Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@H:4]([N:22]1[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]2[S:35][C:34]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[N:33][CH:32]=2)(=[O:30])=[O:29])[C:23]1=[O:41])[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18])[C:12]([NH2:21])=[N:11][CH:10]=[CH:9]2.[CH2:43](O)[CH2:44]C>[Ti+4].CC(C)[O-]>[CH2:1]([O:2][C:3](=[O:42])[C@H:4]([N:22]1[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]2[S:35][C:34]([N:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[N:33][CH:32]=2)(=[O:29])=[O:30])[C:23]1=[O:41])[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][C:17]([F:18])([F:19])[F:20])[C:12]([NH2:21])=[N:11][CH:10]=[CH:9]2)[CH2:43][CH3:44]
Reactant: CCCO
Reactant: COC(=O)[C@@H](Cc1cc2ccnc(N)c2cc1OC(F)(F)F)N1CC[C@H](NS(=O)(=O)c2cnc(N3CCCC3)s2)C1=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCCOC(=O)[C@@H](Cc1cc2ccnc(N)c2cc1OC(F)(F)F)N1CC[C@H](NS(=O)(=O)c2cnc(N3CCCC3)s2)C1=O

Procedure:
To 57 mg (91 μmol) (R)-3-(1-Amino-7-trifluoromethoxy-isoquinolin-6-yl)-2-[(S)-2-oxo-3-(2-pyrrolidin-1-yl-thiazole-5-sulfonylamino)-pyrrolidin-1-yl]-propionic acid methyl ester in 2 ml 1-propanol, 64.4 mg (227 μmol, 2.5 eq) titanium(IV)-isopropoxide are added.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:17](C3CCCCO3)[C:14]2=[CH:15][N:16]=1>>[C:20]1([C:19]2[C:13]3[C:14](=[CH:15][N:16]=[C:11]([C:5]4[CH:6]=[N:1][CH:2]=[N:3][CH:4]=4)[CH:12]=3)[NH:17][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Reactant: OB(O)c1cncnc1
Product: c1ccc(-c2n[nH]c3cnc(-c4cncnc4)cc23)cc1
Yield: 25 %

Procedure:
Following the procedures in Example 136, pyrimidin-5-ylboronic acid and 5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted and the product was deprotected to give 150 as a yellow solid (25 mg, 25%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 9.26 (s, 1H), 9.21 (s, 1H), 8.79 (s, 1H), 8.40 (s, 1H), 8.18 (d, 2H), 7.57 (t, 2H), 7.47 (t, 1H). ESI MS m/z=274 (M+1)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:18]([C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:21]1([CH3:25])[CH:22]=[CH:23][CH:24]=[C:19]([N:18]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH:20]=1
Reactant: Cc1cccc(-n2c([C@H](C)NC(=O)OC(C)(C)C)nc3cccnc32)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(-n2c([C@H](C)N)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
To a solution of [(S)-1-(3-m-tolyl-3H-imidazo[4,5-b]pyridin-2-yl)ethyl]carbamic acid tert-butyl ester (3.01 mmol) in DCM (25 mL) was added TFA (10 mL) and the mixture stirred at RT for 15 min. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) to afford the title compound as a colourless oil (700 mg, 92% over three steps). LCMS (Method C): RT 1.91 min [M+H]+ 253.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C@@H:9]([N:17]([CH2:25][CH:26]=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[NH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([CH2:47][C@H:48]([NH2:53])[CH2:49][C:50]([OH:52])=[O:51])=[CH:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C@@H:9]([N:17]([CH2:25][CH2:26][NH:53][C@H:48]([CH2:49][C:50]([OH:52])=[O:51])[CH2:47][C:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[NH:38][CH:39]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N[C@H](CC(=O)O)Cc1c[nH]c2ccccc12
Reactant: COc1cc(CN(C)C(=O)[C@H](Cc2ccccc2)N(CC=O)C(=O)OC(C)(C)C)cc(OC)c1OC
Agent: Cl
Product: COc1cc(CN(C)C(=O)[C@H](Cc2ccccc2)N(CCN[C@H](CC(=O)O)Cc2c[nH]c3ccccc23)C(=O)OC(C)(C)C)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1 using (S)-N-(3,4,5-trimethoxybenzyl)-N-methyl-2-[N'-(t-butoxycarbonyl)-2-oxo-ethylamino]-3-phenyl-propionamide (0.25 g, 1.0 mmol) and (S)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt ((S)-tryptophan methyl ester hydrochloride salt) (0.41 g, 1.0 mmol). Purify by chromatography eluting sequentially with 1% methanol/dichloromethane and 5% methanol/dichloromethane to give the title compound: TLC Rf =0.83 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=[CH:12]1)[CH3:2].[OH:19][CH2:20][CH2:21][N+:22]([CH3:25])([CH3:24])[CH3:23].C1(C)C=CC=CC=1>O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]1[C:15]([C:16]([O-:18])=[O:17])=[CH:14][N:13]=[CH:12]1)[CH3:2].[OH:19][CH2:20][CH2:21][N+:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CCc1cccc(CC)c1-n1cncc1C(=O)O
Agent: C[N+](C)(C)CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1-n1cncc1C(=O)[O-]
Yield: 97 %

Procedure:
25 pbw (0.10 mole) of 1-(2,6-diethylphenyl)imidazole-5-carboxylic acid and 27.0 pbw (0.11 mole) of a 50% aqueous solution of choline are heated in 100 pbv of toluene in a water separator, until the water has been completely removed. The mixture is allowed to cool and is then evaporated in vacuo. 34.5 pbw (97% of theory) of 2-hydroxyethyltrimethylammonium 1-(2,6-diethylphenyl)imidazole-5-carboxylate, a high-viscosity oil, are obtained; identification is carried out by 1H-NMR spectroscopy.
Reaction SMILES: CSC.ClN1C(=O)CCC1=O.[OH:12][C@@H:13]1[CH2:17][N:16]([C:18](=[O:28])[C@@H:19]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:20]([CH3:22])[CH3:21])[C@H:15]([C:29]2[NH:30][CH:31]=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:41]=[C:42]5[C:47](=[CH:48][CH:49]=4)[CH:46]=[C:45]([C:50]4[NH:54][C:53]([C@@H:55]6[CH2:59][CH2:58][CH2:57][N:56]6[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[N:52][CH:51]=4)[CH:44]=[CH:43]5)=[CH:36][CH:35]=3)[N:33]=2)[CH2:14]1.C(N(CC)CC)C>ClCCl>[CH3:27][O:26][C:24]([NH:23][C@@H:19]([CH:20]([CH3:22])[CH3:21])[C:18]([N:16]1[CH2:17][C:13](=[O:12])[CH2:14][C@H:15]1[C:29]1[NH:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[C:42]4[C:47](=[CH:48][CH:49]=3)[CH:46]=[C:45]([C:50]3[NH:54][C:53]([C@@H:55]5[CH2:59][CH2:58][CH2:57][N:56]5[C:60]([O:62][C:63]([CH3:65])([CH3:64])[CH3:66])=[O:61])=[N:52][CH:51]=3)[CH:44]=[CH:43]4)=[CH:36][CH:35]=2)[N:33]=1)=[O:28])=[O:25]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1nc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)c[nH]1)C(C)C
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1c1nc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Yield: 90.6 %

Procedure:
Dimethyl sulfide (164 μL, 2.23 mmol) was added dropwise to a solution of N-chlorosuccinimide (238 mg, 2.12 mmol) in dichloromethane (10 mL) at 0° C. After 15 minutes the mixture was cooled to −15° C. (ice-salt bath). A solution of (S)-tert-butyl 2-(5-(6-(4-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (809 mg, 1.06 mmol) in dichloromethane (5 mL) was added dropwise. The temperature was not allowed to go above −10° C. After 2 hours a solution of triethylamine (316 μL, 2.23 mmol) in dichloromethane (2 mL) was added dropwise and the mixture was allowed to warm to room temperature at which point the reaction was complete. The mixture was washed with saturated ammonium chloride (3×10 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to yield (S)-tert-butyl 2-(5-(6-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (734 mg, 0.96 mmol, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[C:12](=[NH:17])[NH:11][C:10](=N)[C:9]2=3)=[CH:4][CH:3]=1.Cl.[CH2:20]([C:22]1[CH:34]=[CH:33][C:25]([NH:26][C:27]2[S:28][CH2:29][C:30](=[NH:32])[N:31]=2)=[CH:24][CH:23]=1)[CH3:21].Cl.N=C1NC(=N)CS1>>[NH:17]=[C:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:9]=2[C:10](=[C:29]2[S:28][C:27]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([CH2:20][CH3:21])=[CH:34][CH:33]=3)=[N:31][C:30]2=[NH:32])[NH:11]1
Reactant: N=C1NC(=N)C2=C1CCCC2c1ccc(Cl)cc1
Reactant: CCc1ccc(NC2=NC(=N)CS2)cc1
Agent: Cl
Agent: N=C1CSC(=N)N1
Product: CCc1ccc(NC2=NC(=N)C(=C3NC(=N)C4=C3C(c3ccc(Cl)cc3)CCC4)S2)cc1

Procedure:
Proceeding in a manner similar to that described above in Example 10, part A but substituting equivalent amounts of 4-(p-chlorophenyl)-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(p-ethylanilino)-4-imino-2-thiazoline hydrochloride for 4,5,6,7-tetrahydro-1,3-diiminosioindoline and 2,4-diiminothiazolidine hydrochloride, there is obtained as the product 1-imino-4-(p-chlorophenyl)-4,5,6,7-tetrahydro-3-[2-(p-ethylanilino)-4-imino-2-thiazolin-5-ylidene]isoindoline.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[OH-].[Na+].[CH2:20](O)[CH3:21]>>[NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:20][CH3:21])=[O:4]
Reactant: CCO
Reactant: CCCCCCCCC(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCCCCCCCC(N)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
2-Aminodecanoic acid (J. Am. Chem. Soc., 1946, 68, 450) (16.0 g) was added in portions to a cooled (-10° C.) mixture of absolute ethanol (70 ml) and thionyl chloride (6 ml) with stirring. The resulting solution was set aside for 2 hours, at room temperature, refluxed for 1 hour, cooled, poured into ice-water, and the pH of the solution was adjusted to 9 with aqueous sodium hydroxide. The mixture was extracted with ether, the extract was dried, concentrated, then distilled, giving ethyl 2-aminodecanoate (75%) as a colourless oil, b.p. 82°-4° C./0.2 mm.
Reaction SMILES: N1(C2C=CC=CN=2)CCC(C(O)=O)CC1.C(OC([CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:46])[NH:34][C:35]3[CH:43]=[C:42]4[C:38]([CH:39]=[CH:40][N:41]4[CH2:44][CH3:45])=[CH:37][CH:36]=3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1)=O)C.C(S(N)(=O)=O)(C)(C)C.IC1C=CC(NC(C2C=CC(N3CCCCC3)=NC=2)=O)=CC=1C>>[CH2:44]([N:41]1[C:42]2[C:38](=[CH:37][CH:36]=[C:35]([NH:34][C:33]([C:30]3[CH:31]=[CH:32][C:27]([N:24]4[CH2:25][CH2:26][CH2:21][CH2:22][CH2:23]4)=[N:28][CH:29]=3)=[O:46])[CH:43]=2)[CH:39]=[CH:40]1)[CH3:45]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc4ccn(CC)c4c3)cn2)CC1
Agent: CC(C)(C)S(N)(=O)=O
Agent: Cc1cc(NC(=O)c2ccc(N3CCCCC3)nc2)ccc1I
Agent: O=C(O)C1CCN(c2ccccn2)CC1
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCCCC4)nc3)cc21

Procedure:
4-Methyl-propane-2-sulfonylaminocarbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (1-ethyl-1H-indol-6-yl)-amide was synthesized by the ECU coupling of 5″-ethyl-1H-indol-6-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (prepared by the hydrolysis of 5′-(1-ethyl-1H-indol-6-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester with LiOH monohydrate as described in the synthesis of 5′44-iodo-3-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid above.) with t-butyl sulfonamide in a manner similar to the one described in the synthesis of 442-methyl-propane-2-sulfonylaminocarbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (4-iodo-3-methyl-phenyl)-amide. LCMS calcd for C26H33N5O4S (m/e) 511, obsd 512 (M+H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[CH:18]([C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1)([CH3:20])[CH3:19]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:18]([C:21]1[S:25][C:24]([NH:26][S:14]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:13]3)(=[O:16])=[O:15])=[N:23][N:22]=1)([CH3:20])[CH3:19]
Reactant: CC(=O)NC1Cc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: CC(C)c1nnc(N)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)NC1Cc2ccc(S(=O)(=O)Nc3nnc(C(C)C)s3)cc2C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-Acetylamino-indan-5-sulfonyl chloride (500 mg) was dissolved in 5 ml of pyridine and a catalytic amount of 4-dimethylamino pyridine was added. After addition of 262 mg of 5-isopropyl-[1,3,4]thiadiazol-2-ylamine the mixture was stirred at 60° C. for 1 hour followed by evaporation. The resulting crude material was purified by column chromatography (silica gel, eluent: dichloromethane:methanol=95:5).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][C:7](=O)[C:8]([F:11])([F:10])[F:9])[CH3:2].Cl.[C:15]1([CH3:23])[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1.Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:19]2[C:18](=[CH:17][CH:16]=[C:15]([CH3:23])[CH:20]=2)[NH:21][C:7]=1[C:8]([F:11])([F:10])[F:9])[CH3:2]
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC(=O)CCC(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1c(C(F)(F)F)[nH]c2ccc(C)cc12
Temperature: 0 °C
Yield: 59.4 %

Procedure:
A mixture of 5,5,5-trifluoro-4-oxo-pentanoic acid ethyl ester (6.00 g, 30.3 mmol) and p-tolylhydrazine hydrochloride (4.80 g, 30.3 mmol) in ethanol (25 mL) is cooled to 0° C. The solution is saturated with HCl gas and heated at reflux for 18 h under an argon atmosphere. After cooling to room temperature the reaction mixture is concentrated by rotary evaporation. The residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc. The layers are separated and the aqueous phase is extracted with twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown oil. Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1) affords the title compound as orange crystals (5.14 g, 18.0 mmol, 60%). 1H NMR (400 MHz, CDCl3, 298 K): δ=12.17 (bs, 1H), 7.63 (s, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 4.06 (s, 2H), 2.57 (s, 3H), 1.34 (t, J=7.1 Hz, 3H). MS (ES+): 286 (M(C14H14F3NO2)+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:19])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:29]I.[Cl-].[NH4+]>CN(C)C=O>[CH3:29][N:20]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CI
Reactant: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
Under a nitrogen gas stream, to a solution of 4-(3-phenyl-1,2,4-thiadiazol-5-yl)-N-pyridin-3-ylpiperazine-1-carboxamide (100 mg, 0.273 mmol) in dimethylformamide (1.0 ml) was added, under ice-cooling, sodium hydride (13.1 mg, 0.327 mmol), and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (0.020 ml, 0.327 mmol) was added thereto under ice-cooling, and the mixture was stirred at 0° C. for 30 minutes, followed by stirring at room temperature for 2 hours and half. An aqueous saturated ammonium chloride solution was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 43.0 mg (41.4%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:25])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)=[C:4]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:3]=1.Cl.[CH3:33]O>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:25])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:33])=[O:23])=[CH:17][CH:16]=2)=[C:4]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNC(=O)Cc1ccc(CC(=O)O)cc1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1CCCNC(=O)Cc1ccc(CC(=O)OC)cc1
Reaction time: 8 h

Procedure:
The product from step (i) was dissolved in MeOH (20 mL) then a solution of HCl in dioxane (4M, 0.3 ml) was added and stirred overnight. Solvent was removed and the residue purified by RPHPLC to afford the title compound, 0.032 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ccc(N2CCC(c3ccccc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCC(c4ccccc4)CC3)cc2)CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 76.8 %

Procedure:
A mixture of piperazine-1-carboxylic acid tert-butyl ester (2.02 g), 1-(4-bromophenyl)-4-phenylpiperidine (2.86 g), tris(dibenzylideneacetone)(chloroform)-di-palladium(0) (0.19 g), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.28 g) and sodium tert-butoxide (1.74 g) in toluene (29 ml) was stirred for 6 hours at 90° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica using dichloromethane/methyl alcohol (50:1) as the elution to give 4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (2.93 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][C:29]1[S:33][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:31][C:30]=1[C:40]([OH:42])=O>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:40]([C:30]3[N:31]=[C:32]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[S:33][C:29]=3[CH3:28])=[O:42])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: Cc1sc(-c2ccccc2)nc1C(=O)O
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3nc(-c4ccccc4)sc3C)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 5-methyl-2-phenyl-1,3-thiazole-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[CH:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=2)[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc(OCCc2ccc(C#N)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)cc(OCCc2ccc(C#N)cc2)c1

Procedure:
t-Butyloxycarbonylamino-3-[2-(4-cyanophenyl)ethoxy]-5-methylbenzene (1.55 g; 4.4 mmol; from step (ii) above) was stirred in a mixture of trifluoroacetic acid (10 mL) and methylene chloride (10 mL) for 3 hours. The solvent was removed in vacuo. The residue was dissolved in EtOAc (50 mL), washed with Na2CO3/aq (sat.) and water, dried (Na2CO3) and the solvent was removed to afford a yellow oil, which crystallized upon standing. Yield: 1.19 g (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH:10]([CH3:28])[C:11]([C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]=2[CH:27]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:10]([CH3:28])[C:11]([C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]=2[CH:27]=1)([OH:16])[C:12]([F:13])([F:14])[F:15]
Reactant: COc1ccc(Cl)c(C(C)C(O)(c2ccc3oc(=O)n(C)c3c2)C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
5-[2-(2-Chloro-5-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (34 mg, obtained in Example 192, step 3) was dissolved in CH2Cl2 (5 mL) and cooled to 0° C. Borontribromide (1M in CH2Cl2, 0.33 mL) was added over a period of 10 minutes. Stirring was continued for 1 hour at 0° C. The reaction mixture was poured into ice and basified with sat. NaHCO3 and extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=6:4) to give the title compound as a colorless amorphous foam (22 mg, 67%). MS (neg. ion, m/e)=400.1 [(M−H)−].