Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Br.[CH2:4]1COCC1.[NH2:9][C:10]1[C:11]2[C:37]([CH3:44])([C:38]([NH:40][CH:41]3[CH2:43][CH2:42]3)=[O:39])[C:36](=[O:45])[NH:35][C:12]=2[N:13]=[C:14]([C:16]2[C:24]3[C:19](=[N:20][C:21](Cl)=[CH:22][CH:23]=3)[N:18]([CH2:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[N:17]=2)[N:15]=1.Cl>CN1C(=O)CCC1>[NH2:9][C:10]1[C:11]2[C:37]([CH3:44])([C:38]([NH:40][CH:41]3[CH2:43][CH2:42]3)=[O:39])[C:36](=[O:45])[NH:35][C:12]=2[N:13]=[C:14]([C:16]2[C:24]3[C:19](=[N:20][C:21]([CH3:4])=[CH:22][CH:23]=3)[N:18]([CH2:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[N:17]=2)[N:15]=1
Reactant: C1CCOC1
Reactant: CC1(C(=O)NC2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4nc(Cl)ccc34)nc(N)c21
Agent: C[Mg]Br
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C(=O)NC3CC3)nn(CCC(F)(F)C(F)(F)F)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (0.42 ml, 0.584 mmol, 1.4 M in THF) was added to a THF (1.2 ml) and NMP (0.3 ml) solution containing 4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N-cyclopropyl-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, as described in Example 176, (53 mg, 0.097 mmol) and iron(111) acetylacetonate (34.4 mg, 0.097 mmol). After stirring at rt for 30 min. the reaction mixture was adjusted to pH 7 with 1N HCl at 0° C. The reaction mixture was filtered through a plug of Celite™ (diatomaceous earth) and the filtrate was washed with ethyl acetate (30 mL). The combined organic fractions were evaporated under reduced pressure. The residue was purified by reverse phase HPLC to afford the indicated product. Chiral separation using SFC on a Chiralcel OJ column provided both enantiomers of the title compound. 1H NMR (500 MHz, CD3COCD3): δ 0.58 (m, 2H); 0.73 (M, 2H); 1.78 (s, 3H); 2.68 (s, 3H), 2.80 (m, 1H); 3.10 (m, 2H); 4.94 (t, J=7.1 Hz, 2H); 7.26 (d, J=8.2 Hz, 2H); 7.52 (br, 1H); 7.79 (br, 1H); 8.74 (d, J=8.2 Hz, 1H). m/z=525.17 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH2:20]([O:22][C:23](Cl)=[O:24])[CH3:21]>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:23](=[O:24])[O:22][CH2:20][CH3:21])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1cccc(C(C)=O)c1
Yield: 91.5 %

Procedure:
A mixture of 27.03 g of m-aminoacetophenone, 27.14 g of diisopropylethylamine, 22.8 g of ethylchloroformate and 300 ml of dichloromethane was reacted as described in Example 1, giving 37.9 g of (3-acetylphenyl)carbamic acid, ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:31][O:32][CH2:33]Cl.[Cl-].[NH4+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][CH2:31][O:32][CH3:33])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(CCO)ccc1OCc1ccccc1
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCCc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of methyl 2-benzyloxy-5-(2-hydroxyethyl)benzoate (1.43 g) in dichloromethane (20 ml) were added N,N-diisopropylethylamine (1.0 ml) and chloromethyl methyl ether (460 μl) under ice-cooling, and the mixture was stirred for 17 hours at room temperature. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=4/3) gave methyl 2-benzyloxy-5-(2-methoxymethoxyethyl)benzoate (1.19 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.Cl[C:14]1[C:22]([Cl:23])=[C:21]2[C:17]([C:18]([C:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=3)=[CH:19][NH:20]2)=[CH:16][CH:15]=1>>[Cl:23][C:22]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][CH:19]=[C:18]2[C:24]1[CH2:25][CH2:26][N:27]([C:10]([CH:2]2[CH2:1][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3]2)=[O:12])[CH2:28][CH:29]=1
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1Cl
Product: O=C(C1Cc2ccccc2C1)N1CC=C(c2c[nH]c3c(Cl)cccc23)CC1

Procedure:
Prepared from 9a and 6,7-dichloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH2:48]=[C:49]([CH3:51])[CH3:50]>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:17]([C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=1)[CH2:48][C:49]2([CH3:51])[CH3:50])=[O:12])[CH3:2]
Reactant: O=Cc1cccc(Br)c1
Reactant: C=C(C)C
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Temperature: 0 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
A mixture of 4-aminobenzoic acid ethyl ester (16.5 g, 100 mmol), 3-bromo benzaldehyde (18.5 g, 100 mmol) and ytterbium(III) triflate hydrate (12.4 g, 20 mmol) in acetonitrile (350 mL) was cooled to 0° C. in a sealed reaction bottle. Then a cooled solution of isobutene (28 g, 500 mmol) was added into. The reaction mixture was heated to 90° C. and stirred for 12 h. The solvent was removed in vacuo and the residue was purified on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (16.7 g, 43%) as a white solid: MS (ESI) M+1=388.0.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7](Cl)[S:6]1(=[O:13])=[O:12])([CH3:4])([CH3:3])[CH3:2].[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][OH:14])=[CH:17][CH:18]=2)[S:6]1(=[O:13])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Product: CC(C)(C)N1C(=O)C=C(c2ccc(CO)cc2)S1(=O)=O

Procedure:
This compound was prepared according to the procedure of Example 1.1, Step 4, using 9-A and 4-(hydroxymethyl)phenylboronic acid as the starting materials. 1H NMR (500 MHz, CDCl3): δ 7.77 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H), 6.64 (s, 1H), 4.79 (d, J=5.9 Hz, 2H), 1.86–1.84 (m, 1H), 1.73 (s, 9H); LCMS found for C14H17NO4SNa (M+Na)+: m/z=318.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH3:11])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:11]/[C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(OC)N(C)C
Reactant: COc1cc(C)c([N+](=O)[O-])cc1OC
Solvent: CN(C)C=O
Product: COc1cc(/C=C/N(C)C)c([N+](=O)[O-])cc1OC

Procedure:
A 1-l. three-necked flask fitted with a thermometer and a 15-cm. Vigreux column connected to a descending condenser with a receiver and nitrogen inlet was charged with 98.6 g. of 4,5-dimethoxy-2-nitrotoluene, 500 ml. of N,N-dimethylformamide, and 120 g. of N,N-dimethylformamide dimethyl acetal. The reaction temperature was maintained at 140° for 42 hours. The volatile compounds were removed by vacuum distillation at 25°/0.1 mm. to give a solid residue of crude trans-β-dimethylamino-4,5-dimethoxy-2-nitrostyrene.
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5](B(O)O)=[CH:4][N:3]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.[NH2:27][C:28]1[S:29][CH:30]=[C:31]([CH3:33])[N:32]=1>>[CH3:33][C:31]1[N:32]=[C:28]([NH:27][C:2]2[N:3]=[CH:4][C:5]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=3)=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[S:29][CH:30]=1
Reactant: Cc1csc(N)n1
Reactant: Cc1ccc2c(B(O)O)cnc(Cl)c2n1
Reactant: FC(F)(F)c1cncc(Br)c1
Product: Cc1csc(Nc2ncc(-c3cncc(C(F)(F)F)c3)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=402.3 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-2-methyl-[1,7]naphthyridine-5-boronic acid (Example L), 3-bromo-5-(trifluoromethyl)pyridine and 2-amino-4-methylthiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>>[CH:31]1([CH2:34][N:22]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH2:33][CH2:32]1
Reactant: Cc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Reactant: BrCC1CC1
Product: Cc1ccc(CN(CC2CC2)C(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
N-(Cyclopropylmethyl)-2′-methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and cyclopropylmethyl-bromide using method L. LCMS; retention time 3.85 min, MH+ 452.
Reaction SMILES: Cl.[O:2]=[C:3]([C:23]1([CH2:36][CH2:37][CH3:38])[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:22])[CH2:9][CH2:8]1.[BH4-].[Na+]>CO.ClCCl>[OH:2][CH:3]([C:23]1([CH2:36][CH2:37][CH3:38])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([N:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:22])[CH2:11][CH2:12]1
Reactant: CCCC1(C(=O)CCCN2CCC(N3Cc4ccccc4C3=O)CC2)c2ccccc2-c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCC1(C(O)CCCN2CCC(N3Cc4ccccc4C3=O)CC2)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of Example 311 Part D free amine (300 mg, 0.61 mmol) in 12 ml of methanol was cooled to 0° C. under an argon atmosphere and 2 equiv. of sodium borohydride (48.5 mg, 1.28 mmol) was added. The reaction mixture was stirred at 0° C. for 45 min. The reaction was quenched with 1N hydrochloric acid and extracted with ethyl acetate (3×20 ml). The extract was washed with brine and dried over sodium sulfate. Evaporation yielded an oily residue which was dissolved in dichloromethane, dried over sodium sulfate and evaporated to yield 550 mg of a colorless solid. The crude product was purified on a Merck EM silica column eluting with 5% methanol/dichloromethane yielding 290mg (96%) of title compound as colorless solid.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][C@H:14]([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Si:17]([O:16][CH2:15][C@@H:14]([CH3:24])[CH2:13][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1][CH2:2][C:3]1=[O:11])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19]
Reactant: C[C@@H](CBr)CO[Si](C)(C)C(C)(C)C
Reactant: O=C1CSc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)CSc2ccccc21
Yield: 70.4 %

Procedure:
4H-Benzo[1,4]thiazin-3-one (2.75 g, 16.7 mmol), (R)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (95MF94) (4.04 g, 15.1 mmol) and cesium carbonate (12.3 g, 37.9 mmol) in DMF (20 mL) were reacted according to GP2 to give the title compound (108LM25-22) (3.74 g, 70%). 1H NMR (CDCl3) δ7.35 (d, J=7.6 Hz, 1H), 7.28-7.18 (m, 2H), 6.99 (t, J=7.6 Hz, 1H), 4.13 (dd, J=8.9 Hz, J=13.3 Hz, 1H), 3.95 (dd, J=5.9 Hz, J=13.3 Hz, 1H), 3.52-3.40 (m, 2H), 3.37 (s, CH2), 1.96-2.07 (m, 1H), 0.92-0.83 (m, 12 H), 0.02 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:19](=[N:21]O)C)[CH:17]=[CH:18][C:13]=2[N:12](C)[C:11](=[O:24])[CH:10]([CH3:25])[N:9]=1.[C:26](C1C=CC2NC(=O)C(C)(C)N=C(C3C=CC=CC=3F)C=2C=1)(=O)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:19]#[N:21])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:24])[C:10]([CH3:26])([CH3:25])[N:9]=1
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2
Reactant: CC(=NO)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2C
Product: CC1(C)N=C(c2ccccc2F)c2cc(C#N)ccc2NC1=O

Procedure:
From 33.74 g (0.169 mol) of 5-(o-fluorophenyl)-2,3-dihydro-3,3-dimethyl-2-oxo-1H-1,4-benzodiazepine-7-carbonitrile there is obtained in analogy to paragraph (h) of Example 1 7-acetyl-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-2H-1,4-benzodiazepin-2-one of melting point 206°.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][C@H:14]([NH:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[N:41]([C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]([C:53]([NH2:55])=[O:54])[CH:45]=1)=[C:42]=[O:43].O>C1COCC1>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][C@H:14]([NH:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][N:12]1[C:42](=[O:43])[NH:41][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]([C:53](=[O:54])[NH2:55])[CH:45]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)n1cc(N=C=O)c2ccccc21
Reactant: O=C(N[C@@H]1CN[C@H](C(=O)OCc2ccccc2)C1)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)n1cc(NC(=O)N2C[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C[C@H]2C(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2S,4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester (3.03 g, 5.45 mmol) and Et3N (1.1 mL, 8.2 mmol) in dry THF (60 mL) was added a solution of 3-isocyanato-indole-1-carboxylic acid amide (1.1 g, 5.4 mmol, prepared as described in Scheme A1) in dry THF (60 mL). The resulting solution was stirred at RT under nitrogen for 20 min. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under high vacuum (the temperature of the water bath of the rotary evaporator was kept to RT) to give the title compound. Rf (c-hexane/EtOAc 1:3)=0.39; MS (LCMS): 644.2 [M+H]+, 666.2 [M+Na]+; tR (HPLC conditions a): 4.0 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[NH:15][NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:6]1)[CH2:12]2)=[O:4].[Br:27][C:28]([CH3:33])([CH3:32])[C:29](Br)=[O:30]>>[Br:27][C:28]([CH3:33])([CH3:32])[C:29]([N:15]([CH:8]1[CH:9]2[CH2:10][CH:11]3[CH2:12][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH2:6][CH:7]1[CH2:13]3)[CH2:14]2)[NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:30]
Reactant: CC(C)(Br)C(=O)Br
Reactant: COC(=O)C12CC3CC(C1)C(NNC(=O)OCc1ccccc1)C(C3)C2
Product: COC(=O)C12CC3CC(C1)C(N(NC(=O)OCc1ccccc1)C(=O)C(C)(C)Br)C(C3)C2

Procedure:
Benzyl 2-(5-methoxycarbonyladamantan-2-yl)hydrazinecarboxylate and 2-bromoisobutyrylbromide were used for a similar reaction and treatment as Process 3 of Example 1, and benzyl 2-(2-bromoisobutyryl)-2-(5-methoxycarbonyladamantan-2-yl)hydrazinecarboxylate was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-])[CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c[n+]([O-])cc2ccccc12
Product: Cc1cnc(Cl)c2ccccc12
Yield: 18.75 %

Procedure:
A solution of 4-methylisoquinoline 2-oxide (0.65 g, 4.08 mmol) in POCl3 (6 ml) was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified with solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.17 g, 18.75%) as oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.14-8.12 (d, J=8 Hz, 1H), 7.97 (s, 1H), 7.95-7.93 (d, J=8 Hz, 1H), 7.86 (t, J=4 Hz, 1H), 7.84(t, J=8 Hz, 1H), 2.59 (s, 3H); MS: MS m/z 178.2 (M++1).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:37]Br.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:37][N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:32])=[O:3])[CH:11]=[C:12]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[CH:13]=2)[CH2:17]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3cc(F)cc(C(F)(F)F)c3)C2)c1
Yield: 85 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (44.6 mg, 0.10 mmol) in CH3CN (5 ml) was added 3-Fluoro-5-trifluoromethyl benzyl bromide) (77 mg, 0.3 mmol) and diisopropylethylamine (35 μl, 0.20 mmol). The reaction was microwaved at 130° C. for 10 minutes, then diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (53 mg, 85%). Calcd for C34H36F7N1O2 (M+H) 623.64, Found 624.3
Reaction SMILES: Br[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.[S:29]1[CH:33]=[C:32]([CH:34]=[O:35])[N:31]=[CH:30]1>C1(C)C=CC=CC=1.ClCCl>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[CH:34]([C:32]1[N:31]=[CH:30][S:29][CH:33]=1)[OH:35]
Reactant: O=Cc1cscn1
Reactant: CN(C)CCc1sc2ccccc2c1Br
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)CCc1sc2ccccc2c1C(O)c1cscn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 89.7 %

Procedure:
To a cooled (−78° C.) solution of [2-(3-bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (200 mg, 0.7 mmol) in anhydrous toluene (8 mL), TMEDA (110 uL, 0.7 mmol) was added followed by nBuLi (0.47 mL, 0.75 mmol, 1.6M in hexanes). The mixture was stirred for 40 min at −78° C. and a solution of thiazole-4-carbaldehyde (0.32 g, 2.8 mmol) in dichloromethane (1 mL) was added. The mixture was stirred for 16 hrs during which the temperature reached room temperature. The reaction was quenched with water, the resulting mixture was basified by the addition of NH4OH and extracted with EtOAc. The combined organic layers were concentrated and subjected to mass triggered preparative HPLC to afford [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-thiazol-4-yl-methanol (Compound 14-1) (200 mg). MH+=318.8.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCC(=O)Cl
Reactant: CCC1CNC(c2cccc(C(F)(F)F)c2)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)N1CC(CC)OC1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Four and seven-tenths grams of 2-(m-trifluoromethylphenyl)-5-ethyl-1,3-oxazolidine was combined with 1.6 g of pyridine in 25 ml of methylene chloride and 2.0 g of butyroyl chloride was added dropwise. The mixture was allowed to stir overnight. The mixture was washed with 50 ml of 5% NaOH and 200 ml of water, dried and stripped on the rotary evaporator. Yield was 6.3 g, nD30 1.5015. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:14](Cl)(=O)[C:15](Cl)=O.CN(C)[CH:22]=[O:23]>ClCCl>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([C:15]1[CH:14]=[CH:4][C:3]([O:23][CH3:22])=[CH:2][CH:1]=1)=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2C)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of 2-methyl-5-nitro-benzoic acid (50 g) in dichloromethane (330 mL) is added oxalyl chloride (25.5 mL) followed by dimethylformamide (0.5 mL). The reaction mixture is stirred at ambient temperature for 14 h, then filtered and separated from all volatile constituents in a rotary evaporator. The residue is dissolved in dichloromethane (100 mL), the resulting solution is cooled to −5° C., and anisole (31 mL) is added. Then aluminum trichloride (37.5 g) is added batchwise so that the temperature maintains below 5° C. The solution is stirred for another 1 h at 1 to 5° C. and then poured onto crushed ice. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with aqueous hydrochloric acid (1 mol/L), twice with aqueous sodium hydroxide solution (1 mol/L) and with brine. The organic phase is dried (sodium sulphate), the solvent is removed and the residue is recrystallised from ethanol.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH2:14][CH3:15])[CH2:4][NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][CH2:9][O:8]1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:28][CH2:29][C:30](Cl)=[O:31]>O>[CH3:1][O:2][CH:3]([O:13][CH2:14][CH3:15])[CH2:4][N:5]([CH2:6][CH:7]1[O:8][CH2:9][CH2:10][CH2:11][O:12]1)[C:30](=[O:31])[CH2:29][Cl:28]
Reactant: CCOC(CNCC1OCCCO1)OC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(CN(CC1OCCCO1)C(=O)CCl)OC

Procedure:
N-(2-Methoxy-2-ethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)-amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel eqiuipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2-methoxy-2-ethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)-α-chloroacetamide as the residue.