Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[C:14](O)(=O)[CH3:15]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:14]([CH3:15])=[N:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: NNc1cnc2ccc(Br)cc2n1
Reactant: CC(=O)O
Product: Cc1nnc2cnc3ccc(Br)cc3n12
Yield: 90 %

Procedure:
A mixture of 7-bromo-2-hydrazinylquinoxaline (1 g, 4.18 mmol) in acetic acid (10 mL) was refluxed for 18 h. Half of the acetic acid was removed under vacuum and the residue was poured into ice-water. The precipitate was collected on a filter, washed with water, and dried under vacuo to afford crude 8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline as a dark red solid (1 g, yield 90%) which was used in the next step without further purification. MS (m/z): 263 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1.C(N(C(C)C)C(C)C)C>>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:27]3[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]3)=[CH:4][CH:5]=2)[C:12](=[O:26])[CH:13]=1
Reactant: CC(=O)NC1CCNCC1
Reactant: O=c1cc(OCc2cccc(F)c2)ccn1CCc1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4cccc(F)c4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(3-Fluoro-benzyloxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 8.1c from 120 mg (0.29 mmol) 1-[2-(4-bromomethyl-phenyl)ethyl]-4-(3-fluoro-benzyloxy)-1H-pyridin-2-one (example 8.1b), 61 mg (0.43 mmol) N-piperidin-4-yl-acetamide and 126 μL (0.72 mmol) N-ethyl-diisopropylamine as base.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.CCN(C(C)C)C(C)C.[CH:21]([O:24][C:25]1[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:23])[CH3:22]>C1COCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:30][C:27]2[CH:26]=[C:25]([O:24][CH:21]([CH3:23])[CH3:22])[NH:29][N:28]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Temperature: 60 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (0.51 g, 2.7 mmol) and DIEA (0.39 ml, 2.2 mmol) in THF (10 ml) was added the 5-isopropoxy-1H-pyrazol-3-amine (0.25 g, 1.8 mmol) solution at 0° C. After addition, the reaction mixture was stirred at 25° C. for 3 days and 60° C. for 24 hours. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography (hexane-EtOAc=3:1) to give the title compound as a yellow solid (0.33 g, 63%). 1H NMR (400 MHz) δ 12.25 & 11.66 (s, 1H), 10.46 & 10.13 (s, 1H), 8.58 & 8.55 (d, J=8.8 Hz, 1H), 7.11 & 7.02 (d, J=8.8 Hz, 1H), 6.08 & 5.97 (s, 1H), 4.70 & 4.48 (m, 1H), 1.32 & 1.27 (d, J=6.0 Hz, 6H). MS: Calcd.: 297. Found: [M+H]+ 298.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[CH2:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=O)[CH3:2].[Cl:16][C:17]1[S:21][C:20]([C:22]2[O:26][N:25]=[C:24]([CH2:27][NH:28][NH2:29])[CH:23]=2)=[CH:19][CH:18]=1>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:28]([CH2:27][C:24]2[CH:23]=[C:22]([C:20]3[S:21][C:17]([Cl:16])=[CH:18][CH:19]=3)[O:26][N:25]=2)[N:29]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccco1
Reactant: NNCc1cc(-c2ccc(Cl)s2)on1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccco2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1

Procedure:
A solution of 550 mg 4-Furan-2-yl-2,4-dioxo-butyric acid ethyl ester and 601 mg [5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-hydrazine in 10 ml acetic acid was heated to 80° C. for 2 h. Then the reaction mixture was diluted with 20 ml water and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over MgSO4. The solvents were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with a n-heptane:ethyl acetate gradient 100%->50%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[C:4]([F:21])[CH:3]=1.[CH3:22][N:23](C=O)[CH3:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([N:23]([CH3:24])[CH3:22])=[O:17])=[CH:18][CH:19]=2)=[C:4]([F:21])[CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 51.1 %

Procedure:
To a solution of 4-[3-(4-bromo-2-fluoro-phenyl)-ureido]-benzoic acid (0.5 g, 0.014 mol) in DMF (5 mL) N,N-dimethylamine hydrochloride (0.14 g, 0.0017 mol), HOBt (0.25 g, 0.0.0018 mol), EDC.HCl (0.41 g, 0.0021 mol) and TEA (0.4 mL, 0.0028 mol) were added. The reaction mixture was stirred at room temperature for 10 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×15 mL). The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford the title compound [0.33 g, 65%]; LC-MS (ESI): Calculated mass: 379.0; Observed mass: 382.0 [M+H] (RT: 1.41 min).
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][C:5]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:38]=[C:36]1[C:35]2[C:34](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:33](=[O:43])[N:37]1[CH:2]1[CH2:7][CH2:6][C:5]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)C1(C)CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
Ethyl 4-hydroxy-1-methylcyclohexanecarboxylate (Intermediate 67, 930 mg, 4.99 mmol), triphenylphosphine (3.143 g, 11.98 mmol), and phthalimide (882 mg, 5.99 mmol) were dissolved in 60 mL of THF. DIAD (2.33 mL, 11.98 mmol) was then added and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum, and the residue was chromatographed on silica gel using an ethyl acetate/heptane gradient. The title compound (1 g) was obtained as a clear oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:14](OC)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:14][OH:15])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: OCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 104.3 %

Procedure:
A stirred solution of 76.1 g of methyl 1-benzyl-4-anilino-4-piperidine carboxylate in 1200 ml of toluene is maintained at ambient temperature while 130 ml of a 70% solution of sodium dihydrobis(2-methoxyethoxy)aluminate in benzene is added dropwise. Stirring is continued for one hour after the addition. Two hundred grams of a saturated solution of sodium sulfate is added. The aqueous portion is removed and the organic portion is dried over sodium sulfate and flash evaporated to give 72.5 g of 1-benzyl-4-anilino-4-piperidinemethanol, as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][C:4]=1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][C:4]=1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([OH:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)#[N:2]
Reactant: COC(=O)Cc1ccc(-n2ccc3cc(C(=O)OC(C)(C)C)ccc32)c(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1ccc(-n2ccc3cc(C(=O)O)ccc32)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
tert-butyl 1-(2-cyano-4-(2-methoxy-2-oxoethyl)phenyl)-1H-indole-5-carboxylate (0.380 g, 0.973 mmol, in 2 ml of DCM was added 2 mL of TFA and the reaction stirred at ambient temperature under nitrogen. After 2 hours, the reaction was concentrated to give 1-(2-cyano-4-(2-methoxy-2-oxoethyl)phenyl)-1H-indole-5-carboxylic acid (0.320 g, 0.957 mmol, 98%). MS (APCI negative)=333.2 (M−1).
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1[N:21]3[N:22]=[C:23]([CH2:25][OH:26])[N:24]=[C:20]3[N:19]=[C:18]([CH3:27])[CH:17]=1)=[C:7]2[C:11]([OH:13])=[O:12].[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[OH:38])[C:32](O)=[O:33].B(F)(F)F>C(#N)C>[NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1[N:21]3[N:22]=[C:23]([CH2:25][O:26][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][C:37]([OH:38])=[C:29]([OH:28])[CH:30]=4)[N:24]=[C:20]3[N:19]=[C:18]([CH3:27])[CH:17]=1)=[C:7]2[C:11]([OH:13])=[O:12]
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(CO)nc2n1
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: FB(F)F
Solvent: CC#N
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(COC(=O)c3ccc(O)c(O)c3)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
(6R,7R)-7-Amino-3-[[[2-(hydroxymethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (4.08 g) (known from EPOS 302,633) and 1.54 g of 3,4-dihydroxybenzoic acid are treated with 30 ml of a 20% solution of boron trifluoride in acetonitrile and stirred at room temperature for 2 hours. A further 25 ml of a 20% solution of boron trifluoride in acetonitrile are added; the reaction mixture is stirred at room temperature under argon for 2 days. After the addition of 100 ml of ice-water the reaction mixture is concentrated to about half. The product is precipitated by adjusting the pH value to 2.0 with concentrated aqueous ammonia. The precipitated material is suspended in water, brought into solution with 1N aqueous sodium hydroxide solution and purified by chromatography on RP12-Kieselgel with water/acetonitrile. The product fractions are concentrated to about 50 ml and the product is precipitated by acidification to pH 2.0. After drying in a high vacuum there are obtained 1.60 g of (6R,7R)-7-amino-3-[[[2-[[(3,4-dihydroxybenzoyl)oxy]methyl]-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a white powder.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][CH2:7][C:8](=[O:11])[CH2:9][CH3:10]>P(=O)(O)(O)O>[CH3:6][C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:2][C:1]([OH:5])=[O:4]
Reactant: CCC(=O)CC
Reactant: O=CC(=O)O
Agent: O=P(O)(O)O
Product: CCC(=O)C(C)=CC(=O)O

Procedure:
Prepared from glyoxylic acid (16.1 g, 0.18 mol), 3-pentanone (45.6 g, 0.63 mol) and orthophosphoric acid (30 ml). 1H n.m.r. δ (CDCl3) 1.23, t J 7.2 Hz, 3H, CH3; 2.56, s, 3H, CH3; 2.76, q J 7.2 Hz, CH2; 6.55, s, CH.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16])[CH3:12].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CC(C)=O>[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:12]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCOc1ccccc1N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC(C)=O
Product: CCOc1ccccc1NC(=O)c1ccccc1C
Yield: 94.5 %

Procedure:
A 13.6 g (0.1 mol) portion of o-methylbenzoic acid and 13.7 g of o-ethoxyaniline were dissolved in 200 ml of acetone. A 4.7 g (0.033 mol) amount of phosphorus pentoxide was gradually added to the prepared solution at 30° - 40° C. After the addition, the reaction mixture was refluxed for 3 hours with stirring. The acetone was removed and the residual product was poured into water and was extracted with toluene. The toluene layer was dried over anhydrous sodium sulfate and the toluene was removed to obtain 24.1 g (94.5%) of a clear pink liquid, having a boiling point of 148° C/0.04 mm Hg and nD20 of 1.5929.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:6][CH2:5]2.CC(N=NC(C#N)(C)C)(C#N)C.CCCC[SnH](CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:7]2[C:8]3[C:4](=[CH:3][CH:2]=[CH:10][C:9]=3[NH2:11])[CH2:5][CH2:6]2)(=[O:13])=[O:14])=[CH:16][CH:17]=1
Reactant: COc1ccc(S(=O)(=O)N2CCc3cc(Br)cc(N)c32)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)N2CCc3cccc(N)c32)cc1
Yield: 90 %

Procedure:
To a stirred solution of 18 (2 g, 4.84 mmol), AIBN (0.08 g, 0.48 mmol), Bu3SnH (3.91 ml, 14.50 mmol) in toluene (49 ml) was heated to reflux for 15 h. After cooling, the reaction mixture was evaporated and then extracted by CH2Cl2. The combined organic layer was dried by MgSO4 and concentrated to give a residue that was purified by silica gel flash column chromatography (EtOAc:n-hexane=1:2) to give compound 19, yield 90%.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][N:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[N:24]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:27]3[N:23]([CH3:22])[N:24]=[CH:25][CH:26]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3ccnn3C)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (81 mg, 0.576 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL) and water (2 mL) was added Pd(PPh3)4 (17 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse HPLC to yield 2,8-dimethyl-5-(2-(1-methyl-1H-pyrazol-5-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.32 (s, 1H), 7.18 (s, 1H), 7.0 (d, 1H), 6.9 (d, 1H), 6.01 (s, 1H), 3.6 (s, 2H), 3.2 (s, 3H), 3.0 (m, 4H), 2.7 (m, 4H), 2.52 (s, 3H), 2.4 (s, 3H), 2.2 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:18])[S:12][CH2:13][C:14](=O)[CH2:15][Cl:16].[H][H]>>[Cl:16][CH2:15][C:14]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[C:11](=[S:18])[S:12][CH:13]=1
Reactant: [H][H]
Reactant: O=C(CCl)CSC(=S)Nc1ccc(F)c(F)c1F
Product: Fc1ccc(-n2c(CCl)csc2=S)c(F)c1F

Procedure:
3-Chloro-2-oxopropyl N-(2,3,4-trifluorophenyl)-dithiocarbamate (4.0 g) is added to 30% hydrogen chloridemethanol solution (15 ml), and the mixture is refluxed for 3 hours. The solvent is distilled off under reduced pressure, and cold water is added to the residue and the mixture is extracted with chloroform. The extract is washed with saline solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue is recrystallized from cyclohexane to give the title compound (2.6 9) as pale yellow crystals.
Reaction SMILES: Cl.[Cl:2][CH:3]([CH2:6][CH2:7][CH2:8][Cl:9])[CH2:4][NH2:5].[C:10](Cl)(=[O:12])[CH3:11]>>[C:10]([NH:5][CH2:4][CH:3]([Cl:2])[CH2:6][CH2:7][CH2:8][Cl:9])(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: NCC(Cl)CCCCl
Agent: Cl
Product: CC(=O)NCC(Cl)CCCCl

Procedure:
acetylizing the 2,5 dichloropentylamine hydrochloride with acetyl chloride to form N-acetyl-2,5-dichloropentylamine,
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:10])[O:7][CH2:8][CH3:9])C.[C:11]([C:14]1[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[C:16]([F:22])[CH:15]=1)(=[O:13])[CH3:12].C(O)(=O)C>CCOCC>[Cl:20][C:19]1[CH:18]=[C:17]([Cl:21])[C:16]([F:22])=[CH:15][C:14]=1[C:11]([CH2:12][C:6]([O:7][CH2:8][CH3:9])=[O:10])=[O:13]
Reactant: CC(=O)c1cc(F)c(Cl)cc1Cl
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1cc(F)c(Cl)cc1Cl
Yield: 45 %

Procedure:
To a suspension of prewashed sodium hydride (76.8 g) in ether was added 189 g of diethylcarbonate. The mixture was heated to reflux and a solution of 131.84 g of 6-acetyl-1,3-dichloro-4-fluorobenzene in 1500 ml of ether was added dropwise over 5 hours. The mixture was then refluxed 24 hours, cooled, poured onto a mixture of ice and acetic acid and extracted several times with ether. The ether extracts were combined, washed with water, dried and evaporated. The residue was purified by vacuum distillation giving 80 g of ethyl 2,4-dichloro-5-fluorobenzoylacetate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[CH2:14][O:15][CH3:16]>>[F:11][C:12]([F:19])([F:18])[CH:13]([CH2:14][O:15][CH3:16])[O:17][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: COCC(O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: COCC(Oc1ccc(N)cc1)C(F)(F)F

Procedure:
This material was obtained following the procedures described in example 33 i,ii) from 1-fluoro-4-nitro-benzene and (rac)-1,1,1-trifluoro-3-methoxy-propan-2-ol.
Reaction SMILES: [NH2:1][CH:2]([CH:10]([OH:20])[CH:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([NH:1][CH:2]([CH:10]([OH:20])[CH:11]([NH:19][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:31])=[O:30]
Reactant: NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NS(C)(=O)=O
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
A solution of the resultant compound of Example 12 (0.049 mmol) and 0.032 ml (0.29 mmol) of 4-methylmorpholine in 1 ml of dichloromethane was cooled to 0° C. and treated with 0.008 ml (0.10 mmol) of methanesulfonyl chloride. After 0.5 h, the solution was washed with 10% aqueous citric acid, dried over Na2SO4, and concentrated. Flash chromatography using 5% methanol in chloroform gave 2.6 mg (13%) of the desired compound. 1H NMR (CDCl3) δ 2.16 (s, 3H), 2.34 (s, 3H), 2.93 (m, 4H), 3.41 (d, J=4 Hz, 1H), 3.7-3.8 (m, 2H), 3.92 (m, 1H), 5.06 (d, J=9 Hz, 1H), 5.42 (d, J=9 Hz, 1 H), 7 2-7.4 (m, 10H). Mass spectrum (M+NH4)+ =444.
Reaction SMILES: Br[C:2]([CH3:16])=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1COCC1.C([Li])CCC.Cl[P:28]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O>[C:4]1([C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([P:28]([CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)[CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH3:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: CC(Br)=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Temperature: -70 °C
Reaction time: 1.25 h
Yield: 72.5 %

Procedure:
Into a reactor were introduced 8.50 g (31.1 mmol) of the 2-bromo-1,1-diphenylpropene obtained in Example 1 (2) and 85 ml of THF under a nitrogen atmosphere. The contents were cooled to −70° C. Thereto was gradually added dropwise 21.4 mL (34.2 mmol; 1.6 M hexane solution) of butyllithium. The resultant mixture was stirred for 30 minutes. Thereafter, 8.25 mL (37.3 mmol) of chlorodicyclohexylphosphine was added, and this mixture was stirred for 75 minutes, subsequently heated to room temperature, and then further stirred for 15.5 hours. Water was added to the reaction mixture. The organic layer was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol to obtain 8.80 g (72%) of the target compound as white crystals.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([CH:31]([F:33])[F:32])=[N:11][CH:12]=[C:13]([C:15]2[N:20]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:19]3[C:18](Cl)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][NH2:41]>>[C:1]([NH:5][S:6]([C:9]1[C:10]([CH:31]([F:33])[F:32])=[N:11][CH:12]=[C:13]([C:15]2[N:20]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:19]3[C:18]([NH:41][CH2:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cc(-c2nnc(Cl)c3c(-c4ccccc4)ccn23)cnc1C(F)F
Reactant: NCc1ccccn1
Product: CC(C)(C)NS(=O)(=O)c1cc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)ccn23)cnc1C(F)F
Yield: 62.1 %

Procedure:
A solution of N-(tert-butyl)-5-(1-chloro-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)-2-(difluoromethyl)pyridine-3-sulfonamide (0.050 g, 0.10 mmol) in pyridin-2-ylmethanamine (0.110 g, 1.02 mmol) was heated in a sealed tube at 100° C. for 6 h. The volatile components were removed under reduced pressure and the resulting residue was purified by CombiFlash Isco (REDISEP®, SiO2, 24 g, 0-60% EtOAc/petroleum ether) to obtain N-(tert-butyl)-2-(difluoromethyl)-5-(8-phenyl-1-((pyridin-2-ylmethyl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (0.035 g, 61%) as a brown solid. LCMS Method B-4: retention time 1.12 min, [M+1]=564.5. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.18 (s, 9H), 4.63 (d, J=6.0 Hz, 2H), 6.61 (dd, J=4.4 Hz, J=6.0 Hz, 1H), 6.98 (d, J=2.8 Hz, 1H), 7.33-7.70 (m, 8H), 7.72 (d, J=2.8 Hz, 1H), 7.98-8.05 (m, 1H), 8.32 (d, J=4.8 Hz, 1H), 8.35 (s, 1H), 8.80 (br s, 1H), 9.41 (d, J=2.0 Hz, 1H).