Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:9][CH:10]([C:18]1[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:23]=1)[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH:33]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:9][CH:10]([C:18]1[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:23]=1)[S:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:33]
Reactant: COc1ccccc1OCCNCC(Sc1ccccc1)c1ccc(C)c(S(N)(=O)=O)c1
Reactant: OO
Solvent: CC(=O)O
Product: COc1ccccc1OCCNCC(c1ccc(C)c(S(N)(=O)=O)c1)S(=O)c1ccccc1

Procedure:
In 20 ml of acetic acid was dissolved 2 g of 5-{2-[2-(2-methoxyphenoxy)ethylamino]-1-phenylthioethyl}-2-methylbenzenesulfonamide and after adding thereto 0.5 ml of 30% H2O2, the mixture was heated to 50°-60° C. for 3 hours. After adding thereto 100 ml of water, the reaction mixture was extracted with 200 ml of ethyl acetate. The ethyl acetate extract was washed with an aqueous 1% sodium carbonate solution and then ethyl acetate was distilled off under reduced pressure. The residue was applied to a silica gel column chromatography, the product was eluted with a mixed solvent of chloroform and methanol (9:1 by volume ratio), and the colorless viscous oily product thus obtained was crystallized by the addition of ethyl acetate. The crystals formed were recovered by filtration to provide 1.3 g of 5-{2-[2-(2-methoxyphenoxy)ethylamino]-1-phenylsulfinylethyl}-2-methylbenzenesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]Cl)[N:3]=1.C[O-].[Na+].[SH:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[N:3]=1
Reactant: Nc1ccnc(CCl)n1
Reactant: O=C1c2ccccc2C(=O)N1CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccnc(CSCCN2C(=O)c3ccccc3C2=O)n1
Reaction time: 1 h

Procedure:
A solution of 4-amino-2-chloromethylpyrimidine (11.6 g.) in methanol (20 ml.) was added over 15 minutes to a stirred mixture of sodium methoxide (4.32 g.), N-(2-mercaptoethyl)phthalimide (16.6 g.) and methanol (100 ml.), and the mixture stirred for 1 hour after the addition was complete and then evaporated to dryness. The residue was partitioned between 1 N hydrochloric acid and ethyl acetate, and the aqueous phase separated and neutralised by the addition of sodium bicarbonate. The mixture was extracted with ethyl acetate and the extracts dried and evaporated to dryness, and the residue was recrystallised from acetonitrile to give 4-amino-2-[(2-phthalimidoethyl)thiomethyl)pyrimidine, m.p. 131°-133°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.[NH4+].[Cl-].CC[N:18]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([NH2:18])=[O:13])[NH:6]2
Reactant: O=C(O)c1cc2c(F)cccc2[nH]1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc2c(F)cccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of 34 (179 mg, 1.00 mmol) in anhydrous DMF (2.0 mL) were added NH4Cl (160 mg, 3.00 mmol), EDCI (395 mg, 2.20 mmol), HOBt (297 mg, 2.20 mmol) and TEA (303 mg, 3.00 mmol) at RT. After stirring at RT for 3 h, the mixture was quenched with H2O (10 mL) the resulting mixture was extracted with EtOAc (3×6 mL). The combined extracts were dried and concentrated. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (5:1 to 3:1) to afford 130 mg (73%) of 4-fluoro-1H-indole-2-carboxamide (36) as a white solid. LCMS (ESI) m/z: 179.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1.C([Li])CCC.CCCCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[S:10][C:9]([CH:31]=[O:32])=[N:8][C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2scnc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 (1.75 g, 6.85 mmol) in dry THF (40 mL) at −78° C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 5-chloro-7-morpholinothiazolo[4,5-d]pyrimidine-2-carbaldehyde 43.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[CH3:31][S-:32].[Na+]>CN(C=O)C>[CH:27]1([C:25]([N:22]([CH2:21][C:15]2[CH:16]=[C:17]([S:32][CH3:31])[CH:18]=[CH:19][C:14]=2[C:8]2[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:30])[CH:7]=2)[CH2:23][CH3:24])=[O:26])[CH2:29][CH2:28]1
Reactant: C[S-]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1cc(SC)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To {2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-fluoro-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester 0.186 g, 0.45 mmol) in DMF (0.5 mL) was added sodium thiomethoxide (0.035 g, 0.50 mmol), and the reaction was stirred at 85° C. for 2 hours. Additional sodium thiomethoxide (0.070 g, 1.0 mmol) was added, and the reaction was stirred at 85° C. for another 2 hours. An aqueous work-up was performed, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([CH:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH:13]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][N:12]23)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C(Cl)Cl>[C:1]([N:23]1[CH2:22][CH2:21][CH:13]2[N:12]([CH:11]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14]2)[CH2:25][CH2:24]1)(=[O:3])[CH3:2]
Reactant: c1ccc(C2c3ccccc3CC3CCNCCN32)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC2Cc3ccccc3C(c3ccccc3)N2CC1
Reaction time: 1 h

Procedure:
3.08 of acetyl chloride diluted with 10 ml of methylene chloride was added dropwise to a solution of 9.9 g (7 RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline in 100 ml of methylene chloride. The reaction mixture was stirred for 1 hour, then wasted twice with water, then dried with magnesium sulphate and concentrated to dryness to give (7RS,12aRS)-3-acetyl-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline (M.P. 145°-147°).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]2[CH:14]2[CH:21]3[CH2:22][C:17]4([C:24](O)=[O:25])[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)=[CH:4][CH:3]=1.O.OC1C2N=N[NH:36]C=2C=CC=1.CCN=C=NCCCN(C)C.Cl.N>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]2[CH:14]2[CH:21]3[CH2:22][C:17]4([C:24]([NH2:36])=[O:25])[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)=[CH:27][CH:28]=1
Reactant: CC1(C)C(=O)N(C2C3CC4CC2CC(C(=O)O)(C4)C3)N1Cc1ccc(F)cc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: CC1(C)C(=O)N(C2C3CC4CC2CC(C(N)=O)(C4)C3)N1Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
A solution of 4-[2-(4-fluorobenzyl)-3,3-dimethyl-4-oxo-1,2-diazetidin-1-yl]adamantane-1-carboxylic acid (20.0 mg, 0.0520 mmol) prepared in Example 90 in dichloromethane (1 mL) was added with hydroxybenzotriazole monohydrate (12.0 mg, 0.0890 mmol), WSC.HCl (20.0 mg, 0.100 mmol), 30% aqueous solution of ammonia (0.1 mL) at room temperature, and the resultant was stirred at the same temperature for 30 minutes. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using Preparative Thin-Layer chromatography (ethyl acetate), and the title compound (5.00 mg, 24.9%) was obtained as a white crystalline powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Reaction time: 8 h
Yield: 75.1 %

Procedure:
At room temperature, a mixture of (tetrahydro-pyran-4-yl)-methanol (2.4 g, 20.7 mmol), p-toluenesulfonyl chloride (6.73 g, 35.4 mmol), triethylamine (6.6 mL, 47.6 mmol) and DMAP (0.288 g, 2.36 mmol) in DCM (50 mL) was stirred overnight. The solution was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound as an oil (4.2 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH2:4][CH2:3]1.[H-].[Na+].F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:8]2)[CH2:6][CH2:7]1
Reactant: CN1CCC2(CC1)CNc1ccccc12
Reactant: Fc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC2(CC1)CN(c1ccccc1)c1ccccc12
Reaction time: 45 h

Procedure:
A mixture of 2.1 g of 1'-methylspiro[indoline-3,4'-piperidine] (Example 1b), 3 g of 50% sodium hydride and 12 ml of fluorobenzene in 18 ml of dimethyl sulfoxide is stirred at 65°-70° C. for 45 hours. The well stirred mixture is poured into water and extracted thrice with ether. The combined ether extracts are dried briefly before forming, the hydrochloride salt. The salt is collected, basified and then extracted into ether, giving a yellowish oil which is crystallized from hexane, producing off-white crystals, mp 90°-92° C. of 1'-methyl-1-phenylspiro[indoline-3,4'-piperidine].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C:20](=O)[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.Cl.[NH2:37][OH:38]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C:20](=[N:37][OH:38])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC(=O)C4)n3)c3cc(Cl)cnc32)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC(=NO)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone (0.41 g, 0.81 mmol) in EtOH (8.2 mL) was added hydroxylamine hydrochloride (0.11 g, 1.61 mmol). The reaction mixture was stirred at room temperature overnight. Then the mixture was warmed to 70° C. for 15 min. The reaction mixture was concentrated in vacuo, suspended in EtOAc-DCM, washed with half saturated brine (2×) and filtered through a SiO2 plug. The resulting residue was azeotroped with CH3CN (2×) to provide an off white powder which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:13][CH3:14]
Reactant: CCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccccc1[N+](=O)[O-]
Yield: 87 %

Procedure:
o-Nitrophenol (111.2 g., 0.8 mole), 1-bromopropane (98.4 g., 0.8 mole), anhydrous potassium carbonate (121.4 g., 0.88 mole) and any acetone (800 cc) are refluxed for 70 hrs., filtered the reaction mass, the residue was washed with acetone, and the filtrate rotoevaporated. To the residue of the evaporation was added 200 cc of dichloromethane and rotoevaporated again; the residue was washed with 100 cc of water and separated into two layers. The dichloromethane layer was washed with 100 cc of 10% Na2CO3, separated again, washed again with 100 cc of water, and the dichloromethane layer was fractionated under vacuum. The main fraction distilled at 103°-106° C. at 0.2-0.3 mm Hg., giving 130 g. of product (87% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[CH:13]=[C:12]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[C:12]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Reactant: Oc1ccc(F)cc1
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccc(F)cc3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from 4-fluoro-phenol and (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-6,7-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 395(MH+).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:26][C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([CH:19]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:27]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.O.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH:27]1([C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:26][C:11]4[CH:12]=[N:13][C:14]([NH:16][C:17]([CH:19]5[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])=[CH:15][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CCCCCC1
Reactant: Nc1ccc(-c2nc3cc(NC(=O)C4CCCCCC4)ncc3[nH]2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc2nc(-c3ccc(C(=O)C4CCCCCC4)cc3)[nH]c2cn1)C1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
The amine 19 (0.094 g, 0.27 mmol) was taken in dry Pyridine (5 ml) and cycloheptane carbonyl chloride (0.100 ml, 0.622 mmol) was added and the solution stirred at room temperature overnight. Water was added followed by sat. NaHCO3 solution. The mixture was stirred at room temperature for 1 h. The solid was filtered, dried and passed through a SiO2 gel column, eluting with ethyl acetate afforded a white solid 20 (0.050 g, 39%). M.p. 194° C.; 1H NMR (DMSO-d6, 500 MHz): δ13.40 (1H, brs, NH), 10.09 (2H, s, NH), 8.81 (1H, brs), 8.145 (2H, d, J=9.0 MHz), 7.82 (2H, d, J=9.0 Hz), 2.74 (1H, m), 2.49 (1H, m), 1.91-1.25 (24H, m); EIMS m/z: 474.4 (M+1) and 472.6 (M−1); Anal (C28H35N5O2) C, H, N.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:9](=O)[C:8]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:7]=2[O:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2.[S-:20][C:21]#[N:22].[K+]>C(O)(=O)C>[F:15][C:13]1[CH:12]=[CH:11][C:8]2[C:9]3[NH:22][C:21]([SH:20])=[N:2][C:3]=3[C:4]3[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=3[O:6][C:7]=2[CH:14]=1
Reactant: NC1C(=O)c2ccc(F)cc2Oc2ccccc21
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: Fc1ccc2c(c1)Oc1ccccc1-c1nc(S)[nH]c1-2
Reaction time: 0.25 h

Procedure:
11-Amino-7-fluorodibenz[b,f]oxepin-10(11H)-one hydrochloride (8 g) was suspended in acetic acid (120 ml); potassium thiocyanate (2.82 g) was added and the reaction mixture was heated to reflux. After 10 minutes complete solution was obtained and shortly thereafter a solid began to separate. Heating was continued for 15 minutes. After cooling, the solid product was collected by filtration, washed with water and dried to give 10-fluoro-1H-dibenzo[2,3:6,7]oxepino[4,5-d]-imidazole-2-thiol; m.p. 299°-300°. ##STR18##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][N:20]=[C:19]([OH:22])[CH:18]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(COC)OC>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][N:20]=[C:19]([OH:22])[CH:18]=4)=[CH:13][CH:12]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:26][CH:25]=1
Reactant: Oc1cc(-c2ccc(OCCc3cccc(Cl)n3)cc2)on1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Oc1cc(-c2ccc(OCCc3cccc(-c4ccc(F)cc4)n3)cc2)on1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-(2-(6-chloropyridin-2-yl)ethoxy)phenyl)isoxazol-3-ol (46.5 mg) in dimethoxyethane ethylene glycol dimethyl ether (3 ml), 18 mg of tetrakis triphenylphosphine palladium, 31 mg of 4-fluorophenylboronic acid and 0.2 ml of 2M aqueous sodium carbonate solution were added, and the reaction solution was stirred at 90° C. for 2 hours. The reaction solution was cooled, then diluted with a saturated saline solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified through reversed phase medium pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid). The solvent of the resultant fraction was diluted with ethyl acetate, washed with saturated sodium bicarbonate water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by preparative thin layer chromatography (Kieselgel™ 60 F254, Art5744, made by Merck & Co., methanol/chloroform (1:9)) to afford the title compound as a brown solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[CH3:20])[C:6]=2[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:3]=1.C([O:30][B:31]1OC(C)(C)C(C)(C)[O:32]1)(C)C>>[Cl:19][C:15]1[C:14]([CH3:20])=[C:13]([CH2:12][N:7]2[C:6]3[CH:5]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:3]=[C:2]([B:31]([OH:32])[OH:30])[C:10]=3[N:9]=[C:8]2[CH3:11])[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1c(Cl)cccc1Cn1c(C)nc2c(Br)cc(N3CCOCC3)cc21
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Product: Cc1c(Cl)cccc1Cn1c(C)nc2c(B(O)O)cc(N3CCOCC3)cc21
Yield: 23.4 %

Procedure:
Several batches were prepared, using additional 77 g of 4-bromo-1-[(3-chloro-2-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole (177.11 mmol), either by the method above or by using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as the quenching agent. After standard work up the batches were combined with the above material and purified first by RP-HPLC (Luna C18(2), 5 u, 101×250 mm, 55:45 300 mM Aqueous ammonium trifluoroacetate (pH 2.8):acetonitrile), followed by purification on chiral phase (Chiralpak AD 101×250 mm, 20 u, 80:20 Heptane/EtOH plus 2% HCO2H and 1% Isopropylamine) and recrystallization from EtOAc to give [1-[(3-chloro-2-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazol-4-yl]boronic acid (18.03 g, 45.17 mmol, 23.4% yield) as a beige powder.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H]1[BH2][H][BH2]1>C1COCC1>[CH3:4][C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([CH2:11][OH:12])[CH2:9][CH2:10]1)([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(C(=O)O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 4-tert-butylcyclohexane carboxylic acid (10.0 g, 54.3 mmol of a mixture of cis and trans isomers) in anhydrous THF (distilled over Na/benzophenone) (44 mL) at 0° C., under argon were added dropwise B2H6 in THF (66.5 mL of 0.98M, 65.2 mmol). The reaction mixture was stirred at 0° C. for 2 hrs and then placed in the freezer overnight. The reaction was quenched by addition of saturated NaCl solution (50 mL) and was concentrated. The aqueous residue was extracted with EtOAc (3×200 mL) and the combined organic extracts were washed with sat. NaHCO3 solution (250 mL), followed by saturated brine (250 mL), dried over Na2SO4, and filtered. Concentration to dryness yielded 9.96 g of crude product which was purified via flash chromatography eluting with 25% EtOAc in hexane to yield an amorphous 4-(1,1-dimethylethyl)cyclohexanemethanol (9.18 g, 53.9 mmol) as a mixture of cis and trans isomers in 99% yield.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]2[C:4]=1[NH:5][C:6](=[O:26])[N:7]2[CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.CO>[NH2:2][C:3]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]2[C:4]=1[NH:5][C:6](=[O:26])[N:7]2[CH2:17][CH2:18][CH2:19][N:20]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]
Reactant: O=Cc1ccccc1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCN(C)C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCN(C)C)Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
The product from step (iii) (0.1 g) and benzaldehyde (0.0362 g, 0.0347 ml) were combined in NMP (4 mL) and stirred at RT for 15 mins. Sodium triacetoxyborohydride (0.0904 g) was added. The reaction mixture was stirred for 16 h. The reaction mixture was diluted with methanol and purified by RP-prep-HPLC 75:05 NH3:acetonitrile over 15 mins to give title compound (0.068 g)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH3:31])[NH:27][C@H:26]([C:28]([NH2:30])=[O:29])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:27]3[C:23]([CH3:31])([CH3:22])[CH2:24][CH2:25][C@H:26]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(C)CC[C@@H](C(N)=O)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC[C@@H](C(N)=O)N1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (S)-5,5-dimethylpyrrolidine-2-carboxamide hydrochloride in the presence of TBTU and DIEA to obtain the title compound as colorless foam; MS (EI): m/e=409.5 [MH+].
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:21]=[C:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[S:20][CH:2]3[CH2:10][C:9]=2[CH:8]=1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: NC(=S)c1ccccc1
Product: OC12N=C(c3ccccc3)SC1Cc1cc(Cl)ccc12

Procedure:
This compound is prepared analogously to the process described in Example 6b using 2-bromo-5-chloroindan-1-one and thiobenzamide; melting point: 155° C.