Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:13]=2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36]([C:2]3[CH:3]=[C:4]([C:12]4[CH:17]=[CH:16][N:15]=[C:14]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH:13]=4)[N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CN1CCN(c2cc(-c3cc(Br)c4c(N)ncnn34)ccn2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1CCN(c2cc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)ccn2)CC1
Temperature: 80 °C
Yield: 20.6 %

Procedure:
To a stirred solution of 5-bromo-7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (60 mg, 0.16 mmol), 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (103 mg, 0.31 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II) complex with dichloromethane (5.6 mg, 0.008 mmol) in degassed DME (1.2 mL) was added aqueous sodium carbonate solution (2 M, 232 □L). The reaction was heated (80° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and H2O (25 mL) and the layers were separated. The organic phase was washed with brine (25 mL), dried (Na2SO4), and concentrated. The crude material was purified by preparative HPLC using a gradient elution from 5% to 35% acetonitrile in water to obtain 17 mg (21%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.81-8.79 (m, 1 H), 8.58 (s, 1 H), 8.28-8.21 (s, 1 H), 7.98-7.94 (m, 1 H), 7.87-7.81 (m, 1 H), 7.68 (s, 1H), 7.41-7.29 (m, 5 H), 7.24-7.19 (m, 1H), 7.12-7.08 (m, 1 H), 6.97-6.91 (m, 1 H), 5.67 (s, 2 H), 3.58-3.52 (m, 4 H), 2.44-2.37 (m, 4 H), 2.22 (s, 3 H); ES-MS m/z 516.24 [M+H]+, HPLC RT (min) 2.28.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[NH:17][C:16]([CH:18]=[C:19]4[N:46]=[C:22]([C:23]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:42][CH2:43][CH2:44]O)[CH:36]=5)=[C:24]5[NH:34][C:27](=[CH:28][C:29]6[CH:30]=[CH:31][C:32]=2[N:33]=6)[CH:26]=[CH:25]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>C(Cl)Cl>[CH3:54][S:55]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[NH:17][C:16]([CH:18]=[C:19]4[N:46]=[C:22]([C:23]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:42][CH2:43][CH2:44][S:55]([CH3:54])(=[O:57])=[O:56])[CH:36]=5)=[C:24]5[NH:34][C:27](=[CH:28][C:29]6[CH:30]=[CH:31][C:32]=2[N:33]=6)[CH:26]=[CH:25]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=1)(=[O:57])=[O:56]
Reactant: OCCCOc1cccc(-c2c3nc(cc4ccc([nH]4)c(-c4cccc(OCCCO)c4)c4nc(cc5ccc2[nH]5)C=C4)C=C3)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCCOc1cccc(-c2c3nc(cc4ccc([nH]4)c(-c4cccc(OCCCS(C)(=O)=O)c4)c4nc(cc5ccc2[nH]5)C=C4)C=C3)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
To a solution of 5,15-bis-[3-(3-hydroxypropoxy)phenyl]porphyrin (30 mg, 0.049 mmol) in anhydrous CH2Cl2, under nitrogen atmosphere, at 0° C., triethylamine (29 mg mg, 0.29 mmol) and methansulphonylchloride (17 mg, 0.15 mmol) were added. The mixture was kept under magnetic stirring at 0° C. for 3 hours, then washed with NaHCO3 saturated solution and with water. The organic phase was dried under Na2SO4 and the solvent removed by evaporation. The crude product was purified by chromatography on silica gel (CHCl3), to obtain 17 mg of the pure title product (yield 45%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:11][C:12]([CH3:24])([CH3:23])[C:13](=O)[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:12]([CH3:11])([CH3:23])[CH3:24])=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=O)CC(=O)C(C)(C)C
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C(C)(C)C)n(-c2cccc(Br)c2)n1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A solution of 3-bromophenylhydrazine hydrochloride (0.5 g, 2.2 mmol) and ethyl 5,5-dimethyl-2,4-dioxohexanoate (0.54 g, 2.68 mmol) in acetic acid (10 ml) was refluxed for 16 hours. The reaction was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated bicarbonate and brine, and dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (4.8:0.2 hexanes/ethyl acetate) to give ethyl 1-(3-bromophenyl)-5-tert-butyl-1H-pyrazole-3-carboxylate (0.59 g, 74%) as a syrup.
Reaction SMILES: C(S)(=N)N.[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:11]([NH2:15])(=[O:14])[CH:12]=[CH2:13]>CCO>[N:5]1([CH2:13][CH2:12][C:11]([NH2:15])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C1CCNCC1
Reactant: C=CC(N)=O
Agent: N=C(N)S
Solvent: CCO
Product: NC(=O)CCN1CCCCC1
Yield: 75 %

Procedure:
Carbamimidothioic acid, N'-cyano-N-[3-[4-(diphenylmethylene)-1-piperidinyl]-propyl]-, methyl ester. A solution of piperidine, 4-(diphenylmethylene) (0.10 mole) and acrylamide (8.95 g, 0.062 mole) in EtOH (50 ml) was refluxed overnight. This reaction mixture was filtered and concentrated. The resulting while solid residue was dissolved in CHCl3, washed with H2O (3×150 ml), dried (Na2SO4) and the solvent removed to give thick yellow oil. Crystallization from CH2Cl2 -i-Pr2O afforded 29.01 g (75%) of 1-piperidinepropanamide, 4-(diphenylmethylene)-; mp 105°-7° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:7]=1.[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:6]1[CH:7]=[C:2]([C:34]2[CH:35]=[N:30][CH:31]=[N:32][CH:33]=2)[CH:3]=[CH:4][C:5]=1[F:29])[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2cc(Br)ccc2F)c2cccc(F)c21
Product: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2cc(-c3cncnc3)ccc2F)c2cccc(F)c21
Yield: 58 %

Procedure:
The title compound was synthesized as described for Example 1 in 58% yield, starting from 1-(5-bromo-2-fluorophenyl)-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine (59.0 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (17.17 mg, 0.14 mmol).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:27]([Br:28])=[CH:26][C:10]2[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:13][C:9]=2[CH:8]=1.N1C=CC=CC=1>ClCCl.O>[Br:28][C:27]1[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]=2[CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(Br)cc12
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
MsCl (31.7 g, 277.5 mmol) was added to a solution of ethyl 6-amino-5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (35 g, 92.5 mmol) and pyridine (60 mL) in dichloromethane (300 mL) at 0° C. After stirred overnight at room temperature, the mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo, the resulting residue was purified using crystallized with EtOAc to provide the pure product of ethyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylate (35 g, yield: 82%). 1H-NMR (CDCl3, 400 MHz) δ 8.27 (s, 1H), 8.01˜8.05 (m, 2H), 7.87 (s, 1H), 7.15˜7.19 (m, 2H), 6.87 (s, 1H), 4.38˜4.43 (m, 2H), 3.00 (s, 3H), 1.40 (t, J=40 Hz, 3H). MS (M+H)+: 456/458.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:35][CH2:34][C:33]1[N:29]([C:25]2[CH:24]=[C:23]([C:22]3[CH2:21][C:20](=[O:43])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:18])[F:17])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[N:30]=[N:31][CH:32]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-methyl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M46) (0.90 g, 1.46 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (400 mg, 66%).
Reaction SMILES: [C:1]([O:4]/[CH:5]=[CH:6]/[CH3:7])(=[O:3])[CH3:2].[CH3:8][N:9]([CH:11](N(C)C)OC(C)(C)C)[CH3:10]>>[CH3:8][N:9]([CH3:11])/[CH:10]=[CH:2]/[C:1]([O:4]/[CH:5]=[CH:6]/[CH3:7])=[O:3]
Reactant: C/C=C/OC(C)=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: C/C=C/OC(=O)/C=C/N(C)C
Yield: 90.9 %

Procedure:
A solution of 20.0 g (0.2 mole) of trans-propenyl acetate and 101.0 g (0.6 mole) of bis(dimethylamino)-tert.-butoxymethane under argon was heated at 50° C. overnight (161/2 hours). The excess reagent was removed by vacuum distillation (0.7 mmHg, oil bath at 50° C.). The residue was chromatographed rapidly on 300 g of silica gel 60 eluting with ethyl acetate/hexane (2:3 parts by volume) to give 28.2 g (91%) of trans-3-(dimethylamino)-2-propenoic acid, trans-propenyl ester which was used in the next step with no further purification. This material was sublimed (to remove yellow color) at 40°-50° C. 0.2 mmHg. The analytical sample was recrystallized from pentane. Mp 48°-48.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:31][CH:28]([CH3:30])[CH3:29])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Reactant: CC(C)N
Agent: [H-]
Agent: [Na+]
Product: CC(C)Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.41 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.58 mmol), and isopropylamine (0.14 mL, 1.65 mmol) are treated according to method E yielding the title product.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Br[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[O:24][CH:25]=1>>[CH:1]1([C:4]2[N:5]([CH2:20][C:21]3[N:22]=[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)[O:24][CH:25]=3)[C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Reactant: FC(F)(F)c1cccc(-c2nc(CBr)co2)c1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2coc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and 4-(bromomethyl)-2-[3-(trifluoromethyl)phenyl]-1,3-oxazole (synthesized similarly to Example 353): 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.16 (d, J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.58 (m, 3H), 7.34 (s, 1H), 6.45 (s, 1H), 5.49 (s, 2H), 2.02 (m, 1H), 1.11 (m, 2H), 0.88 (m, 2H); MS (ES) m/z 476 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][C:11]([CH3:13])=[CH2:12].N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:12][C:11]1([CH3:13])[C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[O:9][CH2:10]1
Reactant: C=C(C)COc1ccc(C)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(C)(C)CO2
Yield: 110.2 %

Procedure:
To a solution of 2-bromo-4-methyl-1-[(2-methyl-2-propenyl)oxy]benzene (5.0 g, 20.7 mmol) in toluene (100 ml) were added 2,2′-azobisisobutyronitrile (1.45 g, 8.8 mmol) and tri-n-butyltin hydride (8.34 ml, 31 mmol), and the mixture was heated under reflux overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0, 50:1) to give 3,3,5-trimethyl-2,3-dihydro-1-benzofuran (3.70 g, 100%) as a colorless transparent oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:66]=[CH:65][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH2:63][CH3:64])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:66]=[CH:65][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH2:63][CH3:64])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:46])([CH3:45])[CH3:47]
Reactant: CCOc1cccc(CCNCc2ccc(C(C)(C)C)cc2)c1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cccc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cccc3cc[nH]c23)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32.7 %

Procedure:
To a solution of 120 mg (0.74 mmol) of 1H-indole-7-carboxylic acid and 240 mg of TBTU (0.74 mmol) in 8 ml DMF, were added 0.64 ml (3.72 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 309 mg (0.94 mmol) of (4-tert-butyl-benzyl)-[2-(3-ethoxy-phenyl)-ethyl]-amine were added. After stirring for 4 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:4) to give 110 mg off-white foam (31%). MS (ISP) 455.7 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20](CC([O-])=O)=[CH:19][C:18]=2[CH3:27])=[CH:4][CH:3]=1.Cl.C[OH:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:36])=[CH:19][C:18]=2[CH3:27])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1cc(CC(=O)[O-])ccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Agent: Cl
Product: Cc1cc(O)ccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of [4-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyloxy]-3-methylphenyl]acetate (4.30 g), 37% hydrochloride (3 ml), and methanol (150 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, which was poured into a 10% aqueous solution of sodium hydrogen carbonate. The precipitated crystals were filtered, washed with pure water and air-dried to give crystals of 4-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyloxy]-3-methylphenol (3.90 g, 99%). Recrystallization from tetrahydrofuran-hexane gave colorless prisms (2.56 g, 65%). Melting point 175-176° C.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[N:11]([CH3:12])[C:10](=[O:13])[NH:9][C:8](=[O:14])[CH:7]=1.[N:15]([O-])=O.[Na+]>>[NH2:15][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[N:11]([CH3:12])[C:6]=1[NH2:5]
Reactant: O=N[O-]
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1c(N)c(N)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Glacial acetic acid (4.5 ml, 75 mmol) was added to a suspension of 6-amino-1-methyluracil (5.66 g, 50 mmol) in hot (100 ml). Sodium nitrite (4.14 g) was added in portions and the reaction mixture was stirred for 1 hour. The precipitate was collected by filtration, washed with water (75 ml) and then suspended in water (100 ml). The mixture was warmed to 50° C. and sodium dithionite (10 g) was added in portions keeping the temperature of the reaction between 50-55° C. The mixture was stirred at 50° C. for 1 hr and then cooled to room temperature and filtered. The solid was washed with water (2×25 ml), acetone (2×25 ml) and dried under vacuum to provide 5,6-diamino-1-methyluracil (5.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:23])[C:5]([N:12]2C(=O)C3=CC=CC=C3C2=O)=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2.O.NN>CS(C)=O>[NH2:12][C:5]1[C:4]([F:23])=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][O:10]2
Reactant: O=C1c2ccccc2C(=O)N1c1c(F)cc(Cl)c2c1CCCO2
Agent: NN
Solvent: CS(C)=O
Solvent: O
Product: Nc1c(F)cc(Cl)c2c1CCCO2
Temperature: 0 °C

Procedure:
To a solution of 10.05 g of 41D in 60 mL of DMSO was added 7.58 g of hydrazine hydrate. The mixture was heated to 65°-75° C. for 3 hours, cooled, and poured into ice-water. The mixture was extracted with 3 portions of ether. The ether layer was extracted with water, brine, and dried over MgSO4 to afford 5-amino-8-chloro-6-fluorochromane (41E) as a yellow oil which solidified on standing, m.p.: 47°-50° C.
Reaction SMILES: [C:1]1([P:11]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[P:18](OCC)OCC)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl[Si](C)(C)C>>[C:1]1([P:11]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[PH2:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(OCC)c1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: C[Si](C)(C)Cl
Agent: [Al+3]
Agent: [H-]
Product: Pc1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12

Procedure:
For example, 2-bromophenol (4) is reacted with trifluoromethanesulfonic anhydride to form 2-(trifluoromethanesulfonyl)oxy-bromobenzene (5), which is then reacted with di(1-naphthyl)phosphine in the presence of a palladium complex catalyst to obtain (2-bromophenyl)[di(1-naphthyl)]phosphine (6). Next, the compound (6) is reacted with diethyl chlorophosphite in the presence of n-butyllithium to obtain diethyl 2-[di(1-naphthyl)phosphino]phenylphosphonite (7). Then, the compound (7) is reduced with lithium aluminum hydride in the presence of chlorotrimethylsilane to form [2-[di(1-naphthyl)phosphino]phenylphosphine (8). Thereafter, in the presence of n-butyllithium, the compound is reacted with dimesylate of (2R,5R)-2,5-hexanediol producible, for example, according to the method described in a literature (Tetrahedron: Asymmetry, 1991, 2, 569), whereby the aimed (S,S)-Me-UCAP-(1-Nap) (3) can be produced in a high efficiency.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[C:7]2[N+:17]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:17][C:7]1[C:6]2[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]=1[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12]
Reactant: CON(C)C(=O)c1[nH]c2c(Cl)cccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CON(C)C(=O)c1[nH]c2c(Cl)cccc2c1N
Temperature: 50 °C
Yield: 75.4 %

Procedure:
To a solution of 7-chloro-2-[(N-methoxy-N-methylamino)carbonyl]-3-nitroindole (step 2, 420 mg, 1.5 mmol) in ethanol-water (2:1, 30 ml) was added iron powder (168 mg, 3 mmol) and ammonium chloride (160 mg, 3 mmol). The mixture was heated at 50° C. for 2 h, and then cooled to room temperature. After filtration through a pad of Celite, the filtrate was concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1:10˜1:1) to give 287 mg (75%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li]CCCC.CC([O-])(C)C.[K+].[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:45][CH3:46])=[C:27]([C:29]([CH3:44])([CH3:43])[CH2:30]/[C:31](=[N:36]/S(C(C)(C)C)=O)/[C:32]([F:35])([F:34])[F:33])[CH:28]=1>C(OCC)C.C1COCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:45][CH3:46])=[C:27]([C:29]([CH3:43])([CH3:44])[CH2:30][C:31]([NH2:36])([CH2:1][C:2]2[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:32]([F:35])([F:34])[F:33])[CH:28]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COc1ccc(F)cc1C(C)(C)C/C(=N/S(=O)C(C)(C)C)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(N)(Cc1cc2ccccc2[nH]1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 33 %

Procedure:
To a chilled (−78 C.) solution of 40 mg (0.30 mmol) of 2-methylindole in 3 mL of diethyl ether was added 0.56 mL (0.91 mmol) of a 1.6 M solution of n-BuLi in hexanes. The resulting orange solution was stirred for 5 min and treated with 0.60 mL (0.60 mmol) of a solution of 1 M solution of KOt-Bu in THF. The reaction was slowly warmed until a bright yellow precipitate formed. After 5 min, the reaction mixture was cooled to −78° C. and treated with 138 mg (0.362 mmol) of a solution of 2-methyl-propane-2-sulfinic acid [3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-but-(Z)-ylidene]-amide in 0.5 mL of diethyl ether. Next, the mixture was warmed to room temperature, quenched with aqueous ammonium chloride and extracted with EtOAc (3×). The combined organic layers were dried over (MgSO4), filtered and concentrated. The residue was dissolved in 2 mL of methanol, 3 drops of concentrated HCl were added and the reaction warmed at 75° C. in a sealed tube. After 1 h, the reaction was cooled to room temperature, concentrated in vacuo, neutralized with aqueous sodium bicarbonate and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered and concentrated to leave an oil. The residue was purified by preparative thin layer chromatography eluting with toluene to afford an oil that had to be further purified by preparative thin layer chromatography eluting with hexanes-EtOAc (9:1) to afford 40 mg (33%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][CH2:20]Cl)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].Cl>C(N(CC)CC)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][CH2:20][N:5]2[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(CCCl)cc1OC
Reactant: OCC1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN2CCCC(CO)C2)cc1OC
Yield: 38.1 %

Procedure:
A mixture of 5.75 g of 3-(hydroxymethyl)piperidine, 13.8 ml of triethylamine and 10 g of 2-(3,4-dimethoxyphenyl)-ethyl chloride was heated under reflux for 4 hours. After the reaction mixture had cooled, it was acidified with about 30 ml of aqueous 2N hydrochloric acid solution, and unreacted 2-(3,4-dimethoxyphenyl)-ethyl chloride was separated by extraction with tert-butyl methyl ether. The aqueous phase was then rendered alkaline by addition of sodium hydroxide solution and was extracted with dichloromethane. The organic phase was separated, dried and concentrated. 5.3 g of N-[2-(3,4-dimethoxyphenyl)-ethyl]-3-(hydroxymethyl)-piperidine were obtained.