Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:17])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:27])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(C(=O)c2ccc(OC)cc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-methoxyphenyl)2-phenylethan-1-one (1.0 equiv.) in THF at −78° C. was added dropwise 1.5 equiv. of [(CH3)2Si]2NLi. The solution was stirred for 1 h at −78° C., followed by addition of addition of 1.2 equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10 min at −78° C. and then for 22 h at rt, acidified with 10% citric acid, and extracted with EtOAc. The combined organic layers were washed with water and dried over Na2SO4. Removal of solvent in vacuo provided a crude solid which was purified by flash chromatography (CH2Cl2) to give 1,3-bis(4-methoxyphenyl)-2-phenylpropane-1,3-dione.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C@@:5]1([CH2:11][NH:12]C(OC)=O)[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1.[ClH:18]>O1CCOCC1.O>[ClH:18].[NH2:12][CH2:11][C@:5]1([CH2:4][C:3]([OH:17])=[O:2])[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1
Reactant: COC(=O)C[C@@]1(CNC(=O)OC)CC[C@@H](C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CC[C@](CN)(CC(=O)O)C1
Yield: 25 %

Procedure:
[(1R,3R)-1-(Methoxycarbonylamino-methyl)-3-methyl-cyclopentyl]-acetic acid methyl ester (2.60 g, 37 mmol) was refluxed in a mixture of 1,4-dioxane (15 mL) and 6N Hydrochloric acid (30 mL) for 16 hours. The mixture was allowed to cool, diluted with water (80 mL), and washed with dichloromethane (2×200 mL). The aqueous layer was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate/methanol (95:5) to give 0.55 g (25%) of ((1R,3R)-1-aminomethyl-3-methyl-cyclopentyl)-acetic acid hydrochloride;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)nc23)CC1
Yield: 73.4 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.058 mMol) 4-trifluoromethylbenzoyl chloride, 0.013 gm (73%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[C:24]([CH3:26])[N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[C:24]([CH3:26])[N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Cc1csc(NC(=O)CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)n1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1csc(NC(=O)CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(N(C)C)cc5)nc34)CC2)n1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(4-methylthiazol-2-yl)acetamide (0.034 g, 0.08 mmol), ethanol (3 ml), and 4-dimethylaminobenzaldehyde (0.015 g, 0.10 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.35 ml, 0.35 mmol). The reaction mixture was heated at 70° C. for 3.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 40% ethyl acetate in dichloromethane and then 2.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.010 g, 25%); 1H-NMR (500 MHz, DMSO-d6) 2.27 (s, 3H, CH3), 2.76 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.71 (br s, 4H, piperazine N(CH2)2), 3.37 (s, 2H, NCH2CO), 6.77 (s, 1H, thiazole 5-H), 6.81 (d, J=8.91 Hz, 2H) and 8.01 (d, J=8.88 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 8.03 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.78 (s, 1H, CONH), 13.09 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:20])[CH:14]=[C:15]([CH2:16][N:17]=[N+]=[N-])[C:7]1=2)C.Cl>C1COCC1.O.[Pd]>[NH2:17][CH2:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:21])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([OH:20])[CH:14]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(CN=[N+]=[N-])c21
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(O)cc2c1C(CC(=O)O)OB2O
Reaction time: 8 h
Yield: 16.4 %

Procedure:
To a solution of (4-azidomethyl-1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (15 mg) in THF/water (2:1, 1 mL) was added 10% Pd/C (5 mg), and a drop of 1N HCl. The reaction was degassed and stirred under hydrogen overnight and filtered off. The filtrate was purified by HPLC, yielded 2 mg of product. MS (ESI) m/z: 237.9 [M+1]+; 1H NMR (300 MHz, CD3OD) δ 8.25 (s, 3H), 7.06 (d, 1H), 6.98 (d, 1H), 8.20 (s, 1H), 5.68 (dd, 1H), 4.17 (s, 2H), 3.67 (s, 1H), 2.99-3.04 (m, 1H), 2.71-2.87 (m, 2H), 2.45-2.52 (m, 1H).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH-].[K+]>CCOCC>[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
Cyclopentanol (10 g, 0.116 mol), p-toluenesulfonyl chloride (24.3 g, 0.128 mol) and ether (100 ml) were charged into a 200 cc round-bottom flask and dissolved. Then, potassium hydroxide (32.5 g, 0.58 mol) in a powder form was added slowly thereto while cooling below 10° C. in a water bath. After addition, the mixture was stirred as it was for additional 2 hours. After completion of the reaction, the mixture was poured into ice-water (20 ml), and the organic layer and the aqueous layer were separated. The organic layer was dried, and concentrated under reduced pressure to obtain cyclopentyl p-toluenesulfonate as a pale yellow viscous liquid (22.0 g, 81.8% yield).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:19]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[CH:10]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1nc2ccc(O)cc2o1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccc(OC(=O)c3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a stirred suspension of 2-methyl-1,3-benzoxazol-6-ol (2.99 g, 20 mmol) in dichloromethane (50 mL) was added triethylamine (4.05 g, 5.58 mL, 40 mmol). A solution of benzoyl chloride (3.09 g, 2.56 mL, 22 mmol) in dichloromethane (20 mL) was added dropwise over ca. 10 min. The reaction mixture was stirred at room temperature for 2.5 h, then washed with water (2×50 mL), and dried over Na2SO4, filtered and concentrated in vacuo to give the subtitled compound as a colourless solid (5.05 g, 20 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C=C[S:48]C=3CCC2C)=NC=1CC>[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.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[CH:21]=[CH:22][S:48][C:25]=3[CH2:24][CH2:23][C@@H:19]2[CH3:20])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2c3ccsc3CCC2C)c(CC)nc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccsc2CC[C@@H]1C

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.51, 7.33, 7.11; 6.96, 5.66, 4.52, 2.95-2.62, 2.55, 2.38, 2.05, 1.97, 1.79, 1.26, 1.20, 1.07; HRMS (FAB) calcd for C23H25Cl2N3S+H 446.1224, found 446.1224.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[C:18]3[C:13](=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:23]([F:26])([F:25])[F:24])[CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:30].O>C1COCC1>[CH3:30][O:8][CH:7]([C:9]1[C:18]2[C:13](=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:23]([F:26])([F:24])[F:25])[CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: OC(c1ccccc1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(c1ccccc1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 81.9 %

Procedure:
A solution of α-phenyl-2,8-bis(trifluoromethyl)quinoline-4-methanol (50 mg, 0.13 mmol) in anhydrous THF (4 mL) was treated with NaH (18 mg, 60% dispersion in oil, 0.44 mmol), stirred at room temperature for 2 min, treated with iodomethane (0.8 mL, 1.2 mmol) and stirred for 15 min. The solution was then treated with water (10 mL), extracted with ether (2×10 mL), the extracts washed with water (10 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; heptane-EtOAc (10:1)] to give the title compound (41 mg, 79%) as a pale solid: mp 115-117° C.; IR νmax (liquid film)/cm−1 3070, 2929, 2854, 1589, 1588, 1517, 1491, 1456, 1429, 1378, 1210, 1276, 1211, 1184, 1164, 1129 and 1101; NMR δH (400 MHz, CDCl3) 3.47 (3H, s), 5.90 (1H, s), 7.29-7.35 (5H, m), 7.60-7.64 (1H, t J 8 Hz) and 8.25 (1H, d J 8 Hz).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:27]=1[C:28]([NH2:30])=[O:29].CC([O-])(C)C.[Na+]>CN(C=O)C.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>[F:25][C:26]1[CH:34]=[C:33]([C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)[CH:32]=[CH:31][C:27]=1[C:28]([NH2:30])=[O:29]
Reactant: CN1CCN(c2ccc(Nc3ccc(Cl)n4ncnc34)cc2)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc(Nc3ccc(-c4ccc(C(N)=O)c(F)c4)n4ncnc34)cc2)CC1
Temperature: 110 °C
Yield: 18.4 %

Procedure:
A suspension of (5-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (50 mg, 146 μmol), 2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (97 mg, 360 μmol), Pd(PPh3)4 (51 mg, 40 μmol) and NaOtBu (56 mg, 580 μmol) in 1.2 mL of DMF/water (5:1, degassed) is degassed for 1 min in a sealed tube. The tube is sealed and the reaction mixture heated at 110° C. for forty minutes in the microwave (CEM explorer) and then at the same temperature for thirty minutes in an oil bath. After evaporation of the solvents the residue is taken up in dichloromethane, filtered and evaporated. The crude product is purified by flash chromatography (silica gel, dichloromethane/7N NH3 in methanol 97:3 to 90:10) and triturated (3× with ethyl acetate) affording the title compound (12 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][O:14][CH2:15]3)[N:3]=1.CI.[C:21]([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:21])=[C:4]([N:11]2[CH:12]3[CH2:18][CH2:17][CH:16]2[CH2:15][O:14][CH2:13]3)[N:3]=1
Reactant: Clc1nc(N2C3CCC2COC3)c2nc[nH]c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cnc2c(N3C4CCC3COC4)nc(Cl)nc21
Reaction time: 65 h
Yield: 98.2 %

Procedure:
A mixture of 2-chloro-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9H-purine (650 mg, 2.45 mmol), methyl iodide (183 μL, 2.94 mmol) and K2CO3 (473 mg, 3.43 mmol) in THF (15 mL) was stirred at r.t. for 18 h before further methyl iodide (50 μL, 0.80 mmol) was added. The resulting mixture was allowed to stir for 65 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H2O, the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo affording the title compound as an off-white solid (673 mg, 98%). LCMS (method H): RT 2.63 min [M+H]+ 280.3
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[CH:18][CH:17]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 4-bromoaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:27]([F:30])([F:29])[F:28])=[O:10])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.Cl>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:27]([F:30])([F:28])[F:29])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2cnc3c(C(F)(F)F)cccc3c2-c2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Yield: 78.6 %

Procedure:
(4-Methoxyphenyl)[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (0.174 g) and pyridine hydrochloride are heated at 200° C. for 2 h and then cooled. The resulting solid is taken into methylene chloride and 2N aq HCl. The layers are separated, the aqueous layer is extracted again, and the combined organics are washed with saturated sodium bicarbonate and dried over MgSO4. The residue is chromatographed eluting with 25:75 ethyl acetate:hexane to afford the title compound as a white solid (0.132 g). MS (ES) m/z 392.1; HRMS: calcd for C23H14F3NO2—H, 392.08984; found (ESI, [M−H]−), 392.0883.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[O:6][CH2:7][C:8]#[N:9].[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[NH:25][C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[N:25]([CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:5]([O:6][CH2:7][C:8]#[N:9])[CH:4]=2)[C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1
Reactant: N#CCOc1cccc(CO)c1
Reactant: O=C(Nc1cccc2c1C(=O)NC2=O)c1ccc(Cl)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCOc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.46 g (8.94 mmol) of 2-[3-(hydroxymethyl)phenoxy]acetonitrile, 2.5 g (8.15 mmol) of 5-chloro-N-(1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)-2-thiophenecarboxamide and 4.28 g (16.3 mmol) of triphenylphosphine are, under argon, dissolved in 250 ml of tetrahydrofuran. 2.84 g (16.3 mmol) of DEAD (diethyl azodicarboxylate) are added, and the mixture is stirred at room temperature overnight. 10 g of silica gel are added and the mixture is concentrated under reduced pressure and chromatographed on a silica gel column (gradient: toluene->toluene/ethyl acetate=4:1). This gives 2.37 g (64.4% of theory) of the target compound of melting point 164° C. Rf (SiO2, toluene/ethyl acetate=4:1): 0.45.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH2:41]([N:43]1[C:51](I)=[C:50]2[C:45]([CH:46]=[CH:47][CH:48]=[CH:49]2)=[N:44]1)[CH3:42]>>[CH2:41]([N:43]1[C:51]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:19])[CH3:20])[CH2:16][CH2:17]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:6]=2)=[C:50]2[C:45]([CH:46]=[CH:47][CH:48]=[CH:49]2)=[N:44]1)[CH3:42]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Reactant: CCn1nc2ccccc2c1I
Product: CCn1nc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following the procedures for 165, 2-[1-(9-methyl-6-morpholin-4-yl-2-(tributylstannanyl)-9H-purin-8-ylmethyl)piperidin-4-yl]propan-2-ol and 2-ethyl-3-iodo-2H-indazole were reacted to give 189. LCMS m/z: 519.3 (MH+)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[O:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)(Cl)Cl.OS([O-])=O.[Na+]>[Br:22][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([O:13][CH3:14])=[CH:7][C:8]=1[CH2:11][OH:12]
Reactant: COc1cc(CO)ccc1C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CO)c(Br)cc1C(C)(C)C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
step b—To a solution of 345 (2.08 g, 10.70 mmol) in CCl4 (75 mL) was added NBS (2.10 g, 11.80 mmol). The reaction was stirred for 15 min then diluted with a cold 10% aqueous NaHSO3. The reaction mixture was extracted with DCM. The organic extract was washed with brine, dried (MgSO4), filtered and concentrated. The residue was taken up in hexanes (80 mL) and then concentrated to afford 2.9 g (100%) of 344a as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][CH2:34][NH2:35]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:35][CH2:34][CH2:33][C:29]4[N:28]([CH3:27])[CH:32]=[CH:31][CH:30]=4)=[O:23])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cn1cccc1CCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Product: Cn1cccc1CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Yield: 82 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (13 mg, 0.0365 mmol) described in example 92 and [2-(1-methyl-1H-pyrrol-2-yl)ethyl]amine (45 mg, 0.364 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (13 mg, 86% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.31 (br s, 1 H), 8.56 (s, 1 H), 7.38 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.99 (m, 2 H), 6.56 (m, 1 H), 6.06 (m, 1 H), 5.99 (s, 1 H), 4.12 (s, 2 H), 3.68 (m, 2 H), 3.59 (s, 3 H), 3.57 (s, 3 H), 2.90 (m, 2 H); MS m/z 435 (M+1).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[S:6]1[C:10]2[CH:11]=[C:12]([NH:15][C:16](=[O:20])[CH:17]=NO)[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1>O>[S:6]1[C:10]2[C:9](=[CH:14][CH:13]=[C:12]3[C:11]=2[C:17](=[O:2])[C:16](=[O:20])[NH:15]3)[N:8]=[CH:7]1
Reactant: O=C(C=NO)Nc1ccc2ncsc2c1
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=C1Nc2ccc3ncsc3c2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a 1-L flask was added a magnetic stir bar, 85 g of sodium sulfate, and 100 mL of water. The mixture was magnetically stirred until all the solids were dissolved. To the resultant aqueous solution was added a solution of 6-aminobenzothiazole (4.96 g, 33.0 mmol) in 50 mL of 1N aqueous hydrochloric acid and 10 mL of ethanol. The mixture was stirred, and chloral (6.0 g, (36 mmol) was added. To the resultant solution was added a solution of hydroxyl amine hydrochloride (7.50 g, 108 mmol) in 30 mL of water. The final mixture was heated with stirring to a gentle boil until all solids dissappeared, and heating was continued for an additional 15 min. The flask was removed from the heat, and the solution was poured onto 500 g of ice. The mixture was stirred as the product precipatated from solution. The precipatate was collected by suction filtration, washed thoroughly with water, filtered, and air dried to provide 6.9 g (94%) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide: 1H NMR (DMSO-d6): δ 12.2 (s, 1H), 10.4 (s, 1H), 9.2 (s, 1H), 8.5 (s, 1H), 7.9 (d, 1H), 7.7 (m, 1H), 7.7 (s, 1H); APCI-MS m/z 220 (M−H)−. To a 1-L 3-neck round bottom flask was placed a magnetic stir bar and 100 ml of concentrated sulfuric acid. The flask was fitted with a thermometer to monitor the temperature of the reaction. The sulfuric acid was heated to 100° C., and 10.0 g (45.2 mmol) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide was added slowly. The solution was heated for ˜1 h, and the reaction mixture was poured into 750 g of ice and water. The residual reaction mixture in the reaction vessel was washed out with an additional 20 mL of cold water. The aqueous slurry was stirred for about 1 h and filtered. The solid was washed thoroughly with water, filtered, and air dried to yield 4.3 g (46%) of 6-H-1-thia-3,6-diaza-as-indacen-7,8-dione: 1H NMR (DMSO-d6): δ 11.1 (s, 1H), 9.2 (s, 1H), 8.2 (d, 1H), 7.0 (d, 1H); APCI-MS m/z 203 (M−H)−.