Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]2[O:18][CH2:17]2)=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]([OH:18])[CH2:17][NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cc(OCc2ccccc2)ccc1C1CO1
Reactant: CC(C)(C)N
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(OCc2ccccc2)c[n+]1[O-]

Procedure:
To 0.50 g. (0.0042 mole) of [5-benzyloxy-2-(1,2-epoxyethyl) pyridine N-oxide] in 20 ml. of methanol was added 0.5 ml. tert-butylamine and the resulting mixture heated to the reflux temperature for 4 hours. Solvent and excess tert-butylamine were removed in vacuo to give 280 mg. (43%) of the desired product after recrystallization from ether/ethyl acetate; m.p. 148°-150° (dec.). Mass spec (70 eV) m/e 300 (M-16), m/e 243 [M-H2NC(CH3)3); NMR (DMSO d6) delta 7.90 (d, 1H, H6), 7.30 (m, 6H, benzyl C6H5 and H4), 7.00 (m, 1H, H3), 5.07 (m, 3H, φCH2 and ##STR15## 4.33 (m, 2H, ##STR16## and 1.13 [s, 9H, C(CH3)3 ]; ir (KBr) 1171 (N+ -O-).
Reaction SMILES: [C:1]1([S:7][CH2:8]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([O-:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+]>CN(C)C=O>[O:16]([CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCSc1ccccc1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OCSc2ccccc2)cc1
Yield: 77.1 %

Procedure:
A solution of 47.5 g (0.3 mol) of chloromethyl phenyl sulphide in 50 ml of dimethylformamide was added dropwise to a solution of 40 g (0.34 mol) of sodium phenolate in 200 ml of dimethylformamide at room temperature in the course of 30 minutes, while stirring. The temperature of the reaction mixture thereby rose from 24° C. to 35° C. The mixture was subsequently stirred at room temperature for 14 hours and then concentrated by stripping off the solvent under reduced pressure. The oil which remained was washed successively with water, 0.1N aqueous sodium hydroxide solution and water and, after drying sodium sulphate, subjected to fractional vacuum distillation. 50 g (77.2% of theory) of phenoxy-phenylthiomethane were obtained in this manner in the form of a colourless liquid of boiling point 112°-117° C./0.16 mm Hg.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].[OH-:15].[Na+].II>O.C(O)C>[O:15]=[C:4]([N:6]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])[CH2:3][CH2:2][S:1][S:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5]
Reactant: [OH-]
Reactant: O=C1C[C@@H](C(=O)O)N(C(=O)CCS)C1
Agent: II
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1C[C@@H](C(=O)O)N(C(=O)CCSSCCC(=O)N2CC(=O)C[C@H]2C(=O)O)C1

Procedure:
The product from Example 2 is dissolved in water and the pH adjusted to 6.5 by the addition of 1 N sodium hydroxide. To this stirred solution is added dropwise a 0.5 M iodine solution in 95% ethanol (6.34 g. iodine/50 ml. solution) while maintaining the pH at 5.5 to 6.5 with 1 N sodium hydroxide. Excess iodine is removed with dilute sodium thiosulfate and the solution is concentrated, cooled and acidified with 1:1 hydrochloric acid. Solvent is added and the layers are separated. The organic layer is dried MgSO4) and the solvent evaporated to yield as a residue 1,1'-[dithiobis(1-oxo-3,1-propanediyl)]bis[4-oxo-L-proline].
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl:5][C:6]1[CH:20]=[CH:19][C:9]2[S:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][NH:14][C:8]=2[CH:7]=1.C(N(CC)CC)C>O1CCCC1>[Cl:5][C:6]1[CH:20]=[CH:19][C:9]2[S:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]([C:1]([Cl:4])=[O:2])[C:8]=2[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Clc1ccc2c(c1)NCc1ccccc1S2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cl)N1Cc2ccccc2Sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold (ice-H2O bath), stirred solution of phosgene (1.93M in toluene; 8.6 mL) in anhydrous tetrahydrofuran (40 mL) under a nitrogen atmosphere is added, dropwise, a solution of the product of Example 104 (8-chloro-10,11-dihydrodibenzo[b,f][1,4]thiazepine) (2.00 g) and triethylamine (1.3 mL) in anhydrous tetrahydrofuran (30 mL). The resulting mixture is stirred at room temperature for 90 minutes, and the solvent is then evaporated in vacuo to provide the title product.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[N:12]=[N:13][C:14]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:16]=1)=[O:10].Cl.[CH3:31][O:32][NH2:33]>CO.O>[CH3:31][O:32]/[N:33]=[C:2]1/[C@H:3]([NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]([O:24][CH2:25][C:26]([F:28])([F:29])[F:27])=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH:16]=2)=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7]/1
Reactant: O=C(N[C@@H]1CCCCC1=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CO
Product: CO/N=C1\CCCC[C@H]1NC(=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85.2 %

Procedure:
To a solution of 100 mg of 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid ((R)-2-oxo-cyclohexyl)-amide in 0.5 ml methanol and 0.5 ml water, was added 98 mg O-methylhydroxylamine hydrochloride and the mixture was stirred at ambient temperature for 3.5 h. The solvents were evaporated and the residue was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=95:5 to 50:50 to yield 91 mg of the title compound as white foam. MS (EI): 457.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.C(COC)OC.[CH:32]1(/[CH:35]=[CH:36]/B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33]1.C([O-])([O-])=O.[Na+].[Na+]>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>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](/[CH:36]=[CH:35]/[CH:32]3[CH2:34][CH2:33]3)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Reactant: CC1(C)OB(/C=C/C2CC2)OC1(C)C
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: COCCOC
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(/C=C/C3CC3)c2)N=C1N
Reaction time: 15 h
Yield: 68.5 %

Procedure:
A mixture of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (150 g, 0.36 mmol), dimethoxyethane, 2-[(E)-2-cyclopropylvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105 mg) and Na2CO3 (2 M, 2.5 mL) was degassed under argon for 5 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol). The reaction mixture was stirred for 15 hour, poured into water and extracted with ethyl acetate. The extracts were combined, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by ICSO (EtOAc/MeOH 10/1) gave the title product as a white solid (98 mg), identified by NMR and mass spectral analyses.
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)Cl.[C:11]1([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>>[C:11]1([C:17]2[O:18][C:19]([CH:3]=[O:4])=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(-c2ccco2)cc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2ccccc2)o1
Temperature: 80 °C
Yield: 83.7 %

Procedure:
To a 0° C. solution of N,N-dimethylformamide (1.9 mL, 24.97 mmol) in a three-neck flask equipped with a condenser was added POCl3 (0.65 mL, 6.94 mmol) dropwise via syringe with stirring. When the heat of the reaction subsided, 2-phenylfuran (1.0 g, 6.94 mmol) was added. The reaction was warmed to 80° C. and stirred overnight. The solution was cooled to room temperature and then neutralized to pH 8 with aqueous saturated sodium acetate. The mixture was extracted with ether (3×30 mL), dried over MgSO4, filtered and evaporated. Chromatography (silica gel, 20% ether/hexanes) yielded 1.0 g (83%) of 5-phenyl-2-furaldehyde.
Reaction SMILES: CP(C)C.O1CCCC1.[N:10]([CH2:13][CH2:14][O:15][C:16]([C@:18]1([F:38])[C@@H:23]2[C@H:19]1[CH2:20][C@@H:21]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C@@:22]2([NH2:27])[C:24]([OH:26])=[O:25])=[O:17])=[N+]=[N-]>O1CCCC1.O>[NH2:10][CH2:13][CH2:14][O:15][C:16]([C@:18]1([F:38])[C@@H:23]2[C@H:19]1[CH2:20][C@@H:21]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C@@:22]2([NH2:27])[C:24]([OH:26])=[O:25])=[O:17]
Reactant: [N-]=[N+]=NCCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: NCCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Reaction time: 13 h
Yield: 35.4 %

Procedure:
20 μL of a 1M trimethylphosphine/tetrahydrofuran solution was added to 6 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-azidoethyl)ester dissolved in a mixture of 0.15 mL of tetrahydrofuran and 0.02 mL of water at room temperature, and the mixture was stirred for 13 hours. After the solvent was distilled under reduced pressure, the residue was purified by reverse phase column chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.), eluent: water to a 50% aqueous solution of acetonitrile), and the obtained solids were further washed with tetrahydrofuran, thereby yielding 2 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-aminoethyl)ester.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:33][CH:32]2[N:17]([C:18](=[O:38])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35](O)=[O:36])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:16]1.C1(C2N=C(C3N=C(OC4CC5C(C(=O)N(C)CCCCC=CC6C(C([NH:81][S:82]([CH:85]7[CH2:87][CH2:86]7)(=[O:84])=[O:83])=O)(NC5=O)C6)C4)C4C(C=3)=CC(OC)=CC=4)SC=2)CC1>>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:33][CH:32]2[N:17]([C:18](=[O:38])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35]([NH:81][S:82]([CH:85]4[CH2:87][CH2:86]4)(=[O:84])=[O:83])=[O:36])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:16]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCNC(=O)N4C3)nccc2c1Br
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3nc(C4CC4)cs3)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCNC(=O)N4C3)nccc2c1Br

Procedure:
The title compound was prepared from 18-[5-bromo-6-methoxyisoquinolin-1-yloxy]-2,15-dioxo-3,14,16-triazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (74) following the procedure reported for synthesis of N-[17-[3-(4-cyclopropylthiazol-2-yl)-6-methoxyisoquinolin-1-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]_octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (30): m/z=691 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:33])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][N:42]([CH3:48])[C@H:43]1[CH2:47][CH2:46][NH:45][CH2:44]1>>[C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:33])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([C:30]([N:45]3[CH2:46][CH2:47][C@H:43]([N:42]([CH3:48])[CH3:41])[CH2:44]3)=[O:31])[CH2:28][CH2:29]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)O)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)N5CC[C@H](N(C)C)C5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
1-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperidine-4-carboxylic acid and (S)-3-dimethylamino-pyrrolidine are used as reactants.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Sn](Cl)(Cl)(Cl)Cl.[C:23](Cl)(=[O:25])[CH3:24].O>ClC(Cl)C>[C:23]([C:8]1[C:7]([O:9][CH3:10])=[CH:6][C:5]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:25])[CH3:24]
Reactant: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
To a solution of N-(3,5-Dimethoxy-phenyl)-2,2,2-trifluoro-acetamide (31.8 g, 130 mmol) in anhydrous dichloroethane (450 mL), cooled in an ice bath, was added a solution of tin (IV) chloride (29.9 mL, 260 mmol dissolved in 30 mL anhydrous dichloroethane) dropwise over 10 minutes. Acetyl chloride (9.1 mL, 130 mmol) was added slowly, maintaining the temperature of the reaction below 5° C. After stirring 3 hours at room temperature, the reaction was cooled in an ice bath. Water (300 mL) was added, maintaining the temperature of the reaction below 25° C., and the reaction was stirred at room temperature for 18 hours. The reaction mixture was extracted with dichloromethane, and the organic layer was separated, washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20% to 30% hexanes/ethyl acetate to yield N-(4-Acetyl-3,5-dimethoxy-phenyl)-2,2,2-trifluoro-acetamide (4.8 g, 13%) as a white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)O1.[NH2:27][C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([CH:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)[N:35]=[C:36](I)[C:29]=12.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:27][C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([CH:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)[N:35]=[C:36]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:25])=[CH:13][CH:14]=3)[C:29]=12
Reactant: CC1(C)OB(c2ccc(NC(=O)OCc3ccccc3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
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: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(NC(=O)OCc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A mixture of benzyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (9.54 g, 0.027 mol), tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (10.0 g, 0.0225 mol), tetrakis(triphenylphosphine)palladium (1.56 g, 0.00135 mol) and sodium carbonate (5.97 g, 0.0563 mol) was heated in a mixture of ethylene glycol dimethyl ether (120 mL) and water (60 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between water (150 mL) and dichloromethane (150 mL); the organic phase was washed with brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was triturated in diethyl ether and the precipitate was collected by filtration and dried to yield tert-butyl 4-[4-amino-3-(4-[(benzyloxy)carbonyl]aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (10.1 g, 0.0186 mol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][C:28]1[O:29][C:30]2[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][C:31]=2[N:32]=1.BrC1C=CC2N=C(C)OC=2C=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:35]5[CH:34]=[CH:33][C:31]6[N:32]=[C:28]([CH3:27])[O:29][C:30]=6[CH:36]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cc1nc2ccc(B(O)O)cc2o1
Agent: Cc1nc2ccc(Br)cc2o1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6nc(C)oc6c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-benzoxazol-6-boronic acid (prepared from 6-bromo-2-methyl-benzoxazole in analogy to the procedure described for Intermediate 46) following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.65 min; Mass spectrum (ESI+): m/z=490 [m+H]+.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]1([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][C:23](O)([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])=[CH:28][C:27]=3[F:43])[CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[C:10]1([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][C:23]([F:7])([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])=[CH:28][C:27]=3[F:43])[CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(Nc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)c(F)c1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(C2(F)CCN(C(=O)OCc3ccccc3)CC2)c(F)c1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethylaminosulfur trifluoride (DAST, 0.65 mL) in dry methylene chloride (49 mL) at -78° C. under N2 is added a solution of 4-hydroxy-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 74, Step 1, 2.25 g) in dry methylene chloride (47 mL) over 2 mins. The resulting mixture is stirred at -78° C. for 1 hr and at ambient temperature for 30 mins and is then adjusted to pH 8 with saturated aqueous sodium bicarbonate (50 mL), diluted with water (50 mL), and the layers are separated. The organic phase is washed with water (25 mL) and saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with methanol/methylene chloride (0.5/99.5). Those fractions with an Rf =0.27 by TLC (ethyl acetate/hexane, 25/75) are pooled and concentrated to give the title compound (contaminated with approx. 15% of the elimination side product). An analytical sample is prepared by radial chromatography (1000μ silica gel rotor, ethyl acetate/hexane (20/80) eluent), mp 116-118° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:17])=O.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5]([Cl:17])=[O:6]
Reactant: Cc1ccc(C)c([N+](=O)[O-])c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: Cc1ccc(C)c([N+](=O)[O-])c1C(=O)Cl

Procedure:
3,6-Dimethyl-2-nitrobenzoic acid in an amount of 9.6 g (51 mmol) was dissolved in 100 ml benzene and then followed by an addition of thionyl chloride in an amount of 8.8 g (74 mmol) and pyridine in an amount of 0.1 lg. The mixture was then heated for 2 hours under reflux, and the solvent therein was distillated out under reduced pressure to obtain 3,6-dimethyl-2-nitrobenzoyl chloride in an amount of 10.3 g.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH:11]([C:19](O)=[O:20])[NH:10]1.[ClH:22]>CCOCC>[ClH:22].[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH:11]([C:19]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:20])[NH:10]1
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C1Cc2ccccc2CN1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
Benzyl alcohol, 750 ml, was treated with 150 g of commercial polyphosphoric acid and warmed and stirred at 90° C. to obtain a homogeneous mixture. Solid 1,2,3,4 -tetrahydro-3-isoquinolinecarboxylic acid (S-form) 65.2 g was added. The mixture was stirred 4 hours at 95°-105° C. and then allowed to stand at room temperature for 18 hours. A solution of 18.5 g gaseous hydrochloric acid in 2.5 of anhydrous ether was added, and the product separated slowly on cooling overnight. Filtration gave the crude benzyl 1,2,3,4-tetrahydro-3-isoquinoline carboxylate hydrochloride. This was purified by recrystallization from ethanol twice to give material with mp 190.5°-191° C.; [α]D 23=-83.3° (1% 1:1 methanol/1N hydrochloric acid).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:28]1(I)[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOC(C)=O>CN(C)C=O>[CH:28]1([N:16]2[CH:17]=[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][CH:12]=3)=[N:15]2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)c1c[nH]nc1-c1ccc(Oc2ccccc2)cc1
Reactant: IC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cn(C2CCCC2)nc1-c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
To tert-Butyl 3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate (156 mg, 0.46 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride, 60% in mineral oil (20.8 μg, 0.52 mmol). After the gas evolution ceased (about 5 minutes), cyclopentyl iodide (59 μL, 0.51 mmol) was added dropwise and the mixture was stirred for 16 hours at room temperature. EtOAc was added and the crude mixture was washed with a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc (3 times). The combined organic extracts were washed with water and brine. The organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with petroleum ether/DCM) to afford the title compound as a white solid (0.131 g, 69% yield). MS (ES+) m/e=405. 1H NMR (CDCl3) δH 1.51 (9H, s), 1.70-1.80 (2H, m), 1.85-2.00 (2H, m), 2.02-2.13 (2H, m), 2.18-2.30 (2H, m), 4.71 (1H, quint.), 7.06 (4H, d), 7.12 (1H, t), 7.35 (2H, t), 7.76 (2H, d), 7.95 (1H, s).