Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([O:11]C)OC)[N:3]=1.C(OC(=O)[NH:19][C:20]([C:22]1[S:23][C:24]([S:37][CH3:38])=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32](Br)[CH:31]=2)(=[O:29])=[O:28])[CH:26]=1)=[NH:21])(C)(C)C.C([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1.[Zn].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>[CH:8]([C:4]1[N:3]=[C:2]([C:32]2[CH:31]=[C:30]([S:27]([C:25]3[CH:26]=[C:22]([C:20]([NH2:21])=[NH:19])[S:23][C:24]=3[S:37][CH3:38])(=[O:29])=[O:28])[CH:35]=[CH:34][CH:33]=2)[CH:7]=[CH:6][CH:5]=1)=[O:11]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: COC(OC)c1cccc(Br)n1
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: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2cccc(C=O)n2)c1
Temperature: 65 °C
Yield: 95.8 %

Procedure:
To a slurry of Rieke Zinc (370 mg, 5.64 mmol) in THF (7.4 mL) was added a solution of 2-bromo-6-dimethoxymethyl-pyridine (400 mg, 1.7 mmol) in THF (2.6 mL). The suspension was heated to 65° C. for 2 h and the solution was filtered through a 0.23 μm syringe filter into a THF solution of {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 27: step c) (250 mg, 0.5 mmol)) and Pd(PPh3)4 (0.112 mg, 0.1 mmol). The reaction was heated at 80° C. for 30 min, cooled, and was poured into aqueous NaHCO3. EtOAc (70 mL) was added and the layers were separated. The organic layer was washed with NH4Cl (2×20 mL), NaHCO3 (20 mL) and brine (30 mL) and was dried over sodium sulfate. Concentration of the solution followed by SiO2 flash column chromatography of the residue yielded 200 mg of the title compound which was contaminated with 2-dimethoxymethyl-pyridine. The material was treated with 1:1 TFA/DCM as described in Example 1: step d. Analogous purification by C18-HPLC yielded the title compound (118 mg, 38%) as a white solid. 1H-NMR (CD3OD) (aldehyde exists in hydrated form (acetal)) δ 8.60 (m, 2H), 8.44 (s, 1H), 8.33 (d, 1H, J=7.9), 8.27 (d, 1H, J=7.7), 8.23 (d, 1H, J=7.7), 8.12 (d, 1H, J=7.9), 7.9 (t, 1H, J=7.7), 5.82 (s, 1H), 2.74 (s, 3H). ESI-MS (m/z) (sample in MeOH): Calcd. for C18H15N3O3S3 (M+H): 418.0; found: 449.9 (MeOH adduct).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH:37]1[CH2:42][CH2:41][CH:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:39][CH2:38]1>C(O)CCC>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][C@H:37]3[CH2:42][CH2:41][C@H:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:39][CH2:38]3)[N:7]=2)=[C:9]([C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Solvent: CCCCO
Product: CC(C)(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(N[C@H]3CC[C@H](NS(C)(=O)=O)CC3)n2)s1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
N-{5-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (50 mg, 0.093 mmol) and N-(4-aminocyclohexyl)-methanesulfonamide (19.62 mg, 0.102 mmol) were dissolved in n-butanol (1 mL) and TEA (0.052 mL, 0.371 mmol) was added. The reaction was stirred in a closed vessel at 90° C. for 18 h. The reaction mixture was cooled to rt and solvent was removed. The residue was purified via Gilson Acidic HPLC (10 to 90% gradient, Acetonitrile/H2O+TFA; C18 column). Desired fractions were combined and solvent removed to give the title compound as a white solid (0.006 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.95 (s, 1H), 8.09 (d, J=5.0 Hz, 1H), 7.67-7.78 (m, 1H), 7.41 (d, J=3.5 Hz, 1H), 7.28 (q, J=8.7 Hz, 2H), 7.00 (dt, J=2.6, 1.3 Hz, 1H), 6.10-6.28 (m, 1H), 3.56-3.70 (m, 1H), 3.41-3.52 (m, 1H), 3.09 (td, J=4.2, 1.7 Hz, 1H), 2.92 (s, 3H), 1.83-1.98 (m, 4H), 1.21-1.50 (m, 13H). MS (ESI): 695 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[O:17][CH2:18][O:19][CH3:20])[CH:6]=[CH:7][CH:8]=1)=O.[CH3:21][NH:22][CH3:23].C([BH-](C(=O)C)C(=O)C)(=O)C>C(Cl)Cl>[CH3:21][N:22]([CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[O:17][CH2:18][O:19][CH3:20])[CH:6]=[CH:7][CH:8]=1)[CH3:23]
Reactant: COCOc1cc(C#N)ccc1-c1cccc(C=O)c1
Reactant: CNC
Agent: CC(=O)[BH-](C(C)=O)C(C)=O
Solvent: ClCCl
Product: COCOc1cc(C#N)ccc1-c1cccc(CN(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3′-Formyl-2-methoxymethoxy-biphenyl-4-carbonitrile (128 mg, 0.48 mmol) is dissolved in CH2Cl2 (5 mL), and to which dimethylamine (2 mL, 2 M solution in THF, 4 mmol) is added. Triacetylborohydride (300 mg, 1.59 mmol) is added and the mixture is stirred at room temperature for 1 hour before it is quenched with ice water. The organic layer is washed with NH4OH and dried over Na2SO4. After concentration, the residue is directly used in the next step. MS (ESI): 297 (M+1)+1.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[CH:9]([CH3:14])[NH:8][CH2:7][CH2:6]2.C(=O)(O)[O-].[Na+].[C:20](=O)([OH:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(OCC)(=O)C>O.O1CCOCC1>[C:22]([O:21][C:20]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([OH:13])=[C:3]([OH:2])[CH:4]=2)[CH:9]1[CH3:14])=[O:26])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)O
Reactant: CC1NCCc2cc(O)c(O)cc21
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC1c2cc(O)c(O)cc2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.3 %

Procedure:
6,7-Dihydroxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline monohydrobromide (510 mg, 2.9 mol) was dissolved in water (5 ml) and dioxane (5 ml), and the solution was mixed with sodium bicarbonate (410 mg, 4.9 mmol) and t-butyl bicarbonate (470 mg, 2.2 mmol) and stirred at room temperature for 2.5 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with dilute hydrochloric acid and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure and the thus obtained material was dried under a reduced pressure to obtain crude 2-t-butoxycarbonyl-6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline (610 mg). Crude 2-t-butoxycarbonyl-6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline (610 mg) was dissolved in anhydrous N,N-dimethylformamide (6 ml), and the solution was mixed with sodium hydride (60%, 170 mg, 4.1 mmol) and stirred at room temperature for 45 minutes. The reaction solution was mixed with methyl iodide (580 mg, 4.1 mmol) and again stirred for 1 hour. The reaction solution was mixed with ethyl acetate, washed with water and saturated brined and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 190 mg (0. 62 mmol, 32% in yield) of the title compound.
Reaction SMILES: C(OC([O:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:19]=2)=[O:16])=[CH:9][CH:8]=1)=O)C.N1C=CC=CC=1.[OH-].[NH4+].Cl>O.CC(C)=O>[OH:6][C:7]1[CH:8]=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:23]=2)=[O:16])=[CH:11][CH:12]=1
Reactant: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(OC(=O)OCC)cc2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(O)cc2)cc1
Yield: 96 %

Procedure:
7.65 g (23.45 mmol) 4-pentoxyphenyl (2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}acrylate, 70 ml pyridine and 40 ml acetone were mixed. A solution of 12.5 ml ammonium hydroxide 25% in water and 30 ml acetone were added dropwise. The reaction mixture was subsequently allowed to react for 18 h at 25° C. and acidified to pH=1 with hydrochloric acid 7 N. The product was filtered off, washed with water and dried under vacuum to give 7.35 g 4-pentoxyphenyl (2E)-3-{4-hydroxyphenyl}acrylate as colourless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[N:25][NH:24][C:23]2=[O:27])=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:24]1[C:23](=[O:27])[N:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[CH:26]=[N:25]1)[CH3:13]
Reactant: O=c1[nH]ncn1-c1ccc(F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(-c2ccc(F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 30 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.35 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 963 mg of 4-(4-fluorophenyl)-3(2H,4H)-1,2,4-triazolone, 583 mg of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-fluorophenyl)-3(2H,4H)-1,2,4-triazolone was obtained as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][CH:9]2[C:15]3=[N:16][C:17]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][N:22]=4)=[CH:18][C:19](=[O:20])[N:14]3[CH2:13][CH2:12][NH:11][CH2:10]2)=[O:7])=[C:4]([O:29][CH3:30])[CH:3]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CO.C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][CH:9]2[C:15]3=[N:16][C:17]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][N:22]=4)=[CH:18][C:19](=[O:20])[N:14]3[CH2:13][CH2:12][N:11]([CH3:33])[CH2:10]2)=[O:7])=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(=O)NC1CNCCn2c1nc(-c1ccncn1)cc2=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(Cl)ccc1C(=O)NC1CN(C)CCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 162.9 %

Procedure:
To a solution of 0.040 g (0.09 mmol) of (+/−)-4-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide in 1.9 ml of methanol was added 0.003 g (0.04 mmol) of paraformaldehyde, 0.022 g (0.10 mmol) of sodium triacetoxyborohydride and 40 μL (0.20 mmol) of hydrochloric acid (5-6N in isopropanol). The reaction mixture was stirred at room temperature for 12 hours. To the resulting mixture was added 0.006 g (0.07 mmol) of paraformaldehyde 0.042 g (0.20 mmol) of sodium triacetoxyborohydride and pH was adjusted to 6 with glacial acetic acid. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated; the residue was dissolved in dichloromethane, washed with a saturated aqueous solution of sodium carbonate, saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The free base was transformed into its hydrochloride salt to give 0.035 g of pure product.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:36][CH3:37])[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH2:35])[CH3:21].C(#N)C.N>ClCCl.C1CCCCC1.CO>[CH2:36]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH:35][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH3:37]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CCCCC1CCCCN1CCN
Agent: N
Solvent: CC#N
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCN(CC)CCCCC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 55 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[4-(diethylamino)butyl]-piperidin-1-yl]ethanamine in a yield of 55% of theory. Colourless crystals, m.p. 155°-157° C. (acetonitrile). RF 0.57 (Macherey-Nagel, PolygramRSIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 102/23/23/3 v/v).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13]([F:22])=[C:14]([F:21])[C:15]4[N:16]=[C:17]([CH3:20])[O:18][C:19]=4[C:11]=3[NH:10][C:9]2=[O:23])=[C:4]([F:24])[CH:3]=1.[CH:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1.[H-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13]([F:22])=[C:14]([F:21])[C:15]4[N:16]=[C:17]([CH3:20])[O:18][C:19]=4[C:11]=3[N:10]([S:28]([CH:25]3[CH2:27][CH2:26]3)(=[O:30])=[O:29])[C:9]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: Cc1nc2c(F)c(F)c3c([nH]c(=O)n3-c3ccc(Br)cc3F)c2o1
Reactant: O=S(=O)(Cl)C1CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc2c(F)c(F)c3c(c2o1)n(S(=O)(=O)C1CC1)c(=O)n3-c1ccc(Br)cc1F
Yield: 42.1 %

Procedure:
Intermediate I-26a was prepared from 6-(4-bromo-2-fluoro-phenyl)-4,5-difluoro-2-methyl-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-17a: 200 mg, 0.52 mmol), cyclopropanesulfonyl chloride (111 mg, 0.781 mmol) and NaH (31.2 mg, 0.781 mmol) using procedures analogous to those described above for Intermediate I-19a to afford 110 mg of the product (42.1% yield). H1NMR (CDCl3, 300 MHz): δ 7.52-7.39 (m, 3H), 3.35-3.24 (m, 1H), 2.72 (s, 3H), 1.75-1.60 (m, 2H), 1.35-1.25 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].Br[CH2:15][C:16]#[CH:17]>>[CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH2:17][C:16]#[CH:15])[C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: C#CCBr
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Product: C#CCn1c(C)c(C)c(C=O)c1C(=O)OC

Procedure:
The title compound was prepared as white crystals in 89.3% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-bromo-1-propyne.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:41][CH3:42])[CH2:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.C(=O)(O)[O-].[Na+]>Cl.C(OCC)(=O)C>[F:51][C:2]([F:1])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:47])([F:49])[F:48])[CH:45]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:41][CH3:42])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCN(CCC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCN(CCC(=O)O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-propionate (which is prepared by treating the corresponding starting compound in a same manner as in Example 12(1)-(4)) (205 mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (5 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-propionic acid (133 mg). MS (m/z): 680 [M+H]+
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18]>C(O)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: ClCCCBr
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(OCCCCl)cc1

Procedure:
To a solution of 41 g of potassium hydroxide in 250 ml of ethanol is added 50 g of p-hydroxyphenylacetic acid. To this solution is added 32 ml of 3-bromo-1-chloropropane and the mixture is refluxed for 4 hours. The mixture is cooled in an ice bath and filtered. The filtrate is acidified to pH 2 with concentrated HCl. Filtration gives a solid which is washed with water to give 68 g of product. Recrystallization from acetic acid water gives white crystals, mp 89°-91° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[CH:10][C:3]=12.Br[C:29]1[C:30]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:43])=[CH:37][CH:36]=2)=[N:31][N:32]([CH3:34])[CH:33]=1>>[CH:15]([C:14]1[CH:13]=[CH:12][C:11]([C:9]2[N:8]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:4]3=[N:5][CH:6]=[CH:7][C:2]([C:29]4[C:30]([C:35]5[CH:36]=[CH:37][C:38]([NH:41][C:42]([N:44]6[CH2:45][CH2:46][CH2:47][CH2:48]6)=[O:43])=[CH:39][CH:40]=5)=[N:31][N:32]([CH3:34])[CH:33]=4)=[C:3]3[CH:10]=2)=[CH:18][CH:17]=1)=[O:16]
Reactant: O=Cc1ccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: Cn1cc(Br)c(-c2ccc(NC(=O)N3CCCC3)cc2)n1
Product: Cn1cc(-c2ccnc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N3CCCC3)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 using 4-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]benzaldehyde and then following the procedure described for Intermediate 100 with N-[4-(4-bromo-1-methyl-1H-pyrazol-3-yl)phenyl]-1-pyrrolidinecarboxamide provided the title compound. ESMS [M+H]+: 631.4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[CH3:33][N:34](C)[C:35](=[O:45])[C@H:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH2:37]>O1CCCC1.CN(C)C=O>[CH3:33][NH:34][C:35](=[O:45])[C@H:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH:37][C:16]([C@H:13]1[CH2:12][CH2:11][C@H:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:15][CH2:14]1)=[O:18]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To the compounds (I) (19.15 g) was added dry 1,4-dioxane (50 ml) and 4N hydrogen chloride/1,4-dioxane solution (250 ml), and the mixture was stirred under room temperature for 2 hours. The solvent was removed under a reduced pressure and toluene was added and reevaporated to give L-phenylalanine 4-carbamoylanilide hydrochloride (II) quantitatively as a white powder. On the other hand, trans-4-(t-butoxycarbonylaminomethyl)cyclohexylcarboxylic acid (13.36 g) was dissolved in dry tetrahydrofuran (500 ml), and triethylamine (7.80 ml) was added under ice-cooling, followed by stirring at the same temperature for 10 minutes. Subsequently, a solution of ethyl chlorocarbonate (5.64 g) in dry tetrahydrofuran (50 ml) was added dropwise under ice-cooling for 3 minutes, and the mixture was again stirred at the same temperature for 20 minutes. The above mixture was added to the suspension of the hydrochloride (II) previously obtained and triethylamine (8.53 ml) in N,N-dimethylformamide (150 ml) under ice-cooling, followed by stirring at the same temperature for 2 hours, and under room temperature for 6 hours. Ice-water (1.4 liter) was added and the insolubles were collected by filtration, thoroughly washed with water, and further washed with 10% aqueous citric acid, water 5% aqueous sodium hydrogen carbonate, followed by washing with water at 40° to 50° C., and drying, to give N-[4-trans-(t-butoxycarbonylaminomethyl)cyclohexylcarbonyl]-L-phenylalanine 4-carbamoylanilide (III) (24.63 g). The structure was confirmed by NMR.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In 50 ml of ethanol was dissolved 1.6 g of p-(1-imidazolyl)phenol and 1.4 g of anhydrous potassium carbonate was added to the solution. While stirring, 2.1 g of ethyl α-bromoisobutyrate was dropwise added to the mixture. Thereafter stirring was continued for 20 hours under reflux. After cooling to room temperature, the solvent was removed from the reaction mixture in vaccuo. The residue was dissolved in methylene chloride. After the solution was successively washed with a 5% aqueous hydrogen sodium carbonate solution, water and a saturated aqueous sodium chloride solution, the solution was dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation under reduced pressure and the residue was subjected to silica gel column chromatography. The product was eluted out using chloroform-methanol (9:1) as an eluant. The solvent was removed from the eluate under reduced pressure to give the desired product, ethyl 2-[p-(1-imidazolyl)phenoxy]-2-methylpropionate, as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[I:17]I>CCCCCC.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([I:17])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: II
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
Following the procedures in U.S. Pat. No. 6,492,383, 2.5 M of n-Butylithium (9.4 mL, 22.48 mmol) in hexane solution was added to a mixture of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (3.0 g, 11.74 mmol) in 60 mL of THF at −78° C. The reaction mixture was allowed to warm to −40° C. and stirred for 30 min. A solution of iodine (6.0 g, 23.48 mmol) in 10 mL of THF was added dropwise. After the addition was completed. The reaction mixture was brought to room temperature and stirred for 2 h. The mixture was quenched by diluting with dichloromethane and extracting with H2O (2×100 mL). The organic layer was washed with Na2S2O3 (2×100 mL), H2O (2×100 mL), dried over MgSO4, filtered and evaporated to afford 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (3.4 g, 75%).