Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:14][CH2:15][CH2:16][CH2:17]Cl)[CH3:13].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:14][CH2:15][CH2:16][CH2:17][N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=2)[CH2:31][CH2:30]1)[CH3:13]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CC1(CCCCCl)C(=O)Nc2c(Cl)cc(Cl)cc21
Product: CC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2c(Cl)cc(Cl)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 5,7-dichloro-3-(4-chlorobutyl)-3-methyl-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)-piperazine.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:10]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:9]2[N:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[N:10]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Cn2nnc(C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Next, to a solution of 2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid ethyl ester (1.5 g, 5.72 mmol) in ethanol (10 mL) is added 1N NaOH (10 mL, 10 mmol) and the mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the mixture acidified with 1N HCl. The mixture is extracted with EtOAc and the organic phase is washed with brine and dried over MgSO4. The solvent is removed under reduced pressure to give the title compound; HPLC Retention time 0.73 minutes (condition C): MS 233.2 (M−1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[OH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH:20]1([N:17]2[CH2:18][CH2:19][CH:15]([CH2:14][C:10]3[C:11]([Cl:13])=[CH:12][C:7]([C:34]4[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=4)=[CH:8][C:9]=3[Cl:27])[C:16]2=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Reactant: OB(O)c1ccc(O)cc1
Product: O=C1C(Cc2c(Cl)cc(-c3ccc(O)cc3)cc2Cl)CCN1C1CCCCC1
Yield: 90.8 %

Procedure:
Using the procedure to synthesize Example 81 and using reagents 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (750 mg, 1.58 mmol) and 4-hydroxyphenylboronic acid (650 mg, 4.7 mmol) affords 600 mg (91%) of the title compound: Mass spectrum (apci) m/z=418.2 (M+H—HCl).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14].[I-].[K+].[F:18][C:19]1[CH:20]=[C:21]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>CN(C)C=O>[F:18][C:19]1[CH:20]=[C:21]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:8][CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:27][CH:28]=1
Reactant: CCOC(=O)NCCCl
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Temperature: 95 °C

Procedure:
27.6 g of finely-pulverulent potassium carbonate, 18.2 g of ethyl 2-chloroethylcarbamate and 1 g of powdered potassium iodide are added to a solution of 22.2 g of 4-(3,5-difluorophenoxy)phenol in 80 ml of dimethylformamide. The reaction mixture is heated for 16 hours at 95° C., with stirring. After this, the reaction mixture is filtered, the filtrate is poured into 400 ml of water, and the mixture is extracted repeatedly with diethyl ether. The combined organic phases are washed with water and dried over sodium sulfate, and the solvent is distilled off. The residue is purified by chromatography over silica gel (eluent: n-hexane/diethyl ether 3:1), which gives the pure ethyl 2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate as a colourless compound which soon crystallizes and has a melting point of 54°-56° C. The 1H-NMR spectrum agrees with the indicated structure.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.CN(C=O)C.O.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[N:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][N:6]3[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccn1
Reactant: C[Si](C)(C)CCOCn1ncc2c(Br)cc(C=O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ncc2c(-c3ccncc3)cc(C=O)cc21
Temperature: 120 °C
Yield: 62.6 %

Procedure:
To a solution of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (50 mg, 0.14 mmol) and pyridine boronic acid (20 mg, 0.16 mmol) in 10:1 DMF/water (1 mL) was added K2CO3 (36 mg, 0.26 mmol) and tetrakistriphenylphosphine palladium (7.5 mg, 0.007 mmol). The mixture was heated to 120° C. under microwave irradiation for 20 min. Ethyl acetate (20 mL) was added and the solution was washed with water (2×5 mL) and brine (5 mL), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (3:1 EtOAc/Hex) to give the title compound as a pale yellow solid (31 mg, 62%). MS ESI [M+H]+, calcd for [C19H23N3O2Si+H]+ 354.2; found m/z 354.2.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:22])=[CH:6][C:7]([O:20][CH3:21])=[C:8]([NH:10][C:11](=[S:19])OC2C=CC=CC=2)[CH:9]=1)(=[O:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[C:1]([C:4]1[C:5]([CH3:22])=[CH:6][C:7]([O:20][CH3:21])=[C:8]([NH:10][C:11]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[S:19])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1cc(C)c(C(C)=O)cc1NC(=S)Oc1ccccc1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc(C(C)=O)c(C)cc3OC)CC2)c1
Yield: 82 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:44]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45]1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:49][CH:46]3[CH2:47][CH2:48][O:44][CH2:45]3)=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: NC1CCOC1
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NC1CCOC1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), tetrahydro-furan-3-ylamine (23 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C15H20ClN6O3, 354.13; found 354.2.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])=[CH:26][CH:25]=2)[CH2:6]1)(=O)C.[OH-].[Na+].Cl>CO.O1CCCC1>[SH:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=3)=[O:37])=[CH:26][CH:25]=2)[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@@H](Cc2ccc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)c3ccccc23)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCc1ccc(C[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccccc12)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
To a solution of (2R,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1-naphthylmethyl]pyrrolidine (144 mg, 0.21 mmol) in methanol-tetrahydrofuran (3:1) (4 ml), 1N aqueous sodium hydroxide (0.24 ml, 0.24 mmol) was added in a nitrogen stream under cooling with ice. This reaction solution was stirred for 10 minutes and then 1N hydrochloric acid (0.24 ml, 0.24 mmol) was added thereto. Then the resulting solution was concentrated in vacuo. The resulting residue was poured into a liquid mixture of ethyl acetate with water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude product of (2R,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1-naphthylmethyl]-pyrrolidine as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])([CH3:9])[CH2:5][C:6](=[O:8])[CH:7]=1.[CH2:12]([OH:16])[CH:13](O)[CH3:14].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:14][CH:13]1[CH2:12][O:16][C:6]2([CH2:5][C:4]([CH3:10])([CH3:9])[C:3](=[O:11])[C:2]([CH3:1])=[CH:7]2)[O:8]1
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Reactant: CC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1=CC2(CC(C)(C)C1=O)OCC(C)O2
Yield: 70.2 %

Procedure:
To a 2-liter flask fitted with a reflux condenser, a water separator, and a stirrer is charged 265 g of 2,6,6-trimethylcyclohex-2-en-1,4-dione (prepared by the method described in Helv. Chim. Acta 39, 2041 [1956]), 2669 g of propylene glycol, 500 ml of benzene, and 1 g of p-toluene-sulfonic acid. The reactants are stirred and refluxed until no additional water is collected in the water separator. The product is washed with water to a pH of 6, and the solvent is stripped off. The residue is vacuum distilled through a 9" Goodloe column to yield 257 g of product, boiling point 92° at 1 mm Hg (80% yield).
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([C:34]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:35][CH2:36][CH2:37][NH2:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl>[C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13][NH:38][CH2:37][CH2:36][S:35][C:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(CCl)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Dissolve N-[2-((Triphenylmethyl)thio)ethyl]-chloroacetamide (5.4 g, 13.8 mmol) and 2-[(triphenylmethyl)thio]ethylamine (4.4 g, 13.8 mmol) in 100 mL dichloromethane, then add triethylamine (3.0 mL, 20.8 mmol) into the solution, heat and reflux for 48 hours. After being cooled, wash with 100 mL sodium bicarbonate aqueous solution (NaHCO3) and take the organic layer. After being dried with anhydrous sodium sulfate and concentrated, liquid chromatography (silicon dioxide, ethyl acetate hexane=1:1) is used for separation and purification so as to get light yellow oil product
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Li]N1C(C)(C)CCCC1(C)C.C([O:30][B:31](OC(C)C)[O:32]C(C)C)(C)C.[C:40](#[N:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:40]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[B:31]([OH:32])[OH:30])#[N:47]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
In a 300 ml nitrogen-substituted flask, 21.6 g (0.153 mol) of 2,2,6,6-tetramethylpiperidine was dissolved in 130 ml of THF. Then, to the resulting solution, 96 ml (0.153 mol) of a 15% solution of n-butyllithium in hexane was added dropwise at −10° C. to prepare lithium 2,2,6,6-tetramethylpiperidide. This solution was cooled to −78° C., and then 67 ml (0.291 mol) of triisopropoxyborane was added dropwise thereto. Next, 15 g (0.146 mol) of benzonitrile was added dropwise, and then the resulting solution was aged for 2 hours at the same temperature. The temperature of the reaction solution was increased to room temperature, and then the solution was hydrolyzed by 225 ml of 2N HCl. The solution was charged with 150 ml of ethyl acetate and stirred, and then the acid phase (pH<1) was separated. The aqueous phase was extracted with 105 ml of ethyl acetate. Then, the two organic phases were mixed and washed with 90 ml of saturated brine. The resulting organic phase was then dried with anhydrous magnesium sulfate and concentrated using an evaporator. The concentrated solution was charged with 100 ml of dichloromethane, and then the solution was charged with 50 ml of hexane at 0° C. The precipitated crystals were filtered and dried to obtain 7.3 g of 2-cyanophenylboronic acid crystals. The purity of the 2-cyanophenylboronic acid was 98.7%, in which 0.3 mol % of 1-phenyl-1-(2,2,6,6-tetramethylpiperidin-1-yl)methyl imine was included.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH:5]([CH:10]([OH:12])[CH3:11])[CH2:4][CH:3]=1.[CH:13](O)=[O:14]>O>[CH3:1][C:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[CH:5]([CH:10]([O:12][CH:13]=[O:14])[CH3:11])[CH2:4][CH:3]=1
Reactant: O=CO
Reactant: CC1=CCC(C(C)O)C(C)(C)C1
Solvent: O
Product: CC1=CCC(C(C)OC=O)C(C)(C)C1
Yield: 47.2 %

Procedure:
20.0 g of 1,5,5-trimethyl-4-(1-hydroxyethyl)-cyclohex-1-ene are introduced into a 1 liter three-necked flask provided with a mechanical stirrer, a heater, a dropping funnel and a reflux condenser fitted with a calcium chloride drying tube. 273 g of formic acid are then added in the course of 1/2 hour, whilst maintaining the temperature of the reaction mixture between 0° and 5°. After the end of the addition, the temperature of the composition is maintained at 5°. The composition is then slowly heated over 2 hours to 20°-25°. The mixture is then poured into 200 ml of water and extracted with benzene. The combined benzene extracts are washed successively with water, a solution of sodium bicarbonate and, finally, with water again. After distillation of the solvent over a water bath, the crude ester is distilled under a pressure of 0.05 mm of mercury. 11.0 g of 1,5,5-trimethyl-4-(1-formyloxyethyl)-cyclohex-1-ene are obtained, having the following physical constants:
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][CH2:9][NH2:10])[CH2:4]1)[CH3:2].C(N1CC[C@H](CC#N)C1)C>>[CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][NH2:10])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@@H](CCN)C1
Agent: CCN1CC[C@H](CC#N)C1
Product: CCN1CC[C@H](CCN)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 203, starting from 2-((R)-1-ethylpyrrolidin-3-yl)acetonitrile (Intermediate 209) and used without further characterisation.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17](O)=[O:18])=[CH:8]1.O.[OH-].[Na+]>C1COCC1>[OH:18][CH2:17][CH2:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][CH:8]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 80.4 %

Procedure:
To a stirred suspension of LiAlH4 (3.24 g) in THF (200 mL) at 0° C. and under N2 atmosphere was added dropwise a THF solution (50 mL) containing indole-3-acetic acid (10.0 g). After the addition was complete, the reaction was heated at reflux for 3 h, after which time the mixture was cooled to 0° C. and water (3.3 mL) added, followed by 15% NaOH (3.3 mL), and finally additional water (9.9 mL). The reaction was filtered and the filter cake washed with Et2O. The organic layers were combined, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure to yield 3-(2-hydroxyethyl)indole (VI; 7.4 g; 80%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]([N:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1)([CH3:40])[CH:38]=O.N1CCCCC1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:38][C:37]([CH3:40])([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH3:36])[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Reactant: CN1CCN(C(C)(C)C=O)CC1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CN1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@@H](n3nc(-c4ccc(Oc5ccccc5)cc4F)c4c(N)ncnc43)C2)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of toluene (10 mL), 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (300 mg, 0.64 mmol, 1.00 equiv), 2-methyl-2-(4-methylpiperazin-1-yl)propanal (541.45 mg, 3.18 mmol, 5.00 equiv), and piperidine (108.29 mg, 1.27 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 120° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:MeOH (5:1). The crude product (70 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, H2O (0.5% TFA)/CH3CN=10% increasing to H2O (0.5% TFA)/CH3CN=40% within 10 min; Detector, UV 254 nm. This resulted in 46.4 mg (12%) of 2-[[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile as a white solid. LC-MS-PH-PBF-003-96-0: (ES, m/z): [M+H]+ 625
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].O.[ClH:18].[CH3:19][N:20](C)[CH:21]=[O:22]>C(O)C>[ClH:18].[CH2:1]([N:11]1[CH2:12][CH2:13][N:14]([C:3]2[CH:5]=[C:6]3[C:19](=[CH:1][CH:2]=2)[NH:20][C:21](=[O:22])[CH2:8][CH2:7]3)[CH2:15][CH2:16]1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CN(C)C=O
Reactant: CC(C)=CCC/C(C)=C/CN1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)=CCC/C(C)=C/CN1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Reaction time: 24 h

Procedure:
127 Milligrams of succinimide 3,4-dihydrocarbostyril-6-carbostyril-6-carboxylate and 117 mg of geranylpiperazine were dissolved in 2 ml of dimethylformamide, and the solution was stirred for 24 hours. To the reaction mixture was added a certain amount of water and then extracted with chloroform, the chloroform layer was washed with water and an aqueous solution saturated with sodium chloride. Then the chloroform extract was dried with anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue thus obtained was crystallized by adding diethyl dether, and the crystals formed were dispersed in 20 ml of ethanol, then converted into hydrochloride by adding 1.3 ml of concentrated hydrochloric acid. Recrystallized from ethanol-water to obtain 132 mg of 6-(4-geranyl-1-Piperazinyl)-3,4-dihydrocarbostyril.hydrochloride.mono-hydrate. Colorless needle-like crystals. Melting point: 265°-266° C. (dec.)
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([NH:35][C:36](=[O:47])[C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43](F)(F)F)[CH:38]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:49](F)(F)C1C=C(C=CC=1)C(Cl)=O>>[CH3:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][C:40]=1[CH3:49])[C:36]([NH:35][C:33]1[CH:32]=[CH:31][N:30]=[C:29]([C:9]2[CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:12]=[CH:11][C:10]=2[NH:13][C:14]([C:16]2[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=2)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])[CH:34]=1)=[O:47]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccn2)c1
Product: Cc1ccc(C(=O)Nc2ccnc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)c2)cc1C

Procedure:
This compound was prepared by the route used to prepare 3-((3-((4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzamido)pyridin-2-yl)phenyl)carbamoyl)benzyl)thio)propanoic acid 73, substituting 3,4-dimethylbenzoyl chloride for 3-(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.71-8.65 (m, 2H), 7.96-7.84 (m, 3H), 7.77-7.70 (m, 3H), 7.55-7.41 (m, 4H), 7.33 (d, J=8.1 Hz, 1H), 2.63 (s, 2H), 2.60 (d, J=6.9 Hz, 4H), 2.63-2.58 (m, 2H), 2.52-2.46 (m, 2H), 2.38 (s, 6H), 1.90-1.74 (m, 6H). MS (ES, m/z): 623 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26]>>[CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(CC(=O)N1CCOCC1)CC2

Procedure:
The title compound was prepared from methyl 3-benzyloxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate using a procedure similar to Example 13, Step 1, except that 4-(2-chloroacetyl)morpholine was used in place of iodomethane. 1H NMR (400 MHz, CDCl3) δ 7.53-7.50 (d, 2H), 7.37-7.28 (m, 3H), 5.31-5.30 (m, 3H), 4.49-4.46 (t, 2H), 4.41 (s, 2H), 3.93 (s, 3H), 3.88-3.84 (t, 2H), 3.77-3.71 (m, 3H), 3.65-3.62 (t, 2H), 3.55-3.52 (t, 2H); ES MS (M+1)=429.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[F:18][C:19]([F:34])([F:33])[C:20]([N:22]1[C:27]2[CH:28]=[C:29](I)[CH:30]=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1)=[O:21]>>[OH:15][C:10]1[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]2[O:4][C:3]([C:1]#[C:2][C:29]3[CH:30]=[CH:31][C:26]4[O:25][CH2:24][CH2:23][N:22]([C:20](=[O:21])[C:19]([F:33])([F:18])[F:34])[C:27]=4[CH:28]=3)([CH3:17])[CH2:8][CH2:7][C:6]=2[C:9]=1[CH3:16]
Reactant: O=C(N1CCOc2ccc(I)cc21)C(F)(F)F
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc3c(c1)N(C(=O)C(F)(F)F)CCO3)O2

Procedure:
This compound was prepared by coupling rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol (1,15 g or 5 mmol) with 4-(trifluoroacetyl)-3,4-dihydro-6-iodo-2H-1,4-benzoxazine (1.95 g or 5.5 mmol) under the conditions described in Example 15. The product was isolated by chromatography over the 40 fold amount of silica gel methylene chloride. It was crystallized from ether/hexane and recrystallized twice from methanol to give colorless crystals with m.p. 153°-155°.