Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15](N)=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])[CH3:3].[C:19]([BH3-])#[N:20].[Na+].C(=O)(O)[O-].[Na+]>CO>[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:20][CH2:19][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1ccc(OC2CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 149.4 %

Procedure:
1-Acetyl-4-(4-aminophenyloxy)piperidine hydrochloride (2.5 g) obatined in Example 1, (2) was dissolved in methanol (20 ml) and to the solution were added sodium cyano borohydride (1.2 g) and pentylaldehyde (0.8 g) at room temperature. The mixture was stirred at room temperature for 1 hour. To the mixture was added aqueous saturated solution of sodium bicarbonate (50 ml) and the mixture was extracted with methylene chloride (50 ml×3). The combined extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (delveoping solvent: ethyl acetate/hexane=3/1 (v/v)) to obtain 1-acetyl-4-(4-pentylaminophenyloxy)piperidine (2.1 g) as white crystals, m.p. 69°-71° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:12]=3[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:10](=[O:29])[NH:9]2)=[C:4]([O:30][CH3:31])[CH:3]=1.[Cu][C:33]#[N:34]>CN(C)C=O.CO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:29]=[C:10]1[NH:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]#[N:34])=[CH:3][C:4]=2[O:30][CH3:31])[C:17]2[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:12]=2[N:11]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=1
Reactant: N#C[Cu]
Reactant: COc1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Temperature: 140 °C

Procedure:
Under an atmosphere of argon, a mixture of 4-(4-bromo-2-methoxyphenyl)-1-(3-(trifluoromethyl)phenyl)-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-dione (intermediate 50, 21 mg, 42 μmol), copper(I) cyanide (10 mg, 0.11 mmol) and tetrakis(triphenylphosphine)-palladium(O) (5 mg, 4 μmol) in N,N-dimethylformamide (1 mL) is heated at 140° C. over it) night. The mixture is cooled at room temperature, diluted with methanol and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 4 mg; ESI mass spectrum [M+H]+=442; Retention time HPLC: 0.87 min (Z011_S03).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([C:19]#[N:20])([CH3:18])[CH3:17])[CH:11]=2)=[CH:4][C:3]=1[NH:22][C:23]([C:25]1[S:33][C:28]2=[N:29][CH:30]=[CH:31][N:32]=[C:27]2[CH:26]=1)=[O:24].[Cu][C:35]#[N:36]>CN1C(=O)CCC1.[NH4+].[Cl-].[Cu]I>[C:35]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([C:19]#[N:20])([CH3:18])[CH3:17])[CH:11]=2)=[CH:4][C:3]=1[NH:22][C:23]([C:25]1[S:33][C:28]2=[N:29][CH:30]=[CH:31][N:32]=[C:27]2[CH:26]=1)=[O:24])#[N:36]
Reactant: N#C[Cu]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c(NC(=O)c3cc4nccnc4s3)c2)c1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(NC(=O)c3cc4nccnc4s3)c2)c1
Yield: 16.7 %

Procedure:
A solution of N-(2-bromo-5-(3-(2-cyanopropan-2-yl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 64 (80 mg, 0.154 mmol), copper(I) iodide (29.3 mg, 0.154 mmol) and copper(I) cyanide (13.77 mg, 0.154 mmol) in NMP (1.5 mL) was stirred 10 min in microwave at 150° C. with cooling on. The reaction mixture was poured out in NH4Cl solution and extracted with EtOAc. Organic layer was washed (3×) with water, brine, dried, and evaporated. Purification by chromatography CH2Cl2: MeOH (9:1) and then crystallization in acetonitrile gave the title compound N-(2-cyano-5-(3-(2-cyanopropan-2-yl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 65 (12 mg, 16%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 7.64 (t, d=7.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.87 (dd, J=8.6 and 1.9 Hz, 1H), 7.92-7.99 (m, 2H), 8.05 (m, 1H), 8.21 (d, J=1.9 Hz, 1H), 8.58 (s, 1H), 8.79 (d, J=2.3 Hz, 1H), 8.91 (d, J=2.3 Hz, 1H), 10.82 (s, 1H), 11.25 (s, 1H). (m/z)=467 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[N:24]=[CH:25][C:26]=3[CH:27]([CH3:29])[CH3:28])=[CH:16][C:15]=2[CH3:38])[CH:9]=[CH:10][C:11]=1[CH:12]=[O:13])[CH2:2][CH2:3][CH3:4].[O-:39]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]([C:30]4[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=4[Cl:36])[N:24]=[CH:25][C:26]=3[CH:27]([CH3:28])[CH3:29])=[CH:16][C:15]=2[CH3:38])[CH:9]=[CH:10][C:11]=1[C:12]([OH:39])=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: [O-][Cl+][O-]
Reactant: CCCCOc1cc(-c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)ccc1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCOc1cc(-c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A solution of 3-butoxy-4′-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2′-methyl-biphenyl-4-carbaldehyde (0.125 g, 0.227 mmol) in t-BuOH (2.0 mL) and 2-methyl-2-butene (1.0 mL) at 0° C. is treated with a solution of NaClO2 (205 mg, 2.27 mmol) and NaH2PO4—H2O (313 mg, 2.27 mmol) in water (2.0 mL). The mixture is stirred at 0° C. for 60 minutes. The organic layer is separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified using silica gel chromatography eluting with 50%-100% ethyl acetate in hexanes to give the title compound (0.120 g, 93%). ES/MS m/e 566.8; 568.7 (M+1).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12)=[O:2].[Na+].[C:29]([O:35][CH2:36]I)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.ClCCl>[CH:1]([NH:3][CH2:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O:20][CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:19])[S:10][C:9]=12)=[O:2]
Reactant: CC(C)(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(CNC=O)c4s3)[C@H](C)[C@H]12
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3cn4cnc(CNC=O)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 33 mg of sodium (1S,5R,6S)-2-(7-formylaminomethyl imidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.8 ml of DMF was added 29 mg of pivaloyloxymethyl iodide at −30° C., and the mixture was stirred for 1 hour during which the temperature was raised up to room temperature. The reaction mixture was diluted with 30 ml of dichloromethane, washed with semi-saturated aqueous saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue thus obtained was purified by column chromatography on silica gel (ethyl acetate:methanol=4:1) to give the title compound in a yield of 29 mg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4](Cl)[CH:3]=1.[CH:13](OCC)(OCC)OCC>>[Cl:11][C:6]1[C:7]2[C:8](=[O:9])[NH:10][CH:13]=[N:1][C:2]=2[CH:3]=[CH:4][N:5]=1
Reactant: NC(=O)c1c(N)cc(Cl)nc1Cl
Reactant: CCOC(OCC)OCC
Product: O=c1[nH]cnc2ccnc(Cl)c12
Temperature: 25 °C

Procedure:
A suspension mixture of 4-amino-2,6-dichloronicotinamide (1.12 g, 6.53 mmol) and triethyl orthoformate (20 mL, 17.8 g, 120.3 mmol) was heated at 150° C. for 6 hours in a Teflon screwed pressure vessel. After it was cooled to room temperature, evaporation of triethyl orthoformate afforded crude product that was crystallized from a mixed solvent of toluene and methanol to afford product the title compound. 1H NMR (DMSO-d6) 7.55 (d, J=5.6 Hz, 1H), 8.30 (s, 1H), 8.55 (d, J=5.6 Hz, 1H), 12.72 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 116.4, 121.0, 149.9, 150.9, 151.4, 157.6, 158.0; ESI-MS m/z 181.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[O:8].Br[C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([F:29])[F:28])=[CH:23][CH:22]=1.[In].Cl>CN(C)C=O>[F:28][CH:27]([F:29])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:31])([F:30])[CH:7]([C:6]2[S:5][C:4]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=3)=[N:3][C:2]=2[CH3:1])[OH:8])=[CH:26][CH:25]=1
Reactant: FC(F)c1ccc(C(F)(F)Br)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: Cl
Agent: [In]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(F)(F)c1ccc(C(F)F)cc1
Yield: 37.4 %

Procedure:
To a solution of 1.0 g 4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde and 1.42 g 4-(bromodifluoromethyl)-1-(difluoromethyl)benzene in 10 ml dimethylformamide 508 mg Indium were added and the resulting suspension was stirred in an ultrasonic bath for twelve hours. Then additional 1.42 g 4-(bromodifluoromethyl)-1-(difluoromethyl)benzene and 508 mg Indium were added and the resulting suspension was stirred in an ultrasonic bath for additional twelve hours. Then 20 ml 1 N hydrochloric acid were added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 620 mg 2-(4-Difluoromethyl-phenyl)-2,2-difluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol as a colorless lyophilisate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: O=C(O)C1CCCc2ccc(F)cc21
Product: CCn1cc(CN(C(=O)C2CCCc3ccc(F)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 37.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.51 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) was obtained.
Reaction SMILES: Cl[CH:2]([SiH3:4])Cl.[C:5]([C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]2[C:20]([OH:33])=[C:21]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=2)[C:10]=1[OH:34])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:15]([C:13]1[CH:14]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:10]2[O:34][SiH:4]([CH3:2])[O:33][C:20]3[C:21]([C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:22][C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:24][C:19]=3[C:11]=2[CH:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: [SiH3]C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[SiH]1Oc2c(cc(C(C)(C)C)cc2C(C)(C)C)-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a flame-dried flask under a dry nitrogen atmosphere, a stirred solution of 23.0 grams (0.20 mole) of dichloromethylsilane in 200 ml toluene is treated slowly with a solution of 82.1 grams (0.20 mole) of 3,3',5,5'-tetra-tert-butyl-biphenyl-2,2'-diol and 40.5 grams (0.40 mole) of triethylamine in 250 ml toluene at 5°-10° C. The reaction mixture is stirred at room temperature for 12 hours following the addition, is then filtered to remove triethylamine hydrochloride, and the solvent removed in vacuo. The residue is recrystallized from acetonitrile-toluene giving 69.4 grams (77%) of white crystals, mp 191°-198° C.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:13]=[CH:12][C:7]2[S:8][CH:9]=[C:10]([CH3:11])[C:6]=2[CH:5]=1>C(Cl)(Cl)Cl>[Br:1][C:9]1[S:8][C:7]2[CH:12]=[CH:13][C:4]([Br:3])=[CH:5][C:6]=2[C:10]=1[CH3:11]
Reactant: BrBr
Reactant: Cc1csc2ccc(Br)cc12
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)sc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
A solution of bromine (3.20 g) in chloroform (10 ml) was added dropwise to a stirred solution of 5-bromo-3-methylbenzo[b]-thiophene (4.54 g) in chloroform (40 ml) and the solution was stirred at room temperature for 1.5 hours. It was then washed with dilute sodium hydroxide solution, water and dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallised from petrol (b.p. 80°-100°) to give 2,5-dibromo-3-methylbenzo[b]-thiophene (5.45 g), m.p. 118°-122°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Br-].[CH:10]1([Zn+])[CH2:14][CH2:13][CH2:12][CH2:11]1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=1
Reactant: [Zn+]C1CCCC1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Product: Brc1cccc(C2CCCC2)n1

Procedure:
To 2,6-dibromopyridine (5.9 g, 25 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.2 mmol) was added cyclopentylzinc bromide (50 ml, 0.5 M solution in tetrahydrofuran) and the mixture heated at reflux for 18 h. The reaction was diluted with ethyl acetate and washed with water. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated in vacuo to give an oil. The crude product was chromatographed on silica, eluting on a gradient from 1 to 5% methanol in dichloromethane, to give 2-bromo-6-cyclopentylpyridine (3.25 g) as a white solid: δH (400 MHz, CDCl3) 1.60-1.90 (6H, m), 2.09 (2H, m), 3.17 (1H, m), 7.12 (1H, d, J 7.4), 7.28 (1H, d, J 7.4), 7.44 (1H, t, J 7.2); m/z (ES+) 226:228 (1:1) (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[C:7]([CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[CH:9]=[C:8]([N:18]2[CH2:19][CH2:20][C@H:16]([C:13]([OH:12])([CH3:15])[CH3:14])[C@@H:17]2[CH3:21])[C:7]([CH3:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: Cc1cc(C#N)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1cc(C#N)c(Cl)cc1N1CC[C@H](C(C)(C)O)[C@@H]1C

Procedure:
Using 2-chloro-4-fluoro-5-methylbenzonitrile (848 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.04 g) and lithium carbonate (784 mg, 10.6 mmol), the title compound was obtained as a colorless solid (yield: 590 mg) by an operation similar to that in Example 3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N+:7]2[O-].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:16].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[NH:7]2
Reactant: [O-][n+]1cccc2c(Br)cccc21
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc2c(Br)cccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a solution of 5-bromoquinoline 1-oxide (2.7 g, 12.05 mmol) in DMF (8 mL) was added trifluoroacetic anhydride (8.51 mL, 60.3 mmol) in three portions at 0° C. The reaction was allowed to warm to room temperature where it stirred overnight. At the conclusion of this period, the reaction mixture was poured into a saturated aq. NaHCO3 (100 mL) solution, and extracted with DCM (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound (2.76 g, 98% yield) as a light yellow solid. LCMS, [M+H]+=223.9. 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.05 (d, J=9.8 Hz, 1H), 7.50 (dd, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 6.63 (d, J=9.8 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1.Br[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=[N:26][S:27]([CH3:30])(=[O:29])=[O:28].C(N(CC)CC)C>CN(C)C=O>[CH3:30][S:27]([N:26]=[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][N:20]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1)(=[O:28])=[O:29]
Reactant: COc1cccc2c1CC(CN)CC2
Reactant: CS(=O)(=O)N=c1ccccn1CCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1CC(CNCCCCn1ccccc1=NS(C)(=O)=O)CC2

Procedure:
The compound is prepared from 1.60 g of 2-aminomethyl-8-methoxytetralin (8.4 mmol), 2.28 g of 1-(4-bromobutyl)-2-methylsulfonylimino-1,2-dihydropyridine (7.4 mmol) and 0.85 ml of triethylamine (8.4 mmol) in 32 ml of dimethylformamide analogously to the working directions of Example 51.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[C:20]([CH:23]=1)[CH:21]=[O:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:7]=[C:8]([Cl:13])[CH:9]=[C:10]([O:12][C:19]2[CH:18]=[CH:17][C:16]([Br:15])=[CH:23][C:20]=2[CH:21]=[O:22])[CH:11]=1)[CH3:2]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOC(=O)Cc1cc(O)cc(Cl)c1
Product: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 4, using the following starting materials: (3-chloro-5-hydroxy-phenyl)-acetic acid ethyl ester and 5-bromo-2-fluorobenzaldehyde.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[NH:18]([C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1)[C:19]([CH3:21])=[O:20]>>[NH:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:24][CH:23]=1)[C:19]([CH3:21])=[O:20]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 1 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril and 4-acetamino-thiophenol.
Reaction SMILES: [OH-].[Na+].[CH2:3]=[CH:4][CH2:5][SH:6].[CH2:7]([CH:9]1[CH2:12][N:11](OC(=O)C)[C:10]1=[O:17])[CH3:8]>O>[CH2:5]([S:6][CH:12]1[NH:11][C:10](=[O:17])[CH:9]1[CH2:7][CH3:8])[CH:4]=[CH2:3]
Reactant: C=CCS
Reactant: CCC1CN(OC(C)=O)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCSC1NC(=O)C1CC
Reaction time: 0.17 h

Procedure:
To a solution of 1.06 g of sodium hydroxide in 14 ml of water were added 2.82 ml of allylthiol. The solution was stirred under an argon atmosphere for 10 minutes. To this solution was added, over a period of 1 minute, a solution of 3.79 g of ethyl acetoxyazetidinone in 6 ml of water. After about 15 minutes, when the starting material had been consumed, the solution was extracted three times with dichloromethane. The combined organic extracts were back-extracted with water, then dried over magnesium sulphate, evaporated in vacuo, and chromatographed over silica gel, eluting with ethyl acetate/hexane mixtures. The main product (2.84 g) was trans 4-allylthio-3-ethylazetidinone, which contained a trace amount of the cis isomer. (Yield 2.84 g)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:28][CH2:27][C:23]2([CH2:26][NH:25][CH2:24]2)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:25]3[CH2:26][C:23]4([CH2:27][CH2:28][N:20]([CH3:19])[CH2:21][CH2:22]4)[CH2:24]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC2(CC1)CNC2
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (72 mg, 0.254 mmol) in DCE (7 mL) was added 7-methyl-2,7-diaza-spiro[3.5]nonane (45 mg, 0.321 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (81 mg, 0.382 mmol) was added and stirring was continued for 3 h. To the reaction mixture was added water and the resulting solution was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted with 2 M NH3 in MeOH an concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow oil (31 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.C(O)C.Cl>O>[Cl:1][C:2]1[C:3]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: CCOC(=O)COc1cc2onc(-c3ccccc3F)c2cc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)COc1cc2onc(-c3ccccc3F)c2cc1Cl

Procedure:
A mixture of ethyl {[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate (14 g) sodium hydroxide (8 g), ethanol (500 ml) and water (300 ml) is refluxed for five hours, cooled in an ice bath and acidified with concentrated hydrochloric acid. The suspension is extracted with chloroform, the extract dried with saturated sodium chloride and the chloroform removed to give a solid, mp 214°-215° C. Recrystallization from a 3:2 mixture of acetonitrile-toluene gives {[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:11]2[N:15]3[N:16]=[C:17]([CH3:25])[CH:18]=[C:19]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:14]3=[N:13][C:12]=2[CH3:26])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:33][NH:34][CH3:35]>C1COCC1>[CH2:21]([CH:20]([C:19]1[C:14]2[N:15]([C:11]([C:4]3[S:3][C:2]([N:34]([CH3:35])[CH3:33])=[N:6][C:5]=3[C:7]([F:10])([F:9])[F:8])=[C:12]([CH3:26])[N:13]=2)[N:16]=[C:17]([CH3:25])[CH:18]=1)[CH2:23][CH3:24])[CH3:22]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C(F)(F)F)c(C)nc12
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N(C)C)nc3C(F)(F)F)c(C)nc12
Temperature: 120 °C
Yield: 94 %

Procedure:
100 mg of 3-(2-Bromo-4-trifluoromethyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.22 mmol) and 218 mg of cesium carbonate (0.66 mmol) are placed in 4 ml reaction vial and 3 ml of dimethylamine 2 M in THF is added. The reaction vial is capped with a Teflon cap and heated at 120° C. overnight. The reaction mixture is filtered and concentrated and applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1) to give 85 mg of the title compound. Yield 94%. mass spectrum (m/e): 412 (M+1).