Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccc2cc[nH]c2c1
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1
Yield: 72.2 %

Procedure:
A stirred solution of 6-chloroindole (455 mg, 3.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (650 mg, 3.3 mmol), and pyrrolidine (0.62 mL, 7.4 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue was recrystallized from ethyl acetate and hexanes to afford a yellow solid (721 mg, 72%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.OC1C2N=NNC=2C=CC=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([S:47][CH:48]2[N:51]([CH2:52][C:53](O)=[O:54])[C:50](=[O:56])[CH2:49]2)=[CH:43][CH:42]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:53](=[O:54])[CH2:52][N:51]2[CH:48]([S:47][C:44]3[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3)[CH2:49][C:50]2=[O:56])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCCCc1ccccc1
Reactant: COc1ccc(SC2CC(=O)N2CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(SC2CC(=O)N2CC(=O)NCCCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of 6-phenylhexylamine (Morse M. A. et al., Cancer Research, 1991, 1846), (1.4 g, 8 mmol) in DMF (50 ml) was added to DCC (1.6 g, 8 mmol), hydroxybenzotriazole (1.0 g, 8 mmol) and (4-(4-methoxyphenylthio)-2-oxoazetidin-1-yl)acetic acid (2.1 g, 8 mmol) and the mixture stirred for 2 hours at room temperature. Ethyl acetate (250 ml) was added, the precipitate filtered, the filtrate washed with dil NaHCO3, water (x2), dried (MgSO4) and evaporated to an oil which was purified by flash chromatography on silica gel using hexane/ethyl acetate (1:3). Evaporation of the appropriate fractions gave the product as a colourless oil, 77% yield. 1H NMR δ (CDCl3) 1.34-1.47 (10H, m, (CH2)5), 2.59 (2H, t, J=7.7 Hz, CH2), 2.83 (1H, dd, J=2.2, 15 Hz, H3a), 3.18-3.36 (3H, m, CH2H3b), 3.78 (3H, s, OCH3), 3.80, 3.99 (each 1H, d, J=15 Hz, NCH2), 4.95 (1H, m, H4), 6.23 (1H, bt, NH), 6.87 (2H, d, J=6.8 Hz, 2, 6 Ph--H), 7.14-7.39 (7H, m, 3, 5 Ph--H, Ph--H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:28]=[CH:27][C:23]2=[N:24][O:25][N:26]=[C:22]2[CH:21]=1>>[N:24]1[O:25][N:26]=[C:22]2[CH:21]=[C:20]([CH2:19][N:16]3[CH:11]([C:4]4[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]3=[O:17])[CH:28]=[CH:27][C:23]=12
Reactant: BrCc1ccc2nonc2c1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2nonc2c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 5-(bromomethyl)benzo[c][1,2,5]oxadiazole. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.74 min.; [M+H]+: 368.1 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C@@H:10]([CH3:13])[C:11]#[N:12].P([O-])(OCC)(SCC)=[S:22].C(O)(C)C.C([O-])([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C@@H:10]([CH3:13])[C:11]([NH2:12])=[S:22]
Reactant: C[C@@H](C#N)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Reactant: CCOP([O-])(=S)SCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: C[C@@H](C(N)=S)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 110 °C
Yield: 85.2 %

Procedure:
(2S,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-yl-butyronitrile (50.0 g, 180 mmol), diethyl dithiophosphate (134 mL, 719 mmol), isopropanol (50 mL) and water (40 mL) were mixed together and the mixture was heated in an oil-bath (temp. setting at 110° C.) for 3 h. After cooling to 0° C., 5% Na2CO3 aqueous solution (500 mL) was added slowly and then solid Na2CO3 (25 g) was added portionwise. The mixture was extracted with EtOAc (1 L) and the EtOAc layer was washed with sat. NaHCO3 aqueous solution, water (×2) and brine, dried over MgSO4 and evaporated under reduce pressure. The resulting solid was purified by recrystalization from isopropanol to give pure (2R,3R)-3-(2,5-difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylthiobutyrarnide (47.9 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Br[CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].CCN(C(C)C)C(C)C>C(#N)C>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([N:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CNc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N(C)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
4-Fluoro-N-methylaniline (0.33 g, 2.67 mmol) is added to a solution of ethyl 2-bromo-2-phenylacetate (0.36 mL, 2.06 mmol) in acetonitrile (6.86 mL) and DIPEA (0.47 ml, 2.67 mmol). The dark solution is stirred at 100° C. under microwave irradiation for 1 hour. Then solvent is evaporated and the crude is purified by flash chromatography (Petroleum ether/EtOAc=97/3) to obtain intermediate I118 as a yellow solid (0.59 g, 100% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:28]=[CH:27][C:22]5[O:23][CH2:24][CH2:25][O:26][C:21]=5[CH:20]=4)[CH2:15][CH2:14]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([NH:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:28]=[CH:27][C:22]5[O:23][CH2:24][CH2:25][O:26][C:21]=5[CH:20]=4)[CH2:15][CH2:14]3)[CH:7]=[N:8][C:4]=2[CH:3]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1
Product: CC(=O)Nc1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1

Procedure:
Analogously to Example 7, reaction of 6-[4-(4-(5-aminobenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane ("E") with acetyl chloride gives 6-[4-(4-(5-acetamidobenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][C@@H:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30].[O:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][C@@H:25]4[CH2:29][CH2:28][N:27]([CH:34]5[CH2:35][CH2:36][O:31][CH2:32][CH2:33]5)[CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCNC1)C3
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCN(C2CCOCC2)C1)C3
Yield: 44.5 %

Procedure:
A mixture of Example 80 (150 mg; 0.35 mmol; 1 eq.), tetrahydropyran-4-one (52 mg; 0.52 mmol; 1.5 eq.) and sodium triacetoxyborohydride (74 mg; 0.35 mmol; 1 eq.) in DCE (4 mL) was stirred at 50° C. for 16 hours. The reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA to EA/MeOH/TEA, 90/10/2) afforded the title compound (80 mg, 45%) as white foam. 1H NMR (DMSO-d6) δ 7.41-7.31 (m, 1H), 6.99 (dd, J=11.5, 2.2 Hz, 1H), 6.87 (td, J=8.4, 2.3 Hz, 1H), 5.03-4.94 (m, 1H), 4.85-4.77 (m, 2H), 4.75-4.44 (m, 2H), 3.74-3.59 (m, 2H), 3.22-3.06 (m, 2H), 2.85 (s, 1.5H), 2.81 (s, 1.5H), 2.79-2.64 (m, 3H), 2.62 (s, 1.5H), 2.56 (s, 1.5H), 2.35-2.15 (m, 2H), 2.14-2.00 (m, 1H), 1.82-1.68 (m, 1H), 1.63-1.50 (m, 2H), 1.31-1.03 (m, 2H). HPLC (max plot) 95.1%, Rt 2.83 min. UPLC/MS: (MS+) 514.5 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[O:5][C:4](=[O:6])[CH2:3]1.S([O-])(O)(=O)=O.[Na+].[CH3:19][OH:20]>>[CH3:19][O:20][C:4](=[O:6])[CH2:3][C:2]([CH3:1])([OH:5])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12]
Reactant: CC(C)=CCCC1(C)CC(=O)O1
Reactant: CO
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: COC(=O)CC(C)(O)CCC=C(C)C
Temperature: 10 °C
Reaction time: 1.2 h
Yield: 88.6 %

Procedure:
0.69 g of Na metal were dissolved in 200 g of methanol and cooled to 10° C. 50.47 g (0.279 mol) of 4-methyl-4-(4-methylpent-3-en-1-yl)-2-oxetanone were then added over a period of 17 mins, during which time the temperature rose to 16° C. Next, the mixture was stirred at 20° C. for 1.2 h and then acidified with 4.14 g (30 mmol) of sodium hydrogen sulfate. After being stirred for a further 1.7 h at 20° C., the suspension was filtered. The filtrate was concentrated (80 mbar, 40° C.). The residue (56.56 g) was then fractionated at 1 mbar, and the main fraction distilled at 95° C. to 97° C. 49.52 g (87.1%) of the title product were obtained in the form of an oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][NH:15]C=O)[CH:8]=[CH:7][CH:6]=1)[CH3:3].[OH-].[K+]>CO.C(OCC)C>[CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:8]=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1cccc(OCCCNC=O)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CN(C)Cc1cccc(OCCCN)n1
Yield: 77.2 %

Procedure:
N-[3-(6-dimethylaminomethyl-2-pyridyloxy) propyl]formamide (2.7 g, 0.013 mol) is added to a solution of 85% potassium hydroxide pellets (3.0 g) dissolved in methanol (30 ml) and heated at gentle reflux for 21 hours. The reaction is cooled, diluted with diethyl ether (30 ml), the precipitated salts filtered, and the solvent removed under vacuum. The residue is dissolved in water and the product exhaustively extracted into ethanol/chloroform, dried and evaporated to give 2.1 g of pure product.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]([C:11]1C=[CH:18][CH:17]=[CH:16][C:12]=1C(O)=O)=[O:10]>CN(C=O)C.ClCCl>[Cl:4][C:2]([C:1]1[CH:18]=[CH:17][CH:16]=[CH:12][C:11]=1[C:9]([O:8][CH3:7])=[O:10])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.86 ml, 9.8 mml) and two drops of DMF were added to a solution of 2-(methoxycarbonyl)benzoic acid (590 mg, 3.27 mmol) in dichloromethane (10 ml) and cooled to 0° C. and stirred at RT for 30 min. After 30 min, the solvent was removed to obtain methyl 2-(chloroformyl)benzoate (quantitative). A solution of this intermediate (401 mg, 2.03 mmol) in dichloromethane was added to a solution of intermediate 10 (540 mg, 2.03 mmol) and pyridine (0.19 ml, 2.43 mmol) in dichloromethane (5 ml) at 0° C. and stirred at RT for 30 min. Work-up (CH2Cl2/H2O) and purification gave methyl 2-(3-chloro-3′-ethoxy-5-fluorobiphenyl-4-ylcarbamoyl)benzoate (250 mg) as an off-white solid. Lithium borohydride (20 mg, 0.94 mmol) was added to a solution of this product (200 mg, 0.47 mmol) in THF (5 ml) at 0° C. and the mixture stirred at RT for 2 hrs. Work-up (EtOAc/aq. 10% NH4Cl then H2O) and purification afforded the title compound (30 mg) as a white solid. M.P.: 139.2-141.5° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.22 (s, 1H), 7.76 (s, 1H), 7.73-7.60 (m, 3H), 7.54 (t, J 6.7, 1H), 7.43-7.36 (m, 2H), 7.33-7.26 (m, 2H), 6.97 (dd, J 1.8, 8.1, 1H), 5.32 (t, J 5.6, 1H), 4.72 (d, J 5.6, 2H), 4.12 (q, J 7, 2H), 1.35 (t, J 7, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([CH3:33])[CH:24]=[CH:23][CH:22]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(C)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(m-tolyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10]([CH3:15])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:10]([CH3:15])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C)(C)C1
Temperature: 25 °C

Procedure:
To a solution of 18.5 g (82.0 mmol) 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in 150 mL DCM at RT was added 30.0 mL (174 mmol) DIPEA. The mixture was cooled with ice and a solution of 14.0 mL (93.2 mmol) benzyl chloroformate in 60 mL DCM was added dropwise. The reaction mixture was stirred at RT over night and quenched with saturated aqueous sodium bicarbonate solution. The product was extracted with DCM. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:25][C:26]1[N:27]=[C:28]([C:31]2[NH:32][C:33]3[C:38]([CH:39]=2)=[CH:37][C:36]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:35][CH:34]=3)[O:29][CH:30]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)[CH2:25][C:26]1[N:27]=[C:28]([C:31]2[NH:32][C:33]3[C:38]([CH:39]=2)=[CH:37][C:36]([O:40][C:41]([F:44])([F:42])[F:43])=[CH:35][CH:34]=3)[O:29][CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)Oc1ccc2[nH]c(-c3nc(CCl)co3)cc2c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1coc(-c2cc3cc(OC(F)(F)F)ccc3[nH]2)n1)c1ccc(CCCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [4-(4-[1,2,3]Triazol-1-yl-butyl)-phenyl]-carbamic acid tert-butyl ester (0.297 g, 0.94 mmol) in N,N-dimethyl formamide (5 ml) sodium hydride (0.050 g, 2.1 mmol) was added and the mixture stirred for 30 min at r.t. To this mixture a solution of 2-(4-chloromethyl-oxazol-2-yl)-5-trifluoromethoxy-1H-indole 0.3 g, 0.94 mmol) in N,N-dimethyl formamide (5 ml) was added and stirring continued for 16 h. The mixture was then poured on water (25 ml) and extracted with ethyl acetate (3×25 ml). The combined organic extracts was washed with water, brine and dried over sodium sulfate. After concentration in vacuo the crude product was purified on silica gel (iso-hexanes/ethyl acetate 1:2) to yield [4-(4-[1,2,3]Triazol-1-yl-butyl)-phenyl]-[2-(5-trifluoromethoxy-1H-indol-2-yl)-oxazol-4-ylmethyl]-carbamic acid tert-butyl ester as light yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:46]=[CH:45][C:43]([NH:44][S:48]([CH3:47])(=[O:50])=[O:49])=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Product: CS(=O)(=O)Nc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1

Procedure:
26 mg 4-{4-[3-(2-pyridyl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-3-pyrazolyl}aniline obtained in Example 49 and 9 μL methyl sulfonyl chloride were reacted in the same manner as in Example 20, to give 14 mg of the title compound as a colorless amorphous.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)[CH:2]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])=[CH:24][CH:23]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CC1(C)CN(Cc2cccnc2)c2ccc(O)cc21
Product: COc1ccc(NC(=O)Oc2ccc3c(c2)C(C)(C)CN3Cc2cccnc2)cc1

Procedure:
The title compound was synthesized from 1-(3-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with 4-methoxyphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (4.2 mg, 14%) having the following characteristics.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[CH2:12]([Li])CCC.CI.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:12])[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(C(C)C#N)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
14.7 g (0.10 mole) of p-methoxyphenylacetonitrile was dissolved in 250 ml of dry tetrahydrofuran and placed in a dry ice/isopropanol bath under N2. 69.0 ml of 1.6M n-butyl lithium (0.11 mole) was added dropwise over 30 minutes and the mixture stirred at -78° C. for one hour. The lithium salt of the nitrile precipitated as a yellow solid during this time. 71.0 g (0.50 mole) of methyl iodide was then added and stirring at -78° C. continued for an additional hour. The mixture was then poured into saturated ammonium chloride and the product extracted into diethyl ether, washed with saturated sodium chloride and dried over sodium sulfide. It was filtered and evaporated, redissolved in methylene chloride and passed through Florisel®. Evaporation gave 15.0 g of α-(p-methoxyphenyl)propionitrile as an orange oil.
Reaction SMILES: Cl.C1(NN)C=CC=CC=1.[C:10]1([C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH2:25][CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:30](C(CC)C(O)=O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)(=O)C>[C:30]([N:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27](=[O:28])[CH2:26][CH2:25][CH:24]([C:23]=23)[CH:16]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)CCc1c(-c2ccccc2)[nH]c2ccccc12
Reactant: CCC(C(=O)O)C(=O)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: NNc1ccccc1
Product: O=C1CCC2c3c1cccc3N(C(=O)c1ccccc1)C2c1ccccc1
Yield: 160.1 %

Procedure:
(Step 1) Synthesis of 2-phenylindole-3-propionic acid Phenylhydrazine hydrochloride (50 g) and benzoylbutyric acid (55.4 g) were suspended in acetic acid (500 ml), followed by heating to reflux for 1.5 hours. After allowing the suspension to cool, the insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous solution of sodium chloride, and thereafter dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from an ether/hexane mixed solvent, followed by washing with a methylene chloride/hexane mixed solvent to yield 69 g (90%) of the titled compound as pale brown crystals.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5]CC)[CH3:2].[C:9]([BH2:11])#[N:10].[Si](I)(C)(C)C.CCOC(C)=O>CC#N>[CH2:1]([O:3][P:4]([O-:8])[O-:5])[CH3:2].[C:9]([BH2:11])#[N:10]
Reactant: CCOP([O-])OCC
Agent: BC#N
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOP([O-])[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Diethylphosphite-cyanoborane (7a) (1. 15 g) and Me3SiI (4 equivalents) were taken in anhydrous CH3CN and were heated at reflux in the dark for 2 days. The solvent and excess Me3SiI were removed under reduced pressure. The residue was taken in CH2Cl2 /water (1:1, v/v, 50 ml) and was stirred at room temperature for 1.5 hours. The aqueous layer was separated and washed with CH2Cl2 until the organic layer was colorless. The water was evaporated at room temperature by passing a stream of air over the solution. The residue was taken in EtOAc and filtered to remove a solid. The filtrate was dried and the solvent was removed under reduced pressure to give an oil. Often, the EtOAc solution became dark colored, which could not be removed by treatment with charcoal. To remove this color, the EtOAc was removed and the whole work-up was repeated. The yield of light yellow oil was 0.49 g, 50.72%.
Reaction SMILES: [O-]CC.[Na+].[C:5]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=[O:7])[CH3:6].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(O)(=O)C>CCO>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[O:7])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)c1cccs1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(C=Cc1ccc(F)cc1)c1cccs1
Reaction time: 0.25 h

Procedure:
A solution of sodium ethoxide (21% by weight in EtOH, 0.68 gm, 10 mmol) was added to a solution of 2-acetylthiophene (12.60 gm, 100 mmol, from Aldrich) and 4-fluorobenzaldehyde (12.41 gm, 100 mmol, from Aldrich) in EtOH (50 ml) and the mixture stirred under argon for 15 minutes. More EtOH (25 ml) was then added to make a slurry of the reaction mixture, which had partially solidified. Acetic acid (0.60 gm, 11 mmol) was added and a yellow solid filtered out of solution. The solid was recrystallized from EtOAc and hexane to afford the title compound as long, pale yellow needles (17.679 gm, 71%).
Reaction SMILES: [CH:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]([O:6][CH3:7])=[O:5])=[O:2].[O:24]=O>>[C:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]([O:6][CH3:7])=[O:5])([OH:24])=[O:2].[CH:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]([O:6][CH3:7])=[O:5])=[O:2]
Reactant: O=O
Agent: CCCCCCCCCCCCCCCCC(C=O)C(=O)OC
Product: CCCCCCCCCCCCCCCCC(C(=O)O)C(=O)OC

Procedure:
Friedrich in an article entitled "Oxidation of Methyl Formylstearate with Molecular Oxygen" at J. Am. Oil Chemists' Soc. 53, p. 125-129 (1976) reports the use of air or oxygen to form methyl carboxystearate from methyl formylstearate in an emulsion with a soluble rhodium complex. The reuse of catalyst in hydroformylation reactions is described by Awl in an article entitled "Hydroformylation with Recycled Rhodium Catalyst and One-Step Esterification-Acetalation: A Process for Methyl 9(10)-Methoxymethylenestearate from Oleic Acid" which is printed in J. Am. Oil Chemists' Soc. 53, p. 190-195 (1976).