Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].Br[C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:13][NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16].CC([O-])(C)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:26][C:25]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C@@H:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])=[CH:23][C:24]=1[NH:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: NCc1ccccn1
Reactant: C[C@@H](NCc1ccc(Cl)c(Br)c1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H](NCc1ccc(Cl)c(NCc2ccccn2)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 12.1 %

Procedure:
To a mixture of pyridin-2-ylmethanamine (0.105 g, 1.0 mmol) and (R)—N-(3-bromo-4-chlorobenzyl)-1-phenylethanamine 73 (0.251 g, 0.8 mmol) was added sodium 2-methylpropan-2-olate (0.103 g, 1 mmol), Pd2(dba)3 (0.051 g, 0.06 mmol), 2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen-1-yl)naphthalene (0.210 mg, 0.34 mmol), and toluene (1.5 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for 15 min and heated to 80° C. After 20 h, the reaction mixture was diluted with EtOAc and saturated NaHCO3. The organic phase was washed with brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 60% to 100% EtOAc in hexanes) followed by flash column chromatography on silica gel (eluted with 1% to 5% MeOH (2 M in NH3) in DCM) gave (R)-2-chloro-5-((1-phenylethylamino)methyl)-N-(pyridin-2-ylmethyl)benzenamine 74 (0.034 g, 12% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.31 (d, J=6.5 Hz, 3H), 3.46 (d, J=13.3 Hz, 1H), 3.55 (d, J=13.3 Hz, 1H), 3.72 (q, J=6.5 Hz, 1H), 4.53 (d, J=5.5 Hz, 2H), 5.38 (m, 1H), 6.54-6.58 (m, 2H), 7.20-7.33 (m, 9H), 7.66 (td, J=7.6, 1.8 Hz, 1H), 8.62 (d, J=4.3 Hz, 1H). Mass spectrum: calculated for C21H22ClN3 351.2. found 352.2 (M++1).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([CH3:27])=[N:7][C:8]2[N:9]([CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[N+:2]=[N-:3].O[Li].O>C1COCC1.O>[N:1]([CH2:4][C:5]1[C:6]([CH3:27])=[N:7][C:8]2[N:9]([CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[N+:2]=[N-:3]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CN=[N+]=[N-])c(C)nc2n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2nc(C(=O)O)cn2c(-c2ccc(Cl)cc2Cl)c1CN=[N+]=[N-]
Temperature: 50 °C
Yield: 93.8 %

Procedure:
To a stirred solution of (+)-ethyl 6-(azidomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (1 g, 2.47 mmol) in THF (20 mL) and H2O (2 mL) was added LiOH.H2O (155 mg, 3.70 mmol). After heating to 50° C. for 16 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The aqueous layer was acidified by 1N HCl to pH=1. The organic layer was washed with satd aq NH4Cl and brine before drying over MgSO4. Filtration, concentration under reduced pressure provided (+)-6-(azidomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylic acid (874 mg, 94%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)=[C:14]([C:16]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[O:17])[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.CO.[Ni]>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:13]2[NH:12][C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)=[N:15][C:14]=2[C:16]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:17])=[CH:29][CH:28]=1
Reactant: CC(C)(C)c1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc([N+](=O)[O-])cc3)[nH]2)cc1
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)c1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(N)cc3)[nH]2)cc1
Yield: 46.9 %

Procedure:
2-(4-tert-Butylphenyl)-5-(4-nitrophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (16.3 g) was dissolved in a mixed solvent of dioxane and methanol and hydrogenated with Raney nickel. The catalyst was filtered off and the residue was concentrated and crystallized from ethyl acetate and isopropyl ether to give 5-(4-aminophenyl)-2-(4-tert-butylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (7.13 g). 1.0 g therefrom was converted to hydrochloride to give 5-(4-aminophenyl)-2-(4-tert-butylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide hydrochloride (0.48 g), melting point 270-272° C. (decomposition).
Reaction SMILES: F[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[F:14].[CH3:15][C@H:16]1[O:21][C@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1>>[CH3:22][C@@H:20]1[CH2:19][N:18]([C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:5]3[C:6]([CH3:9])=[N:7][O:8][C:4]=3[C:3]=2[F:14])[CH2:17][C@@H:16]([CH3:15])[O:21]1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: Cc1noc2c(F)c(F)c(C=O)cc12
Product: Cc1noc2c(F)c(N3C[C@@H](C)O[C@H](C)C3)c(C=O)cc12

Procedure:
Starting materials: 6,7-difluoro-3-methylbenzo[d]isoxazole-5-carbaldehyde (Intermediate 374) and (2R,6R)-2,6-dimethylmorpholine.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][C@H:4]([CH3:8])[NH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][N:44]=1>CN(C=O)C>[NH2:42][C:43]1[N:44]=[CH:45][C:46]([C:47]([N:3]2[C@@H:4]([CH3:8])[CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[O:48])=[CH:50][CH:51]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: C[C@H]1COC[C@H](C)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1COC[C@H](C)N1C(=O)c1ccc(N)nc1
Reaction time: 18 h
Yield: 34 %

Procedure:
To a solution of (3S,5S)-3,5-dimethylmorpholine (115 mg, 1.0 mmol) in DMF (2 mL) was added HATU (380 mg, 1.0 mmol), DIPEA (260 mg, 2.0 mmol), and 6-aminonicotinic acid (138 mg, 1.0 mmol) at room temperature. After stirring for 18 h, the reaction mixture was filtered and purified with Combiflash (A: 1‰NH4HCO3/water, B: acetonitrile) to afford 324a (80 mg, 34%) as a yellow solid. MS (ESI): 236.1 (M+H).
Reaction SMILES: C[C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17]([C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1)=[O:18]
Reactant: Cc1c[nH]c(=O)[nH]1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2c[nH]c(=O)[nH]2)cc1OC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 6.5 g of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 14.6 g of aluminum chloride in 65 ml of nitrobenzene is added 17.6 g of 3,4-dimethoxybenzoyl chloride in portions. The mixture is stirred for 3 hours at 60° C., cooled and poured over ice water. The gummy solids are filtered and recrystallized twice from ethyl alcohol-water to afford the title compound. M.P. 257°-259° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH3:16])[C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:23]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:15]([CH:11]([C:12]([NH2:14])=[O:13])[C:8]2[CH:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=2)[CH3:16])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)c1ccc(C(C(N)=O)C(C)c2ccccc2N2CCCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(CO)cc1

Procedure:
Prepared from 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester by lithium aluminum hydride reduction in tetrahydrofuran.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Li].[CH3:26]COCC.[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH2:11][C:12](=[O:13])[CH3:26])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 39 %

Procedure:
Benzyl N-tert-butoxycarbonyl-(2S)-pyroglutamate (20.5 g, 64.2 mmol) was dissolved in THF (500 ml). Methyl lithium (a 1.04M ether solution, 61.7 ml, 64.2 mmol) was added dropwise at −78° C. The temperature of the reaction mixture was caused to rise back gradually to room temperature under stirring, and the resulting mixture was stirred for 18 hours. A saturated aqueous solution of ammonium chloride was added and the resulting mixture was concentrated under reduced pressure. The concentrate was extracted with ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane/ethyl acetate (3/1) eluate fractions, benzyl (2S)-N-tert-butoxycarbonylamino-5-oxohexanoate (8.37 g, 39%) was obtained as a yellow oil.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Cl.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH2:48][C:49](O)=[O:50]>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:49](=[O:50])[CH2:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][N:42]=1)[CH2:19][CH2:18]2
Reactant: O=C(O)Cc1ccccn1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cc3ccccn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure described for the parallel synthesis of C-17 amides above, using 2-pyridylacetic acid hydrochloride as the reacting carboxylic acid. LCMS: m/e 649.6 (M+H)+, 4.23 min (method 3).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)[CH:18]=[CH:19][N:20](C)C)=[N:11]2)=[CH:6][CH:5]=1.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(OC(F)F)cc2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2ccc(OC(F)F)cc2)nc1-c1ccnn1-c1ccccc1
Yield: 22 %

Procedure:
To a solution of 1-[4-(difluoromethoxy)phenyl]-3-[3-(dimethylamino)prop-2-enoyl]pyridazin-4(1H)-one (crude 747 mg, 2.22 mmol) in 20 mL of methanol was added phenylhydrazine (360 mg, 3.33 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-[4-(difluoromethoxy)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (190 mg, 22% for two steps) as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([CH2:16][CH2:17][C:18]#[N:19])([C:11]([O:13]CC)=[O:12])[C:6]([O:8]CC)=[O:7])#[N:2].C[N+](C)(C)C.[OH-].Cl>>[C:18]([CH2:17][CH2:16][C:5]([CH2:4][CH2:3][C:1]#[N:2])([C:11]([OH:13])=[O:12])[C:6]([OH:8])=[O:7])#[N:19]
Reactant: CCOC(=O)C(CCC#N)(CCC#N)C(=O)OCC
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [OH-]
Product: N#CCCC(CCC#N)(C(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 24 h
Yield: 15.8 %

Procedure:
Diethyl 2,2-bis(2-cyanoethyl)malonate (2 g, 7.51 mmol) was added to TMAH (25% in water, 10.95 g, 30.04 mmol) at room temperature. The mixture was stirred for 24 hours, and was then cooled to 0° C. A mixture of 12M HCl (2.69 cm3, 32.1 mmol) and ice (3 g) was added and the mixture was extracted with CH2Cl2 (5×50 cm3). The extracts were evaporated under vacuum to give 2,2-bis(2-cyanoethyl)malonic acid (0.25 g, 15.8%) as a colourless very viscous oil (lit decomposed. 158° C.).
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21]>>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:19]([C:20]([OH:22])=[O:21])[CH:18]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Product: O=C(O)c1cccc(Nc2ncc(Br)c(Nc3ccccc3)n2)c1

Procedure:
Using an analogous method to that described in Method 1, but starting from 4-anilino-5-bromo-2-chloropyrimidine and 3-aminobenzoic acid, the product was obtained. NMR: 7.2-7.4 (m, 4H), 7.55-7.6 (m, 3H), 7.8 (dd, 1H), 7.95 (s, 1H), 8.4 (s, 1H), 9.3 (br s, 1H), 10.2 (br s 1H); MS (MH+): 385, 387.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][CH:8]([O:23][CH3:24])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1[O:19][CH2:20][O:21][CH3:22].CN(C)CCN(C)C.CI.[Cl-].[NH4+]>O1CCCC1>[CH3:6][O:7][CH:8]([O:23][CH3:24])[C:9]1[C:10]([O:19][CH2:20][O:21][CH3:22])=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:13][C:14]=1[CH3:1]
Reactant: COCOc1c(C(OC)OC)cccc1C(F)(F)F
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COCOc1c(C(F)(F)F)ccc(C)c1C(OC)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
A n-butyllithium-1.59M n-hexane solution (40.0 ml, 64.4 mmol) was added dropwise to a solution of 1-(dimethoxymethyl)-2-(methoxymethoxy)-3-(trifluoromethyl)benzene (12.0 g, 42.9 mmol) obtained in Example (6-4) and N,N,N′,N′-tetramethylethylenediamine (9.70 ml, 64.4 mmol) in tetrahydrofuran (100 ml) at −40° C. over 5 minutes. The reaction mixture was stirred at 0° C. for 15 minutes. After the reaction mixture was cooled to −40° C., methyl iodide (5.3 ml, 85.85 mmol) was added thereto and the mixture was further stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=5/1) to give 2-(dimethoxymethyl)-3-(methoxymethoxy)-1-methyl-4-(trifluoromethyl)benzene as an oil (7.19 g, yield: 57%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Cc1cc(Br)cc(C(=O)O)c1N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(C)c1N
Yield: 89.1 %

Procedure:
2-Amino-5-bromo-3-methylbenzoic acid (5.0 g, 21.7 mmol) in dry DMF (35 mL) was stirred with Cs2CO3 (10.62 g, 32.6 mmol) at room temperature for 1 h under nitrogen. Iodomethane (3.4 g, 1.5 mL, 23.95 mmol) in dry DMF (7 ml) was added dropwise to the above stirring reaction mixture over a period of 30 min and continued the reaction for 24 h. Reaction mixture was diluted with water (200 mL) and stirred to observe hetergeneous suspension. The purple solid was collected by filtration and dried to obtain methyl 2-amino-5-bromo-3-methylbenzoate (4.72 g, 89%). 1H NMR (DMSO-d6): δ 7.67 (app d, 1H, J=2.1 Hz), 7.34 (s, 1H), 6.60 (s, 2H), 3.78 (s, 3H), 2.09 (s, 3H).LCMS: rt 7.98 min (A), purity 99%, MS (m/e) 245 (MH+).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[C:11]([OH:13])=[O:12])=O)(C)(C)C.CS(O)(=O)=O.[CH3:29][O:30][C:31]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[C:32]=1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(OCC)(=O)C.C(N(CC)CC)C>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[C:15]([CH:20]=1)[CH2:14][C@@H:10]([CH2:9][NH:8][CH2:6][C:32]1[C:35]([O:41][CH3:42])=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:31]=1[O:30][CH3:29])[C:11]([OH:13])=[O:12]
Reactant: COc1ccc(Cl)cc1C[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(CNC[C@H](Cc2cc(Cl)ccc2OC)C(=O)O)c(OC)c1
Reaction time: 2 h

Procedure:
(2S)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propionic acid (10g) was dissolved in ethyl acetate (120 ml), then methane sulfonic acid (9.4 ml) was added at room temperature, and the resulting mixture was stirred at that temperature for 2 hours. To the reaction solution was added triethylamine (20.3 ml), and the mixture was stirred for 13 hours. Then 2,4,6-trimethoxybenzaldehyde (5.7 g) was added and the mixture was stirred for 30 minutes. Next, to the reaction solution, sodium triacetoxyborohydride (9.3 g) was added and the mixture was stirred for 2 hours. To the reaction solution, a 1N aqueous sodium hydroxide solution was added, and the layers were separated. The aqueous layer was extracted again with ethyl acetate. The organic layer was washed with a 1N aqueous sodium hydroxide solution, then the appeared precipitated crystals were collected by filtration and dried to obtain the title compound (11.5 g) as a colorless crystal.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])[NH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24]>CC(C)=O>[CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])[N:7]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:6]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)CCBr
Reactant: CCCCn1c(=O)cc(C)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCn1c(=O)cc(C)n(CCC(C)C)c1=O
Temperature: 23 °C
Yield: 91 %

Procedure:
To 5.0 g (27 mmol) of 3-butyl-6-methyluracil in 100 mL of acetone was added 14.9 g (108 mmol) of K2CO3 followed by 4.07 g (27 mmol) of 1-bromo-3-methyl butane. The resulting mixture was refluxed for 48 h. After cooling to 23° C., the reaction mixtyre was filtered and evaporated to give the 8.2 g (24 mmol, a 91% yield) of the title compound as a yellow oil. Yield 91%.; 1H NMR (300 MHz, CDCl3); δ 0.91-0.98 (m, 6H), 1.25 (s, 3H), 1.32-1.40 (m, 2H), 1.48-1.80 (m, 5H), 2.15 (s, 3H), 3.67-3.83 (m, 2H), 3.88-3.96 (m, 2H) 5.57 (s, 1H); IR (KBr, cm31 1): 3476w, 2958w, 2933w, 2872m, 1701s, 1538m, 1432m, 1364m; MS (ES) m/z (relative intensity): 253 (M+ +H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[O:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-:3])=[O:2].Br[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([O:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:6]=2)=[N:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: O=[N+]([O-])c1ccc(O)cc1OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OC3CCOCC3)c2)nc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
A mixture of 4-nitro-3-(tetrahydro-2H-pyran-4-yloxy)phenol (23.0 g), 2-bromo-5-(methylsulfonyl)pyridine (22.7 g), cesium carbonate (62.6 g), and N,N-dimethylformamide (200 mL) was stirred at 100° C. for 1.5 hr. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained solid was washed with diethyl ether-hexane to give the title compound (30.0 g, yield 81%) as a brown solid.
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[CH:30]([CH2:32][C:33]1[C:34](=[O:38])[CH2:35][CH2:36][CH:37]=1)=O.[OH-].[Na+]>CS(C)=O>[C:4]([CH2:7][CH2:8][CH2:9][CH2:10]/[CH:30]=[CH:32]\[C:33]1[C:34](=[O:38])[CH2:35][CH2:36][CH:37]=1)([OH:6])=[O:5]
Reactant: O=CCC1=CCCC1=O
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCCC/C=C\C1=CCCC1=O
Temperature: 0 °C

Procedure:
A mixture of 0.194 g. (0.007952 mole) of sodium hydride (free of mineral oil) and 5.5 ml. of dimethylsulfoxide is heated to 70° C. until gas evolution ceases under a nitrogen atmosphere. The resulting solution is cooled below room temperature and treated with a solution of 1.400 g. (0.00316 mole) of 4-carboxybutyltriphenyl phosphonium bromide [E. J. Corey et al., J. Am. Chem. Soc., 91, 5675 (1969)] in 6 ml. of dimethylsulfoxide. To the resulting red solution is added 0.00263 mole of 2-formylmethylcyclopent-2-en-1-one (Example 898) in 2 ml. of dimethylsulfoxide and the mixture is stirred at room temperature for 2.25 hours. The mixture is poured into ice water, sodium hydroxide solution is added to pH 12, and the neutral materials are extracted with diethyl ether. The basic phase is acidified with dilute hydrochloric acid and is extracted with diethyl ether. The organic phase is washed with water and saturated brine, dried (Na2SO4), and evaporated to a semicrystalline mass. The latter is triturated with hot hexane, the solids are filtered off, and the filtrate is evaporated to yield the subject product as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([S:27]([N:3]2[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[CH3:1])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1C
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(Cl)c2)c1C
Yield: 49.3 %

Procedure:
Using ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (1.53 g), sodium hydride (60% in oil, 303 mg) and 3-chlorobenzenesulfonyl chloride (848 mg), a procedure as in Reference Example 41 was performed to give the title compound as a brown oil (yield 800 mg, 30%).