Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[O:26])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)c3cccs3)ccc2C)cc1
Reaction time: 18 h
Yield: 106 %

Procedure:
A mixture of 5′-amino-2′-methyl-biphenyl-4-carboxylic acid ethyl ester (280 mg) and thiophene-2-carbonyl chloride (161 mg) in dichloromethane (5 ml) containing triethylamine (222 mg) was stirred at 20 C for 18 h. The mixture was then partitioned between water and dichloromethane. The dried extracts were then evaporated giving the title compound as a colourless solid (425 mg)
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:42])[N:19]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:31][CH2:30]2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[C].[Pd]>[CH2:35]([CH:32]1[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][CH2:26][N:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:18]([NH:17][CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[O:42])[CH2:34][CH2:33]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(OCc1ccccc1)N1CCC(NC(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(NC1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Yield: 97.9 %

Procedure:
The compound obtained in Example 12 (5.50 g, 9.7 mmol) was dissolved in methanol (60 ml). To the solution was added 10% palladium carbon (water content:50%, 2.2 g), and the mixture was subjected to catalytic hydrogenation reaction at room temperature for 16 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the titled compound (4.11 g, 9.5 mmol, Yield 98%).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH2:11][CH2:10]2.Cl.C(OCC)(=O)C>O1CCOCC1>[O:17]=[C:13]1[C:14]2[C:9](=[CH:8][C:7]([CH2:6][CH:2]=[O:1])=[CH:16][CH:15]=2)[CH2:10][CH2:11][O:12]1
Reactant: O=C1OCCc2cc(CC3OCCO3)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=CCc1ccc2c(c1)CCOC2=O
Temperature: 25 °C

Procedure:
6-(1,3-Dioxolan-2-ylmethyl)-3,4-dihydro-1H-isochromen-1-one (4.42 g, 18.9 mmol) was dissolved in dioxane (25 mL) and treated with 3 M HCl (40 mL). The reaction mixture was stirred at room temperature over night, then was warmed to 50° C. for 2 hours to drive the reaction to completion (however this led to increased side product production based on LCMS). Ethyl acetate was added and the layers were separated. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers were washed with brine and dried over MgSO4 to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)#[N:2].[ClH:27]>O1CCOCC1>[ClH:27].[N+:24]([C:23]1[CH:22]=[CH:21][CH:20]=[C:4]([O:5][CH2:6][C@H:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[C:3]=1[C:1]#[N:2])([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(OC[C@H]2CCCNC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of (S)-tert-butyl 3-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example 1e, 41.74 g) in dioxane (115 mL) cooled to 0° C. in an ice bath was added a solution of 4N HCl in dioxane (70 mL, 280 mmol). The reaction mixture was stirred at room temperature overnight then evaporated under reduced pressure. Et2O (700 mL) was added to the residue and the suspension was refluxed for one hour. The solid was collected by filtration and dried under high vacuum to afford (S)-2-nitro-6-(piperidin-3-ylmethoxy)benzonitrile hydrochloride as a pale peach solid (24.64 g, 89% yield over two steps). 1H NMR (400 MHz, DMSO-d6) δ 1.47-1.30 (m, 1H). 1.77-1.62 (m, 1H), 1.84 (t, J=12.4 Hz, 2H), 2.32 (d, J=9.4 Hz, 1H), 2.87-2.68 (m, 2H), 3.27-3.16 (m, 2H), 4.15 (dd, J=9.7, 7.2 Hz, 1H), 4.25 (dd, J=9.7, 5.4 Hz, 1H), 7.72 (dd, J=7.6, 1.9 Hz, 1H), 7.96-7.86 (m, 2H), 9.20-8.89 (m, 2H). MS 262 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30]CC)=[O:29])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].C(O)(=O)C>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([OH:30])=[O:29])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)C(C)(C)Cn1ncc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(cnn4CC(C)(C)C(=O)O)c3)no2)cc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 3.1 %

Procedure:
A solution of ethyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylpropanoate (D111) (100 mg, 0.21 mmol) in Ethanol (2 ml) was treated with a 2M sodium hydroxide aqueous solution (1 ml) and heated at 80° C. with stirring for 4 hours. The reaction mixture was cooled to room temperature and diluted with water (5 ml). The aqueous solution was acidified with glacial acetic acid, and extracted with EtOAc (2×10 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification of the residue by MDAP gave the desired product (3 mg, 3%) as a colourless solid. MS (ES): C22H22ClN5O4 requires 455; found (MH+) 456.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[O:13][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:10][CH:11]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2cc(Cl)cc(Cl)c2)o1
Product: CCOC(=O)CCc1cccc(NC(=O)c2ccc(-c3cc(Cl)cc(Cl)c3)o2)c1

Procedure:
Carboxylic acid (67) (67 mg, 0.26 mmol) was coupled to aniline (124) (50 mg, 0.26 mmol) using Method C. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]([CH2:19][CH2:20][CH2:21][CH3:22])[N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]([CH2:19][CH2:20][CH2:21][CH3:22])[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CCCCc1nc(Br)sc1C(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nc(N2CC(NC(=O)OC(C)(C)C)C2)sc1C(=O)OCC
Yield: 74.4 %

Procedure:
The same operation as in Example (217a) was performed using 3-tert-butoxycarbonylaminoazetidine (212 mg, 1.23 mmol), ethyl 2-bromo-4-n-butyl-1,3-thiazole-5-carboxylate obtained in Example (220b) (300 mg, 1.03 mmol) and diisopropylethylamine (0.36 mL, 2.06 mmol), to obtain 294 mg of the title compound as a white solid (74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([OH:16])=[CH:8][CH:7]=1.Cl[CH2:22][C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([O:16][CH2:22][C:23]2[S:27][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=3)=[N:25][CH:24]=2)=[CH:8][CH:7]=1
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)s2)cc1
Reactant: CCOC(Cc1ccc(O)c2c1CCCC2)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)s2)c2c1CCCC2)C(=O)OC

Procedure:
In analogy to the procedure described in 14 b], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid methyl ester (example 2 c]) was reacted with 5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole (prepared from [2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol [PCT Int. Appl. (2002), WO 02/62774 A1] and methanesulfonyl chloride, triethylamine in dichloromethane) in N,N-dimethylformamide in the presence of cesium carbonate to give [rac]-2-ethoxy-3-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 1 e], to yield [rac]-2-ethoxy-3-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid as light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH3:31][C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:33]3[C@H:32]([CH3:31])[CH2:36][O:35][C:34]3=[O:37])=[CH:3][C:4]=2[N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 87.5 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (492 mg) described in Preparation Example 181 and (R)-4-methyloxazolidin-2-one (121 mg) described in Preparation Example 25, the title compound (448 mg) was obtained.
Reaction SMILES: [CH:1]([C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH3:11])=[CH2:4])=[O:2].[N+](=C)=[N-].C[OH:27]>C(OCC)C>[C:1]([C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH3:11])=[CH2:4])([OH:27])=[O:2]
Reactant: CO
Reactant: C=C(C=O)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: C=C(C(=O)O)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1

Procedure:
(3S,4S)-4-(1-Carboxyethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone (37 g), which was prepared from (3S,4S)-4-(1-formylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone in the similar procedure to Example 6, was dissolved in methanol and then diluted with diethyl ether. A solution of diazomethane in diethyl ether was added dropwise thereto with ice-cooling, and the resultant mixture was stirred for 0.5 hour. After removal of excess diazomethane, the reaction mixture was concentrated in vacuo to give (3S,4S)-4-(1-methoxycarbonylethenl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][C:16]=2[O:30]CC2C=CC=CC=2)([OH:14])[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:29][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:10]2([OH:14])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[C:16]([OH:30])[CH:17]=1)([CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(C2(O)CCCN(Cc3ccccc3)C2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2(O)CCCNC2)c(O)c1
Yield: 70 %

Procedure:
A mixture of 8.5 g. (17.03 mmoles) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-hydroxypiperidine, 2.0 g. of 10% palladium-on-carbon and 60 ml. of ethanol is stirred under one atmosphere of hydrogen for 2 hours. The reaction mixture is filtered through diatomaceous earth with ethyl acetate and evaporated. The residue is crystallized from ethyl acetate to yield 3.8 g. (70%) of the title compound. A second crop of the title compound 0.396 g. (7%) is obtained from the mother liquor.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:10][CH:9]=2)[C:5]2[C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[OH-].[Na+].[CH3:36]I.Cl>C(O)C>[CH3:36][S:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:12][CH:13]=2)[C:5]2[C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1cccc2nc(S)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cccc2nc(SC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-mercapto-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.68 g) in ethanol (10 ml) containing 1N-NaOH (3.0 ml) was added methyl iodide (0.24 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with dilute hydrochloric acid to give crystals. The crystals were purified by column chromatography on silica gel. Recrystallization from ethyl acetate afforded colorless prisms (0.31 g, 44%), m.p. 207–208° C. (decomp.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][C:19](=[O:23])[NH:20]2)=[CH:15][CH:14]=1.Cl.[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>O>[CH:29]1[CH:28]=[C:27]([N:33]2[CH2:38][CH2:37][N:36]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]4[CH2:17][CH2:18][C:19](=[O:23])[NH:20][C:21]=4[CH:22]=3)[CH2:35][CH2:34]2)[C:26]([Cl:25])=[C:31]([Cl:32])[CH:30]=1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C1CCc2ccc(OCCCCCl)cc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reaction time: 3 h
Yield: 75.1 %

Procedure:
Potassium carbonate (8.39 g) was dissolved in water (140 mL), followed by the addition of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril (19.4 g) and 1-(2,3-dichlorophenyl)piperazine monohydrochloride (16.2 g) thereto. The mixture was refluxed under stirring for about 3 hours. After reaction, the resulting mixture was cooled, and precipitated crystals were filtered. The crystals were dissolved in ethyl acetate (350 mL), and about 210 mL of water/ethyl acetate azeotrope was distilled under reflux. The remaining solution was cooled, and precipitated crystals were filtered. The thus-obtained crystals were dried at 60° C. for 14 hours, thereby obtaining 20.4 g of crude aripiprazole (yield: 74.2%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[S:23][C:22]([C:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)([OH:26])[CH3:25])=[N:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=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>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:26][C:24]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)([C:22]1[S:23][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=3)[CH:14]=2)=[CH:20][N:21]=1)[CH3:25]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2ncc(-c3cccc(N)c3)s2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Yield: 66.2 %

Procedure:
2-Chloro-4-(trifluoromethyl)pyrimidine (0.030 mL, 0.245 mmol), the product of Step 3 (82.4 mg, 0.204 mmol), Cs2CO3 (133 mg, 0.408 mmol), palladium(II) acetate (2.292 mg, 10.21 μmol) and Xantphos (17.72 mg, 0.031 mmol) were stirred in Dioxane (4.0 mL) at 105° C. overnight under N2. The reaction mixture was filtered through a celite pre-pack column with CH2Cl2 and small amount of 2-MeTHF. The filtrate was concentrated and the residue was purified by flash chromatography to give tert-butyl 4-{1-hydroxy-1-[5-(3-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}piperidine-1-carboxylate (Example 15(1), 74 mg, 0.135 mmol, 66%). APCI: [M-Boc+H]+ m/z 450.1. 1H NMR (CDCl3): δ 8.67 (d, J=4.91, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.66 (s, 1H), 7.52 (d, J=8.22, 1H), 7.39 (t, J=7.91, 1H), 7.30-7.25 (m, 1H), 7.08 (d, J=4.91, 1H), 4.19-4.09 (m, 2H), 3.31 (s, 1H), 2.75-2.57 (m, 2H), 1.95 (td, J=12.01, 3.49, 1H), 1.87-1.73 (m, 1H), 1.67 (s, 3H), 1.60-1.49 (m, 1H), 1.45 (s, 9H), 1.50-1.32 (m, 1H). rhSYK activity=++
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])[CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[K+].C(O)C.Cl>O>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])[CH:16]=2)=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(C#Cc2cccc(S(=O)(=O)Nc3ncccc3C)c2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccnc1NS(=O)(=O)c1cccc(C#Cc2ccc(O)c(C(=O)O)c2)c1

Procedure:
Ethyl 2-hydroxy-5-[[3-[(3-methyl-2-pyridinylamino)sulfonyl]-phenyl]ethynyl]benzoate (4 g, 9.2 mmol) was added to a boiling solution of potassium hydroxide (6 g, 90 mmol) in water (100 ml). After 15 min ethanol (50 ml) was added and the solution acidified with hydrochloric acid. The product was collected by filtration and dried at 110 ° C. Yield 3.5 g, 93%.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Br:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH:21]=[CH:22][C:23](O)=O>>[Br:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1cc(C=CC(=O)O)cc(Br)c1OC
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(Br)c(OC)c(OC)c3)nc2n(CCC)c1=O
Yield: 66.6 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 1.5 g (6.64 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.10 g (7.31 mmol) of 3-bromo-4,5-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.11 g (yield 67%) of Compound 59 as white needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([CH3:17])[N:16]=2)C(O)=O)[CH:7]=1.P([N:35]=[N+]=[N-])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(N(CC)CC)C.CC(O)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[CH:9]=[C:10]([NH2:35])[CH:14]=[C:15]([CH3:17])[N:16]=2)[CH:7]=1
Reactant: Cc1cc(C(=O)O)cc(-c2cc(Cl)ccc2F)n1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Cc1cc(N)cc(-c2cc(Cl)ccc2F)n1

Procedure:
2-(5-Chloro-2-fluorophenyl)-6-methylisonicotinic acid (1.1 g, 4.14 mmol), diphenyl phosphorazidate (0.895 ml, 4.14 mmol), triethylamine (0.873 ml, 6.21 mmol), 2-methylpropan-2-ol (0.466 ml, 4.97 mmol) were combined in toluene (12.5 mL) and heated at reflux for 30 minutes, then cooled and concentrated to give a residue. The residue was purified by silica chromatography eluted using a step gradient (0-25% ethyl acetate/hexanes) to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49 (s, 9H) 2.46 (s, 3H) 7.34-7.42 (m, 2H) 7.49-7.56 (m, 1H) 7.76 (s, 1H) 7.94 (dd, J=6.82, 2.78 Hz, 1H) 9.90 (s, 1H). ESI-MS: m/z 337.2 (M+H).
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N:11]1[S:12][N:13]=[C:14]2[CH:19]=[C:18]([C:20](OC)=[O:21])[CH:17]=[CH:16][C:15]=12>ClCCl>[N:11]1[S:12][N:13]=[C:14]2[CH:19]=[C:18]([C:20]([N:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)=[O:21])[CH:17]=[CH:16][C:15]=12
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc2nsnc2c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(c1ccc2nsnc2c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Trimethylaluminum (2M in toluene; 3.0 mL, 6.0 mmol) was diluted into 30 mL dichloromethane to which piperidine (0.55 g, 6.5 mmol) and methyl benzo-2,1,3-thiadiazole-5-carboxylate (1.16 g, 6.00 mmol) were added. The reaction was stirred at room temperature for 2 hours and concentrated to one-half the volume by rotary evaporation. Dry toluene (25 mL) was added and the reaction solution was heated to 80° C. for 1 hour. Additional piperidine (about 0.2 g) was added and the temperature was increased to 100° C. for 1 hour. The solution was allowed to cool to room temperature and stirred overnight, at which time it was quenched with 10% citric acid and hydrochloric acid. The solution was diluted with ethyl acetate and sequentially washed with 10% citric acid, saturated sodium hydrogen phosphate and saturated sodium chloride, and subsequently dried over anhydrous sodium sulfate. The solution was concentrated onto silica and product was eluted with hexane/ethyl acetate (3:1). Purification by distillation in a kugelrohr at 180° C. and 0.5 mmHg yielded 1-(benzo-2,1,3-thiadiazole-5-ylcarbonyl)piperidine, 1 (1.29 g, 87%) as a pale yellow oil. IR: 2920, 2855, 1633, 1478, 1439, 1280, 1223, 1001, 816, and 748 cm-1. 1H NMR (500 MHz): δ 8.06 (1H, d, J=9.1 Hz); 8.02 (1H, s); 7.63 (1H, t, J=9.0 and 1.5 Hz); 3.77 (2H, br s); 3.40 (2H, br s); 1.72 (4H, br s); and 1.57 ppm (2H, br s).
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(O)(=O)C.CO>[Br:20][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.1 %

Procedure:
Into a 2 L Meyer flask was put 24.3 g (100 mmol) of 9-phenylcarbazole, and dissolved in 600 mL of glacial acetic acid. Then, 17.8 g (100 mmol) of N-bromosuccinimide was slowly added thereto, followed by stirring at room temperature for about 12 hours. This glacial acetic acid solution was dropped into 1 L of ice water while being stirred. A white solid substance was precipitated and collected by suction filtration, and then the white solid substance was washed with water three times while being suction filtered. This solid substance was dissolved in 150 mL of diethyl ether, and this solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and water. The resulting organic layer was dried with magnesium sulfate. This mixture was suction filtered, and the obtained filtrate was concentrated to give an oily substance. This oily substance was dissolved in about 50 mL of methanol. The resulting solution was left still to precipitate a white solid. This solid substance was collected by suction filtration and dried. Then, 28.4 g (88% yield) of 3-bromo-9-phenylcarbazole was obtained as a white powder.