Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1C2C(=CC=CC=2)C=C[CH:2]=1.[S].Cl[C:13]([CH2:15][C:16]12[CH2:31][CH2:30][CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=31)[C:22]1[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:14].[H][H]>[Pd].C1(C)C(C)=CC=CC=1>[OH:14][CH:13]([C:2]#[N:1])[CH2:15][C:16]12[CH2:31][CH2:30][CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=31)[C:22]1[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: O=C(Cl)CC12CCC(c3ccccc31)c1ccccc12
Reactant: c1ccc2ncccc2c1
Agent: [Pd]
Agent: [S]
Solvent: Cc1ccccc1C
Product: N#CC(O)CC12CCC(c3ccccc31)c1ccccc12
Reaction time: 7 h

Procedure:
10 g of 10% strength palladium on charcoal, poisoned with quinoline-sulphur, are added to a solution of 46 g of 9 -(chlorocarbonylmethyl)-9,10-dihydro-9,10-ethano-anthracene in 200 ml of xylene, and hydrogen is then passed through the mixture at 120° C. After 7 hours, the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is dissolved in methylene chloride and extracted by shaking with sodium carbonate solution. The organic phase is separated off, dried over sodium sulphate and then diluted to a volume of 250 ml by adding methylene chloride. After 1 ml of triethylamine has been added, 20 ml of hydrogen cyanide are added and the mixture is left to stand for 12 hours at room temperature. It is then extracted by shaking with water and the solvent is evaporated. Crystalline 9-(2-hydroxy-2-cyano-ethyl)-9,10-dihydro-9,10-ethano-anthracene is obtained as the residue and after recrystallisation from methylene chloride-petroleum ether has a melting point of 139°-141° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]#N)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[NH:27][C:28]1C2C(=CC=CC=2)C(C=O)=CC=1)(C)(C)C.C1(C)C(S([N+]#[C-])(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[O:25][CH:26]=[N:27][CH:28]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)c2ccccc12
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [C-]#[N+]S(=O)(=O)c1ccccc1C
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnco2)c2ccccc12
Yield: 44 %

Procedure:
The above mixture of compounds 503A & 503B (3.37 g, 10.0 mmol; corrected for presence of compound 503A), toluene-sulfonylisocyanide (2.15 g, 11.0 mmol) and potassium carbonate (1.66 g, 12.0 mmol) in 50 mL of methanol was refluxed for 4 h. The reaction mixture was partitioned between water (200 mL) and chloroform (200 mL). After extracting the aqueous layer with chloroform (100 mL), the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel eluting with a gradient of 10–40% ethyl acetate in hexane to give 1,35 g (44%) of compound 503C as a white solid. 1HNMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H), 8.57 (s, 1H), 8.20 (m, 2H), 7.76 (m, 2H), 7.64 (s, 1H), 7.62 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[C:25]([C:38](O)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:29]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:25]([C:38]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:28][CH:29]=1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ncnc23)n1
Yield: 52.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-8, 50 mg, 0.164 mmol), 3-chloro-6-(pivalamidomethyl)picolinic acid (Intermediate-3, 88 mg, 0.326 mmol), oxalyl chloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (63 mg, 0.49 mmol) in CH2Cl2 (2 mL) to afford 48 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 11.63 (s, 1H), 9.06 (d, J=7.8 Hz, 1H), 8.86 (s, 1H), 8.33 (br t, 1H), 8.12 (d, J=8.1 Hz, 2H), 7.88-7.82 (m, 2H), 7.76 (m, 3H), 7.48 (d, J=8.4 Hz, 1H), 4.48 (d, J=5.4 Hz, 2H), 1.16 (s, 9H); MS [M+H]+: 558.11.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[CH:16][CH:15]=1.CI.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][C:12]([F:11])([F:23])[F:24])=[CH:15][CH:16]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: FC(F)(F)Oc1ccc(N=C=S)cc1
Solvent: ClCCl
Solvent: CI
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Oc1ccc(Nc2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reaction time: 24 h

Procedure:
A solution of 4,5-dichloro-1,2-phenylenediamine (2 mmol, 354 mg) and 4-trifluoromethoxyphenyl isothiocyanate (2 mmol, 325 μL) in CH2Cl2 (3 mL) was heated at 40° C. for 4 h. MeI (2.2 mmol, 137 μL) and DIEA (2.0 mmol, 348 μL) were added, and the reaction was brought to 40° C. for 24 h. The reaction mixture was partitioned between CH2Cl2 and brine. The organic phase was dried with Na2SO4 and concentrated in vacuo. Chromatography on silica eluting with 20-40% EtOAc in hexanes provided the product as a tan solid. 1H NMR (500 MHz, d6-DMSO) δ 11.2 (br s, 1H), 9.91 (s, 1H), 7.84 (m, 2H), 7.52 (br s, 1H), 7.34 (d, J=9 Hz, 2H). LC-MS (ESI, Method A): 2.96 min, m/z 362.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][C@@H:21]([NH2:23])[CH2:20][CH2:19][C@H:18]2[CH3:24])[N:3]=1.[C:25]([O-:28])(O)=[O:26].[Na+]>C1COCC1.O>[C:8]1([CH2:6][O:28][C:25](=[O:26])[NH:23][C@H:21]2[CH2:20][CH2:19][C@@H:18]([CH3:24])[N:17]([C:4]3[CH:5]=[C:6]([C:8]4[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=4)[N:7]=[C:2]([NH2:1])[N:3]=3)[CH2:22]2)[CH:15]=[CH:14][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CC[C@H](N)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-{2-amino-6-[(2R,5S)-5-amino-2-methyl-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (170 mg, 0.426 mmol) in THF (4 mL) was added saturated aqueous NaHCO3 (2 mL) followed by phenylmethyl chloridocarbonate (0.07 mL, 0.47 mmol), and the reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with 3 mL of water and then extracted with EtOAc (3×30 mL). The organic was then washed with brine, dried over MgSO4, filtered and concentrated. The resulting yellow oil was purified on a Biotage SNAP 10 g column with gradient of 0 to 50% EtOAc in hexane over 30 minutes to afford the title compound (57 mg) as a yellow oil. LC-MS (ES) m/z=327 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[NH2:20])[CH:8]([O:21][CH3:22])[CH2:7]1)=[O:5])[CH3:2].C([O-])(O)=O.[Na+]>C(O)(=O)C(C)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[N:20]=[C:15]2[CH:16]([CH3:19])[CH3:17])[CH:8]([O:21][CH3:22])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(Nc2ccc(C)cc2N)C(OC)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)C(=O)O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(n2c(C(C)C)nc3cc(C)ccc32)C(OC)C1
Temperature: 25 °C
Yield: 106 %

Procedure:
A solution of 4-(2-amino-4-methyl-phenylamino)-3-methoxy-piperidine-1-carboxylic acid ethyl ester (750 mg, 2.44 mmol) in isobutyric acid (15 mL) was subjected to microwave irradiation for 1 h with a resulting temperature of 180° C. The reaction mixture was cooled to rt and then diluted with CH2Cl2 (150 mL) and a saturated NaHCO3 solution (200 mL). The aqueous layer was extracted twice with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (15/1 CH2Cl2/CH3OH) to yield 4-(2-isopropyl-5-methyl-benzoimidazol-1-yl)-3-methoxy-piperidine-1-carboxylic acid ethyl ester (465 mg, 56%) as a waxy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[ClH:15]>O>[Cl:15][C:11]1[NH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:13][C:12]=1[CH3:14]
Reactant: Cl
Reactant: COc1ccc(-c2nc(C)c[nH]2)cc1
Solvent: O
Product: COc1ccc(-c2nc(C)c(Cl)[nH]2)cc1
Reaction time: 8 h
Yield: 17 %

Procedure:
A suspension of 2-(p-methoxyphenyl)-4-methylimidazole, (4.5 g, 0.024 mole) in concentrated HCl (96 ml)--H2O (34 ml) was stirred vigorously while a solution of KClO3 (1 g) in H2O (50 ml) was added dropwise over 11/4 hour. The precipitated hydrochloride salt was collected and suspended in H2O (200 ml), saturated Na2CO3 solution (50 ml). After an overnight period of stirring, the solid was collected, chromatographed on silica gel, the product eluted with 5% CH3OH--CHCl3 and crystallized from 50% CH3CN to yield 0.9 g (17%) of 38, m.p. 182°-186° C. A sample recrystallized from 50% CH3CN melted at 185°-187° C.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4.[H-].[Na+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23]>CN(C=O)C.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: O=C(CCl)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)c1c(n2CC(=O)N2CCCCC2)CCN2CCCC12
Reaction time: 0.08 h

Procedure:
To a solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (80 mg, 0.352 mmol) in DMF (1 mL) was added a suspension of sodium hydride (42 mg, 1.05 mmol) in DMF (1 mL). After stiffing for 5 min at RT, a solution of 2-chloro-1-(piperidin-1-yl)ethanone (114 mg, 0.704 mmol) in DMF (1 mL) was added to the reaction mixture, and stiffing continued for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 2-(10-methyl-2,3,5,6-tetrahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizin-7(11cH)-yl)-1-(piperidin-1-yl)ethanone;
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]#[N:12])=[CH:6][CH:5]=1.[CH3:13][NH:14][C:15](=O)[CH2:16]Cl>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:16][C:15](=[O:1])[N:14]([CH3:13])[C:11]2=[NH:12])=[CH:6][CH:5]=1
Reactant: CNC(=O)CCl
Reactant: N#CNc1ccc(Cl)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CN1C(=N)N(c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In 25 ml. of water containing 0.84 g. of sodium hydroxide was dissolved in 3.2 g. of p-chlorophenylcyanamide. To the clear solution was added 2.25 g. of N-methylchloroacetamide. The reaction mixture was stirred for 48 hours at room temperature. The precipitate was filtered to yield 1.9 g. of product, m.p. 182°-184° C. After the initial product was filtered, the filtrate was left stirring another three days. An additional 1.2 g. of product precipitated from solution. Total yield of product was 3.1 g. (66%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.[ClH:19].C([BH3-])#N.[Na+].C[OH:25]>O.C(OCC)C>[ClH:19].[ClH:19].[Cl:19][C:7]1[CH:6]=[CH:5][C:4]([CH:1]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH3:2])=[C:9]([OH:25])[CH:8]=1
Reactant: CC(=O)c1ccccc1
Reactant: CO
Reactant: NCCCn1ccnc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(NCCCn1ccnc1)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The acetophenone (3.3 g) from (b) and 1-(3-aminopropyl)imidazole (7.1 g) were dissolved in methanol (30 ml). Saturated methanolic hydrogen chloride (3 ml) was added to this solution, followed by sodium cyanoborohydride (0.84 g). The resulting mixture was stirred at ambient temperature for 48 hours and then left standing for 64 hours. Concentrated hydrochloric acid (6 ml) and water (30 ml) were added and the mixture stirred for 10 minutes. The mixture was diluted with water, washed with dichloromethane, basified with 5M sodium hydroxide solution and then extracted with dichloromethane. The combined extracts were dried and evaporated to give an oil which was dissolved in diethyl ether and acidified with ethereal hydrogen chloride. The solid obtained was collected by filtration and dried under vacuum to give 5-chloro-2-{1-[3-(imidazol-1-yl)propylamino]ethyl}phenol dihydrochloride, m.p. >300° C.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:17])[F:18])([C:11]([F:12])([F:13])[F:14])[O:10][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2

Procedure:
72 g of5-nitro-2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole of Example 16a were dissolved in 500 ml of tetrahydrofuran and hydrogenated for 5 hours at room temperature with 15 to 20 bar hydrogen using 5 g of palladium on charcoal (5% strength). The mixture was subsequently filtered and the solvent was stripped off in vacuo. The yield was 60 g (93% of theory), and the boiling point was 80° to 82° C. at 0.1 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -66.5 and -79.4 ppm. 1H-NMR: 4.68 ppm.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[O:19]=[C:20]1[C:25](C(Cl)=O)=[CH:24][CH:23]=[C:22]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:21]1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[CH2:39][NH2:40]>>[C:14]([CH:13]=[C:11]1[CH2:12][N:8]([C:6]([C:25]2[C:20](=[O:19])[O:21][C:22]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:24]=2)=[O:7])[C@H:9]([C:16]([NH:40][CH2:39][C:38]2[CH:41]=[CH:42][C:43]([O:44][CH3:45])=[C:36]([O:35][CH3:34])[CH:37]=2)=[O:18])[CH2:10]1)#[N:15]
Reactant: COc1ccc(CN)cc1OC
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Product: CCCCCc1ccc(C(=O)N2CC(=CC#N)C[C@H]2C(=O)NCc2ccc(OC)c(OC)c2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 65% purity by LC/MS. MS(ESI+): m/z=494.4.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:8]=1)=[O:17])[CH2:23][CH:24]1[CH2:26][CH2:25]1)(=[O:21])[NH2:22]
Reactant: COCCOc1nc(C(=O)O)ccc1C1CC1
Reactant: NC(=O)[C@@H](N)CC1CC1
Product: COCCOc1nc(C(=O)N[C@@H](CC2CC2)C(N)=O)ccc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid (Example 142 d) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=348.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[C:10]=2[O:9]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CNCC1Cc2cccc(Br)c2O1
Product: CNCC1Cc2cccc(-c3ccc(OC)cc3)c2O1

Procedure:
The title compound was prepared (0.052 g, 23%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 4-methoxyphenylboronic acid (0.188 g, 1.24 mmol). mp 214-217° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[N:12]=[C:11]([N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[S:23][CH2:22][CH2:21]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:33]=[O:34]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:33]=[O:34])[CH:17]=2)[N:12]=[C:11]([N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[S:23][CH2:22][CH2:21]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2nc(N3CCSc4ccccc4C3)nc(OCc3ccccc3)c2c1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2nc(N3CCSc4ccccc4C3)nc(OCc3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a cooled solution of 4-(4-benzyloxy-6-bromoquinazolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (500 mg, 1.048 mmol) in anhydrous tetrahydrofuran (10 mL) was added anhydrous N,N-dimethylformamide (150 μL, 1.94 mmol) at −78° C. After being stirred at −78° C. for 30 minutes, the mixture was warmed to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with a saturated aqueous solution of ammonium chloride (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 410 mg of the crude product as a yellow solid. MS obsd. (ESI+) [(M+H)+] 428.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]2[NH:9][NH:10][C:11](=O)[C:6]2=[CH:5][N:4]=1.P(Br)(Br)([Br:15])=O.O.[OH-].[NH4+]>CC#N>[Br:15][C:11]1[C:6]2[C:7](=[N:8][C:3]([S:2][CH3:1])=[N:4][CH:5]=2)[NH:9][N:10]=1
Reactant: CSc1ncc2c(=O)[nH][nH]c2n1
Reactant: O=P(Br)(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CSc1ncc2c(Br)n[nH]c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a suspension of 6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (0.50 g, 2.7 mmol) in CH3CN (15 mL) was added a CH3CN solution of P(O)Br3 (1.57 g, 5.5 mmol) in a pressure vessel. The mixture was sonicated for 30 min before being heated to 100° C. for 16 h (overnight). After it was cooled to 0° C., H2O and aqueous ammonium hydroxide were added to basify the mixture. The mixture was stirred at 0° C. for 1 h. The aqueous layer was extracted with EtOAc (10×). The combined EtOAc layer was dried (Na2SO4), and concentrated to give 3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (0.51 g, 77%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.00 (s, 1H), 5.57 (s, 3H); MS m/z 245.00 [M+H]+.
Reaction SMILES: C([NH:5][C:6]1[CH:11]=[C:10]2[O:12][CH2:13][O:14][C:9]2=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])CCC.C[O-].[Na+]>CO>[CH3:13][O:12][CH:10]([CH2:11][CH2:6][NH2:5])[CH3:9].[N+:15]([C:7]1[CH:6]=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=1)([O-:17])=[O:16]
Reactant: CCCCNc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(C)CCN
Product: O=[N+]([O-])c1cccc(O)c1

Procedure:
A solution of 0.03 mol (6.9 g) of 2-n-butylamino-4,5-methylenedioxy-1-nitrobenzene, prepared according to Example 4, in 45 ml of a 30% strength solution of sodium methylate in methanol is brought for 15 minutes to the refluxing temperature of the methanol.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[N:11][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][S:2]([CH3:1])(=[O:4])=[O:3])=[N:11][CH:12]=1
Reactant: OCc1ccc(F)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(F)cn1
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Add methanesulfonyl chloride (1.8 mL, 23.5 mmol) to a solution of (5-fluoro-pyridin-2-yl)-methanol (2.5 g, 19.7 mmol) and triethylamine (8.2 mL, 59.0 mmol) in DCM (150 mL) at 0° C. under nitrogen. Stir the mixture for 30 min and concentrate in vacuo. Dilute with water (20 mL) and extract the mixture with EtOAc (3×50 mL). Combine the organic extracts and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc to obtain the desired intermediate (2.2 g, 54%).
Reaction SMILES: [CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]([C:10]1[C:15](N2N=CC=N2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1N.[CH2:50]([O:52]C1C(C(O)=O)=NC=CC=1)[CH3:51]>>[CH2:50]([O:52][C:15]1[C:10]([C:8]([NH:7][C@H:3]2[CH2:4][CH2:5][CH2:6][C@:2]2([CH3:1])[NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=1)[CH3:51]
Reactant: CCOc1cccnc1C(=O)O
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Product: CCOc1cccnc1C(=O)N[C@H]1CCC[C@]1(C)Nc1cnc(C(F)(F)F)cn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 80 mg, 0.31 mmol) and 3-ethoxypyridine-2-carboxylic acid (CAS number 103878-09-7; 51 mg, 0.31 mmol) except this was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) followed by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.N1C=CC=CC=1.[Na]>O>[OH:1][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]#[CH:2]
Reactant: c1ccc2occc2c1
Agent: [Na]
Solvent: O
Solvent: c1ccncc1
Product: C#Cc1ccccc1O
Yield: 54 %

Procedure:
In the process described in Bull. Chem. Soc. Japan 29, 470-1(1956), benzofuran is heat-refluxed in the presence of pyridine and metallic sodium and thereafter treated with water to obtain 2-hydroxyphenylacetylene in 54% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].[H][H]>C(O)C.[Pd]>[NH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([OH:12])=[C:4]([CH3:11])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cc(C)c1O
Yield: 86 %

Procedure:
A solution of 1 g (6 mmole) of 2,6-dimethyl-4-nitrophenol in 20 ml of ethanol is placed under 1.5 bar of hydrogen in the presence, of 10% Pd/C for 1 hour. The Pd/C is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure. The evaporation residue crystallizes spontaneously, it is washed twice with 50 ml of heptane and dried overnight under vacuum. A cream coloured solid is obtained with a yield of 86%.