Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]([OH:22])=[O:21])[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].[C:23]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]([O:22][CH3:23])=[O:21])[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]cc(C(=O)O)c3c2)n1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1c[nH]c2ccc(-c3cncc(OC(C)C)n3)cc12
Temperature: 80 °C
Yield: 77.6 %

Procedure:
To a solution of 5-(6-isopropoxy-pyrazin-2-yl)-1H-indole-3-carboxylic acid (8.0 g, 26.9 mmol) in DMF (80 mL) was added K2CO3 (4.50 g, 32.3 mmol) and dimethyl sulfate (2.50 mL, 26.9 mmol) at RT and the reaction was heated to 80° C. for 3 h. The mixture was cooled to RT and partitioned between ice water (80 mL) and EtOAc (80 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified with silica gel chromatography (eluting with 15% EtOAc in petroleum ether) to give methyl 5-(6-isopropoxypyrazin-2-yl)-1H-indole-3-carboxylate (6.5 g, 79%) as an off white solid. MS (ESI, pos. ion) m/z: 311.9 (M+1); 1H-NMR (DMSO-d6) δ ppm; 8.70 (d, J=1.6 Hz, 2H), 8.18 (s, 1H), 8.14 (s, 1H), 7.9 (dd, J=2.0 Hz, 1H), 7.62 (d, J=8.4, 1.6 Hz, 1H), 5.39-5.43 (m, 1H), 3.85 (s, 3H), 1.40 (d, J=6.0 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:15]/[N+:12]([O-:14])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1C
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(/C=C/[N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of 3-methyl-p-anisaldehyde (23.13 g, 154 mmol) and nitromethane (9.40 g, 154 mmol) in MeOH (260 ml) was cooled in an ice bath and treated dropwise with NaOH (162 ml of 1N solution; 162 mmol). The reaction mixture was stirred at rt for 1 hr. Water (50 ml) was then added and the mixture poured into 1N HCl (300 ml). The precipitate was collected and purified by flash chromatography on silica gel eluting with dichloromethane to provide methyl 2-methyl-4-[(E)-2-nitroethenyl]phenyl ether as a yellow solid (14.61 g; 49% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.O.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: C1CCNC1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCCC2)ccc1N
Reaction time: 2 h

Procedure:
To a solution of 4-amino-3-methoxybenzoic acid (167 mg, 1 mmol) in dichloromethane (20 mL) at 0° C. was added pyrrolidine (71 mg, 1 mmol), hydroxybenzotriazole monohydrate (270 mg, 2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (384 mg, 2 mmol) and triethylamine (0.5 mL, 3 mmol). After stirring for 2 hours, the mixture was diluted with water and extracted with dichloromethane. The organic phase was concentrated and the residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 5/1 petroleum ether/ethyl acetate to give the title compound. MS: 220 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Br[C:14]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[S:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]([CH3:43])[CH:15]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]4[S:31][N:30]=[CH:29][N:28]=4)(=[O:24])=[O:25])=[CH:20][CH:21]=3)[N:16]([CH3:43])[CH:15]=2)=[CH:5][C:4]=1[F:12])#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: N#Cc1ccc(B(O)O)cc1F
Product: Cn1cc(-c2ccc(C#N)c(F)c2)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (4-cyano-3-fluorophenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(4-cyano-3-fluorophenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.92 (s, 3 H) 7.60 (dd, J=8.53, 1.55 Hz, 1 H) 7.73-7.80 (m, 2 H) 7.87-7.97 (m, 2 H) 8.02-8.10 (m, 2 H) 8.23 (s, 1 H). m/z (ESI) 413.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19])([O-:11])=[O:10]>N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N+:9]([O-:11])=[O:10])(=[O:19])=[O:20])[O:4][N:3]=1
Reactant: Cc1noc(N)c1C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1noc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 4.04 g (36 mmol) of 3,4-dimethyl-5-isoxazolamine in 15 mL of pyridine, 8.0 g (36 mmol) of 2-nitrobenzenesulfonyl chloride was added and the solution was stirred at room temperature overnight. The mixture was poured into 100 mL of ice water and filtered. The filtrate was acidified to pH 2 using 6 N aqueous hydrochloric acid and the mixture was extracted with 4×125 mL of ethyl acetate. The combined organic extracts were washed with 75 mL of brine, dried and evaporated to provide 9.1 g of a dark brown residue. This material was chromatographed on silica gel using hexanes/ethyl acetate (2:1) to provide 0.5 g of Example 9 as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:13]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: Cl
Product: COC(=O)Cc1ccc(Cl)cc1

Procedure:
4-Chlorophenylacetic acid (5.0 g) was dissolved in 10% hydrogen chloride-methanol solution (50 ml) and heated under reflex for 14 hours. The solvent then was removed under reduced pressure and saturated sodium hydrogencarbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and condensed under reduced pressure to provide methyl 2-(4-chlorophenyl)acetate (5.35 g) as a colorless, oily substance.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33]>CN(C)C(=O)C>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:13]([C:4]3[C:3](=[O:33])[N:2]([N:1]=[CH:3][CH2:4][CH2:5][CH3:6])[C:11]4[C:6]([C:5]=3[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:14][S:15](=[O:32])(=[O:31])[C:16]=2[CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Solvent: CC(=O)N(C)C
Product: CCCC=Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Temperature: 165 °C
Yield: 162.1 %

Procedure:
The product of Example 304F (0.150 g, 0.32 mmol) and butyrlaldehyde (0.29 mL, 3.24 mmol) in N,N-dimethylacetamide (1.5 mL) were reacted at 120° C. for 25 minutes in a microwave reactor in a sealed tube. The reaction was concentrated under a stream of nitrogen warmed through a manifold heated to 165° C. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.134 g, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([O:16][CH3:17])=[CH:8][C:9]=1[C:10]2=[O:15].CO.C[O-].[Na+].Cl[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>ClC1C=CC=CC=1>[CH2:25]([N:26]([CH2:29][CH3:30])[CH2:27][CH2:28][O:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([O:16][CH3:17])=[CH:8][C:9]=1[C:10]2=[O:15])[CH3:24]
Reactant: COc1ccc2c(c1)C(=O)c1cccc(O)c1-2
Reactant: CCN(CC)CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Clc1ccccc1
Product: CCN(CC)CCOc1cccc2c1-c1ccc(OC)cc1C2=O

Procedure:
In a manner analogous to Example 3D1, combine 5-hydroxy-2-methoxy-fluoren-9-one (0.35 g, 1.5 mmole), 3 mL methanol and sodium methoxide (0.12 g, 2.1 mole) in 10 mL chlorobenzene. After cooling, add the specially prepared free base 2-chloroethyldiethyl amine to obtain the hydrochloride salt of the title compound as a yellow-orange powder. m.p. 196°-199° C. (dec.). Yield 0.387 g, 72%.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:8][C:7]=1[O:19][CH3:20])=[O:4].[CH3:23][C:24]([OH:26])=[O:25]>[Pt]=O>[C:24]([OH:26])(=[O:25])[CH3:23].[F:22][C:2]([F:1])([F:21])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:8][C:7]=1[O:19][CH3:20])=[O:4]
Reactant: COc1cc(-c2ccncc2)c(C)cc1NC(=O)C(F)(F)F
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COc1cc(C2CCNCC2)c(C)cc1NC(=O)C(F)(F)F
Reaction time: 24 h
Yield: 98 %

Procedure:
2,2,2-Trifluoro-N-[5-methyl-2-(methyloxy)-4-(4-pyridinyl)phenyl]acetamide (2.37 g, 7.64 mmol) was placed in a 250 mL high pressure vessel and dissolved in 70 mL of HOAc. Platinum oxide (0.173 g, 0.76 mmol) was added followed quickly by a rubber septum. The flask was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (60 psi). The solution stirred for 24 h. The vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to give the title compound (2.83 g, 7.46 mmol, 98%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.11 (s, 1H), 6.86 (s, 1H), 3.76 (s, 3H), 3.14 (d, J=12.27 Hz, 2H), 2.82-2.91 (m, 1H), 2.72-2.81 (m, 2H), 2.20 (s, 3H), 1.81 (s, 3H), 1.64-1.75 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=O)=[CH:23][CH:22]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:29](=[O:31])[CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([OH:20])=[CH:26][CH:25]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCCCCCCNCc1cccc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
N-(2,3-Dimethoxybenzyl)-N-heptylamine (0.70 g, 2.65 mmol) was dissolved in DM (10 ml), 3-(4-hydroxyphenyl)propanoic acid (0.4 g, 2.41 mmol), was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.85 g, 2.65 mmol) and diisopropylethylamine (0.65 g, 5.05 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). EtOAc was removed by evaporation and the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation and gave 0.98 gram N-(2,3-dimethoxybenzyl)-N-heptyl-3-(4-hydroxyphenyl)propanamide (yield 70%).
Reaction SMILES: [OH:1][C:2]1([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH:15]([C@:18]1([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][C:30]([C:36]([F:39])([F:38])[F:37])=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH2:23])[CH2:19]1)([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:15]([C@:18]1([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][C:30]([C:36]([F:39])([F:37])[F:38])=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH:23][CH:5]2[CH2:6][CH2:7][C:2]([C:9]3[N:14]=[CH:13][CH:12]=[CH:11][N:10]=3)([OH:1])[CH2:3][CH2:4]2)[CH2:19]1)([CH3:17])[CH3:16]
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Reactant: O=C1CCC(O)(c2ncccn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC2CCC(O)(c3ncccn3)CC2)C1
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-4-pyrimidin-2-yl-cyclohexanone (59.8 mg, 0.31 mmol) and (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine (110 mg, 0.31 mmol) of Step C-2 of Example 1 in CH2Cl2(10 mL) was added sodium triacetoxyborohydride (131 mg, 0.62 mmol). After being stirred overnight, more sodium triacetoxyborohydride was added to bring the equivalents of the reducing agent to 5 equivalents. After stirring for another 5 hrs, the reaction was quenched with aqueous NaOH. The resulting solution was extracted with EtOAc three times. The combined extracts were dried over MgSO4 and concentrated. Purification by flash chromatography followed by HPLC gave two isomers. Isomer 1 and isomer 2: MS calculated for C29H37F3N4O2: (M+H)+531; found 531.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11](S(C)(=O)=O)[C:10]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)([C:17]([F:20])([F:19])[F:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)([C:17]([F:20])([F:19])[F:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)C1CN(Cc2ccccc2)CC1(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)C=CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
1-Benzyl-3-(3,5-dichlorophenyl)-4-(methylsulfonyl)-3-(trifluoromethyl)pyrrolidine (2.00 g, 95% purity, 4.13 mmol) was dissolved in toluene (40 mL) under a nitrogen atmosphere and sodium carbonate (1.31 g, 12.4 mmol) was added. The reaction mixture was heated to reflux for 150 minutes and cooled to room temperature. Water (20 mL) was added, the mixture stirred for 5 minutes and the phases separated. The water phase was extracted with toluene (20 mL) and solvent of the combined organic phases was evaporated under vacuum. The crude material was dissolved in warm n-heptane and after standing and cooling the forming crystals were filtered off to yield 1-benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,3-dihydro-1H-pyrrole (972 mg, 95% purity, 60% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[OH-].[Na+].NN>[Fe](Cl)(Cl)Cl.C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Agent: [Na+]
Solvent: CC(C)O
Product: Nc1cc(Br)ccc1C(=O)O
Temperature: 75 °C
Yield: 102.3 %

Procedure:
To 4-bromo-2-nitrobenzoic acid (1.80 g, 7.83 mmol) were added 0.88N aqueous sodium hydroxide solution (10 mL), iron(III) chloride (133 mg) and isopropyl alcohol (0.7 mL) and the mixture heated to 75° C. While stirring the mixture, hydrazine (1.1 mL) was slowly added, and the mixture was reacted at 75° C. for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated. The precipitated solid was washed with water to give 4-bromoanthranilic acid (1.73 g, 96%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([CH2:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.O.NN>C1COCC1>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=NOCc1cccc(CN2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnnc1C(=NOCc1cccc(CN)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.1 %

Procedure:
To a solution of 2-({6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}methyl)-1H-isoindole-1,3(2H)-dione (3 g, 6.61 mmol, 1 eq.) in 25 ml of THF was added hydrazine hydrate (1.32 g, 26.46 mmol, 4 eq.). The reaction was stirred overnight at room temperature. The solvent was evaporated and the residue dissolved in EtOAc. Water was added and the layers separated. The aqueous layer was extracted with EtOAc and the organics were combined, dried over MgSO4 and concentrated to give 1-{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}methanamine (2.29 g, 93%) as a clear viscous oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[O:11][C:10]([C:12]2[NH:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]=2[C:17]#[N:18])=[CH:9][CH:8]=1.CN(C)[CH:25]=[O:26].Cl>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH:25]([C:7]1[O:11][C:10]([C:12]2[NH:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]=2[C:17]#[N:18])=[CH:9][CH:8]=1)=[O:26]
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Br)o1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(C=O)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
Butyllithium (3.45 mL, 7.78 mmol) is added dropwise to a solution of 2-(5-bromo-2-furyl)-5-(trifluoromethyl) pyrrole-3-carbonitrile (1.13 g, 3.70 mmol) in tetrahydrofuran at -78° C. The reation mixture is stirred at -78° C. for 30 minutes, warmed to room temperature, treated with N,N-dimethylformamide (1.35 g, 18.5 mmol), poured into one molar hydrochloric acid and extracted with ether and ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over Na2SO4 and concentrated in vacuo to obtain an orange solid. Flash chromatography of the solid using silica gel and 20% to 50% ethyl acetate in hexane solutions give an orange solid which is recrystallized from ethyl acetate to obtain the title product as orange crystals (0.66 g, 70%, mp 224°-225° C.).
Reaction SMILES: [O:1]=[C:2]1[C:9]2[C:8]([C:10]([OH:12])=O)=[CH:7][O:6][C:5]=2[CH2:4][CH2:3]1.[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH3:14]>>[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:10]([C:8]2[C:9]3[C:2](=[O:1])[CH2:3][CH2:4][C:5]=3[O:6][CH:7]=2)=[O:12])=[CH:18][CH:17]=1)[CH3:14]
Reactant: O=C(O)c1coc2c1C(=O)CC2
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc(NC(=O)c2coc3c2C(=O)CC3)cc1

Procedure:
Starting from 4-oxo-5,6-dihydro-4H cylopenta[b]furan-3-carboxylic acid and 4-ethoxyaniline, General Procedure B provided the title compound:
Reaction SMILES: [CH3:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:3][CH2:4][CH:5]=[CH2:6].C([Li])CCC.[C:18]1(=O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1.Cl>O1CCCC1>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([C:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)([CH3:1])[CH2:3][CH2:4][CH:5]=[CH2:6])=[CH:19]1
Reactant: O=C1CCc2ccccc21
Reactant: C=CCCC(C)c1ccccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCC(C)(C1=CCc2ccccc21)c1ccccn1

Procedure:
A solution of 8.95 g (0.0556 mol) of 2-(1-methyl4-pentenyl)pyridine in 50 ml of tetrahydrofuran was cooled to −20° C. and 35 ml of n-butyllithium (15 w.-% in hexane, 0.0556 mol) were subsequently added while stirring. The mixture was allowed to come to room temperature and was stirred for a further one hour. A solution of 7.33 g of 1-indanone in 8 ml of tetrahydrofuran was then added at such a rate that the temperature remained at 25° C. The mixture was stirred for a further 3 hours and hydrolyzed with 150 ml of dilute hydrochloric acid. The organic phase was separated off, the aqueous phase was extracted once with ethyl acetate, the aqueous phase was subsequently neutralized with aqueous ammonia solution and was extracted three times with 80 ml each time of dichloromethane. The organic phases were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off and the solvent was distilled off. The crude product (about 10 g) was purified by column chromatography using a mixture of hexane:CH2Cl2=1:1 for the separation from starting 2-(1-methyl4-pentenyl)pyridine. Then, a mixture of hexane:CH2Cl2=1:2 was used. This gave 4.81 g (31%) of 2-[1-(1H-inden-3-yl)-1-methyl-4-pentenyl]pyridine.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N)CCC1>>[CH3:13][C:12]1[C:7]([NH:6][CH:1]([CH2:5][CH3:4])[CH2:2][CH3:3])=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Agent: NC1CCC1
Product: CCC(CC)Nc1nc(NCc2ccccn2)nc(C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using cyclobutanamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 0.81 (t, J=7.3 Hz, 3H), 1.36-1.43 (m, 2H), 1.50-1.57 (m, 2H), 1.90 (s, 3H), 2.26 (s, 3H), 3.94-4.00 (m, 1H), 4.17 (bs, 1H), 4.72 (d, J=5.9 Hz, 2H), 5.72 (bs, 1H), 7.13 (t, J=7.5 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 8.54 (d, J=4.8 Hz, 1H); MS (ESI) m/z 300.1 (M+1)+.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH2:6][CH2:7][O:8][NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:3].[OH-].[K+]>C(O)C>[C:10]([N:9]1[O:8][CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[CH:2]1[CH3:3])([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)NOCCc1ccccc1C(C)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1OCCc2ccccc2C1C

Procedure:
A solution of 18.5 g. of O-[o-(1-chloroethyl)-phenethyl]-N-carbethoxyhydroxylamine in 130 ml. of ethanol was treated with 3.85 g. of potassium hydroxide in 55 ml. of ethanol according to the procedure described in Example 1. The end product was recovered by distillation collecting the fraction boiling at 115° C./0.1 mm Hg. The fraction boiling at 100° C./0.2 mm Hg which contained the by-product O-(o-vinylphenethyl)-N-carbethoxyhydroxylamine was discarded. There was thus obtained 7.8 g. of 2-carbethoxy-1-methyl-1,2,4,5-tetrahydro-3,2-benzoxazepine.