Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:28](O)=[O:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][NH:35][CH3:36]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:28](=[O:29])[N:35]([CH2:34][C:33]4[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=4[F:31])[CH3:36])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CNCc1ccccc1F
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)N(C)Cc4ccccc4F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-[4′-(4-carboxymethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (2-fluoro-benzyl)-methyl-amine.
Reaction SMILES: O1C(C)C1.[H-].[Na+].[CH2:7]1[O:9][CH:8]1[CH2:10][OH:11].C(S([C:17]1[S:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]23[CH2:36][CH:31]4[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]4)[CH2:28]2)[CH2:34]3)=[O:23])=[CH:20][N:21]=1)(=O)=O)C>O1CCCC1>[O:9]1[CH:8]([CH2:10][O:11][C:17]2[S:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]34[CH2:36][CH:31]5[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]5)[CH2:28]3)[CH2:34]4)=[O:23])=[CH:20][N:21]=2)[CH2:7]1
Reactant: OCC1CO1
Reactant: CCS(=O)(=O)c1ncc(C(=O)NCCC23CC4CC(CC(C4)C2)C3)s1
Agent: CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1cnc(OCC2CO2)s1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
This example illustrates further processes of the invention for preparing the 1,2-epoxypropane compounds of formula B. In this example 0.0525 mole of sodium hydride in a 50% mineral oil mixture is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, then cooled to -30° C and 0.055 mole of glycidol is added dropwise. The mixture is allowed to warm to -5° C and stirred for 10 minutes and then recooled to -30° C. A solution of 0.05 mole of 2-ethylsulfonyl-5-[2-(adamant-1-yl)ethylaminocarbonyl]thiazole in 100 ml. of anhydrous tetrahydrofuran is added dropwise and the resulting mixture allowed to warm to 0° C. Additional solvent is added as needed to facilitate stirring. The mixture is maintained at 30 minutes at 0° C and then poured into 500 ml. of ethyl acetate, extracted with 100 ml. of water, and then with 100 ml. of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under dryness affording oily residue which is then further purified by chromatography on silica gel eluting with 40% ethyl acetate- 60% hexane, by vol., affording 1,2-epoxy-3-[5-(2-[adamant-1-yl]ethylaminocarbonyl)thiazol-2-yloxy]propane.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1.C([Li])CCC.I[C:20]1[CH:21]=[C:22]([Br:26])[CH:23]=[CH:24][CH:25]=1>[Cl-].[Zn+2].[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:26][C:22]1[CH:21]=[C:20]([C:11]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:13])([CH3:12])[CH3:1])[N:8]=[CH:9][N:10]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)CCOCn1cncn1
Reactant: Brc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1ncnc1-c1cccc(Br)c1
Yield: 31.4 %

Procedure:
This reaction was carried out as described in Example 40, step a, using 1-(2-trimethylsilanylethoxymethyl)-1H-[1,2,4]triazole (5.34 g, 26.8 mmol), butyllithium (26.8 mmol, 1.6 M in hexanes, 16.8 ml), zinc chloride (3.65 g, 26.8 mmol), 3-iodobromobenzene (3.42 ml, 26.8 mmol) and dichlorobis(triphenylphosphine)palladium(II) (942 mg, 5 mol %) to yield the title compound (2.98 g, 31%): 1H NMR (360 MHz, CDCl3) δ 8.11 (1H, s), 7.94 (1H, s), 7.86 (1H, d, J 7.7 Hz), 7.62 (1H, d, J 7.8 Hz), 7.37 (1H, t, J 7.8 Hz), 5.49 (2H, s), 3.79 (2H, t, J 8.3 Hz), 0.97 (2H, t, J 8.3 Hz), 0.00 (9H, s).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>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.C1(C)C=CC=CC=1.C(O)C>[C:21]1([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([Br:11])[CH:9]=3)[N:4]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Br)cnc21
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccccc2)c2cc(Br)cnc21
Temperature: 110 °C

Procedure:
To a solution of 3-iodo-5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (250 mg, 0.54 mmol) in a 3:1 toluene/ethanol mixture (17 ml) are added benzene boronic acid (65 mg, 0.54 mmol), K2CO3 (1.6 ml of 2 M solution in water, 3.20 mmol) and Pd(PPh3)4 (1.5 mol %) and the reaction is heated at 110° C. for 3.5 hours under argon.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]([CH3:31])([OH:30])[CH3:29].Cl>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][N:12]([CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: CC(C)(O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(C)(C)O)cc(-c2ccc(F)cc2)c1=O
Temperature: 70 °C
Reaction time: 10 h

Procedure:
Ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (400 mg) was suspended in DMF (5.0 ml). Cesium carbonate (1200 mg), 1-chloro-2-methyl-2-propanol (345 μl) and tetra-n-butylammonium iodide (56 mg) were added sequentially, and the mixture was stirred at 70° C. for 10 hours. A 1 N aqueous hydrochloric acid solution was added at room temperature. The insoluble matter was removed by filtration through celite, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->60:1 (v/v)] to give 57 mg of the title compound as a solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)[CH3:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCc1cc(Cl)n2nccc2n1
Solvent: CCO
Product: CCc1cc(Nc2ccc([N+](=O)[O-])cc2)n2nccc2n1

Procedure:
4.5 g (24.8 mmol) of 7-Chloro-5-ethylpyrazolo[1,5-a]pyrimidine (Example 1, Step B) and 3.5 g (25.3 mmol) 4-nitroaniline were heated in 75 ml dry ethanol for 5 h. During evaporation of the mixture in vacuo crystals precipitated, which were dissolved in dichloromethane. The solution was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, and evaporated to dryness in vacuo to give the title compound as a yellow powder,
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[O:12]1[CH2:20][CH:13]1[CH2:14][O:15][CH2:16][CH:17]1[O:19][CH2:18]1>C(O)C>[OH:12][CH:13]([CH2:20][N:3]1[C:4]([CH3:9])([CH3:10])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:14][O:15][CH2:16][CH:17]([OH:19])[CH2:18][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: C(OCC1CO1)C1CO1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Solvent: CCO
Product: CC1(C)CC(O)CC(C)(C)N1CC(O)COCC(O)CN1C(C)(C)CC(O)CC1(C)C

Procedure:
2,2,6,6-Tetramethyl-4-hydroxypiperidine 15.7 g and bis(2,3-epoxypropyl)ether was dissolved in 30 ml ethanol and refluxed for ten hours. Ethanol was distilled off, and 21.8 g of colorless liquid was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[C:24]([C:33]([NH2:35])=[O:34])=[CH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[C:24]([C:33]([NH2:35])=[O:34])=[CH:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: NC(=O)c1cc2ccccc2cc1N
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc5ccccc5cc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II (but using methanol in place of dimethylether) and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 13.2 mmol) and 3-amino-2-naphthalenecarboxamide (3.00 g, 8.8 mmol), 3-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2-naphthalenecarboxamide was isolated as a white solid (2.56 g, 59% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 3 H), 6.69 (d, J=4.03 Hz, 1 H), 7.42-7.51 (m, 3 H), 7.58 (t, J=7.51 Hz, 1 H), 7.72 (d, J=4.03 Hz, 1 H), 7.78-7.85 (m, 2 H), 7.90 (d, J=8.06 Hz, 1 H), 7.97 (d, J=8.42 Hz, 2 H), 8.40 (s, 2 H), 8.69 (s, 1 H), 11.90 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH2:11][CH2:10][C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]=1[CH:12]=[O:13].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])[O-].[K+].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH2:11][CH2:10][C:5]3([CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:4][C:3]=2[CH:12]=[O:13])=[CH:17][CH:16]=1
Reactant: O=CC1=C(Cl)CCC2(CCCC2)C1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: O=CC1=C(c2ccc(Cl)cc2)CCC2(CCCC2)C1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
To a suspension of EXAMPLE 71A (3 g) in water (50 mL) was added 4-chlorophenylboronic acid (2.83 g), tetrabutylammonium (4.87 g), potassium carbonate (6.26 g) and palladium(II) acetate (0.169 g). The reaction mixture was stirred at 45° C. for 5 hours and extracted with dichloromethane. The organic layer was concentrated and the residue was loaded onto a silica gel column, and eluted with 5-20% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C(N)CCC>C(O)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:14]([N+:11]([O-:13])=[O:12])[CH3:15])=[CH:5][CH:4]=1
Reactant: CC[N+](=O)[O-]
Reactant: CSc1ccc(C=O)cc1
Solvent: CCO
Solvent: CCCCN
Product: CSc1ccc(C=C(C)[N+](=O)[O-])cc1
Reaction time: 21 h
Yield: 44.5 %

Procedure:
The intermediate 1-[4-(methylthio)phenyl]-2-nitro-1-propene was prepared as follows: [U.S. Pat. No. 3,117,160, Example V]; a mixture containing 15.2 g of 4-(methylthio)benzaldehyde, 7.5 g of nitroethane, 0.73 g of n-butylamine and 40 ml of absolute ethanol was refluxed with stirring for 21 hours and the solvent then removed by distilling in vacuo. The residue was recrystallized from absolute ethanol (total volume of 60 ml) washed with a small quantity of cold ethanol and dried in vacuo at room temperature to produce 9.3 g of 1-[4-(methylthio)phenyl]-2-nitro-1-propene, m.p. 74°-76° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1.[OH:32][CH2:33][C:34](O)=[O:35].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:33](=[O:32])[CH2:34][OH:35])[CH2:30][CH2:31]3)=[CH:24][CH:25]=2)=[N:10]1
Reactant: COc1nccc2c1c(-c1ccc(N3CCNCC3)cc1)nn2-c1c(F)cccc1F
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1nccc2c1c(-c1ccc(N3CCN(C(=O)CO)CC3)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-3-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (220 mg) obtained in Step D of Example 311, 2-hydroxyacetic acid (42 mg) and triethylamine (158 mg) in anhydrous THF (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (297 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the residue was purified by thin layer silica gel chromatography (ethyl acetate) to give the title compound (220 mg).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH2:30][C:31]#[C:32][Si](C)(C)C.O>C1COCC1>[CH2:29]([C:21]1[N:20]([CH3:19])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)[CH2:30][C:31]#[CH:32]
Reactant: Cn1c(CCC#C[Si](C)(C)C)nc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#CCCc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
TBAF (0.24 mL, 0.83 mmol) was added to a solution of 1-methyl-2-(4-trimethylsilanyl-but-3-ynyl)-1H-benzoimidazole (178 mg, 0.69 mmol) in THF (2.5 mL) and the reaction mixture was stirred for 2 hours at room temperature. After the addition of water, the solvent was evaporated and the aqueous phase was extracted with DCM. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 90 mg (0.49 mmol, 70%) of 2-but-3-ynyl-1-methyl-1H-benzoimidazole as a brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[C:9]=2[CH3:19])=[O:4].[OH-].[Na+]>C1COCC1.O>[CH3:19][C:9]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[N:16]=[C:17]2[C:8]=1[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:18]2
Reactant: COC(=O)c1ccc2c(C)c3c(nc2c1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2c(nc3cc(C(=O)O)ccc13)CCCC2
Temperature: 70 °C
Yield: 259 %

Procedure:
A solution 9-methyl-5,6,7,8-tetrahydro-acridine-3-carboxylic acid methyl ester (120 mg, 0.04mmols) in THF:water (6 mL:4 mL) added solid sodium hydroxide (75 mg, 0.16mmols) and heated the reaction mixture at 70° C. for 3 h. Reaction completion was monitored by TLC. Alter completion, the reaction mixture was diluted with water and washed with ethyl acetate. The aqueous layer was acidified to pH 3-4 using 1.5N hydrochloric acid solution. Precipitated product was filtered and dried to get the pure product as off white solid (25 mg, 22%). Compound was purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C:11]1[N:12]=[C:13]([NH:16][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[S:14][CH:15]=1
Reactant: COc1cc(F)cc(Cl)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(F)cc(Cl)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
To a solution of 4-(2-chloro-4-fluoro-6-methoxyphenyl)thiazol-2-ylamine (14-2, 0.10 g, 0.39 mmol) in CH2Cl2 (10 mL) was added DMAP (95 mg, 0.78 mmol) followed by isonicotinoyl chloride hydrochloride (90 mg, 0.51 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was collected and recrystallized in toluene to give N-(4-(2-chloro-4-fluoro-6-methoxyphenyl)-thiazol-2-yl)isonicotinamide (14, 55 mg, 0.15 mmol) as white solids in 39% yield: 1H NMR (500 MHz, CDCl3) δ 8.81 (s, 2 H), 7.91 (d, J=4.7 Hz, 2 H), 7.12 (s, 1 H), 6.72 (m, 1 H), 6.50 (m, 1 H), 3.75 (s, 3 H); ESI-MS: m/z 364.2 (M+H)+.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[Cl:47][C:48]12[CH2:57][CH:52]3[CH2:53][CH:54]([CH2:56][C:50]([CH2:58][OH:59])([CH2:51]3)[CH2:49]1)[CH2:55]2>>[Cl:17][C:18]1[C:19]([O:59][CH2:58][C:50]23[CH2:51][CH:52]4[CH2:53][CH:54]([CH2:55][C:48]([Cl:47])([CH2:57]4)[CH2:49]2)[CH2:56]3)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(CC(Cl)(C3)C1)C2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(Cl)(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 3-chloroadamantan-1-yl methanol, the title compound was obtained as a colorless solid (0.15 g, 31%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.23 (d, J=12.3 Hz, 1H), 3.82 (s, 2H), 2.87 (s, 6H), 2.22 (br s, 2H), 2.14-2.02 (m, 6H), 1.70-1.55 (s, 6H); MS (ES−) m/z 477.1, 479.1 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10](O)[C@@H](O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:10][CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1
Reactant: C[C@H](O)CO
Reactant: COc1cscc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1COc2cscc2O1
Yield: 69.5 %

Procedure:
A solution of 3,4-dimethoxythiophene (5.18 g), (S)-1,2-propanediol (3.0 g) and p-toluenesulfonic acid monohydrate (100 mg) in toluene (50 ml) was heated at 95° C. during which a continuous stream of nitrogen was passed over the solution. After 30 h the reaction mixture was poured into ethyl acetate, washed with NaHCO3 and the organic phase was concentrated. Subsequent filtration over SiO2 using n-hexane as eluant resulted in pure product (3.90 g). GC-MS: 156 (purity>99%); 1H-NMR (CDCl3): δ 6.30 (2×d, 2H), 4.26 (m, 1H), 4.15 (dd, 1H), 3.82 (dd, 1H), 1.35 (d, 3H) ppm; specific rotation [α]=−46° at 25° C. and 436 nm in hexane (c=0.066).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:4](=[O:20])[C:3]=1[CH2:21][CH2:22][CH2:23][CH2:24][OH:25].BrBr.N12CCCN=C1CCCCC2.O>C(Cl)Cl>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2](=[O:1])[C:3]3([CH2:21][CH2:22][CH2:23][CH2:24][O:25]3)[C:4]2=[O:20])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(-n2c(=O)c(CCCCO)c(O)c3cccnc32)c1
Agent: BrBr
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COc1cccc(N2C(=O)C3(CCCCO3)C(=O)c3cccnc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-Hydroxy-3-(4-hydroxybutyl)-1-(3-methoxyphenyl)(1,8)-naphthyridin-2(1H)-one (1 g.)in methylene chloride (10 ml),in an ice-acetone bath was added a solution of bromine (0.5 g.) in methylene chloride (5 ml.) over a period of 15 min. The resulting yellow-orange suspension was stirred overnight at room temperature. To the resulting clear yellow solution was added a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (1 g.), in methylene chloride (5 ml.) during 5 mins. The mixture was stirred at room temperature for 3 hrs after which time water (5 ml) was added. The organic layer was separated, dried and evaporated. To the residue was added 50% aqueous ethanol (10 ml.) and after some time the solid was filtered off and recrystallized from isopropanol to yield 1-(3-methoxyphenyl)-3', 4', 5', 6'-tetrahydrospiro[1,8-naphthyridine-3,2'-(2 H)pyran]-2, 4-dione, m.p. 181°-183° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:9][C:10](=[O:31])[C@@H:11]([NH:23]C(OC(C)(C)C)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[CH2:22])=[CH:15][CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[ClH:33]>O1CCOCC1>[ClH:33].[CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:9][C:10](=[O:31])[C@@H:11]([NH2:23])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]=[CH2:22])=[CH:17][CH:18]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OC)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOc1ccc(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)OC)cc1

Procedure:
Methyl ester 1 (4.00 g, 8.92 mmol) was dissolved in 4M HCl in 1,4-dioxane (20 mL). The resultant solution was stirred at rt for 18 h before being concentrated in vacuo to yield a white solid, 3.43 g, 100%.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:13][C:14](=[O:34])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][C:25](=[O:33])[C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:16]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.[BH4-].[Na+]>>[OH:33][CH:25]([C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)[CH2:24][O:23][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[C:14]([NH:13][C:6]1([C:4]([OH:5])=[O:3])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:34]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(OC)c(OCC(=O)c3cccc(C)c3)c2)CCCCCC1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(C(=O)NC2(C(=O)O)CCCCCC2)cc1OCC(O)c1cccc(C)c1

Procedure:
The compound of step 2 was reduced with sodium borohydride in analogy to step 2 of example 53, the ester intermediate purified by RP HPLC (water/ACN gradient) and hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: [O:1]=[C:2]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3](OCC)=[O:4].[NH3:15]>CO>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:2](=[O:1])[C:3]([NH2:15])=[O:4])[CH:10]=1
Reactant: CCOC(=O)C(=O)Nc1cccnc1
Reactant: N
Solvent: CO
Product: NC(=O)C(=O)Nc1cccnc1

Procedure:
A solution of the product from Example 35A and ammonia in methanol was processed as described in Example 1B to provide the title compound.