Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[NH:14][CH:13]=[N:12][C:11]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26].O>CN(C=O)C>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([C:10]2[N:14]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:13]=[N:12][C:11]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)c2[nH]cnc2-c2ccccn2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)c2c(-c3ccccn3)ncn2COCC[Si](C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-[5-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-pyridine (Tetrahedron Lett. 1976, 285) (1.65 g, 5.51 mmol) in dry DMF (15 mL) was added NaH (60% in mineral oil, 0.36 g, 9.0 mmol) at room temperature under N2. After 30 minutes stirring, SEM-Cl (1.21 mL, 6.83 mmol) was added through a syringe. The slurry was further stirred at room temperature for 6 hours, and then poured into cold H2O (100 mL), extracted with dichloromethane (3×50 mL). Combined dichloromethane solution was washed with H2O (2×50 mL) and brine (50 mL). Flash silica gel chromatography (hexane to 2:1 hexane/ethyl acetate) afforded the 2-[5-(Toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-pyridin as a syrup intermediate in the forms of 1:1 regioisomers (1.89 g, 80%). 1H NMR δ −0.09 (s, 9H), 0.75 (t, 2H, J=7), 2.38 (s, 3H), 3.30 (t, 2H, J=7), 5.40 (s, 2H), 7.22 (d, 2H, J=8), 7.4 (t, 1H, J=6), 7.65–7.95 (m, 5 H), 8.70 (d, 1H, J=4) ppm; the other regio-isomer shows chemical shift at δ −0.02 (s, 9H), 0.8 (t, 2H, J=7), 2.41 (s, 3H), 3.41(t, 2H, J=7), 5.65 (s, 2H), 7.2–7.35 (m, 7.70–7.90 (m, 5H), 8.1 (d, 1H, J=8), 8.68 (d, 1H, J=4)ppm; (ESMS calcd for (C21H27N3O3SSI): 429.2; found: 430.4 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C:14]3[CH:23]=[CH:24][C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:28])=[CH:26][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3]>C(Cl)Cl.CO>[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:14]3[CH:23]=[CH:24][C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:28])=[CH:26][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)(=[NH:3])[NH2:4]
Reactant: COC(=O)CCCn1c(-c2ccc(C(=N)N)cc2)nc2cc(C(=O)NCCC(=O)OC)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)N)cc1)n2CCCC(=O)O

Procedure:
Obtained as a by-product in (120) Rf value: 0.19 (silica gel; methylene chloride/methanol=8:2)
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[O:4][N:3]=1.[OH-].[Li+]>C(#N)C.O>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[O:4][N:3]=1
Reactant: CCOC(=O)c1cc(N)no1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Nc1cc(C(=O)O)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a solution of ethyl 3-aminoisoxazole-5-carboxylate (prepared according to Lepage, Francis; Hublot, Bernard; Adolphe, Pierre Sylvie. Preparation of alkyl 3-aminoisoxazole-5-carboxylates. Fr. Demande (1998), FR 2750425) (0.790 g, 5.06 mmol) in acetonitrile (28 mL) and water (9.5 mL) was added lithium hydroxide (0.550 g, 23.0 mmol). The resulting mixture was stirred at rt for 3 h. The reaction was quenched with 1 N HCl. Organic solvent was removed in vacuo. The resulting precipitate was filtered and dried to give the product as white solid (585 mg, 90%). LCMS calculated for C4H5N2O3 (M+H)+: m/z=129.0.
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(F)cc1)C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(c1ccc(F)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
2.20 g (about 88% pure, 6.96 mmol) of (+/−)-tert-butyl cyclopentyl(4-fluorophenyl)acetate were dissolved in 2.9 ml of dichloromethane, and 10.7 ml of trifluoroacetic acid were added at RT. The mixture was stirred at RT for 3 h and then concentrated under reduced pressure. The residue was dried under high vacuum overnight. The solid obtained was triturated with acetonitrile and then filtered off with suction and washed with a little acetonitrile. Drying under high vacuum gave 720 mg of a first solids batch. The filtrate obtained above was concentrated and the residue was purified by preparative RP-HPLC (mobile phase acetonitrile/water). This gave a further 529 mg of the target product (overall yield 80.8% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([N:10]1[CH2:11][CH2:12][CH:7]([NH:6][C:4](=[O:5])[C:3]2[CH:13]=[CH:14][C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=3)[C:20]([F:23])([F:21])[F:22])=[CH:16][C:2]=2[Br:1])[CH2:8][CH2:9]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in CH2Cl2 (10.0 mL) was added TEA (0.046 mL, 0.35 mmol) and stirred for 10 min. Then acetyl chloride (0.014, 0.18 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution and brine solution. The combined CH2Cl2 layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was washed with 5% diethyl ether/n-pentane to afford the title compound as a white solid (0.054 g, 50%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.O.NN.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: OCCc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2ccc(CCO)cc2)c1

Procedure:
20 g (99 mmol) of 2-(4-bromophenyl)ethanol, 20 g (72 mmol) of sodium metaborate octahydrate and 2.0 g (2.8 mmol) of bis(triphenylphosphine)palladium(II) chloride are initially introduced in 30 ml of THF and 120 ml of water, and, after addition of 0.03 ml of hydrazine hydrate, a solution of 15.5 g (85 mmol) of 3,5-dimethoxybenzeneboronic acid in 60 ml of THF is added dropwise. The batch is heated under reflux overnight and subsequently extracted four times with dichloromethane. The combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the crude product is chromatographed on silica gel with heptane/ethyl acetate (2:1), giving 2-(3′,5′-dimethoxybiphenyl-4-yl)ethanol as a colourless solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]#[N:13])=[N:4][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[Cl:21].CC([O-])(C)C.[K+]>CS(C)=O.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:22][C:2]1[C:3]([C:12]#[N:13])=[N:4][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCCSc1ccc(Cl)c(C#N)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCSc1ccc(Oc2ccc(Cl)c(Cl)c2)c(C#N)n1

Procedure:
3-Chloro-6-propylthio-2-pyridinecarbonitrile (6.2 g) was mixed with 5.7 g of 3,4-dichlorophenol and 3.9 g of t-BuOK in 30 ml of DMSO and 30 ml THF. The desired, 3-(3,4-dichlorophenoxy)-6-propylthio-2-pyridinecarbonitrile was recovered, b.p. 203° C. (at 0.2 mm Hg).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:36][CH2:37][CH2:38][C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:26][N:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16]>C1COCC1>[OH:11][N:12]([C@H:13]([CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:33])([F:34])[F:35])=[CH:26][N:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16])[CH2:36][CH2:37][CH2:38][C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH:1]=[O:2]
Reactant: O=CO
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)[C@@H](CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
To formic acid (114 mL, 3.03 mol) at 0° C. was added acetic anhydride (28.6 mL, 0.303 mol) and the mixture was stirred at RT for 10 minutes. The reaction was then recooled to 0° C., and added to a solution of 2-(4-{[2-(hydroxyamino)-5-pyrimidin-2-ylpentyl]sulfonyl}piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidine (30.6 g, 60.5 mmol) and formic acid (114 mL, 3.03 mol) in THF (600 mL). The reaction was brought to room temperature and stirred for one hour. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (2×300 mL). The residue was then dissolved in methanol (300 mL) and heated to 40° C. for one hour. The solution was then cooled to room temperature and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% MeOH in EtOAc) to give the racemic compound as a pale orange foam (22.94 g, 43 mmol, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
Temperature: 25 °C
Yield: 45 %

Procedure:
2-Bromo-4-fluoronitrobenzene (949 mg, 4.31 mmol) was added in two portions to neat N-methypiperazine (8 mL) at 0° C. and allowed to warm to room temperature. The reaction was heated to 60° C. for 1 h, and then it was diluted with 50 mL of EtOAc and poured into H2O (50 mL). The layers were separated and the organic layer was washed with satd aq NaHCO3, dried (Na2SO4), and concentrated in vacuo to afford 580 mg (45%) of the title compound as a yellow solid: Mass spectrum (ESI, m/z): Calcd. for C11H14BrN3O2, 300.0 (M+H). found 300.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(OCC)C.[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[OH-].[Na+]>[CH2:15]([O:22][C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 6.56 g (50 mmoles) of 6-aminohexanoic acid in 25 ml of 2N aqueous sodium hydroxide solution was added 5 ml of ethyl ether. To the mixture, while being cooled in ice and stirred, were added dropwise over a period of 30 minutes 10 ml of benzyloxycarbonyl chloride and 37.5 ml of 2N aqueous sodium hydroxide solution. After the addition, the temperature was brought back to room temperature and the stirring was continued for 2 hours. The reaction mixture was washed twice with 20 ml of ethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted 3 times with 50 ml of ethyl acetate. The extract solutions were combined, washed with saturated saline, dried over anhydrous sodium sulfate and freed from the solvent by distillation to obtain 12.16 g (92% yield) of 6-benzyloxycarbonylaminohexanoic acid with a melting point of 127°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1C#N.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:6]2[C:5]([CH:12]=[C:10]([C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[C:14]([F:24])([F:23])[F:13])[NH:9][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1cc(Cl)ccc1C
Reactant: N#Cc1ccccc1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
45.3 ml of a 1.8 M lithium diisopropylamide THF solution (81.6 mmol) was diluted with 68 ml of THF. Thereafter, 28 ml of a THF solution containing 5.0 g (27.2 mmol) of the 5-chloro-2,N-dimethylbenzamide prepared in Step A was added dropwise to the diluted solution at −78° C. Thereafter, 28 ml of a THF solution containing 4.65 g (27.2 mmol) of 2-trifluoromethylbenzonitrile was further added thereto, and the obtained mixture was then stirred at −78° C. for 2.5 hours. The temperature of the reaction solution was increased to a room temperature, and a saturated ammonium chloride aqueous solution was added thereto, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, a solid generated as a result of vacuum concentration was filtrated, so as to obtain 6.87 g (78%) of 7-chloro-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=1)[C:33](O)=[O:34]>>[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=1)[C:33]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:34]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cncc(Br)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cncc(Br)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-bromo-nicotinic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[CH:15]=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:13][CH2:12]2)=[O:31])=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1cccc(CN2CCC(O)CC2)c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3cccc([N+](=O)[O-])c3)CC2)cc1
Yield: 73.4 %

Procedure:
0.65 g (0.00275 mol) of 1-(3-nitro-benzyl)-piperidin-4-ol and 1.9 ml (0.0136 mol) of triethylamine were dissolved in 27.5 ml of toluene, treated with 1.09 ml (0.00825 mol) of 4-methyl-benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.715 g (73%) of 1-(3-nitro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as yellow crystals; m.p. 90°-93°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([O:19][CH2:20][C:21]3C=CC=CC=3)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].BrCC#[N:32].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([O:19][CH2:20][C:21]#[N:32])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Cc1c[nH]c2c(OCc3ccccc3)cccc12)NC(=O)OC(C)(C)C
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(Cc1c[nH]c2c(OCC#N)cccc12)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 70.2 %

Procedure:
The crude {1-methyl-2-[7-hydroxy-1H-indol-3-yl]ethyl}-carbamic acid tert-butyl ester from above (29.2 g, 102 mmol theory) is dissolved in methyl ethyl ketone (300 mL) and bromoacetonitrile (20.4 mL, 306 mmol) and potassium carbonate (33.8 g, 250 mmol) is added. The mixture is heated at 80° C. for 2 hours. The solids are removed by filtration, the cake is washed with methyl ethyl ketone, and the combined filtrates are concentrated by rotary evaporation. The crude product is purified by flash chromatography (500 g silica gel, eluted with 8×500 mL dichloromethane, 4×500 mL 5% ethyl acetate/dichloromethane, 6×500 mL 10% ethyl acetate/dichloromethane). The fractions containing product are concentrated and hexane is added to the solution to precipitate out the product affording 23.7 g (70.2% yield) of racemic {1-methyl-2-[7-cyanomethoxy-1H-indol-3-yl]ethyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].Cl.[NH2:13][OH:14].[OH-].[Na+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:13][OH:14])=[O:11]
Reactant: NO
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NO)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
A solution of 14.2 g (75 mmol) of 2,4-dichlorophenylisocyanate in 50 mL of toluene was added to a mixture of 8.26 g (120 mmol) of hydroxylamine hydrochloride and 4.8 g (120 mmol) of sodium hydroxide in a two-phase solvent mixture consisting of 50 mL of water and 50 mL of toluene. The resulting mixture was stirred at 25° C. for 30 minutes and filtered. The solid thus obtained was washed with water and then dissolved in 200 mL of ethyl acetate. The solution was dried over magnesium sulfate and the solvent was removed under reduced pressure to yield 12.7 g of the title compound of Step A as a white solid melting at 157-158° C. It was used directly in the next step without further purification.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][N:14]2[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1)(C)(C)C.Cl[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]2)[N:29]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:41][C:39]1([CH3:42])[CH2:40][CH:35]([NH:34][C:30]2[N:29]=[C:28]([C:12]3[C:11]4[C:15](=[CH:16][C:8]([CH2:7][OH:6])=[CH:9][CH:10]=4)[N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[CH:13]=3)[CH:33]=[CH:32][N:31]=2)[CH2:36][C:37]([CH3:44])([CH3:43])[NH:38]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc2ccn(COCC[Si](C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3cn(COCC[Si](C)(C)C)c4cc(CO)ccc34)n2)CC(C)(C)N1

Procedure:
[3-[2-(2,2,6,6-Tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-6-yl]-methanol was prepared as described in Example 215, starting from 6-(tert-butyl-dimethyl-silanyloxymethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by selective cleavage of the TBDMS-protecting group with TBAF. Yield: 7.1 g (93%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[F:16][C:17]1[CH:18]=[C:19]([OH:26])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24]>CN(C)C=O>[CH2:1]([O:26][C:19]1[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([F:16])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In N,N-dimethylformamide (70 mL), 3-fluoro-4-nitrophenol was dissolved, and benzyl bromide (6.53 g, 38.2 mmol) and potassium carbonate (6.59 g, 47.7 mmol) were added thereto and the mixture was stirred at room temperature for 18 hr. Water (100 mL) was added to the reaction mixture and the mixture was extracted three times with ethyl acetate (100 mL). The combined organic layer was washed with 1 mol/L hydrochloric acid and brine. The mixture was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting solid was washed with hexane to afford 4-(benzyloxy)-2-fluoro-1-nitrobenzene as a yellow solid (7.47 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc([N+](=O)[O-])cn2)c1
Yield: 84.4 %

Procedure:
The title compound (612 mg) was prepared from 2-chloro-5-nitropyridine (500 mg, 3.15 mmol) and 3-methoxyphenylboronic acid (623 mg, 4.1 mmol) as a pale yellow solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.50 (d, J 2.6, 1H), 8.53 (dd, J 2.6, 8.8, 1H), 7.91 (d, J 8.8, 1H), 7.69-7.68 (m, 1H), 7.63 (d, J 7.8, 1H), 7.44 (t, J 7.9, 1H), 7.08-7.05 (m, 1H), 3.91 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].C(OC([N:37]1[CH:41]=[CH:40][CH:39]=[C:38]1B(O)O)=O)(C)(C)C>>[NH:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:3]=1[CH3:29]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccc[nH]1)OCC2c1ccc(C(C)C)cc1
Yield: 19 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl) boronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 19%. Melting point: 188-190° C. (ethyl acetate).