Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[BH4-].[Na+]>C1(C)C=CC=CC=1.O.CO>[I:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCOCC1
Reactant: Nc1cccc(I)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: Ic1cccc(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
13bd) A mixture of 2 g of 3-iodoaniline and 1.26 ml of tetrahydro-4H-pyran-4-one is boiled in 50 ml of toluene on a water separator for 4 hrs. The solution of the imine which remains behind is treated with 20 ml of methanol and 520 mg of sodium borohydride are added in portions. The mixture is stirred at room temperature for 16 hrs., then poured into water and extracted with ethyl acetate. Chromatography on silica gel with ethyl acetate/hexane 3:7 gives 559 mg of (3-iodo-phenyl)-(tetrahydropyran-4-yl)-amine as a colourless oil. Yield: 20%. Mass spectrum: peaks inter alia at m/e: 303 (M+, 100%), 245 (40%), 219 (40%), 130 (90%), 117 (62%).
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)[C:37]=1[CH2:45][C:46](O)=[O:47])(C)C.[CH3:49][CH:50]([C:52]1[CH:57]=[C:56]([CH:58]([CH3:60])[CH3:59])[CH:55]=[C:54]([CH:61]([CH3:63])[CH3:62])[C:53]=1C=CCC(O)=O)[CH3:51]>>[O:47]=[C:46]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)[CH:45]=[CH:37][C:53]1[C:54]([CH:61]([CH3:63])[CH3:62])=[CH:55][C:56]([CH:58]([CH3:59])[CH3:60])=[CH:57][C:52]=1[CH:50]([CH3:49])[CH3:51]
Reactant: CC(C)c1cc(C(C)C)c(C=CCC(=O)O)c(C(C)C)c1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Product: CC(C)c1cc(C(C)C)c(C=CC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C(C)C)c1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 3-[2,4,6-tris(1-methylethyl)phenyl]-2-propenyl carboxylic acid, mp 144°-148° C.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]Br)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.[CH2:16]([O:18][P:19]([O:23]CC)[O:20][CH2:21][CH3:22])[CH3:17]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:11]([CH2:12][P:19]([O:20][CH2:21][CH3:22])([O:18][CH2:16][CH3:17])=[O:23])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[C:7]([CH3:14])[CH:8]=2)[N:3]=1
Reactant: Cc1cc2cc(CBr)c(Br)nc2cc1Cl
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cc2cc(C)c(Cl)cc2nc1Br)OCC

Procedure:
A mixture of 2-bromo-3-bromomethyl-7-chloro-6-methylquinoline (4.2 g, 12 mmol), toluene (50 ml) and triethylphosphite (4.2 ml) was refluxed for 20 h. After cooling the solution was concentrated in vacuum and the product precipitated by the addition of hexane. The crystals were filtered off, washed with hexane and dried in vacuo to give 4.5 g of 2-bromo-7-chloro-3-diethylphosphonomethyl-6-methylquinoline.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:25])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:25][C:39]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2nc3ccccc3s2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2nc3ccccc3s2)CC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g (0.56 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(benzothiazol-2-yl)-piperazin-1-yl]-ethyl}-amine and 0.16 mL (1.12 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.086 g (0.59 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane (2 mL). The reaction mixture was allowed to stir under nitrogen for one hour at 0° C. and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.20 g (70%) as a white solid; mp=229-232° C.; MS (+) ESI m/z=469 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:5])[CH2:3][CH3:4].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][N:21]=3)[C:18]=2[OH:19])=[C:10]([CH3:29])[CH:9]=1)#[N:7].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C@H:2]([NH:5][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([N:17]2[C:18]([OH:19])=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]#[N:7])=[CH:9][C:10]=3[CH3:29])[CH:15]=[N:16]2)=[N:21][CH:22]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: CC[C@@H](C)N
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC[C@@H](C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Combined (R)-butan-2-amine (22.8 mg, 0.312 mmol) and a solution consisting of 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (50 mg, 0.156 mmol), HOBT hydrate (35.9 mg, 0.234 mmol), EDCI (44.9 mg, 0.234 mmol), and Hunig's base (0.103 mL, 0.624 mmol) in DMA (1 mL) and stirred at 50° C. for 4 h. The reaction mixture was then purified via preparative HPLC to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.45 Hz, 3H) 1.17 (d, J=6.57 Hz, 3H) 1.44-1.63 (m, 2H) 2.44 (s, 3H) 3.95 (dt, J=14.02, 7.14 Hz, 1H) 7.57-7.90 (m, 3H) 7.92-8.73 (m, 4H) 8.82-8.97 (m, 1H) 13.20 (br. s., 1H). MS m/z [M+H]+ 376.
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[ClH:18]>CC(O)C.CCOCC>[Cl:18][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CC1
Reactant: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: ClCCC=C(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 93 %

Procedure:
Cyclopropyldiphenylmethanol (500 mg, 2.23 mmol) was dissolved in 1M HCl in i-PrOH (4.0 mL). The reaction mixture was then heated at 60° C. for 1 h. The reaction was cooled 20° C. and diluted with Et2O (100 mL). The organic solution was successively washed with H2O, NaHCO3 saturated aqueous solution and brine. It was then dried over MgSO4, filtered, concentrated in vacuo and chromatographed on a silica gel column by elution with Hexanes to give 4-Chloro-1,1-diphenyl-1-butene (506 mg, 93%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ2.59 (q, 2H, J=6.9 Hz), 3.58 (t, 2H, J=6.9 Hz), 6.12 (t, 1H, J=7.3 Hz), 7.16-7.42 (m, 10H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)[CH2:3]1.O.NN.C(N(CC)CC)C.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[S:42](Cl)(=[O:44])=[O:43]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][CH2:9][CH2:10][NH:11][S:42]([C:33]2[CH:34]=[CH:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:32]=2)(=[O:44])=[O:43])[CH2:3]1
Reactant: CN1CCCC(CCCN2C(=O)c3ccccc3C2=O)C1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: NN
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCCC(CCCNS(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
To a stirred solution of the product of step c (437 mg, 1.53 mmol) in ethanol (10 ml) was added hydrazine hydrate (0.37 ml) and the reaction heated at reflux for 1.5 h. The resultant suspension was filtered, the filter-cake was washed with further ethanol (20 ml) and the filtrate was evaporated. The residue was suspended in DCM (20 ml) and the solid was removed by filtration. The filtrate was evaporated at reduced pressure and the residue was dissolved in DCM (5 ml). The solution was treated sequentially, with ice-cooling, with triethylamine (0.290 ml, 2.08 mmol) and 2-naphthalenesulfonyl chloride (217 mg, 1.39 mmol). The coolant was removed and the reaction mixture stirred at ambient temperature for 2 h. The reaction was diluted with DCM (20 ml), washed with water (20 ml) and brine (20 ml), and dried over anhydrous sodium sulfate. The filtrate was evaporated at reduced pressure and the residue was purified by flash column chromatography (90:10:1 DCM:methanol:ammonia) to afford the title compound (240 mg, 45%). 1H NMR 8.44 (1H, d, 1.2), 7.99-7.59 (6H, m), 2.98 (2H, t, 6.9), 2.76-2.69 (2H, m), 2.24 (3H, s), 1.87-1.84 (3H, m), 1.64-1.46 (5H, m), 1.21-1.13 (2H, m), 0.75 (1H, m). Microanalysis found C 64.32 H 7.75 N 7.59. C19H26N2O2S-0.5H2O requires C 64.19 H 7.76 N 7.88.
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][C:8]1=[O:18])=[O:5].[CH2-:21][C:22]([CH3:24])=[O:23].O=[CH:26][C@@H:27]([CH2:29]O)[OH:28].C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[CH3:21][C:22]1([CH3:24])[O:28][C@@H:27]([CH2:29][NH:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][C@@H:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])=[O:5])[CH2:26][O:23]1
Reactant: [CH2-]C(C)=O
Reactant: CC(C)(N)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Reactant: O=C[C@H](O)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC[C@H]1COC(C)(C)O1
Reaction time: 16 h
Yield: 74.2 %

Procedure:
To a solution of 368 mg (1.34 mmol) of 3-amino-3-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step A) in 10 mL of dry methanol was added 1.5 g of dry 4 Å powdered molecular sieves followed by a solution of 520 mg (4.0 mmol) of D-glyceraldehyde acetonide (used crude as prepared according to the procedure of L. W. Hertel, C. S. Grossman and J. S. Kroin, Syn. Comm. 1991, 21, 151-154.) in 5 mL of dry methanol. The pH of the mixture was carefully adjusted to 6 by the addition of 3 drops of acetic acid. The reaction was stirred for 5 hours at room temperature at which time 4.0 mL (4.0 mmol) of a 1.0 M solution of sodium cyanoborohydride in tetrahydrofuran was added by syringe. The reaction was stirred for 16 hours then filtered through a pad of Celite. The solvent was removed under vacuum to afford a clear oil which was purified by flash column chromatography on silica gel eluting with chloroformB 10% aqueous ammonium hydroxide (33%) in methanol (92:8) to afford 387 mg (78%) of the product as a white solid. 1H NMR (200 MHz, CD3OD): δ 1.10 (s, 6H), 1.28 (s, 3H), 1.34 (s, 3H), 2.08 (m, 1H), 2.26 (dd; 16, 15 Hz; 2H), 2.44 (m, 1H), 2.58-2.75 (m, 3H), 2.87 (m, 1H), 3.63 (dd; 8, 7 Hz; 1H), 4.05 (dd; 8, 7 Hz; 1H), 4.20 (m, 1H), 4.38 (dd; 12, 8 Hz; 1H), 4.84 (s, 1H), 7.00-7.40 (m, 4H). FAB-MS: calculated for C21H31N3O4 389; found 390 (M+H, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15]C.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:15]
Reactant: COc1ccc2c(nnn2CC2CC2)c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2c(nnn2CC2CC2)c1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4-Chloro-1-(cyclopropylmethyl)-5-methoxy-1H-benzotriazole (10.5 g, 44.2 mmol) was dissolved in dichloromethane (200 mL), cooled to 0° C. and treated with boron tribromide (88 mL, 1 M dichloromethane solution, 88 mmol, 2 equiv). The ice bath was removed and the mixture was stirred for 4 hours at ambient temperature. The mixture was treated with water (10 mL) and then treated with sodium hydroxide (1 N aqueous) until pH>10. After stirring for an additional 30 minutes, ammonium chloride (aqueous saturated) was added until the pH of the mixture was adjusted to pH 6-7. The aqueous mixture was extracted exhaustively with dichloromethane containing 5% methanol and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound as a light brown solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH2:14]([O:21][P:22]([O:32][CH2:33][CH2:34][OH:35])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:35][CH2:34][CH2:33][O:32][P:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=P(OCCO)(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCOP(=O)(OCc1ccccc1)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
4-Nitrophenyl chloroformate (1.01 g; 5.04 mmol) was added at 0° C. under argon atmosphere to a solution of 2-[di(benzyloxy)phosphoryloxy]ethanol (1.62 g; 5.09 mmol) and triethylamine (0.7 ml; 5 mmol) in dichloromethane (20 ml). The mixture was stirred at ambient temperature for 30 minutes, evaporated and purified by flash chromatography, eluting with petroleum ether/ethyl acetate (40/60) to give 2-[di(benzyloxy)phosphoryloxy]ethyl 4-nitrophenyl carbonate.
Reaction SMILES: [C:1]1([C:7]2([CH2:16][CH2:17][N:18](C(OCC(Cl)(Cl)[Cl:25])=O)[CH3:19])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.C(Cl)Cl.[Zn]>[ClH:25].[C:1]1([C:7]2([CH2:16][CH2:17][NH:18][CH3:19])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(CCC1(c2ccccc2)COc2ccccc21)C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNCCC1(c2ccccc2)COc2ccccc21
Product: Cl
Reaction time: 1 h
Yield: 81.8 %

Procedure:
Activated zinc (14 g, 215 mmole) was added in several portions to a solution of 22 g (54.4 mmole) of 2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-(2,2,2- trichloroethoxycarbonyl)-N-methylethylamine in 125 ml of glacial acetic acid under N2 while cooling the mixture with a water bath. After 1 hour at room temperature, the reaction mixture was diluted with 600 ml CH2Cl2 and filtered through celite, and the solids were washed with CH2Cl2. The combined organics were evaporated to dryness and the resultant oil taken up in 800 ml CH2Cl2. This was washed wit 50 ml saturated Na2CO3 and dried over MgSO4. Filtration and evaporation gave 12.9 g of an oil. This oil was converted to its hydrochloride salt in Et2O and the salt recrystallized from CH3CN to give 9.1 g (61%) of a solid, m.p. 184°-187°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1[C:24]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][C:30]([C:34]5[CH:35]=[N:36][CH:37]=[C:38]([CH2:40][OH:41])[CH:39]=5)([OH:33])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]=2[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:11]1[C:24]2[C:23]3([CH2:26][N:27]4[CH2:28][CH2:29][C:30]([C:34]5[CH:35]=[N:36][CH:37]=[C:38]([CH:40]=[O:41])[CH:39]=5)([OH:33])[CH2:31][CH2:32]4)[CH2:25][CH:16]([C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride (0.597 mL, 6.84 mmol, 2 eq) in methylene chloride (15 mL) under nitrogen was added freshly distilled dimethylsulfoxide (0.971 mL, 13.68 mmol, 4 eq). After 10 min 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(5-(hydroxymethyl)-3-pyridyl)piperidin-4-ol (described in example 70) (1.41 g, 3.42 mmol) was added as a dimethylsulfoxide solution (15 mL). The reaction was stirred at -78° C. for 1 h prior to the addition of triethylamine (3.81 mL, 27.4 mmol, 8 eq). The cooling bath was removed and the reaction warmed to room temperature over 2 h. Water (35 mL) was added to quench the reaction and the product extracted into methylene chloride (3×20 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to a white solid. The reaction product was purified by flash chromatography over silica gel (65 mL, eluent 10% hexane in ethyl acetate ramped to straight ethyl acetate) to yield 1.04 g (74%) of the title compound. TLC analysis (Rf 0.25, 10% hexane in ethyl acetate). MS (CI, CH4) m/z 411 (M+1,100), 439 (M+29,14), 393 (18), 260 (7), 219 (10), 206 (25), 169 (12).
Reaction SMILES: [F:1][C:2]1[C:3]([I:11])=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH3:18]>CN(C=O)C.O.C(#N)C.O>[F:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:15][CH2:16][O:17][CH3:18])[N:10]=[C:4]2[C:3]=1[I:11]
Reactant: Fc1cnc2cn[nH]c2c1I
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COCCn1cc2ncc(F)c(I)c2n1
Reaction time: 1.5 h
Yield: 28.4 %

Procedure:
6-Fluoro-7-iodo-1H-pyrazolo[4,3-b]pyridine (150 mg, 0.570 mmol) was dissolved in DMF (5 mL) and sodium hydride (34.2 mg, 0.855 mmol) was added slowly, followed by 1-bromo-2-methoxyethane (0.080 ml, 0.855 mmol). After 90 minutes, the reaction was quenched with crushed ice and the reaction mixture was purified by preparative HPLC eluting with 20/80 (v/v) water/acetonitrile in 10 mmol NH4HCO3 in water on a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column) to give 6-fluoro-7-iodo-2-(2-methoxyethyl)-2H-pyrazolo[4,3-b]pyridine (52 mg, 28.4% yield) as white solid. MS [M+H] found 322.1
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:6][CH3:7])=[CH:8][CH:9]=1
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNc1ccc(Br)cc1N
Temperature: 70 °C

Procedure:
A suspension of 4-bromo-N-methyl-2-nitroaniline (5328 mg, 22.04 mmol) in EtOH (100 ml) was treated with SnCl2.2H2O (25.61 g, 110.2 mmol) and the resulting mixture heated at 70° C. under an atmosphere of Nitrogen for 5 h. The reaction mixture was then cooled to rt and treated with ice-water (50 ml) followed by aqueous NaOH (4 N) until pH>8. This basic mixture was then extracted with EtOAc (3×150 ml) and the combined extracts washed with brine (3×100 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm=2.68 (s, 3H), 4.74 (brs, 3H), 6.27 (d, 1H, J=8.4 Hz), 6.61 (dd, 1H, J=2.0 & 8.4 Hz) and 6.66 (d, 1H, J=2.0 Hz). MS(ES+): m/z 201.10 and 203.12[MH+].
Reaction SMILES: OO.S(=O)(=O)(O)O.[Cl:8][C:9]1[CH:31]=[CH:30][C:12]2[C:13]3[C:14](=[CH:25][N:26]([CH3:29])[C:27]=3[CH3:28])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1.S(=O)(O)[O-:33].[Na+]>C(O)(=O)C>[Cl:8][C:9]1[CH:31]=[CH:30][C:12]2[C:13]3[CH:27]([CH3:28])[N:26]([CH3:29])[C:25](=[O:33])[C:14]=3[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1
Reactant: O=S([O-])O
Reactant: Cc1c2c(cn1C)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1C2=C(CN=C(c3ccccc3Cl)c3cc(Cl)ccc32)C(=O)N1C
Reaction time: 1 h

Procedure:
In one portion, 0.7 ml (5.9 mmol) of a 30% hydrogen peroxide solution was added to 33 ml of a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 1.8 g (5.0 mmol) of 8-chloro-6-(2-chlorophenyl)-1,2-dimethyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the resulting solution was stirred for 20 minutes. The excess peracid was discharged by the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between methylene chloride and water and basififed with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a yellow residue. Crystallization from ethyl aceatate gave 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1,2-dimethylpyrrolo[3,4-d][2]benzazepin-3(2H)-one as pale yellow prisms, mp 207°-208° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:24]([O:26]CC)=[O:25])[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.CO.O.O[Li].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:29][C:30]([F:31])([F:32])[F:33])[C:24]([OH:26])=[O:25])[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: CCOC(=O)C(CC(F)(F)F)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(CC(F)(F)F)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl) biphenyl-3-yl)-4,4,4-trifluorobutanoate (0.1 g, 0.404 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (85 mg, 2.024 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of the starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL) the combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude material was purified by column chromatography to 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoic acid (38 mg) as sticky syrup. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.71 (m, 4H), 7.39 (s, 1H), 7.19 (s, 1H), 3.92 (m, 1H), 3.41 (d, 2H), 3.08 (m, 1H), 2.54 (m, 1H), 0.96 (m, 1H), 0.40 (d, 2H), 0.00 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C>[N:23]1([CH2:22][CH2:21][N:8]2[C:9]3[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=3)[CH:6]=[N:7]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1cnn2CCN1CCOCC1
Temperature: 60 °C

Procedure:
4-Nitroindazole (1.00 g, 6.13 mmol) and potassium carbonate (2.55 g, 18.4 mmol) in 15 mL of DMF was stirred for 30 min, after which 4-(2-chloro-ethyl)-morpholine hydrochloride (1.71 g, 9.19 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The combined filtrate was concentrated under reduced pressure and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-D6) δ ppm 2.41 (m, 4 H), 2.79 (t, J=6.27 Hz, 2 H), 3.44 (m, 4 H), 4.66 (t, J=6.27 Hz, 2 H), 7.65 (m, 1 H), 8.17 (m, 1 H), 8.29 (m, 1 H), 8.52 (s, 1 H); MS (DCI/NH3) m/z 277 [M+H]+.