Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH3:15])=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][NH:7][CH3:8].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:32].[N:33]1([CH2:39][CH2:40][N:41]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53]([OH:55])=O)[CH:49]=[N:50][C:44]=3[NH:43][C:42]2=[O:56])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[ClH:32].[CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH3:15])=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][N:7]([CH3:8])[C:53](=[O:55])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[N:41]([CH2:40][CH2:39][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[CH2:46][C:45]=2[CH:47]=1
Reactant: CCCOc1c(CNC)cccc1OC
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)C(=O)N3)cccc1OC
Yield: 35 %

Procedure:
According to the procedure of Example 1, except substituting 3-methoxy-2-propoxy-benzyl-methylamine for the me thyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.10 g, 35%) was prepared as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.68 (br s, 1H), 10.13 (m, 1H), 8.40-8.30 (m, 1H), 8.01-7.90 (m, 1H), 7.60-7.42 (m, 1H), 7.29-7.15 (m, 1H), 7.01-6.90 (m, 2H), 6.70-6.60 (m, 1H), 4.80-4.51 (m, 4H), 4.02-3.70 (m, 10H), 3.60-3.50 (m, 2H), 3.42-3.30 (m, 2H), 3.20-2.87 (m, 6H), 1.74-1.67 (m, 2H), 1.00-0.91 (m, 3H); MS (ESI) m/e 524 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[S:12](Cl)(=[O:14])=[O:13].O>O1CCOCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[S:12]([NH:2][CH3:1])(=[O:14])=[O:13]
Reactant: CN
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: C1COCCO1
Solvent: O
Product: CNS(=O)(=O)c1c(Cl)cc(Cl)cc1Cl

Procedure:
40% strength aq. methylamine soln. (36.0 g, 464 mmol) was added dropwise to a soln. of 2,4,6-trichorobenzenesulfonic acid chloride (10.0 g, 35.7 mmol) in 1,4-dioxane (60 ml) and the mixture was stirred at RT for 30 min. Water (500 ml) was then added, with vigorous stirring, whereupon a white precipitate formed, which was filtered out and dried over potassium hydroxide in a desiccator.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([Cl:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[ClH:40].[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)=[CH:14][CH:15]=3)[CH2:20]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(F)cc1)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
2-(4-Fluoro-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline hydrochloride is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (158 mg, 0.45 mmol), NEt3 (0.21 mL, 1.5 mmol), and 4-fluorobenzenesulfonyl chloride (115 mg, 0.55 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give 140 mg of free base product. The free base is converted to the HCl salt (150 mg, 71% yld) via a procedure substantially analogous Procedure D. MS (ES+)433.2(M+H)+ free base.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](CCCO)=[C:20]([O:23][CH2:24][C:25]4C=CC=C[CH:26]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[O:23][CH2:24][CH2:25][CH2:26]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(OCc4ccccc4)c(CCCO)c3O2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4c(c3O2)CCCO4)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 2.0 g (4.1 mmole) of [(2R)-7-(benzyloxy)-8-(3-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 100 mL of methanol was added to a slurry of 0.30 g of 10% palladium on carbon in 30 mL of methanol in 500 mL Parr hydrogenation bottle. The mixture was treated with 50 psi of hydrogen on a Parr shaker for 15 hours. The catalyst was then removed by filtration through celite and the filtrate concentrated in vacuum to 1.6 g of a colorless oil. The oil was dissolved in 100 mL of benzene, 2.1 g (8.0 mmole) of triphenylphosphine and 1.6 g (8.0 mmole) of diisopropylazodicarboxylate added and the mixture stirred at room temperature for 5 days. The solvent was then removed in vacuum and the residue column chromatographed on silica gel with methylene chloride as eluant to give 1.2 g of the (R)-enantiomer of the title compound as a pale yellow oil. 1H-NMR (CDCl3): doublet 7.8 δ (2H); doublet 7.35 δ (2H); doublet 6.6 δ (1H); doublet 6.35 δ (1H); multiplet 4.4 δ (1H); multiplet 4.2 δ (3H); triplet 4.1 (2H); doublet of doublets 4.0 δ (1H); multiplet 2.55 δ (2H); singlet 2.45 δ (3H); multiplet 1.9 δ (2H).
Reaction SMILES: [CH:1]([C:4]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1)=[O:5])([CH3:3])[CH3:2].CC(C)=O>C(O)C>[OH:5][CH:4]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:1]([CH3:2])[CH3:3]
Reactant: CC(C)C(=O)c1cncnc1C(F)(F)F
Solvent: CC(C)=O
Solvent: CCO
Product: CC(C)C(O)c1cncnc1C(F)(F)F
Reaction time: 2 h
Yield: 86.9 %

Procedure:
25 g (115 mmol) of 5-isopropylcarbonyl-4-trifluorometylpyrimidine was dissolved in 100 ml of ethanol, and under cooling with ice, 6 g (69 mmol) of a borane-tert-butylamine complex was added, followed by stirring for 2 hours. Further, 20 ml of acetone was added, followed by stirring for 0.5 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent/n-hexane:ethyl acetate=1:1) to obtain 22 g (yield: 87%) of 5-(1-hydroxy-2-methylpropyl)-4-trifluoromethylpyrimidine as slightly yellow liquid (nD20=1.4481)
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:19])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=2[C:9]=1[CH3:10].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:18][O:17][C:11]1[C:8]2[C:9]([CH3:10])=[C:4]([CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH3:20])[CH2:28][CH2:29]3)[C:5](=[O:19])[O:6][C:7]=2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=1
Reactant: COc1cc(OC)c2c(C)c(CCCl)c(=O)oc2c1
Reactant: Cc1ccccc1N1CCNCC1
Product: COc1cc(OC)c2c(C)c(CCN3CCN(c4ccccc4C)CC3)c(=O)oc2c1
Yield: 14 %

Procedure:
Process A; starting materials: 3-(2-chloroethyl)-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 39) and 1-(2-methylphenyl)piperazine; yield 14% of oily crude product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:16][C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][CH:25]([NH2:30])[CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH:20]=[CH:21][CH:22]=1>C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:30][CH:25]([CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH2:24][CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[CH:18]=2)[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cccc(CCC(N)C2CCC2)c1
Reactant: Cc1nc(N)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(CCC(Nc2nc(C)nc(N)n2)C2CCC2)c1

Procedure:
2.2 g (0.015 mol) of 2-amino-4-chloro-methyl-1,3,5-triazine and 4.1 g (0.03 mol) of K2CO3 are introduced into 50 ml of acetonitrile. 2.5 g (0.015 mol) of 3-(3-methylphenyl)-1-cyclobutyl-1-propylamine, dissolved in 20 ml of acetonitrile, are added dropwise to this solution. The mixture is then refluxed for 3 hours. The solid constituents are subsequently filtered off with suction and the filtrate is evaporated on a rotary evaporator. The residue is purified by means of column chromatography (eluant: ethyl acetate). This gives 4.3 g (92% of theory) of 2-amino-6-methyl-4-[3-(3-methylphenyl)-1-cyclobutyl-1-propylamino]-1,3,5-triazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.Cl[CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH2:31][CH2:32][CH2:33][S:34]3(=[O:36])=[O:35])=[CH:3][C:4]=2[N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3N3CCOCC3)CC2)c(C)c1
Reactant: O=S(=O)(Cl)CCCCl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCOCC3)CC2)c(C)c1

Procedure:
Using [4-amino-2-(morpholin-4-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 151 and 3-chloropropane-1-sulfonyl chloride (0.08 mL) and by the reaction and treatment in the same manner as in Preparation Example 78, the title compound (82 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:25])=[CH:4][C:5]([Cl:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[CH3:26][N:27]1[C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]([CH3:35])=[N:28]1>CN(C)C(=O)C>[Cl:24][C:5]1[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:16]=3)[N:13]=2)=[CH:23][C:2]([NH:1][C:32]([C:31]2[N:27]([CH3:26])[N:28]=[C:29]([CH3:35])[CH:30]=2)=[O:33])=[C:3]([F:25])[CH:4]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c(Cl)cc2F)n(C)n1
Yield: 40.6 %

Procedure:
Using N-[6-(5-amino-2-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.55 mmol), N,N-dimethylacetamide (4.0 mL) and 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (105 mg, 0.66 mmol), and in the same manner as in Example 120, the title compound (108 mg, 40%) was obtained as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH3:8][C:5]1[N:4]=[N:3][C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)=[CH:7][CH:6]=1
Reactant: OCCC1CCNCC1
Reactant: Cc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(N2CCC(CCO)CC2)nn1
Temperature: 150 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of 19.3 parts of 3-chloro-6-methylpyridazine, 19.4 parts of 4-piperidineethanol, 16 parts of sodium carbonate and 0.9 parts of N,N-dimethylacetamide was stirred for 5 hours at about 150° C. After cooling, the reaction mixture was diluted with water and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated, yielding 31.5 parts (95%) of 1-(6-methyl-3-pyridazinyl) -4-piperidineethanol (int. 83).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19](OC)=[O:20].CCOCC>O1CCCC1>[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19](=[O:20])[CH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnn1
Reactant: COC(=O)c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1cccnn1)c1ccc(F)cc1F
Yield: 29.1 %

Procedure:
Treatment of 3-methylpyridazine (4.70 g) with lithium diisopropylamide (0.05 mole) in dry tetrahydrofuran followed by methyl 2,4-difluorobenzoate (8.60 g) according to the method of Example 11(i) gave the title compound, (3.40 g), m.p. 115.5°-117.5° (from ether).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[N:4]([CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]([NH:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[C:2]([Cl:1])=[N:3][N:4]3[CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:35])=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: Nc1cccc2c1c(Cl)nn2CCN1CCCC1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)Nc1cccc2c1c(Cl)nn2CCN1CCCC1
Reaction time: 6 h

Procedure:
A mixture of 3-chloro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-4-ylamine (300 mg, 1.14 mmol), (4-benzyloxy-phenyl)-acetic acid (302 mg, 1.25 mmol), ethyldimethylpropylcarbodiimide hydrochloride (261 mg g, 1.37 mmol), N-hydroxybenzotriazole (184 mg, 1.37 mmol), N-methyl morpholine (290 mg, 2.72 mmol) in 5 mL of DMF was stirred for 6 hours and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, triethylamine/ethyl acetate, 1/10) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 1.60 (m, 4H), 2.43 (m, 4H), 2.85 (t, 2H, J=6.44), 3.69 (s, 2H), 4.48 (t, 2H, J=6.44), 5.10 (s, 2H), 6.99 (d, 2H, J=8.81), 7.28–7.48 (m, 9H), 7.59 (m, 1H), 10.10 (s, 1H); MS (DCI/NH3) m/z 489 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([OH:16])=O.Cl.CN.O[N:21]1[C:25]2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:25][NH:21][C:14]([C:2]1[CH:1]=[C:10]2[C:5](=[CH:4][CH:3]=1)[CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=[CH:9]2)=[O:16]
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc2cc(C(=O)O)ccc2c1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a mixture of naphthalene-2,6-dicarboxylic acid (5 g), methylamine hydrochloride (1.64 g) and 1-hydroxybenzotriazole (3.75 g) in dimethylformamide (50 ml) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (3.79 g) under ice-cooling. The mixture was stirred for 1 hour at the same temperature and then at ambient temperature overnight. The mixture was diluted with water, and the precipitates were collected by filtration to give 6-(methylcarbamoyl)naphthalene-2-carboxylic acid (4.07 g).
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26])([O-:21])=[O:20]>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:26][C:25]([C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OC)cc1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: CCOC(=O)c1nc(-c2cccc([N+](=O)[O-])c2)[nH]c1-c1ccc(OC)cc1
Yield: 45.5 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methoxyphenyl)-3-oxopropionate (20.0 g) and 3-nitrobenzylamine (15.0 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 10 to give ethyl 5-(4-methoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxylate (13.3 g), melting point 208-210° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:23]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: c1ccc(C2CCNC2)nc1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: Nc1c(F)c(N2CCC(c3ccccn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 91 %

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.97 g, 2.9 mmol) and 2-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.12 g, 91%) as a bright yellow solid, mp 206°-208° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=1.B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COc1cc(-c2cccc(O)c2)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
To a solution of 6-bromo-4-(3-methoxy-phenyl)2-methoxy-quinoline (1.31 g, 3.81 mmol) in dichloromethane (CH2Cl2. 30 ml) was added a solution of BBr3 in CH2Cl2 (1 M, 11.4 ml, 1 1.4 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. It was poured into water. The organic layer was washed with brine, dried over MgSO4 and concentratred to give the tiltle compound of example 34A (640 mg, 41% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[C:10](Cl)[CH:9]=1)=[O:7].[CH3:30][S-:31].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[C:10]([S:31][CH3:30])[CH:9]=1)=[O:7]
Reactant: COc1cccc2c1ccc1nc3cc(Cl)cc(C(=O)NCCN(C)C)c3nc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1ccc1nc3cc(SC)cc(C(=O)NCCN(C)C)c3nc12
Temperature: 60 °C
Yield: 42.3 %

Procedure:
A mixture of 9-chloro-4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (85 mg) and sodium thiomethoxide (43 mg) in N,N-dimethylformamide (1 mL) was heated to 120° C. for 6 hours and 60° C. for 16 hours. The reaction mixture was then cooled, diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield a yellow solid which was purified using flash chromatography to yield the desired title compound (37 mg).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=O)[C:6]([NH2:9])=[N:7][CH:8]=1>FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>[OH:12][N:10]1[C:5]2[C:6](=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:4]=2)[N:9]=[C:3]1[C:2]([F:14])([F:13])[F:1]
Reactant: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: On1c(C(F)(F)F)nc2ncc(C(F)(F)F)cc21

Procedure:
5-(Trifluoromethyl)-3-nitro-2-aminopyridine (10.0 grams) in trifluoroacetic anhydride (10 ml.) and pyridine (20 ml.) were heated in a steam bath for two hours. Solvents were then evaporated on a rotary evaporator at 100°C. for one hour, and the residue was taken up in ethyl acetate and hydrogenated over 2.0 g. of 5 percent palladium on carbon. The reaction mixture was then filtered, evaporated, and taken up in ethanol; subsequently, the mixture was washed with 10 percent hydrochloric acid, dried over magnesium sulfate, and evaporated. The resulting 1-hydroxy-2,6-bis(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product was recrystallized from acetone, m.p., 239°-40°C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]#[C:11][CH2:12][C@H:13]([OH:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:33][O:34][CH2:35][CH2:36][O:37][CH2:38]Cl>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]#[C:11][CH2:12][C@H:13]([O:23][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H](CC#CCOCc1ccccc1)COc1ccc(F)cc1
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCO[C@@H](CC#CCOCc1ccccc1)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To an ice cooled solution of (2S)-6-benzyloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (2 g, 6.4 mmol) in dry CH2Cl2 (8 ml) was added N-ethyldiisopropylamine (1.7 ml 9.5 mmol) and stirred for 10 minutes MEM-chloride (1.1 ml, 9.5 mmol) was added to the solution at 0° C. and stirred for 3 h at room temperature. The solvent was concentrated and the residue purified on a silica gel column using EtOAc-light petroleum (1:4) as eluent to yield (2S)-6-benzyloxy-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hex-4-yne (2.2 g, 85%) as a yellow colour liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.5 1H NMR (CDCl3, 200 MHz): δ 2.65-2.75 (m, 2H), 3.39 (s, 3H), 3.55 (t, J=4.8 Hz, 2H 3.78 (t, J=4.8 Hz, 2H), 4.11 (s, 2H), 4.16 (m, 3H), 4.56 (s, 2H), 4.89 (s, 2H), 6.8-7.02 (m, 4H), 7.3-7.35 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:24])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH2:25]=[O:26].[OH-].[Na+]>O1CCCC1.O>[OH:1][C:2]1[C:3]([C:11]2([CH2:25][OH:26])[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:24])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=C1Nc2c(cccc2C(F)(F)F)C1c1cc2c(cc1O)OCO2
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1Nc2c(C(F)(F)F)cccc2C1(CO)c1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a suspension of 3-(6-hydroxy-1,3-benzodioxol-5-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one (5.64 g, 16.7 mmol), para-formaldehyde (1.78 g, 59.4 mmol) in tetrahydrofuran (20.0 mL) and water (50.0 mL) was added the aqueous solution of sodium hydroxide (2.68 g, 66.9 mmol) in water (30.0 mL). The reaction mixture was stirred at 0° C. for 1 h and quenched with 10% hydrochloric acid (50.0 mL). The mixture was extracted with ethyl acetate (3×50.0 mL). The combined organic solution was washed with saturated ammonium chloride (3×50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography to afford 3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one (4.56 g, 73%) as a fluffy solid: 1H NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.16 (s, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 7.01 (s, 1H), 6.94 (dd, J=7.7, 7.7 Hz, 1H), 6.18 (s, 1H), 5.88 (s, 2H), 5.03 (br, 1H), 3.97 (ABq, J=9.9 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 180.5, 150.3, 146.8, 141.5, 140.0, 136.0, 127.5, 123.8, 121.0, 117.7, 109.7, 108.4, 101.2, 97.9, 60.2, 55.2; MS (ES+) m/z 390.2 (M+1).