Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([CH2:9][S:10][C:11]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:12]=2[C:13]([O:15]C)=O)=[CH:7][CH:6]=1.O.Cl>CN(C)C=O>[OH:15][C:13]1[C:12]2[CH:17]=[C:18]([C:21]([F:22])([F:24])[F:23])[CH:19]=[CH:20][C:11]=2[S:10][C:9]=1[C:8]1[CH:25]=[CH:26][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1SCc1ccc(OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3ccc(C(F)(F)F)cc3c2O)cc1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
To a mixture of sodium hydride (50% dispersion in mineral oil) (134 mg, 2.79 mmol) in N,N-dimethylformamide (3 ml) at 75° C. under a nitrogen atmosphere was added dropwise with stirring a solution of methyl 2-(p-methoxybenzylthio)-5-trifluoromethylbenzoate (500 mg, 1.40 mmol) in N,N-dimethylformamide (10 ml). After stirring 30 minutes at 75° C., the mixture was poured into water (50 ml), the mixture brought to pH5 with 2N hydrochloric acid, the product extracted with diethyl ether, the combined extracts washed with water, dried (sodium sulfate), and evaporated. The residue was chromatographed on a column of silica gel (Merck 7734, packed as a slurry in 25:1 hexane-ether). Elution with 25:1 hexane-ether containing 1% acetic acid afforded the desired product as a white solid upon evaporation of the appropriate fractions; yield 385 mg (85%); m/z 324 (M+.).
Reaction SMILES: CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.CS(O[CH2:20][CH2:21][CH:22]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)(=O)=O.[I-:38].[Na+]>C(Cl)Cl.CC(C)=O>[Cl:29][C:25]1[CH:24]=[C:23]([CH:22]([NH:30][C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:21][CH2:20][I:38])[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NC(CCOS(C)(=O)=O)c1cccc(Cl)c1
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCI)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of Intermediate 9C (61 mg, 0.213 mmol) in DCM (5 mL) was added DIEA (0.080 mL, 0.458 mmol) followed by the addition of MeSO2Cl (0.030 mL, 0.385 mmol). The reaction mixture was then stirred at rt for 0.5 h. After 30 min., the reaction mixture was concentrated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution followed by brine. The organic layers were then dried over MgSO4 and concentrated in vacuo to yield a clear oily residue, which was subjected to the next step without further purification. To a solution of 3-((tert-butoxycarbonyl)amino)-3-(3-chlorophenyl)propyl methanesulfonate in acetone (5 mL) was added sodium iodide (128 mg, 0.854 mmol). The yellow suspension was refluxed for ˜4 h, and then stirred at rt for overnight. The reaction mixture was then concentrated followed by addition of small amount of water and DCM. The aqueous layer was then re-extracted with DCM (2×). The combined organic layers were concentrated and then purified by chromatography to give tert-butyl (1-(3-chlorophenyl)-3-iodopropyl)carbamate (68 mg, 81%) as yellow oil which solidified upon standing. MS (ESI) m/z: 395.9 (M+H)+.
Reaction SMILES: C([Mg]Br)(C)C.C([Li])CCC.[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([F:25])[C:22](Br)=[CH:21][C:20]=1[F:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][O:38][C@H:37]([C:41](=[O:46])N(OC)C)[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>O1CCCC1.O>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][O:38][C@H:37]([C:41](=[O:46])[C:22]2[CH:21]=[C:20]([F:27])[C:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:24][C:23]=2[F:25])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: Fc1cc(OCc2ccccc2)c(F)cc1Br
Reactant: CON(C)C(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: CC(C)[Mg]Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@H](C(=O)c2cc(F)c(OCc3ccccc3)cc2F)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
To a solution of 33 mL of isopropylmagnesium bromide (1M in tetrahydrofuran) in tetrahydrofuran (120 mL) was added with cooling (max+3° C.) n-butyllithium (41 mL, 1.6M in hexane). The mixture was cooled to −78° C., 1-benzyloxy-4-bromo-2,5-difluoro-benzene (8.2 g, 27 mmol) was added and stirred for 1.5 hours at this temperature. (S)-2-(Methoxy-methyl-carbamoyl)-morpholine-4-carboxylic acid tert-butyl ester (7.5 g, 27 mmol) was added dropwise within 10 min at −75° C. Stirring at −78° C. continued for 1 h and the reaction mixture was than poured into water (600 mL). Organic material was partitioned into ethyl acetate (3×), organic phases were pooled, washed with brine and dried with MgSO4 before being concentrated in vacuo. The residue was then purified by column chromatography (heptane-ethyl acetate (2:1)/silica gel) to give 7.5 g of the title compound.
Reaction SMILES: [C:1]([CH:3]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:11]2[C:6](=[C:7]3[CH:22]=[CH:21][N:20]=[C:8]3[CH:9]=[CH:10]2)[O:5][C:4]1=N)#[N:2].[OH-:24].[Na+]>Cl.O>[C:1]([CH:3]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:11]2[C:6](=[C:7]3[CH:22]=[CH:21][N:20]=[C:8]3[CH:9]=[CH:10]2)[O:5][C:4]1=[O:24])#[N:2]
Reactant: Cc1cncc(C2=c3ccc4c(c3OC(=N)C2C#N)C=CN=4)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cncc(C2=c3ccc4c(c3OC(=O)C2C#N)C=CN=4)c1
Yield: 35 %

Procedure:
A solution of 3-cyano-2-imino-4-(5-methyl-pyridin-3-yl)-2H-pyrrolo[2,3-h]chromene (83 mg, 0.28 mmol) in 10% HCl (5 mL) was stirred at room temperature for approximately 5 h. The yellow suspension was diluted with water (5 mL), neutralized to approximate pH=10 using 10% NaOH and extracted with EtOAc (3×25 mL). The EtOAc extracts were washed with brine (10 mL), dried over MgSO4, and evaporated to yield a yellow solid. The solid was purified by flash column chromatography (silica gel, EtOAc:hexanes, 50-80% EtOAc) to yield a yellow solid (27 mg, 35%). 1H NMR (DMSO-d6): 12.10 (s, 1H), 8.70 (d, J=1.8 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 7.88 (m, 1H), 7.62 (d, J=3.3 Hz, 1H), 7.45 (dd, J=0.3, 9.0 Hz, 1H), 6.91-6.88 (m, 2H), 2.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12]>C(O)C.C(O)(=O)C.[Pt]>[NH2:9][C:4]1[C:5]([Cl:8])=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[OH:12]
Reactant: O=[N+]([O-])c1c(Cl)ccc(Cl)c1O
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1c(Cl)ccc(Cl)c1O
Yield: 99.7 %

Procedure:
A yellow solution of 2,5-dichloro-6-nitrophenol (10.0 g, 48.0 mmol) in ethanol (200 mL) and acetic acid (13.8 mL) at 0° C. was catalytically reduced in the presence of 5% Platinum on charcoal (0.15 g) under an atmosphere of hydrogen (25 psi) for 1 hour in a Parr hydrogenator. The resultant colorless solution was filtered and concentrated under reduced pressure (15 torr). The residue was then dried under high vacuum (0.02 torr) overnight to yield 8.52 g (100%) of 2-amino-3,6-dichlorophenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][N:10]([CH3:24])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20][C:19](=O)[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(O)C.Cl.[OH:30][NH2:31].C([O-])(=O)C.[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][N:10]([CH3:24])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20]/[C:19](=[N:31]/[OH:30])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/O
Reaction time: 3 h

Procedure:
To a solution of 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid [2-(4-fluorophenyl)-2-hydroxyethyl]-methyl-amide (the compound of Preparation Example 48) (150 mg) in tetrahydrofuran (3 mL) and ethanol (3 mL) was added an aqueous solution (2.5 mL) of hydroxyamine hydrochloride (112 mg) and sodium acetate (133 mg), and the mixture was stirred at 70–80° C. for 3 hours. The organic solvent was removed by evaporation, water and ethyl acetate were added for separation/extraction. The organic layer was dried with anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate; ethyl acetate 10–40%). Among the 2 spots detected by TLC (the solvent system; hexane-ethyl acetate=1:1), the polar fractions (low Rf value on TLC) were collected, and the title compound (116 mg) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1>[CH3:1][N:2]([CH3:10])[CH:3]=[C:4]([C:21](=[O:22])[C:20]1[CH:24]=[C:25]([F:29])[C:26]([Cl:28])=[CH:27][C:19]=1[Cl:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Reactant: CCOC(=O)C=CN(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 83.3 %

Procedure:
14.3 g of ethyl 3-dimethylaminoacrylate and 10.5 g of triethylamine are added dropwise to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 100 ml of anhydrous dioxane at 10° to 20° C., with stirring. The mixture is stirred at room temperature for 3 hours, heated at 40°-50° C. for 1 hour, and the solvent is removed by distillation in vacuo and the residue is taken up in methylene chloride/H2O. The phases are separated, and the aqueous solution is again extracted with methylene chloride. The CH2Cl2 solution is washed with water, dried with sodium sulphate, and the solvent is removed in vacuo. The crystalline residue is recrystallized from cyclohexane/light petroleum. 27.8 g of ethyl 3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate of melting point 94°-95° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:32]1[C:33]2[C:34]3[CH:47]=[CH:46][S:45][C:35]=3[C:36](=[O:44])[NH:37][C:38]=2[CH:39]=[CH:40][C:41]=1[O:42][CH3:43]>>[CH3:43][O:42][C:41]1[CH:40]=[CH:39][C:38]2[NH:37][C:36](=[O:44])[C:35]3[S:45][CH:46]=[CH:47][C:34]=3[C:33]=2[C:32]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(C#N)CC2)cc1
Yield: 24.2 %

Procedure:
Following General Procedure B, 1-(4-bromophenyl)cyclopropanecarbonitrile (1.5 g, 7.1 mmol) was reacted with bis(pinacolato)diboron (2.7 g, 10 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.3 g, 4.2 mmol) to afford the desired product (378 mg, 29%) as a white solid: ESI MS m/z 373 [C22H16N2O2S+H]+.
Reaction SMILES: O[C@H:2]([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:16][CH2:15][C@H:14]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])[CH2:13][C:11]3=2)[CH:6]=[N:5]1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:41]=[N+:42]=[N-:43].[Na+]>C1COCC1>[N:41]([C@@H:2]([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:16][CH2:15][C@H:14]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])[CH2:13][C:11]3=2)[CH:6]=[N:5]1)=[N+:42]=[N-:43]
Reactant: CC(=O)NCCO[C@H]1COc2ccc3cnn(C[C@@H](C)O)c3c2C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCO[C@H]1COc2ccc3cnn(C[C@H](C)N=[N+]=[N-])c3c2C1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a cooled (0° C.) solution of the product from Step D (0.23 g, 0.69 mmol) and triethylamine (0.28 g, 0.38 mL, 2.76 mmol, 4.0 equiv.) in anhydrous THF (50 mL) was added methanesulfonic anhydride (0.19 g, 1.1 mmol, 1.6 equiv.). The mixture was stirred for 30 min, additional triethylamine and methanesulfonic anhydride (1.6 equiv.) were added and stirred for 1 h. Sodium azide (0.45 g, 6.9 mmol, 10 equiv.) was added and the solvent was evaporated to a residue. Anhydrous dimethyl sulfoxide (20 mL) was added and the mixture heated at 90° C. for 3 h. The mixture was cooled, poured into a saturated solution of sodium bicarbonate (60 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by chromatography (silica, ethyl acetate) to give an oil (0.20 g, 81%).
Reaction SMILES: C[O:2][CH2:3][C@@:4]([CH3:10])([CH:8]=[CH2:9])[C:5]([OH:7])=[O:6].B(Br)(Br)Br.[CH3:15]O>ClCCl>[CH3:15][O:7][C:5](=[O:6])[C@:4]([CH2:3][OH:2])([CH3:10])[CH:8]=[CH2:9]
Reactant: C=C[C@](C)(COC)C(=O)O
Reactant: CO
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=C[C@](C)(CO)C(=O)OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A solution of (R)-2-methoxymethyl-2-methyl-but-3-enoic acid (600 mg, 4.2 mmol) in dichloromethane (40 mL) was stirred at 0° C. under nitrogen. Boron tribromide (1 M in dichloromethane, 16.8 mL, 16.8 mmol) was added and the reaction mixture was stirred at 0° C. for 90 minutes. Methanol (20 mL) was cautiously added and the reaction mixture was warmed to room temperature over 30 minutes and then stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 3:1 to 1:1 to afford the title compound (540 mg, 90%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.35 (s, 3H), 2.33 (m, 1H), 3.62 (m, 1H), 3.75 (s, 3H), 3.75-3.80 (m, 1H), 5.21 (dd, J=17.4, 0.5 Hz, 1H), 5.24 (dd, J=10.7, 0.5 Hz, 1H), 5.98 (dd, J=17.4, 10.7 Hz, 1H). LCMS (m/z) 145.1 [M+H], Tr=1.16 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]=[C:16]=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[NH2:18][C:19]1[O:20][CH2:21][CH2:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]2[O:20][CH2:21][CH2:22][C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CCOC(=O)C1=C(N)OCC1
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)OCC1

Procedure:
using isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate and ethyl 2-amino-4,5-dihydrofuran-3-carboxylate there is obtained isopropyl 2-chloro-4-fluoro-5-[3-[3-(ethoxycarbonyl)-4,5-dihydro-furan-2-yl]ureido}-benzoate.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:34]1(=[O:40])[NH:38][C:37](=[O:39])[CH2:36][CH2:35]1>>[CH:31]1([CH2:30][O:29][C:21]2[CH:20]=[C:19]([C:13]3[C:14]([CH3:17])([CH3:18])[C:15](=[O:16])[N:11]([CH:8]4[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:38]5[C:34](=[O:40])[CH2:35][CH2:36][C:37]5=[O:39])[CH2:6][CH2:7]4)[N:12]=3)[CH:24]=[CH:23][C:22]=2[O:25][CH:26]([F:27])[F:28])[CH2:32][CH2:33]1
Reactant: O=C1CCC(=O)N1
Reactant: CC1(C)C(=O)N(C2CCN(C(=O)CCl)CC2)N=C1c1ccc(OC(F)F)c(OCC2CC2)c1
Product: CC1(C)C(=O)N(C2CCN(C(=O)CN3C(=O)CCC3=O)CC2)N=C1c1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A3) and succinimide as starting compounds.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:18]([O:23][CH:24]([O:26][C:27](OC1CC(=O)NC1=O)=[O:28])[CH3:25])(=[O:22])[CH:19]([CH3:21])[CH3:20]>O.C(#N)C.C(OCC)C>[C:18]([O:23][CH:24]([O:26][C:27]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:28])[CH3:25])(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of gabapentin (1.7 g, 10 mmol) and sodium bicarbonate (20 mmol) in water (40 mL) was added a solution of compound (10) (2.73 g, 10 mmol) in acetonitrile (20 mL) over 1 min. The reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with diethyl ether (100 mL) and washed with 0.1 M aqueous potassium bisulfate (3×100 mL). The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound (12) as a white solid (2.7 g, 96%). The product was recrystallized by dissolution in 1:10 ethyl acetate:heptane (10 mL) at 60° C., followed by slow cooling to 4° C. The white crystalline product was isolated by filtration. Melting point: 63-64° C. 1H NMR (CDCl3, 400 MHz): 1.15 (d, 6H), 1.40-1.55 (m, 10H), 1.45 (d, 3H), 2.32 (s, 2H), 2.49-2.56 (m, 1H), 3.23 (d, 2H), 5.41 (t, 1H), 6.75 (q, 1H). MS(ESI) m/z 330.29 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[C@@H:22]([CH3:25])[CH2:23][CH3:24])[C:9]([C@@H:11]2[CH2:13][C@H:12]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:40]1([CH2:44]Br)[CH2:43][CH2:42][CH2:41]1.C(Cl)(=O)C>CO.CN(C=O)C>[NH2:26][C@@H:21]([C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:20][N:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:44][CH:40]2[CH2:43][CH2:42][CH2:41]2)=[CH:7][CH:6]=1)[C:9]([C@@H:11]1[CH2:13][C@H:12]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:10]
Reactant: BrCC1CCC1
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccccn1)c1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CC[C@H](C)[C@H](N)CN(C(=O)[C@@H]1C[C@H]1c1ccccn1)c1ccc(OCC2CCC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of tert-butyl (2S,3S)-1-((1R,2R)—N-(4-hydroxyphenyl)-2-(pyridin-2-yl)cyclopropanecarboxamido)-3-methylpentan-2-ylcarbamate (69 mg, 0.15 mmol), potassium carbonate (63 mg, 0.46 mmol) and DMF (3 mL) was treated with cyclobutylmethyl bromide (21 μL, 0.18 mmol). The resulting reaction mixture was maintained at 70° C. with vigorous stirring overnight. The mixture was allowed to cool to room temperature, then partitioned between H2O (30 mL) and diethyl ether (20 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2×20 mL). Combined organics were washed with H2O (30 mL) and brine (30 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to afford a residue that was purified by column chromatography on silica gel (eluting with 30% ethyl acetate in hexanes) to afford an oil that was dissolved in methanol (2 mL) and cooled to 0° C. The cold solution was then treated dropwise with acetyl chloride (290 μL, 4.0 mmol), and then maintained at room temperature overnight. The reaction was concentrated to dryness to afford (1R,2R)-2-pyridin-2-yl-cyclopropanecarboxylic acid ((2S,3S)-2-amino-3-methyl-pentyl)-(4-cyclobutylmethoxy-phenyl)-amide (56 mg, 88% yield) as a white solid: 1H NMR (400 MHz, MeOD) δ 8.61 (d, J=5.3 Hz, 1H), 8.34 (t, J=8.3 Hz, 1H), 7.79 (t, J=6.7 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.6 Hz, 2H), 6.99 (d, J=8.3 Hz, 2H), 4.28 (dd, J=14.9, 8.8 Hz, 1H), 3.94 (d, J=6.6 Hz, 2H), 3.69 (dd, J=14.9, 2.8 Hz, 1H), 3.34-3.39 (m, 1H), 2.86-2.96 (m, 1H), 2.77 (dt, J=14.6, 7.2 Hz, 1H), 2.08-2.21 (m, 3H), 1.85-2.02 (m, 5H), 1.73-1.84 (m, 1H), 1.67 (dt, J=8.8, 5.5 Hz, 1H), 1.33-1.46 (m, 1H), 1.17-1.30 (m, 1H), 0.98 (d, J=6.8 Hz, 3H), 0.87 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 422.3 [(M+H)+, calcd for C26H36N3O2 422.3].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:26])=[CH:14][C:15]([N+:23]([O-])=O)=[C:16]([N:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([N:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[C:15]([NH2:23])=[CH:14][C:13]=2[F:26])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:8])[F:9]
Reactant: CCCN(C)c1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: CCCN(C)c1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
A solution of 5.2 g (0.013 mole) 5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluoro-N-methyl-2-nitro-N-propylbenzenamine in 100 mL acetic acid was heated to 80° C. under a nitrogen atmosphere. The heat and nitrogen were removed and 2.2 g (0.039) mole iron powder was added in 3 portions over 5 min. The solution was stirred at 80° C. for an additional 30 min. The solution was cooled and filtered through Celite®. The filtrate was diluted with 100 mL water and extracted three times with ethyl acetate. The ethyl acetate extracts were washed with a saturated NaHCO3 solution, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified chromatographically using 30% ethyl acetate in hexane as the eluent to give 3.85 g (80%) of 5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluoro-N-methyl-N-propyl-1, 2-benzenediamine as a light yellow oil, nD25 1.5352.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[CH:5]1([CH2:11][CH2:12]Br)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[N+:1]([CH2:12][CH2:11][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: BrCCC1CCCCC1
Agent: [Na+]
Product: O=[N+]([O-])CCC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.5 %

Procedure:
An oven-dried 1 liter 3-necked flask fitted with dropping funnel, thermometer and 31 g sodium nitrite. The mixture was stirred at 5° C. while 50 g 2-cyclohexylethylbromide (Aldrich) was added over 5 minutes. The cooling bath was removed and the mixture was stirred at 25° C. for 18 hours, poured into 1.5 l cold water and the mixture was repeatedly extracted (4×150 ml) with petroleum ether which was washed with water (2×10 ml) and dried over magnesium sulfate. The solvent was removed at reduced pressure using a rotary evaporator and the residue was distilled through an 8" Vigreux column giving 18.3 g (41%) of the desired product boiling at 70°-80° C. and 2 mm Hg, preceded by 8 g of lower-boiling material gave 16.4 g, 40%, bp 62°-65° C. at 0.5 mm Hg of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[C:7]3[CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([C:22](=[O:27])[C:23]([F:25])([F:24])[F:26])=[C:7]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1
Reactant: O=C(c1c2n(c3cc(Br)ccc13)CCN(C(=O)C(F)(F)F)CC2)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(c1c2n(c3cc(Br)ccc13)CCNCC2)C(F)(F)F
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
A solution of 1-[8-bromo-11-(2,2,2-trifluoroacetyl)-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indol-3-yl]-2,2,2-trifluoro-1-ethanone (105 mg, 0.23 mmol) in methanol (3 mL) is treated with 1M sodium hydroxide (1 mL, 1 mmol). After 30 min, the reaction is diluted with water (15 mL) and extracted twice with dichloromethane (20 mL). The combined organics are washed with brine (15 mL), dried over MgSO4, filtered, and concentrated to give a crude solid. This material is recrystallized from ethyl acetate/heptane to afford 48 mg of a white solid. IR (drift) 1666, 1508, 1464, 1426, 1282, 1248, 1211, 1201, 1181, 1130, 1060, 1043, 956, 939, 757 cm−1.