Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:23][CH:22]=1)(=[O:20])=[O:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][NH2:71])[CH:65]=1>CN(C)C=O.O>[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:71][CH2:70][C:66]3[CH:65]=[N:64][CH:69]=[CH:68][CH:67]=3)=[O:13])=[CH:15][CH:16]=2)=[N:5][C:4]=1[CH2:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:25][CH:26]=1)(=[O:20])=[O:19]
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(CCCN2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(CCCN2CCOCC2)cc1
Reaction time: 0.2 h
Yield: 24.2 %

Procedure:
A solution of 4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid hydrochloride (1.5 g, 2.88 mmol, 1.00 equiv), EDCI (660 mg, 3.46 mmol, 1.20 equiv), HOBt (460 mg, 3.41 mmol, 1.18 equiv), triethylamine (1.16 g, 11.49 mmol, 3.98 equiv) and pyridin-3-ylmethanamine (380 mg, 3.52 mmol, 1.22 equiv) in N,N-dimethylformamide (40 mL) was stirred overnight at 25˜30° C. The resulting solution was diluted with 100 mL of water and extracted with 1×100 mL of ethyl acetate. The organic layer was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (550 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-005(Waters)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and CH3CN (10% CH3CN up to 30% in 12 min, up to 100% in 1 min); Detector, uv 220/254 nm, to give 400 mg (20%) of 4-(5-methyl-4-((4-(3-morpholinopropyl) phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide acid trifluoroacetic acid salt as a white solid. LC-MS: (ES, m/z): 575 [M+H]+, 288, 126. 1HNMR (400 MHz, DMSO-d6, ppm): δ 8.79 (m, 1H), 8.70 (d, J=4.8Hz, 1H), 8.31 (d, J=8.0Hz, 1H), 7.98 (d, J=8.8Hz, 2H), 7.92 (d, J=8.4Hz, 2H), 7.87-7.84 (m, 1H), 7.72 (d, J=8.0Hz, 2H), 7.48 (d, J=8.4Hz, 2H), 4.62 (s, 4H), 3.98-3.94 (m, 2H), 3.64 (s, 2H), 3.42-3.39 (m, 2H), 3.12-3.00 (m, 4H), 2.78-2.73 (m, 2H), 2.09 (s, 3H), 2.00-1.92 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[N:38]=[C:37]([NH2:39])[CH:36]=[CH:35][CH:34]=1.CN1CCOCC1>ClCCl.CN(C)C=O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:39][C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:40])([F:31])[F:41])[N:38]=3)=[O:16])[C:9]2=[O:17])=[CH:19][CH:20]=1
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)Nc1cccc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.192 g, 0.578 mmol; Example 58D) in dichloromethane (3 mL) was added a catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (2.0 Min dichloromethane) (0.578 mL, 1.157 mmol). The reaction was stirred for 30 minutes than concentrated to give an oil. After drying under high vacuum for 20 minutes, the residue was dissolved in dichloromethane (1 mL) and 6-(trifluoromethyl)pyridin-2-amine (0.075 g, 0.463 mmol) and 4-methylmorpholine (0.102 mL, 0.925 mmol) were added. After stirring for 20 minutes, the reaction was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes (Flow=40 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 8.32 (d, J=8.5, 1H), 7.86 (t, J=8.0, 1H), 7.43 (d, J=7.3, 1H), 7.36-7.29 (m, 4H), 7.06-6.96 (m, 4H), 4.22 (s, 2H), 3.54 (t, J=6.5, 2H), 2.83 (t, J=6.5, 2H); MS (ESI+) m/z 476.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Cl[C:13]1[C:18]([CH2:19][OH:20])=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)(O)[O-].[Na+].O1CCOCC1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[C:18]([CH2:19][OH:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: OCc1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2ncccc2CO)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 86.7 %

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (3-methoxyphenyl)boronic acid (1.6 g, 10.53 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv), Pd(dppf)Cl2 (0.57 g, 0.10 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL). The resulting solution was stirred for 1.5 h at 100° C., and then it was diluted with 20 mL of H2O. The resulting solution was extracted with 2×50 mL of ethyl acetate, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50-1:1) as eluent to yield 1.3 g (87%) of [2-(3-methoxyphenyl)pyridin-3-yl]methanol as a colorless oil.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])(=[O:8])[CH3:7]>>[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:1][CH2:5][CH2:4][CH:3]=[CH2:2])(=[O:8])[CH3:7]
Reactant: C=CCCCOC(C)=O
Reactant: C1=CCCC1
Product: C=CCCCC=CCCCOC(C)=O

Procedure:
A process according to claim 17 wherein cyclopentene is reacted with 4-penten-1-yl acetate to produce 4,9-decadien-1-yl acetate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[OH:11][CH2:12][C:13]([CH3:27])([CH3:26])[CH2:14][NH:15][S:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([S:16](=[O:18])(=[O:17])[NH:15][CH2:14][C:13]([CH3:26])([CH3:27])[CH2:12][OH:11])=[CH:20][CH:21]=2)[N:3]=1
Reactant: N#Cc1cnc(Cl)nc1N
Reactant: CC(C)(CO)CNS(=O)(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(CO)CNS(=O)(=O)c1ccc(Nc2ncc(C#N)c(N)n2)cc1
Yield: 51.2 %

Procedure:
A solution of 4-amino-2-chloro-5-cyanopyrimidine (150 mg, 0.97 mmol), 4-[N-(3-hydroxy-2,2-dimethylpropyl)sulphamoyl]aniline (Method 4; 274 mg, 1.07 mmol) in NMP (5 ml) was heated at 120° C. for 24 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate. The organic extracts were combined, dried and the solvent removed by evaporation, the residue was triturated with ether and the product collected by filtration to give the title compound (187 mg, 52%). NMR: 0.72 (s, 6H), 2.52 (d, 2H), 3.08 (d, 2H), 4.40 (t, 1H), 7.19 (t, 1H), 7.60 (s, 1H), 7.64 (d, 2H), 7.96 (d, 2H), 8.40 (s, 1H); m/z 375 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13](=[O:29])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[CH3:28])[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[CH:19])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13](=[O:29])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[CH3:28])[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[C:19][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: Brc1ccccn1
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1C
Product: Cc1cc(F)ccc1N(C(=O)CCC#Cc1ccccn1)C(=O)OC(C)(C)C
Yield: 61 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (129 mg, 0.82 mmol) and (4-fluoro-2-methyl-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (250 mg, 0.82 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 190 mg (0.50 mmol, 61%) of (4-fluoro-2-methyl-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[CH:6]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:5]=1)[CH3:3].[H-].[Na+].[CH3:29][CH:30]([CH3:33])[CH2:31]I>CN(C)C=O>[CH3:29][CH:30]([CH3:33])[CH2:31][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:4]([CH:2]([CH3:1])[CH3:3])=[N:5][CH:6]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:7]1=[O:15]
Reactant: CC(C)CI
Reactant: CC(C)C1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 1,3-dihydro-5-(2-propyl)-3(R,S)-[(benzyloxycarbonyl)-amino]-2H-1,4-benzodiazepin-2-one (500 mg, 1.42 mmol) in dimethylformamide (10 ml) under an atmosphere of nitrogen, was treated with sodium hydride (57 mg of a 57% dispersion in mineral oil, 1.42 mmol) in one portion at 0° C. After 1 h, 2-methylpropyl iodide (0.17 ml, 1.50 mmol) was added and the resulting mixture was stirred at room temperature for 16 h. The solvent was then evaporated and the crude residue partitioned between water (15 ml) and dichloromethane (2×20 ml). The combined organic phase was washed with brine (20 ml), dried (MgSO4) and evaporated. The residue was chromatographed on silica using 1:3 ethyl acetate:petrol as eluent, to afford 1,3-dihydro-1-(2-methylpropyl)-5-(2-propyl) -3(R,S)-[(benzyloxycarbonyl)-amino]-2H-1,4-benzodiazepin-2-one (530 mg, 92%) as a colourless solid. 1H NMR (250 MHz, CDCl3) δ 0.72 (3H, d, J=8 Hz), 0.80 (3H, d, J =8 Hz), 1.02 (3H, d, J=7 Hz), 1.30 (3H, d, J=7 Hz), 1.64 (1H, m), 3.10 (1H, m), 3.42 (1H, dd, J=15 Hz, 5 Hz), 4.30 (1H, dd, J=12.5 Hz, J=7.5 Hz), 5.12 (3H, m), 6.55 (1H, d, J=10 Hz), 7.10-7.70 (9H, m).
Reaction SMILES: O1CCCCC1OC1CCCCO1.C(OC([CH:19]1[CH2:26][CH:25]2[N:27]([CH2:28][C:29](OCC)=[O:30])[CH:21]([CH2:22][CH:23]([OH:34])[CH2:24]2)[CH2:20]1)=O)C.CC(C)([O-])C.[K+].Cl>C1(C)C=CC=CC=1.C(O)=O>[CH2:20]1[CH:19]2[CH2:26][C@@H:25]3[N:27]([CH2:28][C:29]2=[O:30])[C@H:21]1[CH2:22][CH:23]([OH:34])[CH2:24]3
Reactant: CCOC(=O)CN1C2CC(O)CC1CC(C(=O)OCC)C2
Agent: C1CCC(OC2CCCCO2)OC1
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=C1CN2[C@@H]3CC(O)C[C@H]2CC1C3
Temperature: 100 °C

Procedure:
A solution of 34 g of the tetrahydropyranyl ether of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonan-3-ol in 800 ml of anhydrous toluene was treated with 19 g of potassium tert-butoxide and the stirred mixture heated at 100° C. for 2 hours. Anhydrous formic acid (7.85 g) was added to the cooled mixture, the potassium formate was filtered off, and the toluene solution evaporated to give a syrup. The syrup was treated with 300 ml of 5 N hydrochloric acid and the stirred solution refluxed overnight. The cooled mixture was clarified by an extraction with methylene chloride and the aqueous acid solution evaporated to dryness. The residue was dissolved in a little water and the solution treated with a large excess of saturated potassium carbonate solution. Extraction of the resulting mixture with ethyl acetate and evaporation of the dried ethyl acetate solution gave endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one as an oil which crystallized on standing. The base was converted to its camphorsulfonate salt, m.p. 178° C., using one equivalent of camphorsulfonic acid in ethanol.
Reaction SMILES: [OH:1][C@:2]1([C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C:19](=[CH:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH2:15][CH2:16]2)[C:11](=[CH2:25])[CH2:10]3)[CH2:7][C@@H:6]1[CH3:26])[C:3](=[O:5])[CH3:4].F[C:28](F)(F)[C:29](OC(=O)C(F)(F)F)=[O:30]>C(O)(=O)C>[C:29]([O:1][C@:2]1([C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C:19](=[CH:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH2:15][CH2:16]2)[C:11](=[CH2:25])[CH2:10]3)[CH2:7][C@@H:6]1[CH3:26])[C:3](=[O:5])[CH3:4])(=[O:30])[CH3:28]
Reactant: C=C1C[C@@H]2C(=CC[C@@]3(C)[C@H]2C[C@H](C)[C@]3(O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(=O)O
Product: C=C1C[C@@H]2C(=CC[C@@]3(C)[C@H]2C[C@H](C)[C@]3(OC(C)=O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Reaction time: 1 h

Procedure:
A solution of 3.3 g of 17α-hydroxy-16β-methyl-6-methylene-4,9(11)-pregnadiene-3,20-dione in 40 ml of glacial acetic acid is cooled to 0° C. and stirred, after adding 15 ml of trifluoroacetic acid anhydride dropwise, for one hour at room temperature. After precipitation into ice water-sodium chloride, the mixture is filtered off and worked up as usual. The crude product is purified on 450 g of silica gel with a hexane-ethyl acetate gradient (0-50% ethyl acetate), thus obtaining 2.3 g of 17α-acetoxy-16β-methyl-6-methylene-4,9(11)-pregnadiene-3,20-dione, mp 197°-198° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][NH:4][C:3]1=[S:13].[OH-].[Na+].[CH3:16]I>C(O)C>[CH3:1][N:2]1[C:3]([S:13][CH3:16])=[N:4][N:5]=[C:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CI
Reactant: Cn1c(-c2ccccc2)n[nH]c1=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nnc(-c2ccccc2)n1C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-methyl-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (5.0 g, 2.6×10-2 mole) and 1 molar aqueous NaOH (59 ml, 5.9×10-2 mole) was added a solution of methyl iodide (2.6 ml, 4.2×10-2 mole) and ethanol (13 ml). The reaction was stirred for 3 hours and it was then placed in the refrigerator. After standing in the refrigerator overnight, the precipitate was collected by filtration. Crystallization from isopropanol afforded colorless needles, Mp 134°-135° C.
Reaction SMILES: [CH:1]([Si:4]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([O:16]C)=[O:15])[CH2:9][CH2:8]1)([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[CH:21]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:18]([CH3:20])[CH3:19])[O:5][CH2:6][CH:7]1[CH2:8][CH2:9][CH:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:11][CH2:12]1)([CH3:22])[CH3:23]
Reactant: COC(=O)CC1CCC(CO[Si](C(C)C)(C(C)C)C(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[Si](OCC1CCC(CC(=O)O)CC1)(C(C)C)C(C)C

Procedure:
To a solution of 8.8 g (25.7 mmol) of methyl ester from Step E in 50 mL of THF and 50 mL of methanol was added 25 mL (24.9 mmol) of 1 N aqueous sodium hydroxide. The resultant mixture was stirred at room temperature overnight, and the solvent was removed under vacuum. The residue was diluted with ice water, and then acidified with 1 N aqueous hydrochloric acid. The mixture was extracted with three portions of ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, and concentrated to provide a quantitative yield of the title compound. 1H NMR (500 MHz, CDCl3) δ 3.58 (d, 0.6H, J=6.7 Hz), 3.39 (d, 1.4H, J=6.2 Hz), 2.38 (d, 0.6H, J=4.4 Hz), 2.24 (d, 1.4H, J=3.9 Hz), 1.82–1.60 (m, 4H), 1.54 (m, 1H), 1.45 (m, 1H), 1.1–1.05 (m, 23H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.[CH:24](OCCCC)=[O:25]>>[F:23][C:19]1[CH:18]=[C:17]([S:14]([NH:13][C:7]2[CH:6]=[CH:5][C:4]3[CH:3]([CH2:2][NH:1][CH:24]=[O:25])[CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Reactant: CCCCOC=O
Product: O=CNCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21

Procedure:
A solution of 0.28 grams (0.837 mmoles) N-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-fluoro-benzenesulfonamide in 6 mL n-butyl formate was heated under reflux for 1.5 hours. The solution was concentrated under reduced pressure. 3-Fluoro-N-(5-formylaminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide was obtained by recrystallization of the residue from 2-propanol/ethyl ether to provide 0.27 grams (89%) of 3-fluoro-N-(5-formylaminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide, m.p. 143-144° C., M+H=363
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[NH:37]1[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]1>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:37]3[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O[C@@H]1CCNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC[C@@H](O)C3)ccc2n1CC1CCC(F)(F)CC1

Procedure:
Following the same procedure in Example 1, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (50 mg, 0.12 mmol), N,N-diisopropylethylamine (0.1 mL, 0.48 mmol) and (R)-(−)-3-pyrrolidinol hydrochloride (23 mg, 0.19 mmol) in (1 mL) methylene chloride. The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 42 mg (61% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.43-1.52 (m, 2 H), 1.56 (s, 9 H), 1.60-1.69 (m, 3 H), 1.90-2.01 (m, 3 H), 2.09-2.21 (m, 1 H), 3.05-3.11 (m, 1 H), 3.20-3.25 (m, 2 H), 3.26-3.34 (m, 3 H), 4.13-4.18 (m, 1 H), 4.44 (d, J=7.62 Hz, 2 H), 7.81 (dd, J=8.79, 1.76 Hz, 1 H), 7.89-7.93 (m, 1 H), 8.04 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=455.2; Anal. Calc. for C22H31F2N3O3S+1.3 TFA+0.50H2O+0.2 CH3CN: C, 48.75; H, 5.46; N, 7.16. Found: C, 48.78; H, 5.48; N, 7.11.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[CH3:23][O:24][CH:25]1[CH2:28][NH:27][CH2:26]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH2:9]([S:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:27]2[CH2:28][CH:25]([O:24][CH3:23])[CH2:26]2)[N:7]=1)[CH3:10]
Reactant: COC1CNC1
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCSc1nc(N2CC(OC)C2)cc(C)c1C(=O)NCc1cccc(F)c1
Yield: 31 %

Procedure:
A solution of 410 mg (1.2 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2), 125 mg (1.0 mmol) 3-methoxy-azetidine and 824 mg (2.53 mmol) Cs2CO3 in 1,4-dioxane (7 ml) was heated at 110° C. for 24 h. Subsequently the RM was concentrated in vacuo. The residue obtained was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 122 mg (0.31 mmol, 31%) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(3-methoxy-azetidin-1-yl)-4-methyl-pyridine-3-carboxylic acid amide (example 6). [M+H]+ 390.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:28]=[N:27][N:26]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH:25]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccn1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)ccc(F)c32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)ccc(F)c32)cn1
Yield: 73.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.79 g) and 2-(chloromethyl)pyridine hydrochloride (0.49 g) as starting materials, 5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.69 g) was obtained.
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].S(=O)(=O)(O)O.[CH3:10][C:11](O)([CH:13]([CH3:15])[CH3:14])[CH3:12].[OH-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(O)(=O)C.CCOCC.O>[CH2:1]([NH:4][C:11]([CH3:12])([CH:13]([CH3:15])[CH3:14])[CH3:10])[CH2:2][CH3:3]
Reactant: CC(C)C(C)(C)O
Reactant: CCC#N
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: CCCNC(C)(C)C(C)C
Yield: 45.6 %

Procedure:
To a solution of 8.25 g (0.15 mole) propionitrile in 25 mL glacial acetic acid, 15 g concentrated sulfuric acid was added dropwise while controlling the reaction temperature at about 38° C., then 5.2 g (0.051 mole) of 2,3-dimethyl-2-butanol was added dropwise at the temperature below 40° C. with stirring. The mixture was stirred overnight while maintaining the temperature, then poured into glacial water, basified with 40% sodium hydroxide solution and extracted with ether. The ether extract was combined, washed once with water, and dried over anhydrous magnesium sulfate. After recovering the ether, 6.2 g light yellow liquid was obtained and solved in 80 mL anhydrous ether. The resulting solution was added dropwise to a suspension of 3.04 g (0.08 mol) lithium aluminium hydride in 80 mL anhydrous ether. The mixture was refluxed for 10 hours, then cooled. To the mixture, proper amount of 40% aqueous sodium hydroxide was added dropwise and the upper layer of ether was carefully poured out. The lower layer of solid was then washed with ether (×3). The resulting washing and extract ether were combined, dried over anhydrous potassium carbonate and filtered. To the filtrate, HCl-Et2O was added under cooling until the solution is acidic. The solid was collected by filtering and recrystallized three times from iso-propanol and acetone to give a white lamellar crystal 3.33 g (yield 46.33%), mp 183-185° C. Elemental analysis for C9H22NCI (%): Calculated C, 10.15; H, 12.34; N, 7.79. Found C, 60.20; H, 13.80; N, 7.85. 1H-NMR(D2O, ppm) 0.98(d, 6H), 1.00(t, 3H), 1.24(s, 6H), 1.63(m, 2H), 2.05(m, 1H), 2.98(t, 2H). MS(m/z) 143(M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[N+:13]([O-])([OH:15])=[O:14]>>[CH3:12][O:11][C:10]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH:6]=[O:7])=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C=O)cc1OC
Product: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 61 %

Procedure:
After reacting 135 g of 3,4-dimethoxybenzaldehyde and 500 ml of conc. nitric acid at 10° C. for 20 hours, the reaction mixture was poured in 3 l of ice water and the resultant crystals were collected by filtration. The crystals were dissolved in a mixed solvent of 8 l of toluene and 500 ml of ethyl acetate. After washing the resultant solution once with a saturated aqueous solution of sodium bicarbonate, three times with water and then once with saturated saline, the solution was concentrated to about 500 ml under reduced pressure. The concentrate was cooled to room temperature and the resultant yellowish crystals (77.71 g) were then collected by filtration (yield: 61%).