Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]([F:22])([F:21])[F:20])[C:8]([CH2:23]O)=[CH:7]2.C(Cl)(Cl)[Cl:26].S(Cl)(Cl)=O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]([F:22])([F:21])[F:20])[C:8]([CH2:23][Cl:26])=[CH:7]2
Reactant: OCc1cc2cccc(Cl)c2nc1-c1ccccc1OC(F)(F)F
Reactant: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cl
Product: FC(F)(F)Oc1ccccc1-c1nc2c(Cl)cccc2cc1CCl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of (8-chloro-2-(2-(trifluoromethoxy)phenyl)quinolin-3-yl)methanol (0.5470 g, 1.546 mmol) in chloroform (5.155 mL, 1.546 mmol) was treated with thionyl chloride (0.5626 mL, 7.732 mmol) dropwise, and the reaction mixture was stirred at room temperature. After 2.5 h, the mixture was concentrated under reduced pressure and co-evaporated three times with CH2Cl2 to give 8-chloro-3-(chloromethyl)-2-(2-(trifluoromethoxy)phenyl)quinoline hydrochloride as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1 H, s), 8.10 (1 H, dd, J=8.2, 1.2 Hz), 8.03 (1 H, dd, J=7.5, 1.3 Hz), 7.64-7.74 (3 H, m), 7.53-7.63 (2 H, m), 4.75 (2 H, br. s.), 89676-3-1-1H-NMR; LC-MS (ESI) m/z 372.0 [M+H]+ (Exact Mass of neutal form: 371.009). The yellow syrup was carried on crude without purification for the next step.
Reaction SMILES: CC1C=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[C:9](=[O:13])[CH:10]([CH3:12])C)=CC=1.[Li][CH2:22]CCC.Cl[P:27]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH:28]1([P:27]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:8]2[CH:5]=[CH:6][CH:12]=[CH:10][C:9]=2[O:13][CH3:22])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: [Li]CCCC
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: Cc1ccc(C(C(=O)C(C)C)c2ccc(C)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.4 %

Procedure:
A solution of 1 (535 mg, 2.03 mmol) in THF (20 mL) was cooled to −78° C. under argon, then n-BuLi (1.6 M in hexane, 1.35 mL, 2.16 mmol) was added dropwise. After 2.5 h at −78° C., a solution of chlorodicyclohexylphosphine (570 mg, 2.45 mmol) in THF (3 mL) was added over 10 min. The reaction mixture was then allowed to warm to room temperature overnight, then quenched with saturated aqueous NaHCO3 and concentrated in vacuo. The resulting aqueous suspension was extracted with ether (2×50 mL), and the combined ethereal layers were dried (Na2SO4), filtered and concentrated in vacuo. The resulting crude solid was recrystallized from ethanol to afford 420 mg (54%) of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:56][O:57][CH:58]1[CH2:63][CH2:62][N:61]([CH2:64][C:65]2[CH:73]=[CH:72][C:68]([CH2:69][NH:70][CH3:71])=[CH:67][CH:66]=2)[CH2:60][CH2:59]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:70]([CH2:69][C:68]3[CH:67]=[CH:66][C:65]([CH2:64][N:61]4[CH2:62][CH2:63][CH:58]([O:57][CH3:56])[CH2:59][CH2:60]4)=[CH:73][CH:72]=3)[CH3:71])=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc(CN2CCC(OC)CC2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(OC)CC4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-furan-3-carboxylic acid (35 mg, 0.10 mmol), EDCI (26 mg, 0.13 mmol), HOBt (20 mg, 0.15 mmol), DIPEA (0.04 mL, 0.20 mmol), [4-(4-methoxy-piperidin-1-ylmethyl)-benzyl]-methyl-amine hydrochloride (32 mg, 0.10 mmol) and DCM (10 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.[Br:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][N:13]1[C:14](=[O:16])[C:15]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][CH:31]=3)[C:8]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=3)=[N:9][C:10]=2[N:11]([CH3:18])[C:12]1=[O:17]
Reactant: BrCCOCCBr
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCOCCBr)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 62.3 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (120 mg, 0.26 mmol, intermediate 9) in DMF (3 mL) was added 1-bromo-2-(2-bromoethoxy)ethane (77 mg, 0.33 mmol), potassium carbonate (71 mg, 0.51 mmol). The reaction was heated at 60° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give crude product (100 mg, 70% of purity by HPLC), which was used without purification. LCMS retention time 2.054 min; LCMS MH+ 617
Reaction SMILES: Cl.C(O[C:5]([C:7]1([CH3:26])[C:24]2[C:10](=[CH:11][C:12]3[NH:16][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[N:14][C:13]=3[CH:23]=2)[NH:9][C:8]1=[O:25])=[O:6])C.C(O)C.O.[NH2:31][NH2:32]>CO>[NH:31]([C:5]([C:7]1([CH3:26])[C:24]2[C:10](=[CH:11][C:12]3[NH:16][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[N:14][C:13]=3[CH:23]=2)[NH:9][C:8]1=[O:25])=[O:6])[NH2:32]
Reactant: NN
Reactant: CCOC(=O)C1(C)C(=O)Nc2cc3[nH]c(-c4ccncc4)nc3cc21
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC1(C(=O)NN)C(=O)Nc2cc3[nH]c(-c4ccncc4)nc3cc21

Procedure:
A solution of 1 g. (2.7 mmol) 7-ethoxycarbonyl-7-methyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one hydrochloride in 30 ml. ethanol is stirred at 80° C. for about 8 hours with 6 ml. hydrazine hydrate. Subsequently, the reaction mixture is filtered with suction, the product obtained is boiled up with a solution of 1000 ml. methanol and 500 ml. methylene chloride, concentrated somewhat and the crystals obtained are filtered off with suction, washed with methanol and dried. Yield: 0.6 g. (70% of theory); m.p.>300° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH3:10].[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.O>O1CCCC1.BrC1C=CC=CC=1SC.II>[CH3:10][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[B:11]([OH:16])[OH:12]
Reactant: CSc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccccc1B(O)O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Magnesium (9.52 g) was suspended in 119 mL of tetrahydrofuran, and to the suspension were added 3.00 g of 2-bromothioanisole and about 20 mg of iodine. After the reaction was started by heating employing a dryer, 72 g of 2-bromothioanisole was dropped to the mixture during 20minutes. After being heated for 1 hour, the reaction mixture was diluted with 1000 mL of tetrahydrofuran, and cooled to 0° C. To the mixture was added 102 mL of triisopropyl borate at the same temperature, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the solvent was removed under reduced pressure. The residue was added 500 mL of 2 mol/L hydrochloric acid, and the mixture was extracted with 300 mL of diethyl ether. The organic layer was extracted with 500 mL of 2 mol/L aqueous sodium hydroxide solution, and the aqueous layer was acidified by addition of concentrated hydrochloric acid under ice-cooling. The residual diethyl ether was removed under reduced pressure, and the precipitate was collected by filtration to give 45.95 g of 2-(methylthio)-phenylboronic acid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9][CH:10]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:4][C:3]=1[CH3:27].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH2:47]([O:49][C:50](=[O:54])[CH2:51][CH2:52][NH2:53])[CH3:48]>ClCCl.O>[CH2:47]([O:49][C:50](=[O:54])[CH2:51][CH2:52][NH:53][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([CH:10]([S:9][C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:27])[CH:4]=2)[CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:15])[F:16])=[CH:19][CH:20]=1)[CH3:48]
Reactant: Cc1cc(SC(CCCC(F)(F)F)c2ccc(C(=O)O)cc2)cc(C)c1Br
Reactant: CCOC(=O)CCN
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Racemic 4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-benzoic acid (0.190 g, 0.410 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.0747 g, 0.430 mmol) and 4-methylmorpholine (0.050 mL, 0.430 mmol) are combined in anhydrous dichloromethane (2.0 mL) under nitrogen. The reaction is allowed to stir under nitrogen at room temperature overnight. The beta alanine ethyl ester hydrochloride (0.0695 g, 0.450 mmol) and 4-methylmorpholine (0.100 mL, 0.860 mmol) is added to the reaction mixture and allowed to stir at room temperature. Some water (<10% volume) is added to help solubility. The reaction is monitored by HPLC, and upon complete consumption of the acid, the reaction is diluted with dichloromethane. The reaction is diluted with water and rinsed with 1N hydrochloric acid. Upon acidification, the two layers are separated. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and concentrated. Flash column chromatography gave the title compound (0.200 g, 0.360 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.[CH3:22]CN(C(C)C)C(C)C.CI>CN(C=O)C.C(OCC)(=O)C.Cl>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]2[O:1][C:2]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:11]=2)=[CH:15][CH:14]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]2[O:18][C:2]3[C:3](=[C:4]([C:5]([O:7][CH3:22])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:11]=2)=[CH:15][CH:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2oc(-c3ccc(Cl)cc3)nc12
Product: O=C(O)c1cccc2oc(-c3ccc(Cl)cc3)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
2-(4-Chlorophenyl)benzoxazole-4-carboxylic acid was prepared from 3-hydroxyanthranilic acid and 4-chlorobenzoyl chloride using the method described in Step A of Example 1. This crude material (2.90 g, 10.6 mmol) was directly dissolved in DMF (40 mL), DIPEA (5.46 g, 42.4 mmol) and methyl iodide (5.93 g, 42.4 mmol) added and the reaction stirred at room temperature for 18 h. After this time the reaction was diluted with ethyl acetate (100 mL) and 2 N HCl (50 mL). The organic layer was separated and then washed with 2 N HCl (25 mL), water (50 mL) and brine (50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated to dryness to yield light yellow oil. This material was purified using silica gel chromatography to afford 0.532 g (30% yield) of methyl 2-(4-chlorophenyl)benzoxazole-4-carboxylate as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.28 (dd, J=6.9, 1.8 Hz, 2H), 8.04 (d, J=8.1 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.43 (t, J=7.8 Hz, 1H), 4.06 (s, 3H); MS (ESI) m/z 288 [M+H]+
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH:11]([N:13]1[CH:16]([S:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][C:14]1=[O:37])O)([OH:10])=[O:9].S(Cl)([Cl:40])=O>C(Cl)Cl>[C:8]([CH:11]([N:13]1[CH:16]([S:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][C:14]1=[O:37])[Cl:40])([OH:10])=[O:9]
Reactant: O=C(O)C(O)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(Cl)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A cooled (ice bath) solution of the triethylamine salt of 1-(1'-carboxy-1'-hydroxymethyl)-4-tritylthio-2-azetidinone (1.04 g, 2.0 mmol) in methylene chloride (5 ml) was treated dropwise, under N2, with thionyl chloride (0.16 ml, 2.2 mmol) in methylene chloride (2 ml). The solution was stirred at room temperature for 20 min and concentrated. The residue was diluted with benzene and filtered over a Celite/charcoal bed. The filtrate was evaporated in vacuo to give 870 mg (quantitative) of the title compound as an amorphous solid. It was used in the next step without further purification. ir νmax : 1775 cm-1 ; 1Hmr (CDCl3) δ: 9.22 (1H, bs), 7.27 (15H, m), 5.3 and 5.2 (1H, 2d, J=2 Hz), 4.6 (1H, m) and 2.8 ppm (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][C:11](=O)[CH2:10]2)=[CH:5][CH:4]=1.Cl.[C:16]1([NH:22]N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.COC1C=CC(C2C3C4C=CC=CC=4NC=3CC2)=CC=1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][C:12]3[NH:22][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:11]=3[CH2:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccccc1
Reactant: COc1ccc(C2CCC(=O)C2)cc1
Agent: COc1ccc(C2CCc3[nH]c4ccccc4c32)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(C2Cc3[nH]c4ccccc4c3C2)cc1
Reaction time: 1 h

Procedure:
A mixture of 3-(4-methoxyphenyl)-1-cyclopentanone (15.22 g) and phenyl hydrazine hydrochloride (11.57 g) in glacial acetic acid (112 ml) under nitrogen was stirred magnetically and slowly heated to 90° with a heating mantle. A white precipitate, which formed at approximately 60°, dissolved to give a red solution as the temperature rose exothermically to 110°. As soon as the solid had dissolved, the heating mantle was removed and the temperature allowed to return to 90° for 1 hr. The cooled solution was poured into 400 ml of water. After refrigeration, the supernatant liquid was filtered. The filter pad and residual material were dissolved in chloroform and the solution was washed with saturated sodium bicarbonate solution. The dried (MgSO4) solution was evaporated to a syrup which was subjected to an oil pump vacuum; wt. 19.4 g (92%). This material was chromatographed on a column (60×7.6 cm) of silica gel prepacked in chloroform. Elution with chloroform afforded a mixture of the titled product and 1,2,3,4-tetrahydro-1-(4-methoxyphenyl)-cyclopent[b]indole in a ratio of 3:2 as determined by a reverse phase HPLC system (see Example 2). After solvent removal the residual syrup was coevaporated with acetonitrile to give 11.90 g (56.5%) of a red syrup which began to crystallize on standing. Crystallization from acetonitrile-water (seeding) gave crude product; wt. 5.25 g (24.9%), mp=107°-109°. Recrystallization from acetonitrile-water gave the titled product as pale yellow crystals, wt. 4.39 g, mp=109°-111°.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[C:30]([F:32])[CH:31]=2)=[N:6][N:7]([C:9]2([CH2:22][C:23]#[N:24])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:8]=1)(=[O:3])[NH2:2].[ClH:33]>O1CCOCC1>[Cl-:33].[C:1]([C:4]1[C:5]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[C:30]([F:32])[CH:31]=2)=[N:6][N:7]([C:9]2([CH2:22][C:23]#[N:24])[CH2:10][CH2:11][NH2+:12][CH2:13][CH2:14]2)[CH:8]=1)(=[O:3])[NH2:2]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3cncc(F)c3)n2)CC1
Solvent: C1COCCO1
Product: N#CCC1(n2cc(C(N)=O)c(Nc3cncc(F)c3)n2)CC[NH2+]CC1
Product: [Cl-]
Temperature: 25 °C

Procedure:
tert-Butyl 4-(4-carbamoyl-3-(5-fluoropyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Example 13-14) (305 mg, 0.688 mmol) was dissolved in 4 M HCl in 1,4-dioxane (7 mL). The resulting solution was maintained at ambient temperature for 2 hours. The mixture was then concentrated in vacuo to afford the title compound, Intermediate #39.
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[C:4]1([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH2:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:18]1([CH2:24][CH:25]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)=O>C(O)C>[C:12]1([CH:10]([NH:11][CH:25]([PH:1](=[O:2])[OH:3])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[PH2]O
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=CCc1ccccc1
Solvent: CC(C)=O
Solvent: CCO
Product: O=[PH](O)C(Cc1ccccc1)NC(c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 62.9 %

Procedure:
A solution of 21 g (84.3 mmol) of α-phenylbenzenemethanamine phosphinate in 60 ml of anhydrous ethanol is brought to reflux. 20.25 g (168.5 mmol) of phenylacetaldehyde in 20 ml of anhydrous ethanol are added dropwise. An abundant white precipitate forms. After addition, refluxing is continued for 2.5 hours. After cooling, 100 ml of acetone are added. The precipitate obtained is filtered off and washed with the same solvent. 18.6 g of product are recovered (yield=62.9%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[CH:22][C:18]3[N:19]=[CH:20][NH:21][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(OCC)(=O)C>CN(C=O)C.O>[S:26]([N:19]1[C:18]2[CH:22]=[CH:23][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[CH:16][C:17]=2[N:21]=[CH:20]1)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].[S:26]([N:21]1[C:17]2[CH:16]=[C:15]([NH:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[CH:23]=[CH:22][C:18]=2[N:19]=[CH:20]1)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc3nc[nH]c3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cnc3cc(NC4CCN(C(=O)OC(C)(C)C)CC4)ccc32)cc1
Product: Cc1ccc(S(=O)(=O)n2cnc3ccc(NC4CCN(C(=O)OC(C)(C)C)CC4)cc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-((N-(tert-butoxycarbonyl)piperidin-4-yl)amino)benzimidazole (1.50 g, 4.75 mmol) in DMF (30 mL) at 0° C. was added NaH (210 mg, 5.2 mmol). The solution was stirred for 0.5 hours when tosyl chloride (1.0 g, 5.2 mmol) was added. The reaction mixture was stirred for 1 hour at 0° C. when it was worked up with ethyl acetate and water, dried (MgSO4), and concentrated to an oil to afford 1-tosyl-5-((N-(tert-butoxycarbonyl)piperidin-4-yl)amino)benzimidazole and its regioisomer, 1-tosyl-6-((N-(tert-butoxycarbonyl)piperidin-4-yl)amino)benzimidazole. The resulting oil was taken up in DMF (30 mL) when it was charged with K2CO3 (4 g) and methyl iodide (3 mL). After 12 hours at ambient temperature, the reaction mixture was worked up with ethyl acetate and water, dried (MgSO4), and concentrated to an oil. The resulting tosylated product, 1-tosyl-5-((N-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)benzimidazole and the corresponding regioisomer, was taken up in methanol (80 mL) and NaOH (0.3 g, 7.5 mmol) was added. After 1 hour at ambient temperature, the methanol was removed in vacuo and the product recovered via chromatography on silica gel eluting with 5% to 10% methanol in methylene chloride to give 473 mg (30%) 5-((N-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)benzimidazole.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:23][CH3:24])=[C:7]([CH:22]=1)[CH2:8][NH:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=O.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].N1CCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[O:31]=[C:26]1[NH:27][C:28](=[O:30])[C:29](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([O:23][CH3:24])=[C:7]([CH:22]=2)[CH2:8][NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)[S:25]1
Reactant: COc1ccc(C=O)cc1CNC(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: COc1ccc(C=C2SC(=O)NC2=O)cc1CNC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
1.5 g of N1-(5-formyl-2-methoxybenzyl)-4-(trifluoromethyl)benzamide was dissolved in 15 ml toluene, and 0.52 g of 2,4-thiazolidine dione, 36 mg pyrrolidine and 30 mg acetic acid were added thereto, and the mixture was heated under reflux for 2 hours with a Dean-Stark apparatus. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with ethyl acetate and then dried, to give 1.4 g of N1-[5-[(2,4-dioxo-1,3-thiazolane-5-ylidene)methyl]-2-methoxybenzyl)-4-(trifluoromethyl)benzamide.
Reaction SMILES: [Na].[CH3:2][CH:3]([O:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=1)[CH2:4][CH3:5].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Cl)[N:19]=1>>[Cl:17][C:18]1[N:19]=[C:20]([O:14][CH2:13][CH2:12][O:11][C:10]2[CH:15]=[CH:16][C:7]([O:6][CH:3]([CH3:2])[CH2:4][CH3:5])=[CH:8][CH:9]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CCC(C)Oc1ccc(OCCO)cc1
Agent: [Na]
Product: CCC(C)Oc1ccc(OCCOc2cccc(Cl)n2)cc1

Procedure:
Following the same procedures, the sodium salt of 2-[4-(1-methylpropoxy)phenoxy]ethanol is reacted with 2,6-dichloropyridine to give 6-chloro-2-{2-[4-(1-methylpropoxy)phenoxy]ethoxy}pyridine.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[C:7]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[I-].ClCC[S+](C)C.O>C(O)(C)(C)C>[CH2:1]1[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]2=[O:14])[CH2:2]1
Reactant: O=C1CCCCCC1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)CCCl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1CCCCCC12CC2

Procedure:
To a suspension of potassium tert-butoxide (3.48 g) in tert-butanol (32 mL) was added cycloheptanone (1.9 mL) while stirring under nitrogen atmosphere, followed by stirring the mixture at room temperature for 0.5 hour. Then, to the reaction mixture was added (2-chloroethyl)-dimethylsulfonium iodide (3.7 g) in eight portions over 1.6 hours, followed by stirring the mixture at room temperature for 16.5 hours. To the reaction mixture was added water, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (diethyl ether:hexane (volume ratio)=1:15) to give spiro[2.6]nonan-4-one (1.40 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:21]3[CH2:23][CH2:22]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.[CH:24]([O:27][C:28](Cl)=[O:29])([CH3:26])[CH3:25]>N1C=CC=CC=1.C1(C)C=CC=CC=1.O>[CH:24]([O:27][C:28](=[O:29])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:21]3[CH2:23][CH2:22]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: COc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CC3)c2c1
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc2c(C#N)c(-c3ccc(NC(=O)OC(C)C)cc3)n(C3CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of the compound obtained in step E (61 mg, 0.2 mmol) in dry pyridine (2.0 mL) is added isopropylchloroformate (0.3 mL, 1.0 M, 0.3 mmol) in toluene. The mixture is stirred at room temperature overnight and diluted with water (10 mL). The organic layer is extracted with DCM (10 mL) and washed with HCl (2N, 2×3 mL), water (2×4 mL) and brine (3 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the product, [4-(3-cyano-1-cyclopropyl-6-methoxyindol-2-yl)phenyl]carbamic acid isopropyl ester (66 mg, 85%).