Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1(C)[CH:15]=CC=C[CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O-]Cl.[Na+]>O>[CH2:1]([OH:9])[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:10]([CH3:15])[CH3:11]
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: CC(C)CCCCCCCO
Temperature: 100 °C
Yield: 98.3 %

Procedure:
2 moles); benzoic acid (250 grams; 2.05 moles), toluene (100 ml) and para toluene sulfonic acid (2 grams) were placed into a glass reaction flask equipped with stirrer, thermometer, heating mantle, 12" column packed with 1/4" glass rings, Dean-Stark water trap, and condenser. The temperature increased from 26° C. to 187° C. as the reaction proceeded with stirring Then the reaction mixture was cooled to 100° C. Soda ash (100 ml; 20% solution) was added to the mixture and was followed by the addition of a mixture of soda ash (50 ml; 20% solution) and chlorox (100 ml) at 81°-100° C. The alkaline bottom layer was separated from the mixture. After the mixture was dried, the toluene was removed by heating the mixture to 178° C. at 45 mmHg. The desired product (515 grams) was obtained after filtration, representing a yield of 98.3%.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:17][C:18]1[CH:19]=[C:20]([CH2:26][C:27](O)=[O:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[C:27](=[O:28])[CH2:26][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([OH:17])[CH:19]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(CNC2CCN(C)CC2)cc1
Reactant: COc1ccc(CC(=O)O)cc1O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C)CC2)cc1O
Reaction time: 1 h
Yield: 280 %

Procedure:
N-((4-methylphenyl)methyl)-4-amino-1-methylpiperidine (50ELH25) (105 mg, 0.48 mmol) and 3-hydroxy-4-methoxyphenylacetic acid (88 mg, 0.48 mmol) were dissolved in DMF (10 ml). Diisopropylethylamine (DIEA, 250 μL, 1.44 mmol) was added followed by bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 336 mg, 0.72 mmol), and the mixture was stirred at r.t for 1 h. Water (50 mL) was added, and the reaction mixture was extracted with EtOAc (2×50 mL). Drying by Na2SO4 and concentration yielded 514 mg crude material, which was purified by flash chromatography (0-30% MeOH in CH2Cl2). This gave 105 mg (57%) of the title compound as a white solid. Rf=0.20 (10% MeOH in CH2Cl2). HPLC-MS (method A) showed MH+=383. UV/MS(%)=100/92. 1H-NMR (400 MHz, CD3OD, Rotamers 52:48): δ 7.18-6.58 (m, 7H), 4.53 (s, 2H), 4.31 and 3.97 (2m, 1H), 3.82 and 3.81 (2s, 3H), 3.80 and 3.55 (2s, 2H), 3.04 and 2.85 (2m, 2H), 2.41 and 2.32 (2s, 3H), 2.35 and 2.12 (2m, 2H), 2.29 and 2.27 (2s, 3H), 1.83 and 1.74 (2m, 2H), 1.72 and 1.33 (2m, 2H)
Reaction SMILES: [CH:1]([O:4]C(C)C)(C)[CH3:2].[C:8]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)(=[O:11])[CH:9]=[CH2:10].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:8]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:1](=[O:4])[CH3:2])=[CH:18][CH:19]=1)(=[O:11])[CH:9]=[CH2:10]
Reactant: CC(C)OC(C)C
Reactant: C=CC(=O)OCc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: C=CC(=O)OCc1ccc(OC(C)=O)cc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
1400 g of isopropyl ether, 100 g of 4-hydroxybenzyl acrylate and 53 g of pyridine were charged into a separable flask of the same type as used in Reference Example 1, and the flask inside gas was replaced with a nitrogen gas over 30 minutes, while ice cooling the flask. Then, 125 g of acetic anhydride was dropwise added thereto at 3° C. over 2 hours, and stirring was continued at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed with 0.5N hydrochloric acid and then with water. By distilling off isopropyl ether from the reaction mixture, 113 g of 4-acetoxybenzyl acrylate of the following chemical formula was obtained (yield:91%): ##STR12##
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P>CC(C)=O.C(Cl)C=CC1C=CC=CC=1.[Pd]>[C:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:2][C:1](=[O:8])[CH3:9])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: P
Solvent: CC(C)=O
Product: CC(=O)Cc1ccc(C(=O)c2ccccc2)cc1
Yield: 163.8 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are 4-Benzoylphenyl chloride (216.3 mg, 1.0 mmol), palladium cinnamyl chloride (7.8 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino) henyldicyclohexyl)phosphine (24.5 mg, 0.060 mmol), Cs2OC3 (651.5 mg, 2.0 mmol) in 4.0 mL acetone at 90° C. for 12 h. 1-(4′-Benzoylphenyl)-2-propanone (195.2 mg) was obtained with a yield of 82% as liquid. 1H NMR (300 MHz, CDCl3) δ 7.83-7.75 (m, 4H, ArH), 7.62-7.54 (m, 1H, ArH), 7.52-7.43 (m, 2H, ArH), 7.35-7.28 (m, 2H, ArH), 3.81 (s, 2H, CH2), 2.22 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 205.1, 196.1, 138.8, 137.4, 136.1, 132.3, 130.3, 129.8, 129.3, 128.1, 50.5, 29.5; IR (neat) v (cm−1) 3059, 3003, 2917, 1715, 1660, 1651, 1606, 1579, 1447, 1416, 1358, 1317, 1278, 1227, 1178, 1159, 1113, 1075, 1020, 1001; MS (70 eV, EI) m/z (%): 239 (M++1, 0.98), 238 (M+, 5.45), 196 (100).
Reaction SMILES: O1CCCC1.Cl[C:7]1[N:12]=[C:11]([Cl:13])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29]2)=[CH:24][CH:23]=1>C(OCC)(=O)C.O>[Cl:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]([NH:33][C@@H:30]2[CH2:31][CH2:32][N:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[CH2:29]2)[N:12]=1
Reactant: N[C@@H]1CCN(c2ccc(F)cc2)C1
Reactant: Clc1ncnc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(N2CC[C@@H](Nc3ncnc(Cl)n3)C2)cc1

Procedure:
To a tetrahydrofuran solution (2.0 mL)-water (0.80 mL) solution of 2,4-dichloro-1,3,5-triazine (166 mg, 1.11 mmol) and sodium carbonate (141 mg, 1.33 mmol), (R)-1-(4-fluorophenyl)pyrrolidin-3-amine hydrochloride (200 mg, 1.11 mmol) synthesized in Reference Synthesis Example 30 was added at 0° C. and the resultant mixture was stirred for 3 hours. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.ClCCCl.CC(O)(C)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[C:25]([CH3:42])[CH:24]=1.CCN(CC)CC>CO.[Cl-].[Zn+2].[Cl-]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:31][CH2:30]3)=[C:25]([CH3:42])[CH:24]=2)[N:7]=1
Reactant: Cc1cc(N)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: Cc1cc(Nc2ncc(C(F)(F)F)c(Cl)n2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Zinc(II) chloride (1.0 M in Et2O; 0.661 mL, 0.661 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.132 g, 0.606 mmol) in 1:1 DCE/t-BuOH (5 mL) at 0° C. under nitrogen. The resulting mixture was stirred for 1 hour at 0° C. then tert-butyl 4-(4-amino-2-methylphenyl)piperidine-1-carboxylate (A39) (0.160 g, 0.551 mmol) in 1:1 DCE/t-BuOH (5 mL) was added. A solution of Et3N (840 μL, 0.606 mmol) in 1:1 DCE/t-BuOH (5 mL) at 0° C. was then added and the resulting mixture was vigorously stirred for a further 30 minutes at 0° C. then at room temperature for 16 hours. The volatiles were removed in vacuo to afford a brown residue which was purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to yield a pale yellow solid. The solid was suspended in MeOH (10 mL) and water (10 mL) and the resulting suspension filtered to give the title compound A40 as a white solid (0.231 g, 89%); 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.27 (brs, 1H), 7.24 (d, J=2.3 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.32-4.04 (m, 2H), 2.79-2.73 (m, 3H), 2.30 (s, 3H), 1.67 (d, J=13.0 Hz, 2H), 1.62-1.45 (m, obscured), 1.42 (s, 9H). LCMS-A: rt 6.895 min; m/z 469.1 [M−H]−.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:21][CH:22]2[CH2:25][CH:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:23]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=2[N:7]=1.[CH3:34][N:35]1[CH:39]=[C:38]([NH2:40])[CH:37]=[N:36]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O1CCOCC1>[C:11]([C:10]1[C:5]2[C:4]([O:21][CH:22]3[CH2:25][CH:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:23]3)=[N:3][C:2]([NH:40][C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)=[N:7][C:6]=2[N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=1)#[N:12]
Reactant: CC(C)(C)OC(=O)NC1CC(Oc2nc(Cl)nc3c2c(C#N)cn3COCC[Si](C)(C)C)C1
Reactant: Cn1cc(N)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Nc2nc(OC3CC(NC(=O)OC(C)(C)C)C3)c3c(C#N)cn(COCC[Si](C)(C)C)c3n2)cn1
Temperature: 140 °C
Yield: 86.5 %

Procedure:
To a microwave reaction vial was added tert-butyl {3-[(2-chloro-5-cyano-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}carbamate (508 mg, 1.0 mmol), 1-methyl-1H-pyrazol-4-amine (110 mg, 1.1 mmol), 1,4-dioxane (10 mL), Cs2CO3 (670 mg, 2.1 mmol, 2 mol eq), Xantphos (62 mg, 0.1 mmol) and Pd2(dba)3 (94 mg, 0.1 mmol). The reaction vial was flushed with nitrogen, capped, stirred and heated to 140° C. in a Biotage microwave reactor for 1 hr and 45 min. The reaction was diluted with EtOAc (120 mL) and water (20 mL). The organic layer was separated, washed with water (20 mL), brine (10 mL), and dried over Na2SO4. After concentrating the extract to dryness, the product was purified via flash chromatography eluting with a gradient of 0%-60% EtOAc in heptanes to afford the title compound (480 mg, 84 yield) as a light yellow solid. 1:1 cis:trans mixture: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.42 (s, 1H) 8.11 (s, 1H) 7.96 (br. s., 1H) 7.49-7.60 (m, 1H) 7.20-7.46 (m, 1H) 5.53 (br. s., 2H) 4.11-5.13 (m, 1H) 3.82 (s, 3H) 3.56 (t, J=7.55 Hz, 2H) 2.83 (d, J=6.80 Hz, 1H) 2.39-2.48 (m, 2H) 2.02-2.16 (m, 1H) 1.39 (d, J=5.54 Hz, 9H) 0.84 (t, J=8.06 Hz, 2H) −0.12 (br. s., 9H). m/z (APCI+) for C26H38N8O4Si 555.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(O)(=O)C.[I:16]N1C(=O)CCC1=O>>[CH2:1]([C:3]1[C:11]([I:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1cc2ccccn2n1
Solvent: CC(=O)O
Product: CCc1nn2ccccc2c1I
Yield: 75.2 %

Procedure:
2-Ethylpyrazolo[1,5-a]pyridine (4.1 g, 22 mmol) was stirred in acetic acid (2.6 g, 18 mmol) and N-iodosuccinimide (8 g, 40 mmol) was added in portions over 5 hrs. The mixture was evaporated and purified on silica gel with ethyl acetate in hexanes (0-15%) to give the desired compound (4.5 g, 93%). LCMS for C9H10N2 (M+H)+: m/z=273.1. 1H NMR (300 MHz, DMSO-d6): δ 8.62 (m, 1H), 7.40 (m, 1H), 7.27 (m, 1H), 6.82 (m, 1H), 2.72 (m, 2H), 1.22 (m, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([CH3:30])[N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([F:31])[CH:9]=1>>[F:31][C:10]1[CH:9]=[C:8]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH:13]=[CH:12][C:11]=1[C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([CH3:30])[N:23]=2)[CH2:20][CH2:21]1)=[O:15]
Reactant: O=C1CCCN1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3F)CC2)nc1C
Yield: 89.7 %

Procedure:
Using pyrrolidin-2-one (94 mg) and (4-bromo-2-fluorophenyl) [4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (406 mg) described in Preparation Example 128 and by the reaction and treatment in the same manner as in Example 1, the title compound (368 mg) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:42])[CH2:37][C:38](=O)[CH2:39][CH3:40])=[CH:32][CH:31]=1>>[CH2:39](/[C:38](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[CH:37]/[C:36]([C:33]1[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=1)=[O:42])[CH3:40]
Reactant: CCC(=O)CC(=O)c1ccc(F)cc1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: CC/C(=C/C(=O)c1ccc(F)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(F)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 500 mg (1.56 mmol) of Intermediate 46 and 315 mg (1.56 mmol) of Intermediate 32 to yield 412 mg of Example 9: TLC (DCM/MeOH, 4/1): Rf=0.53; 1H NMR (DMSO-d6, 300 MHz) δ11.53 (d, 1H, J=9.3), 7.99 (m, 2H), 7.95 (m, 2H), 7.39 (t, 2H, J=8.7), 7.26 (t, 2H, J=8.7), 7.17 (d, 2H, J=8.1), 6.86 (d, 2H, J=8.1), 5.60 (s, 1H), 4.20 (t, 2H, J=6.6), 4.12 (m, 1H), 3.21 (m, 2H), 2.94 (t, 2H, J=6.6), 2.78 (dd, 1H, J=13.8, 8.4), 2.38 (s, 3H), 2.05 (m, 2H), 0.96 (t, 3H, J=7.5); low resolution MS (ES+)m/e 561.4 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH:26]3[CH2:30][O:29]C(C)(C)[O:27]3)[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[OH:27][CH:26]([CH2:30][OH:29])[CH2:25][O:24][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([O:22][CH3:23])[CH:19]=1)[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:33]
Reactant: COc1cc(OCC2COC(C)(C)O2)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OCC(O)CO)cc(C(=O)NC2CCNCC2)c1
Reaction time: 16 h
Yield: 136.9 %

Procedure:
1.45 g (3.1 mmol) of rac-4-[3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-5-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 14 mL of MeCl2; while stirring, 2.39 mL (3.559 g=31.2 mmol) of trifluoroacetic acid was added drop by drop. After 16 hours, the reaction mixture was warmed up to reflux and stirred for another 21 hours; it was then evaporated and dried at high vacuum to yield 1.86 g of the crude title compound, which was used without further purification. MS: 325.4 (MH+).
Reaction SMILES: C(OCC)C.C(=O)(OC(C)(C)C)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[CH2:19]([O:18][C:10]1[CH:9]=[C:8]([OH:7])[CH:13]=[CH:12][C:11]=1[C:14]([CH3:16])([CH3:15])[CH3:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc(O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a diethylether (100 ml) solution of 3-(benzyloxy)-4-tert-butylphenyl tert-butyl carbonate (7.1 g, 20 mmol) was added lithium aluminum hydride (0.75 g, 20 mmol) at 0° C. The reaction mixture was 10 stirred at ambient temperature for 3 hours. To the mixture was added H2O (10 ml) carefully to form a white prepicitate. The organic layer was dried over magnesium sulfate. After filtration to separate solvent and magnesium sulfate and precipitate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane =1/6 to furnish 4.9 g (96% yield) of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([Cl:29])[CH:23]=2)[N:17]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([Cl:29])[CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: Cc1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1Cl
Yield: 111.6 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-3-(1-(3-chloro-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.400 g), KOH (0.400 g), water (5 mL) and THF (10.0 mL) to afford 0.350 g of the desired product.
Reaction SMILES: [C:1]([N:5]([CH3:34])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:9]=1[CH2:32][OH:33])=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:38].O>C1COCC1>[C:1]([N:5]([CH3:34])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:9]=1[CH2:32][O:33][CH3:38])=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c(CO)c(C(=O)N(C)C(C)(C)C)n1CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1c(-c2cccs2)c2n(c1C(=O)N(C)C(C)(C)C)CCc1cc(OC)c(OC(C)C)cc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product of example 40 (20 mg), sodium hydride (3.3 mg, 60% dispersion in oil) and iodomethane (13 μl) in THF (2.5 ml) was stirred for 18 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1/0→1/1 (v/v)] as eluent.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]1[S:15][CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=1)CC(C)C)=[O:7])(C)(C)C.[C:24]([NH:34][C@H:35](C(O)=O)[CH2:36][CH:37]([CH3:39])[CH3:38])([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(N[C@H](C(N[C@H](C(O)=O)CC(C)C)=O)CC(C)C)(OCC1C=CC=CC=1)=O>>[CH2:27]([O:26][C:24]([NH:34][C@@H:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:6]([NH:8][CH2:9][C:14]1[S:15][CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=1)=[O:7])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)c1csc([C@H](CC(C)C)NC(=O)OC(C)(C)C)n1
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Product: CCOC(=O)c1csc(CNC(=O)[C@H](CC(C)C)NC(=O)OCc2ccccc2)n1

Procedure:
Following the procedure of Example 13, except substituting 1-(tert-butoxycarbonyl)amino-1-(4-carboethoxytiazol-2-yl)methane for (1S)-1-(tert-butoxycarbonyl)amino-1-(4-carboethoxythiazol-2-yl)-3-methylbutane, and N-Cbz-L-leucine for N-Cbz-L-leucinyl-L-leucine, the title compound was prepared (0.120 g, 32%). MS (MH+): 434.2.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])C>O>[O:8]=[PH:4]1[O:5][CH2:6][C:7]2([CH2:6][O:5][PH:4](=[O:8])[O:3][CH2:1]2)[CH2:1][O:3]1
Reactant: CCOP([O-])OCC
Solvent: O
Product: O=[PH]1OCC2(CO1)CO[PH](=O)OC2
Temperature: 135 °C

Procedure:
3,9-Dioxo-3,9-diphospha-2,4,8,10-tetraoxa-spiro[5.5]undecane was prepared as follows. Under stirring and a nitrogen atmosphere a suspension of 68 g of pentaerythitol, 152 g of diethylphosphite, and 73 g of water-free tetraline was heated to 135° C. At 135° C., 55% of the theoretical amount of ethanol were removed from the reaction mixture over a period of 3 h. The pressure was diminished slowly to 10 kPa and more ethanol was removed at 135° C. After cooling to 80° C., 60 g of methanol were added after which the methanol layer with the product was separated from the tetraline layer. After evaporation at a 95° C. and a pressure of 0.2 kPa, 100 g of a viscous product were obtained, which crystallized on standing at room temperature.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:17][CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1>>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH:18]1[NH:17][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Reactant: NC1Cc2ccccc2C1
Product: c1ccc(-c2csc3ncnc(NC4Cc5ccccc5C4)c23)cc1
Yield: 100 %

Procedure:
Using 4-chloro-5-phenylthieno[2,3-d]pyrimidine (50 mg, 0.20 mmol) and 2-aminoindan (110 mg, 0.80 mmol), a similar procedure to Production Example 190 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (67 mg, 0.20 mmol) having the following physical properties:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:15]=[C:16]([C:20]([NH:22][C:23]3[CH:35]=[C:34]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)[CH:33]=[CH:32][C:24]=3[C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH:17]=[N:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]2[CH:15]=[C:16]([C:20]([NH:22][C:23]3[CH:35]=[C:34]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)[CH:33]=[CH:32][C:24]=3[C:25]([OH:27])=[O:26])=[O:21])[CH:17]=[N:18][CH:19]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccs2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2cccs2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (4.0 mL) was added to the obtained tert-butyl 2-(5-phenylpyridine-3-carboxamido)-4-(thiophen-2-yl)benzoate, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 54 mg of 2-(5-phenylpyridine-3-carboxamido)-4-(thiophen-2-yl)benzoic acid as a white solid.