Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([I:15])=[CH:14][C:6]1=2.[H-].[Na+].I[CH3:24]>CN(C)C=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:24])[C:7]2[N:11]=[CH:12][C:13]([I:15])=[CH:14][C:6]1=2
Reactant: CI
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2cc(Cl)ccc2Cl)c2cc(I)cnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 56 %

Procedure:
To a solution of 1-(2,5-dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (305 mg) in anhydrous N,N-dimethylformamide was added NaH (1.6 eq) followed by iodomethane (1.4 eq). The reaction mixture was stirred at room temperature for 48 hours and then concentrated. Column chromatography gave the title compound as a yellow solid (56% yield). LCMS: m/z=434.17 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.09 (3H, s), 3.42 (2H, m), 3.48 (2H, m), 4.36 (2H, s), 6.54 (1H, d, J=1.8 Hz), 7.17 (1H, d, J=2.3 Hz), 7.21 (1H, dd, J=8.6, 2.5 Hz), 7.34 (1H, d, J=4.3 Hz), 7.72 (1H, d, J=1.8 Hz).
Reaction SMILES: [NH2:1][N:2]1[C@H:6]([CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][C:3]1=[O:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)=O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:9]([O:8][CH2:7][C@H:6]1[N:2]([N:1]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[CH2:24][C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=2)[C:3](=[O:16])[CH2:4][CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NN1C(=O)CC[C@H]1COCc1ccccc1
Reactant: Cc1cccc(C(=O)Cc2ccc(F)cc2)n1
Solvent: Cc1ccccc1
Product: Cc1cccc(C(Cc2ccc(F)cc2)=NN2C(=O)CC[C@H]2COCc2ccccc2)n1

Procedure:
A mixture of (S)-1-amino-5-benzyloxymethyl-pyrrolidin-2-one (0.5 g, 2.27 mmol) and 2-(4-fluoro-phenyl)-1-(6-methyl-pyridin-2-yl)-ethanone (0.52 g, 2.27 mmol) in toluene (2.5 mL) in a round bottom flask equipped with a Dean-Stark apparatus is refluxed for 1 h. The mixture is concentrated in vacuo and the residue chromatographed on SiO2 (40% ethyl acetate/hexanes) to yield the title compound, 500 mg (52%), as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N:13]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cc2ccc(F)cc2)cc1
Reactant: ClCCNCCCl
Agent: Cl
Product: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of 500 mg of 4-(4-fluorophenyl) methylaniline and 445 mg of bis(2-chloroethyl)amine hydrochloride was stirred at 100° C. for 2 hours, then gradually raised in temperature to 200° C. and then further stirred for 2 hours. This was then cooled to room temperature, then the product was purified by silica gel column chromatography (chloroform:methanol:water (2% acetic acid)=65:35:5) to obtain the above-referenced compound (5) in an amount of 503 mg (yield of 75%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:5]=2[N:6]=1>Br>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccc2nc(N)sc2c1
Agent: Br
Product: Nc1nc2ccc(O)cc2s1
Temperature: 20 °C

Procedure:
1800 g of 2-amino-6-methoxy-benzothiazole were dissolved in 6 l of a 48% by weight aqueous hydrobromic acid and refluxed. The obtained reaction product was cooled over night and the precipitate was removed by suction filtering. The filtrate was brought at pH 6 with a 30% by weight aqueous hydroxide solution and cooled to 20° C. The obtained precipitate was separated by suction filtering, washed with water and dried at 30° C. Melting point: 257° C. (sublimation).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](NCC(OC(C)(C)C)=O)[CH:23]=2)=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]([O:41]C(N[C@@H](CC1C=CC(OS(C(F)(F)F)(=O)=O)=CC=1)C(OCC)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:37]=[O:41])[CH:23]=2)=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2cccc(NCC(=O)OC(C)(C)C)c2)cc1)NC(=O)OC(C)(C)C
Product: CCOC(=O)[C@H](Cc1ccc(-c2cccc(C=O)c2)cc1)NC(=O)OC(C)(C)C
Yield: 61 %

Procedure:
In a manner similar to the preparation of ethyl (S)-2-tert-butoxycarbonylamino-3-[3′-(tert-butoxycarbonylmethylamino)biphenyl-4-yl]propionate (Example 1e), using 173 g (391 mmol) of ethyl (S)-2-tert-butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxyphenyl)propionate and 82 g (547 mmol) of 3-boronic acid-benzaldehyde, 95.7 g of coupled product are isolated with a 61% yield.
Reaction SMILES: C(N(CC)C1C=CC=CC=1)C.O[C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([S:20][CH2:21][C:22]([NH2:24])=O)[N:14]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([S:20][CH2:21][C:22]#[N:24])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(SCC(N)=O)n1
Solvent: CCN(CC)c1ccccc1
Product: Cc1cc(Cl)nc(SCC#N)n1

Procedure:
To a solution of 19.4 g. (0.13 mole) of N,N-diethylaniline in 250 ml of phosphorus oxychloride was added 25.8 g (0.13 mole) of 2-(4-hydroxy-6-methyl-2-pyrimidinylthio)acetamide, the mixture was heated under reflux for 1 hour. The phosphorus oxychloride was removed in a rotary evaporator and the residue was poured onto 1 liter of cracked ice. The precipitate which resulted was collected, dried, and recrystallized from heptane to give 13.0 g. of pure white product, m.p. 62°-65°.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)Cl)([CH3:9])([CH3:8])[CH3:7].Cl.[CH3:25][O:26][C:27](=[O:32])[CH:28]([CH2:30][OH:31])[NH2:29]>CN(C)C=O>[Si:10]([O:31][CH2:30][C@@H:28]([C:27]([O:26][CH3:25])=[O:32])[NH2:29])([C:6]([CH3:9])([CH3:8])[CH3:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C(N)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 16 h

Procedure:
Imidazole (2.82 g, 41.43 mmol) and tert-butyldiphenylchlorosilane (3.23 mL, 12.43 mmol) was added to a solution of DL-serine methyl ester hydrochloride (1.41 g, 11.84 mmol) in dimethylformamide (6 mL). After 16 h, the mixture was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane=10% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound. MS 358.22 (M+1)
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[N:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.O>CN(C)C=O>[Br:1][C:2]1[S:3][C:4]([O:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[N:5][N:6]=1
Reactant: COc1ccc(O)cc1
Reactant: Brc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2nnc(Br)s2)cc1
Temperature: 90 °C
Yield: 98.2 %

Procedure:
2,5-dibromo-1,3,4-thiadiazole (2 g, 8.16 mmol), (prepared according to Example 1 as described in U.S. Pat. No. 5,847,149) was dissolved in N,N-dimethyl formamide (65 mL) and the resulting solution was treated with K2CO3 (1.69 g, 12.24 mmol) and 4-methoxyphenol (1.01 g, 8.16 mmol). The reaction mixture was heated at 90° C. for 1.5 hours, cooled to 25° C., poured into water (150 mL) and extracted with diethyl ether (2×150 mL) The combined organic layers were washed with 1N NaOH (1×100 mL), water (3×100 mL) and brine (1×100 mL), dried (Na2SO4), filtered and evaporated to provide 2.3 g of a light yellow oil. The residue was purified by flash chromatography on silica gel eluting with a solvent gradient from 1% to 14% ethyl acetate in hexanes to provide 1.86 g (79%) of the title compound, 1H NMR (300 MHz, DMSO-d6) δ ppm 7.40 (d, J=9.19 Hz, 2H) 7.04 (d, J=9.19 Hz, 2H) 3.79 (s, 3H); MS (APCI) m/z 289 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:7]1([CH2:11][CH2:10][NH:9][CH2:8]1)[CH2:6][CH:5]2[OH:15].[C:16]([OH:23])(=O)/[CH:17]=[CH:18]/[C:19]([O-])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:12]([C:16](=[O:23])[CH2:17][CH2:18][CH2:19][N:9]2[CH2:10][CH2:11][C:7]3([C:12]4[C:4](=[CH:3][C:2]([F:1])=[CH:14][CH:13]=4)[CH:5]([OH:15])[CH2:6]3)[CH2:8]2)=[CH:13][CH:14]=1
Reactant: O=C([O-])/C=C/C(=O)O
Reactant: OC1CC2(CCNC2)c2ccc(F)cc21
Product: O=C(CCCN1CCC2(CC(O)c3cc(F)ccc32)C1)c1ccc(F)cc1

Procedure:
5-Fluorospiro[indan-1,3'-pyrrolidin]-3-ol is reacted in a manner analogous to that described in Example 1(A) or Example 2(A). The hydrogen fumarate of the title compound has a M.P. of 143°-145° (from ethanol/ether).
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21]C)=O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:41][CH2:42][CH2:43][CH2:44][NH2:45]>ClCCl>[NH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:19]([C:17]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)=[C:10]([NH:9][CH2:8][CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:18]=1)=[O:21]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Reactant: NCCCN
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCCN)nc32)[C@H](O)[C@@H]1O
Temperature: 100 °C
Yield: 58.4 %

Procedure:
A mixture of methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylate (Preparation 9) (0.35 g, 0.64 mmol) and 1,3-diaminopropane (0.45 g, 6.1 mmol) was heated at 100° C. for 3 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (80:20:1.2, by volume) changing to dichloromethane:methanol:concentrated aqueous ammonia (88:12:2, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.22 g, 58%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:22])[NH:11][CH:12]([CH2:15][CH:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)[C:13]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[CH2:29]([O:14][C:13]1[CH:12]([CH2:15][CH:16]2[CH2:17][CH2:18][S:19][CH2:20][CH2:21]2)[NH:11][C:10](=[O:22])[C:9]=1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(C)c(C2=C(O)C(CC3CCSCC3)NC2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C)c(C2=C(OCc3ccccc3)C(CC3CCSCC3)NC2=O)c1

Procedure:
A solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-5-(tetrahydro-thiopyran-4-ylmethyl)-1,5-dihydro-pyrrol-2-one (compound P2.5) (1.0 g, 3.15 mmol), potassium carbonate (0.87 g, 6.3 mmol) and benzyl bromide (0.81 g, 4.7 mmol) in 10 ml of acetone was refluxed for 2 h. Then, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel. Yield: 640 mg of 4-benzyloxy-3-(2,5-dimethyl-phenyl)-5-(tetrahydro-thiopyran-4-ylmethyl)-1,5-dihydro-pyrrol-2-one as a solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:18][CH:17]=1
Reactant: CCCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCOc1ccc(Br)cc1

Procedure:
Quantities: anhydrous potassium carbonate (34.8 g, 0.25 mol), 1-bromoheptane (19.6 g, 0.11 mol) and 4-bromophenol (17.3 g, 0.1 mol). The experimental procedure was as described in Example 119.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:19]([OH:21])=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.[CH3:32][NH:33][CH3:34].CCN=C=NCCCN(C)C.Cl>O.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:19](=[O:21])[N:33]([CH3:34])[CH3:32])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)N(C)C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
THF (5 ml) charged in to a R B flask followed by the addition of piperidine-1,4,4-tricarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.5 g) and 1-hydroxybenzotriazole (0.38 g). Allowed to stir the reaction mixture at 25-300 C for 30 mins. Dimethylamine (0.75 mL) followed by EDC HCl (0.38 g) was added in to the above reaction mixture at 25-300 C. Allowed the reaction mixture to stir at 25-300 C for 1-2 hrs. Reaction is followed by TLC. The reaction mixture concentrated under vacuum using rota vapour and the product slurry obtained is suspended in D M Water (5 mL). The product extracted in to ethyl acetate (2×5 mL). The combined product layer dried with sodium sulphate and concentrated under vacuum to yield crude product which in turn purified by a column chromatography to yield pure 4-dimethylcarbamoyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.C(O)(=O)C.[CH:29](N)=[NH:30]>CN(C)C=O>[OH:9][C:7]1[C:6]2[CH:5]=[C:4]([CH2:12][CH2:13][N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[S:3][C:2]=2[N:1]=[CH:29][N:30]=1
Reactant: N=CN
Reactant: CCOC(=O)c1cc(CCN2C(=O)c3ccccc3C2=O)sc1N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCc1cc2c(O)ncnc2s1
Temperature: 100 °C
Yield: 54.8 %

Procedure:
To a 250-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was added a solution of ethyl 2-amino-5-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethyl]thiophene-3-carboxylate (3.4 g, 9.87 mmol, 1.00 equiv) and formamidine acetate (1.5 g, 14.41 mmol, 1.46 equiv) dissolved in 50 mL of N,N-dimethylformamide. This solution was heated at 100° C. for 12 hrs. The reaction was cooled to room temperature and quenched with water. The resulting mixture was extracted with 3×100 mL of ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to yield 1.76 g (55%) of 2-(2-[4-hydroxythieno[2,3-d]pyrimidin-6-yl]ethyl)-2,3-dihydro-1H-isoindole-1,3-dione as an off-white solid. MS (ES): m/z 326 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:12](=[O:14])[CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[CH:4]=1>CO.O1CCOCC1.[C].[Pd]>[NH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[N:2]([CH3:1])[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)N(C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)N(C)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A mixture of N-methyl-3′-nitroacetanilide (5.13 g) and 10% palladium carbon (0.6 g) in methanol (50 ml) and 1,4-dioxane (50 ml) and stirred under hydrogen (3 atm) at room temperature for 2 hours. The catalyst was removed by filtration and the solvent was evaporated. The resultant solid was collected and washed with isopropyl ether to give 3′-amino-N-methylacetanilide (4.06 g).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:29]=[C:30]([S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1)N>>[CH3:38][N:37]([CH3:39])[S:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([N:26]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=1)(=[O:35])=[O:36]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: CN(C)S(=O)(=O)c1cccc(NN)c1
Product: CN(C)S(=O)(=O)c1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 3-hydrazino-N,N-dimethyl-benzenesulfonamide according to the method described for example 91.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:39][CH2:38][C:37]4[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=566.97 (M+H+); retention time=0.90 minutes.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4]1.[C:19]([C:21]1[CH:34]=[CH:33][C:24]([CH2:25][N:26]2[C:30]([CH:31]=O)=[CH:29][N:28]=[CH:27]2)=[CH:23][C:22]=1[F:35])#[N:20].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO>[F:35][C:22]1[CH:23]=[C:24]([CH2:25][N:26]2[C:30]([CH2:31][NH:2][C@@H:3]3[CH2:7][CH2:6][N:5]([C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=5)[CH:11]=[CH:10][CH:9]=4)[CH2:4]3)=[CH:29][N:28]=[CH:27]2)[CH:33]=[CH:34][C:21]=1[C:19]#[N:20]
Reactant: N[C@@H]1CCN(c2cccc3ccc(O)cc23)C1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CN[C@@H]2CCN(c3cccc4ccc(O)cc34)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-Amino-1-[7-hydroxynaphthalen-1-yl]pyrrolidine hydrochloride, as described in Step J, (85 mg, 0.32 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described in Example 1, Step G, (75 mg, 0.33 mmol), were stirred in MeOH (1 mL) and N,N-diisopropylethylamine was added dropwise to adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hour at ambient temperature then NaCNBH3 (26 mg, 0.42 mmol) was added and stirring was continued for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 (1 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (3 mL) and CH2Cl2 (10 mL). The aqueous layer was extracted further with CH2Cl2 (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2—1% to 6% MeOH—0.1% to 0.6% NH4OH to yield the titled product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[C:18]1([C:24]2[S:25][CH:26]=[C:27]([CH2:29][C:30](O)=[O:31])[N:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:30](=[O:31])[CH2:29][C:27]2[N:28]=[C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[S:25][CH:26]=2)[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1csc(-c2ccccc2)n1
Product: O=C(Cc1csc(-c2ccccc2)n1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 53.7 %

Procedure:
Example 36 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.056 g) and (2-phenyl-1,3-thiazol-4-yl)acetic acid (0.042 g) to give the title compound (0.049 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH3:16])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH3:16])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.6 %

Procedure:
Ethyl 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetate (syn isomer, 5 g.) was added to a mixture of 1N sodium hydroxide (45.9 ml.) and ethanol (30 ml.) and stirred at room temperature for 5 hours. After removing ethanol from the resultant solution under reduced pressure, the residue was dissolved in water (60 ml.) and adjusted to pH 2.0 with 10% hydrochloric acid. The solution was subjected to salting-out, and the precipitates were collected by filtration and dried to give 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetic acid (syn isomer, 2.9 g.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[CH:4][CH:3]=1.[OH:25]O>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:25])=[CH:4][CH:3]=1
Reactant: O=C1CCc2cc(OCCCCSc3ccc(O)cc3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCS(=O)c3ccc(O)cc3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[4-(4-hydroxy-phenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[NH2:13][C:14]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CN>C1COCC1>[NH2:13][C:14]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:3][CH3:1])=[O:17]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(F)cccc1C(=O)O
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(F)c1N
Reaction time: 18 h
Yield: 80.2 %

Procedure:
1,1′-Carbonyldiimidazole (1.946 g, 12.00 mmol) was added in one portion to 2-amino-3-fluorobenzoic acid (1.551 g, 10 mmol) in THF (25 mL) at room temperature and the resulting suspension stirred for 18 hours. A 2N solution of methylamine in THF (7.50 mL, 15.00 mmol) was added and the resulting solution stirred at room temperature for 1 hour. The mixture was evaporated and the residue dissolved in EtOAc (100 mL). The solution was washed sequentially with water (2×50 mL) and a saturated solution of NaCl (50 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was dissolved in EtOAc (100 mL) and the mixture washed sequentially with a 2M solution of NaOH (50 mL), water (50 mL), and then with a saturated solution of NaCl (50 mL). The organic layer was dried over MgSO4 and then evaporated to afford 2-amino-3-fluoro-N-methylbenzamide (1.349 g, 80% yield); 1H NMR spectrum: (300 MHz, CDCl3) δ 2.91 (3H, d), 5.52 (2H, s), 5.97 (1H, s), 6.49 (1H, td), 6.93-7.04 (2H, m); Mass spectrum: m/z (ESI+) (M+H)+ =169.34.