Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[N:3]=1.[Cl-].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH3+:27])[CH:22]=[C:21]2[CH3:28].CN1CCOCC1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C.O>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH:27][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[N:5][CH:6]=1)=[O:10])[CH:22]=[C:21]2[CH3:28]
Reactant: Cc1cn([NH3+])c2ccc(F)cc12
Reactant: Cc1nc(-c2nccs2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1nc(-c2nccs2)ncc1C(=O)Nn1cc(C)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
A mixture of 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (221 mg, 1 mmol), 5-fluoro-3-methyl-indol-1-yl-ammonium chloride (200 mg, 1 mmol) and N-methylmorpholine (101 mg, 1 mmol) in DMF (5 mL) is stirred at rt for 5 min. 4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride (277 mg, 1 mmol) is added and the reaction is heated to 50° C. for 4 h. The reaction mixture is then poured into water (50 mL). The precipitate is collected via filtration and dried in vacuo to provide 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (68%). MS: 368 (M+H); 1H NMR (300 MHz, CDCl3): δ=2.27 (s, 3H), 2.76 (s, 3H), 7.06 (dt, 1H), 7.35-7.38 (m, 2H), 7.42-7.47 (m, 1H), 8.07 (d, 1H), 8.14 (d, 1H), 9.22 (s, 1H), 11.9 (s, 1H).
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:29]/[CH:30]=[O:31])[CH:23]=1>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:30](=[O:31])[CH:29]([CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:32])[CH:23]=3)[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: Cc1cccc(/C=C/C=O)c1
Product: Cc1cccc(CC2C(=O)Oc3[nH]c(-c4cc(F)ccc4F)nc3C2c2ccccc2)c1
Yield: 61 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(m-tolyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 8 as an off-white solid (78 mg, 61%). Analytical data for 8: 1H NMR (500 MHz, CDCl3) δ 9.39 (d, J=7.3 Hz, 1H), 7.88 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.37-7.29 (m, 3H), 7.20-7.12 (m, 3H), 7.11-7.01 (m, 2H), 6.97 (ddd, J=6.2, 4.9, 1.9 Hz, 3H), 4.18 (d, J=6.9 Hz, 1H), 3.62 (ddd, J=9.7, 6.9, 4.8 Hz, 1H), 3.27 (dd, J=15.3, 4.8 Hz, 1H), 2.53 (dd, J=15.3, 9.8 Hz, 1H), 2.04 (s, 3H); 13C NMR (CDCl3, 126 MHz) δ 169.1, 159.1 (d, JCF=243.5 Hz), 155.4 (dd, JCF=241.0, 2.4 Hz), 148.8, 137.2, 136.7, 136.4, 135.9, 130.7, 129.3, 128.7, 128.3, 127.9, 126.7, 126.0, 118.4 (dd, JCF=12.8, 8.9 Hz), 117.1 (dd, JCF=25.8, 8.6 Hz), 116.6 (dd, JCF=24.8, 9.5 Hz), 114.5 (dd, JCF=26.8, 3.8 Hz), 110.9 (d, JCF=3.8 Hz), 45.6, 38.5, 29.5, 19.4; IR (film) cm−1 11773, 1636, 1618, 1529, 1481, 1463, 1452, 1411, 1240, 1171, 1122, 1100, 1078, 766, 747, 700; LRMS (ESI): Mass calcd for [M+H]+ C26H21F2N2O2: 431.2. found 431.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 4% IPA/2% MeOH/hexanes; 0.7 mL/min, 280 nm), Rt1 (minor)=39.1, Rt2 (major)=69.4 min; er=97:3.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[OH:29].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[O:29][C:2]1[C:3]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CSc1nc(Cl)c2c(n1)CCN(C(=O)OC(C)(C)C)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc2c(c(Oc3ccc(Cl)cc3Cl)n1)CN(C(=O)OC(C)(C)C)CC2
Yield: 37.1 %

Procedure:
A mixture of tert-butyl 4-chloro-2-methylthio-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate (100 mg, 0.317 mmol), 2,4-dichlorophenol (57 mg, 0.348 mmol) and sodium bis(trimethylsilyl)amide (1.0 M solution in THF, 412 μl, 0.412 mmol) in tetrahydrofuran (2 ml) was heated at reflux over night. The mixture was partitioned between ethyl acetate and water. Organic layer was separated and washed with brine, dried (MgSO4) and filtered. Concentration of filtrate afforded crude product (180 mg), which was purified by flash chromatography (0.5% methanol in dichloromethane as eluent) to give tert-butyl 4-(2,4-dichlorophenoxy)-2-methylthio-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate as a white foam (52 mg, yield 37%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1O>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: Oc1ccccc1F
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Oc1ccccc1F
Yield: 17 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 2-fluorophenol (17 mg, 0.15 mmol) as the coupling partner. Concentration (no chromatography) yielded 11 mg (17%) of the titled compound. ESI-MS m/z 386 (MH+), 384 (M−H−).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[C:11]([S:13]([NH:16][C:17]([NH:19][C:20]2[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=2)=[O:18])(=[O:15])=[O:14])[CH:12]=1>CC(N(C)C)=O>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([O:28][CH3:29])[N:21]=[C:20]([NH:19][C:17]([NH:16][S:13]([C:11]2[CH:12]=[C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=[CH:9][C:10]=2[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])(=[O:15])=[O:14])=[O:18])[N:25]=1
Reactant: CCC(=O)Cl
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(N)ccc2C(=O)N(C)C)n1
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1ccc(C(=O)N(C)C)c(S(=O)(=O)NC(=O)Nc2nc(OC)cc(OC)n2)c1

Procedure:
0.13 ml of propionyl chloride is added slowly dropwise to a solution of 0.64 g of 5-amino-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-dimethylaminocarbonylbenzenesulfonamide in 10 ml of dimethylacetamide. After the end of reaction, the reaction mixture is concentrated under reduced pressure and the residue is washed with water and ethyl acetate, to give 0.45 g of the desired product in high purity (>92%, HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]=[O:26])[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]([Si](C)(C)C)([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]([OH:26])[C:28]([F:30])([F:29])[F:27])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C=O)cc2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C(O)C(F)(F)F)cc2=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a semi-suspension of 1-(3-bromophenyl)-5-[(4-methoxybenzyl)oxy]-4-oxo-1,4-dihydropyridine-2-carbaldehyde (500 mg, 1.21 mmol) in THF (5 mL) at 0° C. was added (trifluoromethyl)trimethylsilane solution (5.3 mL of 0.5 mL solution in THF) followed by tetrabutylammonium fluoride solution (0.1 mL of a 1 M solution in THF). The reaction mixture was stirred at 0° C. for 1 h and then quenched by adding water. The quenched reaction mixture was then diluted with dichloromethane, washed with brine (1×), dried over Na2S04, filtered, and concentrated in vacuo. Purification by flash chromatography (24 g silica gel, linear gradient of 0 to 5% methanol in dichloromethane) afforded 1-(3-bromophenyl)-5-[(4-methoxybenzyl)oxy]-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][NH2:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][NH:30][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCc1cccc(-c2ccccc2)c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: c1ccc(-c2cccc(CNc3nccc(-n4cnc5ccccc54)n3)c2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-phenylbenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 378.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.60 (s, 1H); 8.44 (br s, 1H); 8.09 (br s, 1H); 7.85 (m, 1H); 7.65 (s, 1H); 7.59 (d, J=7.3 Hz, 2H); 7.56 (m, 1H); 7.41-7.49 (m, 4H); 7.36 (m, 3H); 6.85 (d, J=5.2 Hz, 1H); 5.83 (br s, 1H); 4.83 (d, J=5.9 Hz, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:18]([N:20]3[CH2:24][CH2:23][C@@:22]4([C:32]5[CH:31]=[CH:30][N:29]=[CH:28][C:27]=5[C:26](=[O:33])[O:25]4)[CH2:21]3)=[O:19])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.CO>[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:18]([N:20]3[CH2:24][CH2:23][C@@:22]4([C:32]5[CH:31]=[CH:30][N:29]=[CH:28][C:27]=5[C:26](=[O:33])[O:25]4)[CH2:21]3)=[O:19])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(/C=C/c5ccccn5)cc4)CC3)C2)c2ccncc21
Agent: [Pd]
Solvent: CO
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(CCc5ccccn5)cc4)CC3)C2)c2ccncc21
Reaction time: 1.5 h

Procedure:
A mixture of (1R)-1′-[(1-{4-[(E)-2-pyridin-2-ylvinyl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (20 mg, 0.00004 mol, example 488), 10% Pd—C in methanol (1 mL, 0.02 mol) was stirred under a hydrogen atmosphere (balloon) for 1.5 h. The reaction mixture was then filtered and concentrated to afford the desired product. LCMS: m/z 440.2 (M+H)+; 462.2 (M+Na)+.
Reaction SMILES: C1(OC2C=CC=CC=2[N+:14]([O-:16])=[O:15])C=CC=CC=1.O(C1C=CC=CC=1N)C1C=CC=CC=1.[O:31]([C:38]1[CH:47]=[CH:46][CH:45]=[CH:44][C:39]=1[NH:40][C:41](=[O:43])[CH3:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[N+]([O-])(O)=O>C(O)(=O)C>[N+:14]([C:46]1[CH:45]=[CH:44][C:39]([NH:40][C:41](=[O:43])[CH3:42])=[C:38]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:47]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1Oc1ccccc1
Reactant: CC(=O)Nc1ccccc1Oc1ccccc1
Agent: Nc1ccccc1Oc1ccccc1
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1Oc1ccccc1
Yield: 60 %

Procedure:
o-Nitrophenyl phenyl ether was reduced catalytically to o-phenoxyaniline, m. 43°-5°, which was acetylated to 2'-phenoxyacetanilide, m. 82°-4°. Yields from both reactions were essentially quantitative. The 2'-phenoxy-acetanilide was dissolved in acetic acid and treated at 60°-80° with red fuming nitric acid to produce a 60-70% yield of 4'-nitro-2'-phenoxy-acetanilide, m. 176°-183°. This was deacetylated by refluxing with methanolic hydrochloric acid to 4-nitro-2-phenoxyaniline, m. 116°-8°. The yield was 99% of theoretical.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1.O[C:12]1C=CC(CCCO)=CC=1.C1C=CN=CC=1.O=S(=O)=O>CS(C)=O.C(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: O=CCc1ccc(O)cc1
Reactant: OCCCc1ccc(O)cc1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C=O)c1ccc(O)cc1
Yield: 75 %

Procedure:
4-hydroxyphenylpropionaldehyde was prepared by a synthesis analogous to that for 4-hydroxyphenylacetaldehyde (Heterocycles, 2000, 53, 777-784). 3-(4-Hydroxyphenyl)-1-propanol (1.0 g, 6.6 mmol, Aldrich) was dissolved in dimethylsulfoxide (8 mL, Aldrich). TEA (2.0 mL, 14 mmol, Aldrich) was added slowly with stirring. Pyridine-sulfur trioxide (SO3.py) complex (2.3 g, 15 mmol, Aldrich) was completely dissolved in dimethylsulfoxide (9 mL, Aldrich) and this solution was added drop-wise to the alcohol, with vigorous stirring. After stirring for 1 h at room temperature, the reaction was diluted with CH2Cl2, then washed with ice-cold water. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. Purification using silica gel chromatography with hexane-ethyl acetate as eluent (5:1, then 2:1) yielded 745 mg (75%) of 4-hydroxyphenylpropionaldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([NH2:22])[N:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CCO>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:22])[N:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)c(N)n2)C1
Reaction time: 48 h
Yield: 282.8 %

Procedure:
The mixture of [1-(6-amino-5-nitro-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (2 g, 2.17 mmole), Pd/C (148 mg, 1.23 mmole), and EtOH (100 ml) was shaken under H2 gas for 2 days. Reaction solution was filtered and filtrate was concentrated to afford [1-(5,6-diamino-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (1.8 g, ˜100%) as a dark green solid. 1H NMR (400 MHz, CD3OD) δ 1.17 (m, 1H), 1.44 (s, 9H), 1.86 (m, 16H), 2.18 (m, 12H), 3.14 (m, 1H), 3.42 (m, 1H), 3.59 (m, 1H), 4.505 (m, 1H), 6.67 (d, J=6.53 Hz, 1H), 6.920 (m, 1H). MS(ESI) m/z 294 [M+1].
Reaction SMILES: BrC1C(NC2C=C(OC(C)C)NN=2)=NC(N[C@H:9]([C:11]2[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=NC=1.C1C[O:31]CC1.C[Mg+].[Br-]>CCOCC>[F:17][C:14]1[CH:13]=[N:12][C:11]([C:9](=[O:31])[CH3:10])=[N:16][CH:15]=1
Reactant: C1CCOC1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Br)n[nH]1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(=O)c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A round-bottom-flask containing 5-fluoropyrimidine-2-carbonitrile (Method 6, 1.50 g, 12.19 mmol) was charged with anhydrous THF (30 ml) under N2. The solution was cooled to 0° C., and a solution of MeMgBr (4.90 ml of a 3.0 M solution in ether, 14.62 mmol) was added dropwise. After 2 hours at 0° C., the reaction mixture was quenched with ice water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, and evaporated to dryness to give the title compound as an oil (0.778 g, yield 46%). GC-MS, 140 (M); 1H NMR (CDCl3) δ 8.65 (s, 2H), 2.65 (s, 2H).
Reaction SMILES: Cl.Cl.[OH:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH:17]1([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27](F)[C:28]=3[F:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH2:19][CH2:18]1>CS(C)=O>[CH:17]1([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27]([N:7]4[CH2:8][CH2:9][N:4]([OH:3])[CH2:5][CH2:6]4)[C:28]=3[F:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH2:18][CH2:19]1
Reactant: ON1CCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCN(O)CC3)c(F)cc2c1=O
Temperature: 130 °C
Yield: 71.3 %

Procedure:
1-Hydroxypiperazine dihydrochloride (4.64 g), triethylamine (8.9 g) and dimethylsulfoxide (25 ml) are added to 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (5.0 g), which is prepared according to the procidures described in Japanese Patent First Publication No. 212474/1984, and the mixture is stirred with heating at 130° C. for 45 minutes. After cooling of the mixture to room temperature, the resulting crystals are filtered. To the crystals is added water (20 ml) and the mixture is stirred at 50° C. for 1 hour. The insoluble substance is filtered and recrystallized from a mixture of dimethylformamide and water to afford 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (4.6 g) as pale yellow prisms, m.p. 223°-227° C. (decomposed with foaming).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH2:14]Cl)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[NH:16]1[CH:20]=[CH:19][CH:18]=[N:17]1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]([CH2:14][N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: c1cn[nH]c1
Reactant: Cc1cccc(C)c1N(CCl)C(=O)CCl
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1N(Cn1cccn1)C(=O)CCl

Procedure:
43.9 parts by weight of 2-chloro-2',6'-dimethyl-N-chloromethyl acetanilide and 25.8 parts by weight of pyrazole are stirred for 7 hours at 90° C. in 120 parts by volume of toluene. After the mixture has cooled it is filtered, and the filtrate is washed 3 times with water, each time with 50 parts by volume, and dried over sodium sulfate. The solvent is evaporated and the residue pasted with 50 parts by volume of petroleum ether to give 39.1 parts by weight of 2-chloro-2',6'-dimethyl-N-(pyrazol-1-yl-methyl)-acetanilide, m.p.: 81° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][OH:25].CCOC(/N=N/C(OCC)=O)=O.[CH2:39]([C:41]1[CH:63]=[CH:62][CH:61]=[CH:60][C:42]=1[NH:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([O:55][CH3:56])=[C:51](O)[CH:52]=2)[N:47]=[CH:46][C:45]=1[C:57]([NH2:59])=[O:58])[CH3:40]>C(Cl)Cl.C1COCC1>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][O:25][C:51]1[CH:52]=[C:53]2[C:48](=[CH:49][C:50]=1[O:55][CH3:56])[N:47]=[CH:46][C:45]([C:57]([NH2:59])=[O:58])=[C:44]2[NH:43][C:42]1[CH:60]=[CH:61][CH:62]=[CH:63][C:41]=1[CH2:39][CH3:40]
Reactant: CN(C)CCCO
Reactant: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(OC)c(O)cc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(OC)c(OCCCN(C)C)cc12

Procedure:
Polymer-bound Triphenylphosphine (0.15 g, 0.44 mmol) and 3-dimethylamino-1-propanol (26 μl, 0.22 mmol) was suspended and dissloved in CH2Cl2 and THF at −15° C. and stirred for 30 min. DEAD (70 μl, 0.44 mmol) was added dropwise at −15° C. 4-(2-Ethylanilino)-6-hydroxy-7-methoxy-3-quinolinecarboxamide (50 mg, 0.15 mmol) was suspended in THF and then added to the reaction. The reaction was stirred over night, allowing the temperature rise to ˜10° C. The polymer was filtered off and the filtrate concentrated in vacuo. The product was purified using preparative HPLC according 15 mg (24%) of white crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[OH:22][CH2:23][C@@H:24]1[O:28][C:27]([C:29]2[NH:33][C:32]([C:34]3[CH:35]=[C:36]([OH:46])[CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=3)=[CH:31][CH:30]=2)=[N:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:22][CH2:23][C@@H:24]1[O:28][C:27]([C:29]2[NH:33][C:32]([C:34]3[CH:35]=[C:36]([CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=3)[O:46][C:2]3[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=3)=[CH:31][CH:30]=2)=[N:26][CH2:25]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Reactant: COc1ccc(CN(C)S(=O)(=O)c2ccc(Cl)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
5-Chloro-N-(4-methoxybenzyl)-N-methylpyridine-2-sulfonamide (427 mg, 1.31 mmol) synthesized in Example (121b) and 3-{5-[(5R)-5-(hydroxylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (568 mg, 1.64 mmol) synthesized in Example (125g) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (361 mg, 2.61 mmol) was added, followed by stirring at 100° C. for 2 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (40 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-3.5%) to afford the desired compound (228 mg, yield 27%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:26][N:27]1[C:31]([SH:32])=[N:30][N:29]=[N:28]1.COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[CH3:26][N:27]1[C:31]([S:32][CH2:1][O:2][C:3](=[O:6])[CH3:4])=[N:30][N:29]=[N:28]1.[CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5]
Reactant: Cn1nnnc1S
Agent: COC(=O)CO
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCSc1nnnn1C
Reaction time: 2 h

Procedure:
After glycolic acid methyl ester (300 mg, 3.33 mmol), triphenylphosphine (1052 mg, 4.00 mmol), 1-methyl-5-mercapto-1H-tetrazole (465 mg, 4.00 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (937 mg, 4.00 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for two hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using ethyl acetate (10 ml,×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 70% ethyl acetate-hexane solution) to give acetic acid (1-methyl-1H-tetrazole-5-ylsulfanyl)methyl ester as a colorless oily substance (549 mg, yield: 88%/glycolic acid methyl ester).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[CH2:7]CN)([CH3:3])[CH3:2].[CH3:16][NH:17]CC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:32].[N:33]1([CH2:39][CH2:40][CH2:41][N:42]2[CH2:48][C:47]3[CH:49]=[C:50](/[CH:53]=[CH:54]/[C:55]([OH:57])=O)[CH:51]=[N:52][C:46]=3[NH:45][C:44](=[O:58])[CH2:43]2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:32].[CH:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[CH2:7][N:17]([CH3:16])[C:55](=[O:57])/[CH:54]=[CH:53]/[C:50]1[CH:51]=[N:52][C:46]2[NH:45][C:44](=[O:58])[CH2:43][N:42]([CH2:41][CH2:40][CH2:39][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:48][C:47]=2[CH:49]=1)([CH3:2])[CH3:3]
Reactant: CCCc1c(CNC)ccc2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)CC(=O)N2
Reactant: COc1cccc(CCN)c1OC(C)C
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: COc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCCN2CCOCC2)CC(=O)N3)c1OC(C)C
Yield: 44 %

Procedure:
According to the procedure of Example 1, except substituting (2-isopropoxy-3-methoxy-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[4-(3-morpholin-4-yl-propyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-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 (0.17 g, 44%) was prepared as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ 11.01 (br s, 1H), 10.66 (br s, 1H), 8.62 (br s, 1H), 8.35-8.22 (m, 1H), 7.57-7.52 (m, 1H), 7.40-7.32 (m, 1H), 7.05-6.93 (m, 2H), 6.66-6.62 (m, 1H), 4.80-4.64 (m, 2H), 4.60-4.45 (m, 1H), 4.08 (br s, 2H), 3.87-3.81 (m, 6H), 3.79 (s, 3H), 3.68 (br s, 2H), 3.50-3.38 (m, 4H), 3.21 (br s, 2H), 3.10-2.72 (m, 3H), 2.01 (br s, 2H), 1.27-1.15 (m, 6H); MS (ESI) m/e 552 (M+H)+.