Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]=[O:24])=[C:17]([CH3:25])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1.[CH:28]([Mg]Br)=[CH2:29].[Cl-].[NH4+]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]([OH:24])[CH:28]=[CH2:29])=[C:17]([CH3:25])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1
Reactant: C=C[Mg]Br
Reactant: Cc1c(C=O)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Temperature: -78 °C
Yield: 39.6 %

Procedure:
To a 50 mL round bottom flask equipped with a stir bar was added 2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (0.415 g, 1.03 mmol) and THF (12 mL). The reaction mixture was cooled to −78° C. To the stirred suspension was added vinylmagnesium bromide (5 mL, 1 M in THF, 5 mmol) in one portion. The solution was allowed to gradually warm to −30° C. over 1 h. Additional vinylmagnesium bromide (3 mL, 1 M in THF, 3 mmol) was added and the reaction mixture was further warmed to 0° C. over 1.5 h. The cold reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (3×50 mL). The organic fractions were collected, washed with brine (3×25 mL) and concentrated. The resulting solid was further purified by flash chromatography, eluting with EtOAc:Hexane (0-100%) to give 2-(2,6-dichloro-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.175 g, 40%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.43 (s, 1H), 7.77-7.75 (m, 4H), 7.59 (t, 1H, J=8.6 Hz), 6.06-5.98 (m, 1H) 5.42 (app d, 1H, J=5.5 Hz), 5.32 (app d, 1H, J=17.2 Hz), 5.16 (app d, 1H, J=10.2 Hz), 4.26 (s, 3H), 2.27 (s, 3H); ESMS (m/z): found, 429.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH:15]=[CH2:16])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH3:6])[CH:2]=[CH2:3].[Li]CCCC.[CH3:22][C:23]([CH3:25])=[O:24]>C1COCC1>[CH2:1]([N:4]([CH2:14][CH:15]=[CH2:16])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([C:23]([OH:24])([CH3:25])[CH3:22])=[CH:9][CH:8]=1)[CH3:6])[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)[C@H](C)c1ccc(Br)cc1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCN(CC=C)[C@H](C)c1ccc(C(C)(C)O)cc1
Temperature: -78 °C
Yield: 64 %

Procedure:
2.76 g (9.9 mmol) (R)-diallyl-[1-(4-bromo-phenyl)-ethyl]-amine was dissolved in 30 ml THF (dry) under N2 atmosphere. The mixture was then cooled to −78° C. and 5.0 ml (12 mmol) of 2.5M n-BuLi in hexanes was added drop-wise. The mixture was then cooled to −90° C. and acetone was added, while stirring continued at −90° C. for 10 m. The mixture was then allowed to warm to room temperature and the reaction was thereafter quenched with MeOH. Water was then added and the resulting mixture was extracted with ether. The ether extracts were combined; washed with water and brine; dried over MgSO4; and filtered and concentrated in vacuo. Chromatography on silica gel using 15% ethyl acetate/hexanes yielded 1.6 g (64%) of the desired final product.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[P:24](Cl)([Cl:33])([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25].ClCCl>C(N(CC)CC)C>[P:24]([Cl:33])(=[O:25])([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[O:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOCC(COP(=O)(Cl)Oc1ccccc1)OC
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A 1 mmol portion of 3-(hexadecyloxy)-2-methoxy propanol is added to a 0°-5° C. solution of 1 mmol of phenyl dichlorophosphate in 2 ml of anhydrous dichloromethane containing 1.2 mmol of triethylamine. The mixture is stirred under argon for 1 hour at 5° C., then for 2.5 hours at room temperature and then used as is.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[C:15]([C:17]([O-])=[O:18])[S:16][C:9]=12.[Li+]>>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:17]([C:15]1[S:16][C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[Cl:7])[CH:14]=1)=[O:18]
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CN(C)CCN
Agent: [Li+]
Product: CN(C)CCNC(=O)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 2-dimethylaminoethyl amine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 284/286 (MH+); HPLC Rf: 3.47 min.; HPLC purity: 95%.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[O:14]1[CH2:17][CH:16]([NH2:18])[CH2:15]1.C(N(C(C)C)CC)(C)C>C(#N)C>[N+:11]([C:6]1[CH:7]=[C:8]2[CH2:9][N:18]([CH:16]3[CH2:17][O:14][CH2:15]3)[CH2:2][CH2:3][N:4]2[N:5]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Reactant: NC1COC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc2n(n1)CCN(C1COC1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
To a solution of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (500 mg, 1.6 mmol) in acetonitrile (20 mL) was added oxetan-3-amine (140 mg, 1.92 mmol) and diisopropylethyl amine (372 mg, 0.50 ml, 2.88 mmol) drop wise and the resulting mixture was stirred at room temperature for 24 h. The solution was concentrated and the residue dissolved in ethyl acetate (50 mL), washed with water (50 mL) and dried over magnesium sulfate. The resulting mixture was filtered and evaporated and the residue purified by flash chromatography (SF25-40 g, 50% to 100% ethyl acetate in hexanes) to give 2-nitro-5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (255 mg, 71%) as a light yellow solid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH3:8]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(=O)c1ccccc1
Product: CCCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccccc21
Yield: 78.1 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 6 and benzhydrazide according to the synthetic method D. The resulting solid was washed with ethanol. Yield: 78.1%. 1H NMR (DMSO-d6): δ 0.90 (t, J=6.5 Hz, 3H), 1.34-1.36 (m, 4H), 1.63-1.68 (m, 2H), 3.80 (t, J=7 Hz, 2H), 7.22 (t, Hz, J=7.5 Hz, 1H), 7.26 (d, J=7.5 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.65-7.70 (m, 3H), 7.74 (t, Hz, J=7 Hz, 1H), 7.96 (d, (d, J=7, 2H), 13.95 (br s, 1H). 13C NMR (DMSO-d6): δ 14.30 (CH3), 22.27 (CH2), 27.15 (CH2), 28.89 (CH2), 39.75 (CH2), 110.66 (CH), 119.65 (C), 121.26 (CH), 123.69 (CH), 127.88 (CH), 129.67 (CH), 132.23 (CH), 132.42 (C), 133.40 (CH), 137.80 (C), 143.43 (C═N), 161.58 (C═O), 163.36 (C═O). HRMS (ES+) calcd for C20H22N3O2 (M+H+) m/e, 336.1713; found 336.1707.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:15])[C:4]=1[F:16].[K+].[Br-].[CH3:19]O>>[NH2:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([O:9][CH3:19])=[O:8])=[C:5]([F:15])[C:4]=1[F:16]
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Reactant: CO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Reaction time: 23 h
Yield: 70 %

Procedure:
Hydrogen chloride gas was dissolved in anhydrous methanol (30 ml) until the solution was warm. The solid 4-amino-2,3-difluoro-5-nitrobenzoic acid (0.47 g; 0.00215 mol) was dissolved in this solution and the reaction mixture was brought to reflux with vigorous stirring for 23 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool slowly on the bench. A yellow precipitate formed and was collected by vacuum filtration and dried with suction to afford 0.35 g of yellow microfilaments; 70% yield; m.p. 183.5-184° C.; 1H-NMR (400 MHz; DMSO) δ8.36 (dd, 1H, J=7.3, 1.7 Hz), 8.06 (s, 2H), 3.78 (s, 3H); 19F-NMR (376 MHz; DMSO) δ−128.85 to −128.92 (m), −153.29 (d); MS (APCl−) 231 (M−1, 100); IR (KBr) 3433, 3322, 1700, 1650, 1549, 1343, 1285 cm−1; Anal. calcd/found for: C8H6F2N2O4 C, 41.39/41.40; H, 2.61/2.50; N, 12.07/11.98; F, 16.37/16.58.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:6]([CH:32]=1)[CH2:7][N:8]([CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:11][CH:10]=1>C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[C:6]([CH:32]=1)[CH2:7][N:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)[CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N(Cc2ccc(C(=O)O)cc2)Cc2cc(Br)ccc2OCc2ccccc2)cc1
Solvent: O=CO
Product: O=C(O)c1ccc(CN(Cc2cc(Br)ccc2OCc2ccccc2)c2ccc(C(=O)O)cc2)cc1
Reaction time: 18 h
Yield: 75 %

Procedure:
tert-Butyl 4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-carboxybenzyl)-amino]benzoate (example 3) (500 mg) was suspended in formic acid (2 ml) and heated on a steam bath until a clear solution was obtained. This solution was left at ambient temperature for 18 hours and the resulting solid filtered, washed with formic acid (2×1 ml) and dried under vacuum at 60° C. to give the title product (340 mg) m.p. 271° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][OH:20])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1>CCO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Solvent: C1COCCO1
Solvent: CCO
Product: OCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 20.1, 3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol in EtOH/dioxane was converted to yield 3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-propan-1-ol as a brown oil, MS: 303 (M, 1Cl).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:31])(=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:10][CH:9]=1)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)(=[O:30])=[O:31])=[CH:17][C:16]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:10][CH:9]=1.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]
Reactant: CC(C)c1ccc2c(Nc3cc(S(=O)(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(S(=O)(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(N)cc3)ncnc2n1

Procedure:
The product from Example 78E (44 mg, 0.061 mmol) was treated with trifluoroacetic acid (2 mL) in methylene chloride (2 mL) at room temperature for 30 minutes. The solvents were removed by rotary evaporation under vacuum and the residual oil dried under hi-vacuum. Purification by silica gel chromatography using 5% methanol/methylene chloride as eluent provided the title compound as a trifluoroacetic acid salt (25 mg, 48%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J=6.62 Hz, 6 H), 3.13-3.38 (m, 1 H), 6.63 (d, J=8.46 Hz, 2 H), 6.87 (d, J=7.72 Hz, 1 H), 7.01-7.09 (d, J=8.82 Hz, 2 H), 7.12 (d, J=8.46 Hz, 2 H), 7.44 (d, J=8.82 Hz, 2 H), 7.61 (dd, J=7.72, 1.47 Hz, 1 H), 7.71 (s, 1 H), 7.81 (dd, J=6.62, 1.47 Hz, 1 H), 8.66-8.80 (m, 1 H), 8.90 (d, J=6.99 Hz, 1 H), 10.55 (s, 1 H); MS (ESI+) m/z 621/623 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]2[CH2:35][CH2:34]2)=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]3[CH2:35][CH2:34]3)=[CH:28][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:19][CH:20]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: Brc1ccc(OC2CC2)cc1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2n1-c1ccc(OC2CC2)cc1

Procedure:
The sub-title compound was prepared in accordance with Example 1(b) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and 1-bromo-4-cyclopropoxybenzene (see step (c) above).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([Li])CCC.[Sn:29](Cl)([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33]>C1COCC1>[C:1]([NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Sn:29]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(N[C@@H](Cc1ccc(Cl)cc1)C(=O)O)OCc1ccccc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-CBZ p-chloro phenylalanine 1 (one equivalent) in anhydrous THF at 100° C. is added n-butyllithium (3.3 equiv.). After one hour, a solution of Bu3SnCl (excess) is added. Other tri-alkyl-Sn compounds may be used in place of Bu3SnCl. The solution is warmed to 0° C. and quenched by the addition of saturated NH4Cl. Extractive work-up into diethyl ether affords the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][NH2:12])=[C:4]([F:13])[CH:3]=1.[C:14]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O)(=O)[CH3:15].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:11]2[C:14]([CH3:15])=[C:17]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:12]2)=[C:4]([F:13])[CH:3]=1
Reactant: NNc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: CC(=O)C1CCCCC1=O
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: Cc1c2c(nn1-c1cc([N+](=O)[O-])c(Cl)cc1F)CCCC2
Yield: 38.2 %

Procedure:
In the same manner as in Example 4 but using 4-chloro-2-fluoro-5-nitrophenylhydrazine (4 g), 2-acetylcyclohexanone (2.8 g), a catalytic amount of acetic acid and xylene (10 ml), there was produced 2.3 g of 2-(4-chloro-2-fluoro-5-nitrophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole. m.p., 143°-144° C.
Reaction SMILES: C([C@@H]1C(OC)=[N:8][C@@H:7]([CH2:12][CH2:13][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([F:18])([F:17])[F:16])[C:6]([O:25][CH3:26])=N1)(C)C.O.FC(F)(F)C(O)=[O:31].[Cl-].[NH4+]>C(#N)C>[CH3:26][O:25][C:6](=[O:31])[C@@H:7]([NH2:8])[CH2:12][CH2:13][CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([F:18])([F:17])[F:16]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCC(c1ccccc1)C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@@H](N)CCC(c1ccccc1)C(F)(F)F
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-(4,4,4-trifluoro-3-phenyl-butyl)-2,5-dihydro-pyrazine (1.86 g) in acetonitrile (18 ml) were added water (7 ml) and trifluoroacetic acid (3.8 ml). The mixture was stirred overnight at 40° C. Saturated ammonium chloride solution was added and the mixture was extracted with dichloromethane three times. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/MeOH=98:2 to yield a light yellow solid, (0.98 g, 71%); MS (ISP): 276.1 ((M+H)+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10](I)[C:5]2=[CH:4][CH:3]=1.[CH:18]1([N:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26](B4OC(C)(C)C(C)(C)O4)[CH:27]=3)[C:22]2=[O:39])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10]([C:26]3[CH:27]=[C:28]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:39])[N:21]([CH:18]3[CH2:20][CH2:19]3)[CH2:29]4)[C:5]2=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Reactant: Clc1ccc2c(I)nn(C3CCCCO3)c2n1
Product: O=C1c2ccc(-c3nn(C4CCCCO4)c4nc(Cl)ccc34)cc2CN1C1CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 72, Step 3 starting from 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (Example 72, Step 2) and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=409.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[C:36]#[N:37]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=5[C:36]#[N:37])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: N#Cc1ccc(F)c(C#N)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(C#N)cc5C#N)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-fluoro-isophthalonitrile following a procedure analogous to that described for Intermediate 12. LC (method 6): tR=1.14 min; Mass spectrum (ESI+): m/z=485 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([OH:16])=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([NH:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)=[O:16]
Reactant: O=C(O)c1cc(Cl)cc(Br)c1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2ccc(Cl)cc2)cc1)c1cc(Cl)cc(Br)c1
Temperature: 25 °C

Procedure:
Neat i-Pr2NEt (0.21 mL, 1.19 mmol) was added to a DCM mixture (5 mL) of 3-bromo-5-chlorobenzoic acid (140 mg, 0.60 mmol), 4′-chloro-[1,1′-biphenyl]-4-amine (145 mg, 0.71 mmol), HOBt (92 mg, 0.60 mmol) and EDCI (114 mg, 0.60 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting precipitate was filtered off, washed with water and MeOH, and dried in vacuo to yield the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2c3c(sc2n1)CCCC3
Reactant: c1c[nH]cn1
Product: c1cn(-c2nc(NCc3ccc4c(c3)OCCO4)c3c4c(sc3n2)CCCC4)cn1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)C.[OH-].[Na+].Cl>CO.O>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:19])=[O:3])[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (5.28 g) obtained in the above (1) is dissolved in methanol (32 ml), and thereto is added 1N aqueous sodium hydroxide solution (23.4 ml), and the mixture is stirred at room temperature for three hours. The reaction mixture is diluted with water, and the pH value thereof is adjusted to pH 2 with 1N hydrochloric acid, and extracted three time with ethyl acetate. The extract is washed twice with a saturated brine, and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (5.18 g).
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3][CH:2]2[CH3:10].[OH:11]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(#N)C>[CH:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3][C:2]2([OH:11])[CH3:10]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC1CCC2CC1C2(C)C
Agent: O=O
Solvent: CC#N
Product: CC1(O)CCC2CC1C2(C)C
Yield: 82 %

Procedure:
To 25 milliliters of acetonitrile were added 1.38 grams (10 millimoles) of pinane, 0.13 gram (0.8 millimole) of N-hydroxyphthalimide and 0.015 gram (0.06 millimole) of Co(AA)2, and the resultant mixture was stirred in an oxygen atmosphere at a temperature of 100° C. for six hours. Pinane was transformed into 2-pinanol (selectivity for pinane 91%, yield 82%) with a transformation rate of 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[C:5]2[CH2:19][CH2:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22].[CH3:29][C:30]([CH3:35])([CH3:34])[CH2:31][CH:32]=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[C:5]2[CH2:19][CH2:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH2:32][CH2:31][C:30]([CH3:35])([CH3:34])[CH3:29])[CH2:27][CH2:28]1)=[O:22]
Reactant: CC(C)(C)CC=O
Reactant: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)N2CCNCC2)c2cc(Cl)ccc21
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)N2CCN(CCC(C)(C)C)CC2)c2cc(Cl)ccc21

Procedure:
Prepared from 1-{3-[5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indol-3-yl]-1-oxopropyl}piperazine (Description 31) and 3,3-dimethylbutanal according to the method of Example 145. 1NMR (360 MHz, CDCl3) δ7.58 (1H, d, J 1.7 Hz), 7.48 (2H, d, J 6.5 Hz), 7.31 (2H, d, J 6.5 Hz), 7.24 (1H, d, J 8.6 Hz), 7.20 (1H, dd, J 8.6, 1.7 Hz), 3.58 (2H, m), 3.54 (3H, s), 3.23 (2H, m), 2.98 (2H, m), 2.50 (2H, m), 2.33 (2H, m), 2.28 (2H, m), 2.20 (2H, m), 1.37 (2H, m), and 0.90 (9H, s). m/z (ES+) 500, 502 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:3]2[C:2]([Cl:1])=[CH:10][C:6]([C:7](=[O:8])[NH2:9])=[CH:5][N:4]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: NC(=O)c1cnc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(N)=O)cc2Cl)CC1

Procedure:
The nicotinamide from step (b) above (1.3 g, 6.8 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.27 g, 6.8 mmol, Aldrich) reacted under the conditions Example 3a to give the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 341 (M+1).