Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[CH3:24][C:25]1[CH:43]=[CH:42][CH:41]=[CH:40][C:26]=1[C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][C:31]=1[Cl:39])=[O:28]>ClCCl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:34]([C:33]3[CH:37]=[CH:38][C:30]([NH:29][C:27](=[O:28])[C:26]4[CH:40]=[CH:41][CH:42]=[CH:43][C:25]=4[CH3:24])=[C:31]([Cl:39])[CH:32]=3)=[O:35])[CH2:6][C:5]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
To a mixture of 1.38 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 1.11 g of N,N-diisopropylethylamine in 50 ml of dichloromethane is added 2.61 g of 4-[(2-methylbenzoyl)amino]-3-chlorobenzoyl chloride in 25 ml of dichloromethane. The mixture is stirred at room temperature overnight and then washed with H2O and saturated NaHCO3. The organic layer is dried (Na2SO4) and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated, the residue (4.0 g) dissolved in dichloromethane and again filtered through a pad of hydrous magnesium silicate. The filtrate is evaporated to give the product as a glass (3.62 g). A 1.8 g sample of the glass is crystallized from ethyl acetate to give 1.4 g of crystals, m.p. 176°-178° C.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccccc1OC1CN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.5 %

Procedure:
To a stirred solution of 3-(2-tert-butylphenoxy)azetidine (0.30 g, 1.46 mmol) in pyridine (5.0 mL) was added benzenesulfonyl chloride (0.28 g, 1.61 mmol). After stirring for 16 h at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 1.0 N hydrochloric acid, water, saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting yellow solid was recrystallized from heptane/ethyl acetate to provide 3-(2-tert-butylphenoxy)-1-(phenylsulfonyl)azetidine (0.29 g, 57%) as a pale brown powder.
Reaction SMILES: C(O[C@@H]1CC[C@H](N)C1)C=C.FC1C=C(C[C@H](NC(=O)OCC2C=CC=CC=2)[C@H]2CO2)C=C(F)C=1.[CH2:35]([O:38][C@H:39]1[CH2:43][CH2:42][C@@H:41]([NH:44][CH2:45][C@@H:46]([OH:68])[C@@H:47]([NH:57]C(=O)OCC2C=CC=CC=2)[CH2:48][C:49]2[CH:54]=[C:53]([F:55])[CH:52]=[C:51]([F:56])[CH:50]=2)[CH2:40]1)[CH:36]=[CH2:37].C(O[C@@H]1CC[C@H](NC[C@@H](O)[C@@H](NC(=O)OCC2C=CC=CC=2)CC2C=C(F)C=C(F)C=2)C1)C=C>>[CH2:35]([O:38][C@@H:39]1[CH2:43][CH2:42][C@H:41]([NH:44][CH2:45][C@@H:46]([OH:68])[C@@H:47]([NH2:57])[CH2:48][C:49]2[CH:54]=[C:53]([F:55])[CH:52]=[C:51]([F:56])[CH:50]=2)[CH2:40]1)[CH:36]=[CH2:37]
Reactant: C=CCO[C@H]1CC[C@@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OCc2ccccc2)C1
Agent: C=CCO[C@@H]1CC[C@H](N)C1
Agent: C=CCO[C@@H]1CC[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OCc2ccccc2)C1
Agent: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Product: C=CCO[C@@H]1CC[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)C1
Yield: 51 %

Procedure:
Step Y (3): Racemic cis-3-(allyloxy)cyclopentanamine from step Y (2) was reacted with benzyl (S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethylcarbamate according to the conditions described in Step V (1). Purification by silica gel column chromatography provided 726 mg (51% yield) of a mixture of benzyl (2S,3R)-4-((1R,3S)-3-(allyloxy)cyclopentylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate and benzyl (2S,3R)-4-((1S,3R)-3-(allyloxy)cyclopentylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate. LC-MS (M+H)+=475.3; 1H NMR (500 MHz, CDCl3) δ ppm 1.61-1.92 (m, 3H) 1.93-2.30 (m, 3H) 2.72 (dd, J=13.89, 10.83 Hz, 1H) 3.00 (d, J=9.16 Hz, 1H) 3.18 (t, J=14.34 Hz, 1H) 3.31-3.48 (m, 1H) 3.55-4.18 (m, 5H) 4.39 (dd, J=36.01, 4.88 Hz, 1H) 4.91-5.07 (m, 2H) 5.10-5.31 (m, 2H) 5.43 (dd, J=15.87, 8.55 Hz, 1H) 5.77-5.94 (m, 1H) 6.55-6.81 (m, 3H) 7.00-7.51 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[CH2:14]([C:16]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH:31]=O)[CH:17]=1)[CH3:15]>C1COCC1.O>[CH2:14]([C:16]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18](/[CH:31]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])[CH:17]=1)[CH3:15]
Reactant: CCOC(=O)c1c(C=O)cc(CC)cc1C(F)(F)F
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(/C=C/C(=O)OC)cc(CC)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a solution of trimethyl phosphonoacetate (1.60 mL, 9.90 mmol) in 100 mL of THF was added sodium hydride (0.24 g of 60% dispersion in mineral oil, 9.90 mmol) portionwise. The mixture was stirred at ambient temperature for 30 min and then ethyl 4-ethyl-2-formyl-6-(trifluoromethyl)benzoate (1.81 g, 6.60 mmol) as a solution in THF. The reaction mixture was allowed to stir at ambient temperature for 30 min and then was diluted with water. The mixture was extracted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 15% EtOAc/hexane) to afford 2.1 g (96%) of the title compound as an off-white solid. 1H NMR (CDCl3): δ 7.72 (d, 1H, J=15.9 Hz), 7.62 (s, 1H), 7.53 (s, 1H), 6.44 (d, 1H, J=15.9 Hz), 4.45 (q, 2H, J=7.2 Hz), 3.81 (s, 3H), 2.75 (q, 2H, J=7.6 Hz), 1.40 (t, 3H, J=7.2 Hz), 1.28 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:46][C:47]([F:52])([F:51])[CH2:48][CH2:49][NH2:50]>C(#N)C>[F:46][C:47]([F:52])([F:51])[CH2:48][CH2:49][NH:50][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: NCCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NCCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25 %

Procedure:
5-(methoxycarbonyl)pyridine-2-carboxylic acid (100 mg, 0.55 mmol) was dissolved in acetonitrile (1 mL). Triethylamine (0.230 mL, 1.66 mmol) and O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (314 mg, 0.83 mmol) were added. The reaction mixture was stirred at rt for 5 min. 3,3,3-trifluoropropylamine hydrochloride (83 mg, 0.55 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the crude was pardoned between ethyl acetate and 1M sodium hydroxide. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude was purified by column chromatography using a gradient of ethyl acetate in heptane yielded 38 mg (25%) of the title compound as a white solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (t, 1 H), 9.11 (d, 1 H), 8.48 (dd, 1 H), 8.18 (d, 1 H), 3.92 (s, 3 H), 3.53-3.60 (m, 2 H), 2.54-2.66 (m, 2 H); MS (ESI) m/z 277[M+H+], m/z 275[M−H+];
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[C:45]([F:46])=[CH:44][C:43]([F:47])=[C:42]2[C:37]=1[CH:38]=[C:39](OS(C(F)(F)F)(=O)=O)[N:40]=[CH:41]2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:39]4[N:40]=[CH:41][C:42]5[C:37]([CH:38]=4)=[C:36]([Cl:35])[C:45]([F:46])=[CH:44][C:43]=5[F:47])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Oc1cc2c(Cl)c(F)cc(F)c2cn1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5c(Cl)c(F)cc(F)c5cn4)c3)cn2)CC1
Temperature: 100 °C

Procedure:
To a solution of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (18.3 mg, 0.0391 mmol), trifluoromethanesulfonic acid 5-chloro-6,8-difluoroisoquinolin-3-yl ester (0.0326 mmol), and Pd(PPh3)4 (2.51 mg, 0.00215 mmol) in 1,4-dioxane (0.90 ml) in a sealable microwave tube was added a solution of Cs2CO3 (21.4 mg, 0.0651 mmol) in H2O (0.30 ml). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 100° C. for 30 min. The reaction mixture was diluted with EtOAc (40 ml), washed with water (2×20 ml) and brine (20 ml), and dried over MgSO4. After concentration in vacuo, a brown oil was obtained. It was then purified by prep. TLC eluting with 4% MeOH/CH2Cl2 to give the title compound as a brown oil. 1H NMR (400 MHz, CDCl3): δ=1.49 (s, 9H), 1.94-2.05 (m, 2H), 2.16-2.24 (m, 2H), 2.87-2.98 (m, 2H), 4.24-4.38 (m, 3H), 6.45 (brs, 2H), 7.18 (t, J=9.6 Hz, 1H), 7.68 (d, J=0.8 Hz, 1H), 7.79 (d, J=0.8 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.34 (m, 1H), 9.53 (d, J=1.2 Hz, 1H). MS(ES+): m/z=540.92/542.87 (100/86) [MH+]. HPLC: tR=3.15 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].CI.[C:16]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:16])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(C#N)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a stirred solution of methyl 3-cyano-4-hydroxybenzoate (2.0 g, 11.20 mmol) in DMF (20 mL) were added CH3I (2.40 g, 16.01 mmol) and K2CO3 (2.30 g, 16.01 mmol) at 0° c. under a N2 atmosphere. The reaction mixture was stirred at 80° C. for 2 h. After completion of starting material (monitored by TLC), reaction mixture was diluted with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (2×50 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation in vacuo, the crude material was purified by silica gel column chromatography to afford methyl 3-cyano-4-methoxybenzoate (1.1 g, 52%), as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)([CH3:10])[CH2:7][C:6]=2[CH:24]=1.C(O)(C(F)(F)F)=O.FC1C2OC(C3(O)CCN(C4N=CC(CCC)=CN=4)CC3)CC=2C=C(C2CCNCC=2)C=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)([CH3:10])[CH2:7][C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(Br)ccc3O2)CC1
Agent: CCCc1cnc(N2CCC(O)(C3Cc4cc(C5=CCNCC5)cc(F)c4O3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C2CCNCC2)Cc2cc(Br)ccc2O1

Procedure:
Compound 11D was prepared from Compound 11C and TFA in a similar manner to the procedure described for Compound 1J in Example 1. LC/MS (m/z)=296 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([Cl:30])=[CH:18][C:17]=1[C:31]1[O:35][N:34]=[C:33]([C:36]([O:38]CC)=O)[CH:32]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.CCOC(C)=O>CCO>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([Cl:30])=[CH:18][C:17]=1[C:31]1[O:35][N:34]=[C:33]([C:36]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:38])[CH:32]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CN1CCN(C(=O)c2cc(-c3cc(Cl)c(OCc4ccccc4)cc3OCc3ccccc3)on2)CC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
N-methylpiperazine (25.4 mmol) was added to a suspension of ethyl 5-(2,4-bis(benzyloxy)-5-chlorophenyl)isoxazole-3-carboxylate (2.1 mmol) in EtOH (5 ml) and the reaction mixture was heated to 90° C. under stirring for 18 h. The reaction mixture was poured into a mixture of water (15 ml) and AcOEt (30 ml). After standard extraction, the organic layer was washed with water and brine, dried over Na2SO4, and evaporated. The resulting solid was purified by silica gel column chromatography (CHCl3/MeOH: 95/0.5) to give the desired compound (620 mg, 57%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:14][C:15](=[O:19])[NH:16][CH2:17][CH3:18])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:14][C:15]([NH:16][CH2:17][CH3:18])=[O:19])=[CH:22][CH:23]=1
Reactant: CCNC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(4-chloro-benzyl)-ethylcarbamoylmethyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.31 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%) The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI-MS m/z: 296 (M+1), UV retention time: 1.02 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[S:10].[H-].[Na+].Cl[C:14]1[S:15][C:16]([CH:19]=[O:20])=[CH:17][N:18]=1>O1CCCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:14]1[S:15][C:16]([CH:19]=[O:20])=[CH:17][N:18]=1
Reactant: S=c1[nH]c2ccccc2[nH]1
Reactant: O=Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cnc(Sc2nc3ccccc3[nH]2)s1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
1,3-Dihydro-benzimidazole-2-thione (1.0 g, 6.66 mmol) is suspended into 50 mL of tetrahydrofuran under argon. Then, 479 mg (9.99 mmol) of sodium hydride is added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 2-Chloro-1,3-thiazole-5-carbaldehyde (983 mg, 6.66 mmol) is then added and the reaction mixture is stirred at room temperature for 2 h, upon which it is filtered. The solid is washed with tetrahydrofuran and dried under reduced pressure. The residue is diluted with water and extracted twice with ethyl acetate and once with dichloromethane. The organic extracts are combined, dried on magnesium sulfate, filtered and concentrated under reduced pressure. 1.23 g of 2-(1H-benzimidazol-2-ylsulfanyl)-thiazole-5-carbaldehyde is obtained as a pale yellow powder. mp: 188° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11]CC)=O)=[C:6]([Cl:14])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.O.CN(C=O)C>[Cl:14][C:6]1[C:7]2[CH2:8][C:9](=[O:11])[N:29]([CH2:28][C:27]3[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:26]=3[O:25][CH3:24])[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: CCOC(=O)Cc1c(Cl)ncnc1Cl
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)Cc3c(Cl)ncnc32)c(OC)c1
Temperature: 26.5 °C
Yield: 77.9 %

Procedure:
Charge 175 L of DMF and ethyl 2-(4,6-dichloropyrimidin-5-yl)acetate (25 kg) into a reactor at RT. Charge 17.55 Kg of DIPEA into the reactor over a period of 5-10 minutes while maintaining the temperature at 25-28° C. Cool the contents of the reactor to 10-15° C. and stir the reaction for 5-10 minutes. Charge 20.8 Kg of 2,4-Dimethoxybenzylamine into the reactor by while maintaining the temperature at 10-15° C. Heat the reaction slowly to a temperature of 60-65° C. and stir 3 hours. Cool the reaction slowly to 25-28° C. and add 250 L of water into the reactor while maintaining the temperature at 10-15° C. Stir the reaction mass for 10-15 minutes then heat the reaction to 25-28° C. Charge 125 L of DCM into the reaction, stir for 15 minutes and separate the layers. Wash the aqueous layer with 75 L of DCM. Wash the combined organic layers with 75 L of 1N HCl solution followed by water (100 L) and finally with 15% brine (100 L). Distill the organic layer under vacuum at 45-50° C. Charge 50 L of Hexane into the reaction at 45-50° C. and distill the reaction under vacuum at 45-50° C. (2×). Cool the reaction to 0-5° C. and stir for 30 minutes. Filter the resulting solid and wash the wet cake with 50 L of chilled n-Hexane (0-5° C.). Dry the resulting solids under vacuum at 40-45° C. Charge toluene (375 L) the dried solids and 1.025 Kg of para-Toluene to a reactor. Heat the reaction to 85-90° C. for 2 h. Cool the reaction to 80-85° C. and adjust the pH to 6.5-7.0 by adding 10% Sodium bicarbonate solution. Distill the reaction under vacuum at 45-50° C. Cool the contents of the reactor to 25-28° C., charge 3×L of Toluene into the reaction and heat to 85-90° C. Stir for 1 hour then cool the contents of the reactor to 25-28° C. Further cool to 0-5° C. and filter the solids. Wash the wet cake with 75 L of chilled Toluene (0-5° C.). Slurry the solids with 75 L of chilled water (0-5° C.) and filter. Wash the wet cake with 37.5 L of chilled water (0-5° C.) and dry the material under vacuum at 40-45° C. to afford 4-chloro-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (26.5 Kg, 73% yield, 98.89% purity by HPLC).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.Br[CH2:11][C:12]#[N:13]>>[N:1]1([CH2:11][C:12]#[N:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: N#CCBr
Product: N#CCn1cnc2ccccc21

Procedure:
The title compound is synthesized by coupling of Benzimidazole and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless solid; ES-MS: M+H=158.0: CtRet=3.42.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]1[C@H:24]2[C@H:19]([CH2:20][CH2:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)[NH:18][CH2:17][CH2:16]1.[C:29]1([C:35]2[CH:48]=[CH:47][C:38]([C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH:45]=O)=[O:40])=[CH:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ClCCl>C(O)(=O)C.ClCCCl>[C:29]1([C:35]2[CH:36]=[CH:37][C:38]([C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][N:18]3[C@@H:19]4[C@@H:24]([C:23]5[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=5[CH2:21][CH2:20]4)[CH2:15][CH2:16][CH2:17]3)=[O:40])=[CH:47][CH:48]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(NCCCCN1CCC[C@@H]2c3ccccc3CC[C@@H]21)c1ccc(-c2ccccc2)cc1
Reaction time: 16 h
Yield: 68.4 %

Procedure:
Sodium triacetoxyborohydride (170 mg, 0.8 mmol) was added to a stirred mixture of cis-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (D8b, 100 mg, 0.5 mmol), 4-(4-phenylbenzoylamino)butyraldehyde (143, 0.54 mmol) and acetic acid (1 drop) in 1,2-dichloroethane (8 ml) at room temperature. After stirring for 16 h, dichloromethane (10 ml) was added and the mixture was then washed with saturated aqueous K2CO3 (2×20 ml) and brine (20 ml). Drying (Na2SO4) and evaporation in vacuo afforded an oil which was purified by preparative TLC on Kieselgel using 10% methanol-ethyl acetate as eluent to give the title compound as a gum (150 mg, 68%). Mass spectrum: found M+ 438.2679; C30H34N2O requires 438.2671.
Reaction SMILES: N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.[OH-].[K+].[Br:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.[CH3:27][CH:28]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][CH2:30]Cl>C(O)C>[CH3:27][CH:28]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][CH2:30][O:26][C:22]1[CH:21]=[C:20]([Br:19])[CH:25]=[CH:24][CH:23]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)CCCC(C)CCCl
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCCC(C)CCOc1cccc(Br)c1
Temperature: 32.5 °C
Reaction time: 2 h

Procedure:
450 ml of ethanol were initially introduced, and Nal (10.5 g; 70 mmol) and KOH (67.3 g; 1.2 mol) were added. A temperature increase from 25 to 40° C. after addition of the KOH was observed. After the mixture had been cooled to room temperate, 3-bromophenol (176.5 g; 1 mol) was added, during which the white suspension became beige. 3,7-Dimethyloctyl chloride (186.32 g; 212.94 ml; 1.05 mol) was added over the course of 3 minutes via a dropping funnel. The mixture was stirred at RT for a further 2 hours and subsequently stirred at an internal temperature of 80° C. for 96 hours. Ethanol was distilled off. The residue was taken up in ethyl acetate, and the precipitate was separated off by filtration. The organic phase was extracted three times with 10% strength by weight aqueous NaOH solution and washed once with H2O, three times with H2O which had been acidified using CO2 and again with H2O. After the mixture had been dried using MgSO4, the solvent was stripped off again in a rotary evaporator, and the crude product was purified by fractional distillation under reduced pressure.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[CH:15]=[CH:14][C:9]=2[C:10]=1[CH:11]([CH3:13])[CH3:12])=[O:5])C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:11]([C:10]1[C:9]2[CH:14]=[CH:15][C:16]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:26])[CH3:27])[CH2:21][CH2:20]3)=[CH:17][C:8]=2[O:7][C:6]=1[C:4]([OH:5])=[O:3])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1oc2cc(OC3CCN(C(C)C)CC3)ccc2c1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1c(C(=O)O)oc2cc(OC3CCN(C(C)C)CC3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 150.4 %

Procedure:
The above prepared 3-isopropyl-6-(1-isopropyl-piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester (0.720 g, 1.54 mmol, corrected for purity) was dissolved in 4 mL of THF/ethanol=1/1 and treated with 0.771 mL of aq. NaOH (3M, 1.5 eq.). The mixture was stirred for 3 h at ambient temperature and was then neutralized by adding 1.16 mL of 2M HCl (1.5 eq.). Careful evaporation of all solvents and drying afforded then 0.800 g of the title compound as light yellow foam contaminated with innocouos inorganic salts.