Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C:6](=O)[CH2:5][CH2:4][C@@H:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[NH:15][NH2:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[CH2:12]([O:11][C:9]([C@H:3]1[CH2:4][CH2:5][C@@H:6]([NH:16][NH:15][C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C@H:2]1[CH3:1])=[O:10])[CH3:13]
Reactant: CCOC(=O)[C@H]1CCC(=O)C[C@H]1C
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CC[C@@H](NNC(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
To a 500-mL 3-neck round-bottomed flask was added (1S,2R)-ethyl 2-methyl-4-oxocyclohexanecarboxylate (10.00 g, 54.3 mmol) in chloroform (201 ml). Then AcOH, glacial (3.13 ml, 54.3 mmol), and tert-butyl carbazate (7.89 g, 59.7 mmol) was added into the reaction mixture. The flask was placed into a pre-heated bath (30° C.) and allowed to stir 10 min. Then NaBH(OAc)3 (34.5 g, 163 mmol) was slowly added into the reaction mixture in small portions. The bath was removed after the addition and the overall mixture was allowed to stir under inert atmosphere 16 h. The progress of the reaction was monitored by LC/MS and TLC (30% EtOAc/DCM; Ninhydrin stain) which suggested reaction completion. The mixture was neutralized with the slow addition of sat. aq. NaHCO3 into the reaction mixture. After the material was neutralized, the layers were separated and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in-vacuo. The crude sample was analyzed by TLC (30% EtOAc/hexane; ninhydrin stain; Peak 1: Rf=0.46 & Peak 2: Rf=0.38) The crude material was divided into two portions and purified by chromatography through an Interchim (25 micron) silica-gel column (300 g)*(Two 300 Gram Columns were used), eluting with a gradient of 0-30% EtOAc in hexane, to provide tert-butyl 2-((1R,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (8.512 g, 28.3 mmol, 52.2% yield) (Peak 1; Cis)1H NMR (400 MHz, CDCl3) δ 6.03-6.28 (m, 1H), 4.07-4.16 (m, 2H), 3.59-3.90 (m, 1H), 2.76-2.97 (m, 1H), 2.55 (d, J=2.74 Hz, 1H), 2.01 (dd, J=3.03, 13.40 Hz, 1H), 1.59-1.77 (m, 3H), 1.49-1.56 (m, 2H), 1.46 (s, 10H), 1.19-1.31 (m, 3H), 1.02 (d, J=7.04 Hz, 3H); LCMS (ESI) m/z 301.1 (M+H)+ and tert-butyl 2-((1S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (5.089 g, 16.94 mmol, 31.2% yield) (Peak 2; trans)1H NMR (400 MHz, DMSO-d6) δ 7.89-8.27 (m, 1H), 5.75 (s, 1H), 4.08-4.19 (m, 1H), 2.74-2.93 (m, 1H), 2.21-2.46 (m, 2H), 1.99 (s, 1H), 1.66 (d, J=3.91 Hz, 3H), 1.38 (s, 9H), 1.14-1.26 (m, 5H), 0.79 (d, J=7.04 Hz, 3H); LCMS (ESI) m/z 301.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:25][CH:22]2[CH2:24][CH2:23]2)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1
Reactant: NC1CC1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(NC3CC3)nc(N)nc21

Procedure:
A solution of 2-amino-4-chloro-7-(2-C-methyl-Θ-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (Example 118, Step B) (21 mg, 0.07 mmol) in cyclopropylamine (0.5 mL) was heated at 70° C. for two days, then evaporated to an oily residue and purified on a silica gel column with CH2Cl2/MeOH, 20/1, as eluent to give the title compound as a white solid (17 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>O>[CH3:1][NH:2][C:3]1[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][N:4]=1
Reactant: CNc1ccc(C(F)(F)F)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CNc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 86.6 %

Procedure:
To a mixture of N-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine (17.3 g) and sulfuric acid (100 ml), nitric acid (12.3 g) was added drop-wise, and stirred with heating at 80° C. for 2 hours. The mixture was cooled to room temperature, and then the reaction mixture was poured into water. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 18.8 g of N-methyl-(3-nitro-5-trifluoromethyl-pyridin-2-yl)-amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH:18]([CH3:20])[CH3:19])[O:15][C:14](=[O:16])[CH:13]=[C:12]([OH:17])[CH2:11]2)=[CH:4][CH:3]=1.[CH:21]([C:24]1[C:25]([S:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:26][C:27]2[S:31][CH:30]=[N:29][C:28]=2[CH:32]=1)([CH3:23])[CH3:22].CCN(CC)CC>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2([CH:18]([CH3:20])[CH3:19])[O:15][C:14](=[O:16])[C:13]([S:33][C:25]3[C:24]([CH:21]([CH3:23])[CH3:22])=[CH:32][C:28]4[N:29]=[CH:30][S:31][C:27]=4[CH:26]=3)=[C:12]([OH:17])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc3scnc3cc2C(C)C)cc1
Reactant: CC(C)C1(CCc2ccc(F)cc2)CC(O)=CC(=O)O1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1cc2ncsc2cc1SC1=C(O)CC(CCc2ccc(F)cc2)(C(C)C)OC1=O

Procedure:
The title compound was prepared according to General Method 16b using 6-[(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one (Example E-27; 0.5 g, 1.8 mmol), toluene-4-thiosulfonic acid S-(5-isopropyl-benzothiazol-6-yl)ester (Example BB-4; 0.65 g, 1.8 mmol), NEt3 (0.22 g, 2.16 mmol), and acetonitrile (10 mL). The crude compound was purified by flash silica gel chromatography (25% EtOAc in hexanes to 100% EtOAc to 5% MeOH in EtOAc as eluents), mp 104-105° C. MS (APCI): 486.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:26]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][NH:32][C:31](=[O:35])[CH:30]=1>>[F:24][C:25]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:26]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=4[N:8]([CH3:11])[C:9]=3[CH:10]=2)[C:31](=[O:35])[CH:30]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5F)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 59.2 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (155 mg, 0.411 mmol) and 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (97 mg, 0.41 mmol) was reacted following the procedure for Example 2 (step d) to provide the title compound (130 mg, 59%) as a green oil: ESI MS m/z 536 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[CH:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1)([CH3:12])[CH3:11].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=2)[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: Cc1cccc(Cl)c1O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Cc2ccc(C(C)C)cc2)cc(Cl)c1O
Temperature: 60 °C
Reaction time: 5.5 h

Procedure:
85.8 g (0.6 mol) 2-chloro-6-methylphenol and 33.8 g (0.2 mol) 4-isopropylbenzyl chloride, dissolved in 160 ml chloroform, are reacted with 18 g water-free zinc chloride. At a bath temperature of 60° C. the reaction mixture is stirred 5-6 h, and then washed three times each with 150 ml water for the purpose of removing excess zinc chloride, dried across sodium sulfate and subjected to a driving-off of the solvent chloroform in a vacuum.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[N:5][N:4]=[N:3]1.S(Cl)([Cl:16])=O>C1C=CC=CC=1.CN(C=O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:16])=[O:13])=[N:5][N:4]=[N:3]1
Reactant: O=S(Cl)Cl
Reactant: Cn1nnnc1SCCCC(=O)O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cn1nnnc1SCCCC(=O)Cl

Procedure:
2.2 g of 4-(1-methyltetrazol-5-ylthio)-butyric acid are stirred in 20 ml of absolute benzene with 1.03 ml of thionyl chloride and 4 drops of DMF for 20 minutes at the reflux temperature. The solvent is then concentrated by evaporation under reduced pressure. After dissolving and concentrating by evaporation twice more in toluene, the pure title compound is obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.[N:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:14]=[O:15].[H-].[Na+].Cl>O.O1CCCC1>[CH2:16]([N:13]1[C:7](=[O:9])[C:6]2[CH:5]=[C:4]([CH2:11][CH3:12])[S:3][C:2]=2[NH:1][C:14]1=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCc1cc(C(=O)OC)c(N)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc2c(=O)n(Cc3ccccc3)c(=O)[nH]c2s1
Temperature: 60 °C
Reaction time: 5 h
Yield: 25 %

Procedure:
To a mixture of methyl 2-amino-5-ethylthiophene-3-carboxylate (5 g), (isocyanatomethyl)benzene (3.33 mL) and tetrahydrofuran (50 mL) was added sodium hydride (1.18 g), and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was diluted with water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound as colorless crystals (2.1 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:29]=[CH:30][CH:31]=2)[C:12]([NH:14][C:15]2[CH:16]=[C:17]([NH:21]C(=O)OC(C)(C)C)[CH:18]=[CH:19][CH:20]=2)=[O:13])[C:5]([Cl:32])=[CH:4][N:3]=1.Cl>COCCO.O1CCOCC1>[ClH:1].[Cl:32][C:5]1[CH:4]=[N:3][C:2]2[NH:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH:16]=3)[NH:14][C:12](=[O:13])[C:11]3[CH:10]=[C:9]([NH:8][C:6]=1[N:7]=2)[CH:31]=[CH:30][CH:29]=3
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: O=C1Nc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Temperature: 150 °C
Yield: 12.7 %

Procedure:
To a solution of tert-butyl [3-({3-[(2,5-dichloropyrimidin-4-yl)amino]benzoyl}amino)phenyl]carbamate (20.0 mg, 0.042 mmol) in 2-methoxyethanol (0.2 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (63 μL). The resulting mixture was heated at 150° C. in the microwave for 15 min. After filtration of the reaction mixture, the crude was triturated with MeOH/EtOAc to give the desired product as an off-white powder (2 mg, 14%). LCMS for C17H12ClN5O (M+H)+: m/z=338.0. 1H NMR (400 MHz, CD3OD): δ 9.57 (s, 1H), 9.42 (s, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.29 (dd, J=7.9, 7.6 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 7.10-7.05 (m, 2H), 6.90 (dd, J=8.2, 0.9 Hz, 1H), 6.84-6.81 (m, 1H), 4.11 (s, 2H).
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[CH2:10][CH2:9][CH2:8]2>C1COCC1.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([CH3:1])[CH2:10][CH:9]=[CH:8]2
Reactant: [Li]C
Reactant: COc1ccc2c(c1)CCCC2=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C=CCC2C
Yield: 51 %

Procedure:
Methyllithium (1M solution in THF; 27 ml, 27 mmol) was added slowly to a solution of 6-methoxy-1-tetralone (3.16 g, 18 mmol) in THF (15 ml) under N2. The reaction mixture was allowed to react under N2 at RT overnight (12 h). It was then diluted with ethyl acetate and quenched with ice-cooled HCl (2M). The aqeous phase was extracted further with ethyl acetate, dried, and concentrated in vacuo. Chromatographic purification of the crude material on silica gel, using 5% ether in petroleum ether as eluent, gave the title compound as a gum (1.6 g, 52%). 1H-NMR (250 MHz CDCl3): 2.1 (t, 3H, Me), 2.2 (m, 2H), 2.8 (t, 2H), 3.8 (s, 3H, OMe), 5.8 (t, 1H), 6.8-7.2 (m, 3H), 13C-NMR (250 MHz, CDCl3) 19.3, 23.2, 28.9, 55.2, 110.8, 113.7, 122.9, 123.9, 129.1, 131.8, 138.1, 158.4; Mass Spectrum (M+1) m/e=175.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)=O)=[CH:11][CH:10]=1)([O-])=O.[H][H]>C(O)(=O)C.[Pd]>[CH3:25][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH2:6])=[CH:14][CH:13]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc(/C=C/C(=O)c2ccc([N+](=O)[O-])cc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cccc(CCCc2ccc(N)cc2)c1
Yield: 103.3 %

Procedure:
46 g (0.47 mole) of concentrated sulfuric acid and 8 g of palladium on 80% active carbon are added to a solution of 130 g (0.49 mole) of E-(3-methylstyryl) 4-nitrophenyl ketone in 1.3 l of glacial acetic acid, and the mixture is saturated with nitrogen. Thereafter, hydrogen gas is passed into the stirred mixture under atmospheric pressure. After about 30 l of hydrogen has been absorbed, the mixture is heated to 50°-70° C. and hydrogenated until the theoretical amount of hydrogen (about 66 l) has been consumed. The mixture is filtered under suction over kieselguhr, the filtrate is evaporated to dryness and the residue is stirred with 1 l of ice water, 200 ml of 50% strength sodium hydroxide solution and 800 ml of methyl tert-butyl ether. The aqueous phase is washed with 3 times 250 ml of methyl tert-butyl ether, and the combined organic phases are washed once with 250 ml of water and once with 250 ml of saturated NaCl solution, dried over Na2SO4 and evaporated down under reduced pressure to give 114 g of a brown oil of boiling point 158°-163° C./0.3 mm, which is about 95% pure (corresponding to 98% of theory) according to the gas chromatogram.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9]>CC(C)=O>[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([N:3]=[C:2]=[S:1])=[O:9]
Reactant: N#C[S-]
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=C(N=C=S)c1cccnc1Cl

Procedure:
1.891 g (12.0 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride and two droplets of DMF were heated under reflux for 2 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure. 2-Chloronicotinoyl chloride thus obtained was then dissolved in 10 ml of acetone. 770 mg of ammonium thiocyanate was it then dissolved in 15 ml of acetone with stirring. To the solution thus obtained was then added dropwise the acetone solution of 2-chloronicotinoyl chloride in 5 minutes. The mixture was then stirred. The mixture was then stirred over a 40° C. oil bath for 5 minutes. The insoluble matters thus precipitated were then removed by filtration to obtain an acetone solution of 2-chloronicotinoyl isothiocyanate. To the solution thus obtained was then added dropwise a mixture of 2.151 g of N-ethyl-3,4-ethylenedioxyaniline and 10 ml of acetone with stirring at room temperature in 5 minutes. The reaction mixture was stirred at room temperature for 16 hours, and then poured into about 1,000 ml of ice-water. The resulting crystal was collected by filtration, washed with water, and then dried under reduced pressure. The resulting product was then recrystallized from ethanol to obtain 2.18 g of 2-[N-(2,3-dihydro-1,4-benzodioxan-6-yl]-N-ethylamino-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][CH:22]([F:33])[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([O:23][CH:22]([F:21])[F:33])=[CH:25][CH:26]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(OC(F)F)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(OC(F)F)cc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-difluoromethoxybenzoic acid.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O)([O-:3])=[O:2].O.[CH3:12][NH:13][CH3:14]>CO>[CH3:12][N:13]([CH3:14])[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][N+:1]([O-:3])=[O:2]
Reactant: CNC
Reactant: COC(=O)CCC[N+](=O)[O-]
Solvent: CO
Solvent: O
Product: CN(C)C(=O)CCC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.9 %

Procedure:
To a solution of methyl 4-nitrobutyrate (1.0 g, 6.80 mmol) in methanol (10 ml) was added 40% dimethylamine water solution (12.5 ml, 102 mmol). The solution was stirred at room temperature for 48 h, concentrated by vacuum, and diluted with ethyl acetate (20 ml). The organic layer was dried and evaporated. The residue was purified by flash chromatography over silica gel (Hexane-EtOAc, 1:1) to give the title product (0.99 g, 91%). 1H NMR (CDCl3): 4.53 (t, J=6.6 Hz, 2H), 3.02-2.94 (m, 6H), 2.48-2.43 (m, 2H), 2.36-2.31 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[NH:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH3:24])[C:13]([OH:15])=[O:14]>C(O)(=O)C.O>[CH2:21]([C:20]1[N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]2[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[CH:16]=[CH:17][C:18]=2[N:19]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(=O)Nc1ccc(C(=O)O)cc1NCc1ccccc1Cl
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Yield: 86.9 %

Procedure:
A solution of 3-[(2-chlorophenyl)methyl]amino-4-(valeryl)aminobenzoic acid (1.5 g, 4.16 mmol) in glacial acetic acid (10 mL) was refluxed for 5 hours, cooled, diluted with water (75 mL), and the crystals that separated were filtered, washed with water and dried to afford 1.33 g of crude product. Crystallization from methanol gave 1.24 g (87%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-6-carboxylic acid; mp 238°-241° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]>CO.[Ni]>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=[N+]([O-])c1ccc(I)c(C(F)(F)F)c1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(I)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1-iodo-4-nitro-2-trifluoromethyl-benzene (see WO 00/09495) (0.500 g, 1.58 mmol) and Raney Ni (˜0.100 g) in MeOH (10 mL) is stirred for 2 h at rt under a hydrogen atmosphere. The reaction mixture is filtered through a pad of Celite and concentrated to afford the title compound as a brown solid: ES-MS: 285.8 []−; single peak at tR=4.49 min (System 1); Rf=0.33 (Hexane/CH2Cl2, 2:3).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8](I)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:18]=[N+:19]=[N-:20])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1CC(I)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 4-iodo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in DMF is added NaN3, the resulting mixture is heated to about 65 centigrade and stirred overnight. The mixture is diluted, extracted and dried. After removal of solvent, the residue is purified to give 4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl (8).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:3]=12.[F:25]C1C=CC(C2C=C(N)N(C)N=2)=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:25])=[CH:19][CH:18]=3)[C:3]=12
Reactant: Cn1nc(-c2ccc(F)cc2)cc1N
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Product: Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 14 was synthesised following similar procedures outlined in Example 1 (Compound 37), starting from Step 2 using 3-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-amine instead of 3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-amine.
Reaction SMILES: [C:1]([O:10]C)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]([OH:19])[C:13]([NH2:18])([CH2:16][OH:17])[CH2:14][OH:15]>CN(C=O)C.O>[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]([OH:19])[C:13]([NH2:18])([CH2:16][OH:17])[CH2:14][OH:15]
Reactant: COC(=O)c1ccccc1O
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: O
Product: O=C([O-])c1ccccc1O

Procedure:
Methyl salicylate (2.3g, 15. 1mmole) was reacted with Tris (14.8 g, 120.8 mmole) in DMF (182 ml) and water (121 ml) at pH 9.0 and 60° C. for 48 h. The formation of the title product (Rt 3.95) from methyl salicylate (Rt 7.66) was monitored by HPLC (System A) until the reaction stopped at 75% of completion. The mixture was then evaporated to dryness under reduced pressure and the sample dissolved in water. The pH was adjusted to 4.5 and the title product purified by preparative HPLC followed by ion exchange chromatography (Amberlite IR63 resin) to give the chromatographically pure salicylate-Tris (3.66, 65% of theoretical).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([CH3:14])[CH2:9]2.Cl[C:25]1[CH:30]=[C:29]([Cl:31])[N:28]=[CH:27][C:26]=1[C:32]#[N:33]>C1COCC1.CCOC(C)=O>[Cl:31][C:29]1[N:28]=[C:27]([NH:3][C:4]2[CH:5]=[CH:6][C:7]([N:15]3[CH2:16][CH2:17][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:20]3)=[C:8]3[C:12]=2[C:11](=[O:13])[N:10]([CH3:14])[CH2:9]3)[C:26]([C:32]#[N:33])=[CH:25][CH:30]=1
Reactant: N#Cc1cnc(Cl)cc1Cl
Reactant: CC(C)N1CCN(c2ccc(N)c3c2CN(C)C3=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2ccc(Nc3nc(Cl)ccc3C#N)c3c2CN(C)C3=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
Sodium hydride (0.557 g, 13.93 mmol) was added portionwise to 7-amino-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one (1.004 g, 3.48 mmol), in THF (30 mL) at room temperature under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 30 minutes and then 4,6-dichloropyridine-3-carbonitrile (0.602 g, 3.48 mmol) was added portionwise and the mixture heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (50 mL). The mixture was washed sequentially with water (50 mL), a saturated solution of NaHCO3 (50 mL), water (25 mL) and finally with a saturated solution of NaCl (20 mL). The mixture was filtered and the organic layer separated, dried over Na2SO4 and then evaporated. The residue was triturated in Et2O and MeOH and the mixture filtered. The filtrate was evaporated and the residue purified by chromatography on silica, eluting with a gradient of 5-10% MeOH in CH2Cl2. Fractions containing product were combined and evaporated to leave 6-chloro-[[2-methyl-3-oxo-7-(4-propan-2-ylpiperazin-1-yl)-1H-isoindol-4-yl]amino]pyridine-3-carbonitrile (316 mg, 21% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 1.02 (6H, d), 2.60 (4H, t), 2.70 (1H, t), 3.02-3.08 (7H, m), 4.51 (2H, s), 7.04 (1H, d), 7.15 (1H, dd), 7.44 (1H, dd), 8.53 (1H, d), 9.68 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=425.30.