Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5]C)(=[O:4])[CH:2]=[CH2:3].[C:7]([O:16]CC)(=[O:15])/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11]>>[CH2:8]([C:7]([OH:16])=[O:15])[CH:9]([C:10]([OH:12])=[O:11])[C:2]([C:1]([OH:5])=[O:4])=[CH2:3]
Reactant: CCOC(=O)/C=C/C(=O)OCC
Reactant: C=CC(=O)OC
Product: C=C(C(=O)O)C(CC(=O)O)C(=O)O

Procedure:
A mixture of 4.3 parts by weight of methyl acrylate, 7.7 parts by weight of diethyl fumarate and 0.5 parts by weight of diphenyl(4-oxy-butyl)phosphine is boiled and refluxed for 10 hours in a nitrogen stream. Distillation of the reaction product mixture gave a 3-butene-1,2,3-tricarboxylic acid (1,2-diethyl, 3-methyl) ester. The ester of the tricarboxylic acid is converted to a high molecular weight carboxylic acid-producing composition by reacting same with a chlorinated polyisobutene having a molecular weight of about 1000 and a chlorine content of about 4.5% at a temperature ranging from about 80°-120° C. A mixture of approximately 2000 parts by weight of mineral oil, 3.0 equivalents of a polyoxyethylene triamine having an average molecular weight of about 1000 and approximately 3.0 equivalents of the above-mentioned high molecular weight tricarboxylic acid-producing composition is heated to temperatures of 150°-200° C. over a period of 15 to 20 hours. The resulting product is filtered to give a homogeneous mineral oil solution of the acylated polyamine.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1>[Pd]>[NH2:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1)OCc1ccccc1
Agent: [Pd]
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
A Schlenk flask charged with Z-Trp-NHPh (1.7 g, 4.11 mmol) and 10% Pd/C (437.4 mg) was flushed under H2 before adding MeOH/DMF (41 mL, 1/1). The reaction mixture was stirred under atmosphere of H2 overnight followed by filtration through a pad of celite. The solvent was removed in vacuo and the crude was purified by flash column chromatography on silica gel (2-8% MeOH/CH2Cl2). The amine was isolated as a yellow solid (841 mg, 73%). mp 114-116° C. 1H NMR (300 MHz, CDCl3) δ 1.89 (broad s, 2H, NH2), 3.06 (dd, J=14.5 Hz, J=8.8 Hz, 1H, CH2), 3.55 (dd, J=14.5 Hz, J=3.9 Hz, 1H, CH2), 3.89 (dd, J=8.8 Hz, J=3.8 Hz, 1H, CHα), 7.06-7.41 (m, 7 aromatic H), 7.61 (d, J=7.9 Hz, 2 aromatic H), 7.72 (d, J=7.8 Hz, 1 aromatic H), 8.24 (broad s, 1H, NH amide), 9.48 (s, 1H, NH indole). 13C NMR (75 MHz, CDCl3) δ 30.5 (CH2 Trp), 56 (CHα), 111.4, 118.8, 119.5, 119.7, 122.3, 123.2, 124.1, 127.5, 129, 129.1, 136.5, 137.8 (14 aromatic C), 173.2 (CO amide).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[F:13][C:14]([F:22])([F:21])[CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1>>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([N:17]2[CH2:18][CH2:19][CH2:20][CH:15]([C:14]([F:22])([F:21])[F:13])[CH2:16]2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: FC(F)(F)C1CCCNC1
Product: CC#CCOc1cc(N2CCCC(C(F)(F)F)C2)ncn1
Reaction time: 10 h
Yield: 61.4 %

Procedure:
0.3 g of 4-chloro-6-(2-butynyloxy)pyrimidine and 0.25 g of 3-trifluoromethylpiperidine were mixed and left for 10 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.30 g of 4-(2-butynyloxy)-6-(3-trifluoromethylpiperidino)pyrimidine (hereinafter, referred to as Compound (24)).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[C:23]([CH3:27])=[N:24][O:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[OH:29][CH:28]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[C:23]([CH3:27])=[N:24][O:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 23 %

Procedure:
3-Methyl-isoxazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.935 g, 2.59 mmol) and ethyl formate (0.621 mL, 7.72 mmol) were dissolved in anhydrous ethanol (25 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (4.83 mL, 12.94 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a brown precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 3-Methyl-isoxazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.232 g, 0.595 mmol, 23%).
Reaction SMILES: C([O:8][C:9]1[C:14]2[C:15]([O:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:23][CH2:22]3)=[N:16][O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[OH:8][C:9]1[C:14]2[C:15]([O:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:23][CH2:22]3)=[N:16][O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C1(CN2CCC(CCOc3noc4cccc(OCc5ccccc5)c34)CC2)CCOCC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1(CN2CCC(CCOc3noc4cccc(O)c34)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
A mixture of methyl 4-{[4-(2-{[4-(benzyloxy)-1,2-benzisoxazol-3-yl]oxy}ethyl)piperidin-1-yl]-methyl}tetrahydro-2H-pyran-4-carboxylate (3.2 g, 6.3 mmol, EXAMPLE 7, step 5) and 10% Pd—C (0.30 g) in tetrahydrofuran (20 mL) and methanol (40 mL) was stirred at room temperature for 10 min under hydrogen atmosphere. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 3:1 to 3:2) to give 2.2 g (83%) of the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.Br[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([N:6]4[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]4=[O:7])=[N:14][CH:13]=3)=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: CC1CCC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)nc3)CC2)c(C)c1
Yield: 43.5 %

Procedure:
Using 5-methylpyrrolidin-2-one (99 mg) and (6-bromopyridin-3-yl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 127 and by the reaction and treatment in the same manner as in Example 1, the title compound (171 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O[N:21]=[C:22]([C:24]1[CH:32]=[C:31]([CH3:33])[C:27]2[NH:28][CH:29]=[N:30][C:26]=2[CH:25]=1)[NH2:23]>CCOCC>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:21]=[C:22]([C:24]3[CH:32]=[C:31]([CH3:33])[C:27]4[NH:28][CH:29]=[N:30][C:26]=4[CH:25]=3)[N:23]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: Cc1cc(C(N)=NO)cc2nc[nH]c12
Solvent: CCOCC
Product: COCc1cc(-c2nc(-c3cc(C)c4[nH]cnc4c3)no2)ccc1-c1ccccc1C

Procedure:
Title compound was prepared following general procedure 2 starting from Intermediate 14 (308 mg; 1.2 mmol) and Intermediate 3 (228 mg; 1.2 mmol). The reaction mixture was diluted with Et2O, washed with water and brine and evaporated under vacuum. Purification by silica column chromatography (EtOAc/c-Hex, 30/70 to 70/30) afforded the title compound as a pink powder. 1H NMR (DMSO-d6) δ 12.92 (br s, 0.5H), 12.71 (br s, 0.5H), 8.38 (d, J=6.0 Hz, 1H), 8.34 (d, J=1.3 Hz, 1H), 8.26-8.12 (m, 2H), 7.80 (d, J=6.8 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.39-7.25 (m, 3H), 7.16 (d, J=7.0 Hz, 1H), 4.27-4.14 (m, 2H), 3.26 (s, 3H), 2.65 (s, 1.5H), 2.62 (s, 1.5H), 2.05 (s, 3H). LC/MS (method B): 409.3 (M−H)−; 411.3 (M+H)+. HPLC (Method A) Rt 4.11 min (Purity: 100.0%).
Reaction SMILES: [O:1]([CH:9]([C:39]([F:47])([F:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:10][CH2:11][C@H:12]1[C@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C@@H:14]([OH:24])[CH:13]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.CS(C)=O>ClCCl.C(N(CC)CC)C>[O:1]([CH:9]([C:39]([F:47])([F:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:10][CH2:11][C@H:12]1[C@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C:14](=[O:24])[CH:13]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34])[Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:3])[CH3:4]
Reactant: CCCCCCC(F)(F)C(CC[C@@H]1C(CCCCCCCCC(=O)OC(C)C)[C@H](O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCCCCC(F)(F)C(CC[C@@H]1C(CCCCCCCCC(=O)OC(C)C)C(=O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C

Procedure:
A solution of the compound (12-10)(1.09 g) in dichloromethane (2 ml) was subjected to Swan oxydation using oxalyl chloride(2.0M, CH2Cl2 solution, 1.58 ml), a solution of DMSO (0.45 ml) in dichloromethane (10 ml) and triethylamine (0.88 ml). The crude product obtained by the conventional treatment was purified by silica gel chromatography (n-hexane/ethyl acetate=8/2) to give the titled compound (12-11).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH:30][C:35]([NH:34][CH2:32][CH3:33])=[O:36])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)NCCNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
The product of Example 157 (42.5 mg., 0.0001 mol) stirring at 23° in dry THF (5 mL), under Ar, was treated with ethyl isocyanate (9.6 mg, 0.0001 mol) in one portion. After 30 min., the resulting red solution was stripped to dryness; taken up in methylene chloride (5 mL) and applied to a Chromatotron™ Rotor Plate (1000 u thickness); plate eluted with methylene chloride-methanol gradient (0% to 2% MeOH), to afford 30 mg (60.4%) of pure title compound. (m.p. 130°-133°). LC MS (m/e)=497 (MH+). Rt=2.04 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]3[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 70 μmol), (4-chloro-phenyl)-acetic acid (13 mg, 79 μmol) and DIPEA (31 μL, 237 μmol) in THF (3 mL), T3P (151 μL, 237 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid (74%, 35 mg).
Reaction SMILES: C(OC1[C:6](=CC=CC=1)[C:7]([O:9][C:10](=[O:21])[C:11]1[C:12](=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:13][C:14](=[O:16])[CH3:15])=O)(=O)C.OC(C)[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH:36]([OH:38])[CH3:37])[CH2:31][CH2:30]1>C(OCC)(=O)C>[C:14]([O:13][C:12]1[C:11](=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([O:9][CH:7]([CH3:6])[CH2:28][N:29]1[CH2:30][CH2:31][N:32]([CH2:35][CH:36]([O:38][C:10](=[O:9])[C:11]2[C:12](=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:13][C:14](=[O:16])[CH3:15])[CH3:37])[CH2:33][CH2:34]1)=[O:21])(=[O:16])[CH3:15]
Reactant: CC(O)CN1CCN(CC(C)O)CC1
Reactant: CC(=O)Oc1ccccc1C(=O)OC(=O)c1ccccc1OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccccc1C(=O)OC(C)CN1CCN(CC(C)OC(=O)c2ccccc2OC(C)=O)CC1
Temperature: 25 °C

Procedure:
Dissolve acetylsalicylic anhydride (17.1 g; 0.05 moles) in an apolar organic solvent represented for example by ethyl acetate; add 1,4-bis-(2-hydroxypropyl)piperazine (5.06 g; 0.025 moles) to the solution, and heat up to the boiling point until the reaction is completed. After cooling at room temperature, wash the reaction mixture with a 5 percent aqueous solution of potassium carbonate, and then with water. Anhydrify the organic phase (K2CO3), filter, and treat it with anhydrous hydrochloric acid dissolved in diethylether causing by this procedure the precipitation of the raw product that, after collection and drying, can be recrystallized from a low molecular weight alcohol.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[C@@H:17]12[CH2:23][C@@H:20]([CH:21]=[CH:22]1)[CH2:19][C@H:18]2[CH2:24][C:25](O)=[O:26]>>[C@@H:17]12[CH2:23][C@@H:20]([CH:21]=[CH:22]1)[CH2:19][C@H:18]2[CH2:24][C:25]([NH:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16])=[O:26]
Reactant: O=C(O)C[C@@H]1C[C@@H]2C=C[C@H]1C2
Reactant: Nn1nc(C2CCC2)c2ccccc2c1=O
Product: O=C(C[C@@H]1C[C@@H]2C=C[C@H]1C2)Nn1nc(C2CCC2)c2ccccc2c1=O

Procedure:
The product of Example 67A and 2-((1S,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.34-8.28 (m, 1H), 8.00-7.93 (m, 1H), 7.92-7.83 (m, 2H), 6.22 (dd, J=5.7, 3.0, 1H), 6.07 (dd, J=5.7, 2.9, 1H), 4.10-3.99 (m, 1H), 2.91 (s, 1H), 2.79 (s, 1H), 2.49-2.42 (m, 1H), 2.41-2.22 (m, 4H), 2.14-2.02 (m, 3H), 1.95-1.87 (m, 1H), 1.86-1.77 (m, 1H), 1.39-1.31 (m, 1H), 1.26 (d, J=8.0, 1H), 0.61 (ddd, J=11.5, 4.2, 2.6, 1H); MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH:8]=[O:9])=[CH:6][NH:5][N:4]=1.Cl[CH2:13][C:14]1[NH:15][C:16](=[O:24])[C:17]2[CH:22]=[C:21]([CH3:23])[S:20][C:18]=2[N:19]=1.CC(C)([O-])C.[K+].Cl>C1COCC1.CCOC(C)=O.O.CN(C=O)C>[CH3:23][C:21]1[S:20][C:18]2[N:19]=[C:14]([CH2:13][N:5]3[CH:6]=[C:7]([CH:8]=[O:9])[C:3]([C:2]([F:1])([F:10])[F:11])=[N:4]3)[NH:15][C:16](=[O:24])[C:17]=2[CH:22]=1
Reactant: Cc1cc2c(=O)[nH]c(CCl)nc2s1
Reactant: O=Cc1c[nH]nc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2c(=O)[nH]c(Cn3cc(C=O)c(C(F)(F)F)n3)nc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.4 %

Procedure:
3-(Trifluoromethyl)-1H-pyrazole-4-carbaldehyde (3.82 g, 23.3 mmol) and 2-(chloromethyl)-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (5.00 g, 23.3 mmol) were suspended in THF:DMF (180 mL:20 mL) and potassium tert-butoxide (5.23 g, 46.6 mmol) added. The resulting mixture was stirred at RT for 18 h. The mixture was then diluted with EtOAc (500 mL) and shaken with water (200 mL). The separated aqueous phase was acidified to pH 5 with dilute HCl solution and reshaken with the organic layer. The separated organics were then washed with brine (2×200 mL) and dried over MgSO4 before concentration in vacuo. Purification by flash column chromatography-silica gel and elution with 50% isohexane:EtOAc, then EtOAc, gave the desired product as a pale yellow solid (4.65 g, 13.6 mmol, 58%).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].Cl[CH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>CN(C)C=O>[S:32]1[CH:33]=[CH:34][N:35]=[C:31]1[CH2:30][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:15]2[CH:14]=[C:13]([C:12]3[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=3)[O:17][N:16]=2)=[CH:20][CH:21]=1
Reactant: ClCc1nccs1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4nccs4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (50 mg, 0.18 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (35.4 μL, 0.18 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a suspension of this solid in N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-thiazole (28.4 mg, 0.21 mmol) described in manufacturing Example 88-1-2, which was stirred for 3 hours at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (43.0 mg, 64%).
Reaction SMILES: [OH:1][CH:2]1[CH2:28][O:27][C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([N:11]([CH2:13][C@@H:14]([NH:16]C(=O)OCC4C=CC=CC=4)[CH3:15])[N:10]=[CH:9]3)=[C:4]2[CH:3]1[O:29][CH3:30].FC(F)(F)C(O)=O>CO>[NH2:16][C@@H:14]([CH3:15])[CH2:13][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]3[O:27][CH2:28][CH:2]([OH:1])[CH:3]([O:29][CH3:30])[C:4]3=2)[CH:9]=[N:10]1
Reactant: COC1c2c(ccc3cnn(C[C@H](C)NC(=O)OCc4ccccc4)c23)OCC1O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC1c2c(ccc3cnn(C[C@H](C)N)c23)OCC1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 130.6 %

Procedure:
To a solution of the product from Step A (0.22 g, 0.58 mmol) in methanol (5 mL) was added trifluoroacetic acid (5 mL) and the mixture was stirred at ambient temperature for 2 days. The mixture was evaporated to a residue, which was stirred with a 2 N solution of hydrogen chloride in ethanol (5 mL) and evaporated to afford a solid (0.21 g): mp 105-108° C.; LC/MS (+APCI) m/z 278(M+H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:11][C:12]\2=[O:13])[CH:3]=[N:2]1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].N12CCCN=C1CCCCC2.[Cl-].[Na+]>C(#N)C>[CH2:38]([O:37][C:33]([CH2:34][CH2:35][N:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][CH2:11][C:12]\2=[O:13])[CH:3]=[N:2]1)=[O:36])[CH3:39]
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cn[nH]c1
Reactant: C=CC(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CCn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of (E)-3-[(1H-pyrazol-4-yl)methylidene]-1-(triphenylmethyl)piperidin-4-one (Example 98(a), 6.0 g) in acetonitrile (100 ml) were added ethyl acrylate (4.7 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (6.4 ml). The resulting mixture was stirred at room temperature for 15 minutes, and the reaction was stopped by an addition of a saturated aqueous sodium chloride solution. The products were extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and solvents were evaporated in vacuo. The residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (2:1:1) as the eluent to afford the title compound as a yellow amorphous solid (6.12 g, yield: 82%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[N:12]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:21]2[CH2:20][CH2:19][CH:18]([CH:15]3[CH2:14][CH2:13][N:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17][CH2:16]3)[CH2:23][CH2:22]2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 4-methylthiophenylboronic acid (240 mg; 1.43 μmol) in dichloromethane (6 mL) was treated with activated powdered 4 Å molecular sieves (1.5 g), Cu(OAc)2 (87 mg; 0.477 mmol), tert-butyl 4,4′-bipiperidine-1-carboxylate (128 mg; 0.477 mmol) and triethylamine (134 μL; 0.954 mmol). The reaction vessel was purged with oxygen and the mixture stirred under an oxygen atmosphere at ambient temperature for 18 hr. The now brown mixture was filtered through Celite. The eluant was adsorbed onto silica gel. The silica gel was exhaustively eluted without fractionation (1:1 hex/MTBE). The eluant was evaporated to a yellow oil and chromatographed (PTLC; 2:1 hex/MTBE). The major band was collected affording the title compound. LRMS calc: 390.2 obs: 391.1 (M+H), 291.1 (M-BOC+H).