Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[O:6][CH2:7][CH:8]([OH:24])[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:12][CH2:11]1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:34]O>>[CH3:34][O:2][C:1]([C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[O:6][CH2:7][CH:8]([OH:24])[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:12][CH2:11]1)=[O:3]
Reactant: CO
Reactant: COc1ccccc1N1CCN(CC(O)COc2ccccc2C(=O)O)CC1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1OCC(O)CN1CCN(c2ccccc2OC)CC1
Temperature: 25 °C

Procedure:
A solution of crude 1-(2-carboxyphenoxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-2-ol (43 g.) in 250 ml. of methanol containing 25 ml. of concentrated sulfuric acid was refluxed for 1.5 hours and then allowed to cool to room temperature. Upon completion of this step, the resulting solution was concentrated in vacuo to a volume of approximately 100 ml., then poured into 250 ml. of water and made alkaline with aqueous sodium hydroxide solution. The latter basified solution was next thoroughly extracted with chloroform, and the chloroform extracts subsequently combined and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there were ultimately obtained 34 g. of crude product as residual material. Crystallization of a portion of the latter material from methanol then gave pure 1-(2-methoxycarbonylphenoxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-2-ol, m.p. 127°-128°C.
Reaction SMILES: FC1C(O[C:9]([CH:11]2[CH2:15][C:14](=[O:16])[NH:13][CH2:12]2)=[O:10])=C(F)C(F)=C(F)C=1F.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(Cl)Cl>C1COCC1>[N:21]1([C:9]([CH:11]2[CH2:12][NH:13][C:14](=[O:16])[CH2:15]2)=[O:10])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: O=C1CC(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)CN1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CC(C(=O)N2CCNCC2)CN1
Temperature: 25 °C
Reaction time: 10 h
Yield: 107 %

Procedure:
To a suspension of 5-oxo-pyrrolidine-3-carboxylic acid pentafluorophenyl ester 17 (40.1 mg, 0.0578 mmol) in 2 mL THF extra dry was added piperazine (19.9 mg, 0.231 mmol) at room temperature. The reaction mixture was stirred for 10 hours at room temperature. Afterwards, 20 mL methylene chloride were added. The resulting organic layer was washed with 20 mL of a saturated aqueous solution of sodium hydrogenocarbonate, dried over magnesium sulfate and the solvent was removed in vacuo. Finally, the crude product was purified by chromatography on silica gel (ethyl acetate:methanol 9:1→1:1) to afford the desired 4-(piperazine-1-carbonyl)-pyrrolidin-2-one 18 as a white solid (12.2 mg, 45.91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].Cl>CN(C)C=O.O>[CH2:27]([O:26][C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1)OCc1ccccc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A suspension of 6.9 g (30 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 10 g (100 mmol) of potassium bicarbonate, and 100 ml of water is stirred at room temperature and 300 ml of dimethylformamide is added followed by 6.0 ml (43 mmol) of benzyl chloroformate. The mixture is stirred at room temperature for 2 hrs and 6.0 ml of benzyl chloroformate and 6.0 g of potassium bicarbonate are added. The reaction is stirred overnight at room temperature and poured into 700 ml of ice water. The pH is adjusted to 3 with hydrochloric acid and the precipitate is filtered, washed with water, and dried to give 9.44 g of 6-[4-(benzyloxycarbonylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid after recrystallization from N,N-dimethylacetamide-methanol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=1.[NH2:18][C@@H:19]([CH3:35])[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[CH:27]=2)=[N:22]1>>[Cl:34][C:28]1[CH:27]=[C:26]([C:23]2[CH:24]=[CH:25][N:21]([CH2:20][C@@H:19]([NH:18][C:15]([C:12]3[CH:11]=[C:10]([CH2:9][CH2:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[O:14][N:13]=3)=[O:17])[CH3:35])[N:22]=2)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc(CCOC2CCCCO2)on1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CCOC2CCCCO2)on1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)isoxazole-3-carboxylic acid (0.222 g, 0.921 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The product was purified with reverse phase flash-chromatography. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d, 3H), 1.34-1.51 (m, 4H), 1.52-1.69 (m, 2H), 3.06 (t, 2H), 3.37-3.45 (m, 1H), 3.61-3.71 (m, 2H), 3.85-3.93 (m, 1H), 4.28-4.34 (m, 2H), 4.41-4.50 (m, 1H), 4.57-4.61 (m, 1H), 6.51 (d, 1H), 6.93 (d, 1H), 7.81 (d, 1H), 7.92 (dd, 1H), 7.97 (dd, 1H), 8.08 (dd, 1H), 8.74 (d, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:26]([OH:27])=[CH:25][C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[CH:18]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:35][O:27][C:26]4[CH:25]=[C:24]5[C:19](=[CH:18][C:17]3=4)[CH2:20][CH2:21][CH2:22][CH2:23]5)[C:9]2=[O:28])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1C(c2cc3c(cc2O)CCCC3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)CCCC3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1H)-one was obtained (81%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.37-7.32 (m, 10H), 7.17-7.14 (m, 1H), 7.07 (s, 1H), 7.05-6.94 (m, 2H), 6.67 (s, 1H), 6.52 (d, J=7.6 Hz, 1H), 6.33 (s, 1H), 4.96 (d, J=8.9 Hz, 1H), 4.69 (d, J=8.9 Hz, 1H), 2.73 (br s, 2H), 2.54 (br s, 1H), 1.72-1.70 (m, 4H); MS (ES+) m/z 457.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1.S(Cl)(Cl)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>>[N:21]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH:4]=1)[O:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: OCc1ccc(F)c(Oc2cnccn2)c1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=NCc1ccc(F)c(Oc2cnccn2)c1

Procedure:
The product of Example 128C, thionyl chloride and sodium azide were processed according to the method of Example 115A to provide the product. MS (ESI+) m/z 237 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH:12]([N:25]1[CH2:28][CH:27](OS(C)(=O)=O)[CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH:12]([N:25]1[CH2:28][CH:27]([O:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:26]1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1Cl
Reaction time: 0.17 h

Procedure:
A solution of 3,4 dichlorophenol (4.12 g, 25.3 mmol) in DMF (150 ml) under argon is treated with a 60% dispersion of sodium hydride in mineral oil (40.4 mmol) and the reaction mixture stirred for 10 minutes. A solution of Methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (7.27 g, 22.96 mmol) in DMF (50 ml) is added and the reaction mixture left to stir at 60° C. for 20 hours. The reaction mixture is partitioned between ethylacetate and water. The organic phase is washed with water (×2), dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (elution with 1:4 ethylacetate/isohexane) to afford 1-Benzhydryl-3-(3,4-dichloro-phenoxy)-azetidine. [M+H] 383.8
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]([C:13]1[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=1)=[C:11]=[O:12]>>[C:1]([NH:9][C:11]([NH:10][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Product: COc1cc(NC(=O)NC(=O)c2ccccc2)cc(OC)c1OC
Temperature: 140 °C
Yield: 76 %

Procedure:
A mixture of benzamide (0.5 g, 4.13 mmol, 1.0 equiv) and 5-isocyanato-1,2,3-trimethoxy-benzene (1.30 g, 6.19 mmol, 1.5 equiv; commercially available) was heated by microwave irradiation to 140° C. for 30 min. Recrystallization from ethanol provided 1.04 g (76%) of the title compound. MS (ISP): 331.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[Cl:9].[Cu][C:11]#[N:12].C(OCC)(=O)C>CN(C)C=O>[Cl:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: Cc1ccc(Br)c(Cl)c1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)c(Cl)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
25.0 g 4-bromo-3-chlorotoluene and 21.8 g copper (I) cyanide were dissolved in 200 ml dimethylformamide and stirred at 150° C. for three hours. The cooled reaction mixture was diluted by addition of 300 ml ethyl acetate and washed three times with portions of 150 ml saturated NH4Cl solution. The precipitates were filtered off and the filtrate dried over MgSO4 and then reduced in vacuo to obtain 17.3 g 2-Chloro-4-methyl-benzonitrile. This material was used without purification in the next step.
Reaction SMILES: C([O:8][C:9]1[C:13](Br)=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:11]([CH:23]([CH3:25])[CH3:24])[N:10]=1)C1C=CC=CC=1.C([Li])CCC.[CH3:31][O:32][C:33]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:34]=1[CH:35]=O>O1CCCC1>[CH:23]([N:11]1[C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[C:13]([CH2:35][C:34]2[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:33]=2[O:32][CH3:31])[C:9](=[O:8])[NH:10]1)([CH3:24])[CH3:25]
Reactant: COc1ccc(-c2c(Br)c(OCc3ccccc3)nn2C(C)C)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2c(Cc3ccc(OC)cc3OC)c(=O)[nH]n2C(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 3-benzyloxy-4-bromo-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole in tetrahydrofuran (2 mL) was added n-butyllithium (2.6 mol/L hexane solution, 0.89 mL) at −78° C. under argon atmosphere, and the mixture was stirred for 30 minutes. A solution of 2,4-dimethoxybenzaldehyde (0.51 g) in tetrahydrofuran (2 mL) was added to the reaction mixture, and the mixture was stirred at −78° C. for 1 hour. The reaction mixture was directly purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). The obtained semi purified [3-benzyloxy-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl (2,4-dimethoxyphenyl) methanol was dissolved in ethanol (9 mL), and a catalytic amount of 10% palladium-carbon powder was added to the solution. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. Dichloromethane was added to the reaction mixture, and the insoluble material was removed by filtration. The solvent of the filtrate was removed, and diethyl ether and hexane were added to the residue. The insoluble material was collected by filtration and dried under reduced pressure to give the title compound (0.09 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16](=[O:28])[NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[N:19]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(C)(C)C.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH2:7][C@@H:8]([CH2:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:16]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH2:23][C:24]([OH:27])([CH3:25])[CH3:26])[N:19]=1)=[O:28]
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@@H](N)CC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of {(S)-2-cyclohexyl-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-ethyl}-carbamic acid t-butyl ester (0.61 g 1.5 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 0.5 h, and concentrated to afford (S)-2-amino-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide trifluoroacetate (630 mg, 100%) as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=2)[C:7]([NH:9][CH3:10])=[O:8])[CH2:20][CH2:19]1
Reactant: OCCN1CCNCC1
Reactant: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(N2CCN(CCO)CC2)ccc1[N+](=O)[O-]

Procedure:
A solution of 5-fluoro-N-methyl-2-nitrobenzamide, 1-(2-hydroxyethyl)piperazine, and Hunig's base in 20 mL of DMF was stirred at room temperature over the weekend. The resulting mixture was rotavaped to dryness, and the residue was purified by flash column SF40-150 at 2%-10% MeOH/CH2Cl2. Product came out at 7% MeOH/CH2Cl2. MS(ES) m/e 309 [M+H].
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3](=[O:12])[CH:4]=[CH:5][C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH3:11].CO>C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][CH:2]([CH3:13])[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH3:11]
Reactant: Cc1ncsc1C=CC(=O)C(C)C
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ncsc1CCC(=O)C(C)C

Procedure:
The title compound was prepared as described in General Method 3 using 1.73 g (8.86 mmol) of 4-methyl-1-(4-methyl-thiazol-5-yl)-pent-1-en-3-one (prepared in Example B-1) and 0.4 g of 5% Pd/BaSO4 in THF:MeOH (25 mL:25 mL). The crude product was chromatographed on silica gel, eluting with 2:1 hexane:EtOAc, to give the title compound. 1H NMR (CDCl3): δ1.03 (d, 6 H), 2.35 (s, 3 H), 2.49-2.56 (m, 1 H), 2.72 (t, 2 H), 2.98 (t, 2 H), 8.49 (s, 1 H).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O.C1OCCOCCOCCOCCOCCOC1.[CH2:40]([O:42][C:43](=[O:53])[NH:44][CH2:45][CH:46]([O:48]S(C)(=O)=O)[CH3:47])[CH3:41]>CS(C)=O>[CH2:40]([O:42][C:43](=[O:53])[NH:44][CH2:45][CH:46]([O:48][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:19]=[CH:20][CH:21]=[C:8]([Cl:7])[CH:9]=2)=[CH:13][CH:14]=1)[CH3:47])[CH3:41]
Reactant: CCOC(=O)NCC(C)OS(C)(=O)=O
Reactant: Oc1ccccc1Oc1cccc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)NCC(C)Oc1ccc(Oc2cccc(Cl)c2)cc1
Reaction time: 5 h

Procedure:
A solution of 15 g of potassium tert.-butoxide in 45 ml of dimethyl sulfoxide is added, with stirring and with slight external cooling, to a solution of 25.2 g of 3-chlorophenoxyphenol in 40 ml of dimethyl sulfoxide; 1.5 g of 18-Crown-6 are added, a solution of 28.3 g of 2-methylsulfonyloxypropylcarbamic acid ethyl ester in 30 ml of dimethyl sulfoxide is added dropwise at 15° C. within a period of one hour, and then the mixture is stirred firstly at 20° C.-22° C. for 5 hours and then at +55° C. for 19 hours. After cooling, the reaction mixture is poured onto ice-water and extracted repeatedly with ether, the combined ether phases are washed with water, and the solvent is distilled off. The crude product is purified further by chromatography over silica gel (eluant: diethyl ether/hexane, 1:9), yielding 2-[4-(3-chlorophenoxy)phenoxy]-propylcarbamic acid ethyl ester in the form of a pale yellow, viscous oil, n20D : 1.5500.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH:34]1[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH:34]1([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:36][CH2:35]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)C1CC1
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)C3CC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-bromo-2-(cyclopropylsulfonyl)benzene. MS (ESI): mass calcd. for C19H16FN3O2S, 369.10; m/z found, 370.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=1.5, 2H), 8.14 (dd, J=7.9, 1.5, 1H), 7.70-7.63 (m, 1H), 7.62-7.54 (m, 1H), 7.45 (m, 1H), 7.41-7.28 (m, 3H), 5.23 (s, 2H), 2.19-2.06 (m, 1H), 1.16-1.07 (m, 2H), 0.93-0.81 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=O.[NH2:13][C:14]([NH2:16])=[S:15]>CO>[NH2:16][C:14]1[S:15][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])[N:13]=1
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: NC(N)=S
Solvent: CO
Product: N#Cc1cccc(-c2csc(N)n2)c1
Temperature: 0 °C

Procedure:
16.9 g of 3-bromoacetyl-benzonitrile were placed in 50 ml of methanol and treated at room temperature with 8 g of thiourea. The mixture was boiled for 21/2 hours and then cooled to 0° C. while stirring slowly. The product separated as the salt, was filtered off and converted into the base by the addition of 100 ml of 2N sodium hydroxide solution. The aqueous suspension was extracted with a total of 700 ml of methylene chloride and the organic phase was dried with magnesium sulphate. 9.6 g of 3-(2-amino-thiazol-4-yl)-benzonitrile separated upon concentration.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1>C(OCC)(=O)C.[Pd]>[NH2:21][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc([N+](=O)[O-])cc2F)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N)cc2F)C1

Procedure:
3-Fluoro-4-(3(S)-(t-butoxycarbonyl)aminopyrrolidin-1-yl)nitrobenzene (33.5 g, 0.103 M) was dissolved in ethyl acetate (500 ml) treated with palladium catalyst (10% on carbon, 5 g) and hydrogenated at atmospheric pressure until the theoretical uptake of gas. After filtration through celite and evaporation, the required product was obtained as a red gum of sufficient quality for use without purification (30.4 g). NMR (DMSO-d6) δ: 1.35 (s, 9H); 1.71 (m, 1H); 2.06 (m, 1H); 2.87 (dd, 1H); 3.05 (m, 1H); 3.11 (m, 1H); 3.26 (m overlapping H2O, ˜1H); 3.97 (m, 1H); 4.68 (s, 2H); 6.25 (dd, 1H); 6.31 (dd, 1H); 6.51 (t, 1H); 7.03 (d, 1H). MS (ESP): 296 (MH+) for C15H22FN3O2
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.Br[CH2:14][CH2:15][O:16][CH2:17][CH3:18]>CC#N>[CH2:15]([O:16][CH2:17][CH2:18][C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)[CH3:14]
Reactant: CCOCCBr
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Solvent: CC#N
Product: CCOCCc1c[nH]c2cc(N)ccc12

Procedure:
3-(2-Ethoxy-ethyl)-1H-indol-6-ylamine (B-16) was synthesized following the general scheme above starting from 6-nitroindole and 1-bromo-2-ethoxy-ethane. Overall yield (15%). HPLC ret. time 1.56 min, 10-99% CH3CN, 5 min run; ESI-MS 205.1 m/z (MH+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:30])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:27][CH:26]4[N:28](C)[CH:23]([CH2:24][CH2:25]4)[CH2:22]3)[CH:20]=2)[CH:15]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1(C)C=CC=CC=1.O>[CH2:41]([O:40][C:38]([N:28]1[CH:26]2[CH2:25][CH2:24][CH:23]1[CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:14]3[CH:13]=[N:12][C:11]([NH2:30])=[C:10]([C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)[CH:15]=3)[CH:17]=[N:18]1)[CH2:27]2)=[O:39])[CH3:42]
Reactant: CCOC(=O)Cl
Reactant: CN1C2CCC1CC(n1cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C2CCC1CC(n1cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn1)C2
Temperature: 110 °C

Procedure:
To a solution of 3-benzothiazol-2-yl-5-[1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl]-pyridin-2-ylamine (50.8 mg, 0.122 mmol; 1 eq) and K2CO3 (1.2 mg, 0.0087 mmol, 7 mol %) in toluene (3 mL), ethyl chloroformate (67.0 mg, 0.617 mmol, 5 eq) in toluene (1 mL) was added. The solution was heated to reflux for a total of 10 h (temp=110° C.). The residue was dissolved in water. The aqueous mixture was extracted with CH2Cl2 (3×) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was purified by column chromatography on silica gel [0.5″×10″ column, eluting with CH2Cl2:EtOAc 1:0→2:1→1:1→1:2→0:1]. Fractions containing product were combined and concentrated in vacuo to give the title compound. MS (ES+): m/z=475.13 (100) [MH+]. HPLC: tR=3.41 min (ZQ2, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[C:19](=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-4-nitrobenzoic acid (10 g, 0.06 mol) in MeOH (120 mL) was added H2SO4 (5 mL). The resulting mixture was stirred at 60° C. overnight. After cooling to room temperature, the mixture was brought to pH=8 using sodium bicarbonate solution. After removal of MeOH, the resulting crude mixture was purified by column chromatography (20% CH2Cl2/PE) to afford 4 g of the title compound. LC-MS: m/z 216.6 (M+H)+