Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([C:42]([F:45])([F:44])[F:43])[O:24][N:23]=[C:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([C:35]([NH:37][CH2:38][CH2:39][S:40][CH3:41])=[O:36])=[CH:27][CH:26]=3)[CH2:21]2)[CH:16]=[C:17]([Cl:19])[CH:18]=1>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([C:42]([F:43])([F:45])[F:44])[O:24][N:23]=[C:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([C:35]([NH:37][CH2:38][CH2:39][S:40]([CH3:41])=[O:6])=[O:36])=[CH:27][CH:26]=3)[CH2:21]2)[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Solvent: ClCCl
Product: CS(=O)CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: -74 °C
Reaction time: 2.5 h

Procedure:
m-Chloroperoxybenzoic acid (47 mg, 70% purity) was added at −78° C. to a stirred solution of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-(methylthio)ethyl]-1-naphthalenecarboxamide (i.e. the product of Example 1, Step D, 100 mg) in dichloromethane (10 mL). The reaction mixture was stirred at −78 to −70° C. for 2.5 h, then quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound (102 mg), a compound of this invention, as a white solid. 1H NMR (CDCl3): δ 8.78 (d, 1H), 8.29 (d, 1H), 7.42-7.64 (m, 7H), 7.37 (br t, 1H), 4.23 (d, 1H), 4.00 (q, 2H), 3.88 (d, 1H), 3.18 (dt, 1H), 2.89 (dt, 1H), 2.62 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:10]([OH:17])[CH2:11]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]1[O:17][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)COS(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-methanesulfonyloxybutane(the 2-hydroxy-1-sulfonate compound:the 1-hydroxy-2-sulfonate compound:the diol compound:the 1,2-disulfonate compound=97.1:0.1:0.4:2.3 according to the HPLC area ratio) 50 g dissolved in ethyl acetate 510 ml was added 28% sodium methylate methanol solution 58.2 g under ice-cooling and stirred for 10 min. The reaction solution was diluted with water and adjusted with 6N-HCl to pH7 to separate an organic phase, which was distilled to remove the solvent. The concentrated residue was mixed with n-heptane, stirred at the ambient temperature for 1 hr to deposit crystals, which were filtered to remove. The filtrate was washed with water to separate an organic phase, which was mixed with active charcoal 2 g, stirred at the ambient temperature for 1 hr and filtered to remove charcoal. The filtrate was cooled down to −20° C. to deposit crystals, which were filtered and dried in vacuum to obtain the N-tert-butoxycarbonyl-3(S)-amino-1,2(R)-epoxy-4-phenylbutane(98.5% according to the HPLC area ratio) 28.8 g. The diol compound and the 1,2-disulfonate compound contained in a concentration of 0.5% or less in the crystals according to the HPLC area ratio respectively.
Reaction SMILES: [NH2:1][CH:2]1[CH2:13][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[N:4]2[C:3]1=[O:14].O=[C:16]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17]([OH:19])=[O:18].[OH-].[Na+].C([BH3-])#N.[Na+]>O>[C:17]([CH:16]([NH:1][CH:2]1[CH2:13][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[N:4]2[C:3]1=[O:14])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:19])=[O:18]
Reactant: NC1CN2CCCC(C(=O)O)N2C1=O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(CCc1ccccc1)NC1CN2CCCC(C(=O)O)N2C1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 32.4 %

Procedure:
0.51 g of 2-amino-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (racemate B) was dissolved in 4 ml of water. 1.37 g of 2-oxo-4-phenylbutyric acid were added and the mixture was adjusted to pH 6 using 2N aqueous sodium hydroxide solution. 0.33 g of sodium cyanoborohydride was then added and the mixture was left to stir at room temperature for 22 hours. The product was absorbed on to a strong acidic ion-exchange resin and eluted with water containing 2% pyridine to give 0.62 g of crude product. Crystallization from water gave 0.3 g (32%) of 2-(1-carboxy-3-phenylpropylamino)-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (2 racemates: racemates C and D) in the form of a white solid.
Reaction SMILES: [Mg].Cl[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].Cl[P:9]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:10]([CH2:13][CH3:14])[CH2:11][CH3:12]>BrCCBr.C(OCC)C>[CH2:18]([N:15]([P:9]([N:10]([CH2:11][CH3:12])[CH2:13][CH3:14])[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[CH2:16][CH3:17])[CH3:19]
Reactant: C[Si](C)(C)CCl
Reactant: CCN(CC)P(Cl)N(CC)CC
Agent: [Mg]
Solvent: BrCCBr
Solvent: CCOCC
Product: CCN(CC)P(C[Si](C)(C)C)N(CC)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
In a 50 ml three-necked flask equipped with a dropping funnel and a magnetic stirrer, 0.36 g (14.8 mmol) of magnesium and 10 ml of anhydrous diethyl ether were charged at room temperature in a nitrogen gas atmosphere. After several drops of 1,2-dibromoethane were added so as to activate magnesium, 2.0 ml (14.2 mmol) of chloromethyltrimethylsilane were added dropwise carefully to avoid heat build-up. When the reaction solution was stirred for 1 hour while it was heated mildly with a drier, the solution darkened. Then, after the solution was cooled to −78° C., 3.0 g (14.2 mmol) of chlorobis(diethylamino)phosphine synthesized in (a) were added dropwise to the solution, and the resultant mixture was then returned to room temperature and refluxed for 1 hour. The resulting crystals were filtered off, washed with anhydrous diethyl ether, and purified by vacuum-distillation (0.2 kPa, 74.3-79.5° C.) to obtain 2.29 g of bis(diethylamino)(trimethylsilylmethyl)phosphine in the form of a colorless transparent liquid; the yield was 62%.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].C[C:16]1[CH:25]=[C:24](C)[CH:23]=[C:22]2[C:17]=1[CH2:18][C:19](=[O:57])[CH:20]([C:27]1[CH:32]=[C:31](OCC3C=CC=CC=3)[C:30](OCC3C=CC=CC=3)=[C:29](OCC3C=CC=CC=3)[CH:28]=1)[O:21]2.O1C2C(=CC=CC=2)CC(O)C1C1C=CC=CC=1>>[O:21]1[C:22]2[C:17](=[CH:16][CH:25]=[CH:24][CH:23]=2)[CH2:18][C@H:19]([OH:57])[C@@H:20]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(C)c2c(c1)OC(c1cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c1)C(=O)C2
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OC1Cc2ccccc2OC1c1ccccc1
Agent: [Li+]
Product: O[C@H]1Cc2ccccc2O[C@H]1c1ccccc1

Procedure:
Preparation of (2,3-Cis)-5,7-dimethyl-2-(3,4,5-tribenzyloxyphenyl)chroman-3-ol (30): The cis 3-flavanol 30 was synthesized by the stereoselective L-selectride reduction of the 3-flavanone 29 in the same manner as given for 3-flavanol 23 (Scheme 3). The final product was obtained as a colorless oil (62% yield), after flash chromatography on silica gel using 20% of ethyl acetate in hexanes. 1H NMR (300 MHz, CDCl3): δ 1.73 (s, 1H, OH), 2.20 (s, 3H, CH3), 2.27 (s, 3H, CH3), 2.83 (d, J=17.1 Hz, 1H, 4-H), 2.95 (dd, J=4.2, 17.1 Hz, 1H, 4-H), 4.23–4.28 (m, 1H, 3-H), 4.87 (s, 1H, 2-H), 5.06 (s, 2H, OCH2Ph), 5.13 (s, 4H, OCH2Ph), 6.66 (s, 1H, 8-H), 6.68 (s, 1H, 6-H), 6.81 (s, 2H, 2′, 6′-H), 7.25–7.43 (m, 15H, Ar—H). MS (ESI, positive ion) 595 (M+Na), 1167 (2M+Na).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](=[S:28])[NH2:27])=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.Br[CH2:41][C:42](=O)[C:43]([O:45][CH2:46][CH3:47])=[O:44]>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]4[S:28][CH:41]=[C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:27]=4)=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(N)=S)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Yield: 66 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenethioamide (0.45 gmmol), ethyl bromopyruvate (0.20 g) and ethanol (30 mL) was heated under reflux for 1 hr. The reaction mixture was concentrated and ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 2-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl)-1,3-thiazole-4-carboxylate as yellow crystals (0.35 g, yield 66%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave yellow prism crystals. melting point: 156-157° C.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:23]([F:26])([F:25])[F:24])=[CH:5][C:4]=2[N:3]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>O1CCOCC1.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]2[C:10]3[C:9]4[CH:8]=[CH:7][C:6]([C:23]([F:26])([F:25])[F:24])=[CH:5][C:4]=4[N:3]=[C:2]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:11]=3[N:12]=[CH:13]2)=[CH:16][CH:17]=1
Reactant: NCCCO
Reactant: COc1ccc(-n2cnc3c(Cl)nc4cc(C(F)(F)F)ccc4c32)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-n2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4c32)cc1
Reaction time: 19 h
Yield: 85.4 %

Procedure:
To a solution of 4-chloro-1-(4-methoxy-phenyl)-7-trifluoromethyl-1H-imidazo[4,5-c]quinoline (153 mg; 0.41 mmol; 1 eq) in anhydrous 1,4-dioxane (18 mL), 3-aminopropanol (77 μL; 1.0 mmol; 2.5 eq) is added. The resulting solution is heated to reflux and allowed to stir for 19 hours after which period the reaction is still not complete on TLC. Thus, additional 3-aminopropanol (523 μL; 6.9 mmol; 17 eq) is added and the stirring is continued under reflux for 4 hours. The crude mixture is diluted with ethyl acetate (40 mL) and washed three times with a 1M aqueous solution of NaOH (3×40 mL). Aqueous layers are combined and re-extracted with ethyl acetate (75 mL). All organic layers are combined, dried over sodium sulfate and concentrated. The crude residue is purified on silica gel (cyclohexane/ethyl acetate 2:8) to afford the title compound as an off-white powder (145 mg; 0.35 mmol; 85%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([OH:24])=O)[C:4]=2[N:3]=1.C(Cl)CCl.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>CN(C)C=O.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:24])[C:4]=2[N:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc2c(C(=O)NS(C)(=O)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 60 °C
Yield: 39 %

Procedure:
To the mixture of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxylic acid, prepared as described in Example 20 (100 mg, 0.249 mmol) in N,N-Dimethylformamide (DMF) (2 mL) in a 20 mL vial was added EDC (57.3 mg, 0.299 mmol), methane sulfonamide (47.4 mg, 0.498 mmol) and DMAP (21.30 mg, 0.174 mmol). The mixture was stirred at 60° C. and monitored by LC/MS. After stirring for 5 days the DMF was removed in-vacuo and the remaining residue was dissolved in 2 mL of DMSO and purified by reverse phase chromatography with 2 injections eluting with a 27% to 57% AcCN/H2O gradient over 12 minutes. The fractions containing the desired compound, as determined by LC/MS, were combined and concentrated in-vacuo to provide the desired compound (47 mg, 0.097 mmol, 39.0% yield) as bright yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52 (s, 3H), 3.12 (t, 4H), 3.50 (s, 3H), 3.73 (t, 4H), 6.15 (s, 2H), 6.38 (d, 1H), 7.35 (t, aH), 7.50 (s. 1H), 7.51-7.75 (m, 2H), 7.88 (d, 1H), 8.05 (d, 1H), 8.25 (2, 1H), 8.35 (s, 1H), 12.8 (br. s, 1H); LC-MS: m/e=480 [M+1]+
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][O:69][C:70]1[CH:75]=[CH:74][C:73]([CH:76]=O)=[CH:72][CH:71]=1>C(O)C.CN(C=O)C>[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:76]([C:73]3[CH:74]=[CH:75][C:70]([O:69][CH3:68])=[CH:71][CH:72]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(c1ccncc1)N1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(C(C)c5ccncc5)CC4)c(Cl)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 42.8 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-chloro-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (19 mg, 0.052 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.16 mmol, 0.16 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.058 mmol, 8 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (10 mg, 42%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.35 (d, J=6.7 Hz, 3H, CHCH3), 2.52-2.55 (m, 2H, piperazine NCH2), 2.63-2.66 (m, 2H, piperazine NCH2), 3.58 (q, J=6.7 Hz, CHCH3), 3.68 (s, br, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.9 Hz, 2H, methoxyphenyl H-2 & H-6), 7.39 (d, J=6.0 Hz, 2H, pyridine H-3 & H-5), 8.06 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.11 (d, J=8.9 Hz, 2H, methoxyphenyl H-3 & H-5), 8.54 (d, J=6.0 Hz, 2H, pyridine H-2 & H-6), 13.30 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH:23]([CH3:39])[C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:37][CH3:38])[C:32]=2[Cl:36])[CH:27]=1)=[O:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:36].[ClH:1].[CH3:21][O:20][C:16]1[CH:15]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[C:17]=1[O:18][CH3:19])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH:23]([C:24]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:37][CH3:38])[C:32]=3[Cl:36])[CH:27]=2)=[O:25])[CH3:39])[CH2:11][CH2:10]1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CN2CCN(C(C)C(=O)c3ccc4c(Cl)c(OC)ccc4c3)CC2)cc(OC)c1OC
Yield: 122.7 %

Procedure:
A mixture of N1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.9 g, 2.7 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (1.05 g, 3.2 mmol) and K2CO3 (1.3 g, 9.5 mmol) in 25 ml of DMF was treated according to general preparation 2 to give 1.15 g of compound (IV-34), yield 72.7%, mp 219-222° C., M+ 512.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([CH3:26])[CH:17]=2)[CH:3]=1.[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Sn](CCCC)(CCCC)CCCC)[N:42]=2)[CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[N:42]=[C:43]([C:6]3[CH:5]=[C:4]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[C:18]([CH3:26])[CH:17]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:44]=[CH:45][CH:46]=2)[CH:36]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)n1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)cc(OS(=O)(=O)C(F)(F)F)n1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1

Procedure:
A stirred mixture of trifluoro-methanesulfonic acid 6-methyl-4-(3-methyl-4-trifluoromethyl-phenyl)-pyridin-2-yl ester (Example A.64) (0.250 g, 0.626 mmol), N-tert-butyl-3-(6-tributylstannanyl-pyridin-2-yl)-benzenesulfonamide (Example F.6) (0.363 g, 0.626 mmol), tetrakis(triphenyl-phosphine)palladium (0.036 g, 5 mol %) in toluene (5 mL) was heated under reflux conditions for 18 h. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the title compound after trituration with diethyl ether as a white solid (300 mg, 88%). MS (ISP) 539.8 [(M+H)+]; mp 150° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([Cl:25])[CH:27]=3)[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C2C(=O)Nc3cc(Cl)ccc32)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 60 °C

Procedure:
A mixture of rac-4-(6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.21 g, 0.6 mmol) (from Example 12b supra), 3-chlorobenzyl bromide (0.15 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 8 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, 3% then 10% ethyl acetate in dichloromethane as solvent). Combined fractions were recrystallized from dichloromethane-hexanes to give rac-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester as white crystals. (Yield 0.14 g, 49.1%).
Reaction SMILES: C(OC([N:8]1[CH2:29][CH2:28][N:11]2[C:12](=[O:27])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:15][C:14]=3[C:23]([F:26])([F:25])[F:24])=O)(C)(C)C.[ClH:30]>CCOCC.O>[ClH:30].[CH3:21][CH:20]([CH3:22])[CH2:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:27])[N:11]3[CH2:28][CH2:29][NH:8][CH2:9][C@H:10]32)=[C:14]([C:23]([F:25])([F:24])[F:26])[CH:15]=1
Reactant: CC(C)Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methylpropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (25 mg, 0.06 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 16 mg of a white solid. MS (ESI) 313 (M−Cl).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:30])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:17]=1.C=O.[BH3-][C:34]#N.[Na+]>CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:30])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH3:34])[CH2:27][CH2:28]2)[CH:17]=1
Reactant: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(CN2CCNCC2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(Cc2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CC1
Temperature: 27 °C
Reaction time: 4 h
Yield: 17.6 %

Procedure:
The solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(piperazin-1-ylmethyl)benzamide (78 mg, 0.19 mmol) and HCHO solution (0.5 mL) in MeOH (10 mL) was stirred at 27° C. for 1 h. Then NaBH3CN (14.5 mg, 0.23 mmol) was added to the solution and stirred at 27° C. for 4 h. The solution was concentrated and the residue was purified by column chromatography to give the title product (14.1 mg, Yield 17.5%). 1H NMR (CD3OD, 400 MHz): δ 7.79 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H), 7.39-7.32 (m, 1H), 7.20-7.07 (m, 3H), 7.06-6.98 (m, 1H), 4.13 (quin, J=6.0 Hz, 1H), 3.75 (s, 2H), 3.63-3.44 (m, 4H), 2.95-2.83 (m, 4H), 2.78-2.62 (m, 3H), 2.62-2.30 (m, 7H), 2.28 (s, 3H). LCMS (m/z): 423.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:5]2[CH:6]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH:22](=O)C1C=CC=CC=1.Cl.[OH-].[Na+]>C(O)=O.O>[Cl:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:5]2[CH:6]([C:11]3[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=3)[CH2:7][N:8]([CH3:22])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1Cl)CCNCC2c1ccc(Br)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: COc1cc2c(cc1Cl)CCN(C)CC2c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of benzazepine 3 (7.20 g, 19.6 mmol) in formic acid (2.3 g) was added 37% benzaldehyde (1.8 g). The mixture was heated to 90°-100° C. for four hours. After cooling the reaction mixture to room temperature, 4N hydrochloric acid solution (5.16 mL) was added. The mixture was condensed to dryness under reduced pressure. The residue was dissolved in water and then made basic with 25% sodium hydroxide solution. The mixture was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated to obtain a solid which was purified by column chromatography (silica gel; CH2Cl2 :MeOH:NH4OH;95:5:1) to give 4, 6.0 g (80%): mp 116°-118° C.; FT-IR (KBr)λ1500, 1380, 1270 and 1060 cm-1 ; 1H NMR (CDCl3)δd 7.65-7.35 and 7.21-6.90 (AA'BB',4H, ArH'), 7.13 (S, 1H, ArH #6), 6.38 (S, 1H, ArH #9), 4.40-4.10 (m, 1H, CH), 3.70 (S, 3H, OCH3), 3.10-2.45 (m, 6H, (CH2)3), 2.37 (S, 3H, NCH3). Anal. Calcd for C18H19BrCINO: C,H,N.