Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][NH:7][C:6](=O)[C:5]=2[CH:4]=[CH:3]1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:5]2[CH:4]=[CH:3][N:2]([CH3:1])[C:10]=2[C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][N:7]=1
Reactant: COC(=O)c1c[nH]c(=O)c2ccn(C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cnc(Cl)c2ccn(C)c12
Reaction time: 0.83 h

Procedure:
A suspension of methyl 1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (47.4 g) in phosphorus oxychloride (64.4 ml) was heated to reflux and stirred for 50 minutes then allowed to cool. The phosphorus oxychloride was removed in vacuo and the residue partitioned between dichloromethane (600 ml) and saturated sodium carbonate (600 ml). The aqueous layer was separated and further extracted with dichloromethane (600 ml). The organic layers were combined, dried (MgSO4) and the solvent removed. The residue was purified by column chromatography on a Biotage silica column (800 g) eluting with dichloromethane to yield the title compound as a white solid (42.7 g).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].O1CCCC1.C(N(CC)CC)C.[CH2:40]([NH:58]CCCCCCCCCCCCCCCCCC)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>>[CH2:40]([NH:58][C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH:8]1[C:12]2([CH3:27])[CH:11]([CH:16]3[CH:15]([CH2:14][CH2:13]2)[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([OH:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Yield: 172.2 %

Procedure:
Lithocholic acid (81) (9.78 g, 26 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) Isobutylchloroformate (3.55 g, 3.55 mL, 26 mmol) was added followed by the addition of triethylamine (5.26 g, 7.25 mL, 52 mmol) and dioctadecylamine (7 g, 26 g). The reaction mixture was brought to ambient temperature and allowed to stir over night. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (250 mL) The organic layer was washed with 5% sodium bicarbonate, 3% aqueous HCl and water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to afford amide 88 (14.5 g) in 89% yield. This was used as such for the next step.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:5]=1[CH:22]=[C:23]([C:29]#[N:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>C(O)C>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:5]=1[CH:22]1[O:1][C:23]1([C:29]#[N:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: OO
Reactant: CCOC(=O)C(C#N)=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C#N)OC1c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl

Procedure:
1.4 g (12 mmol) of 30% strength aqueous hydrogen peroxide solution were added to 2.7 g (6 mmol) of ethyl 3-(2,4-dichloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)Phenyl)-2-cyanopropenoate in 30 ml of ethanol. After 12 hours the mixture was poured into water. The product was extracted from the aqueous phase using ethyl acetate, after which the organic phase was dried over magnesium sulfate and then concentrated. Purification of the crude product was carried out by means of column chromatography on silica gel (eluent: hexane/ethyl acetate=4:1). Yield: 1 g.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH:9]([OH:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:16](C)=O.[Na+].C(O)(=O)C>ClCCCl.C(OCC)(=O)C.[OH-].[Na+]>[CH:1]1([N:7]([CH3:16])[CH2:8][CH:9]([OH:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(O)CNC1CCCCC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(O)CN(C)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(cyclohexylamino)-propan-2-ol (crude 2.6 g) in DCE (30 mL) were added successively HCHO (35% in water, 2.1 mL, 24.8 mmol), Na(OAc)3BH (10.5 g, 49.6 mmol) and acetic acid (1 mL) at ice-cold conditions. The resulting mixture was allowed to stir at rt for 16 hours. The reaction was diluted with ethyl acetate and basified with 1N NaOH. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography on silica-gel (230-400 mesh) eluting with 5% MeOH/DCM to provide 1-(cyclohexyl(methyl)amino)propan-2-ol. Yield: 1.0 g
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=[O:31])[C:28](Cl)=[O:29].[CH2:33]([OH:35])[CH3:34]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([C:27](=[O:31])[C:28]([O:35][CH2:33][CH3:34])=[O:29])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: FC(F)(F)c1ccc(-c2ccc3ccn(Cc4ccccc4)c3c2)cc1
Reactant: CCO
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3ccc(C(F)(F)F)cc3)ccc12
Yield: 62 %

Procedure:
Following the procedure described in Step 3 of Example 1, ethyl 2-[1-benzyl-6-(4-trifluoromethyl)-1H-indol-3-yl]-2-oxoacetate was prepared from 1-benzyl-6-[4-(trifluoromethyl)phenyl]-1H-indole (0.392 g, 1.12 mmol), oxalyl chloride (0.11 mL, 1.2 mmol), and ethanol (1.4 mL). Purification by flash chromatography using 5-10% ethyl acetate in hexane as an eluant followed by trituration with hexane yielded the title compound as a light yellow solid (0.314 g, 62%), mp: 109-110° C. Mass spectrum (+APCI, [M+H]+) m/z 452; 1HNMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.25 (d, 1H, J=8.3 Hz), 8.05 (d, 1H, J=0.98 Hz), 7.95 (d, 2H, J=8.1 Hz), 7.8 (d, 2H, J=8.3 Hz), 7.7 (dd, 1H, J=8.3 Hz and 1.5 Hz), 7.25-7.35 (m, 5H), 5.7 (s, 2H), 4.35 (q, 2H, J=7.2 Hz), and 1.35 ppm (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:13]#N)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][Mg]Cl)=[CH:18][CH:17]=1.ClC1C=CC(CCl)=CC=1.[Mg].CC[O:37]CC>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][C:13]([C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:12][CH2:11][CH2:10]2)=[O:37])=[CH:18][CH:17]=1
Reactant: Cl[Mg]Cc1ccc(Cl)cc1
Reactant: CCOCC
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: ClCc1ccc(Cl)cc1
Agent: [Mg]
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(Cl)cc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile (6.56 g) in toluene (100 ml) was added dropwise under nitrogen to a stirred solution of 4-chlorobenzylmagnesium chloride [prepared in the usual manner from 4-chlorobenzyl chloride (9.07) and magnesium (1.08 g)] in ether (100 ml). When the addition was complete, ether was distilled from the mixture until the internal temperature rose to 95° C., then the mixture was stirred at this temperature for 19 h, cooled to ambient temperature, and quenched by the dropwise addition of water (50 ml) followed by concentrated hydrochloric acid (10 ml). The mixture was stirred at 95° C. for 3 hours, then it was cooled to ambient temperature. The organic phase was separated, washed with water (100 ml) and saturated brine (100 ml), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified via flash chromatography over silica using 1:9-1:4 mixtures of ethyl acetate and petroleum ether (b.p. 60-80° C.) as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-(4-chlorophenyl)-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone as a yellow oil (7.51 g) which solidified slowly at ambient temperature to give a yellow solid, m.p. 82-84° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:16][CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:16][CH3:17])[CH:3]=1
Reactant: Oc1cncc(Br)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cncc(Br)c1
Yield: 54.2 %

Procedure:
A solution of 5-bromopyridin-3-ol (70 g, 402 mmol), K2CO3 (111 g, 805 mmol) and iodoethane (69.0 g, 443 mmol) in DMF (700 mL) was stirred for 16 h at 25° C. Then the mixture was concentrated to give the residue which was extracted with DCM (2×200 mL), dried over Na2SO4 and concentrated to give 3-bromo-5-ethoxypyridine (53 g, 218 mmol, 54.2% yield): 1H NMR (400 MHz, CD3OD) δ 8.19-8.17 (m, 2H), 7.60-7.59 (m, 1H), 4.13-4.07 (m, 2H), 1.40 (t, J=7.0 Hz, 3H); ES-LCMS m/z 202 (M+H).
Reaction SMILES: C(#N)C1C=CC=CC=1.ON1C(=O)C2=CC=CC=C2C1=O.[C:21]([OH:30])(=O)[CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=O>C1CCCCC1>[C:21]1(=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1.[CH:21]1([OH:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(O)CCCCC(=O)O
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: C1CCCCC1
Solvent: N#Cc1ccccc1
Product: O=C1CCCCC1
Product: OC1CCCCC1
Yield: 10 %
Yield: 0.8 %

Procedure:
To 10 ml of benzonitrile were added 10 mmol of cyclohexane, 1 mmol of N-hydroxyphthalimide, 0.01 mmol of cobalt acetate Co(OAc)2, and 0.1 mmol of acetylacetonatochromium Cr(AA)3 and the resultant mixture was stirred under an oxygen atmosphere at a temperature of 75° C. for 16 hours. The products in the reaction mixture were analyzed by gas chromatography, and, as a result, cyclohexane was converted into cyclohexanone (yield 10%), cyclohexanol (yield 0.8%) and adipic acid (trace amount) with a conversion of 33%.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Br:8][CH2:9][C:10](Br)=[O:11]>O1CCCC1>[Br:8][CH2:9][C:10]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:11]
Reactant: O=C(Br)CBr
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.68 g×60%) was added to a stirred solution of methanesulfonamide (2.0 g) in dry tetrahydrofuran (20 ml) at room temperature. The resulting solution was stirred at room temperature for 1 h, at which time it was treated with a solution of bromoacetyl bromide (4.2 g) in dry tetrahydrofuran (10 ml). After 1 h the solvent was removed under reduced pressure and the residue taken up in water and acidified to pH3. The acidic solution was extracted into ethyl acetate, dried (MgSO4), filtered and the solvent removed under reduced pressure. Recrystallisation from isopropanol afforded the product as white needles: mp 112°-114° C.
Reaction SMILES: Br[CH:2]1[CH2:19][CH2:18][C:5]2=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH2:10][CH2:11][CH3:12])=[C:4]2[C:3]1=O.[C:21]([NH2:29])(=[S:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C>O>[C:22]1([C:21]2[S:28][C:2]3[CH2:19][CH2:18][C:5]4=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH2:10][CH2:11][CH3:12])=[C:4]4[C:3]=3[N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=S)c1ccccc1
Reactant: CCCSc1sc(C(=O)OCC)c2c1C(=O)C(Br)CC2
Solvent: O
Solvent: CCO
Product: CCCSc1sc(C(=O)OCC)c2c1-c1nc(-c3ccccc3)sc1CC2
Yield: 34.9 %

Procedure:
A mixture of ethyl 5-bromo-4,5,6,7-tetrahydro-4-oxo-3-propylthiobenzo[c]thiophene-1-carboxylate (9.43 g), thiobenzamide (6.86 g) and ethanol (190 ml) was refluxed under heating for 4 hours, after which it was poured over water (600 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:10, v/v) to yield ethyl 4,5-dihydro-2-phenyl-8-propylthiothieno[3,4-e]benzothiazole-6-carboxylate (3.63 g, 34.9%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 125-126° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)=[CH:4][CH:5]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(CN[C@H]2CC[C@H](O)CC2)cc1
Temperature: 80 °C

Procedure:
Methyl 4-(bromomethyl)benzoate (5.0 g, 22 mmol) was dissolved in DMF (50 mL) and trans-4-aminocyclohexanol (3.04 g, 26 mmol) was added followed by addition of potassium carbonate (6.08 g, 44 mmol). The reaction mixture was heated to 80° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and water (200 m) was added. The aqueous phase was extracted with ethyl acetate (100 mL), and the combined organic phases were washed with water (2×100 mL) and dried (MgSO4). The organic phase was concentrated in vacuo to give 2.5 g of trans-4-[(4-hydroxycyclohexylamino)methyl]benzoic acid methyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:23]=2[S:24][C:25]=1[CH2:26][CH3:27])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:28][C:23]=2[S:24][C:25]=1[CH2:26][CH3:27])=[O:20]
Reactant: CCc1sc2cc(O)ccc2c1C(=O)NC
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)NC
Yield: 56.7 %

Procedure:
This material was prepared by reacting 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (87 mg, 0.35 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide 134d (99 mg, 0.42 mmole) and Cs2CO3 (342 mg, 1.05 mmole) in a manner analogous to that described for example 1 to give a yellow solid (89 mg, 37%). 1H NMR (DMSO-d6, 300 MHz), δ 8.52 (1H, d, J=5.56 Hz), 8.33 (1H, m), 7.98 (1H, d, J=2.27 Hz), 7.89 (1H, s), 7.81 (1H, d, J=8.59 Hz), 7.40 (1H, s), 7.33 (1H, dd, J=2.27, 8.84 Hz), 7.02 (1H, s), 6.97 (1H, d, J=5.31 Hz), 3.98 (3H, s), 3.00 (2H, q, J=7.58 Hz), 2.83 (3H, d, J=4.80 Hz), 1.28 (3H, t, J=7.58 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:25]([O-])=O)=[C:6]([CH:24]=1)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=2[C:9]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:25][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=2[C:9]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(OC)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2cc(OC)ccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(5-fluoro-2-nitroanilino)-6-methoxybenzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-5-fluoroanilino)-6-methoxybenzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=[N:9]1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=[N:9]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccnn1-c1ccccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccnn1-c1ccccc1CBr
Temperature: 80 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
To a solution of methyl 1-[2-methylphenyl]pyrazole-5-carboxylate (1.00 g, 4.62 mmol) in 20 mL of carbon tetrachloride was added N-bromosuccinimide (0.823 g, 4.62 mmol) and AIBN (76 mg, 0.46 mmol). This mixture was stirred at 80° C. for 18 h. The volatiles were removed and the residue was taken up in ether, filtered through a pad of silica gel and concentrated to afford 1.3 g (95%) of the title compound which was used without further purification. LRMS (ES+): 295.0/297.0 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.O[CH2:13]/[CH:14]=[C:15](/[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])\[CH3:16]>ClCCl.[Cl-].[Na+].O>[Cl:1][CH2:13]/[CH:14]=[C:15](/[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])\[CH3:16]
Reactant: C/C(=C\CO)c1cccc(C#N)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CSC
Product: C/C(=C\CCl)c1cccc(C#N)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-chlorosuccinimide (9.8 g, 73.1 mmol) in dichloromethane (25 ml) at −10° C. was added dropwise over 15 minutes dimethylsulfide (5.4 ml, 73.1 mmol). The mixture was stirred at −10° C. for 30 min, then a solution of 3-[(E)-3-hydroxy-1-methyl-1-propenyl]benzonitrile (from Preparation 33, 11.9 g, 69.6 mmol) in dichloromethane (20 ml) was added dropwise over 15 minutes at −10° C. The mixture was stirred at 0° C. for 1 h, and was then poured onto saturated brine (50 ml). The layers were separated, and the aqueous layer was extracted with diethyl ether (2×50 ml). The extracts were combined, washed with water (50 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude pale yellow oil (13.1 g, 100%) was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:38])[CH2:34][C:35](O)=[O:36])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:38])[CH2:34][C:35]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:16]4[CH:15]=[CH:14][N:13]=[C:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:11]=4[CH:10]=[CH:9]3)=[CH:4][CH:3]=2)=[O:36])=[CH:30][CH:31]=1
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)Nc1nccc2c1ccn2-c1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1nccc2c1ccn2-c1ccc(NC(=O)CC(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56524596 %

Procedure:
A solution of tert-butyl 1-(4-aminophenyl)-1H-pyrrolo[3,2-c]pyridin-4-ylcarbamate (27 mg, 0.083 mmol, Compound B of Example 1) in DMF (1 mL) was treated with 3-(4-fluorophenylamino)-3-oxopropanoic acid (25 mg, 0.13 nmol), DIPEA (21 μL, 0.13 mmol) and TBTU (40 mg, 0.13 mmol) and the mixture stirred at RT for 16 h. The mixture was concentrated in vacuo to remove the DMF and the residue was partitioned between EtOAc (2 mL) and saturated sodium bicarbonate solution (2 mL). The EtOAc phase was washed with 10% aqueous LiCl (2 mL), brine (2 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified using a Chromatotron (1 mm SiO2 GF rotor, 2-5% MeOH-CHCl3 gradient elution) to give the title compound (37 mg, 88%) as an off-white solid. LCMS (ESI+) m/z 504 (M+H)+; HPLC tR=3.49 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:14]2[CH:18]=[N:17][N:16]=[C:15]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]2=[O:37])[CH2:27][CH2:26]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:14]2[CH:18]=[N:17][N:16]=[C:15]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:11][N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[CH2:36][CH2:35][CH2:34][NH:33][C:32]3=[O:37])[CH2:27][CH2:26]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CCC(Cn1cnnc1-c1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NCCCN1C1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cl
Product: O=C1NCCCN1C1CCN(CCC(Cn2cnnc2-c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.67 h
Yield: 159.7 %

Procedure:
3-(3,4-Dichlorophenyl)-4-(2-phenyl-1,3,4-triazol-1-yl)butyraldehyde (0.80 g) in methanol (4 mL) was added to a solution of 1-(piperidin-4-yl)tetrahydropyrimidin-2-one (0.408 g) and acetic acid (0.13 mL) in methanol (4 mL). After 40 minutes, sodium cyanoborohydride (0.140 g) in methanol (4 mL) was added in a single portion. After being stirred overnight, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (gradient 95:5, 70:30) as eluent. The purified material was dissolved in dichloromethane, precipitated out as the hydrochloride salt with ethereal hydrogen chloride, evaporated, and placed under high vacuum overnight to give the title compound as a white solid (1.0 g); NMR (CD3OD): 9.55 (s,1), 7.74 (m,1), 7.62 (m,2), 7.42 (m,2), 7.29 (d,1, J=8.3), 7.16 (d,1, J=2.1), 6.89 (dd,1, J=2.1, 8.3), 4.83 (dd,1, J=4.7, 14.3), 4.64 (dd,1, J=10.2, 14.2), 4.36 (m,1), 3.60 (m,2), 3.26 (m,5), 3.03 (m,3), 2.75 (m,1), 2.22 (m,4), 1.91 (m,4); MS: m/z=527(M+1). Analysis for C27H32Cl2N6O·4.20HCl·0.20 Et2O: Calculated: C, 48.01; H, 5.53; N, 12.08; Found: C, 48.09; H, 5.64; N, 12.06.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[N:4]([CH3:8])[N:5]=[CH:6][CH:7]=1.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=1)[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Cl.FC(F)(F)C1C=CC=C[C:31]=1[O:32]C1CCNCC1>>[CH3:8][N:4]1[C:3](=[O:9])[C:2]([NH:1][C:31]([N:19]2[CH2:18][CH2:17][CH:16]([O:15][C:14]3[CH:13]=[C:12]([C:11]([F:10])([F:25])[F:26])[CH:24]=[CH:23][CH:22]=3)[CH2:21][CH2:20]2)=[O:32])=[CH:7][CH:6]=[N:5]1
Reactant: Cn1nccc(N)c1=O
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: FC(F)(F)c1cccc(OC2CCNCC2)c1
Agent: Cl
Product: Cn1nccc(NC(=O)N2CCC(Oc3cccc(C(F)(F)F)c3)CC2)c1=O
Yield: 36 %

Procedure:
Compound 58 is prepared from intermediate 4c and from 4-(3-trifluoromethyl-phenoxy)-piperidine (obtained following the method described for intermediate 1a), applying synthesis method 7 (yield: 36%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:21])[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16]C)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([O:5][C:6]([N:8]([CH3:21])[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([OH:16])=[O:15])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1cccc(CCN(C)C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(CCc1cccc(C(=O)O)c1)C(=O)OC(C)(C)C
Temperature: 22 °C
Reaction time: 2 h

Procedure:
To a solution of 0.580 g (1.98 mmol) of methyl 3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate in 5 mL of dioxane was added 10 mL of 1 N NaOH. The mixture was stirred at 22° C. for 2 h and then acidified to ca. pH 1 with 1 N HCl. The mixture was then extracted with DCM (4×25 mL), dried (Na2SO4) and evaporated to give 3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoic acid as a foamy white solid which was subsequently used without purification.