Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>CCCCCCC>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C=C(Cl)C#N
Solvent: CCCCCCC
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 g) and 2-chloroacrylonitrile (26.6 g) is stirred at about 80° C. for 24 hours. n-Heptane (125 ml) is allowed to run in, and unreacted 2chloroacrylonitrile and 2,6-difluorobenzyl azide as well as n-heptane are distilled off (distillate 50 ml) by raising the external temperature to about 130° C. The mixture is cooled to about 20° C. and the suspension is stirred at about 20° C. for 1 hour. The product is isolated by filtration and washed with n-heptane (100 ml). The product is dried in vacuo at about 60° C. Yield: 31.55 g=71.6% (beige powder).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.[H-].[Na+].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: Fc1cc(F)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cc(F)cc(F)c1
Yield: 71.8 %

Procedure:
Using 0.21 g of 3,5-difluorobenzyl bromide, 3 ml of N,N-dimethyl-formamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.21 g of 2-(3,5-difluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (71)).
Reaction SMILES: ClCC1(COC2C=CC(Cl)=CC=2Cl)CO1.[Cl:16][C:17]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:18]=1[O:19][CH2:20][C:21]1([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[CH2:23][O:22]1.[NH:39]1[CH:43]=[N:42][CH:41]=[N:40]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][C:17]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:18]=1[O:19][CH2:20][C:21]([OH:22])([CH2:23][N:39]1[CH:43]=[N:42][CH:41]=[N:40]1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33]
Reactant: Clc1ccc(OCC2(COc3ccc(Cl)cc3Cl)CO2)c(Cl)c1
Reactant: c1nc[nH]n1
Agent: ClCC1(COc2ccc(Cl)cc2Cl)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OC(COc1ccc(Cl)cc1Cl)(COc1ccc(Cl)cc1Cl)Cn1cncn1

Procedure:
23.5 g of a mixture of 2-chloromethyl-2-(2,4-dichlorophenoxymethyl)-oxirane and 2,2-bis(2,4-dichlorophenoxymethyl)-oxirane are added dropwise to a solution of 20.7 g (0.3 mole) of 1,2,4-triazole and 13.8 g (0.1 mole) of potassium carbonate in 200 ml of acetone. The reaction mixture is stirred under reflux for 20 hours. It is then filtered cold and the filtrate is concentrated in vacuo. The residue is dissolved in chloroform and the solution is washed with water, dried over sodium sulphate and purified and separated by chromatography (silica gel 60 Merck). Chloroform is first used as the eluting agent. The eluate thereby obtained is concentrated by distilling off the solvent and the residue is stirred with diethyl ether. 4.8 g of 1,3-bis-(2,4-dichlorophenoxy)-2-hydroxy-2-(1,2,4-triazol-1-yl-methyl)-propane (Example 5) of melting point 136° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[C:18]([O:20]C)=[O:19])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[I-].[Li+]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[C:18]([OH:20])=[O:19])(=[O:11])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cccn1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1cccn1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 82.5 %

Procedure:
To a solution of methyl 1-(4-nitrophenylsulfonyl)-1H-pyrrole-2-carboxylate (Int. 4) (550 mg, 1.773 mmol) in pyridine (25 ml), lithium iodide (1661 mg, 12.41 mmol) was added and the resulting mixture was refluxed for 8 hours. The solution was concentrated under vacuum and the crude was dissolved in DCM (150 ml) and washed with 1N HCl (50 ml×2) and then with brine (50 ml); the organic layer was dried over sodium sulfate and the solvent was removed affording 1-(4-nitrophenylsulfonyl)-1H-pyrrole-2-carboxylic acid (Int. 5) (433 mg, 1.462 mmol).
Reaction SMILES: [CH:1]1([C:7]2[CH:37]=[CH:36][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[N:20]=[C:21]([N:24]([CH2:26][C:27]5[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=5)[CH3:25])[S:22][CH:23]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+:39]>>[CH:1]1([C:7]2[CH:37]=[CH:36][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[N:20]=[C:21]([N:24]([CH2:26][C:27]5[CH:28]=[CH:29][C:30]([C:31]([O-:33])=[O:32])=[CH:34][CH:35]=5)[CH3:25])[S:22][CH:23]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[K+:39]
Reactant: CN(Cc1ccc(C(=O)O)cc1)c1nc(-c2ccc(OCc3ccc(C4CCCCC4)cc3)cc2)cs1
Agent: [K+]
Agent: [OH-]
Product: CN(Cc1ccc(C(=O)[O-])cc1)c1nc(-c2ccc(OCc3ccc(C4CCCCC4)cc3)cc2)cs1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.9 %

Procedure:
Under an argon atmosphere, to a suspension of 4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoic acid (30.0 g, 58.5 mmol) obtained in Example 2(5) was added 1N aqueous potassium hydroxide solution (56.0 ml) at 50° C. and the mixture was heated under reflux for 40 min. After stirring at room temperature for 45 min., the crystals were collected by filtration, washed with a tetrahydrofuran-ethanol mixed solvent (3:1, 150 ml) and ethanol (210 ml), and dried to give the title compound (28.0 g, yield 90.9%).
Reaction SMILES: C[Mg]Cl.[S:4]([N:14]1[C:18]2=[N:19][CH:20]=[C:21]([CH:23]=[O:24])[N:22]=[C:17]2[CH:16]=[CH:15]1)([C:7]1[CH:13]=[CH:12][C:10]([CH3:11])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH4+].[Cl-].[CH3:27]COC(C)=O>C1COCC1.C(Cl)Cl>[S:4]([N:14]1[C:18]2=[N:19][CH:20]=[C:21]([CH:23]([OH:24])[CH3:27])[N:22]=[C:17]2[CH:16]=[CH:15]1)([C:7]1[CH:8]=[CH:9][C:10]([CH3:11])=[CH:12][CH:13]=1)(=[O:5])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Reactant: CCOC(C)=O
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)O)cnc32)cc1
Temperature: 25 °C
Yield: 23 %

Procedure:
To a solution of methylmagnesium chloride (0.232 mL, 0.697 mmol) in THF (10 mL) at about −78° C. was added a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (0.210 g, 0.697 mmol, Example #10, Step B) in DCM (10.0 mL). After about 10 min saturated aqueous NH4Cl was added to the reaction mixture. After warming to room temperature, EtOAc (30 mL) was added to the reaction mixture and the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 20-80% EtOAc/heptane to provide 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanol (0.050 g, 23%) as a yellow oil. LC/MS (Table 2, Method a) Rt=2.04 min; MS m/z: 318 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][OH:8])[N:3]=1.CCO/[CH:12]=[C:13](/[CH:15]=O)\[CH3:14]>C(O)(=O)C>[CH3:15][C:13]1[CH:12]=[N:1][C:2]2[N:6]([N:5]=[C:4]([CH2:7][OH:8])[N:3]=2)[CH:14]=1
Reactant: CCO/C=C(\C)C=O
Reactant: Nc1nc(CO)n[nH]1
Solvent: CC(=O)O
Product: Cc1cnc2nc(CO)nn2c1
Temperature: 80 °C

Procedure:
To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (16.6 g, 87.6 mmol) from step 6 of example A(1) in acetic acid was added 3-ethoxymethacrolein (10 g, 87.6 mmol). The mixture was heated to 80° C. for 4 hours. Upon cooling of the reaction, the product cyrstallized out of solution. The collected product was awhite solid (14 g, 92%). 1H NMR (300 MHz, DMSO-d6): δ 2.38 (s, 3 H), 4.63 (s, 2 H), 5.52 (s, 1 H), 8.75 (s, 1 H), 9.21 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:8][C:4]1[N:3]=[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Dibromopyridine (1.0 g) and tert-butyl piperazine-1-carboxylate (870 mg) are dissolved in N,N-dimethylformamide (10 ml) and stirred at 80° C. in the presence of potassium carbonate (1.17 g) for 5 hours. To the reaction mixture is added tert-butyl piperazine-1-carboxylate (200 mg). The mixture is stirred at room temperature overnight, and then water is added. The aqueous phase is removed and extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives tert-butyl 4-(6-bromopyridin-2-yl)piperazine-1-carboxylate (900 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2C(OC(C)(C)C)=O)=[O:26])[C:10](=[O:23])[N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][NH:28]2)=[O:26])[C:10](=[O:23])[N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2)CC1)[C@@H]1Cc2ccccc2CN1
Yield: 37.7 %

Procedure:
tert-Butyl 3-(N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-(4-phenylpiperazinyl)ethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step 2) (127 mg, 0.211 mmol) was treated with 10 mL of EtOAc satd with HCl in a 50 mL round bottomed flask equipped with magnetic stirring. The resulting solid was filtered, washed with hexane and dried in vacuo to yield N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-(4-phenyl-piperazinyl)ethyl}((3S)(3-1,2,3,4-tetrahydro-isoquinolyl))carboxamide (40 mg). MS (ESI, pos. ion) m/z: 503 (M+H), (ESI, neg. ion) m/z: 501 (M−H). Calc'd for C29H31ClN4O2: 502 21.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][C:13](Cl)=[N:14][CH:15]=3)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[N-:20]=[N+:21]=[N-:22].[Li+]>CN(C=O)C>[C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[N:20]=[N+:21]=[N-:22])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: OC[C@H]1O[C@@H](n2cnc3cnc(Cl)nc32)[C@@H](O)[C@@H]1O
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.3 %

Procedure:
A solution of 4 (170 mg, 0.63 mmol) in DMF (5 ml) was treated with lithium azide (270 mg, 5.52 mmol) and stirred for two days at room temperature. The solvent was evaporated under reduced pressure at 40° C. and the crude oil was recrystallizd from MeOH to obtain pure 5 (67 mg, 38.4%): mp 185-190° C. (dec.); UVλmax (water) pH 2: 205.0 (15,506), 287.0 (6,496); pH 7: 208.5 nm (12,943), 287.5 nm (6033); pH 11: 222.5 nm (6,730); 1H NMR (DMSO-d6) δ 3.66-3.90 (m, 3H, H-5′, H-4′), 4.16-4.33 (m, 2H, H-2′, H-3′), 5.14 (t, 1H, 5′-OH, exchangeable with D2O), 6.50 (d, 1H, H-1′), 8.75 (s, 1H, H-8), 10.12 (s, 1H, H-2); IR (KBr) 2037, 1649; Anal. (C10H11N7O4.0.65 CH3OH): C, H, N.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([OH:23])[CH2:20][CH:19]3[C:24]([N:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[CH3:27])=[O:25])=[O:17])[CH2:12][CH:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:36][C:37]1[N:42]=[C:41](Cl)[CH:40]=[CH:39][N:38]=1>CN(C=O)C>[CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([O:23][C:39]4[CH:40]=[CH:41][N:42]=[C:37]([Cl:36])[N:38]=4)[CH2:20][CH:19]3[C:24]([N:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[CH3:27])=[O:25])=[O:17])[CH2:12][CH:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(Oc2ccnc(Cl)n2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Compound 10e (43 mg, 89.3 mmol) was dissolved in DMF (2 ml) and the solution was cooled to 0° C. and NaH (11 mg, 0.27 mmol) was added. After 0.5 h 2,4-dichloro-pyrimidine was added. The reaction was stirred at 0° C. for 2 h and then quenched by addition of citric acid. The reaction mixture was extracted with DCM (3×10 ml) and the combined organic phases were washed with citric acid, water and brine. The organic phase was dried over MgSO4 and filtered. The solvent was removed in vacuo to yield the crude target compound (43 mg, 81%); LC/MS m/z (ESI+)=595 (MH+).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH:21]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.[CH3:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[CH3:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:19][CH2:20][CH:21]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH2:22][CH2:23]4)=[CH:14][C:13]=3[O:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Reactant: COCc1ccccc1B(O)O
Product: COCc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCC(N5CCN(C)CC5)CC4)cc3OC)nn12
Yield: 52.3 %

Procedure:
Following the procedure of example 532 (D), (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine (0.062 g, 0.00012 mol) and 2-Methoxymethyl phenylboronic acid (0.0226 g, 0.000132 mol) were reacted. Purification by prep plate chromatography gave [7-(2-Methoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine (0.034 g, 51%) as a tan solid MP: 96-101 C; 1H-NMR (DMSO-d6, 400 MHz) δ 8.92 (s, 1H), 7.65-7.62 (m, 2H), 7.55 (m, 2H), 7.47-7.45 (t, 2H, J=3.56 Hz), 6.94-6.87 (q, 2H, J=4.56 Hz), 6.61-6.60 (d, 1H, J=2.28 Hz), 6.42-6.38 (d, 1H), 6.30-6.27 (d, 1H), 4.33 (s, 2H), 3.81 (s, 3H), 3.64-3.61 (d, 2H) 3.17 (s, 3H), 2.67-2.57 (m, 6H), 2.33 (br, 5H), 2.16 (s, 3H), 1.84-1.81 (m, 2H), 1.50-1.48 (m, 2H), 1.23-1.17 (br, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]([O:13][CH2:14][O:15][CH3:16])=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]([O:13][CH2:14][O:15][CH3:16])=[C:6]([CH:12]=1)[CH2:7][OH:8]
Reactant: CCOC(=O)c1cc(Br)c(Cl)cc1OCOC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1cc(Cl)c(Br)cc1CO
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
In THF (800 ml) was dissolved ethyl 5-bromo-4-chloro-2-methoxymethoxybenzoate (161.4 g). To the solution was added lithium aluminum hydride (19.2 g) at 0° C. over a period of 30 minutes, and the mixture was stirred for further 30 minutes. The reaction mixture was poured into a saturated aqueous saline solution, to which was added ethyl acetate, followed by subjecting the mixture to filtration with celite. The organic layer was washed with a saturated aqueous saline solution, dried (anhydrous magnesium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 5-bromo-4-chloro-2-methoxymethoxybenzyl alcohol (137.9 g) (Compound B-34). The physical properties are shown in Table 8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:27])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34]C(N(C)C)N(C)C)(C)(C)C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[CH:30][OH:34])=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1cc(CCNC(=O)Cc2ccc(C)cc2)ccc1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CCNC(=O)C(=CO)c2ccc(C)cc2)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
11.68 g (30.0 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(4-methylphenyl)acetamide and 15.67 g (90.0 mmol) of t-butoxybis(dimethylamino) methane were mixed and stirred at 80° C. for 2 hours. The reaction mixture was cooled and tetrahydrofuran was added thereto. The reaction mixture was acidified with 5% hydrochloric acid and stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, water and 5% hydrochloric acid were added to the residue, which was followed by extracted with chloroform twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 11.30 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH3:42])[C:6]([CH2:22][C:23]2[N:27](COCC[Si](C)(C)C)[C:26]3[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=3[N:24]=2)=[C:7]2[C:11]=1[N:10]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:9]=[CH:8]2.OCC1C=C(C)C(CC2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C=1N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2.B(F)(F)F.CCOCC>C(Cl)Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH3:42])[C:6]([CH2:22][C:23]2[NH:27][C:26]3[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=3[N:24]=2)=[C:7]2[C:11]=1[N:10]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:9]=[CH:8]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C)cc(CO)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C)cc(CO)c32)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc5cc(C#N)ccc5[nH]4)c(C)cc(CO)c32)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of a mixture of 2-((7-(hydroxymethyl)-5-methyl-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-((7-(hydroxymethyl)-5-methyl-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (14 mg, 0.023 mmol) in DCM (0.23 mL), BF3.OEt2 (15 μL, 0.117 mmol) was added at 0° C. After stirring for 5 minutes, the mixture was warmed up to room temperature. After 30 minutes the reaction mixture was diluted with sat. aq. NaHCO3 and EtOAc, extracted with EtOAc, and the organic extract was dried over MgSO4, filtered and concentrated to provide the title compound, which was used without further purification. MS (ESI+) m/z 471.2 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([CH3:11])[CH:5]=[CH:6][CH2:7][CH:8]([CH3:10])[CH3:9].[I-:12].[Na+]>CC(CC(C)C)=O.CCOCC>[I:12][CH2:2][CH2:3][C@H:4]([CH3:11])/[CH:5]=[CH:6]\[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: [I-]
Reactant: CC(C)CC=C[C@@H](C)CCCl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)CC(C)C
Product: CC(C)C/C=C\[C@@H](C)CCI
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A solution of 4.4 g of (S)-1-chloro-3,7-dimethyl-4-octene in 30 ml of isobutyl methyl ketone is stirred at 130° for 37 hours with 7.55 g of sodium iodide. A further 3.75 g of sodium iodide are added thereto and the mixture is stirred further for 4 hours. After cooling to room temperature, the mixture is diluted with ether, washed with water, dried and concentrated under reduced pressure. The residue is prepurified by adsorption on silicagel (elution agent: n-hexane), pure fractions are combined and distilled at 14 Torr and 130°. There are obtained 5.6 g (83.5%) of (S)-cis-1-iodo-3,7-dimethyl-4-octene as a colourless liquid. [α]D20 =+14.3° (2.21% in CHCl3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].COCCOC.CCO.O>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=2)[CH:3]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COc1cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)ccn1
Temperature: 150 °C
Yield: 54 %

Procedure:
1-(3-Bromophenyl)-4-fluoro-1-(2-methoxypyridin-4-yl)-1H-isoindol-3-amine (100 mg, 0.24 mmol), 5-pyrimidinylboronic acid (31.6 mg, 0.25 mmol), [1,1′-bis (diphenylphosphino)ferrocene]palladium(II) chloride (9.90 mg, 0.01 mmol), cesium carbonate (0.058 mL, 0.73 mmol) and DME:EtOH:water (6:3:1) (3.00 mL) were mixed in a microwave vial and heated in a microwave reactor at 150° C. for 20 min. The resulting product mixture was filtered and purified by preparative-HPLC to give 58 mg (54% yield of the title compound (after pooling and freeze drying of the fractions).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH2:7][CH3:8].II.[I:31](O)(=O)=O>O.C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH2:6]([C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:16][CH2:17][C@H:18]([CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([I:31])=[CH:27][CH:28]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)[CH2:7][CH3:8]
Reactant: [O-][I+2]([O-])O
Reactant: CCCc1ccc([C@H]2CC[C@H](CCc3ccccc3)CC2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1ccc([C@H]2CC[C@H](CCc3ccc(I)cc3)CC2)cc1

Procedure:
To a liquid mixture comprising 50 ml of acetic acid, 5 ml of carbon tetrachloride, 5 ml of concentrated sulfuric acid, and 10 ml of water, were added 5.8 g of the (2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)benzene mentioned above, 2.4 g of iodine, and 2 g of iodic acid, and they were stirred under a reflux for 2 hours. After cooled, the mixture was washed with a saturated aqueous solution of sodium thiosulfate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain a yellow-brown oily product. This product was purified by a column chromatography over an alumina by using heptane as an eluent, and further recrystallized from heptane to obtain 5.8 g of 4-(2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)iodobenzene.