 129.71, 126.58, 125.29, 124.24, 121.18, 116.30, 114.97, 111.10, 56.06, 28.33. Anal. Calcd. for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found C, 76.90; H, 5.74; N, 5.08. m.p.: 68-71° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:7]=1.C(OC([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)[C:27](=[CH:35][C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2[O:43][C:44]2([C:48]([O:50][CH3:51])=[O:49])[CH2:47][CH2:46][CH2:45]2)[C:26]1=[O:52])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[Cl:34][C:31]1[CH:32]=[C:33]2[NH:25][C:26](=[O:52])[C:27]3([CH:35]([C:36]4[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=4[O:43][C:44]4([C:48]([O:50][CH3:51])=[O:49])[CH2:45][CH2:46][CH2:47]4)[CH2:12][C:10](=[O:11])[NH:9][CH:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:17])[C:28]2=[CH:29][CH:30]=1
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C=C2C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CCC1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a toluene solution of 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene in toluene (2 M, 5 mL, 10 mmol) was added E/Z 6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.5 g, 2.9 mmol). The reaction mixture was heated at 80° C. overnight under argon protection, then TFA (5 mL) was added, and the resulting mixture was stirred at room temperature for 20 min, evaporated in vacuo. The residue was partitioned between ethyl acetate and NaOH aq. (1 M). The organic layer was washed with water, dried over anhydrous Na2SO4, concentrated and purified by column chromatography to give the title compound as a white solid (340 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH:29]=O)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[CH2:31]([NH:35][CH3:36])[CH:32]([CH3:34])[CH3:33].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][N:35]([CH3:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[O:4][N:3]=1
Reactant: CNCC(C)C
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2C=O)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)CC(C)C)c1C
Yield: 74.1 %

Procedure:
After briskly stirring a mixture of N-(3,4-dimethyl-5-isoxazolyl)-2'-formyl-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (100 mg; 0.24 mmol; prepared as in Step (F) of Example 21), isobutylmethylamine (0.087 ml; 0.71 mmol), AcOH (0.08 ml; 1.34 mmol) and 3 Å molecular sieves (670 mg) in 2 ml of CH2Cl2 for 1 hour at room temperature, sodium triacetoxyborohydride (150 mg; 0.71 mmol) was added. After stirring 18 hours at room temperature, the reaction mixture was filtered through celite and the filtrate was partitioned between EtOAc (40 ml) and saturated NaHCO3 solution (20 ml). The organic layer was washed with water (20 ml) followed by brine (20 ml). Drying (Na2 SO4) and concentration afforded a residue that was chromatographed on a 2.5×12 cm silica gel column using a stepwise gradient of 300 ml @CH2Cl2 to 5% MeOH/CH2Cl2 in 1% increments. The pure fractions were concentrated to afford 88 mg of the title compound of this Example as a white powder.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:20])[CH2:4][N:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].C(Cl)(Cl)Cl>O>[CH2:6]([N:5]([CH2:4][CH:3]1[CH2:2][O:20]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC(CCl)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: c1ccc(CN(Cc2ccccc2)CC2CO2)cc1
Yield: 76 %

Procedure:
50.7 g (0.175 mol) of 1-chloro-3-dibenzylamino-2-propanol, 9.5 g (0.24 mol) of sodium hydroxide and 5 ml of water are stirred together for 1 hour at 95° C. After the addition of 50 ml of chloroform and 20 ml of water, the phases are separated and the organic phase is washed with 20 ml of water, dehydrated with sodium sulphate and concentrated by evaporation. Vacuum distillation of the yellow oil obtained yields 33.7 g (76%) of the oxirane as a colourless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[CH3:3])=[CH:13]2
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1

Procedure:
3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9) (0.72 mmol), 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (344 mg, 1.44 mmol) and DIPEA (279 mg, 2.16 mmol) were dissolved in n-BuOH (20 mL), and the resulting mixture was stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the product, 8-chloro-2-phenyl-3-((1S)-1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one (Compound 10), as a white solid (60% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]S(C)(=O)=O)=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[C:17]([N+:20]([O-:22])=[O:21])[C:16]([CH3:23])=[N:15]1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[C:17]([N+:20]([O-:22])=[O:21])[C:16]([CH3:23])=[N:15]1
Reactant: Cc1nn(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)c(C)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(-c2cc(O)c(Cl)cc2F)c(C)c1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of 1-(2-fluoro-4-chloro-5-methylsulfonyloxyphenyl)-3,5-dimethyl-4-nitropyrazole (36.5 g), 2N aqueous sodium hydroxide solution (100 ml) and ethanol (50 ml) was stirred at 40° C. for 30 minutes. After cooling, the reaction mixture was acidified with an aqueous hydrochloric acid solution and extracted with toluene. The toluene layer thus obtained was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (28.1 g) as a pale yellow crystalline solid. Recrystallization of this solid from a mixture of n-hexane and ethyl acetate afforded a white crystalline solid. m.p. 157°-158° C.