Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19](Cl)=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([N:9]2[CH2:10][CH2:11][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)=[O:20])=[CH:15][CH:14]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: O=C(Cl)COc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COc1ccc(F)cc1)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and (4-fluoro-phenoxy)-acetyl chloride (471.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 2-(4-fluorophenoxy)-1-(3-phenylpyrrolidin-1-yl)ethan-1-one are collected and the solvent is removed in vacuo to give 495 mg of colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:26]/[C:27](/B(O)O)=[CH:28]/[CH3:29].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1/[C:27](/[CH3:26])=[CH:28]\[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(Br)c1
Reactant: C/C=C(/C)B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C/C=C(/C)c1cc(C(=O)OC)ccc1OCc1ccccc1
Yield: 40.5 %

Procedure:
Methyl 4-benzyloxy-3-bromobenzoate (1.61 g, 5.0 mmol), caesium carbonate (4.89 g, 15.0 mmol), (E)-2-buten-2-yl boronic acid (600 mg, 6.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocenyl]palladium (II) chloride (204 mg, 0.25 mmol) were dissolved in anhydrous tetrahydrofuran (100 ml), water (10 ml) was added and the mixture was stirred and held at reflux under an atmosphere of nitrogen for 16 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between dichloromethane and water. The organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 5% ethyl acetate in petroleum ether afforded methyl (Z)-4-benzyloxy-3-(1-methyl-propenyl)-benzoate (600 mg, 41%) as a colourless solid. 1H NMR (DMSO-d6) 7.88 (1H, dd), 7.59 (1H, d), 7.40 (4H, m), 7.34 (1H, m), 7.23 (1H, d), 5.57 (1H, q), 5.21 (2H, s), 3.82 (3H, s), 1.94 (3H, s), 1.38 (3H, d).
Reaction SMILES: [I-:1].[Na+].C(N(C(C)C)CC)(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([N:21]2[CH2:26][CH2:25][CH2:24]/[C:23](=[CH:27]\[C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]4)=[C:30]([O:40][CH3:41])[CH:29]=3)/[C:22]2=[O:42])[CH3:20])=[CH:15][CH:14]=1.[C:43]([O:46][CH2:47]Cl)(=[O:45])[CH3:44]>COCCOC>[I-:1].[C:43]([O:46][CH2:47][N+:36]1[C:37]([CH3:39])=[CH:38][N:34]([C:31]2[CH:32]=[CH:33][C:28](/[CH:27]=[C:23]3/[C:22](=[O:42])[N:21]([C@H:19]([C:16]4[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=4)[CH3:20])[CH2:26][CH2:25][CH2:24]/3)=[CH:29][C:30]=2[O:40][CH3:41])[CH:35]=1)(=[O:45])[CH3:44]
Reactant: COc1cc(/C=C2\CCCN([C@@H](C)c3ccc(F)cc3)C2=O)ccc1-n1cnc(C)c1
Reactant: CC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C2\CCCN([C@@H](C)c3ccc(F)cc3)C2=O)ccc1-n1cc(C)[n+](COC(C)=O)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Sodium iodide (54 mg) and IPEA (0.05 mL) were added to a DME solution (2 mL) of (E)-1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one (CAS Registry No. 870843-42-8, 100 mg) and chloromethyl acetate (0.03 mL), and the resulting reaction solution was stirred at 80° C. for 1 hr. The reaction solution was allowed to cool to room temperature, and the precipitated solid was collected by filtration. The obtained solid was washed with diethylether and dried in air to give 70 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:20]([CH3:23])[O:21][N:22]=3)[C:6](=[O:19])[N:7]([C@H:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]([NH2:18])[CH2:13]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:20]([CH3:23])[O:21][N:22]=3)[C:6](=[O:19])[N:7]([C@H:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:18][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])[CH2:13]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1onc2c1c(=O)n([C@H]1CCC[C@@H](N)C1)c1cccc(Cl)c21
Reactant: O=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1onc2c1c(=O)n([C@H]1CCC[C@@H](NC(=O)Nc3ccccc3)C1)c1cccc(Cl)c21

Procedure:
To the suspension of cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-amino-cyclohexane (0.0446 g, 0.121 mmol) in 1 mL anhydrous THF at RT was added 2N NaOH (0.60 mL, 0.121 mmol). After 5 min. the phenylisocyanate (0.013 mL,0.121 mmol). After 20 min. the reaction was diluted with EtOAc, washed with water and concentrated to near dryness. After sonication and filtration a white solid (0.0412, 75%) was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@:10]1([CH2:16][OH:17])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:33](Cl)(=[O:47])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@:10]1([CH2:16][O:17][C:33](=[O:47])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC[C@](CO)(COCc2ccccc2)O1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)OC[C@]1(COCc2ccccc2)CCC(=O)O1
Yield: 91.8 %

Procedure:
A solution of 2.14 (0.024 g, 0.1 mmol) in CH2Cl2 (5 mL) was stirred with pyridine (0.032 mL, 0.4 mmol), a catalytic amount of dimethylaminopyridine, and tetradecanoyl chloride (0.054 mL, 0.2 mmol) for 2 h at room temperature. The solution was concentrated and the residue was purified by flash column chromatography over silica gel with hexane:EtOAc (2:1) as eluant to give 2.15 (0.041 g, 92%) as an oil; [α]22D +1.43° (c 4.2, CHCl3); IR (neat) 1783 and 1743 cm-1 (C=O); 1H NMR (CDCl3) δ 0.85 (distorted triplet, 3 H, CH3), 1.10-1.40 (m, 20 H, CH3 (CH2)10CH2CH2CO), 1.60 (br m, 2 H, CH3 (CH2)10CH2CH2CO), 2.00-2.30 (m, 2 H, H-4), 2.30 (t, J=7.5 Hz, 2 H, CH3 (CH2)10CH2CH2CO), 2.50-2.75 (m, 2 H, H-3), 3.60 (br s, 2 H, CH2OCH2Ph), 4.20 (AB q, J=11.9 Hz, 2 H, CH2OCO), 4.55 (br s, 2 H, CH2OCH2Ph), 7.20-7.40 (m, 5 H, Ph); 13C NMR (CDCl3) δ 14.09, 22.65, 24.81, 26.40, 28.78, 29.07, 29.20, 29.32, 29.42, 29.57, 29.61, 29.64, 31.89, 34.03, 65.99, 72.21, 73.76, 84.94, 127.63, 127.93, 128.49, 137.33, 173.14, 176.30. Anal. Calcd for C27H42O5 : C, 72.61; H, 9.48. Found: C, 72.70; H, 9.50.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH4+:20].[OH-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:20])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(N)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 160.9 %

Procedure:
To a solution of 4-methyl-2-nitrobenzoic acid (1.0 g, 5.52 mmol) in toluene (5 mL) was added oxalyl chloride (1.04 g, 8.28 mmol) at 0° C. and the reaction mixture was stirred at rt for 2 h. Then the reaction mixture was concentrated and the concentrate was dissolved in THF (5 mL). Then NH4OH (1.93 g, 55.20 mmol) was added to the solution at 0-5° C. and the reaction mixture was stirred at rt for 4 h before it was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated to afford 1.6 g of the desired product. 1H NMR (300 MHz, DMSO-d6): δ 8.08 (br s, 1H), 7.79 (s, 1H), 7.62 (br s, 1H), 7.57-7.50 (m, 2H), 2.41 (s, 3H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([NH:21]O)=[NH:20])[CH:13]=[CH:12]2>CC1C=C(C)C=C(C)N=1>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1[N:20]=[C:5]([CH3:6])[O:7][N:21]=1)[CH:13]=[CH:12]2
Reactant: CC(=O)OC(C)=O
Reactant: N=C(NO)c1ccc2cc(Br)ccc2c1
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1nc(-c2ccc3cc(Br)ccc3c2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.11 ml acetic anhydride are added to 4.40 g 6-bromo-N-hydroxy-naphthalene-2-carboxamidine in 30 ml 2,4,6-trimethylpyridine. The reaction mixture is stirred for one hour at ambient temperature and then heated to 130° C. for four hours. After the reaction has ended the mixture is evaporated down in vacuo and the flask residue is stirred with ethyl acetate and petroleum ether, suction filtered and dried.
Reaction SMILES: [N:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]2[CH2:15][C@H:14]([S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][N:12]2[C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[CH2:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N>N1C=CC=CC=1>[NH2:1][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]2[CH2:15][C@H:14]([S:16][C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][N:12]2[C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[CH2:6][CH2:5]1
Reactant: [N-]=[N+]=NN1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: NN1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of (2S,4S) 2-[(4-azidopiperizin-1-yl)-methyl]-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (3.76 g) in pyridine (12 ml) was added triphenylphosphine (2.38 g) and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added conc. ammonia (0.76 ml) and the mixture was allowed to stand overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(4-aminopiperizin-1-yl)methyl]-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (2.66 g).
Reaction SMILES: [C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14]>>[C:12]([O:16][CH:2]([O:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)[CH:1]([CH3:10])[CH3:8])(=[O:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)O
Reactant: OC12CC3CC(CC(C3)C1)C2
Product: C=CC(=O)OC(OC12CC3CC(CC(C3)C1)C2)C(C)C
Yield: 74 %

Procedure:
By following the same procedures as in Examples 1-1-1 to 1-1-3 aside from using 1-adamantanol instead of 2-adamantanol and acrylic acid instead of methacrylic acid, 1-(1-adamantyloxy)-2-methylpropyl acrylate was produced (four step yield 74%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1>>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:10]=[CH:11][C:12]5[N:13]([C:15]([C:18]([F:20])([F:21])[F:19])=[N:16][N:17]=5)[N:14]=4)[CH2:3]3)[CH2:6]2)[CH:23]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: O=Cc1cccnc1
Product: FC(F)(F)c1nnc2ccc(N3CC4CN(Cc5cccnc5)CC4C3)nn12

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with pyridine-3-carbaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[2-(pyridin-3-ylmethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>CCOCC>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1COc1cccnc1N
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccccc1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (1.19 g, 0.0056 mol), 4-chlorophenyl isothiocyanate (1.15 g, 0.0068 mol) and toluene (10 ml) was refluxed for 2.5 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 1.63 g (77%), m.p. 181°-183 ° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[C:5]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:4]1=2.C(N(CC)CC)C.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27].C([O-])(O)=O.[Na+]>C1COCC1>[C:25]([NH:2][CH:3]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[C:5]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:4]1=2)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)Cl
Reactant: NC1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NC1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reaction time: 18 h
Yield: 90.8 %

Procedure:
Under N2 was added 5,6-dihydro-4-amino-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxidehydrochloride (3.2 g, 0.01 mol), triethylamine (2.2 g, 0.022 mol) and THF (100 ml). The mixture was stirred at room temperature while a solution of isobutyryl chloride (1.12 g, 0.0105 mol) in THF (10 ml) was added dropwise. After 18 hours, the mixture was poured onto saturated NaHCO3 and the suspension was extracted with ethyl acetate (3X). The combined organic extracts were dried, filtered and concentrated to dryness to yield 3.2 g (91%) of product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH2:34]([CH2:36][NH2:37])[OH:35]>C1COCC1.CCOC(C)=O>[OH:35][CH2:34][CH2:36][NH:37][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: NCCO
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NCCO)c3)n2)n1
Yield: 43 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.275 g, 0.5 mmol) by treatment with excess ethanolamine in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.110 g, 43%) as a white solid. MS (ISP) 513.9 [(M+H)+]; mp 110° C. (dec.).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCC(=O)Nc1ccc(OC)c(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1ccc(OC)c(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 22 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}butanamide according to the procedures described in Scheme 8: ESMS m/e: 528.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:30]([OH:33])[CH2:31][OH:32])[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][CH2:15][C:16]1[CH:17]=[C:18]([NH:22]C(=O)OC(C)(C)C)[CH:19]=[CH:20][CH:21]=1)=[O:3].Cl.O1CCOCC1>CO>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:14][C:9]1[C:8]2[C:13](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=[C:6]([CH:30]([OH:33])[CH2:31][OH:32])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNc2ncnc3c(C(N)=O)cc(C(O)CO)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)c1cc(C(O)CO)cc2c(NCc3cccc(N)c3)ncnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [3-({[8-(aminocarbonyl)-6-(1,2-dihydroxyethyl)quinazolin-4-yl]amino}methyl)phenyl]carbamate (25.00 mg; 0.06 mmol; 1.00 eq.) in methanol was added 4.0M hydrogen chloride in dioxane (0.14 ml; 4.00 M; 0.55 mmol; 10.00 eq.). The reaction mixture was stirred at RT for 1 h and evaporated off the solvent to obtain the title compound MS (M+1) 354
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1.[O-:11][CH2:12][CH3:13].[Na+]>CN(C=O)C>[CH2:12]([O:11][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1)[CH3:13]
Reactant: CC[O-]
Reactant: COc1ccc(I)nc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1nc(I)ccc1OC
Temperature: 100 °C

Procedure:
In a microwave vial, 2-bromo-6-iodo-3-methoxypyridine (10-1 or 3-3, 150 mg, 0.48 mmol, 1 equiv) was dissolved in DMF (300 uL). Sodium ethoxide (268 uL, 21 wt % in EtOH, 0.72 mmol, 1.5 equiv) was added to the solution, and the reaction was heated in the microwave for 5 minutes at 100° C. The reaction mixture was partitioned between saturated NaHCO3 and DCM. The organic phase was washed once with brine, dried over Mg2SO4 and concentrated. The residue was purified by normal phase column chromatography (0-20% EtOAc in hexanes) to give the title compound (10-2). ESI+MS [M+H]+ C8H11INO2: 280.0 found, 280.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=[O:5].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:13])=[O:12])=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Reactant: C1CCNCC1
Solvent: ClCCl
Product: O=C(O)c1c(Cl)ccc(S(=O)(=O)N2CCCCC2)c1Cl

Procedure:
2,6-Dichloro-5-chlorosulfonylbenzoic acid (960 mg.; 3.3 m moles) is added portion-wise to 1.95 g. (0.0165 mole) of piperidine in 15 ml. of dry methylene chloride, and the mixture heated to reflux for 1.5 hrs. Th solvent and excess amine are removed under reduced pressure and the residue dissolved in 15 ml. of 2N sodium hydroxide. The aqueous base solution is extracted (2 × 50 ml.) with ether and acidified with 6N hydrochloric acid. The precipitated gum is filtered, dried and allowed to crystallize in hexane, 1.1 g., m.p. 145°-150° C. A small sample is recrystallized from acetonitrile, m.p. 142°-145° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)cn2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 02: tR=1.02 min; [M+H]+=420.12.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([O:1][CH2:10][CH2:11][OH:12])=[CH:7][CH:6]=1
Reactant: OCCBr
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCCO)cn1
Reaction time: 8 h

Procedure:
5.00 g (45.82 mmol) of 3-hydroxy-6-methylpyridine are dissolved in 65 ml of dry DMF, 6.87 g (54.98 mmol) of 2-bromoethanol and 25.33 g (183.27 mmol) of potassium carbonate are added and the mixture is stirred at +150° C. for 8 h. The mixture is then filtered, and the filtrate is concentrated on a rotary evaporator. After addition of 100 ml of ethyl acetate and 30 ml of saturated aqueous sodium bicarbonate solution, the phases are separated and the aqueous phase is extracted two more times with in each case 30 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is removed on a rotary evaporator. Without further purification, the residue is used for the subsequent reaction.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NCc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
Following the procedure described in Example 1A, step 1, 4-(trifluoromethoxy)benzaldehyde and 4-isopropylaniline gave the title compound as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=[C:14]([NH2:24])[N:13]=1)C.[OH-].[K+]>CO>[NH2:24][C:14]1[N:13]=[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([OH:25])=[O:3])[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=1
Reactant: CCOC(=O)c1ccccc1Nc1cc(-c2ccccc2)nc(N)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(Nc2ccccc2C(=O)O)cc(-c2ccccc2)n1

Procedure:
2-(2-Amino-6-phenyl-pyrimidin-4-ylamino)-benzoic acid was prepared by hydrolyzing 2-(2-amino-6-phenyl-pyrimidin-4-ylamino)-benzoic acid ethyl ester (0.2 g, 0.59 mmol) in methanol (5 mL) using aqueous solution of potassium hydroxide (6 N KOH). The mixture was concentrated under vacuum, diluted with water (5 mL), neutralized with cold 2N HCl. The solid precipitated was filtered and dried to give the desired product.