Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:19](=[O:22])[CH2:20][CH3:21])[C:15](=[O:18])[CH2:16][CH3:17])=[CH:4][CH:3]=1.[CH2:23]([O:25][CH2:26][CH2:27]Br)[CH3:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:23]([O:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:15](=[O:18])[CH2:16][CH3:17])[C:19](=[O:22])[CH2:20][CH3:21])=[CH:6][CH:7]=1)[CH3:24]
Reactant: CCC(=O)C(CCCCCCc1ccc(O)cc1)C(=O)CC
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCCOc1ccc(CCCCCCC(C(=O)CC)C(=O)CC)cc1
Reaction time: 72 h

Procedure:
A mixture of 3.9 g. of 4-[6-(4-hydroxyphenyl)hexyl]3,5-heptanedione, 12 g. of 2-bromoethyl ethyl ether, 4 g. of potassium carbonate and 1 g. of potassium iodide in 40 ml. of acetone was heated at reflux for 48 hours and then allowed to stand at room temperature for three days. The reaction mixture was then filtered and concentrated to remove the solvent. The residue was distilled at 200°-205° C. (0.001 mm.) to give 4-{6-[4-(2-ethoxyethoxy)phenyl]hexyl}-3,5-heptanedione as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][N:18]1[N:22]=[N:21][C:20]([NH2:23])=[N:19]1.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:23][C:20]1[N:21]=[N:22][N:18]([CH3:17])[N:19]=1
Reactant: Cn1nnc(N)n1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)benzaldehyde (4 g, 16.5 mmol), 2-methyl-2H-tetrazol-5-amine (1.96 g, 19.8 mmol) and molecular sieves (5-10 Å beads) in toluene (50 mL) was heated at reflux for 4 hours, after which time the solvent was removed. Ethanol (50 mL) and sodium borohydride (1.25 g, 33 mmol) were added. The resulting mixture was stirred at room temperature for 30 minutes and then partitioned between saturated NH4Cl (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (4.7 g). 1H NMR (400 MHz, CDCl3) δ 4.2 (s, 3H) 4.7 (s, 1H) 4.7 (s, 1H) 5.0 (t, J=6.0 Hz, 1H) 7.8 (s, 1H) 7.9 (s, 2H). MS (ES+) Calc: 325.08, Found: 325.8 (M+1).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8](OC2C=C3C(=CC=2)N=C(C)C=C3C(F)(F)F)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([OH:38])[CH:32]=[CH:31]2.O=O>>[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([O:38][CH:8]1[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1)[CH:32]=[CH:31]2
Reactant: Cc1cc(C(F)(F)F)c2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reactant: Oc1ccc2cc(Br)ccc2n1
Agent: O=O
Product: CC(C)(C)C1CCC(Oc2ccc3cc(Br)ccc3n2)CC1

Procedure:
Synthesized as per 6-(trans-4-tert-Butyl-cyclohexyloxy)-2-methyl-4-trifluoromethyl-quinoline using 6-Bromo-quinolin-2-ol as starting material. Alkylation was confirmed to be on the oxygen by 2D NMR (HMQC) of the subsequent intermediate. ESI-MS(M+H+): 362.1/364.10).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[Br:13]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.S(=O)(=O)(O)O>[Br:13][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
A solution of 3-nitrobenzoic acid (16.7 g, 100 mmol) in trifluoroacetic acid (50 mL) and sulfuric acid (20 mL) at 50° C. N-Bromosuccinimide (26.7 g, 150 mmol) was added in three portions over 3 hours. The mixture was stirred for 16 hours and then cooled to room temperature. The mixture was poured into ice water (200 mL) and extracted three times with ethyl acetate. The combined organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The residue was recrystallized from dichloromethane to provide a white solid (17.7 g, 72%). 1H NMR (300 MHz, DMSO-d6) δ13.8 (bs, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 8.37 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(Nc2cc(Cl)nc(N)n2)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
A mixture of 4,6-dichloro-pyrimidin-2-yl-amine (3.3 g, 20 mmol), p-tolylamine (3.4 g, 32 mmol) and N,N-diisopropylethylamine (12 ml) in ethanol (150 ml) was heated under reflux for 40 hours. After cooling to room temperature, filtration provided 6-chloro-N*4*-p-tolyl-pyrimidine-2,4-diamine (2.8 g, 60% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][OH:11]>CCO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:10][OH:11])[NH2:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ccc(Cl)cc1
Yield: 76.2 %

Procedure:
A solution of 4-chlorobenzonitrile (1 g, 7.23 mmol) and hydroxylamine (50% in water, 0.67 cm3, 10.9 mmol, 1.5 eq) in EtOH (12.5 cm3) was stirred under reflux for 48 hours. The solvent was removed under reduced pressure and the residue was washed with CH2Cl2 (10 cm3) to give the product 4-chloro-N′-hydroxybenzimidamide (0.94 g, 76%) as a white solid, mp 133-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@@H:7]([CH3:18])[CH2:6][NH:5]2.N1C=CC=CC=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:28]([CH:25]1[CH2:27][CH2:26]1)=[O:29]
Reactant: O=C(Cl)C1CC1
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CN(C(=O)C2CC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
A 250-mL, three-necked, round bottomed flask fitted with a nitrogen inlet, magnetic stir bar, and thermocouple was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-2,2,2-trifluoroethanone (7.0 g, 21.66 mmol), dichloromethane (140 mL), and pyridine (2.63 mL, 32.5 mmol). The mixture was cooled to 0° C. and cyclopropanecarbonyl chloride (2.36 mL, 26.0 mmol) was slowly added while maintaining the internal temperature below 7° C. The reaction mixture was stirred cold for 30 min. and then warmed to rt. The reaction mixture was washed with 1 M aqueous HCl solution (25 mL) and water (25 mL), and the combined organic layers were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 4:1 hexanes-ethyl acetate) to afford (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (8.26 g, 97%) as an off-white solid. MS (ESI, pos. ion) m/z 392 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]([O:12]C)=[O:11])=[CH:6][N:5]2[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[OH-].[Li+].C1COCC1>O>[NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][N:5]2[C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc2nc(N)c(-c3ccccc3)n2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2ccc(C(=O)O)cn2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.2 %

Procedure:
The 2-amino-3-phenyl-6-(carbomethoxy)imidazo-[1,2-a]-pyridine (83.9 g, 0.314 mol), lithium hyroxide monohydrate (65.9 g, 1.57 mol), 1113 ml of THF, and 371 ml of H2O were combined and stirred for 18 hours at RT. The reaction was concentrated in vacuo and the residue taken up in 5 L of H2O. The pH was adjusted to 5 with 5N HCl. The resulting precipitate was filtered and air dried for 72 hours to give 80.5 g of product. (quant. yeild). NMR, MS(FD).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:12])[C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:12][N:4]1[C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=[C:3]1[CH2:2][O:1][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2cncnc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cncnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.37 g of 2-hydroxymethyl-3-methylimidazo[5,4-d]pyrimidine (prepared as described in Preparation 50), 2.51 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4 dione, 1.34 ml of tributylphosphine, 1.36 g of 1,1'-(azodicarbonyl)dipiperidine and 50 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in a ratio of 2:1 by volume, and then in ratios ranging from 1:1 to 1:2 by volume, and subsequently a 6:1 by volume mixture of ethyl acetate and ethanol as the eluent. The desired fractions were collected and concentrated by evaporation under reduced pressure. The concentrate was further purified by preparative reverse-phase high speed liquid chromatography through YMC-Pack ODS-A (a product of YMC Inc.) using a 100:100:1:1 by volume mixture of acetonitrile, water, acetic acid and triethylamine as the eluent, to give 0.24 g of the title compound, melting at 55-65° C. (softening).
Reaction SMILES: C1N(P(N2CC2)(NC(C2C(I)=CC=CC=2)=O)=O)C1.[CH3:19][N:20]([CH3:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][CH:23]=1.I[C:32]1[C:40]2[C:35](=[CH:36][C:37]([CH:41]=[O:42])=[CH:38][CH:39]=2)[N:34]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[N:33]=1>>[CH3:19][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:32]2[C:40]3[C:35](=[CH:36][C:37]([CH:41]=[O:42])=[CH:38][CH:39]=3)[N:34]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[N:33]=2)=[CH:24][CH:23]=1)[CH3:30]
Reactant: C=Cc1ccc(CN(C)C)cc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Agent: O=C(NP(=O)(N1CC1)N1CC1)c1ccccc1I
Product: CN(C)Cc1ccc(/C=C/c2nn(COCC[Si](C)(C)C)c3cc(C=O)ccc23)cc1

Procedure:
The title compound was synthesized according to the method of Example A103, utilizing N,N-dimethyl-1-(4-vinylphenyl)methanamine (42 mg, 0.26 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (70 mg, 0.17 mmol). Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a pale orange gum (33.4 mg, 44%). 1H NMR (400 MHz, CD3OD) δ ppm 10.13 (s, 1H), 8.27 (m, 2H), 7.81 (d, J=9.29 Hz, 1H), 7.69 (d, J=8.28 Hz, 2H), 7.61 (d, J=16.6 Hz, 1H), 7.50 (d, J=16.6 Hz, 1H), 7.43 (d, J=8.28 Hz, 2H), 5.86 (s, 2H), 3.82 (s, 2H), 3.62 (t, J=8.03 Hz, 1H), 2.50 (s, 6H), 0.87 (t, J=8.03 Hz, 2H), −0.09 (s, 9H); MS ESI 436.3 [M+H]+, calcd for [C25H33N3O2Si+H]+ 436.6.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCCC4)c23)C1
Temperature: 160 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide (205 mg, 0.629 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butyl piperidin-3-ylcarbamate (629 mg, 3.14 mmol) and stirred at 160° C. for 18 hours in a sealed tube. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (50 mL) and washed with water (2×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-80% CH3CN/water gradient; 25 CV) to yield a solid, which was crystallized from CH3CN to provide (R)-tert-butyl 1-(5-bromo-3-(cyclopentane carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (70 mg, 22% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.56 (s, 1H), 9.36 (s, 1H), 8.14 (s, 1H), 7.64 (br s, 1H), 6.90 (br s, 1H), 3.56-3.47 (m, 1H), 3.20-3.11 (m, 2H), 3.04-2.97 (m, 1H), 2.81-2.74 (m, 1H), 1.91-1.80 (m, 4H), 1.78-1.70 (m, 3H), 1.67-1.59 (m, 3H), 1.55-1.50 (m, 2H), 1.42-1.34 (m, 1H); LCMS (APCI+) m/z 407.9 [(M-Boc)+H]+, Retention time=4.03 minutes (Method 2).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>CC#N>[O:19]([CH2:18][CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1
Yield: 79.5 %

Procedure:
To a stirred suspension of 4-hydroxybenzaldehyde (0.500 g, 4.012 mmol) and anhydrous potassium carbonate (0.833 g, 6.019 mmol) in dry MeCN (15 ml) at room temperature was added 2-bromo-1-tert-butyldimethylsiloxyethane (83%, 1.730 g, 6.019 mmol), and the reaction mixture was heated under reflux for 20.5 h. Water (25 ml) was added and the reaction mixture was extracted with Et2O (4×25 ml). The combined organic extracts were washed with brine (50 ml), dried (Na2SO4), and the solvent was removed under reduced pressure to give a pale yellow oil that was purified by flash chromatography (3:1 Hexane/Et2O) to give the title compound (0.895 g, 79.5%) as a colourless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:14])=[CH:8]2.C[N:16](C=O)C>>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([NH2:16])[C:9]([CH3:14])=[CH:8]2
Reactant: COc1ccc2[nH]c(C)cc2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)cc(C)n2N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (1.25 g, 51 mmol, 60% in mineral oil) in DMF (47 mL) at 0° C. is treated with 5-methoxy-2-methylindole (500 mg, 3.1 mmol) and stirred at 0° C. for 0.5 h. The mixture is treated with HOSA (1.92 g, 17.0 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 5-methoxy-2-methyl-indol-1-ylamine, which is used in the next step without further purification.
Reaction SMILES: ClC1C2C(=CC(C(O)(C3[N:17]=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3)C(C)C)=CC=2)C=CC=1C(OC)=O.[Cl:45][C:46]1[C:55]2[C:50](=[CH:51][C:52]([C:56]([OH:84])([C:60]3[N:61]=[CH:62][N:63](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:64]=3)[CH:57]([CH3:59])[CH3:58])=[CH:53][CH:54]=2)[CH:49]=[CH:48][C:47]=1[C:85](O)=[O:86].[NH4+].ON1C2C=CC=CC=2N=N1>>[Cl:45][C:46]1[C:55]2[C:50](=[CH:51][C:52]([C:56]([OH:84])([C:60]3[N:61]=[CH:62][NH:63][CH:64]=3)[CH:57]([CH3:59])[CH3:58])=[CH:53][CH:54]=2)[CH:49]=[CH:48][C:47]=1[C:85]([NH2:17])=[O:86]
Reactant: CC(C)C(O)(c1ccc2c(Cl)c(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Product: CC(C)C(O)(c1ccc2c(Cl)c(C(N)=O)ccc2c1)c1c[nH]cn1

Procedure:
In a manner to that described in Example 9-(i), methyl 1-chloro-6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.83 g) was converted to 1-chloro-6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with 1-hydroxybenzotriazole ammonium salt (533 mg) in a similar manner as described in Example 24-(i) to give the titled compound (904 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:40])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:41]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:40][C:3]1[C:2]2[N:1]=[CH:41][N:12]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:17][CH2:16]3)[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CCOC([O-])[O-]
Reactant: Nc1c(Cl)nc2ccccc2c1NCCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1nc2ccccc2c2c1ncn2CCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
A solution of 19.9 g of 3-amino-2-chloro-4-[2-(N-triphenylmethyl-4-piperidyl)-ethylamino]quinoline, 24.1 ml of ethyl orthoformate and 0.68 g of p-toluenesulfonic acid monohydrate in 200 ml of toluene was refluxed for 6 hours. After cooling, the precipitated crystals were collected by filtration, and washed with diisopropyl ether to give 16.4 g of colorless crystals. Recrystallization from a mixture of methanol and tetrahydrofuran gave colorless crystals having the melting point of from 229 to 234.5° C. (decomposition).
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([OH:13])[CH:5]=1.[CH3:14]N(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: CN(C)C=O
Reactant: CC(=O)c1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1cc(Br)ccc1C(C)=O
Temperature: 25 °C

Procedure:
Iodomethane (11.2 mL) was added to a mixture of compound 6b (32.6 g), DMF (100 mL), and potassium carbonate (62.5 g) at 0° C. The mixture was stirred and allowed to warm to RT over 2 hr. Water (200 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to afford 1-(4-bromo-2-methoxyphenyl)-1-ethanone (compound 6c, 33.1 g) as a tan solid.
Reaction SMILES: Cl[CH2:2][S:3][CH3:4].[C:5]1([C:11]2[NH:16][C:15](=[S:17])[NH:14][C:13](=[O:18])[C:12]=2[CH3:19])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:4][S:3][CH2:2][N:16]1[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[C:12]([CH3:19])[C:13](=[O:18])[NH:14][C:15]1=[S:17]
Reactant: Cc1c(-c2ccccc2)[nH]c(=S)[nH]c1=O
Reactant: CSCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSCn1c(-c2ccccc2)c(C)c(=O)[nH]c1=S
Yield: 8.1 %

Procedure:
To 4 ml of dimethylformamide, 0.17 ml (2.0 mmol) of chloromethylmethylsulfide, 0.47 g (2.0 mmol) of 6-phenylthiothymine, 0.56 ml (2.0 mmol) of triethylamine were added and allowed to react for 22 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was adsorbed on a silica gel column and eluted with chloroform. The eluate was concentrated and crystallized from ethyl acetate to obtain 45 mg of the target compound (Yield: 8%).
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@@H:8]([C:12]([OH:14])=O)[CH:9]([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@H:49]([NH2:51])[CH3:50])[S:48][C:44]=2[CH:43]=1>C1(C)C=CC=CC=1>[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@H:49]([NH:51][C:12]([C@H:8]([NH:7][C:5](=[O:6])[O:4][CH:1]([CH3:2])[CH3:3])[CH:9]([CH3:10])[CH3:11])=[O:14])[CH3:50])[S:48][C:44]=2[CH:43]=1
Reactant: CC(C)OC(=O)N[C@@H](C(=O)O)C(C)C
Reactant: C[C@@H](N)c1nc2ccc(F)cc2s1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N[C@@H](C(=O)N[C@H](C)c1nc2ccc(F)cc2s1)C(C)C
Yield: 60.8 %

Procedure:
In 500 ml of toluene, 10.2 g (0.05 mol) of N-isopropoxycarbonyl-D-valine was dissolved. Thereto were dropwise added, at −5° C., 12.4 g (0.0125 mol) of N-methylmorpholine and 6.8 g (0.05 mol) of isobutyl chlorocarbonate. Thereto was added, at −5° C., 18.3 g (0.05 mol) of (R)-1-(6-fluoro-2-benzothiazolyl)ethylamine p-toluenesulfonate. A reaction and a post-treatment were conducted in the same manner as in Reference Example 1, and the suspension of a solid in toluene was filtered to collect the solid. The solid was subjected to Soxhlet extraction for 1 week, and the extract was concentrated to obtain a solid. The solid was recrystallized from xylene to obtain 11.6 g (yield: 62.7%) of isopropyl {(R)-1-[(R)-1-(6-fluorobenzothiazol-2-yl)ethylcarbamoyl]-2-methylpropyl}carbamate. The compound obtained was confirmed for the structure by IR analysis and NMR analysis in comparison with its authentic material and identified.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:15]=1[C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)[CH3:13]>>[CH2:12]([C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:15]=1[C:26]1[N:27]=[CH:28][N:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH:30]=1)[CH3:13]
Reactant: CCc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: CCc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Yield: 33 %

Procedure:
As described for 1f, 1-fluoro-4-trifluoromethyl-benzene was converted, using 5-ethyl-3-(4-fluoro-phenyl)-4-(1H-imidazole-4-yl)-isoxazole (100 mg, 0.39 mmol) instead of 4-(1H-imidazol-4-yl)-3-phenyl-isoxazole was converted to the title compound (52 mg, 33%) which was obtained as an off-white solid. MS: m/e=402.1 [M+H]+.