Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][OH:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:20]([CH3:22])=[CH2:21]>CC(C)=O.B(F)(F)F.CCOCC>[CH3:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[CH2:16][O:17][C:20]([CH3:22])([CH3:21])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: C=C(C)OC
Reactant: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
(S)-Methyl 4-(tert-butoxycarbonylamino)-5-hydroxypentanoate (24 g, 97.2 mmol) and isopropenyl methyl ether (88.8 g, 854.6 mmol) was dissolved in acetone (2000 mL) and BF3.Et2O (0.82 mL, 5.84 mmol) was added at rt. The mixture was stirred for 1 hr at rt. The reaction was quenched by addition of Et3N (11.6 mL). The reaction solution was washed with aqueous saturated NaHCO3 (200 mL) and evaporated, and (S)-tert-butyl 4-(3-methoxy-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate (25.1 g, 90%) was obtained as an oil, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:38])[CH:23]2[CH2:26][CH:25]([NH:27]C(=O)OCC3C=CC=CC=3)[CH2:24]2)[O:12]1.C(Cl)Cl>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:38])[CH:23]2[CH2:24][CH:25]([NH2:27])[CH2:26]2)[O:12]1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(NC(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(N)C1
Temperature: 35 °C
Reaction time: 5 h
Yield: 42.3 %

Procedure:
To a solution of benzyl (3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)carbamate (190 mg, 0.17 mmol) and Pd(OH)2 (14 mg, 0.1 mmol) in MeOH (5 mL) was charged with H2. The reaction was stirred at 35° C. for 5 h. The reaction was filtered with Celite and concentrated to dryness. The residue was purified by prep-TLC (DCM:MeOH=10:1) to the desired compound (28 mg, yield 42%). 1HNMR (500 MHz, MeOD): δH 8.29 (s, 1H), 8.21 (s, 1H), 6.19 (d, J=2.0 Hz, 1H), 5.51 (dd, J=6.5 and 2.0 Hz, 1H), 5.00 (dd, J=6.0 and 3.5 Hz, 1H), 4.34 (d, J=8.5 Hz, 1H), 3.14-3.11 (m, 1H), 2.60-2.57 (m, 1H), 2.52-2.48 (m, 2H), 2.34-2.31 (m, 2H), 2.10 (s, 3H), 1.66 (q, J=10.0 Hz, 1H), 1.58 (s, 3H), 1.48 (q, J=10.0 Hz, 1H), 1.37 (s, 3H) ppm; ESI-MS (m/z): 390.2[M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH3:23]I.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1)[N:17]([CH3:23])[N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: CI
Reactant: Fc1ccc(C(Nn2cncn2)c2ccc(Cl)cc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(c1ccc(F)cc1)c1ccc(Cl)cc1Cl)n1cncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A solution of 40.0 g (0.119 mol) of N-[1-(2,4-dichlorophenyl)-1-(4-fluorophenyl)methyl]-1H-1,2,4-triazol-1-amine and 40 mL (0.64 mol) of methyl iodide in 250 mL dimethyl formamide was cooled to 0° C. Sodium hydride (4.5 g; 0.19 mol, freed from oils) was added portionwise. The reaction mixture was warmed to room temperature, stirred 1 h and quenched by dropwise addition of aqueous ammonium chloride. The mixture was diluted with ether, and washed three times with water and with brine. Drying (MgSO4) and removal of solvent gave product as an oil. Crystallization from hexanes afforded 27.7 g (66% yield) of the desired product as a white solid; mp 118°-119° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.[C:34](O)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[N:38]1[CH:39]=[CH:40][C:35]([C:34]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]3[O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[CH:5][CH:4]=2)=[O:41])=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(O)c1ccncc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(=O)c3ccncc3)cc2)C(OCc2ccc3ccccc3c2)C1
Yield: 20.9 %

Procedure:
A solution of 60 mg (0.13 mmol) of tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine--carboxylate, 16 mg (0.13 mmol) of isonicotinic acid, 34 mg (0.26 mmol) of ethyidiisopropylamine and 58 mg (0.13 mmol) of benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP) in 5 ml of acetonitrile was stirred at room temperature for 2 hours. Subsequently, the reaction mixture was evaporated under reduced pressure and the residue, without further working-up, was chromatographed on silica gel using a 3:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 15 mg (21% of theory) of (3RS,4RS)-4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzyl pyridine-4-carboxylate as a colourless solid; MS: 552 (M)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:19]([CH3:20])=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[CH3:21])(C(C)(C)C)(C)C.[NH2:22][C:23]1[CH:41]=[CH:40][CH:39]=[CH:38][C:24]=1[C:25]([NH:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)=[O:26]>CCO>[OH:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([CH3:21])=[CH:14][C:15]([C:16]2[N:27]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)[C:25](=[O:26])[C:24]3[C:23](=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:22]=2)=[CH:18][C:19]=1[CH3:20]
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2N)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Solvent: CCO
Product: COC(=O)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3ccccc3c2=O)cc1
Temperature: 25 °C
Yield: 34.1 %

Procedure:
Isatoic anhydride (4.0 g, 24.5 mmol) and methyl 4-aminobenzoate were combined and heated at 140° C. for 4 hours. The reaction was cool to room temperature and purified by flash chromatography on silica gel, eluting with 90-100% CH2Cl2 in heptane, to afford methyl 4-(2-aminobenzamido)benzoate (5.2 g, 78%). 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (1.0 g, 3.30 mmol) and anhydrous CuCl2 (1.3 g, 9.90 mmol) were added to a solution of methyl 4-(2-aminobenzamido)benzoate (0.900 g, 3.30 mmol) in anhydrous EtOH (70 mL) and heated to reflux for 6 hours, before being cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% MeOH in CH2Cl2, followed by further purification on silica gel, eluting with 30-100% EtOAc in heptane, afforded the title compound as a white solid (0.500 g, 34%). 1H-NMR (300 MHz, DMSO-d6): δ 8.18 (dd, J=7.9, 1.1 Hz, 1H), 7.88-7.93 (m, 3H), 7.75 (d, J=6.7 Hz, 1H), 7.57-7.62 (m, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.03 (s, 2H), 4.82 (t, J=5.5 Hz, 1H), 3.84 (s, 3H), 3.60-3.72 (m, 4H), 2.07 (s, 6H). MS (APCI) m/z: 445 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:22])=[CH:7][CH:8]=2)[N:3]=1.[CH3:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CC#N>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.O>[F:22][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[C:2]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][CH3:23])=[N:3]2)=[CH:8][CH:7]=1
Reactant: CSc1ccccc1B(O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cc2ccc(F)cc2nc1Cl
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: [Na+]
Solvent: O
Solvent: CC#N
Product: CSc1ccccc1-c1nc2cc(F)ccc2cc1[C@H](C)NC(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 92.9 %

Procedure:
A mixture of (S)-tert-butyl (1-(2-chloro-7-fluoroquinolin-3-yl)ethyl)carbamate (382 mg, 1.2 mmol), 2-(methylthio)phenylboronic acid (257 mg, 1.3 eq), Na2CO3 (623 mg, 5.0 eq), Pd(PPh3)4 (93 mg, 5%), MeCN (9 mL) and water (3 mL) was heated to 85° C. under N2 overnight. After cooling to rt, the reaction was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was separated, washed, dried and concentrated. The residue was purified by column chromatography on silica gel to give a white solid (S)-tert-butyl (1-(7-fluoro-2-(2-(methylthio)phenyl)quinolin-3-yl)ethyl)carbamate (460 mg, 94.8%). Mass Spectrum (ESI) m/e=413 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.O>[CH:10]([C:9]1[CH:8]=[C:5]([CH2:6][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:4]([CH3:13])=[CH:3][C:2]=1[OH:1])([CH3:12])[CH3:11]
Reactant: Cc1cc(O)c(C(C)C)cc1C=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)c(C(C)C)cc1CN1CCCC1
Yield: 76.5 %

Procedure:
4-Hydroxy-5-isopropyl-2-methyl-benzaldehyde (1.0 g, 5.6 mmol) was added in portions for 30 min to a mixture of pyrrolidine (0.58 mL, 7 mmol) and NaB(OAc)3H (1.49 g, 7 mmol) in CH2Cl2 (10 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 12 h and cooled with an ice bath. Water (25 mL) and 5N NaHSO4 (to pH 1) were added. The organic layer was separated and discarded. The aqueous one was alkalized with saturated K2CO3 to pH 6 and extracted with chloroform (2×25 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (1.0 g, 80%) was obtained as dark-yellow crystals. LCMS-data: (M+H)+ 234.1 and 235.1 (calculated for C15H23NO 233.4). 1H NMR data (DMSO-d6): 8.88 (br. s, 1H ArOH), 6.90 (s, 1H, Ar—H), 6.54 (s, 1H, Ar—H); 3.40 (s, 2H, ArCH2), 3.13 (m, 1H, CH(CH3)2), 2.33-2.45 (m, 4H, pyrrolidine (CH2)2N), 2.17 (s, 3H, CH3), 1.60-1.70 (m, 4H, CH2CH2CH2CH2), 1.12 (d, 6H, J=6.9 Hz, CH(CH3)2).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]([O:16][C:17]([CH3:22])([CH3:21])[C:18]([NH2:20])=[O:19])(=[O:15])[CH3:14]>>[C:13]([O:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:20][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:19])(=[O:15])[CH3:14]
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Reactant: CC(=O)OC(C)(C)C(N)=O
Product: COC(=O)c1cc(C)nc(NC(=O)C(C)(C)OC(C)=O)c1
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (0.89 g, a yellow solid) from methyl 2-chloro-6-methylisonicotinate (0.70 g, 3.8 mmol) and 1-amino-2-methyl-1-oxopropan-2-yl acetate by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:14]([OH:16])=O)=[N:11][NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1([C:23]2[C:24]([CH3:31])=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:10]([C:14](=[O:16])[NH:30][C:25]2[CH:24]=[CH:31][C:28]([CH2:23][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:27][C:26]=2[NH2:29])=[N:11][NH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(N2CCOCC2)ccc(N)c1N
Reactant: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)Nc1ccc(CN2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
A mixture of 4-tert-butoxycarbonylamino-1H-pyrazole-3-carboxylic acid (10.0 g, 44.1 mmol), 4-morpholin-4-yl methyl-benzene-1,2-diamine (10.0 g, 48.5 mmol), EDC (10.14 g, 52.9 mmol) and HOBt (7.15 g, 52.9 mmol) in DMF (150 mL) was stirred at ambient temperature for 20 h and then the majority of the solvent removed in vacuo. The residue was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (150 mL), the layers separated and the organic portion washed with brine, dried over MgSO4 and reduced in vacuo to give [3-(2-amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-1H-pyrazol-4-yl]-carbamic acid tert-butyl ester (17.6 g, 96%) as a brown solid. LC/MS analysis indicates product contains ˜15% of the di-amide. This shows at approx. 5% level in 1H NMR. Di-amide is cleaved in subsequent step.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[S:20][CH:21]=2)=[O:16])=[CH:10][CH:9]=1)(C)(C)C.Cl.[O:28]1CCOC[CH2:29]1>C(Cl)(Cl)Cl>[S:20]1[CH:21]=[C:17]([C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:5])=[O:26])=[CH:9][C:10]=2[O:28][CH3:29])=[O:16])[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]1=2
Reactant: CC(C)(C)OC(=O)Cc1ccc(NC(=O)c2csc3ccccc23)cc1
Reactant: C1COCCO1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(CC(=O)O)ccc1NC(=O)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]phenylacetic acid tert-butyl ester (2.12 g, 5.33 mmol) and a 4N—HCl-dioxane solution (20 mL) were mixed, and the mixture was stirred for hours at room temperature, and for 8 hours at 70° C. After cooling the mixture naturally, the mixture was diluted with chloroform (200 mL), washed with water (100 mL) and saturate brine (100 mL), and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified with a column (40S) of Biotage AB (5% methanol-chloroform), to obtain the title compound (3.47 g, 94%) as a crystalline powder.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCO
Reactant: O=C1CCC(O)N1
Product: CCCCCCCCCOC1CCC(=O)N1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 5 g of 5-hydroxy-pyrrolidin-2-one 2.5 g of Amberlite IR 120H in 100 cm3 of n-nonanol is agitated at 60° C. for 3 hours. It is then cooled. the resin is filtered off, and the solvent is eliminated by distilling at 70° C. under 0.5 mbar. The residue is taken up in 50 cm3 of n-hexane, which is maintained for 16 hours at 5° C. After separating, 6.8 g of the expected product is obtained, m.p. 46°-48° C. After recrystallizing from n-hexane, m.p. 51°-52° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[Cl:10][CH2:11][C:12](Cl)=[O:13]>C(Cl)Cl>[Cl:10][CH2:11][C:12]([N:4]1[CH2:5][CH2:6][CH2:7][CH:3]1[C:2]([F:9])([F:8])[F:1])=[O:13]
Reactant: O=C(Cl)CCl
Reactant: FC(F)(F)C1CCCN1
Solvent: ClCCl
Product: O=C(CCl)N1CCCC1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(trifluoromethyl)pyrrolidine (500 mg, 3.59 mmol) in DCM (10 ml) was treated with chloroacetyl chloride (0.31 ml, 3.77 mmol) and stirred at RT for 1 h. The resulting mixture was concentrated in vacuo to afford the title compound as a yellow oil which was used without further purification; 1H NMR (400 MHz, CDCl3) δ 4.84 (1H, m), 4.11 (2H, s), 3.71 (2H, m), 2.23 (2H, m), 2.07 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[CH2:17](OC(OCC)(OCC)C)[CH3:18]>O>[CH3:17][C:18]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:5])[C:3]2[C:2](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1ccccc1C(=O)Nc1ccccc1
Solvent: O
Product: Cc1nc2ccccc2c(=O)n1-c1ccccc1
Yield: 75.2 %

Procedure:
A mixture of 2-amino-N-phenyl-benzamide 26 (2 g, 0.009 mol) and 1,1,1-triethoxy-ethane (5.2 mL, 0.028 mol) were heated for 5 hours. The reaction mixture was poured into water, filtered off, washed with water yielding 2-methyl-3-phenyl-3H-quinazolin-4-one 27 (1.6 g, 82%). After recrystallization it was used in next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Product: CN1CCN(c2ccc(Nc3nc4cccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75 mg, 0.26 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (73 mg, 0.28 mmol) in a manner analogous to Example 77 to yield [5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21](=[O:23])[NH2:22])([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24](OCC)(OCC)OCC.C(O)(=O)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:24]=[N:22][C:21]2=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccccc2)(C(N)=O)C1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)N=CN2c1ccccc1

Procedure:
To a solution of 3-carbamoyl-3-phenylamino-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.94 mmol) in toluene (10 ml) was added triethyl orthoformate (0.47 ml, 2.8 mmol) and acetic acid (0.5 ml, 8.7 mmol). The mixture was heated at reflux overnight. The reaction mixture was cooled and washed with a saturated solution of sodium bicarbonate (25 ml). The organics were separated and the aqueous extracted with EtOAc (10 ml). The organics portions were combined, dried (MgSO4) and concentrated in vacuo to afford an oil. Purification of the crude product by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:5].[F:31][C:32]([F:43])([F:42])C1C=CC(C(Cl)=O)=CC=1>>[F:31][C:32]([F:43])([F:42])[C:29]1[CH:30]=[CH:2][C:3]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[O:5])=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)c1ccccc1F
Product: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)c1ccc(C(F)(F)F)cc1
Yield: 74 %

Procedure:
According to the method used for synthesis of the compound 28a, the titled compound (592 mg) is synthesized by using tert-butyl((2-trimethylstannylphenyl)-(2-(3-m-tolylureido)acethyl)amino)acetate (1.0 g) and 4-trifluoromethylbenzoylchloride (364 mg). Yield 74%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:6]=2[CH:26]=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:7]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:32][CH2:31][CH2:30][N:29]([CH2:34][CH3:35])[CH2:27][CH3:28])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:6]=2[CH:26]=1
Reactant: CCN(CC)CCCCl
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(-c3ccccc3)oc3ccc(Cl)cc23)cc1

Procedure:
Reaction of 5-chloro-3-(4-hydroxyphenylsulfonyl)-2-phenylbenzofuran with 3-diethylaminopropyl chloride according to the procedure of Example 1 gives the title compound.
Reaction SMILES: [C:1](C1C=CC=CN=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH3:20])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)Cl>>[CH3:20][C:12]1[S:11][C:10]2[N:9]=[CH:1][N:2]=[CH:15][C:14]=2[CH:13]=1
Reactant: CCOC(=O)c1cc(C)sc1N
Reactant: N#Cc1ccccn1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2cncnc2s1

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyridine and 2-amino-5-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([Mg]Br)C.[CH2:5]([OH:9])[CH2:6][C:7]#[CH:8].Cl[Si:11]([CH3:14])([CH3:13])[CH3:12].S(=O)(=O)(O)O>O1CCCC1>[CH3:12][Si:11]([CH3:14])([CH3:13])[C:8]#[C:7][CH2:6][CH2:5][OH:9]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCCO
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A solution of 2 mol of ethyl magnesium bromide (2.0 molar solution in tetrahydrofuran) is cooled in an ice bath and a solution of 50.5 g of 3-butyn-1-ol (0.72 mol) in 50 ml of tetrahydrofuran is slowly added. After addition is complete, the mixture was allowed to warm to room temperature and was stirred overnight. The mixture was then cooled in an ice bath and 254 ml (2 mol) of chlorotrimethylsilane was slowly added. This mixture was heated under reflux for two hours and then cooled to 20° C. and 800 ml of 1.4M aqueous sulfuric acid were added. The mixture was extracted with diethyl ether and the ether solution was dried and concentrated under vacuum. The residue was distilled to yield 72.8 g of 4-trimethylsilyl-3-butyne-1-ol, bp 43°-48° C. at 1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([O:21]CC)=[O:20])[O:16]2)=[CH:11][CH:10]=1.I[CH2:37][CH3:38]>>[Cl:1][C:2]1[CH:27]=[C:26]([O:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH2:37][CH3:38])([C:19]([OH:21])=[O:20])[O:16]2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1CCc2ccc(OCCCOc3ccc(Oc4ccc(F)cc4)cc3Cl)cc2O1
Reactant: CCI
Product: CCC1(C(=O)O)CCc2ccc(OCCCOc3ccc(Oc4ccc(F)cc4)cc3Cl)cc2O1

Procedure:
The title compound was synthesized following the procedure described in Example 2 employing ethyl 7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-chromane-2-carboxylate (Example 20) instead of ethyl 7-(3-(2-propyl-4-phenoxyphenoxy)propoxy)-chromane-2-carboxylate, and iodoethane instead of iodopropane.