Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=C(Br)[CH:14]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:23]([Li])CCC.CCCCCC.[Cl-].[NH4+].[CH3:36][C:37]([CH3:39])=[O:38]>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:14]=[C:36]([C:37]([OH:38])([CH3:23])[CH3:39])[CH:16]=[C:17]([CH3:19])[CH:18]=2)[CH3:11])=[CH:21][CH:22]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(Br)cc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Reactant: CC(C)=O
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(CN(C)Cc2ccc(C(C)(C)C)cc2)cc(C(C)(C)O)c1
Temperature: -75 °C
Yield: 30.6 %

Procedure:
Compound 85 (1.42 g; 3.94 mmol) was dissolved in tetrahydrofuran (20 ml). While the solution was stirred at −75° C. under nitrogen atmosphere, n-butyl lithium in n-hexane (1.56 M: 2.5 ml; 3.94 mmol) was added dropwise. The mixture was stirred for 15 minutes, and acetone (2 ml) was added dropwise thereto. The resultant mixture was brought to room temperature over 2 hours, and the reaction was stopped by dropwise addition of saturated aqueous ammonium chloride solution, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1→4:1), to thereby yield 0.41 g of the target compound as yellow oily matter (yield: 30.6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NC(c2ccccc2)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NC(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 200-205° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22].Cl.N1C=CC=CC=1>CC(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Cl
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Yield: 74.9 %

Procedure:
A stirred mixture of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile (10.7 g, 40 mmol), 3-chloro-4-fluoroaniline (7.0 g, 48 mmol), pyridine hydrochloride (4.6 g, 40 mmol), and 200 ml of 2-propanol was heated to reflux temperature and maintained for 1 h. The 2-propanol was evaporated off, and the residue was stirred in water with potassium bicarbonate (pH˜8). The resulting solid was filtered, washed with water and 5:1 hexane-DCM, and dried. Recrystallization from EtOH gave 11.3 g of yellow solid, mp 259-263°; ms 377.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:31])([CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)[C@H:10]([C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:16]=1)[CH3:11].[CH3:32][C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([CH3:56])[C:40]=1[O:41][C:42]([C@@H:44]1[CH2:48][CH2:47][CH2:46][N:45]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:43])[CH2:36][Br:37].CC1C=C(C=C(C)C=1O)C=O>C(#N)C>[Br-:37].[C:21]([C:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:12]([C@H:10]([CH3:11])[C@:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:31])[CH2:25][N:26]3[CH:30]=[N+:29]([CH2:36][C:35]4[CH:38]=[C:39]([CH3:56])[C:40]([O:41][C:42]([C@@H:44]5[CH2:48][CH2:47][CH2:46][N:45]5[C:49]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:50])=[O:43])=[C:33]([CH3:32])[CH:34]=4)[CH:28]=[N:27]3)[S:13][CH:14]=2)=[CH:24][CH:23]=1)#[N:22]
Reactant: Cc1cc(CBr)cc(C)c1OC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1cc(C=O)cc(C)c1O
Solvent: CC#N
Product: Cc1cc(C[n+]2cnn(C[C@](O)(c3ccc(F)cc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc(C)c1OC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Product: [Br-]
Reaction time: 15 h
Yield: 93.2 %

Procedure:
A mixture of 1.06 g of (1R,2R)-4-[2-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]thiazol-4-yl]benzonitrile and 1.1 g of 3,5-dimethyl-4-[(S)-N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy]benzyl bromide, prepared from 3,5-dimethyl-4-hydroxybenzaldehyde in 3 steps, in 20 mL of acetonitrile was stirred for 15 h at reflux temperature and then concentrated. The residue was chromatographed on silica gel (Wakogel C-200, solvent: CH2Cl2 /MeOH=12/1) to give 1.92 g (94%y.) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide as a white solid.
Reaction SMILES: [S:1]([CH2:5][C:6]([OH:8])=[O:7])(O)(=[O:3])=[O:2].[CH3:9][CH2:10]O.O=P(Cl)(Cl)Cl.[CH:17]([C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:21]=1[NH2:22])([CH3:19])[CH3:18]>C(Cl)Cl>[CH3:29][CH:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:20]([CH:17]([CH3:19])[CH3:18])[C:21]=1[NH:22][S:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])=[O:2])[CH3:28]
Reactant: O=C(O)CS(=O)(=O)O
Reactant: CCO
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 125 °C
Reaction time: 18 h

Procedure:
Sulfoacetic acid (52 g, 371 mM) and EtOH (500 mL) were heated under reflux for 20 hours. The reaction mixture was cooled, and the excess ethanol was removed under vacuum to give 2 (see Chart I). A mixture of 2 (16.82 g, 100 mM) and POCl3 (30.67 g, 200 mM) was heated at 125° C. for 5 hours. The mixture was cooled and filtered, and excess POCl3 was removed to give 3 (see Chart I). Compound 3 (8.18 g, 43.83 mM) was added dropwise with stirring to a solution of 2,6-diisopropylaniline (15.54 g, 87.66 mM) in 50 mL CH2Cl2 maintained at 0° C. The mixture was stirred at room temperature for an additional 18 hours. The solvent was removed and the residue was redissolved in 100 mL ethyl acetate and washed with 1 N HCl and brine. The ethyl acetate was evaporated and the pure compound was isolated by chromatography over silica gel (EtOAc/hexane, 1:4 as eluant) as a white powder, 7.0 g (~50%), mp 114°-116° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:11]([OH:42])[C:12]2[N:13]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[C:6]([F:10])=[C:7]([OH:9])[CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH2:50][CH3:51]>CN(C=O)C.CCOC(C)=O>[CH2:50]([O:9][C:7]1[C:6]([F:10])=[C:5]([CH:11]([C:12]2[N:13]([C:23]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[OH:42])[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=1)[CH3:51]
Reactant: CCI
Reactant: CCc1cc(O)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(CC)cc(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 100.1 %

Procedure:
To a solution of Intermediate 448.2 (1.00 g, 1.80 mmol) in 10 mL DMF at rt, were added K2CO3 (229 mg, 2.16 mmol) and iodoethane (432 μL, 5.4 mmol). The mixture was stirred at rt for 19 h, then diluted with EtOAc. The organic phase was washed with H2O (2×), sat. Na2SO3 and brine, dried (Na2SO4), filtered through 1″ SiO2 and concentrated to afford 1.05 g of Intermediate 448.3 as a colorless solid. LCMS (2 min gradient) RT=1.92 min, 583.3 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[CH:4][N:3]=1.[NH2:45][C:46]1[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[N:50][CH:51]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:9]=[C:8]([C:7]3[C:2]([NH:45][C:46]4[CH:51]=[N:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=4)=[N:3][CH:4]=[C:5]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:37][CH:36]=4)[CH:6]=3)[N:13]=[C:12]([CH3:14])[N:11]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3F)n2)cc1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Yield: 70 %

Procedure:
4-(2-Fluoro-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (503 mg, 0.820 mmol) and 5-amino-2-methoxypyridine (112 mg, 0.905 mmol) were dissolved in THF (8.0 mL) and the flask was cooled in an ice water bath while the reaction was stirred under nitrogen. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran (2.5 mL, 2.500 mmol) was added via syringe, and the reaction was stirred for 40 min. Then, the reaction was treated with ice water (0.60 mL) and the reaction was diluted with DCM, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; DCM to100:1 DCM/MeOH to 50:1 DCM/MeOH). The pure fractions were set aside, while the impure ones were collected, concentrated, and purified on another silica gel filter (30 mL fritted filter with about 1 inch of silica gel; DCM to 100:1 DCM/MeOH). The fractions with product were combined with the pure fractions from the first column and concentrated to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (412 mg). 1H NMR (CDCl3, 400 MHz) δ 11.58 (s, 1H), 8.61 (d, J=2.35 Hz, 1H), 8.26 (d, J=2.54 Hz, 1H), 8.13 (d, J=2.35 Hz, 1H), 7.87 (dd, J=8.90 Hz, 2.64 Hz, 1H), 7.81 (d, J=8.22 Hz, 2H), 7.37 (d, J=8.22 Hz, 2H), 7.21 (d, J=8.61 Hz, 2H), 7.15 (d, J=8.61 Hz, 2H), 6.87 (d, J=8.61 Hz, 2H), 6.82 (d, J=8.41 Hz, 2H), 6.70 (d, J=8.80 Hz, 1H), 4.85 (s, 2H), 4.77 (s, 2H), 4.00 (s, 2H), 3.93 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 2.98 (s, 3H), 2.57 (s, 3H). m/z (ESI, +ve ion) 718 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11]([C:19]#[N:20])[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:4][CH2:3]1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=O.C(O)(=O)C>CC(O)C>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[N:1][N:2]1[CH2:3][CH2:4][N:5]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11]([C:19]#[N:20])[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:6][CH2:7]1
Reactant: N#CC1=Cc2ccccc2C(N2CCN(N)CC2)c2ccccc21
Reactant: O=Cc1ccccn1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: N#CC1=Cc2ccccc2C(N2CCN(N=Cc3ccccn3)CC2)c2ccccc21

Procedure:
A mixture of 40 parts of 5-(4-amino-1-piperazinyl)-5H-dibenzo[a,d]cycloheptene-10-carbonitrile, 50 parts of 2-pyridinecarboxaldehyde, 3 parts of glacial acetic acid, and 400 parts of 2-propanol is heated at the boiling point under reflux for 5 hours, then refrigerated until precipitation is complete. Insoluble solids are removed by filtration, consecutively washed with absolute ethanol and hexane, and air-dried. Recrystallization of this material from a mixture of chloroform and hexane affords 5-[4-(2-pyridylmethylene)amino-1-piperazinyl]-5H-dibenzo[a,d]cycloheptene- 10-carbonitrile as a light tan solid which, dried in air, melts at 182.5°-184°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14].Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(Br)cc1
Temperature: 80 °C

Procedure:
A suspension of 31.4 g (178 mmol) 4-bromophenol, 30.6 g (178 mmol) (2-chloro-ethyl)-diethyl-amine (used as the hydrochloride) and 61.5 g (445 mmol) K2CO3 in 300 mL DMF is heated to 80° C. for 8 h. The solvent is evaporated down i.vac., the residue combined with water, the aqueous phase exhaustively extracted with EtOAc, the combined organic phases washed with water again and dried over MgSO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+].C(O)C>O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:21]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:20][C:2]=2[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1
Reactant: NC(=S)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Yield: 68.2 %

Procedure:
A mixture of 2-bromo-4′-chloropropiophenone (45.0 g), thiobenzamide (24.7 g), sodium acetate (14.8 g) and ethanol (400 mL) was stirred with heating under reflux for 3 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 4-(4-chlorophenyl)-5-methyl-2-phenylthiazole (35.1 g, 68%) as crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 90–91° C.
Reaction SMILES: [C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:7]=1[CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])([CH3:4])([CH3:3])[CH3:2].[CH2:32](Br)[CH:33]=[CH:34][CH3:35]>CC1C=CC(C)=CC=1.[Cl-].[Cl-].[Zn+2]>[C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[C:13]=2[CH2:32][CH:33]=[CH:34][CH3:35])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:7]=1[CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=CCBr
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccc(C)cc1
Product: CC=CCc1c(O)ccc2c1c(SC(C)(C)C)c(CC(C)(C)C(=O)OC)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of KH (35% dispersion in oil, 547 mg, 4.78 mmol) in p-xylene (20 mL) there was added methyl 3-[3-tert-butylthio-1-(4-chlorobenzyl)-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate from Example 1, Method A, Step 3 (2.0 g, 4.35 mmol) and the mixture was refluxed for 20 minutes; after cooling, there was added freshly fused ZnCl2 (68 mg, 0.5 mmol) and the mixture was again refluxed for one hour, then cooled down to r.t. To the solution was added crotyl bromide (882 mg, 6.53 mmol) and stirring was continued at room temperature overnight. The mixture was quenched with saturated aqueous NH4Cl (20 mL) and 2 mL of 1N HCl. The organic phase was collected and the aqueous phase extracted with EtOAc. The combined organic phases were washed with H2O 3 times, dried and evaporated. The residue was chromatographed to afford the title compound as the minor component, as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:1][CH2:2][CH2:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: Fc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(Br)cc2)CC1
Yield: 127 %

Procedure:
The procedure described in Example 4.1. is repeated. Starting from 1.93 g (8.4 mmol) of 1,1-dimethylethyl 4-(2-hydroxyethyl)-1-piperidine-carboxylate and 5.88 g (33.6 mmol) of 1-bromo-4-fluorobenzene gives 4.1 g of crude product in oil form.
Reaction SMILES: C1(C([NH:9][CH:10]([CH3:19])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)C)C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].CO>[NH2:9][CH:10]([CH3:19])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: CC(Cc1ccc(O)cc1)NC(C)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(N)Cc1ccc(O)cc1

Procedure:
5.80 g (20.0 mmol) 4-[2-(1-phenyl-ethylamino)-propyl]-phenol (I37) are added to 300 mL MeOH and charged with 0.60 g palladiumhydroxide (20%) on activated carbon. The mixture is stirred in a hydrogen atmosphere (50 psi) at 50° C. for 1 h 15 min. Then the mixture is filtrated, the solvent is removed in vacuo and the residue is triturated diethylether. The residue is dried at 80° C. in vacuo.
Reaction SMILES: [C:1](=[O:7])([O-])[O:2][CH2:3][CH2:4]Cl.[CH2:8]1[CH:13]2[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:12]2[CH2:11][CH2:10][N:9]1[CH2:27][CH2:28][O:29][CH2:30]C(O)=O.C(O)C>C(Cl)(Cl)Cl>[CH2:8]1[CH:13]2[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:12]2[CH2:11][CH2:10][N:9]1[CH2:27][CH2:28][O:29][CH2:30][C:1]([O:2][CH2:3][CH3:4])=[O:7]
Reactant: O=C(O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Reactant: O=C([O-])OCCCl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
0.11 g of chloroethyl carbonate was added to a solution of 0.5 g of 2-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)ethoxyacetic acid (prepared as described in Example 2) in 10 ml of chloroform containing 2% by volume ethanol, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour. At the end of this time, it was washed with water, and the solvent was removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel eluted with ethyl acetate, to give 0.25 g of the title compound as a colorless oil. The infrared absorption spectrum of this compound is identical with that of the compound prepared as described in Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:3][CH:2]=1.[Br:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>C(#N)C>[BrH:17].[CH3:22][O:21][C:19](=[O:20])[CH2:18][N:1]1[CH:2]=[CH:3][C:4](=[N:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH:5]=[CH:6]1
Reactant: c1ccc2c(Nc3ccncc3)noc2c1
Reactant: COC(=O)CBr
Solvent: CC#N
Product: Br
Product: COC(=O)Cn1ccc(=Nc2noc3ccccc23)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 3-(4-pyridinylamino)-1,2-benzisoxazole (0.9g, 4.3 mmol) and methyl bromoacetate (0.44 mL, 1. 1 eq) in acetonitrile (25 mL) was heated at reflux for one hour. The mixture was then allowed to cool to room temperature and the precipitated product was collected by filtration. The white solid was washed with diethyl ether and dried under vacuum to provide the title compound (1 g, 70%), mp 235-236° C.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:16])[C:9]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:10][C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>CN(C=O)C>[CH3:23][N:24]([CH3:29])[S:25]([N:6]1[C:5]2[CH:7]=[C:8]([Cl:16])[C:9]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:10][C:4]=2[N:3]=[C:2]1[Cl:1])(=[O:27])=[O:26]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: FC(F)(F)Oc1cc2nc(Cl)[nH]c2cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1c(Cl)nc2cc(OC(F)(F)F)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,6-Dichloro-5-trifluoromethoxy-1H-benzoimidazole (160 g, 0.59 mol, 1.0 equiv.) was dissolved in dry DMF (1.5 L) and then K2CO3 (98 g, 0.71 mol, 1.2 equiv.) and dimethylsulfamoyl chloride (85 g, 0.59 mol, 1.0 equiv.) were added sequentially. The reaction mixture was stirred at room temperature for 16 hours to afford 2,6-dichloro-5-trifluoromethoxy-benzoimidazole-1-sulfonic acid dimethylamide. Without isolation of 2,6-dichloro-5-trifluoromethoxy-benzoimidazole-1-sulfonic acid dimethylamide, 1H-pyrazole-4-carboxylic acid ethyl ester (91 g, 0.65 mol, 1.1 equiv.) and K2CO3 (98 g, 0.71 mol, 1.2 equiv.) were added to the reaction mixture. The reaction mixture was stirred at 70° C. for 10 hours and cooled to room temperature, to afford 1-(6-chloro-1-dimethylsulfamoyl-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester. To crude reaction mixture was added LiOH H2O (124 g, 2.95 mol, 5.0 equiv.) in 2.5 L water. The reaction solution was heated at 70° C. for 6 hours and then cooled to room temperature. Concentrated HCl was added to adjust pH=4.0. The precipitated solid was collected by filtration, washed with water and dried. The solid was recrystallized from hot EtOAc (˜3 L). After cooling to room temperature and filtration, the pure compound was obtained as a white solid (109 g, 0.31 mol, 54% over 3 steps). MS (ESI/CI): mass calcd. for C12H6ClF3N4O2, 346.0; m/z found, 347.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.79 (s, 1H), 13.06 (s, 1H), 8.91 (s, 1H), 8.33 (s, 1H), 7.79 (br d, 2H).
Reaction SMILES: B(Br)(Br)[Br:2].[CH2:5]([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([O:22]C)[CH:15]=2)[CH2:9]1)[CH2:6][CH3:7].O>C(Cl)Cl>[BrH:2].[CH2:5]([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]([OH:22])[C:17]([OH:20])=[CH:18][CH:19]=2)[CH2:9]1)[CH2:6][CH3:7]
Reactant: BrB(Br)Br
Reactant: CCCN1CCC=C(c2ccc(OC)c(OC)c2)C1
Solvent: ClCCl
Solvent: O
Product: Br
Product: CCCN1CCC=C(c2ccc(O)c(O)c2)C1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
A solution of 2.4 ml of boron tribromide in 33 ml of methylene chloride was added dropwise over 15 minutes at 0° to 5° C. under an inert atmosphere to a mixture of 6.68 g of the product of Step A in 67 ml of methylene chloride and the mixture was stirred at 0° C. for 7 hours. Then, 1.35 ml of water were added thereto dropwise and the mixture was evaporated to dryness under reduced pressure. The residue was taken up in 30 ml of hot ethanol and the solution was filtered. Crystallization was induced and the filtrate was iced for 16 hours and then vacuum filtered. The product was washed with ethanol and dried under reduced pressure to obtain 3.33 g of 4-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-benzene-1,2-diol hydrobromide which melted at 175° C. after crystallization from ethanol.