Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH3:31][C@H:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:39][C@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:31])[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccnc(S(C)(=O)=O)n2)c(-c2cccc(C(F)(F)F)c2)n1
Reactant: C[C@H](N)c1ccccc1
Product: CCOC(=O)c1cn(-c2ccnc(N[C@@H](C)c3ccccc3)n2)c(-c2cccc(C(F)(F)F)c2)n1

Procedure:
A solution of 1-(2-methylsulfonylpyrimidin4-yl)-2-(3-trifluoromethylphenyl)-1H-imidazole4-carboxylic acid ethyl ester (4.5 g, 0.0102 mol) in (S)-α-methylbenzylamine (20 mL) was stirred at room temperature for 30 min. The reaction was partitioned between 300 mL ethyl acetate and 300 mL pH 4.5 citric acid solution (buffered with NaOH) and the ethyl acetate dried over anhydrous magnesium sulfate. Concentration of the ethyl acetate afforded 4.8 g of the title compound. A portion of this material was purified by reverse phase HPLC on C18 silica eluting with a gradient of 100% water to 30% water: 70% acetonitrile (both containing 0.1% trifluoroacetic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH:4]([C:8]1[CH:9]=[C:10](C2C=CC=CC=2)[CH:11]=[C:12](C(F)(F)F)[CH:13]=1)[C:5]([OH:7])=[O:6].[Cl-].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][Zn+]>>[CH3:24][CH:2]([CH3:1])[CH2:3][CH:4]([C:8]1[CH:9]=[C:10]([C:33]2[CH:30]=[CH:29][C:28]([C:27]([F:37])([F:36])[F:26])=[CH:35][CH:34]=2)[CH:11]=[C:12]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([C:27]([F:37])([F:36])[F:26])[CH:29]=2)[CH:13]=1)[C:5]([OH:7])=[O:6]
Reactant: CC(C)CC(C(=O)O)c1cc(-c2ccccc2)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1cccc(C[Zn+])c1
Agent: [Cl-]
Product: CC(C)CC(C(=O)O)c1cc(Cc2cccc(C(F)(F)F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Nigishi coupling of 4-methyl-2-(5-trifluoromethyl-biphenyl-3-yl)pentanoic acid (intermediate compound 1g) with 3-trifluoromethylbenzyl zinc chloride under the conditions described in Example 2; 1H NMR (400 MHz, MeOD) δ ppm 0.76-0.86 (m, 6 H), 1.36 (dt, J=13.51, 6.82 Hz, 1 H), 1.54-1.62 (m, 1 H), 1.80-1.91 (m, 1 H), 3.62 (t, J=7.83 Hz, 1 H), 4.05 (s, 2 H), 7.16 (s, 1 H), 7.33-7.44 (m, 6 H), 7.64 (q, J=8.56 Hz, 4 H); Calcd for C27H24F6O2 (M+Na) 517.17, Found 517.2.
Reaction SMILES: [S:1]([O:6]C)([O:4][CH3:5])(=[O:3])=[O:2].[NH2:8][C:9]1[N:13]2[CH2:14][CH2:15][CH2:16][N:12]2[C:11](=[O:17])[C:10]=1/[N:18]=[N:19]/[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>C1COCC1>[CH3:5][O:4][S:1]([O-:6])(=[O:3])=[O:2].[NH2:8][C:9]1[N:13]2[CH2:14][CH2:15][CH2:16][N:12]2[C:11](=[O:17])[C:10]=1/[N:18]=[N:19]/[C:20]1[CH:21]=[N+:22]([CH3:5])[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1c(/N=N/c2cccnc2)c(=O)n2n1CCC2
Reactant: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COS(=O)(=O)[O-]
Product: C[n+]1cccc(/N=N/c2c(N)n3n(c2=O)CCC3)c1
Reaction time: 2 h

Procedure:
1 mmol of dimethyl sulphate is added to a mixture of 5 mmol of 3-amino-2-[(E)-pyridin-3-yldiazenyl]-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one and 20 ml of THF. The temperature of the medium is brought to 75° C. for 2 hours.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.CC(N1[C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=3)[NH:32][CH:31]=[C:30]4[CH:39]3[CH2:44][CH2:43][N:42]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])[CH2:41][CH2:40]3)=[CH:23][CH:22]=2)=[O:18])=[CH:15][C:14](C)=N1)(C)C.CC(N1C(C(NCC2C=CC(B(O)O)=CC=2)=O)=CC(C)=N1)(C)C>>[CH:16]1([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=3)[NH:32][CH:31]=[C:30]4[CH:39]3[CH2:44][CH2:43][N:42]([S:45]([CH2:48][CH3:49])(=[O:46])=[O:47])[CH2:41][CH2:40]3)=[CH:23][CH:22]=2)=[O:18])[CH2:15][CH2:14][CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)c5cc(C)nn5C(C)(C)C)cc4)cc23)CC1
Reactant: O=C(O)C(F)(F)F
Agent: Cc1cc(C(=O)NCc2ccc(B(O)O)cc2)n(C(C)(C)C)n1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)C5CCCC5)cc4)cc23)CC1
Yield: 47 %

Procedure:
The title compound was prepared according to the general procedure of 5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (4-{[(cyclopentylcarbonyl)amino]methyl}phenyl)boronic acid (119 mg, 0.480 mmol) for {4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid to afford 30 mg of the title compound (47%).
Reaction SMILES: [N:1](=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[Cl:9])[OH:2].C1C=CC=CC=1.[Br:16][CH2:17][C:18](Br)=[O:19]>C(N(CC)CC)C>[Br:16][CH2:17][C:18]([OH:19])=[O:2].[Cl:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:3]1=[N:1][OH:2]
Reactant: O=C(Br)CBr
Agent: ON=C1CCCCC1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)CBr
Reaction time: 0.5 h

Procedure:
Approximately 5.9 grams (0.04M) of 1-oximino-2-chlorocyclohexane is dissolved in 90 ml. of benzene and the solution is cooled to 10° C. About 8.1 gm. (0.04M) bromoacetyl bromide, diluted with 10 ml. of benzene, and 4.9 grams (6.7 ml.) of triethylamine are added dropwise simultaneously to the solution. Stirring is continued for 30 minutes and the mixture is allowed to come to room temperature. The mixture is then washed twice with water, twice with a mild NaHCO3 solution, and again with water. The mixture is then dried over MgSO4, and the solvent is evaporated to give the product 2-chlorocyclohexanone oxime bromoacetate.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>CN(C)C=O>[ClH:1].[CH3:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(N2CCc3ccccc3C2)c2ccccc2n1
Reactant: Cc1ccccc1N
Solvent: CN(C)C=O
Product: Cc1ccccc1Nc1nc(N2CCc3ccccc3C2)c2ccccc2n1
Product: Cl
Yield: 22 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 3.05 g of the compound (10.3 mM) prepared in Example 1 and 15 ml of dimethylform-amide, 2.2 ml of 2-methylaniline(20.6 mM) was added, 0.9 g of the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][N:3]=1.[C:10]([CH2:12][C:13](=O)[CH3:14])#[N:11]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:13]([CH3:14])=[CH:12][C:10]#[N:11])=[CH:4][N:3]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: CC(=O)CC#N
Product: CC(=CC#N)NCc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 85 %

Procedure:
1.4 g of 2-chloro-5-pyridylmethylamine and 0.8 g of 1-cyano-2-propanone were mixed and the mixture was stirred at room temperature over night. The solvent was then distilled off and the residue was purified by column chromatography on silica gel to afford 1.7 g of compound No. 528. m.p. 95°-98° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([S:15][C:16]1[N:17]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)[C:18](=[O:29])[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:20]([CH3:22])[N:21]=1)[CH3:14]>O>[CH2:13]([S:15][C:16]1[N:17]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[NH:3][C:4](=[O:7])[O:5][N:44]=3)=[CH:35][CH:36]=2)[C:18](=[O:29])[C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:20]([CH3:22])[N:21]=1)[CH3:14]
Reactant: CCSc1nc(C)c(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1nc(C)c(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.27 g), sodium hydrogen carbonate (0.38 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[2-(ethylthio)-4-methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.20 g) was added, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.11 g, 50%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[S:12][N:11]=[C:10](SC)[N:9]=2)[CH2:4][CH2:3]1.Cl[C:16]1C=C(C=CC=1)C(OO)=O.[S:26]([O-:29])(O)=[O:27].[Na+]>C(Cl)(Cl)Cl>[CH3:16][S:26]([C:10]1[N:9]=[C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)[S:12][N:11]=1)(=[O:29])=[O:27]
Reactant: CSc1nsc(C2CCC(C)CC2)n1
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1CCC(c2nc(S(C)(=O)=O)ns2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
900 mg of 5-(4-methylcyclohexyl)-3-methylthio-1,2,4-thiadiazole was dissolved in 8 ml of chloroform, 2.22 g of 3-chloroperoxybenzoic acid (content>65%) was added thereto taking for 20 minutes, and the reaction mixture was stirred for 4 hours at room temperature. Then, the reaction mixture was added to saturated sodium hydrogensulfite aqueous solution, and separated. The organic layer was washed with sodium hydrogencarbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated to give 1.11 g of 3-methylsulfonyl-5-(4-methylcyclohexyl)-1,2,4-thiadiazole.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[CH:10]=[CH:9][C:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:7][C:6]=2[C:5]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:4]1=2.C=O.[C:28]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C.C(OCC)(=O)C>[CH3:28][N:23]1[CH2:22][CH2:21][C:5]2[C:6]3[CH:7]=[C:8]([S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)(=[O:13])=[O:14])[CH:9]=[CH:10][C:11]=3[N:3]([CH3:2])[C:4]=2[CH2:25][CH2:24]1
Reactant: [BH3-]C#N
Reactant: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCNCC2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCc2c(n(C)c3ccc(S(=O)(=O)c4ccccc4)cc23)CC1
Reaction time: 5 h

Procedure:
A mixture of 6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (EXAMPLE 13, 341 mg, 1.00 mmol) in acetonitrile (5 mL) is treated with formaldehyde (37%, 0.400 mL, 5.00 mmol), sodium cyanoborohydride (101 mg, 1.60 mmol) and glacial acetic acid (1 drop). After 5 hr, the mixture is diluted with ethyl acetate and then washed with water and saline. The organic layer is dried, filtered, and concentrated. The concentrate is dissolved in methylene chloride/methanol and treated with methanolic hydrochloric acid. The solvent is then removed and the residual solid crystallized from hot ethyl acetate/methanol to give the title compound, mp=283–286°; IR (drift) 2523, 2477, 2453, 2428, 1479, 1311, 1304, 1283, 1150, 1094, 756, 730, 694, 644 and 623 cm−1; NMR (300 MHz, DMSO-d6) δ 11.00, 8.16, 7.85–7.95, 7.50–7.65, 3.70, 3.15–3.45 and 2.89; MS (FAB) m/z 355 (MH+), 354, 353, 58 and 44; HRMS (FAB) calculated for C20H23N2O2S=355.1480, found=355.1488.
Reaction SMILES: BrC1C=CC([C:8]2C3C=CC(O)=CC=3O[N:9]=2)=CC=1.BrC/C=C/CBr.Br[CH2:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]1[CH:45]=[CH:44][C:33]2[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=3)=[N:35][O:36][C:32]=2[CH:31]=1.C(NC)C=C>>[Br:43][C:40]1[CH:41]=[CH:42][C:37]([C:34]2[C:33]3[CH:44]=[CH:45][C:30]([O:29][CH2:28][CH:27]=[CH:26][CH2:25][NH:9][CH3:8])=[CH:31][C:32]=3[O:36][N:35]=2)=[CH:38][CH:39]=1
Reactant: Oc1ccc2c(-c3ccc(Br)cc3)noc2c1
Reactant: BrC/C=C/COc1ccc2c(-c3ccc(Br)cc3)noc2c1
Agent: BrC/C=C/CBr
Agent: C=CCNC
Product: CNCC=CCOc1ccc2c(-c3ccc(Br)cc3)noc2c1

Procedure:
Analogously to Example 1, from 3-(4-bromo-phenyl)-benzo[d]isoxazol-6-ol and (E)-1,4-dibromo-2-butene via (E)-6-(4-bromo-but-2-enyloxy)-3-(4-bromo-phenyl)-benzo[d]isoxazole and by reaction with N-allyl-methyl-amine there is obtained (E)-allyl-[4-[3-(4-bromo-phenyl)-benzo[d]isoxazol-6-yloxy]-but-2-enyl-methyl-amine which is converted into the fumarate, MS: m/e 412 (M30 , 1 Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C@@:8]2([F:25])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([C:21](Cl)=[O:22])[C:9]2=[O:24])[CH:7]=1.N1C=CC=CC=1.[C:34]([O:38]CC1C=CC=CC=1)(=[O:37])[CH2:35][OH:36]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C@@:8]2([F:25])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=3)[N:10]([C:21]([O:36][CH2:35][C:34]([OH:38])=[O:37])=[O:22])[C:9]2=[O:24])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)Cl)c2cc(C(F)(F)F)ccc21
Reactant: O=C(CO)OCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCC(=O)O)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C

Procedure:
To a solution of (S)-XI in toluene and methylene chloride was added 0.6 mL of pyridine followed by the addition of benzyl glycolate (0.878 mL). The resulting mixture was stirred at room temperature for an hour. This reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and condensed by rotary evaporation. The residue was chromatographed on a silica gel flash column packed with ethyl acetate: hexane (v/v, 10:1) and washed with dichloromethane to afford 1.32 g of the title compound.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C.[C:31]([NH:39][C@@H:40]1[CH2:45][CH2:44][O:43][CH2:42][C@@H:41]1[C:46]([O:48][CH3:49])=[O:47])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:31]([NH:39][C@H:40]1[CH2:45][CH2:44][O:43][CH2:42][C@H:41]1[C:46]([O:48][CH3:49])=[O:47])(=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)[C@H]1COCC[C@H]1NC(=O)c1ccccc1
Agent: O=C(O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1COCC[C@@H]1NC(=O)c1ccccc1
Reaction time: 20 h
Yield: 91 %

Procedure:
A mixture of (3S,4S)- and (3R,4R)-methyl 4-aminotetrahydro-2H-pyran-3-carboxylate, HBr (prepared in a similar manner as described in International Patent application No. WO 2003/024899, 500 mg, 2.083 mmol), benzoic acid (254 mg, 2.083 mmol), HOBt (383 mg, 2.499 mmol), EDC (479 mg, 2.499 mmol) and triethylamine (0.581 mL, 4.17 mmol) were mixed in methylene chloride (10 mL) at 25° C. and stirred for 20 hours. At the conclusion of this period, the reaction was worked up by adding methylene chloride and then rinsing the mixture with saturated sodium carbonate (1×). The methylene chloride layer was dried over sodium sulfate and concentrated to give an off-white solid. The off-white solid was purified over silica gel in 3:1 to 1:1 hexanes/EtOAc to 100% EtOAc to yield a mixture of (3R,4R)-methyl 4-benzamidotetrahydro-2H-pyran-3-carboxylate and (3S,4S)-methyl 4-benzamidotetrahydro-2H-pyran-3-carboxylate (500 mg, 1.899 mmol, 91% yield) as a white solid. MS (ESI+)=264.24 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][Cl:5].B(F)(F)F.CCOCC.[CH2:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[Cl:1][CH2:2][CH:3]([O:6][CH:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH3:27])[CH2:4][Cl:5]
Reactant: OC(CCl)CCl
Agent: C=CCCCCCCCCCC
Agent: FB(F)F
Solvent: CCOCC
Product: CCCCCCCCCCC(C)OC(CCl)CCl
Temperature: 95 °C
Yield: 191.9 %

Procedure:
To a 1000 ml round bottom flask equipped with condenser, overhead stirrer, and nitrogen inlet system is added 526.2 g of 1,3-dichloro-2-propanol, 7.8 ml of boron trifluoride diethyl etherate, 101 g of 1-dodecene, and 101 g of the olefin isomer mixture obtained from a previous run such as Example II-5 at room temperature. The mixture is heated to 95° C. for 1 hour. The reaction mixture is cooled to room temperature and is then transferred to a 1000 ml separation funnel; 200 ml of heptane are added and two phases are separated. The lower phase is extracted with 200 ml of heptane three more times. The heptane solutions are combined and heptane is removed on a rotary evaporator. Distillation under reduced pressure affords 85.1 of dodecene isomers mixture and 171.2 g of sec-dodecyl 1,3-dichloro-2-propyl ether and isomers. Yield=96% (Based on 1-dodecene). The 13C NMR spectrum is collected. The component ratio corresponding to the C-2, C-3, and higher C linked ethers is determined from the area integration of the peaks as 64:20:16.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][CH2:24][O:25][CH3:26])[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:27](OCC)C.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:27][O:21][C:20](=[O:22])[C@@H:19]([NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])[CH2:23][CH2:24][O:25][CH3:26]
Reactant: CCOCC
Reactant: COCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC
Temperature: 25 °C
Yield: 94 %

Procedure:
In a flask was placed (S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-methoxy-butyric acid (500 mg, 1.41 mmol), diethyl ether (20 mL) and methanol (5 mL) and cooled to 0° C. in an ice bath. To this mixture was added a 2M solution of (trimethylsilyl)diazomethane in diethyl ether (1.41 mL, 2.82 mmol) dropwise. The mixture was stirred and warmed to 25° C. The mixture was then concentrated to afford (S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-methoxy-butyric acid methyl ester (489 mg, 94%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:14]([CH2:16][N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([CH:26]=[CH2:27])=[N:18]3)=[N:15][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)(=O)C>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:14]([CH2:16][N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([CH:26]=[CH2:27])=[N:18]3)=[N:15][C:11]=2[CH:10]=1
Reactant: C=Cc1nn(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCO)c2ccccc12
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1nn(Cc2nc3cc(CN)ccc3n2CCCCO)c2ccccc12
Reaction time: 2.5 h

Procedure:
To a suspension of [1-(4-hydroxy-butyl)-2-(3-vinyl-indazol-1-ylmethyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (17 mg, 0.036 mmol) in DCM (1 mL) was added TFA (82 μL, 1.1 mmol). The solution was allowed to stir for 2.5 hrs. followed by the removal of the volatiles in vacuo. The resulting trifluoroacetate was dissolved in methanol (3 mL) followed by the addition of acetyl cloride (26 μL, 0.36 mmol) and concentrated after 10 min. This procedure was repeated once allowing the reaction to run for 3 hrs. The solution was concentrated in vacuo and the residue stripped with DCM (thrice). The product was triturated in diethyl ether and the ether decanted to yield 4-[5-aminomethyl-2-(3-vinyl-indazol-1-ylmethyl)-benzoimidazol-1-yl]-butan-1-ol; HCl salt (10 mg, 67%) as an off white solid:
Reaction SMILES: [C:1]([N:5]=[C:6]=[S:7])([CH3:4])([CH3:3])C.C1([NH2:11])CC1.[C:12]1(C)C=C[CH:15]=[CH:14][CH:13]=1>>[CH:1]1([N:5]([CH2:12][CH2:13][CH2:14][CH3:15])[C:6]([NH2:11])=[S:7])[CH2:3][CH2:4]1
Reactant: Cc1ccccc1
Reactant: NC1CC1
Reactant: CC(C)(C)N=C=S
Product: CCCCN(C(N)=S)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl isothiocyanate (11.6 ml, 0.1 mol) and cyclopropylamine (6.9 ml, 0.1 mol) were mixed in toluene (200 ml) and stirred at room temperature overnight. The resulting mixture was evaporated to a residue and crystallized from cyclohexane to yield N-cyclopropyl-N-butyl thiourea. N-cyclopropyl-N-t-butyl thiourea (5 g) was suspended in 5M HCl (50 ml) and heated to 80° C. for 10 minutes. The resulting solution was cooled, poured into a saturated sodium bicarbonate (250 ml), and extracted with ethyl acetate (2×125 ml). The solution was dried (MgSO4), evaporated to a residue and crystallized from ethyl acetate to yield a white solid, cyclopropyl thiourea, 110 mg.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+].[N:36]#[N:37]>O1CCOCC1.O>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:16]2[CH:17]=[C:12]([N:8]3[CH:7]([CH3:26])[CH2:6][C:5]4[C:10](=[CH:11][C:2]([C:2]5[CH:3]=[CH:4][N:37]([CH2:11][C:10]6[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=6)[N:36]=5)=[CH:3][CH:4]=4)[CH2:9]3)[N:13]=[C:14]([NH2:25])[N:15]=2)[CH2:23][CH2:22]1
Reactant: N#N
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3ccn(Cc4cccnc4)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
The residue was dissolved in 1,4-dioxane (0.50 mL) and water (0.10 mL), to this solution was added 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.018 g, 0.043 mmol, Peak 1, Example 49, Step 7), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (1.76 mg, 0.00216 mmol), potassium carbonate (11.9 mg, 0.0862 mmol) and the mixture was vacuumed and refilled with N2 for 3 times. The reaction was stirred at 110° C. overnight. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=496.3.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=[C:5]2[C:4]1=[O:16].[SH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[N+:13]([C:10]1[CH:9]=[C:6]2[C:7](=[O:8])[N:3]([CH2:2][S:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:4](=[O:16])[C:5]2=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: Sc1ccncc1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CSc1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
N-Chloromethyl-4-nitrophthalimide [2.89 g (12 mmol)] was added under ice-cooling with stirring to a suspension of 1.11 g (10 mmol) of 4-mercaptopyridine and 1.4 ml (12 mmol) of triethylamine in 50 ml of ethanol. The mixture was stirred at room temperature for 16 hours. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.99 g of the desired compound (yield: 63.1%, yellow crystals).