Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:33])C2C=CC=CC=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][C:24]([CH:26]3CC(=O)[NH:28][CH2:27]3)=[O:25])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:32])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.C(OI([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)OC(=O)C)(=O)C.Cl.[C:50](#N)C>O>[NH2:28][CH:27]1[CH2:50][N:23]([C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:32])[CH:19]=3)[N:14]=[C:13]([N:5]3[CH2:6][C:48]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=4[S:2](=[O:33])(=[O:1])[CH2:3][CH2:4]3)[CH:22]=2)[C:24](=[O:25])[CH2:26]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C3CNC(=O)C3)c2c1
Reactant: CC#N
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: Cl
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CC(N)CC3=O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-5-oxopyrrolidine-3-carboxamide (100 mg, 0.22 mmol, byproduct of Example 47-2) in acetonitrile (2 mL) and water (2 mL) was added (diacetoxyiodo)benzene (91 mg, 0.28 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, acidified with concentrated hydrochloride acid (12 N), and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1-10% methanol in dichloromethane) to give 10 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94-7.87 (m, 2 H), 7.60 (td, J=1.2, 7.2 Hz, 1 H), 7.55 (d, J=8.8 Hz, 1 H), 7.47-7.43 (m, 2 H), 7.37 (dd, J=2.0, 8.8 Hz, 1 H), 7.22 (s, 1 H), 5.13 (s, 2 H), 4.42 (brs, 2 H), 4.02 (dd, J=2.0, 9.6 Hz, 1 H), 3.87 (td, J=3.6, 6.8 Hz, 1 H), 3.62 (dd, J=4.8, 9.6 Hz, 2 H), 3.45 (dd, J=3.2, 9.6 Hz, 1 H), 3.14-3.13 (m, 1 H), 2.85 (dd, J=7.2, 16.8 Hz, 1 H), 2.36 (s, 3 H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=[O:29])OCC(Cl)(Cl)Cl)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>CCCCCC.C(OCC)(=O)C>[OH:34][CH2:33][C:32]([NH:31][C:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:14]=2[C:15]=1[CH3:30])=[O:29])([CH3:36])[CH3:35]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: CC(C)(N)CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)NC(C)(C)CO)C(c1ccc(C(C)C)cc1)CO2
Yield: 39 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 2-amino-2-methyl-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 39%. Melting point: 157-158° C. (hexane-ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1
Reactant: CN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(C(O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 4-fluorophenyl 1-methylpiperidin-4-yl methanone 10.10 g (5 mmol) in 30 ml methanol was added in small portions sodium borohydride 0.378 g (10 mmol). The reaction mixture was stirred at room temperature for two hours, concentrated, added water and extracted with methylene chloride 2×50 ml. The combined organic solution was dried over sodium sulfate and concentrated to give 1.0 g of desired product in 90% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.S(Cl)([Cl:15])(=O)=O.O>C(O)(=O)C>[Cl:15][C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:11])=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=1.[Cl:15][C:3]1[C:4]([OH:11])=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1ccc(F)cc1O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(F)cc1O
Product: CC(=O)c1ccc(F)c(Cl)c1O
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 1-(4-fluoro-2-hydroxyphenyl)ethanone (1.7 g, 11.03 mmol) in glacial acetic acid (24 mL) at 10° C. was slowly added sulfuryl chloride (2.23 g, 16.54 mmol). The mixture was heated to 120° C. and was allowed to stir for overnight. The solution was cooled down to room temperature and poured into water (30 mL). The water layer was extracted with EtOAc for three times. The EtOAc was washed with satd. Aq NaHCO3, water, brine, dried (Na2SO4) and concentrated recrystallized The mix was purified by column chromatography using 1:10 Hexanes:Ethyl acetate to yield 234 mg of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone and 400 mg of 1-(3-chloro-4-fluoro-2-hydroxyphenyl)ethanone. These compounds were used in the next step without characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C(OP([CH2:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])(OCC)=O)C.[H-].[Na+].CN(C)C=O>O1CCCC1.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOP(=O)(C/C=C/C(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)/C=C/C=C/c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of 500 mg of o-chlorobenzaldehyde and 840 mg of methyl 4-diethylphosphonocrotonate dissolved in 5 ml of tetrahydrofuran, 142 mg of sodium hydride (60% oily dispersion) was added under ice-cooling. Imeediately, 2 ml of dimethylformamide was added and the mixture was stirred at room temperature for 2 hours. The mixture was poured into water and extracted twice with ether. The organic layer was washed twice with water, dried and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (solvent: hexane-ethyl acetate=20:1) to give 650 mg of methyl (2E, 4E)-5-(2-chlorophenyl)-2,4-pentadienoate as an oily substance.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[N:19]=2)=[C:9]1[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]=2[CH3:38])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:28])=[O:29]
Reactant: Cc1c(C2=NN(Cc3cccc(F)c3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(Cc3cccc(F)c3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(3-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.17 (d, 1H), 7.95 (t, 1H), 7.86 (t, 1H), 7.42 (m, 3H), 7.19 (m, 3H), 6.89 (dt, 1H), 6.61 (dd, 1H), 5.09 (bs, 2H), 4.53 (s, 2H), 2.09 (s, 3H) ppm. MS calculated for C25H19F2N3O48-H: 494, observed: 494.
Reaction SMILES: [OH-].[Na+].[C:3](OC(=O)C)(=[O:5])[CH3:4].O1CCCC1.Br.[CH2:16]1[CH2:20][O:19][C:18]2[CH:21]=[CH:22][C:23]3[CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][NH2:30])[C:27]=3[C:17]1=2>O>[CH2:16]1[CH2:20][O:19][C:18]2[CH:21]=[CH:22][C:23]3[CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][NH:30][C:3](=[O:5])[CH3:4])[C:27]=3[C:17]1=2
Reactant: CC(=O)OC(C)=O
Reactant: NCCC1CCc2ccc3c(c21)CCO3
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCCC1CCc2ccc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Aqueous 1 N sodium hydroxide solution (1.5 ml) and acetic anhydride (0.050 ml, 0.528 mmols) were added to a tetrahydrofuran (1.5 ml) solution of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrobromide (0.10 g, 0.352 mmols), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether/hexane to obtain 0.057g (yield: 66%) of the target compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]3[CH2:14][O:13]3)[CH:9]=2)[C:4](=[O:15])[O:3]1.[OH:16][CH2:17][C@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1>>[OH:16][CH2:17][C@H:18]1[N:23]([CH2:14][CH:12]([OH:13])[C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:15])[O:3][C@H:2]([CH3:1])[CH2:11]3)[CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Product: C[C@@H]1Cc2cc(C(O)CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO)ccc2C(=O)O1

Procedure:
A solution of (3R)-3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (325 mg, 1.59 mmol) and tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (345 mg, 1.59 mmol dissolved in EtOH (7 mL)) was heated in a sealed tube to 155° C. for 3 hours in the microwave. The reaction was cooled and concentrated to give crude product which was purified via MPLC (40-100% EtOAc/Hexane) to give the title compound as a mixture of diastereomers.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>C(Cl)Cl>[C:21]([CH2:20][CH2:19][C:18]([O:17][C:15]1[CH:14]=[CH:13][C:3]([C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])=[C:2]([OH:1])[CH:16]=1)=[O:24])([OH:23])=[O:22]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCOC(=O)c1ccc(O)cc1O
Solvent: ClCCl
Product: CCCCCCOC(=O)c1ccc(OC(=O)CCC(=O)O)cc1O
Reaction time: 8 h

Procedure:
n-Hexyl 2,4-dihydroxybenzoate (2 g) is dissolved in 25 mL of methylene chloride. To the solution, 0.85 g of succinic anhydride and 1.05 g of 4-N,N-dimethylpyridene are added. The reaction mixture is allowed to stir at ambient conditions overnight. The reaction mixture is extracted with 1 N HCl, water and saturated sodium chloride solution. The organic layer is dried over anhydrous sodium sulfate. Solvent is removed under reduced pressure to yield the product as an off-white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18]C)=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#[N:2].CO.[OH-].[Na+]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#[N:2]
Reactant: COC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn(C(C)C)c2cc(C#N)cc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.2 %

Procedure:
To a 50 ml round bottom was added methyl 6-cyano-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (230 mg, 0.897 mmol), followed by methanol (1 mL) and THF (1 mL). To the solution was added 3 M NaOH (0.449 mL, 2.69 mmol). The reaction stirred at rt for 20 h. The reaction was evaporated and treated with acidic water to pH 5. A brown solid crashed out and was collected by filtration. The solid was an impurity. The pH of the liquid was adjusted to 3 and the liquid was evaporated leaving a residue. Trituration of the residue with water, followed by filtration yielded 6-cyano-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (155 mg, 0.576 mmol, 64.2% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-δ6) δ ppm 13.16 (br. s., 1H) 8.33 (s, 1H) 7.78 (s, 1H) 7.66 (s, 1H) 4.81-4.98 (m, 1H) 2.33 (s, 4H) 1.45 (d, J=6.57 Hz, 6H). MS (ES) [M+H]+ 243.3.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([NH2:23])([C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:16])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.C1COCC1.[Li+].[OH-].Cl>CO.O>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:5][C:4]([NH2:23])([C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[C:3]([OH:24])=[O:2])=[CH:7]1
Reactant: COC(=O)C(N)(Cc1c[nH]c2ccccc12)C(=O)c1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NC(Cc1c[nH]c2ccccc12)(C(=O)O)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 3(1H-indol-3-yl)-2-[pyridine-3-carbonyl]-amino-propionic acid methylester (0.5 g, 1.6 mmol), in methanol (5 mL), THF (9 mL) was added LiOH (0.39 g, 7.70 mmol), dissolved in water (3 mL), The mixture was allowed to stir at room temperature (25° C.) over 2 h. Stripped off solvent, acidified reaction mass with 1.5N HCl, extracted with ethylacetate (100 mL) dried over sodium sulphate and concentrated to obtain product as colorless solid (0.48 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CN=C(C(OC)=O)C=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].BrC1C=CN=C(C(OC)=O)C=1.Br[C:47]1[S:51][C:50]([CH2:52][OH:53])=[N:49][CH:48]=1>>[CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:48]3[N:49]=[C:50]([CH2:52][OH:53])[S:51][CH:47]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: OCc1ncc(Br)s1
Reactant: COC(=O)c1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)ccn1
Agent: COC(=O)c1cc(Br)ccn1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4csc(CO)n4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to methyl 4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)picolinate except that methyl 4-bromopicolinate was replaced with (5-bromothiazol-2-yl)methanol. LCMS, [M+H]+=437.1. 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=7.0 Hz, 1H), 7.26-7.19 (m, 2H), 7.06 (s, 1H), 7.03-6.95 (m, 1H), 6.73 (d, J=7.5 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 5.01 (s, 2H), 3.92 (t, J=5.2 Hz, 2H), 3.79 (t, J=6.9 Hz, 2H), 2.74 (t, J=7.3 Hz, 2H), 2.62 (t, J=6.2 Hz, 2H), 2.25-2.11 (m, 5H), 1.93 (s, 3H), 1.89-1.80 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[CH2:29]([O:36][C:37]([C@@H:39]([NH:45]C(OC(C)(C)C)=O)[CH2:40][CH2:41][C:42](O)=[O:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl>ClCCl.C(N(CC)CC)C>[NH2:45][C@H:39]([C:37]([O:36][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:38])[CH2:40][CH2:41][C:42]([NH:28][CH2:27][CH2:26][O:25][CH2:24][C:7]1[NH:8][C:9]([CH3:23])=[C:10]([C:19]([O:21][CH3:22])=[O:20])[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:6]=1[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:43]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCCNC(=O)CC[C@H](N)C(=O)OCc2ccccc2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 17.2 %

Procedure:
The title compound (0.29 g) was prepared as an oil by the reaction of amlodipine (1.1 g), (S)-4-benzyloxycarbonyl-4-t-butoxycarbonylaminobutanoic acid (1.0 g) (commercially available), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.57 g), 1-hydroxybenzotriazole (0.40 g) and triethylamine (0.30 g) according to method of part (a) of Example 5 followed by treatment of the resulting intermediate in dichloromethane with gaseous hydrogen chloride according to the method of part (b).
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH:3]1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
Ethyl (RS)-1-(2-Methoxyphenyl)-3-(3,4-methylene-dioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-hydroxy-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (100 mg, 0.23 mmol) in CH2Cl2 (5 ml) was added triethylsilane (32 mg, 0.28 mmol), followed by boron trifluoride etherate (0.13 ml, 1.05 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 10 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to provide the title compound (91 mg, 96%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1N=C[N:36](C(N2C=NC=C2)=O)C=1.N>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH2:36])=[O:31])=[CH:32][CH:33]=4)[CH2:23][CH2:24]3)=[O:18])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(C(=O)O)cc4)CC3)n2)cc1OC
Agent: N
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(C(N)=O)cc4)CC3)n2)cc1OC
Temperature: 60 °C
Reaction time: 6 h
Yield: 39.9 %

Procedure:
To a THF (5 ml) solution of 171 mg of 4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}benzoic acid was added 63 mg of CDI, followed by stirring at 60° C. Further, 52 mg of CDI was added in twice thereto, and the whole was stirred at 60° C. for 24 hours in total. After the reaction solution was cooled to room temperature, 0.25 ml of aqueous ammonia was added thereto, followed by 6 hours of stirring at room temperature. Further, 0.5 ml of aqueous ammonia was added thereto and the whole was stirred at room temperature. Thus precipitated crude crystals were collected by filtration and recrystallized from methanol-THF to obtain 68 mg of 4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}benzamide as colorless crystals.
Reaction SMILES: [CH2:1]1[C@@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Cl[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].CC(C)CC(=O)C>[CH2:1]1[C@@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNC[C@H]21
Reactant: CCOC(=O)COCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
32.48 g of (S)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine (prepared as described in Preparation 3), 22.7 g of ethyl 2-chloroethoxyacetate, 48.9 g of sodium carbonate and 0.79 g of sodium iodide were added to 340 ml of 4-methyl-2-pentanone, and the mixture was heated under reflux for 16 hours. At the end of this time, it was cooled to room temperature and was filtered using a Celite filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel eluted with a 1:1 by volume mixture of ethyl acetate and hexane, to give 44.85 g (yield 91%) of the title compound as a pale yellow oil.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:17]=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CO.O>[CH3:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:2])[C:7]=2[N:17]=1
Reactant: [NH4+]
Reactant: Cc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)C
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2c(N)nc3cccnc3c2n1CC(C)C
Temperature: 10 °C

Procedure:
Under a nitrogen atmosphere, aqueous ammonium hydroxide (four equivalents) was quickly added with continuous stirring to a suspension of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-5-oxide in methanol (6 mL/g) while maintaining the reaction temperature at 20° C. to 24° C. Methanol was used to rinse the addition vessel and added to the reaction. The reaction was stirred until all material was dissolved. With continuous stirring, benzenesulfonyl chloride (2 equivalents) was added over a period of 15 to 45 minutes while maintaining the reaction temperature at 20° C. to 30° C. Methanol was used to rinse the addition vessel and added to the reaction. The reaction was stirred for 45 to 75 minutes at 20° C. to 24° C. Aqueous sodium hydroxide (3 equivalents of 10% w/w) was added to the reaction mixture over a period of 15 to 45 minutes while maintaining the reaction temperature between 20° C. and 25° C. Water (10 L), used to rinse the addition vessel, was added to the reaction mixture. The resulting mixture was cooled to 10° C. and stirred for 2 to 24 hours. A precipitate was present and was isolated by filtration and washed with deionized water until the filtrate was pH 7. The solid was dried at 50° C. under vacuum to provide 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as an off-white solid.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[F:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [F-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1F
Temperature: 140 °C
Reaction time: 28 h
Yield: 41 %

Procedure:
Potassium fluoride (69.6 g; 1.2 mole) and benzyltriethylammonium chloride (10.7 g; 0.05 mole) were added to molten 2-chloronitrobenzene (157.5 g; 1.0 mole). After stirring at 140° C. for 28 hours and a similar work-up to Example 1, 2-fluoronitrobenzene was obtained in 41% yield together with 7% recovered 2-chloronitrobenzene.