Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[C:6]1([N:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[N:22]=[CH:23][NH:24][C:14]=3[C:13]2=[S:25])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH2:28]([S:25][C:13]1[N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:14]=1[N:24]=[CH:23][N:22]=2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: S=c1c2[nH]cnc2c2cccnc2n1-c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CSc2c3ncnc-3c3cccnc3n2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
Into 30 ml of dimethylformamide was dissolved 0.79 g (2.5 mmol) of Compound 1 obtained in Example 1. Furthermore, 0.13 g (3.4 mmol) of 60% sodium hydride was added thereto with stirring at room temperature. The mixture was stirred for 1 hour. Then, 0.41 ml (3.4 mmol) of benzyl bromide was added thereto, followed by further stirring for 1 hour. The mixture was cooled with ice and then water was added thereto. The precipitated solid was collected by filtration. The solid was dried, dissolved into chloroform and purified by silica gel column chromatography (eluent: chloroform) to give 0.25 g (24%) of Compound (II) as the first fractions and 0.40 g (38%) of Compound 3 as the second fractions.
Reaction SMILES: C([Li])CCC.[S:6]1(=[O:12])(=[O:11])[CH:10]=[CH:9][CH2:8][CH2:7]1.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>O1CCCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:10]1[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][CH:9]=1)[CH2:23][CH2:24][CH3:25]
Reactant: O=S1(=O)C=CCC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCS1(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
n-Butyllithium (6.72 mL of a 1.6 M solution in hexanes, 10.7 mmol) was added over 5 min to a solution of 2,3-dihydro-thiophene 1,1-dioxide (1.21 g, 10.2 mmol, prepared as described in J. Organomet. Chem., 665, 167 (2003)) in tetrahydrofuran (60 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 min, then tributyltin chloride (3.04 mL, 11.2 mmol) was added over 5 min. After stirring at −78° C. for 45 min, the mixture was warmed to 25° C. and stirred for an additional 45 min then was concentrated in vacuo. The residue was diluted with chloroform (50 mL) and filtered. The filtrate was partitioned between water (100 mL) and a 1:1 mixture of ethyl acetate and hexanes (1×200 mL). The organic layer was dried over sodium sulfate, filtered and was concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 20-30% ethyl acetate in hexanes) afforded the desired product, tributyl-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-stannane (1.13 g, 2.77 mmol, 27% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 0.90-0.95 (9H, m), 1.15-1.21 (6H, m), 1.29-1.40 (8H, m), 1.50-1.67 (6H, m), 2.96-3.00 (1H, m), 3.11-3.14 (1H, m), 6.57 (1H, t, J=3.1 Hz).
Reaction SMILES: [CH2:1]([C:5]([CH:7]1[CH2:12][CH2:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH2:8]1)=[O:6])[CH:2]([CH3:4])[CH3:3].[CH2:15]([OH:17])C.C=O.[OH-].[K+]>CO.C(O)(=O)C>[CH2:1]([C:5]([C:7]1([CH2:15][OH:17])[CH2:12][CH2:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH2:8]1)=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC1=C(C)CC(C(=O)CC(C)C)CC1
Reactant: CCO
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC1=C(C)CC(CO)(C(=O)CC(C)C)CC1

Procedure:
A mixture of 65.6 g (0.338 mole) of 3,4-dimethylcyclohex-3-enyl isobutyl ketone (Example XXII), 120 ml of ethanol and 109.6 g of 37% strength formaldehyde solution (=1.35 moles) is brought to a pH of 11-12 with a 15% strength solution of potassium hydroxide in methanol, and is then refluxed for 44 hours, the pH being checked. Thereafter the solution is brought to pH 5 with glacial acetic acid and the solvent is distilled off under reduced pressure. Water is added to the residue and after saturation with sodium chloride the mixture is extracted five times with toluene. The organic phases are dried over anhydrous sodium sulfate, the solvent is distilled off on a rotary evaporator and the residue is distilled under reduced pressure. 37.7 g of 3,4-dimethyl-1-hydroxy-methyl-cyclohex-3-enyl isobutyl ketone pass over at 112°-116° C./0.1 mm Hg.
Reaction SMILES: C1COCC1.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1)[CH:13]=O.[C:24]([O:27][CH2:28][CH3:29])(=[O:26])[CH3:25]>O>[CH2:28]([O:27][C:24](=[O:26])/[CH:25]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:17]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)=[C:10]([O:9][CH3:8])[CH:11]=1)[CH3:29]
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a THF (15 mL) solution of sodium hydride (814 mg) triethylphosphonoacetic acid (4.1 mL) was added at 0° C., and the reaction solution was agitated at 0° C. for 30 minutes and at room temperature for 1 hour. After cooling the reaction solution at 0° C., the THF (5 mL) solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (4.0 g) synthesized in Example 1 was added dropwise to the reaction solution. The reaction solution was further agitated at 0° C. for 30 minutes and then at room temperature for 2 hours. Ethyl acetate and water was added to the reaction solution, and the organic layer was separated and washed with a saturated ammonium chloride solution. After drying with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. By re-crystallizing the obtained solid using a mixed solution of hexane and ethyl acetate, the 4.55 g (86%) title compound was obtained. The physical properties of the compound are as follows.
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+].[CH2:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)[CH2:19][CH3:20]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(CCC)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.7 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.00045 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.20 g, 0.0036 mol) and allowed to stir for 10 min at RT. 2-propyl-5-vinyl-pyridine (0.2 g, 0.00136 mol) was added and stirred for further 24 h. at 100° C. After completion (TLC), reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was semi-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 further purified by preparative TLC, to give the desired compound as yellow oil (0.016 g, 9.6% yield). 8-Chloro-5-[2-(6-isopropyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.016 g, 0.0000435 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.005 g, 0.00007 mol) 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 (0.010 g, 52% yield).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.[F-].[K+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:12]([C:8]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)[N:11]=[CH:10][CH:9]=1)#[N:13]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1c(C#N)ccnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1c(C#N)ccnc1-c1cnn(C)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A mixture of methyl 2-chloro-4-cyanonicotinate (730 mg, 3.71 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (927 mg, 4.46 mmol), trans-dichlorobis(triphenylphosphine)palladium (261 mg, 0.371 mmol) and potassium fluoride (2697 mg, 14.85 mmol) in DME (15 mL) was stirred at 120° C. for 1 h under microwave irradiation. The mixture was filtered through Celite, and the filtrate was diluted with H2O and EtOAc. The organic phase was washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 to give the title compound as a pale yellow solid (470 mg, 52.3%). 1H NMR (500 MHz, CDCl3) δ ppm 3.97 (s, 3 H), 4.03 (s, 3 H), 7.41 (d, J=4.88 Hz, 1 H), 7.82 (s, 1 H), 7.91 (s, 1 H), 8.79 (d, J=4.88 Hz, 1 H). [M+H] calc'd for C12H10N4O2, 243; found, 243.
Reaction SMILES: CO.Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:13][S-:14].[Na+]>O>[CH3:13][S:14][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSc1ncccc1[N+](=O)[O-]
Reaction time: 17 h
Yield: 63.5 %

Procedure:
A methanol (50 ml) solution of 2-chloro-3-nitropyridine (4.30 g, 27.1 mmol) was added dropwise to a methanol (30 ml) solution of sodium thiomethoxide (2.10 g, 28.5 mmol) while being cooled with ice, and the mixed solution was stirred for 17 hours. Water was then added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crystals were recrystallized from a mixture of an ethyl acetate-hexane mixture to obtain 2.93 g (yield 64%) of 2-methylthio-3-nitropyridine as a yellow needle crystal.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4]1.[OH-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>O1CCOCC1.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:2][N:3]2[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]2)=[O:20])=[CH:14][CH:13]=1
Reactant: NN1CC=CCC1
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)cc1)NN1CC=CCC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
N-Amino-1,2,3,6-tetrahydropyridine hydrochloride (3.42 g) was dissolved in a mixture of dioxane (30 ml) and water (20 ml). The solution was adjusted to pH 7.5 with 1N-aqueous sodium hydroxide and to the resultant mixture was added a solution of 4-fluorophenylisocyanate (0.548 g) in dioxane (5 ml). Then, the mixture was kept to pH 7.5 and stirred for 2 hours at 5° C. After evaporation of organic solvent, the crystalline product was collected by filtration and recrystallized from diisopropyl ether to give white needles of N-[[(4-fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine (0.73 g). mp: 156°-157° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:26][CH2:27][Cl:28].C([O-])([O-])=O.[K+].[K+]>CCCCCC.C1COCC1>[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][C:16]([CH2:26][CH2:27][Cl:28])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: ClCCBr
Reactant: CCOC(=O)C1CCCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1(CCCl)CCCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To DIPA (3.22 mL) was added dropwise a 2.64 M solution of n-butyl lithium in hexane (7.97 mL) at −78° C., followed by stirring for 30 minutes. To the reaction mixture was added ethyl 1-benzylazepane-4-carboxylate (5.0 g), followed by stirring for 30 minutes. Next, a solution of 1-bromo-2-chloroethane (3.02 g) in THF was added dropwise thereto, followed by warming to room temperature and stirring for 2 hours. To the reaction mixture was added an aqueous K2CO3 solution, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia). Desired fractions were collected, and concentrated under reduced pressure. After concentration under reduced pressure, to the residue, a part of which was solidified, was added EtOAc, followed by purification by silica gel column chromatography (EtOAc) to obtain ethyl 1-benzyl-4-(2-chloroethyl)azepane-4-carboxylate (4.11 g) as a colorless oily substance.
Reaction SMILES: [C:1]([C:3]1[S:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]=1Cl)#[N:2].[CH3:13][NH:14][NH2:15].O>CS(C)=O>[CH3:13][N:14]1[C:4]2[C:5]3[C:6]([S:11][C:3]=2[C:1]([NH2:2])=[N:15]1)=[N:7][CH:8]=[CH:9][CH:10]=3
Reactant: N#Cc1sc2ncccc2c1Cl
Reactant: CNN
Solvent: CS(C)=O
Solvent: O
Product: Cn1nc(N)c2sc3ncccc3c21
Yield: 81.6 %

Procedure:
15 Grams (0.066 mole) of 2-cyano-3-chlorothieno (2,3-b)pyridine and 17.5 ml (0.33 mole) of methylhydrazine were dissolved in 110 ml of dimethylsulfoxide and heated to 75° for 15 hr under nitrogen. The reaction was cooled and poured into water. The solid was filtered and dried to give 11 g of 1-methyl-1H-pyrazolo(3',4':4,5)thieno(2,3-b)pyridine-3-amine. m.p. 194°-196° C. NMR(CDCl3) δ4.0(s,3); 5.2(s,2); 7.4(dd,1); 8.4(m,2).
Reaction SMILES: Cl.[NH2:2][NH2:3].[C:4]([CH:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:8]([CH3:19])([CH3:18])[C:7]1=O)#[N:5]>CCO>[NH2:5][C:4]1[C:6]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:8]([CH3:19])([CH3:18])[C:7]=2[NH:2][N:3]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C(=O)C1(C)C
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2c(N)n[nH]c2C1(C)C
Temperature: 85 °C
Reaction time: 18 h
Yield: 45.2 %

Procedure:
Hydrazine hydrochloride (4.95 g, 72.4 mmol) was added to a solution of tert-butyl 4-cyano-2,2-dimethyl-3-oxopyrrolidine-1-carboxylate (11.5 g, 48.2 mmol) in EtOH (300 mL) and the reaction mixture was stirred at 85° C. for 18 hours then concentrated in vacuo. The residue was taken up in EA (200 mL), washed with sat. aq. NaHCO3, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (3% MeOH in EA) afforded the title compound (5.5 g, 46%) as an off-white solid. 1H NMR (DMSO-d6) δ 11.12 (s, 1H), 5.05 (s, 2H), 4.11-4.07 (m, 2H), 1.50-1.48 (m, 6H), 1.44-1.41 (m, 9H).
Reaction SMILES: O=[C:2]1[NH:6][N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3]1.C(#N)C.P(Cl)(Cl)([Cl:23])=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:23][C:2]1[CH2:3][CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C1CC(=O)NN1c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1CC(Cl)=NN1c1cccnc1
Temperature: 60 °C
Yield: 79.7 %

Procedure:
A 3-neck round bottomed flask (100 mL) was charged with ethyl 5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (8.50 g, 36.1 mmol) and acetonitrile (40 mL). Phosphoryl trichloride (4.05 mL, 43.4 mmol) was charged and the reaction was heated at 60° C. for 2 hours. The reaction was cooled to 20° C. and water (100 mL) was added. Sodium carbonate was added to adjust pH to 8 and the mixture was extracted with ethyl acetate (3×100 mL). The organic layers were concentrated to dryness and the residue was purified by flash column chromatography using 30-80% ethyl acetate/hexanes as eluent to provide the title compound as a yellow oil (7.30 g, 79%): 1H NMR (400 MHz, CDCl3) δ 8.30 (dd, J=2.9, 0.8 Hz, 1H), 8.17 (dd, J=4.7, 1.4 Hz, 1H), 7.38 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.18 (ddd, J=8.4, 4.7, 0.7 Hz, 1H), 4.79 (dd, J=12.4, 6.9 Hz, 1H), 4.24 (qd, J=7.1, 1.1 Hz, 2H), 3.55 (dd, J=17.7, 12.4 Hz, 1H), 3.33 (dd, J=17.8, 6.9 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.65, 141.90, 141.33, 141.09, 135.13, 123.53, 120.37, 62.89, 62.35, 42.45, 14.03; ESIMS m/z 254 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:14]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3=CCCC3)c3ccccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Yield: 97.4 %

Procedure:
In a 3 gallon autoclave, charge 4-(3-Cyclopent-1-enyl-indole-1-sulfonyl)-benzoic acid methyl ester (475 g), ethyl acetate (2.5 L), absolute ethanol (2.5 L) and 10% Pd—C (45 g, w/w) under 35 psi hydrogen at ambient temperature for 5 hours. Filter the crude reaction over Hyflo. Concentrate the filtrate under vacuum to give a light yellow solid (465 g) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.BrC1C=CC([C:19]2([O:22]C)CC2)=CC=1.[Li]CCCC.CN(C=O)C>>[CH3:19][O:22][C:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: COC1(c2ccc(Br)cc2)CC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COC1(c2ccc(C=O)cc2)CC1
Yield: 58 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 1-bromo-4-(1-methoxycyclopropyl)-benzene (250 mg, 1.10 mmol), n-BuLi (722 μl, 1.6M solution in hexane, 1.16 mmol) and DMF (171 μl, 2.20 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 4-(1-methoxycyclopropyl)-benzaldehyde (90 mg, 58%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 10.0 (s, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 3.29 (s, 3H), 1.35-1.30 (m, 2H), 1.09-1.05 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][N:16]=[CH:17][C:18]([F:21])([F:20])[F:19].[Br:22]N1C(=O)CCC1=O.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][N:16]=[C:17]([Br:22])[C:18]([F:21])([F:19])[F:20]
Reactant: Cc1cc(F)c(NN=CC(F)(F)F)cc1SCC(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(F)c(NN=C(Br)C(F)(F)F)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
3.7 g of trifluoroacetaldehyde {2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}hydrazone was dissolved in 50 ml of N,N-dimethylformamide, and 2.0 g of N-bromosuccinimide was added at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.4 g of N-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}trifluoroacetohydrazonoyl bromide.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3Br)[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3[C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4Br)CC3)n2)ccn1
Product: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4-c4cccnc4)CC3)n2)ccn1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “8” by using 6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine and 3-pyridinylboronic acid as the starting materials. LC-MS (M+H=524, obsd=524). 1H NMR (400 MHz, DMSO-d6) δ 8.59-8.50 (m, 2H), 8.38 (dd, J=5.1, 0.8 Hz, 1H), 8.11 (s, 1H), 7.80-7.72 (m, 2H), 7.53-7.47 (m, 2H), 7.43 (dd, J=5.1, 1.6 Hz, 1H), 5.92 (s, 2H), 3.85 (t, J=6.1 Hz, 2H), 3.40-3.27 (m, 5H), 3.63 (d, J=3.1 Hz, 1H), 3.12 (s, 5H), 3.01 (p, J=6.9 Hz, 1H), 2.85 (dt, J=10.1, 5.0 Hz, 1H), 2.77-2.63 (m, 4H), 2.01-1.87 (m, 2H), 1.65-1.52 (m, 4H), 1.25 (d, J=6.9 Hz, 6H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[N:10]=3)=[CH:20][CH:21]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-chlorophenyl isocyanate (94 mg, 0.61 mmoles), the title compound was isolated as a white solid. Yield; 60 mg (30%); (M+H)=496.3
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][N:13]([C:16](=[O:37])[CH2:17][C@H:18]([NH:29]C(OC(C)(C)C)=O)[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[F:28])[CH2:12][C:11]1[CH:38]=[CH:39][CH:40]=[CH:41][C:10]2=1)=[O:5])[CH3:2].[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(Cl)Cl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][N:13]([C:16](=[O:37])[CH2:17][C@H:18]([NH2:29])[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[F:28])[CH2:12][C:11]1[CH:38]=[CH:39][CH:40]=[CH:41][C:10]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)Cc1ccccc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncn2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of (R)-5-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-5,6-dihydro-4H-2,5,10b triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (100 mg, 0.174 mmol) in DCM (5 mL), was added trifluoroacetic acid (0.52 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for 1 h. After completion of the reaction, as confirmed by TLC, excess of trifluoroacetic acid and DCM were evaporated in vacuo to afford a gummy solid which was crystallised from hexane to afford trifluoroacetic acid salt of 5-[(R)-3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (80 mg, 79%).