Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])#[N:26].O1CCOCC1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:30]2[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[C:28]([F:36])[CH:29]=2)[N:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(Cl)nc(N)n2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To N-[(3R,5R)-1-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-3-piperidinyl]-N,3,3-trimethylbutanamide (80 mg, 0.23 mmol) and (4-cyano-3-fluorophenyl)boronic acid (49 mg, 0.29 mmol) were added 1,4-dioxane (4 mL) and sat. aq. NaHCO3 (2 mL), and the resulting mixture was purged (“degassed”) with N2 into a sealable tube. Pd(Ph3P)4 (26 mg, 0.023 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100° C. The reaction was allowed to cool down to room temperature and poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexanes to 75% EtOAc/Hexanes) afforded the title compound (84 mg) as a solid. LC-MS (ES) m/z=439 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@@H:9]([N:11]1[CH2:16][CH2:15][N:14]2[C:17](=[O:27])[C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[CH:19][CH:20]=[C:13]2[C:12]1=[O:28])[CH3:10].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1[S:39]([F:44])([F:43])([F:42])([F:41])[F:40]>O1CCCC1.O>[CH3:26][C:24]1[N:23]=[CH:22][N:21]([C:18]2[C:17](=[O:27])[N:14]3[CH2:15][CH2:16][N:11]([C@@H:9]([CH3:10])[CH2:8][O:7][C:30]4[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=4[S:39]([F:42])([F:43])([F:44])([F:40])[F:41])[C:12](=[O:28])[C:13]3=[CH:20][CH:19]=2)[CH:25]=1
Reactant: Cc1cn(-c2ccc3n(c2=O)CCN([C@@H](C)CO)C3=O)cn1
Reactant: O=[N+]([O-])c1ccc(F)c(S(F)(F)(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(-c2ccc3n(c2=O)CCN([C@@H](C)COc2ccc([N+](=O)[O-])cc2S(F)(F)(F)(F)F)C3=O)cn1
Reaction time: 0.17 h

Procedure:
A solution of potassium tert-butoxide in tetrahydrofuran (1 M, 1.97 mL, 1.97 mmol) was added to a slurry of 2-[(2S)-1-hydroxypropan-2-yl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (C54) (541 mg, 1.79 mmol) in tetrahydrofuran (6 mL), and the mixture was allowed to stir for 10 minutes. A solution of 1-fluoro-4-nitro-2-(pentafluoro-λ6-sulfanyl)benzene (P15) (478 mg, 1.79 mmol) in tetrahydrofuran (4 mL) was added, and the reaction mixture was stirred at room temperature for 18 hours. At that point, it was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluents: ethyl acetate, then 10% methanol in ethyl acetate) afforded the product as a yellow foam. Yield: 695 mg, 1.26 mmol, 70%. LCMS m/z 550.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.53 (d, J=7.1 Hz, 3H), 2.34 (d, J=1.0 Hz, 3H), 3.73-3.85 (m, 2H), 4.30-4.47 (m, 4H), 4.99-5.08 (m, 1H), 7.16-7.21 (m, 2H), 7.28 (d, J=7.7 Hz, 1H), 7.52 (d, J=7.7 Hz, 1H), 8.40 (dd, J=9.2, 2.7 Hz, 1H), 8.44 (br s, 1H), 8.71 (d, J=2.6 Hz, 1H).
Reaction SMILES: [CH:1]([CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5])=O.Cl.[NH2:13][NH:14][C:15]([NH2:17])=[O:16].[OH-].[Na+]>CO.O>[NH2:5][C:4]1[N:14]([C:15](=[O:16])[NH2:17])[N:13]=[CH:1][C:3]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CC(C=O)c1ccccc1
Reactant: NNC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)n1ncc(-c2ccccc2)c1N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
The α-formylphenylacetonitrile obtained above is dissolved in methanol-water (1:1-10:1, 200 ml), and to the solution is added with stirring semicarbazide hydrochloride (9.95 g) under ice cooling. After taking off the ice bath, the mixture is reacted for 12 hours. The reaction mixture is neturalized with 5N sodium hydroxide solution. The mixture is stirred for 20 minutes, and the resulting precipitate is separated by filtration, washed with water and dried to give 3-amino-2-carbamoyl-4-phenylpyrazole (16.82 g). This product is used in the subsequent procedure without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)[CH3:2].[CH:14]1C=CC=C[CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].C=C>ClCCl.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[CH2:10][C:11](=[O:13])[CH2:15][CH2:14]2)[CH3:2]
Reactant: c1ccccc1
Reactant: CCOc1ccc(CC(=O)O)cc1
Agent: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc2c(c1)CCC(=O)C2
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 5.0 g of p-ethoxyphenyl acetic acid, 7.0 g of phosphoric pentachloride and 10 ml of anhydrous benzene was heated at 80° C. for 2 hours. The reaction solution was concentrated under reduced pressure and the residue obtained was dissolved in 20 ml of anhydrous dichloromethane. This solution was added dropwise to a mixture, cooled to -50° C., of 7.3 g of anhydrous aluminum chloride and 80 ml of anhydrous dichloromethane. Then, ethylene gas was fed into the solution for 20 minutes. Subsequently, the solution was stirred at room temperature (about 25° C.) for 4 hours. Into the reaction solution cooled with ice was added dropwise 30 ml of water. The dichloromethane layer was removed and washed with an 8% hydrochloric acid aqueous solution, water, a saturated sodium bicarbonate aqueous solution and water in this order. Then the dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 6-ethoxy-2-tetralone as a pale-yellow oily product. The crude product, 6-ethoxy-2-tetralone obtained as described above, was catalytically reduced in the presence of hydrogen in a mixture of 0.4 g of platinum oxide and 40 ml of a 20% ethylamine-ethanol solution. After take up of hydrogen had been completed, the platinum oxide catalyst was filtered from the reaction solution and the filtrate was concentrated under reduced pressure. Then the residue was extracted with chloroform and the chloroform layer as washed with a 2 N-NaOH aqueous solution and water in this order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Adding an ethanolic solution of hydrogen chloride having a concentration of about 18% to the residue, the solution was concentrated under reduced pressure to cause crystals to form. The crystals were recrystallized from a mixed solution of ethanol and diethyl ether to obtain 1.4 g of N-ethyl-6-ethoxy-1,2,3,4-tetrahydro-2 -naphthylamine hydrochloride as colorless needles having a melting point of 207°-209° C.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][C:34]=1[C:41]([F:44])([F:43])[F:42]>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:37][C:36]3[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[C:34]([C:41]([F:42])([F:43])[F:44])[CH:35]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Product: COc1ccc(Cn2ccc3c(-c4ccc5c(c4)CCCO5)c(C(OC(C)(C)C)C(=O)O)c(C)nc32)cc1C(F)(F)F

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 4-methoxy-3-(trifluoromethyl)benzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (s, 1 H), 7.50-7.37 (m, 2 H), 7.26-7.19 (m, 1 H), 7.04-7.00 (m, 1 H), 6.98-6.89 (m, 2 H), 6.27-6.20 (m, 1 H), 5.62-5.56 (m, 1 H), 5.53-5.44 (m, 1 H), 5.43-5.34 (m, 1 H), 4.32-4.24 (m, 2 H), 3.89 (s, 3 H), 2.96-2.79 (m, 2 H), 2.72 (s, 3 H), 2.15-2.06 (m, 2 H), 1.00-0.92 (s, 9 H); LC/MS (m/z) ES+=583.38 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([CH3:8])=[O:7])[CH3:2].C([Mg]Cl)(C)C.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>C1COCC1.N1C=CN=C1>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([C:18]([CH:15]1[CH2:17][CH2:16]1)=[O:19])[C:6](=[O:7])[CH3:8])[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(C)[Mg]Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)C(=O)C1CC1
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a solution of ethylacetoacetate (11.0 g, 85 mmol) in THF (20 ml) at 0° C. under argon atmosphere was added isopropylmagnesium chloride (42 ml, 2 M in THF, 85 mmol) dropwise. The reaction was stirred for 0.5 h. This solution was then transferred by cannula to a solution of cyclopropylcarbonylchloride (8.8 g, 85 mmol) and imidazole (0.3 g, 4 mmol) in THP (30 ml), also under argon at 0° C. The reaction was stirred for 2 h at 0° C. and 1 h at room temperature before the reaction was quenched by addition of 10% citric acid solution. The reaction was then extracted with EtOAc, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc:n-heptane 5:95) afforded the title compound (11.9 g, 71%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.99-1.02 (2H, m), 1.22-1.24 (2H, m), 1.35 (3H, t, J=6 Hz), 2.32 (3H, s), 2.41-2.51 (1H, m), 4.30 (2H, q, J=6 Hz), 17.95 (1H, s).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=CC=C[CH:9]=1.[CH3:21]C(C)C(=O)C(=NO)C.CC1C=C(C=CC=1C)C=O>>[CH3:21][C:18]1[CH:19]=[C:14]([C:5]2[O:6][C:7]([CH:8]([CH3:9])[CH3:13])=[C:3]([CH2:2][I:1])[N:4]=2)[CH:15]=[CH:16][C:17]=1[CH3:20]
Reactant: CC(=NO)C(=O)C(C)C
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: Cc1ccc(C=O)cc1C
Product: Cc1ccc(-c2nc(CI)c(C(C)C)o2)cc1C

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 4-methylpentane-2,3-dione-2-oxime and 3,4-dimethylbenzaldehyde gave 2-(3,4-dimethylphenyl)-4-iodomethyl-5-isopropyloxazole.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na].[H-].[Na+].[CH:18]([O:20][CH2:21][CH2:22]Cl)=[CH2:19]>CS(C)=O.O>[CH:18]([O:20][CH2:21][CH2:22][C:13]1([CH2:22][CH2:21][O:20][CH:18]=[CH2:19])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[CH2:19]
Reactant: c1ccc2c(c1)Cc1ccccc1S2
Reactant: C=COCCCl
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: C=COCCC1(CCOC=C)c2ccccc2Sc2ccccc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of thioxanthene (29.7 g.) in dimethyl sulphoxide (1,200 ml.) is added gradually to a solution of sodium methylsulphinylmethide [prepared in the usual way from sodium hydride (24 g. of a 60% dispersion in mineral oil) and dimethyl sulphoxide (300 ml.)]. The dark red mixture is cooled in ice and chloroethyl vinyl ether (44 g.) is added dropwise. The mixture is stirred under nitrogen for a further 16 hours, allowed to warm to ambient temperature (18°to 20° C.), poured into water (3 1.) and extracted with ether. The ethereal solution is washed with water, dried, and then evaporated to give crude oily 9,9-bis(2'-vinyloxyethyl)thioxanthene.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[C:20]2=[CH:21][N:22]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[N:23]=[C:19]2[C:18]([F:32])=[CH:17][N:16]=1)(C)(C)C>C(Cl)Cl>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[N:22]1[CH:21]=[C:20]2[C:15]([NH2:14])=[N:16][CH:17]=[C:18]([F:32])[C:19]2=[N:23]1
Reactant: CC(C)(C)OC(=O)Nc1ncc(F)c2nn(-c3c(Cl)cccc3Cl)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(F)c2nn(-c3c(Cl)cccc3Cl)cc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76.1 %

Procedure:
TFA (2.0 ml) was added to a mixture of [2-(2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-carbamic acid tert-butyl ester (390 mg, 1 mmol) in DCM (5 mL) and the reaction mixture was stirred at room temperature for 3.5 h. The volatiles were removed under reduced pressure and the resultant residue was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution (×2) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid (226 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.74 (d, J=3.0 Hz, 1H), 7.82-7.78 (m, 2H), 7.72-7.68 (m, 1H), 7.53 (d, J=4.3 Hz, 1H), 6.86 (br s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.Br[C:22]1[CH:23]=[CH:24][C:25]([F:30])=[C:26]([CH:29]=1)[C:27]#[N:28]>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:20]=[C:2]([C:22]3[CH:23]=[CH:24][C:25]([F:30])=[C:26]([CH:29]=3)[C:27]#[N:28])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(F)c(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-2-fluorobenzonitrile generally according to the procedures described in examples 82 and 1. An off-white solid: mp 197-199° C.; 1H NMR (DMSO-d6): δ 10.09 (s, 1H), 8.25 (dd, J=6.35, 2.44 Hz, 1H), 8.02-8.05 (m, 1H), 7.68 (dd, J=8.3, 1.95 Hz, 1H), 7.61 (d, J=1.95 Hz, 1H), 7.7 (dd, JHF=9.28 Hz, JHH=9.28 Hz, 1H), 7.56 (dd, J=5.37, 1.47 Hz, 1H), 7.27 (d, J=8.79 Hz, 1H), 7.0 (dd, J=4.88, 3.42 Hz, 1H), 6.95 (dd, J=3.9, 1.47 Hz, 1H), 4.08 (d, J=15.62 Hz, 1H), 3.94 (d, J=15.13 Hz, 1H), 2.46-2.57 (m, 2H), 0.76 (t, J=6.83 Hz, 3H); MS (ESI) m/z 393 ([M+H]+); MS (ESI) m/z 391 ([M−H]−); Anal. calcd for C22H17FN2O2S: C: 67.33; H: 4.37; N: 7.14. Found: C: 67.26; H: 4.38; N: 6.90.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1>>[C:7]([C:6]1[CH:9]=[C:2]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)[CH:3]=[CH:4][C:5]=1[F:10])#[N:8]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1cc(Br)ccc1F
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)c(C#N)c2)CC1

Procedure:
The title compound was prepared from 5-bromo-2-fluorobenzonitrile and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate using a method similar to that described for D10a.
Reaction SMILES: [CH2:1]([NH:9][C:10]([NH2:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[CH:14]([C:20]([C:22]([F:25])([F:24])[F:23])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:1]([NH:9][C:10]1[O:11][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([C:22]([F:23])([F:25])[F:24])[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: CCCCCCCCNC(N)=O
Product: CCCCCCCCNc1nc(C(F)(F)F)c(C(=O)OCC)o1
Yield: 17.8 %

Procedure:
By the procedure of Example 4, 5.16 g (30 mmol) of n-octyl urea was reacted with 5.4 g (25 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 18 hours. The product was separated and then recrystallized from petroleum ether to yield 1.5 g of a white powder product (m.p.=36°-37° C.) identified in Table I.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[S:23][CH:24]=[CH:25][C:5]=2[C:4](=[O:26])[N:3]1[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:42]=[O:43]>C(Cl)(Cl)Cl>[CH:42]([C:24]1[S:23][C:6]2[N:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)[C:2](=[O:1])[N:3]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4](=[O:26])[C:5]=2[CH:25]=1)=[O:43]
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3ccsc32)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3cc(C=O)sc32)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 4′-{[2,4-dioxo-3-(2-phenylethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (2 g), phosphorus oxychloride (30 mL) and N,N-dimethylformamide (10 mL) was stirred at 50° C. for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (1.96 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[N:30]([C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[C:31]=[O:32]>>[CH3:28][C:11]1[N:10]([CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:31]([NH:30][C:33]3[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=3)=[O:32])=[CH:7][CH:6]=2)=[O:29])[C:14](=[O:15])[C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(NC(=O)Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Synthesis in analogy to Example 6 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and 1-isocyanato-4-nitro-benzene to yield 1-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-3-(4-nitro-phenyl)-urea. LC/MS at 254 nm; [M+H] 548; Rt 3.601 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cnc(C)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ncc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.3 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.075 g, 0.34 mmol) in N-methyl 2-pyrolidone (0.5 mL) was added powdered potassium hydroxide (0.095 g, 1.7 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrimidine (0.102 g, 0.85 mmol) was added and stirred for further at 80 deg C. 3 h. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) then purified through preparative TLC to get the desired compound as yellow oil (0.020 g, 13% yield). 8-Chloro-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.020 g, 0.06 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.008 g, 0.06 mmol) in THF (0.5 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.008 g, 32% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[OH:11].[F:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>N1C=CC=CC=1>[F:12][C:13]1[CH:14]=[C:15]([S:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[OH:11])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc2[nH]nc(O)c2c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2[nH]nc(O)c2c1)c1cccc(F)c1
Yield: 5.7 %

Procedure:
3-Fluoro-N-(3-hydroxy-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 2 from 51 mg of 5-amino-3-hydroxy-1H-indazole, 1.5 ml of pyridine and 69 mg of 3-fluorobenzenesulfonyl chloride. 6 mg of 3-fluoro-N-(3-hydroxy-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:19]([OH:21])=[O:20])[N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:3]1.O.O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Ce+3].[C:33](O)(=O)[CH3:34]>C(O)C>[OH:1][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:19]([O:21][CH2:33][CH3:34])=[O:20])[N:7]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCC(=O)C[C@@H]2C[C@H]1C(=O)O
Reactant: CC(=O)O
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](O)CC[C@H]2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a −78° C. solution of (3S, 4aS, 8aR) 6-oxo-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (6.88 g, 21.14 mmol)(see Preparation 2, Steps A and B, below and Scheme III, Step A generally) and cerium trichloride heptahydrate (7.9 g, 21.2 mmol) in absolute ethyl alcohol (90 mL), under nitrogen sodium borohydride (1.24 g, 32.73 mmol) was added in portions. The resulting mixture was slowly warmed up to room temperature over 5 hours. The reaction mixture was cooled down to 0° C. and acetic acid (50% in water, 25 mL) was carefully added. The resulting mixture was stirred for 1 hour at room temperature and the solvent was removed in vacuo. To the resulting material water and ethyl acetate were added and the phases separated. Aqueous layer was extracted with ethyl acetate (3×). The combined organic phases were dried, filtered and concentrated in vacuo. Flash chromatography (silicagel, 70% ethyl acetate/hexane) gave ethyl (3S, 4aS, 6S, 8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (2.4 g, 35%) and the title compound (4.15 g, 60%)