Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH:5]=[CH:6][C:7]1[S:8][C:9]([CH3:14])=[C:10]([CH2:12][CH3:13])[N:11]=1.[H][H]>[C].[Pd].C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]2[S:8][C:9]([CH3:14])=[C:10]([CH2:12][CH3:13])[N:11]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCc1nc(C=Cc2cccc(N)c2)sc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1nc(CCc2cccc(N)c2)sc1C
Reaction time: 12 h
Yield: 89.3 %

Procedure:
An amount of 1.0 g of 2-(3-aminostyryl)-4-ethyl-5-methylthiazole and 200 mg of 5% palladium-carbon were added to 20 ml of ethanol and catalytic reduction was carried out in a hydrogen gas atmosphere at room temperature and normal pressure for 12 hours. After the reaction mixture was filtered, the solvent was evaporated under reduced pressure to give 0.90 g (yield 90%) of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:17])[S:8][C:7]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23]Cl)=[O:20])([O:3][CH2:4][CH3:5])=[O:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:1]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:17])[S:8][C:7]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23][N:36]1[CH2:35][CH2:34][N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])[CH2:38][CH2:37]1)=[O:20])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)c1c(NC(=O)NCCCl)sc(C)c1-c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(NC(=O)NCCN2CCN(c3ccccc3OC)CC2)sc(C)c1-c1ccccc1
Yield: 63.4 %

Procedure:
A solution of Example 2A (0.60 g, 1.6 mmol), 1-(2-methoxyphenyl)piperazine (0.84 g, 6.5 mmol) and diisopropylethylamine (0.35 mL) in acetonitrile (25 mL) was processed as in Example 1B. Purification of the crude product on silica gel with 2% triethylamine 50% ethyl acetate/hexane provided 0.53 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:28](=[O:29])[C:18]3=[CH:19][NH:20][C:21]4[C:22]([F:27])=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]3=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[F:27][C:22]1[C:21]2[NH:20][CH:19]=[C:18]3[C:28](=[O:29])[N:15]([C:12]4[CH:13]=[CH:14][C:9]([NH:8][C:3](=[O:4])[CH:2]([CH3:1])[CH2:6][CH3:7])=[CH:10][CH:11]=4)[N:16]=[C:17]3[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Reactant: CCC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)C(=O)Nc1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
(±)-2-Methylbutyryl chloride (13.6 μl, 0.11 mmol) was added dropwise over 30 sec to a stirred solution of 2-(4-amino-phenyl)-6-fluoro-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one (Intermediate 2) (30 mg, 0.10 mmol), triethylamine (14 μl, 0.11 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol) in dichloromethane (1 ml) at room temperature. The mixture was stirred at room temperature for 16 h. The yellow solid was then filtered and purified by washing sequentially with a saturated solution of sodium bicarbonate (1 ml), ethyl acetate (1 ml) and ethyl alcohol (0.5 ml) and finally dried under suction to give the title compound (10 mg, 26%) as a bright yellow solid, LCMS m/z 379.36 [M+H]+ @ RT 1.18 min. δH(400 MHz, (CD3)2SO) 9.89 (1H, s), 8.52 (1H, s), 8.15 (2H, d J 9.0 Hz), 8.01 (1H, d J 7.0 Hz), 7.69 (2H, d J 9.0 Hz) 7.57-7.46 (2H, m), 2.46-2.39 (1H, m), 1.69-1.36 (2H, m), 1.11 (3H, d J 6.8 Hz), 0.91(3H, t J 7.3 Hz).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[C:38]1[S:39][C:40]([CH3:43])=[N:41][N:42]=1.C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:3][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:38]3[S:39][C:40]([CH3:43])=[N:41][N:42]=3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:1]
Reactant: Cc1nnc(Br)s1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3nnc(C)s3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 52) (223 mg, 0.536 mmol), potassium carbonate (222 mg, 1.607 mmol), tetrakis(triphenylphosphine)palladium(0) (61.9 mg, 0.054 mmol) and 2-bromo-5-methyl-1,3,4-thiadiazole (125 mg, 0.696 mmol) then filled with ethanol (3 mL) and toluene (3 mL). The resulting mixture was degassed for 15 min under house vacuum (with several quenches with nitrogen) then stirred at 100° C. for 2 h before being cooled to room temperature and left stand still for 16 h. The insoluble material was filtered off and rinsed with AcOEt. Most of the solvent was removed in vacuo and the residue was dissolved in AcOEt. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient: 25 to 100% AcOEt in hexanes) gave a material which was then further purified by MDAP (modifier: ammonium bicarbonate) to give 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(5-methyl-1,3,4-thiadiazol-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (60 mg, 0.154 mmol, 28.8% yield) as a white foam.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[F:26][CH:27]([F:37])[CH2:28][N:29]([CH3:36])[C@@H:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1>>[F:37][CH:27]([F:26])[CH2:28][N:29]([CH3:36])[C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:31]1
Reactant: CN(CC(F)F)[C@@H]1CCCNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@@H](N(C)CC(F)F)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)—N-(2,2-difluoroethyl)-N-methylpiperidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.58 (m, 1H) 1.61-1.94 (m, 2H) 1.97-2.07 (m, 1H) 2.33 (d, J=2.27 Hz, 3H) 2.54-2.87 (m, 3H) 3.11 (br. s., 3H) 3.40-3.97 (m, 2H) 4.20-4.76 (m, 1H) 6.03-6.58 (m, 1H) 7.64 (br. s., 1H) 7.68-7.80 (m, 1H) 7.94-8.62 (m, 4H). ESI-MS m/z [M+H]+ 499.3.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][N:37]([CH3:39])[CH3:38])[CH:31]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][N:37]([CH3:38])[CH3:39])[CH:31]=3)=[CH:28][CH:29]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(CN(C)C)c3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(CN(C)C)c3)cc2)cc1)C(=O)O
Yield: 48.6 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(3′-dimethylaminomethylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (263 mg), which is the product of Example 38, was reacted with aqueous sodium hydroxide solution (1N, 1.00 ml) and the reaction mixture was treated to give the title compound (121 mg) as a white powder.
Reaction SMILES: O.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C@@H:12]1[O:17][C@H:16]([C:18]([OH:20])=[O:19])[C@@H:15]([NH2:21])[C@H:13]1[OH:14].[C:22]([O:26][C:27]([NH:29][C@H:30]([C:48](O)=[O:49])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:47])=[CH:34][CH:33]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C@@H:12]1[O:17][C@H:16]([C:18]([OH:20])=[O:19])[C@@H:15]([NH:21][C:48](=[O:49])[C@H:30]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[C:41]([Cl:47])=[CH:42][CH:43]=[CH:44][C:45]=3[Cl:46])=[CH:34][CH:33]=2)[NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])[C@H:13]1[OH:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](N)[C@H]1O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1C(=O)O
Yield: 49.4 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-O-(2,6-dichlorobenzyl)-L-tyrosylamino]-β-D-ribofuranuronic acid (260 mg) was prepared by reacting 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid monohydrate (223.5 mg) prepared in Example 99 with N-hydroxysuccinimide ester of N-tert-butoxycarbonyl-O-(2,6-dichlorobenzyl)-L-tyrosine (388 mg) according to a similar manner to that of Example 5, mp. 166°-176° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH:18]=2)C#N)[CH:5]=[CH:4][CH:3]=1.[CH:19](O)=[O:20]>[Ni]>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:15][C:14]([CH:19]=[O:20])=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CCOc2cccc(C#N)c2)n1
Reactant: O=CO
Agent: [Ni]
Product: Cc1cccc(CCOc2ccc(C=O)cc2)n1

Procedure:
A mixture of 5-[2-(6-methyl-2-pyridyl)ethoxy]benzonitrile (9.62 g), Raney nickel alloy (10.0 g) and 75% formic acid (150 ml) was heated under reflux for 1 hour. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with water, alkalinized with 4N-KOH, and extracted with ethyl ether. The ethyl ether layer was washed with water and dried (MgSO4) and the solvent was distilled off. The residue was recrystallized from ethyl etherhexane to give 4-[2-(6-methyl-2-pyridyl)ethoxy]benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[C:11]1(=O)[O:16][C:14](=[O:15])[CH:13]=[CH:12]1.[Sn](Cl)Cl>>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[N:4]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Agent: Cl[Sn]Cl
Product: O=C1C=CC(=O)N1c1c(Cl)cc(Cl)cc1Cl
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4,6-trichloroaniline (1.20g, 6.11 mmol), maleic anhydride (0.80g, 8.2 mmol) and tin(II) chloride (0.068g, 0.36 mmol) is heated to 140° C. with mixing and held at this temperature for 2.0 hours. The reaction mixture is cooled, extracted with xylene, filtered and the resulting filtrate water washed. Solvent removal yielded N-(2,4,6-trichlorophenyl)maleimide. HPLC analysis showed conversion of 2,4,6-trichloroaniline was 96.4% and selectivity to N-(2,4,6-trichlorophenyl)maleimide based on reacted 2,4,6-trichloroaniline was 88.0%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Solvent: C1CCOC1
Product: OCc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
Added BH3 (1M in THF, 40 mL) to a solution of 2-bromo-4-chlorobenzoic acid (3.14 g, 13.33 mmol) in THF (3 mL) drop wise at 0° C. The reaction mixture was stirred at room temperature overnight. Extracted with ethyl acetate twice, and washed the organic phase with brine and dried with anhydrous Na2SO4, concentrated to give the title compound (2.5 g, 85%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:15])=[C:4]2[O:8][C:7](Cl)=[N:6][C:5]2=[C:10]([C:13]#[N:14])[C:11]=1[CH3:12].[CH:16]([N:19](C(C)C)[CH2:20]C)(C)C.CNC>ClCCl>[Br:1][C:2]1[C:3]([F:15])=[C:4]2[O:8][C:7]([N:19]([CH3:20])[CH3:16])=[N:6][C:5]2=[C:10]([C:13]#[N:14])[C:11]=1[CH3:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1c(Br)c(F)c2oc(Cl)nc2c1C#N
Agent: CNC
Solvent: ClCCl
Product: Cc1c(Br)c(F)c2oc(N(C)C)nc2c1C#N
Yield: 56.3 %

Procedure:
6-Bromo-2-chloro-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-167) (1.93 g, 6.67 mmol) was dissolved in dichloromethane (40 ml), then diisopropylethylamine (1.20 ml, 7.06 mmol) and dimethylamine (2.0 M tetrahydrofuran solution, 5.00 ml, 10.0 mmol) were added. After stirring with heating under reflux overnight, this was diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, then the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=70:1) to obtain a yellow solid (1.12 g, 56%).
Reaction SMILES: Br[C:2]1[O:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=1.C(N(CC)CC)C.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)#[CH:18]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:7]([C:4]1[O:3][C:2]([C:18]#[C:17][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:6][CH:5]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(Br)o1
Reactant: C#Cc1ccc(C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(C#Cc2ccc([N+](=O)[O-])o2)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-5-nitrofuran (1.65 g) and triethylamine (34 ml) in anhydrous acetonitrile (55 ml) under nitrogen was added bis(triphenylphosphine)palladium dichloride (130 mg) and cuprous iodide (35 mg). 4-Ethynylbenzonitrile (1.09 g) was added and the reaction mixture was stirred under nitrogen overnight. The mixture was evaporated to dryness and the residue was dissolved in dichloromethane (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (ethyl acetate/hexane 1:10) and triturated with ethyl acetate/hexane (1:3) to give 4-[(5-nitro-2-furyl)-ethynyl]benzonitrile.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[S:16][C:15]([C:18]([NH:20][C@@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)=[O:19])=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([Cl:36])=[O:35]>>[ClH:36].[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([NH:20][C:18]([C:15]1[S:16][C:17]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:34]([C:30]5[O:29][CH:33]=[CH:32][CH:31]=5)=[O:35])[CH:4]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=1)=[O:19])[CH2:22]2
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Product: O=C(Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1)c1ccco1

Procedure:
50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 31.5 mg (0.24 mmol) of furan-2-carbonyl chloride are reacted together by general method F. 29.1 mg (51.1% of theory) of the title compound are obtained.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.CO[CH:14](OC)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[OH:25][CH2:26][CH2:27][C@H:28]([OH:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(OCC)(=O)C>CN(C)C=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]2[O:40][C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:27][CH2:26][O:25]2)=[CH:16][CH:17]=1
Reactant: CCCCCCCCCCC[C@@H](O)CCO
Reactant: COc1ccc(C(OC)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCC[C@@H]1CCOC(c2ccc(OC)cc2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
p-Toluenesulfonic acid (152 mg, 0.80 mmol) and 4-methoxybenzaldehyde dimethylacetal (2.9 g, 16.0 mmol) was added to a solution of (R)-1,3-dihydroxytetradecane (1.85 g, 8.0 mnuol) in dimethylformamide (20 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate. The ethyl acetate layer was successively washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using cyclohexane:ethyl acetate=9:1 as the eluant to give the desired product (2.78 g, yield 99%).
Reaction SMILES: [Na].C(O)C.[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8][CH2:9][CH3:10])=O.C([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])C.Cl>C1(C)C=CC=CC=1>[CH2:9]([O:8][CH:6]([C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])[C:5]([O:12][CH2:13][CH3:14])=[O:11])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOCC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)C(OCC)C(=O)OCC
Temperature: 45 °C
Yield: 87 %

Procedure:
A stirred mixture of molten sodium metal (24.15 g, 1.05 mol) in toluene is treated with ethanol (55.2 g, 1.2 mol) over a 1 hr period at 100° C.-110° C., heated at reflux temperatures for 0.5 hr, cooled to 45° C., treated with a mixture of diethyl oxalate (160.6 g, 1.1 mol) and ethyl ethoxyacetate (132 g, 98%, 0.98 mol) over a 1 hr period at 45° C.-50° C., heated at 55° C.-60° C. for 1.5 hr and poured into 328 g of 14% HCl with cooling. The resultant mixture is separated. The title product is obtained as a 32% solution in the organic phase, identified by HRGC analysis, total yield is 198.2 g (87% yield).
Reaction SMILES: [OH:1][C@H:2]([CH2:25]O)[C@@H:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:11]1=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:38]1C=CC=C[CH:39]=1>C(OCC)(=O)C>[OH:1][C@H:2]([CH2:25][NH:38][CH3:39])[C@@H:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:11]1=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1N([C@@H](c2ccccc2)[C@H](O)CO)c2ccccc2C12CCCCC2
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: CNC[C@@H](O)[C@H](c1ccccc1)N1C(=O)C2(CCCCC2)c2ccccc21
Reaction time: 5 h
Yield: 32 %

Procedure:
1′-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one (250 mg, 0.71 mmol) was dissolved in pyridine (2.5 mL) and para-toluenesulfonyl chloride (169 mg, 0.89 mmol) was added. The reaction was stirred for 5 hours, then the reaction mixture was diluted with ethyl acetate and washed with water, a saturated aqueous solution of copper sulfate, a 2N aqueous solution of hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was immediately dissolved in methylamine (8M solution in ethanol, 15 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via flash column chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 85 mg (32%) 1′-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclo-hexane-1,3′-indol]-2′(1′H)-one as a colorless oil. The freebase was dissolved in diethyl ether (5 mL) and treated with a 1 N ethereal solution of hydrochloric acid (0.23 mL, 0.23 mmol, 1 equivalent). The white precipitate was collected and dried under vacuum to give 193 mg (60%) of 1′-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclo-hexane-1,3′-indol]-2′(1′H)-one hydrochloride. HRMS: calcd for C23H28N2O2+H+, 365.22235; found ([M+H]+), 365.2226;
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[N:4][C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[C:34]1(C)C=CC=CC=1.CO.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[CH3:34][O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=1[NH:24][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)[N:4]=1
Reactant: Cc1ccccc1
Reactant: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)O)n3)cc2CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)OC)n3)cc2CC1
Reaction time: 8 h
Yield: 21.6 %

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester (1.168 g, 2.355 mmol) was dissolved in tetrahydrofuran (117 mL, 1440 mmol). Lithium hydroxide (67.7 mg, 2.82 mmol) dissolved in water (23.4 mL, 1.30 mol) was added and the reaction was stirred for 48 hours. The reaction was concentrated under reduced pressure and azetroped twice with toluene. The reaction was then further dried under high vacuum to obtain 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid. 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid (1.55 g, 3.31 mmol) was placed in toluene (40.0 mL, 376 mmol) and methanol (10.0 mL, 247 mmol). 2.00 M of Trimethylsilyldiazomethane in hexane (4.50 mL) was added and the reaction was stirred overnight. The reaction was quenched with acetic acid and then concentrated under reduced pressure. The residue was taken up in DCM (50 mL) and washed with sat. NaHCO3 (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-60% EtOAc/hex as the eluting solvent to obtain 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid methyl ester as a pale yellow solid (344 mg, 21%). m.p.=152-156° C.; LCMS (m/e) 482 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.13 (s, 1H), 8.86 (d, 1H, J=8.6 Hz), 8.14 (s, 1H), 8.09 (d, 1H, J=8.0 Hz), 7.55-7.46 (m, 1H), 7.35 (s, 1H), 7.30-7.22 (m, 1H), 7.14-7.02 (m, 2H), 6.92 (s, 1H), 3.99 (s, 3H), 3.56 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.98-2.89 (m, 4H), 2.80-2.71 (m, 6H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].O>CCOCC>[Br:1][CH2:2][C:3]([N:8]([CH2:9][CH3:10])[CH2:6][CH3:7])=[O:4]
Reactant: CCNCC
Reactant: O=C(Br)CBr
Solvent: O
Solvent: CCOCC
Product: CCN(CC)C(=O)CBr
Temperature: -15 °C

Procedure:
Under a nitrogen atmosphere, a 1-liter flask is charged with 2-bromoacetylbromide (46.34 g, 230 mmol) and 300 ml ether. The flask is chilled to −15° C., and a solution of diethylamine (33.72 g, 460 mmol) in 200 ml ether is added over 1 hour to the flask. The resulting thick slurry is stirred cold for 1 additional hour, then warmed slowly to room temperature, and stirred overnight. The mixture is added to 250 ml cold water, and the resulting aqueous solution is extracted with ether (3 times, 200 ml ether each time). The combined ether extracts are washed with phosphoric acid (5 wt percent, 200 ml), aqueous potassium carbonate (8 wt percent, 200 ml) and thereafter brine (150 ml). The ether extract is then dried over sodium sulfate and concentrated in vacuo to a light brown residue. The residue is vacuum distilled to yield 2-bromo-N,N-diethylacetamide as a clear, colorless oil (22.99 g, 52% yield). 1H NMR (300 MHz, CDCl3), δ (PPM): 1.08 (t, 3H), 1.20 (t, 3H), 3.33 (q, 4H), 3.79 (s, 2H).