Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[C:6](=[CH:7][C:8]([CH2:19][OH:20])=[CH:9][CH:10]=2)[N:5]=1.Cl.Cl[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[CH3:3][C:4]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[C:6](=[CH:7][C:8]([CH2:19][O:20][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[CH:9][CH:10]=2)[N:5]=1
Reactant: Clc1ccncc1
Reactant: Cc1cc(N2CCCC2)c2ccc(CO)cc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(N2CCCC2)c2ccc(COc3ccncc3)cc2n1
Temperature: 90 °C
Reaction time: 24 h
Yield: 24.4 %

Procedure:
Sodium hydride (55-65% dispersion in mineral oil, 40 mg, 1.0 mmol) was added to a mixture of (2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-methanol (example 2, 100 mg, 0.41 mmol) and 4-chloropyridine hydrochloride (62 mg, 0.41 mmol), and the mixture was heated at 90° C. for 18 h. Then another portion of sodium hydride (40 mg) and 4-chloropyridine hydrochloride (62 mg) was added, and stirring at 90° C. was continued for 24 h. After cooling, the reaction mixture was partitioned between 1 M aq. sodium carbonate solution and ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 9:1) afforded the title compound (32 mg, 24%). Yellow solid, ISP-MS: m/e=320.4 ([M+H]+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]#[C:10][CH2:11][OH:12]>C1(C)C=CC=CC=1>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][C:9]#[C:10][CH2:11][OH:12])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: OCC#CCCl
Solvent: Cc1ccccc1
Product: OCC#CCN1CCOCC1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a mixture of morpholine (4.36 g) in toluene (15 mL) was added 4-chlorobut-2-yn-1-ol (2.09 g) in toluene (5 mL). The mixture was stirred at 85° C. for three hours. After cooling, the solid was filtered off. The filtrate was subjected to vacuum distillation to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:16]=3[O:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:3]1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:32]=2[C:33]([NH:35][CH3:36])=[O:34])[C:27]([Cl:42])=[CH:26][N:25]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][C:20]([NH:22][C:24]4[N:29]=[C:28]([NH:30][C:31]5[C:32]([C:33](=[O:34])[NH:35][CH3:36])=[CH:37][CH:38]=[CH:39][C:40]=5[F:41])[C:27]([Cl:42])=[CH:26][N:25]=4)=[CH:21][C:16]=3[O:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:3]1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCCC(OC(=O)N2CCCOc3cc(N)ccc32)C1
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC2CCCN(C)C2)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 1-methyl-piperidin-3-yl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as an orange foam (84 mg, 44%). LCMS (m/e) 584 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.98-8.75 (m, 1H), 8.09 (s, 1H), 7.40-7.17 (m, 4H), 7.16-6.97 (m, 2H), 6.95-6.84 (m, 1H), 6.40-6.22 (m, 1H), 4.91-4.70 (m, 1H), 4.15-3.95 (m, 2H), 3.82-3.58 (m, 2H), 2.98-2.77 (m, 4H), 2.64-2.48 (m, 1H), 2.38-2.13 (m, 4H), 2.11-1.75 (m, 5H), 1.65-1.40 (m, 1H), 1.30-1.10 (m, 1H); 19F-NMR (CDCl3, 400 MHz) δ −111.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[O:21]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:29]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(Oc2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-phenoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.99 min.; [M+H]+: 432.27 g/mol.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:2]1.O[N:28]=[C:29]([NH2:34])[CH2:30][CH2:31][O:32][CH3:33]>>[CH3:33][O:32][CH2:31][CH2:30][C:29]1[N:34]=[C:24]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[CH2:13][N:8]([C:6]([N:3]3[CH2:4][CH2:5][S:1][CH2:2]3)=[O:7])[CH2:9]2)[O:25][N:28]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSC2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCSC3)C2)n1
Yield: 12.5 %

Procedure:
250 mg (0.644 mmol) of 1-(1,3-thiazolidin-3-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 102A) and 112 mg (0.708 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide (Example 64A) were reacted according to the General Method 1. Enantiomer separation of the racemate according to Method 16D gave 35.0 mg of the title compound from Example 317 and 38.0 mg of the title compound from Example 318 (24% of theory).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH:35]=O)[C:27]3[C:26](=[O:37])[N:25]([CH3:38])[C:24](=[O:39])[N:23]([CH3:40])[C:22]=3[N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH:35]=[CH2:1])[C:27]3[C:26](=[O:37])[N:25]([CH3:38])[C:24](=[O:39])[N:23]([CH3:40])[C:22]=3[N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2C=O)n(C)c1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 200.8 %

Procedure:
Potassium tert-butoxide (9 mg) was dissolved in tetrahydrofuran (1 ml), and methyl triphenyl phosphonium bromide (31 mg) was added thereto. The reaction mixture was stirred at room temperature for 30 minutes, and a solution of 4-[7-(2-formylphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (20 mg) in tetrahydrofuran (1 ml) was added thereto. The reaction solution was stirred at room temperature for 1 hour, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 40 mg of 4-[7-(2-vinylphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. This product (12 mg) was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reversed phase high performance liquid chromatography to give 4.38 mg of the title compound.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH2:5][CH3:6])[CH3:3].[C:19]1([N:25]2[C:29]3(CCNCC3)[C:28](=[O:35])[NH:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[C:19]1([N:25]2[C:29]3([CH2:6][CH2:5][N:4]([CH2:7][CH:8]4[CH2:17][CH2:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[C:9]4=[O:18])[CH2:2][CH2:3]3)[C:28](=[O:35])[NH:27][CH2:26]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCN(CC)CC1CCc2ccccc2C1=O
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: Cl
Solvent: CO
Product: O=C1c2ccccc2CCC1CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
2-[(Diethylamino)methyl]-3,4-dihydro-1 (2H)-naphthalenone, hydrochloride (6.93 g) and 1-phenyl-1,3,8-triazaspiro-[4.5]decan-4-one (6.0 g.) are dissolved in 75 ml of methanol by brief heating, followed by stirring at room temperature for 16 hours. The resulting precipitate is filtered, washed with ethanol and dried at 80° C under vacuum to yield 8.58 g of the title compound, melting point 170°-173° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:15]([OH:17])=O)[CH3:2].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][C@H:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][C@H:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:15]([C:4]3[N:3]([CH2:1][CH3:2])[C:11]4[C:6]([CH:5]=3)=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=[CH:9][CH:10]=4)=[O:17])=[CH:33][CH:32]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(N)cc2)C1
Reactant: CCOc1cccc2c1cc(C(=O)O)n2CC
Product: CCOc1cccc2c1cc(C(=O)Nc1ccc(O[C@H]3CCN(C(=O)OC(C)(C)C)C3)cc1)n2CC

Procedure:
The above nitro compound was hydrogenated under conditions as described in previous intermediate to provide (S)-3-(4-amino-phenyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester. The amide formation of N-ethyl-4-ethoxy-indole-2-carboxylic acid with (S)-3-(4-amino-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester under the same conditions as described in earlier intermediates preparation provided (S)-3-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS for C28H35N3O5 calcd. (m/e) 493, observed 494 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].C.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S([O-])(O)(=O)=O.[Na+]>O.C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O:5][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:4]
Reactant: CSCCC(O)C(=O)O
Reactant: CCCCCCO
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCOC(=O)C(O)CCSC
Temperature: 25 °C

Procedure:
To a 4 neck 1 L round bottom flask fitted with a reflux condenser, dean stark trap, thermocouple, and mechanical overhead stirrer was added 2-hydroxy-4-(methylthio)butanoic acid (100 g, 666 mmol, obtained for example by stirring Alimet over activated charcoal, filtering and concentrating in a rotovap), 1-hexanol (125.4 mL, 999 mmol), sodium hydrogen sulfate (1.60 g, 13.32 mmol), and toluene (500 mL). The reaction was heated to reflux with removal of water (20 mL) during the course of about 5.5 hours and the reaction was monitored by GC analysis. The reaction was cooled to room temperature overnight and the organic layer was washed with saturated NaHCO3 (1×250 mL), DI water (1×250 mL) and brine (2×250 mL), dried over sodium sulfate, filtered and evaporated to give a brown oil (253.3 g). The oil was purified by kugelrohr distillation at 100° C. and 0.1 Torr vacuum to give a colorless oil (100.0 g, 64.1%). m/z 257 (MNa+).
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]([Cl:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[Na+].[H][H]>C(O)C.[Pt]>[Cl:12][C:9]([F:10])([F:11])[CH2:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [H][H]
Reactant: CCOC(=O)C(Cl)CC(F)(F)Cl
Agent: [Pt]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCC(F)(F)Cl
Yield: 75 %

Procedure:
22.1 g of ethyl 2,4-dichloro-4,4-difluorobutyrate are dissolved in 200 ml of absolute ethanol. 8.2 g of anhydrous sodium acetate and 2.0 g of 5% platinum/carbon catalyst are added and then gaseous hydrogen is passed in under atmospheric pressure until the hydrogen uptake is 100% of theory. The catalyst is removed by filtration and the ethanol is removed by distillation and then the remaining oil is poured onto water, and the organic phase is separated off, dried with sodium sulfate, filtered and distilled under atmospheric pressure. 14.0 g of ethyl 4-chloro-4,4-difluorobutyrate are obtained in the form of a colourless oil of boiling point 154°-156° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:36])[N:24]([CH:33]([CH3:35])[CH3:34])[CH2:25][CH2:26][C:27]2[N:31]([CH3:32])[N:30]=[N:29][N:28]=2)[CH:20]=[C:19]([Cl:37])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:37][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=1)[C:23]([N:24]([CH:33]([CH3:35])[CH3:34])[CH2:25][CH2:26][C:27]1[N:31]([CH3:32])[N:30]=[N:29][N:28]=1)=[O:36]
Reactant: CC(C)N(CCc1nnnn1C)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCc1nnnn1C)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reaction time: 2 h

Procedure:
A solution of [2-(3-chloro-5-{isopropyl-[2-(1-methyl-1H-tetrazol-5-yl)-ethyl]-carbamoyl}phenoxy)-ethyl]-pyridin-4-yl-carbamic acid tert-butyl ester (0.028 g) in a mixture of dichtoromethane (0.5 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.023 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:28])=[CH:25][CH:24]=1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=398.6 (M+H+), was prepared in accordance with the general method 8 of example 49 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 4-fluorobenzoyl chloride.
Reaction SMILES: C[C@@]12[C@H]3[C@@H](O)C[C@]4(C)[C@@](O)(C(CO)=O)CC[C@H]4[C@@H]3CCC1=CC(=[O:6])CC2.[CH:27]1([N:33]=[C:34]=[N:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.ClCCl>N1C=CC=CC=1>[C:34]([NH:33][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)([NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:6]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Yield: 73.5 %

Procedure:
To a solution of hydrocortisone (3.62 g, 0.01 mole) and N,N-(N'-methyl-3'-azapentamethylene)succinamic acid (2.00 g, 0.01 mole) in 15 ml pyridine at room temperature was added dicyclohexylcarbodiimide (2.00 g, 0.01 mole). After stirring the reaction mixture 10 minutes, 25 ml dichloromethane was added to it to keep the suspension, which had resulted, sufficiently fluid for stirring. After stirring overnight, the reaction was filtered. The residue was washed twice with CH2Cl2 and air dried to give 1.65 g (84% yield) dicyclohexylurea. The filtrate was concentrated in vacuo to give a light brown foam which was in turn triturated 2 hours with 10 ml CH2Cl2 to give a suspension which was filtered. The residue was dried in the vacuum oven 3 hours at 40° C. after a preliminary NMR showed contamination of the product with CH2Cl2. The resulting finely crystalline, off-white powder was the desired product: 2.70 g, 51% yield; mp 159°-163° C.; NMR (DMSO-d6) δ5.53 (s, 1, O=C-CH=C-), 5.32 (m, 1, C-OH), 4.91 (ABq, 2, JAB=17 Hz, ΔνAB =18 Hz, O=C-CH2 -O), 4.29 (m, 2, CH-OH), 3.41 (m, 8, -N(CH2CH2)N-), 2.59 (s, 3, N-CH3), 1.37 (s, 3, C-CH3), 0.78 (s, 3, C-CH3), 2.7-0.8 (m, 21, CH, CH2); IR (KBr) 3400 cm-1 (s) (OH), 1730 cm-1 and 1710 cm-1 (s) (C-C=O and O-C=O) and 1640 and 1615 cm-1 (s) (O=C-CH=C, N-C=O); [α]24D=+122° (C=0.5, dioxane); TLC (silica gel, MeOH) Rf 0.27.
Reaction SMILES: [OH-].[Na+].[CH:3]([NH:5][C:6]1[N:11]=[C:10]([C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:9]=[CH:8][CH:7]=1)=[O:4].Cl.[O:20]([NH2:23])[CH2:21][CH3:22]>C(O)C>[CH:3]([NH:5][C:6]1[N:11]=[C:10]([C:12](=[N:23][O:20][CH2:21][CH3:22])[C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: CCOC(=O)C(=O)c1cccc(NC=O)n1
Reactant: CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(C(=O)O)c1cccc(NC=O)n1
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
1 N Sodium hydroxide solution (8.5 ml.) was added to a stirred solution of ethyl 2-(6-formamidopyridin-2-yl)-glyoxylate (1.9 g.) in ethanol (30 ml.) at room temperature and stirred at the same temperature for 30 minutes. After adding ethoxylamine hydrochloride (912 mg.) to the solution, the solution was stirred at room temperature for 4 hours. The resultant solution was concentrated under reduced pressure, and ethyl acetate and an aqueous solution of sodium bicarbonate were added to the residue. The aqueous layer was separated and ethyl acetate was added to the solution. The solution was adjusted to pH 1 with 10% hydrochloric acid. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with a mixture of diethyl ether and petroleum ether to give 2-(6-formamidopyridin-2-yl)-2-ethoxyiminoacetic acid (920 mg.), mp. 155° to 156° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:20]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NC2CC2)s1
Yield: 43 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (40 mg, 43%) which was obtained as a light yellow solid after recrystallization from heptane/ethyl acetate. MS: m/e=371.1 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19](C(OCC)=O)=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])C.[CH3:27][O:28][C:29](=[O:38])[CH2:30]C1C=CC(I)=CC=1>C(N(CC)CC)C.[Cu]I.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>[CH3:27][O:28][C:29](=[O:38])[CH2:30][C:19]1[CH:25]=[CH:26][C:16]([C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3([O:4][CH2:1][C:3]4[CH:9]=[CH:8][CH:5]=[CH:6][CH:7]=4)[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 161.4 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 71, 60.0 mg, 0.20 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 66.0 mg, 0.24 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (15.0 mg, 0.08 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-7% EtOAc-hexanes) afforded 64.0 mg (81%) of the title compound as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(I)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(I)cc1
Yield: 45 %

Procedure:
A mixture of 4.36 g (20.0 mmol) of p-iodotoluene (purchased from Tokyo Kasei), 3.9 g (22 mmol) of N-bromosuccinimide (purchased from Tokyo Kasei) and 60 ml of carbon tetrachloride (purchased from Wako Junyaku Kogyo) was refluxed under the irradiation by means of an incandescent lamp for 4 hours to give 2.67 g (yield: 45.0%) of 4-iodobenzyl bromide (as a white crystalline). Subsequently, to 0.49 g (10 mmol) of sodium cyanide (purchased from Kokusan Kagaku) in 10 ml of dimethyl sulfoxide (purchased from Aldrich) solution heated at 50° C. was added 1.48 g (5.00 mmol) of the above 4-iodobenzyl bromide, the mixture was stirred at ambient temperature for 3 hours, the resultant reaction mass was dissolved in water and extracted with hexane, and hexane was removed to give 0.84 g (yield: 68.9%) of 4-iodophenylacetonitrile as a white crystalline.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[CH3:12][O:13][C:14](=[O:21])/[CH:15]=[CH:16]\[C:17]([O:19][CH3:20])=[O:18]>>[CH3:12][O:13][C:14](=[O:21])[C@H:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: COC(=O)/C=C\C(=O)OC
Product: COC(=O)C[C@H](NCCC[Si](OC)(OC)OC)C(=O)OC

Procedure:
179.0 g (1.0 mol) of 3-aminopropyl-trimethoxysilane and 144.0 g (1.0 mol) of maleic acid dimethyl ester were reacted by the same procedure used in Example 2. The viscosity of the clear, pale yellow liquid was about 30 mPa.s (23° C.). Base titration showed an amine equivalent weight of about 331 g (theory: 323 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:19]2[C:18]([CH3:17])=[CH:22][N:21]=[CH:20]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cncn1-c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of p-nitrofluorobenzene (2 g, 14 mmol) in DMF (20 mL) was treated with potassium carbonate (8 g, 58 mmol) and 4-methylimidazole (1.2 g, 14 mmol). After refluxing for 18 h, the reaction mixture was cooled down and concentrated at reduced pressure. The residue was treated with water and the mixture was extracted with ethyl acetate and dried over magnesium sulphate. The organic layer was concentrated and the residue was purified by flash-chromatography (methanol/methylene chloride, 0.5:9.5) affording 1.8 g (62%) of p-nitro-4 (5)-methyl-imidazol-1-yl as 7:1 mixture of regioisomers.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2([C:12]3[CH:24]=[CH:23][C:15]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[C:14]([N+:25]([O-:27])=[O:26])[CH:13]=3)[CH2:11][CH2:10]2)=[O:8])[CH:2]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2([C:12]3[CH:24]=[CH:23][C:15]([N:16]([C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])[CH3:28])=[C:14]([N+:25]([O-:27])=[O:26])[CH:13]=3)[CH2:11][CH2:10]2)=[O:8])[CH:2]=1
Reactant: O=C(Nc1ccc(C2(C(=O)c3cccnc3)CC2)cc1[N+](=O)[O-])C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)c1ccc(C2(C(=O)c3cccnc3)CC2)cc1[N+](=O)[O-]

Procedure:
1.15 g (3.0 mmol) of 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-trifluoroacetylaniline are dissolved in 50 ml acetone and after the addition of 2.0 g potassium carbonate and 0.8 ml methyl iodide refluxed for two hours. The insoluble matter is filtered off and the solution is evaporated down. The residue is chromatographed on silica gel, eluting with petroleum ether/ethyl acetate (1:1 and 1:4).