Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([NH2:17])[C:11]=3[N:10]=[CH:9]2)=[CH:3][CH:2]=1.[N:18]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[O:31][CH3:32])=[C:19]=[O:20]>CN(C)C=O.ClCCl>[CH3:32][O:31][C:22]1[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=1[NH:18][C:19]([NH:17][C:16]1[C:11]2[N:10]=[CH:9][N:8]([CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:20]
Reactant: Nc1cccc2c1ncn2Cc1ccncc1
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cccc2c1ncn2Cc1ccncc1

Procedure:
Compound 3d (75 mg, 0.334 mmol) is dissolved in dimethylformamide/dichloromethane (1:4, 5.0 mL) and 2-isocyanato-1-methoxy-4-trifluoromethyl-benzene (1.0 equiv., 73 mg, 0.334 mmol) is added at room temperature and allowed to react for 16 hours under nitrogen atmosphere. All solvent is then removed on a rotary evaporator and toluene (3×25 mL) is added and stripped off to remove residual dimethylformamide. The crude solid is then triturated using ethyl ether, and the resulting solid is then filtered and dried yielding title compound as a white solid.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([O-])(O)=O.[Na+].OP([O-])([O-])=O.[K+].[K+].[O-]S([O-])(=O)=O.[Mg+2].[Br:28]Br>O.C(Cl)Cl>[Br:28][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:1][CH:2]=1
Reactant: c1cnc2sccc2c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: Brc1csc2ncccc12
Yield: 48.4 %

Procedure:
2.30 g of Thieno[2,3-b]pyridine (17 mmol), 1.43 g of NaHCO3 (17 mmol), 4.44 g of K2HPO4 (25.5 mmol) and 2.66 g of MgSO4 (22.1 mmol) are placed into the flask with 80 ml of dichloromethane. The reaction mixture is stirred under reflux. 1.05 ml of bromine (20.4 mmol) is added slowly to the mixture and is stirred overnight. CH2Cl2 and water are added to the cooled reaction mixture and separated. The CH2Cl2 layer is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane: AcOEt=3:1) to give 1.76 g of the title compound. Yield 48%. mass spectrum (m/e): 215 (M+1); 1H-NMR (CDCl3): 8.67 (m, 1H), 8.13 (m, 1H), 7.59 (s, 1H), 7.45 (m, 1H) ppm.
Reaction SMILES: C(N(CC)CC[N:6]1[C:14]2[CH:13]=[CH:12][C:11](NC(=O)CN(CCOCC3C=CC=CC=3)CC3C=CC=CC=3)=[C:10]3[O:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=4[C:8]([C:9]=23)=[N:7]1)C.CO>O1CCCC1>[N:7]1[NH:6][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[O:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=4[C:8]=1[C:9]=23
Reactant: CCN(CC)CCn1nc2c3c(c(NC(=O)CN(CCOCc4ccccc4)Cc4ccccc4)ccc31)Oc1ccc(O)cc1-2
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)-c1n[nH]c3cccc(c13)O2
Reaction time: 24 h

Procedure:
To a mixture of 2.45 g of N-[2-[2-(diethylamino)-ethyl]-9-hydroxy-2H-[1]benzopyrano[4,3,2-cd]indazol-5-yl]-2-[[2-(phenylmethoxy)ethyl](phenylmethyl)amino]acetamide in 80 ml of dry tetrahydrofuran under argon was added 40 ml of 1M solution of borane tetrahydrofuran complex in tetrahydrofuran. After 24 hours at 50° C., an additional 3 ml of borane tetrahydrofuran complex was added and the reaction continued for another three hours at 50° C. The mixture was poured into 150 ml of methanol, heated under reflux overnight, evaporated to dryness, and the residue of crystallized from diethyl ether to afford 1.36 g of 2-[2-diethylamino)ethyl]-5-[[2-(phenylmethoxy)ethyl](phenylmethyl)amino]ethyl]amino]-2H-[1]benzopyrano[4,3,2-cd]indazol-9-ol.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11]C)=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(SC)nc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 5 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate, 250 mL of methanol and 5 mL of 30% sodium methoxide in methanol was stirred under nitrogen at room temperature for 5 hrs, quenched with 10 mL of acetic acid and concentrated under reduced pressure. The residue was partitioned between 100 mL of saturated sodium bicarbonate and 200 mL of ethyl acetate and the extracts dried over MgSO4. Concentration under reduced pressure gave a white crystalline solid: MS (m+1)=215.1; 1H NMR (400 MHz, CDCl3) 8.85 (s, 1H), 4.1 (s, 3H), 4.05 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[CH2:25][NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:8]=2)[N:3]=1
Reactant: CC(C)(C)N
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccc(F)cc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)NCc1cc(F)ccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
95 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-5-fluorobenzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 34 μl of tert-butylamine and 18 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 103 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[I:1]
Reactant: N#Cc1ccc(N)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: N#Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
Iodine (0.645 g; 2.54 mmol) was added to a stirred mixture of silver sulphate (0.791 g; 2.54 mmol) and 4-aminobenzonitrile (0.300 g; 2.54 mmol) in ethanol (10 mL). The reaction mixture was then stirred at room temperature for 18 hours and filtered over celite. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulfate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to afford 0.222 g (36%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([O:12]CC)=[O:11])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+:17]>C1COCC1.O>[C:1]([C:5]1[S:9][C:8]([C:10]([O-:12])=[O:11])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3].[Li+:17]
Reactant: CCOC(=O)c1nnc(C(C)(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nnc(C(=O)[O-])s1
Yield: 104.1 %

Procedure:
A solution of ethyl 5-tert-butyl-1,3,4-thiadiazole-2-carboxylate (0.21 g, 1.0 mmol) and lithium hydroxide hydrate (42 mg, 1.0 mmol) in THF (2 mL) and water (2 mL) was stirred at room temperature for 18 hours. The solvent was removed under vacuum to give lithium 5-tert-butyl-1,3,4-thiadiazole-2-carboxylate (0.2 g) as a white solid which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:20])=O>CN(C)C=O>[Br:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:15]2[Cl:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
Suspend 6-bromo-4-hydroxyquinoline-3-carboxylic acid ethyl ester (11 g, 37 mmol) in anhydrous dimethylformamide (148.6 mL) under nitrogen atmosphere. Add phosphoryl chloride (20.7 mL, 222 mmol, 6 eq.) via syringe over 5 minutes and stir vigorously at room temperature for 3 hours. Quench the reaction by pouring the mixture into ice water (1.5 L) and continue stirring until all the ice has melted. Obtain the solid formed by filtration, rinse with water and allow complete drying to afford the titled compound (11.4 g, 94%). MS (ESI) m/z (M+H)+314.0, 316.0.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=4[Cl:25])[CH2:13][C@H:12]3[CH3:26])=[N:10][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.C(B(CC)[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)C>>[Cl:25][C:18]1[CH:19]=[C:20]([CH2:23][OH:24])[CH:21]=[N:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([C:9]2[NH:8][C:7]3[C:2]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[CH:3][C:4]([C:27]([F:29])([F:30])[F:28])=[CH:5][C:6]=3[N:10]=2)[C@H:12]([CH3:26])[CH2:13]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: CCB(CC)c1cccnc1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cccnc3)c2[nH]1

Procedure:
{6-[(3R)-4-(7-Bromo-5-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-methanol (152 mg, 0.3 mmol, Example 151) and 3-diethylboranyl-pyridine (118 mg, 0.6 mmol, Aldrich) reacted under the conditions of Example 158 to give the title compound. MS (ESI, pos. ion) m/z: 503 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13].[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(O)C>CN(C)C=O>[CH3:13][C:5]1[NH:6][C:7]2[C:12]([C:4]=1[CH2:3][CH2:2][N:23]1[CH2:24][CH2:25][CH:20]([C:17]3[CH:16]=[CH:15][C:14]([CH3:26])=[CH:19][CH:18]=3)[CH2:21][CH2:22]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1[nH]c2ccccc2c1CCBr
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1ccc(C2CCN(CCc3c(C)[nH]c4ccccc34)CC2)cc1

Procedure:
A solution of 11.8 g of 3-(2-bromoethyl)-2-methylindole, 20.3 g of 4-(4-toluyl)piperidine [Example 5(a)] in 500 ml of dimethylformamide is treated according to the manipulative procedure described in Example 3(b) to give the off-white solid, mp 192°-194° C., 2-methyl-3-{2-[4-(4-toluyl)piperidyl]ethyl}indole from ethanol.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]>ClCCl>[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)c[nH]c34)no2)cc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1C#N
Reaction time: 2 h
Yield: 68.1 %

Procedure:
Trifluoroacetic acid (0.37 mL) was added to a solution of 1,1-dimethylethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D9) (45 mg) in dichloromethane (0.5 mL) at RT. The resulting solution was stirred for 2 hours. The reaction mixture was concentrated. The residue was recrystallized from dichloromethane to afford 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E3) (27 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.40 (6H, d), 2.67 (2H, t), 3.03 (2H, t), 5.01 (1H, m), 7.22 (1H, t), 7.28 (1H, d), 7.46 (1H, d), 7.83 (1H, d), 7.95 (1H, dd), 8.21 (1H, dd), 8.39 (1H, d), 10.86 (1H, s), 12.12 (1H, br s). MS (ES): C23H20N4O4 requires 416; found 417.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2([CH2:10][CH2:9][CH2:8]2)[S:6](=[O:12])(=[O:11])[C@@H:5]2[CH2:13][CH2:14][O:15][C:16]3[N:21]=[CH:20][C:19](Br)=[CH:18][C:17]=3[C@@:4]2([CH3:23])[N:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[NH4+].[Cl-].[NH4+].[OH-]>[Cu]I.CCO.O>[NH2:1][C:2]1[C:7]2([CH2:10][CH2:9][CH2:8]2)[S:6](=[O:12])(=[O:11])[C@@H:5]2[CH2:13][CH2:14][O:15][C:16]3[N:21]=[CH:20][C:19]([N:24]=[N+:25]=[N-:26])=[CH:18][C:17]=3[C@@:4]2([CH3:23])[N:3]=1
Reactant: C[C@]12N=C(N)C3(CCC3)S(=O)(=O)[C@@H]1CCOc1ncc(Br)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@]12N=C(N)C3(CCC3)S(=O)(=O)[C@@H]1CCOc1ncc(N=[N+]=[N-])cc12
Temperature: 95 °C

Procedure:
A mixture of (4a′R,11b′R)-2′-amino-10′-bromo-11b′-methyl-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazine]-4′,4′-dioxide (1.08 g, 2.70 mmol), (+)-sodium 1-ascorbate (0.053 g, 0.270 mmol), sodium azide (0.526 g, 8.09 mmol), and copper(i) iodide (0.103 g, 0.540 mmol) was purged with N2 followed by the addition of (1r,2r)-(−)-n,n″-dimethylcyclohexane-1,2-diamine (0.128 ml, 0.809 mmol) and EtOH/water (2/0.5 mL). The resulting mixture was heated at 95° C. for 3 h. The mixture was brought to rt, poured into a 9:1 mixture of saturated NH4Cl/NH4OH and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to afford (4a′R,11b′R)-2′-amino-10′-azido-11b′-methyl-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazine]-4′,4′-dioxide to be used without further purification. This product was dissolved in THF (20 mL) and DMF (10 mL) followed by the addition of triethylamine (0.450 ml, 3.24 mmol) and di-tert-butyl dicarbonate (0.707 g, 3.24 mmol) and the resulting mixture was stirred at rt over the weekend. The mixture was poured into saturated NH4Cl and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to afford tert-butyl ((4a′R,11b′R)-10′-azido-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-2′-yl)carbamate as a yellow product. The yellow residue was poured into water (50 mL) and extracted again with EtOAc to remove DMF. The combined organics were dried over Na2SO4, filtered and concentrated. The yellow oil obtained was dissolved in THF/water (10/5 mL) followed by the addition of trimethyl phosphine (0.559 ml, 5.40 mmol) and the resulting mixture was stirred at rt for 1.5 h. Some starting material was still observed, so more trimethyl phosphine (0.559 ml, 5.40 mmol) was added and stirred for 1 h more. The reaction was poured into water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-100% EtOAc/hexanes to afford a pale yellow solid as tert-butyl ((4a′R,11b′R)-10′-amino-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-2′-yl)carbamate (0.300 g, 0.687 mmol, 25.5% yield). LC/MS (ESI+) m/z=437 (M+H).
Reaction SMILES: [BH4-].[Na+].[C:3]1(=[O:23])[N:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:6](=[O:18])[C:5]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:4]12>C(O)C>[OH:23][CH2:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)=[O:18]
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCCOc1ccncc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
Sodium borohydride [3.78 g (100 mmol)] was added to a solution of 2.82 g (10.0 mmol) of 4-(3-phthalimidopropyloxy)pyridine in 150 ml of ethanol. The mixture was stirred at room temperature for 3 hours. After the solvent was distiled off, brine was added to the residue. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was distilled off and then the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10) to obtain 1.488 g of the desired compound (yield: 52.0%, colorless crystals).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[Cl:10].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[Cl:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:1])[CH2:6][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: Fc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)cc1Cl

Procedure:
Using 4-fluoro-3-chlorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 155. 1H NMR(CDCl3): 7.42 (dd, 1H, J=7.0, 2.2 Hz), 7.27-7.20 (m, 1H), 7.12 (t, 1H, J=8.6 Hz), 6.32 (d, 1H, J=2.2 Hz), 6.21 (d, 1H, J=2.2 Hz), 4.23 (broad s, 2H), 3.67 (ABq, 2H, JAB=15.2 Hz), 3.57-3.48 (m, 1H), 3.38-3.30 (m, 2H), 3.19-3.08 (m, 1H), 3.05-2.90 (m, 4H), 2.65-2.55 (m, 2H), 2.02-1.88 (m, 2H). LRMS (ES)+: 404.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH2:4][C:5](=O)[CH3:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.Cl>COCCO.C(O)(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]1[CH:4]=[C:5]([CH3:6])[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[N:20]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: COCCO
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(C(F)(F)F)cc2C)cc1
Yield: 87.8 %

Procedure:
A mixture of 1,1,1-trifluoro-2,4-pentanedione (0.02 mol, 2.4 ML) and 4-methoxyphenyl hydrazine.HCl (4.54 g, 1.3 eq.) in 2 -methoxyethanol (100 mL) and acetic acid (30 mL) was refluxed for 6 h. The reaction mixture was evaporated and purified by flash chromatography on a silica gel column (400 g) eluted with 4:1 hexane:ethyl acetate to give 4.5 g of pure product (88%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[CH2:14][CH2:13]1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[CH2:13][CH2:14]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C2CC2)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C2CC2)c(Br)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-bromo-4-cyclopropylbenzoate (compound 10.2, 500 mg, 1.96 mmol) in methanol (10 mL) and a solution of sodium hydroxide (500 mg, 12.5 mmol) in water (5 mL). The resulting solution was stirred overnight at 50° C., then the volatiles were removed under reduced pressure. The pH of the residual solution was adjusted to 6-7 with aqueous HCl (6 M). The resulting solids were collected by filtration to yield 0.3 g (63%) of the title compound as a white solid.
Reaction SMILES: N(CCO)(CCO)CCO.[CH2:11]([O:21][C:22]1[C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[C:25](C(O)=O)[NH:24][C:23]=1C(O)=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)=O>O>[CH2:11]([O:21][C:22]1[C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][NH:24][CH:23]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCOc1c(C(=O)O)[nH]c(C(=O)O)c1OCCCCCCCCCC
Agent: O=C=O
Solvent: OCCN(CCO)CCO
Solvent: O
Product: CCCCCCCCCCOc1c[nH]cc1OCCCCCCCCCC
Temperature: 180 °C
Yield: 90.6 %

Procedure:
Into a 300-ml three-necked flask, 100 ml of triethanolamine was put, and was heated to 180° C. and stirred. Then, 23.4 g (50.0 mmoles) of the 3,4-didecyloxypyrrole-2,5-dicarboxylic acid was added thereto at one time. The mixture was vigorously stirred until carbon dioxide stopped being generated. The reaction product formed was cooled (for about 5 minutes) to room temperature, and 200 ml of water was added thereto, followed by extraction with chloroform. The organic layer formed was dried with magnesium sulfate, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: chloroform/hexane=2/1) to obtain 17.2 g of 3,4-didecyloxypyrrole (yield: 90.7%).
Reaction SMILES: [CH:1]([NH:3][C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[ClH:26]>O1CCCC1.C(OCC)(=O)C.C(O)(C)C>[ClH:26].[CH3:1][NH:3][C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(Cc1ccccc1)(NC=O)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CNC(C)(Cc1ccccc1)c1ccccc1
Temperature: 35 °C
Yield: 84 %

Procedure:
N-formyl-1,2-diphenyl-2-propylamine (23.6 g, 0.1 mol) was added to a stirred suspension of LiAlH4 (15.0 g, 0.395 mol) in 1 L of dry tetrahydrofuran. After 2 hours the mixture was heated at 35° C. for 22 hours, then refluxed for 2 hours, and allowed to cool to room temperature. Water was added to decompose the excess LiAlH4, and the mixture filtered to remove the solid salt. Evaporation of the solvent gave 23.0 g of the crude product as a yellow oil. This was dissolved in 180 ml of ethyl acetate and 20 ml of isopropanol and acidified with HCl gas. Upon standing a white solid crystallized which was collected by filtration and vacuum dried at 65° C. to give 21.7 g (84% of N-methyl-1,2-diphenyl-2-propylamine hydrochloride, mp 200°-201° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=O)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:33][N:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)N>>[CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:34]([CH3:33])[C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCc3c(-c4ccccc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(7-oxo-7-phenylheptyl)-4-piperidinyl]phenyl}propanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 522.3 (M+H)+.