Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH3:11][C:12]([SH:15])([CH3:14])[CH3:13].N12CCCN=C1CCCCC2>C(OCC)(=O)C>[C:12]([S:15][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)S
Reactant: OCCOCCOCCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CC(C)(C)SCCOCCOCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a mixture of 2-[2-(2-chloroethoxy)ethoxy]ethanol (11.0 g, 65.24 mmol) and tert-butylthiol (7.35 mL, 65.23 mmol) cooled in an ice bath was slowly added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 9.75 mL, 65.23 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. This mixture was then diluted with ethyl acetate and filtered. The crude product in the filtrate was purified on a filter column eluted with ethyl acetate to give yellowish oil (14.4 g, 64.6 mmol, 99%): 1H NMR (300 MHz, CDCl3): d 3.73 (br s, 2H), 3.69-3.60 (m, 8H), 2.75 (t, J=7.4, 2H), 2.62 (br s, 1H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3): d 72.47, 71.08, 70.33, 70.27, 61.71, 42.09, 30.95, 27.87; MS (ESI): m/e (M+1) Calcd. for C10H23O3S: 223, obsd.: 223.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[O:6][CH2:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.C1COCC1.Cl.[OH-].[Na+]>O.CCO>[O:6]1[CH2:7][CH2:8][NH:9][C:4]2[CH:3]=[C:2]([NH2:1])[CH:12]=[CH:11][C:5]1=2
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)NCCO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
6-Amino-2H-benzo[b][1,4]oxazin-3(4H)-one (590 mg, 3.6 mmol) was added to a THF solution of borane tetrahydrofuran complex (9 mL, 1M solution) and the reaction mixture was refluxed for 2.5 h. EtOH (2 mL) was added and stirred at 70° C. for 1 h before 1 mL HCl (conc.) was added. The mixture was stirred at 80° C. overnight then the volatiles were removed under vacuum to leave a crude reside. The residue was dissolved in water, NaOH was added until pH˜10, and the mixture was extracted with CH2Cl2. The organic phase was washed with water and the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel to give the product (274 mg, 51%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1Br
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccccc1OCc1ccccc1
Yield: 94.5 %

Procedure:
A mixture of 35 g of 1-bromo-2-hydroxybenzene, 30.5 g of benzyl chloride and 50 g of K2CO3 in 500 ml of acetone is refluxed for 12 hours. The reaction mixture is concentrated under vacuum, the residue is taken up in a water/EtOAc mixture, the organic phase is washed with 1N NaOH solution and with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The resulting oil is distilled under reduced pressure to give 50.3 g of the expected product, b.p.=155° C. at 40 Pa.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24](O)=[O:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[NH2:58][CH2:59][C:60]1[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24]([NH:58][CH2:59][C:60]1[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=1)=[O:25]
Reactant: NCc1cccnc1
Reactant: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Reaction time: 16 h
Yield: 54.7 %

Procedure:
To a stirred mixture of 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)-imidazolidin-1-yl)thiophene-2-carboxylic acid (3.68 g, 9.56 mmol), 1-hydroxybenzotriazole (1.94 g, 14.36 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (2.75 g, 14.3 mmol) in N,N-dimethylformamide (40 mL) was added N,N-diisopropylethylamine (5.00 mL, 5.00 mmol), followed by the addition of 3-(aminomethyl)pyridine (0.97 mL, 9.57 mmol). The resulting reaction mixture was stirred for 16 h, then was diluted with ethyl acetate (300 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (3×100 mL), water (100 mL) and brine (100 mL). The combined water/brine layer was extracted with dichloromethane (200 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by recrystallization from 50% ethyl acetate in hexanes to afford the title compound as a colorless solid (2.48 g, 55%): mp 102-104° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.52 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.29-7.22 (m, 1H), 6.20 (t, J=5.6 Hz, 1H), 6.10 (s, 1H), 4.58 (d, J=5.6 Hz, 2H), 4.50 (s, 2H), 3.85-3.77 (m, 2H), 3.50-3.42 (m, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.5, 155.8, 149.1, 148.7, 142.3, 141.4, 140.1, 135.5, 134.2, 130.1 (d, JC-F=32.6 Hz), 128.4, 125.7 (q, JC-F=3.8 Hz), 123.5, 122.1, 119.2, 112.5, 47.7, 42.7, 41.6, 41.1, 16.0; MS (ES+) m/z 475.3 (M+1).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]([CH2:22][CH3:23])[CH2:20]O>>[CH3:18][CH:19]([CH2:22][CH3:23])[CH2:20][O:16][C:15](=[O:17])[C@H:11]([CH:12]([CH3:13])[CH3:14])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: CCC(C)CO
Product: CCC(C)COC(=O)[C@@H](NC(=O)Cc1ccccc1)C(C)C

Procedure:
Following General Procedure BC and using the N-(phenylacetyl)valine prepared in Step A above and 2-methylbutan-1-ol (Aldrich), the title compound was prepared as a diastereomeric mixture. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>ClC1C=CC=CC=1Cl>[F:8][C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][CH:5]=1)[N:9]1[C:10]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:12]=[C:13]1[C:21](=[O:22])[NH:1]2
Reactant: CCOC(=O)CCc1nccn1-c1ccc(F)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)CCc1ncc2c(=O)[nH]c3cc(F)ccc3n12
Reaction time: 3 h

Procedure:
Ethyl 3-[1-(2-amino-4-fluorophenyl)-1H-imidazol-2-yl]-propanoate as synthesized in Production Example 92, 94 mg, 1,1′-carbonyldiimidazole 83 mg and 1,2-dichlorobenzene 1 mL were mixed and heated under reflux for 0.5 hour. Further 1 mL of 1,2-dichlorobenzene was added and the heating under reflux was continued for further 3 hours. Allowing the reaction liquid to cool off, the precipitate was recovered by filtration, and washed with diethyl ether and ethyl acetate, by the order stated. The resulting crystals were dissolved in a liquid mixture of tetrahydrofuran and methanol, and the insoluble matter was separated by filtration. Distilling the solvent off under reduced pressure, 70 mg of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.[NH2:23][C:24]1[C:25]([C:31](O)=[O:32])=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1>>[NH2:23][C:24]1[C:25]([C:31]([NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:22])[C:6]=2[O:7][CH2:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[O:32])=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1
Reactant: Cn1ncc(N)c1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1ccc(Br)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(Br)ccc2N)c1OCC1CCNCC1

Procedure:
Following the procedures for Example 141, tert-butyl 4-((4-amino-1-methyl-1H-pyrazol-5-yloxy)methyl)piperidine-1-carboxylate and 3-amino-6-bromopicolinic acid were reacted to give 3-amino-6-bromo-N-(1-methyl-5-(piperidin-4-ylmethoxy)-1H-pyrazol-4-yl)picolinamide, which was reacted with 2-fluorophenylboronic acid under palladium catalyzed Suzuki conditions to give 117 as a white solid (6.7 mg, 7.2%) over three steps. 1H NMR (400 MHz, DMSO) δ 9.66 (s, 1H), 8.10 (t, J=7.2, 1H), 7.71 (dt, J=37.9, 19.0, 1H), 7.60-7.25 (m, 5H), 7.03 (s, 2H), 3.97 (d, J=6.2, 2H), 3.72-3.42 (m, 3H), 2.76 (t, J=31.9, 2H), 2.36 (t, J=12.2, 2H), 1.88-1.53 (m, 3H), 1.25-0.99 (m, 2H). ESIMS m/z=425.1 (M+1)
Reaction SMILES: II.[Br:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:21])[F:20])=[C:14]([Cl:22])[CH:13]=2)=[CH2:11])[CH:7]=[CH:8][CH:9]=1.N.[NH2:24][C:25]([NH2:27])=[O:26]>C(OCC)(=O)C.C(#N)C.[Ag]OC#N.ClCCl>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:20])[F:21])=[C:14]([Cl:22])[CH:13]=3)[CH2:11][O:26][C:25]([NH2:27])=[N:24]2)[CH:7]=[CH:8][CH:9]=1
Reactant: C=C(c1cccc(Br)c1)c1ccc(OC(F)F)c(Cl)c1
Reactant: NC(N)=O
Agent: N#CO[Ag]
Agent: II
Agent: N
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC1=NC(c2cccc(Br)c2)(c2ccc(OC(F)F)c(Cl)c2)CO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
A solution of iodine (1.71 g, 6.74 mmol) in ethyl acetate (40 mL) was added dropwise over 25 min to a mixture of 4-[1-(3-bromo-phenyl)-vinyl]-2-chloro-1-difluoromethoxy-benzene (2.2 g, 6.13 mmol) and silver cyanate (1.10 g, 7.35 mmol) in acetonitrile (24 mL) and ethyl acetate (11 mL), cooled in an ice bath. After complete addition, the reaction suspension was stirred for another 15 min at room temperature when TLC indicated the complete conversion of starting material. The reaction mixture was filtered, and the filtrate concentrated to give a dark grey oil. 50 mL of aqueous ammonia (25%) was added to the oil, and the mixture was stirred and warmed to 60° C. for 4 hours. LC-MS at this point indicated complete conversion of the intermediate urea to the desired aminoxazoline. Dichloromethane (40 mL) was added to the crude and the two phases were separated; organic layer was collected, dried over magnesium sulfate anhydrous, filtered and evaporated under reduced pressure. The crude product was purified by silica gel chromatography eluting with dichloromethane/methanol (gradient: 0-6%) to give 1.02 g of desired product as a yellow oil (40%)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (1.0 g, 2.94 mmol), 3-[(methyloxy)-carbonyl]benzoic acid (0.58 g, 3.24 mmol), HBTU (1.34 g, 3.53 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (30 mL) was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and the solution extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layer was dried over sodium sulfate, filtered, concentrated and purified using CombiFlash chromatography, eluting with 80% ethyl acetate in hexane. The product fractions were combined and concentrated to give methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-carbonyl]benzoate as an oil (1.40 g, 99%). LC-MS m/z 467 (M+H)+.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].B(Cl)(Cl)Cl.CS[C:28]#[N:29].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClCCCl>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:28]#[N:29])[CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CSC#N
Reactant: CCCCCCCCc1ccc(-c2ccc(O)cc2)cc1
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCCCCCCc1ccc(-c2ccc(O)c(C#N)c2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a suspension of 2.82 g of 4-(4-n-octylphenyl) phenol in 40 ml of 1,2-dichloroethane were added under ice cooling, 6 ml of a solution of boron trichloride (2M) in 1,2-dichloroethane, and then 0.82 ml of methyl thiocyanate and 1.33 g of aluminum chloride. The mixture was stirred at room temperature until the aluminum chloride is dissolved, further stirred for 3 hours at 80° C. and cooled to room temperature. To the resulting mixture was added further 33 ml of 4N-sodium hydroxide solution. The mixture was stirred for 30 minutes at 75° to 80° C. After cooling, the reaction mixture was washed with methylene chloride. The aqueous phase was adjusted to pH2 with 6N hydrochloric acid and extracted with ether. The extract was dried and evaporated under reduced pressure to obtain crude crystals. The crystals were purified by a silica gel column chromatography to give 2.03 g of 4-(4-n-octylphenyl)-2-cyanophenol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].C(O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([Sn](=O)CCCC)CCC>>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH2:1][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCc1ccccc1
Agent: CCCC[Sn](=O)CCCC
Product: O=C(OCc1ccccc1)c1ccc(O)cc1
Yield: 97.1 %

Procedure:
152.1 g (1 mole) of methyl p-hydroxybenzoate, 216.2 g (2 moles) of benzyl alcohol and 0.304 g (0.4% based on the weight of methyl p-hydroxybenzoate) of dibutyltin oxide were fed into a four-necked glass flask, and reacted at 200° C. for 6 hours with stirring. Methanol which distilled out during the reaction was recovered for re-use in methyl esterification. After the reaction, the excess of benzyl alcohol was recovered under reduced pressure to give 221.6 g (yield 97.1%) of crude benzyl p-hydroxybenzoate. The ratio of benzyl p-benzyloxybenzoate formed was 1.1%.
Reaction SMILES: [CH2:1]([C:3]1[S:38][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Cl.Cl[CH2:41][CH2:42][N:43]([CH3:45])[CH3:44].CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[CH3:44][N:43]([CH3:45])[CH2:42][CH2:41][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:38][C:6]=3[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[C:8]2=[O:22])=[CH:20][CH:19]=1
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(O)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OCCN(C)C)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 60 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
To a mixture of 4′-{[6-ethyl-3-[2-(4-hydroxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile, 2-chloro-N,N-dimethylethanamine hydrochloride (0.62 g) and N,N-dimethylformamide (7 mL) was added cesium carbonate (2.8 g), and the mixture was stirred at 60° C. for 12 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.41 g, 48%).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH:15]=1)[CH:13]=O.Cl.[NH2:18][OH:19].O>C(O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH:15]=1)[CH:13]=[N:18][OH:19]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: ON=Cc1cc(Cl)ccc1O
Reaction time: 18 h
Yield: 77.6 %

Procedure:
Pyridine (20 ml) was added to a stirred suspension of 5-chloro-2-hydroxybenzaldehyde (5.0 g) and hydroxylamine hydrochloride (2.77 g) in ethanol (20 ml) and stirring was continued for 18 hours. The mixture was then added to water (150 ml) and extracted with ether (3×50 ml). The combined extracts were washed with water (2×50 ml), dried (MgSO4) and concentrated to give a yellow oil which slowly crystallised on standing. The solid was collected by filtration and washed with hexane to give 5-chloro-2-hydroxybenzaldoxime (4.25 g) as white crystals, m.p. 125°-126° C.; NMR: 6.91(1H,d,J=5 Hz), 7.15(1H,d,J=2.5Hz), 7.22(1H,dd,J=8,2.5Hz); 7.55(1H,b), 8.16(1H,s), 9.26(1H,b).
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c12
Product: CS(=O)(=O)N1CCC(c2cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 34 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 331 and using 5-(2-benzyl-1,3-benzothiazol-5-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and methanesulfonyl chloride as starting material, 20 mg (34%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.49 (s, 1H), 8.39 (d, 1H), 8.32 (s, 1H), 7.92 (d, 1H), 7.84-7.78 (m, 5H), 7.04 (s, 1H), 4.91 (s, 2H), 4.38-4.33 (m, 2H), 3.84-3.78 (m, 1H), 3.38-3.30 (m, 2H), 3.23 (s, 3H), 2.74-2.69 (m, 2H), 2.38-2.30 (m, 2H); LC-MS m/z [M+H]+ 519.2, RT 3.13 min.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)=[CH:3][CH:2]=1.[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[Na+].[Na+].[ClH:23]>CCOCC.C1(C)C=CC=CC=1>[ClH:23].[CH2:14]([N:9]1[CH2:10][CH:11]2[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=3)([CH2:12]2)[CH2:8]1)[CH3:15]
Reactant: Cc1ccc(C23CNCC2C3)cc1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN1CC2CC2(c2ccc(C)cc2)C1

Procedure:
A mixture of 7.4 g. of 1-(p-tolyl)-3-azabicyclo[3.1.0]hexane (Example 32), 7.3 g. of ethyl iodide and 8.9 g. of sodium carbonate in 60 ml. of toluene is heated at reflux for 18 hrs. Filtration and evaporation of this mixture gives a residue which is dissolved in ether. Addition of ethanolic hydrogen chloride gives a precipitate which is recrystallized from acetonitrile to give the desired product as colorless crystals, m.p. 175°-176° C.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3Br)[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:14][C:15]([C:16]3[C:17]([C:28]4[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:23])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(=O)NC1Cc2ccc(NC(=O)c3ccccc3Br)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(=O)NC1Cc2ccc(NC(=O)c3ccccc3-c3ccc(F)cc3)cc2C1
Temperature: 25 °C

Procedure:
To a solution of N-(2-acetylamino-indan-5-yl)-2-bromo-benzamide (the title C compound; 0.150 g, 0.40 mmol) and 4-fluorobenzeneboronic acid (0.0.84 g, 0.60 mmol) in DME (7 mL) is added PdCl2(dppf) (0.010 g, 0.012 mmol) followed by K3PO4 (0.25 g, 1.20 mmol). The reaction mixture is degassed and heated at reflux under N2 atmosphere for 16 h. After cooling to room temperature, the reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give a tan solid. Trituration with ethyl acetate gives 4′-fluorobiphenyl-2-carboxylic acid (2-acetylamino-indan-5-yl)-amide as a grey solid, mp 218-220° C. MS (ES+), m/z 389 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[C:9]1([C:14](OCC)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.C([O-])(O)=O.[Na+].[OH-].[Na+]>CCOCC>[OH:15][CH2:14][C:9]1([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[OH:7])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C1(C(O)c2ccccc2Cl)CCCC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCC1(C(O)c2ccccc2Cl)CCCC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
Lithium aluminum hydride (0.64 g, 16.8 mmol) was mixed with ether (20 ml) and cooled to −10° C. Thereto was added dropwise a solution of ethyl 1-(1-hydroxy(2-chlorophenyl)methyl)cyclopentanecarboxylate (3.1 g, 11.2 mmol) in ether (5 ml) at the same temperature over 15 min, and the mixture was stirred at −10° C. for 1 h, and at room temperature for 3 h. The mixture was cooled to −20° C. and 10%—NaHCO3 aq. (2 ml) was added dropwise, then 20%—NaOH aq. (2 ml) was added dropwise. The mixture was stirred for 30 min and sludge was removed by decantation. The organic layer was washed with water (50 ml), dried over anhydrous sodium sulfate, concentrated to dryness, and purified by silica gel column chromatography (hexane:ethyl acetate =2:1) to give the title compound 2.2 g (quant.) as a colorless oil.