Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:23](=[O:41])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([CH3:40])[CH:34]=2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][C:35]1[CH:34]=[C:33]([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:41])[NH:22][C:9]4[CH:10]=[C:11]([C:18]([F:21])([F:19])[F:20])[C:12]([O:14][CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:38]=[C:37]([CH3:39])[N:36]=1
Reactant: CCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-propoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M199) (319 mg, 0.545 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (172 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[NH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=1)=[O:8]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COc1ccc2sc(C(=O)Cl)c(Cl)c2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a 0° C. solution of 3-chloro-5-methoxybenzo[b]thiophene-2-carbonyl chloride (500 mg, 1.9 mmol) in 20 mL of THF is added methyl p-aminobenzoate (318 mg, 2.1 mmol) followed by triethylamine (293 μL, 2.1 mmol). The reaction mixture is allowed to warm to room temperature and stirring is continued overnight. The mixture is partitioned between ethyl acetate and 1N HCl, then washed with 1N NaOH, saturated NaHCO3, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane provides 225 mg of methyl 4-[[[3-chloro-5-methoxybenzo[b]thien-2yl]carbonyl]amino]benzoate; mp=205°-206° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18].Cl[C:21]1[S:22][C:23]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:24]=2[N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][N:15]([C:21]3[S:22][C:23]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:24]=4[N:25]=3)[CH2:14][CH2:13]2)[C:4]1=[O:18]
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2nccnc21
Reactant: FC(F)(F)c1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)C(=O)N(C2CCN(c3nc4ccc(C(F)(F)F)cc4s3)CC2)c2nccnc21
Temperature: 110 °C
Yield: 67.2 %

Procedure:
A mixture of 7,7-dimethyl-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one hydrochloride (Intermediate 78) (0.088 g, 0.311 mmol), 2-chloro-6-(trifluoromethyl)benzo[d]thiazole (0.089 g, 0.373 mmol), and potassium carbonate (0.172 g, 1.245 mmol) in DMSO (3 mL) was heated at 110° C. overnight. The reaction mixture was cooled, H2O was added, and the solid was collected, dried and purified by ISCO (35% EtOAc/Hexanes) to give the title compound (93.5 mg, 67%). MS (M+1): 448. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (1 H, s), 8.03-8.18 (2 H, m), 7.52-7.68 (2 H, m), 4.51-4.68 (1 H, m), 4.23 (2 H, d, J=12.5 Hz), 3.36-3.49 (2 H, m), 2.52-2.61 (2 H, m), 1.86 (2 H, d, J=10.4 Hz), 1.33 (6 H, s).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1
Reactant: OCC1CCC2CNCCN2C1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OCC1CCC2CN(c3ncccn3)CCN2C1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 4.5 g (26 mmol) of (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (U.S. Pat. No. 5,326,874), 3.0 g (26 mmol) of 2-chloropyrimidine, and 6.7 g (63 mmol) of sodium carbonate in 100 mL of water is heated at 95° C. for 16 h. The mixture was cooled to room temperature, extracted with methylene chloride (3×), the combined organic layers were washed with water and brine, dried, filtered and evaporated to give 4.68 g (72%) of the title compound which was used without purification in subsequent reactions.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[Cl:6][CH2:7][CH:8]=O>Cl>[Cl:6][CH2:7][CH:8]1[NH:5][S:1](=[O:3])(=[O:2])[NH:4][CH:8]([CH2:7][Cl:6])[NH:5][S:1](=[O:3])(=[O:2])[NH:4]1
Reactant: NS(N)(=O)=O
Reactant: O=CCCl
Agent: Cl
Product: O=S1(=O)NC(CCl)NS(=O)(=O)NC(CCl)N1
Reaction time: 0.08 h
Yield: 70 %

Procedure:
0.01 mole of sulphamide in 5 ml of concentrated hydrochloric acid are added to 0.012 mole of chloroacetaldehyde, at room temperature whilst stirring. After 5 minutes, the precipitate which has formed is filtered off and washed with ice water, dried and recrystallised from acetone/petroleum ether. 3,7-Di-(chloromethyl)-1,5-dithia-2,4,6,8-tetra-aza-cyclooctane-1,1,5,5-tetraoxide is obtained as colourless crystals of melting point 175° C (decomposition) in a yield of 70% of the theoretical yield.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:33][C:34]#[C:35][Si:36]([CH3:39])([CH3:38])[CH3:37].O>C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:33][C:34]#[C:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)C#CCBr
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (27.4 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (1.37 g). To the solution was added 60% sodium hydride (0.27 g) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the mixture was added 3-bromo-1-(trimethylsilyl)-1-propyne (1.48 ml), and the mixture was stirred at 65° C. for 90 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-trimethylsilyl-2-propynyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.78 g).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=N)N.[CH:13]1(C(Cl)=O)[CH2:18][CH2:17]C[CH2:15][CH2:14]1>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[C:17]2[C:7](=[CH:15][CH:14]=[CH:13][CH:18]=2)[NH:6][CH:5]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
A stock solution of 9.1 mg/mL α-interferon in 20 mM sodium phosphate buffer at pH 7.2 was prepared. A stock solution of perturbant was prepared by dissolving 800 mg of perturbant (L-arginine acylated with cyclohexanoyl chloride) in 2 mL of 20 mM Sodium Phosphate buffer (pH 7).
Reaction SMILES: [F:1][C:2]([CH3:9])([CH3:8])[CH2:3][C@@H:4]([CH2:6][OH:7])[NH2:5].CC(=C)C[C@H]1C[O:16][C:15](=O)N1.C1C=CN=CC=1.F>>[F:1][C:2]([CH3:9])([CH3:8])[CH2:3][C@H:4]1[CH2:6][O:7][C:15](=[O:16])[NH:5]1
Reactant: CC(C)(F)C[C@H](N)CO
Reactant: C=C(C)C[C@H]1COC(=O)N1
Agent: F
Solvent: c1ccncc1
Product: CC(C)(F)C[C@H]1COC(=O)N1

Procedure:
The 4-fluoroleucinol can also be synthesized according to Scheme 8. 4,5-Dehydroleucine is converted to (4S)-4-(2-methylprop-2-enyl)-1,3-oxazolidin-2-one as described in the scheme below. This intermediate is then treated with a hydrofluorination reagent such as HF-pyridine to give (4S)-4-(2-fluoro-2-methylpropyl)-1,3-oxazolidin-2-one. Basic hydrolysis (i.e. Ba(OH)2 or NaOH) then affords (2S)-2-amino-4-fluoro-4-methylpentan-1-ol.
Reaction SMILES: C(ON=O)(C)(C)C.[F:8][CH:9]([F:31])[C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12](N)[C:11]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].N#N.[ClH:34]>CC#N.[Cu](Cl)Cl>[F:8][CH:9]([F:31])[C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]([Cl:34])[C:11]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1N
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: N#N
Solvent: CC#N
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Cl

Procedure:
To a mechanically stirred mixture of 11.52 g (0.087 mol) of copper (II) chloride, and 11.18 g (0.108 mol) of t-butylnitrite in 350 ml of CH3CN, was added a solution of 25.00 g (0.070 mol) of product of Example 100 in 25 ml of CH3CN in such a rate that a slow evolution of N2 was observed. After 18 hours the mixture was poured into 3.7% HCl, and extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4). This was concentrated in vacuo to 24.03 g of a yellow oil. The crude product was purified by HPLC in 5% ethyl acetate/cyclohexane affording 13.2 g (50%) of product as a yellow solid; mp 35°-40° C.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.F[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1>O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.9 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.8 g) was added to a DMF (20 ml) solution of 4-methoxyphenol (2.4 g). The reaction mixture was stirred at room temperature for 5 minutes, to which was added 4-fluorobenzenecarbonitrile (2.4 g). The reaction mixture was stirred at room temperature for 4 hours, which was further stirred at 50° C. for one hour. The reaction mixture was poured into water, which was extracted with toluene. The organic layer was washed with water, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1), and then recrystallized from toluene-hexane to obtain 4-[(4-methoxyphenyl)oxy]benzenecarbonitrile (2.0 g).
Reaction SMILES: [CH:1]1([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:11]2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:39]>CO>[ClH:39].[CH:1]1([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][NH:24][CH3:25])=[CH:11]2)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(Cc1cn(S(=O)(=O)C2CCCCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)C2CCCCC2)c(-c2cccnc2F)c1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
tert-Butyl {[1-(cyclohexylsulfonyl)-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (420 mg) was dissolved in methanol (10 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was stirred at 70° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 256 mg, 71%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH:12]1([C:16]2([CH2:20][OH:21])[CH2:19][O:18][CH2:17]2)[CH2:15][CH2:14][CH2:13]1>ClCCl.C(OCC)C>[CH:12]1([C:16]2([CH:20]=[O:21])[CH2:19][O:18][CH2:17]2)[CH2:15][CH2:14][CH2:13]1
Reactant: OCC1(C2CCC2)COC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC1(C2CCC2)COC1
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a stirred suspension of pyridinium chlorochromate (10 g, 45 mmol) in dry dichloromethane (100 ml) was added 3-cyclobutyl-3-hydroxymethyloxetane (5 g, 35 mmol). The mixture was stirred for 2 hours, diluted with diethylether and then purified on a florisil column with an ether rinse. Evaporation afforded 3-cyclobutyl-3-formyloxetane (3.72 g, 75%) as a liquid.
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][CH2:17][CH2:18][CH3:19])=[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])[CH2:17][CH2:18][CH3:19]
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: CCCCN=C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCn1c(=O)[nH]c2sc(CC)cc2c1=O
Temperature: 60 °C
Yield: 54 %

Procedure:
To a mixture of methyl 2-amino-5-ethylthiophene-3-carboxylate (2.5 g), 1-isocyanatobutane (1.52 mL) and tetrahydrofuran (20 ml) was added sodium hydride (1.2 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, the precipitated solid was collected by filtration. The obtained solid was recrystallized from ethyl acetate to give the title compound as colorless crystals (1.85 g, 54%).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.CCCCCC>C(OCC)(=O)C>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=3)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cccc(-c2ccc3c(c2)C2(CCCCC2)C(=NOCc2ccccc2)N3)c1
Yield: 73.1 %

Procedure:
Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol) and 3-methoxyphenyl boronic acid (0.79 g, 5.2 mmol) according to Example 45 procedure A. The product was purified by flash silica gel chromatography; (eluant: 10:0.5 hexane:ethyl acetate) to give the desired product (0.80 g, 1.9 mmol, 75%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ 1.43-1.78 (8H, m), 1.95-2.00 (2H, q), 3.80 (3H, s), 5.00 (2H, s), 6.82-6.86 (2H, m), 7.10-7.16 (2H, m), 7.28-7.53 (10H, m), 9.57 (1H, s); MS (ESI(−ve)) m/z 411 (M−H)−.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[C:31]4[N:35]([CH:36]=3)[CH:34]=[CH:33][S:32]4)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:39][N:38]=[N:37][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[C:31]4[N:35]([CH:36]=3)[CH:34]=[CH:33][S:32]4)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn4ccsc4n3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3cn4ccsc4n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cccc(Br)c2C1=O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(=O)c2c(Br)cccc21
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a stirred solution of 4-bromoisatin (90.4 g, 400 mmol) in N,N-dimethylformamide (400 mL) was added cesium carbonate (196.0 g, 600 mol) at ambient temperature. The reaction mixture was stirred for 30 min, iodomethane (37.4 mL, 600 mmol) was added and the mixture was stirred at ambient temperature for 18 h. The solid was removed by filtration, the filtrate was concentrated in vacuo, and the residue was triturated in water and washed with diethyl ether to afford 4-bromo-1-methyl-1H-indole-2,3-dione (82.0 g, 85%): 1H NMR (300 MHz, DMSO-d6) δ 7.95-7.89 (m, 1H), 7.68-7.64 (m, 1H), 7.53-7.49 (m, 1H), 3.50 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:14][C:15]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][OH:25])[C:21]3[C:26]([O:29][CH3:30])=[N:27][NH:28][C:20]=3[CH:19]=2)=[O:16])[C:10]([OH:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:14][C:15]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][OH:25])[C:21]3[C:26]([O:29][CH3:30])=[N:27][NH:28][C:20]=3[CH:19]=2)=[O:16])[C:10]([OH:13])([CH3:11])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1n[nH]c2cc(NC(=O)NC(c3ccc(Cl)c(Cl)c3)C(C)(C)O)nc(CO)c12
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1n[nH]c2cc(NC(=O)N[C@@H](c3ccc(Cl)c(Cl)c3)C(C)(C)O)nc(CO)c12
Reaction time: 0.1 h
Yield: 83 %

Procedure:
The enantiomers of 1-(1-(3,4-dichlorophenyl)-2-hydroxy-2-methylpropyl)-3-(4-(hydroxymethyl)-3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)urea, TFA (15 mg, 0.033 mmol) were separated by SFC (Berger Multigram II, Column: Chiralcel OJ-H, 2.1×25 cm, 5 uM, UV wavelength: 220 nM, mobile phase: 85%/15% Methanol+0.25% dimethyl ethylamine/CO2(l), flow rate: 70 mL/Min, 10 min run time). Elution was observed at 5.8 min. The fractions were collected and the solvent evaporated in vacuo to afford (S)-1-(1-(3,4-dichlorophenyl)-2-hydroxy-2-methylpropyl)-3-(4-(hydroxymethyl)-3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (107, 6.2 mg, 0.014 mmol, 83.0% yield). MS: [M+H]+ m/z 454. 1H NMR (600 MHz, DMSO): 7.51-7.55 (m, 2H); 7.31 (dd, J=8.3, 2.0 Hz, 1H); 7.04 (s, 1H); 4.77 (s, 2H); 4.59 (d, J=8.6 Hz, 1H); 3.94 (s, 3H); 1.16 (s, 6H).
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:27]([C:29]1[C:30](=[C:45]([C:48]#[N:49])[C:46]#[N:47])[O:31][C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:35]([F:38])([F:37])[F:36])[C:33]=1[CH3:34])#[N:28]>C(O)C.O1CCCC1>[CH2:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:34][C:33]3[C:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:35]([F:38])([F:36])[F:37])[O:31][C:30](=[C:45]([C:48]#[N:49])[C:46]#[N:47])[C:29]=3[C:27]#[N:28])=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)c(OC)c1
Temperature: 70 °C
Yield: 92.7 %

Procedure:
In 8 ml of ethanol and 2.5 ml of tetrahydrofuran were dissolved 226 mg (0.61 mmol) of 5-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]thiophene-2-carboaldehyde and 210 mg (0.62 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 70° C. for 4 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 378 mg of a dark brown powdered crystal (yield: 92.9%; mp: 203-204° C.)
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]1[NH:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1.O1CCCC1.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>O>[CH3:3][CH:4]1[CH2:5][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:8][N:9]1[C:22]([O:23][CH2:24][CH3:25])=[O:26]
Reactant: CC1CN(Cc2ccccc2)CCN1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(Cc2ccccc2)CC1C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
580 Parts of a sodium hydroxide solution 1 N in water were cooled in an ice bath and then there were added 44 parts of 3-methyl-1-(phenylmethyl)piperazine and 82.8 parts of tetrahydrofuran. A solution of 27.13 parts of ethyl carbonochloridate in 103.5 parts of tetrahydrofuran was added dropwise at a temperature at about 5° C. Upon completion, stirring was continued for 4 hours in an ice bath. The product was extracted with dichlormethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 55 parts (87.8%) of ethyl 2-methyl-4-(phenylmethyl)-1-piperazinecarboxylate as a residue (int. 36).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][NH2:23])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:23][CH2:22][CH2:21][N:20]([CH2:24][CH3:25])[CH2:18][CH3:19])=[N:7][C:6]=2[CH:17]=1
Reactant: CCN(CC)CCN
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Product: CCN(CC)CCNC1=Nc2cc(Cl)ccc2Nc2ccccc21
Yield: 11.4 %

Procedure:
8-Chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (25 mg, 0.1 mmol) and N,N-diethylethylenediamine (58 mg, 0.5 mmol) were reacted according to GP4 to give 3.9 mg of the title compound (160FE16E). MS (ESI) 343 (MH+). Purity for MH+ (UV/MS) 99/94.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:30])=[C:20]([C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][N:23]=2)[CH:21]=1>>[F:28][C:27]1[C:22]([C:20]2[CH:21]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:17]=[CH:18][C:19]=2[F:30])=[N:23][CH:24]=[C:25]([F:29])[CH:26]=1
Reactant: Fc1c(C(F)(F)F)ccn2ccnc12
Reactant: Fc1cnc(-c2cc(Br)ccc2F)c(F)c1
Product: Fc1cnc(-c2cc(-c3cnc4c(F)c(C(F)(F)F)ccn34)ccc2F)c(F)c1
Yield: 31.6 %

Procedure:
8-Fluoro-7-trifluoromethylimidazo[1,2-α]pyridine (102 mg, 0.5 mmol) and 2-(5-bromo-2-fluorophenyl)-3,5-difluoropyridine (216 mg, 0.75 mmol) were coupled following the procedure given in Example 6 to afford 3-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridine (65 mg, 32%) as an off-white solid: δH (360 MHz, CDCl3) 6.97 (1H, dd, J 7 and 6), 7.35-7.42 (2H, m), 7.61-7.65 (1H, m), 7.78 (1H, dd, J 7 and 2), 7.87 (1H, s), 8.16 (1H, d, J 7), 8.49 (1H, d, J 2); m/z (ES+) 412 (100%, [MH]+).