Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH:18]2[CH2:19][CH2:20][CH:9]1[CH2:10][C:11]1[CH:12]=[C:13]([CH2:21][CH2:22][CH:23]=O)[CH:14]=[CH:15][C:16]=1[CH2:17]2)([CH3:4])([CH3:3])[CH3:2].Cl.[F:27][C:28]([F:36])([F:35])[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH:18]2[CH2:19][CH2:20][CH:9]1[CH2:10][C:11]1[CH:12]=[C:13]([CH2:21][CH2:22][CH2:23][N:32]3[CH2:33][CH2:34][CH:29]([C:28]([F:36])([F:35])[F:27])[CH2:30][CH2:31]3)[CH:14]=[CH:15][C:16]=1[CH2:17]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1C2CCC1Cc1cc(CCC=O)ccc1C2
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1C2CCC1Cc1cc(CCCN3CCC(C(F)(F)F)CC3)ccc1C2
Yield: 44.4 %

Procedure:
The product from Step 2 (140 mg, 0.408 mmol), 4-trifluoromethylpiperidine hydrochloride (78 mg, 0.408 mmol) and sodium cyanoborohydride (77 mg, 1.22 mmol) in methanol (15 ml) were stirred at room temperature for 18 hours. The mixture was quenched with water and then with sodium bicarbonate solution (sat). The product was extracted with DCM and the organic phase was dried and concentrated. The crude product was purified by column chromatography on silica gel eluting with 40:1 DCM-2M NH3 in MeOH to give a colourless oil. The product was re-purified by column chromatography on silica gel eluting with 7:1 isohexane-ethyl acetate to give a colourless oil 87 mg (44%). 1H NMR (CDCl3, 400 MHz) δ 6.99 (1H, d, J=8.0 Hz), 6.89 (2H, m), 4.98 (1H, m), 4.02 (1H, m), 2.95–3.02 (4H, m), 2.45–2.62 (6H, m), 2.35 (2H, m), 1.58–2.04 (11H, m), 1.47 (9H, m), 1.19 (2H, m). m/z 481 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH:5]=[N:6][OH:7].[O:12]1[CH:16]=[CH:15][CH2:14][CH2:13]1.O>C(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH:14]3[CH2:15][CH2:16][O:12][CH:13]3[O:7][N:6]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: C1=COCC1
Reactant: ON=Cc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(C2=NOC3OCCC23)cc1Cl
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a suspension of 3,4-dichlorobenzaldehyde oxime (1 eq) in DCM (10 vol) was added a 50% aqueous bleach solution (10 vol). 2,3-Dihydrofuran was then added and the resultant biphasic system was stirred vigorously at room temperature for 21 hours. Water (25 vol) and brine (25 vol) were added and the organic layer was separated. The aqueous phase was further extracted with (2×5 vol) DCM. The combined organic phases were washed with a 1:1 mixture of water and brine (50 vol), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash column chromatography (eluent: EtOAc:heptane) to yield 3-(3,4-Dichloro-phenyl)-3a,4,5,6a-tetrahydro-furo[3,2-d]isoxazole.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]#[CH:8])[CH2:3][CH2:4][OH:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C.Cl>O1CCCC1>[CH3:9][S:10]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][C:7]#[CH:8])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCC(C)CCO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCC(C)CCOS(C)(=O)=O
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2.9 g of 3-methyl-5-hexyn-1-ol and 3.0 g of methanesulfonyl chloride in 50 ml of tetrahydrofuran was added dropwise 4 ml of triethylamine at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture was 10% hydrochloric acid and the extracted with ethyl acetate. The organic layer was washed sequentially with 10% hydrochloric acid and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.88 g of 3-methyl-5-hexynyl methanesulfonate.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.Cl.[F:38][C:39]([F:62])([F:61])[C:40]1[CH:41]=[C:42]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][C@@H:54]3[CH2:59][CH2:58][C@H:57]([NH2:60])[CH2:56][CH2:55]3)[CH2:48][CH2:47]2)[CH:43]=[CH:44][CH:45]=1>ClCCl>[C:1]([CH2:3][C:4]([NH:60][CH:57]1[CH2:58][CH2:59][CH:54]([CH2:53][CH2:52][N:49]2[CH2:48][CH2:47][N:46]([C:42]3[CH:43]=[CH:44][CH:45]=[C:40]([C:39]([F:62])([F:61])[F:38])[CH:41]=3)[CH2:51][CH2:50]2)[CH2:55][CH2:56]1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: N[C@H]1CC[C@@H](CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC(=O)NC1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reaction time: 0.25 h

Procedure:
To a solution of 43 mg (0.5 mmol) of cyanoacetic acid in 5 mL of dichloromethane stabilized on amylene are successively added 68 mg (0.5 mmol) of 1-hydroxybenzotriazole, 96 mg (0.5 mmol) of 3-ethyl-1-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 0.21 mL (1.5 mmol) of triethylamine. The mixture is stirred for 15 minutes then 214 mg (0.5 mmol) of the 80%/20% trans/cis 4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylamine dihydrochloride is added. The mixture is stirred overnight at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Yield: 94.9 %

Procedure:
A solution of tert-butyl N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}carbamate (380 mg, 0.705 mmol) was stirred in dichloromethane (7 mL) and trifluoroacetic acid (3 mL) for 16 h. The reaction was concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with saturated NaHCO3. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with brine and dried with MgSO4. The crude material was purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate to yield 294 mg (95%) of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-amine. Compound was determined to be 95% pure by 1H NMR and was carried forward into further chemistry. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31-1.54 (m, 2 H) 1.92-2.08 (m, 2 H) 2.92-3.12 (m, 1 H) 3.27 (t, J=11.87 Hz, 2 H) 5.42 (br. s., 2 H) 7.07-7.61 (m, 8 H) 8.38 (s, 1 H), [M+H]+ 439.4.
Reaction SMILES: C(OC([N:8]([C:25]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=[O:24])[NH2:23])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl>CO>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:25]2[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:15][CH:14]=1)(=[O:24])[NH2:23]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2C(N)=O)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2C(N)=O)cc1
Yield: 71.3 %

Procedure:
A mixture of the compound (2.8 g) obtained in Example (54b) in methanol (15 ml) and 1N-HCl (6 ml) was heated for 2 hours under reflux. After removal of the solvent, the residue was made alkaline with an aqueous solution of NaHCO3, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel, and the product was recrystallized from ethyl acetate - hexane to afford yellow needles (1.6 g, 73%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:12])[CH3:11])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[C:4]=1[NH:9][C:10](=[O:12])[CH3:11])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccccc1NC(C)=O
Solvent: CC(=O)O
Product: CCc1cccc([N+](=O)[O-])c1NC(C)=O
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To a mixture of N-(2-ethylphenyl)acetamide (6.2 g, 38 mmol) in acetic acid (50 mL) was added dropwise fuming HNO3 (13 mL, 310 mmol) at a temperature of 50° C. to 55° C. The mixture was allowed to react at 55° C. for 2 hours and was subsequently cooled to RT, poured onto ice, and extracted with DCM. The organic layer was washed with water until the pH of the aqueous phase was >7. The organic layer was washed again with water, dried over Na2SO4, and the solvent evaporated. The residue was purified using flash chromatography eluting with MeOH/DCM (1:400) to give the title compound as a yellow solid (2.4 g, 30%; 48% purity). 1H NMR (400 MHz, CD3OD) δ 7.75 (1H, d, J=7.6 Hz), 7.62 (1H, d, J=7.6 Hz), 7.43 (1H, t, J=7.6 Hz), 2.71 (2H, q, J=7.6 Hz), 2.14 (3H, s), 1.21 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH3:1][CH:2]([CH:5]([CH3:8])[CH:6]=[CH2:7])[CH:3]=[O:4].[CH2:9]=[O:10].[OH-].[Na+]>>[CH3:1][C:2]([CH:5]([CH2:6][CH3:7])[CH3:8])([CH2:9][OH:10])[CH2:3][OH:4]
Reactant: C=O
Reactant: C=CC(C)C(C)C=O
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)C(C)(CO)CO

Procedure:
50 g. of 2,3-dimethyl-pent-4en-aldehyde is added to 100 ml. of 37% formaldehyde in a 250 ml. round bottom flask. 70 g. of a 50% w/w solution of sodium hydroxide is dripped into the mixture with stirring and the temperature maintained at 35°-40° C. with an ice bath. When the addition is complete the mixture is stirred one-half hour at room temperature and the two layers separated. The aqueous layer is extracted with 75 ml. ethyl acetate and the extract combined with the organic layer. The organic layer is washed twice with 100 ml. of water. The organic layer is placed in a Parr hydrogenation bottle and diluted to 150 ml. with methanol. 1 g. wet Raney Nickle catalyst is added and the mixture reduced at 50 p.s.i. until no more hydrogen is absorbed. The catalyst is removed by filtration and the filtrate concentrated and distilled. A yield of 45.4 g. of 2-methyl-2(sec butyl)-1,3-propanediol BP 139°-140° C. at 10 mm. pressure and refractive index ND22 =1.4610 is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[NH:19][N:18]=2)[N:3]=1.[C:25](B1OC(C)(C)C(C)(C)O1)([CH3:27])=[CH2:26]>>[CH:22]1([C:20]2[NH:19][N:18]=[C:17]([NH:16][C:4]3[N:3]=[C:2]([C:25]([CH3:27])=[CH2:26])[C:11]4[C:6]([CH:5]=3)=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[CH:21]=2)[CH2:24][CH2:23]1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(Cl)c2cc1OC
Product: C=C(C)c1nc(Nc2cc(C3CC3)[nH]n2)cc2cc(OC)c(OC)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-Chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-cyclopropyl-1H-pyrazol-3-yl)-amine and isopropenylboronic acid pinacol ester to give (5-Cyclopropyl-1H-pyrazol-3-yl)-(1-isopropenyl-6,7-dimethoxy-isoquinolin-3-yl)-amine. LC-MS m/e 351(MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][N:33]1[CH:37]=[C:36]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[N:34]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([C:36]1[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=1)(=[O:40])=[O:39]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1cc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)cn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 1-methyl-1H-pyrazole-4-sulfonyl chloride (13 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[CH2:11].[Si]([C:16]([F:19])(F)[F:17])(C)(C)C.[Na+].[I-]>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:11][C:16]1([F:19])[F:17]
Reactant: C=Cc1ccc(OC)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C2CC2(F)F)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The solution of 2-chloro-4-methoxy-1-vinylbenzene (290 mg, 1.72 mmol) in dry THF (4 mL) was degassed, and then TMS-CF3 and NaI were added. The mixture was stirred at 80° C. overnight. TLC (100% Hexane) showed the reaction as complete. The mixture was diluted with hexane (20 mL). The inorganic salt was removed by filtration. The filtrate was concentrate in vacuo. The residue was purified via Isolera One (Hexane=100%).
Reaction SMILES: C(ON=O)(C)(C)C.[C:8]1([C:14]([CH2:16]Br)=[CH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)N)([O-:20])=[O:19].NC1C=CC=CC=1>CC#N>[N+:18]([C:21]1[CH:22]=[C:23]([CH2:16][C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH2:15])[CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)([O-:20])=[O:19]
Reactant: C=C(CBr)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CC(C)(C)ON=O
Solvent: Nc1ccccc1
Solvent: CC#N
Product: C=C(Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Temperature: 25.5 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of t-butylnitrite (119 μl, 1.0 mmol) and 2-phenyl-3-brompropene (0.99 g, 5.0 mmol) in CH3CN (0.5 ml) was 3,5-dinitroaniline (92 mg, 0.5 mmol) added during 10 minutes, while maintaining the temperature of the reaction mixture at 23-28° C. At the end of the addition of the aniline extra t-butylnitrite (119 μl, 1.0 mmol) was added to the reaction mixture which then was heated to 35° C. for 5 minutes. The reaction mixture was stirred at 22° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 23:2) succeeded by crystallization from heptane gave 50 mg (35%) of 3,5-dinitro-1-(2-phenyl-2-propenyl)benzene as bright yellow needles. 1H NMR (CDCl3, 400 MHz) δ 8.88, (t, 1H, J=2.1 Hz), 8.42, (d, 2H, J=2.1 Hz), 7.42-7.37, (m, 2H), 7.36-7.24, (m, 3H), 5.65, (s, 1H), 5.22, (d, 1H, J=0.8 Hz), 4.08, (s, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1)[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=[CH:10]1)(=O)=O.[C:33](#[N:35])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:19]([O:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[N:9]([C@@H:8]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1)[CH2:7][CH2:6][C:33]#[N:35])[CH:10]=[CH:11]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC#N
Reactant: CS(=O)(=O)OCC[C@H](c1cccc(Br)c1)n1ccc2cccc(OCc3ccccc3)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: N#CCC[C@H](c1cccc(Br)c1)n1ccc2cccc(OCc3ccccc3)c21
Yield: 74 %

Procedure:
A solution of (3R)-3-(3-bromophenyl)-3-(7-benzyloxyindol-1-yl)propan-1-yl methanesulfonate (2.50 g, 4.86 mmol prepared as in Example 3, step (i)) and tetrabutylammonium cyanide (1.96 g, 7.30 mmol) in dry acetonitrile (40.0 ml) under nitrogen was heated under reflux for 24 h. The cooled solution was evaporated to yield an orange/brown oil which was taken up in ethyl acetate (200 ml), washed with water (3×100 ml), dried (Na2SO4) and the solvent removed in vacuo. Column chromatography (ethyl acetate--light petroleum (b.p. 40-60° C.), 1:4) gave the title compound as a pale yellow oil (1.60 g, 74%). [α]D19 -129 (c=0.005 gml-1, CHCl3); Vmax (thin film)/cm-1 3064, 3033, 2932, 2872, 2247 (CN), 1575; δH (270 MHz) 2.10 (2H, m 2×propyl 3-H); 2.38 (2H, m, 2×propyl 2-H); 5.09 (2H, q, CH2Ph, 2J=10.9 Hz); 6.39 (1H, dd, propyl 1-H, 3J1,2 =9.7, 3J1,2 =5.8 Hz); 6.55 (1H, d, 3-H, 3J3.2 =3.3 Hz); 6.70 (1H, d, 6-H, Jo =7.6 Hz); 6.83 (1H, d, 4-H, Jo =7.6 Hz); 7.00 (2H, m, 5-H, 5'-H); 7.05 (1H, d, 2-H, 3J2,3 =3.0 Hz); 7.15 (1H, s, 2'-H); 7.21 (1H, d, 6'-H, Jo =8.0 Hz); 7.30 (1H, d, 4'-H, Jo =8.6 Hz); 7.38 (5H, m, 5ArH).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[C:13](OC)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C1COCC1>[O:20]=[C:13]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1cccnc1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of n-butyl lithium in hexanes (9.0 mL, 1.6 M, 14 mmol) was added over 10 min. to a solution of dimethyl methylphosphonate (1.50 mL, 1.72 g, 13.8 mmol) in THF (60 mL) cooled in a dry ice/isopropanol bath. After 30 min., a solution of methyl nicotinate (757 mg, 5.52 mmol) in THF (6 mL) was added over 2 min. The solution was stirred in the cooling bath for 45 min. before being allowed to warm to 0° C. over 1 h. The reaction was quenched with saturated aq. NHCl (50 mL) and then partitioned between saturated aq. brine (50 mL) and methylene chloride (200 mL). The aq. layer was extracted with methylene chloride (2×100 mL). The combined organic layers were dried (sodium sulfate) decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with ethyl acetate followed by 97:3 v/v methylene chloride/CH3OH, gave material containing some residual impurity. Further purification by flash column chromatography on silica gel, eluting with 50:50:5 v/v/v to 50:50:10 v/v/v toluene/ethyl acetate/CH3OH gave 1.15 g of the title compound. For the title compound: 1H NMR (500 MHz, CDCl3) δ 9.26-9.20 (bs, 1H), 8.83 (d, J=4, 1H), 8.34 (dt, J=8, 2, 1H), 7.70 (dd, J=8, 4, 1H), 3.82 (d, J=11, 6H), 3.67 (d, J=24, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.S(Cl)(Cl)=O.[CH3:22]O>>[CH3:22][O:16][C:15](=[O:17])[C@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:11][CH:10]=1)[NH2:14]
Reactant: N[C@@H](Cc1ccc(-c2ccsc2)cc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc(-c2ccsc2)cc1
Temperature: 25 °C

Procedure:
A solution of 3-[4-(3-thienyl)phenyl]alanine in methanol (2 ml) is slowly added to a solution of thionyl chloride (6.8 ml, 94 mmol) in methanol (5 ml) at -10° C. The mixture is slowly warmed to room temperature, then refluxed overnight. The reaction mixture is concentrated in vacuo, diluted with ethyl acetate (10 ml), and extracted with water (10 ml×3). The aqueous layer is made basic with sodium bicarbonate and extracted with ethyl acetate (10 ml×3). The organic layer is dried over magnesium sulfate and concentrated in vacuo to give a crude 3-[4-(3-thienyl)phenyl]-alanine methyl ester.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH2:28])[C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:28][C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[NH:32][CH:33]=[N:34]2)[C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: N[C@@H](CCOCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1ccc2nc([C@H](CCOCc3ccccc3)Nc3ncnc4nc[nH]c34)n(-c3ccccn3)c2c1
Temperature: 90 °C
Yield: 100 %

Procedure:
A mixture of (S)-3-benzyloxy-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)propylamine (355 mg, 0.94 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (230 mg, 0.94 mmol) and DIPEA (0.82 mL, 4.7 mmol) in IPA (2 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford the title compound as a yellow solid (465 mg, 86%). LCMS (Method B): RT 3.56 min [M+H]+ 495.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[O:20])[CH:15]=[CH:16][CH:17]=3)=[N:9][NH:10][CH:11]=2)=[CH:3][CH:2]=1.C1COCC1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH2:41]([O:40][C:38]([N:10]1[CH:11]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[O:20])[CH:13]=2)=[N:9]1)=[O:39])[CH3:42]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)n1cc(-c2ccncc2)c(-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)n1
Reaction time: 0.08 h
Yield: 77 %

Procedure:
To a suspension of 1-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea (100 mg, 0.236 mmol) (prepared as described in Example 6) in THF (10 mL) DIPEA (61 mg, 81 uL, 0.427 mmol) was added. The mixture was stirred for 5 minutes before adding ethyl chloroformate (31 mg, 27 uL, 0.283 mmol). After 2 hours the mixture was evaporated to dryness, taken up with ethyl acetate and washed three times with water. The organic phase was dried over Na2SO4, evaporated to dryness and triturated with diisopropyl ether to yield 4-pyridin-4-yl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazole-1-carboxylic acid ethyl ester (90 mg, 77%).