Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](/[C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH3:25])([CH3:24])[CH2:17][CH2:18][C:19]2([CH3:23])[CH3:22])=[CH:14][C:13]=1[CH3:26])=[CH:3]\[C:4]1[CH:11]=[CH:10]C(C#N)=[CH:6][CH:5]=1.[OH2:27].[CH2:28]([OH:30])[CH3:29]>[OH-].[Na+]>[CH3:1]/[C:2](/[C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH3:25])([CH3:24])[CH2:17][CH2:18][C:19]2([CH3:23])[CH3:22])=[CH:14][C:13]=1[CH3:26])=[CH:3]\[C:4]1[CH:11]=[CH:10][C:29]([C:28]([OH:27])=[O:30])=[CH:6][CH:5]=1
Reactant: O
Reactant: CCO
Reactant: C/C(=C\c1ccc(C#N)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
13.5 g of E-4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzonitrile in a mixture of 200 ml of ethanol and 200 ml of 10N sodium hydroxide solution were heated at the boil for 3 hours. The mixture was then cooled, after which it was poured onto 1 liter of water, and the colorless precipitate was filtered off under suction and dried to give 14.9 g of E-4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid of melting point 204°-206° C. (cf. Example 2).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[C:23]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:21]=[C:20]([CH3:30])[N:19]=1>>[CH3:17][C:18]1[C:23]([N:24]2[CH2:29][CH2:28][N:27]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:16])=[CH:15][CH:14]=3)=[O:13])[CH2:26][CH2:25]2)=[CH:22][CH:21]=[C:20]([CH3:30])[N:19]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)n1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C)n1
Yield: 34.3 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (270 mg) described in Preparation Example 16 and 1-(2,6-dimethylpyridin-3-yl)piperazine (215 mg) described in Preparation Example 94 and by the reaction and treatment in the same manner as in Example 87, the title compound (159 mg) was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:13][NH:14][C:15]([C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1)=[O:16].O>CN(C=O)C>[CH3:13][NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:3]([S:2][CH3:1])[S:4][C:5]=3[CH:11]=2)[CH:20]=[CH:19][N:18]=1)=[O:16]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: CSc1nc2ccc(O)cc2s1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc3nc(SC)sc3c2)ccn1
Temperature: 70 °C
Yield: 61.4 %

Procedure:
To the solution of 2-methylsulfanyl-benzothiazol-6-ol (3.76 g, 19.08 mmol, 1.0 eq) in DMF (25 mL), was added CsCO3 (15.54 g, 47.70 mmol, 2.5 eq) at room temperature. After stirring for a while, 4-chloro-pyridine-2-carboxylic acid methylamide (4.86 g, 28.62 mmol, 1.5 eq) was added to the mixture and the mixture was stirred at 70° C. under reflux condenser overnight. After cooling the reaction mixture in ice bath, water (100 mL) was added and the aqueous layer was extracted with ethyl acetate (3×150 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified using 20 g of ISCO Silica Gel column (0%-50%-80%-100% ethyl acetate-hexane mixture over 45 min 40 mL/min run) to yield 4-(2-methylsulfanyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (3.88 g, 62%) as a white solid. M+H=332.1
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:57])C(=O)C1>CC#N>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[C:36]([Cl:57])[N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3c(Cl)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (56 mg, 0.083 mmol, 1 equiv) in MeCN (1 mL) was added NCS (11 mg, 0.083 mmol, 1 equiv). After 1 h, the reaction was concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (51 mg, 87%) as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 8.40 (t, J=1.5 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.31 (s, 1H), 7.03 (d, J=10.3 Hz, 1H), 6.87 (d, J=6.8 Hz, 1H), 6.28-5.83 (m, 1H), 4.54-4.46 (m, 1H), 4.12-4.06 (m, 1H), 3.71 (s, 3H), 3.62-3.57 (m, 1H), 3.49-3.42 (m, 1H), 3.31 (br. s., 1H), 2.48 (s, 3H), 2.48-2.36 (m, 1H), 2.31 (d, J=1.3 Hz, 3H), 2.17-2.09 (m, J=6.0 Hz, 1H), 2.00-1.61 (m, 10H), 1.29 (s, 3H), 1.26 (s, 9H), 1.11 (d, J=6.0 Hz, 3H); LCMS (ESI, M+1):706.25.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Cl[S:16](O)(=O)=O.C(Cl)(=O)C(Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>C(Cl)Cl.CN(C)C=O.Cl>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:4]2[CH:3]=[CH:2][C:1]([SH:16])=[CH:6][CH:5]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Sc1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
A solution of 4-bromodiphenyl ether (50 g, 200.7 mmol) in methylene chloride (118 mL) was cooled to 0° C. and chlorosulfonic acid (14.7 mL, 220.8 mmol) was added dropwise over a 20 minute period. The solution was stirred an additional 10 minutes, warmed to room temperature and stirred an additional 1 hour. To this mixture was added oxalyl chloride (23.6 mL, 270.9 mmol), followed by N,N-dimethylformamide (1.5 mL) as a catalyst, and the mixture refluxed for 2 hours. The mixture was cooled to room temperature, and additional oxalyl chloride (23.6 mL, 270.9 mmol) was added, the mixture refluxed for 3 hours, cooled to room temperature and stirred 12 hours more. The solution was concentrated to an oil, azeotroped several times using methylene chloride and put under high vacuum (1 torr) for several hours until the mixture had completely solidified. This mixture was immediately dissolved in methylene chloride (160 mL) which was added dropwise to a solution of triphenylphosphine (157.0 g, 602 mmol) in methylene chloride (160 mL) containing N,N-dimethylformamide (4 mL, 52.2 mmol). The mixture was stirred 2 hours, diluted with 1M aqueous hydrochloric acid (300 mL) and stirred for 1 hour. The aqueous layer was separated, extracted with methylene chloride (200 mL), and the organic layers were combined, washed with 200 mL of brine, dried (MgSO4) and concentrated in vacuo. The resulting solid was further purified through trituration with 750 mL of hexane. The solid was then dissolved in 750 mL of diethyl ether, extracted with 2M aqueous sodium hydroxide (2×350 mL), and the basic aqueous layer back extracted using diethyl ether (2×400 mL). The aqueous layer was adjusted to pH 2, extracted with diethyl ether (3×200 mL) and the combined organic layers dried (MgSO4) and concentrated to afford 4-(4-bromophenoxy)thiophenol (45.6 g, 81%). 1HNMR (CDCl3) δ 3.43 (s, 1H), 6.86 (d, J=8.9 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 7.28 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.9 Hz, 2H).
Reaction SMILES: [C:1]([O:4]CC(=O)CC1C=CC(Cl)=C(Cl)C=1)(=[O:3])[CH3:2].[S:17]1[CH:21]=[C:20]([CH2:22][C:23](=[O:26])[CH2:24]Cl)[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]1=2.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:24][C:23](=[O:26])[CH2:22][C:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[S:17][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(CCl)Cc1csc2ccccc12
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)Cc1csc2ccccc12
Yield: 51 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-(benzo[b]thiophen-3-yl)-3-chloropropan-2-one (0.661 g, 2.94 mmol) with acetic acid (0.34 mL, 0.35 g, 5.9 mmol) and triethylamine (0.82 mL, 0.59 g, 5.9 mmol). Flash chromatography over silica gel (10-40% ethyl acetate in hexanes) gave pure product (0.372 g, 51% yield): 1H NMR (400 MHz, CDCl3) δ 2.14 (s, 3H) 3.98 (s, 2H) 4.71 (s, 2H) 7.34-7.44 (m, 3H) 7.67-7.70 (m, 1H) 7.86-7.89 (m, 1H).
Reaction SMILES: COC(=O)[C@H:4]([NH:12][CH2:13][CH2:14][NH:15][C:16]([O:18]C(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:5]([C@H:4]1[N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:14][NH:15][C:16]1=[O:18])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NCCNC(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCCN(Cc2ccccc2)[C@@H]1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
(3R)-3-Benzylpiperazin-2-one (4.1 g; 21.6 mmol, prepared as described in Example 1) was dissolved in methanol (40 ml). Benzaldehyde (2.3 g; 21.6 mmol) was added followed by 4 Å molsieves (2 g) and the mixture was stirred under an atmosphere of nitrogen for 1/2 h. Acetic acid (1.2 ml) was added and sodium cyanoborohydride (2.0 g; 32.4 mmol) was added portion wise during 20 minutes. The reaction mixture was stirred overnight and the filtered. From the filtrate the solvent was evaporated and the residue was dissolved into ethyl acetate (15 ml) and purified on silica gel using ethyl acetate as eluent. This afforded 2.6 g of (3R)-3,4-dibenzylpiperazin-2-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[CH2:11][CH2:10]2)=O)=[CH:3][CH:2]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:13]3[N:12]([CH:16]=[CH:15][N:14]=3)[CH:10]=[CH:11][CH:9]=2)=[CH:5][CH:6]=1
Reactant: c1c[nH]cn1
Reactant: O=C(c1ccncc1)C1CC1
Product: c1cc(-c2ccncc2)c2nccn2c1

Procedure:
Combine 15 g (0.10 mol) of cyclopropyl 4-pyridinyl ketone with 30 g (0.44 mol) of imidazole and heat to 180°-200° C. for 24 hr. Isolation from 200 g silica gel using 5% methanol/methylene chloride followed by crystallization from ether provides the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si:27]([O:34][CH2:35][CH2:36]Br)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:36][CH2:35][O:34][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Combine 3,4-dichlorophenylacetonitrile (10 g, 53.8 mmol) and anhydrous tetrahydrofuran (50 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of lithium bis(trimethylsilyl)amide (64.5 mL, 1 M in THF, 64.5 mmol). Add dropwise, 2-(t-butyldimethylsilyloxy)-1-bromoethane (15.43 g, 64.5 mmol). When the addition of 2-(t-butyldimethylsilyloxy)-1-bromoethane is complete, warm the reaction mixture to ambient temperature. After 12 hours, partition the reaction mixture between ethyl acetate and water. Extract the aqueous layer twice with ethyl acetate. Combine the organic layers and extract with 1 M hydrochloric acid solution, dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 10% ethyl acetate/hexane to give the title compound: Rf=0.42 (silica gel, 10% ethyl acetate/hexane).
Reaction SMILES: [C:1]1(C=CC(O)=C[CH:3]=1)[OH:2].[C:9]1(N2CCC(=O)N2)[CH:14]=CC=C[CH:10]=1.P(=O)(O)(O)O.[C:26](=[O:29])([O-])[OH:27].[Na+]>O>[C:26]([O:27][CH2:3][CH:1]=[O:2])(=[O:29])[C:9]([CH3:14])=[CH2:10]
Reactant: Oc1ccc(O)cc1
Reactant: O=C1CCN(c2ccccc2)N1
Reactant: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)OCC=O
Temperature: 25 °C
Yield: 27.6 %

Procedure:
In a 2 L four-necked flask, 180 g of potassium methacrylate (made by Wako Pure Chemical Industries Ltd., purity: 98.0%) was put, and 900 g of N,N-dimethylformamide was added thereto, and a stirrer, a thermometer and a Dimroth cooling tube were connected thereto. Then, 308 g of 2-bromo-1,1-diethoxyethane (made by ALDRICH Corporation, purity: 97%), 0.9 g of p-methoxyphenol and 1.32 g of tetramethylammonium iodide were added thereto, and the resulting mixture was allowed to react for 2 hours at 150° C. under stirring. The reaction mixture was cooled to room temperature, a precipitate was separated by filtration, and then N,N-dimethylformamide was distilled off, and the resulting product was distilled under reduced pressure to obtain 174 g of a reaction product (GC purity: 98.5%). From the thus obtained reaction product, 19 g was put into a 1 L four-necked flask subjected to replacement with nitrogen, stirred and dispersed into 430 mL of water, and 0.21 g of hydroquinone, 0.41 g of 1-phenyl-3-pyrazolidinone (made by Tokyo Kasei Kogyo Co., Ltd., purity: 98.0% or more) and 2.8 g of 85% phosphoric acid were added thereto, and the resulting mixture was allowed to react at 70 to 80° C. for 3 hours under stirring. The reaction mixture was cooled to room temperature, and neutralized using a 10% sodium hydrogen carbonate aqueous solution, and repeatedly extracted with diethyl ether. An organic layer was dried over magnesium sulfate, separated by filtration, and distilled under reduced pressure to give 5.6 g of 2-oxoethyl methacrylate (yield: 27.6% based on potassium methacrylate).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[O:15]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:14])[N:5]1[CH2:4][CH2:3][CH2:2][P+:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: O=C1c2ccccc2C(=O)N1CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
2.50 g (9.33 mmol) of 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione in 25 ml of xylene were degassed with argon, and 2.45 g (9.33 mmol) of triphenylphosphine were added. The mixture was stirred under reflux for 24 h and then filtered at 70° C. The filter cake was washed with a little di-ethyl ether and dried under high vacuum. This gave 3.50 g (70.8% of theory) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][C:34]=1[N+:35]([O-])=O)[C:12]([N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:17](=[O:31])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCOCC1>[NH2:35][C:34]1[CH:33]=[CH:32][C:11]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:17](=[O:31])[CH2:16][CH2:15]2)=[O:13])=[CH:10][C:9]=1[OH:8]
Reactant: [H][H]
Reactant: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c2ccccc21
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc(N)c(O)c2)c2ccccc21
Yield: 89.5 %

Procedure:
A solution of 5-(3-benzyloxy-4-nitrobenzoyl)-1-ethoxycarbonylmethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (2.2 g), 10% palladium on carbon (220 mg) in ethanol (30 ml) and 1,4-dioxane (15 ml) was stirred under 4 atmospheric pressure of hydrogen at ambient temperature for 7 hours. The reaction mixture was filtered through a bed of celite, concentrated and purified by silica gel column chromatography (SiO2 60 g, ethyl acetate:n-hexane =2:1) to give 5-(4-amino-3-hydroxybenzoyl)-1-ethoxycarbonylmethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.5 g).
Reaction SMILES: [F-:1].[K+].[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]=[C:14]=[O:15].[F:16][C:17]([F:24])([F:23])[C:18]([F:22])=[C:19]([F:21])[F:20]>CN(C=O)C>[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][C:14](=[O:15])[C:18]([F:22])([C:19]([F:1])([F:21])[F:20])[C:17]([F:24])([F:23])[F:16]
Reactant: [F-]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1Br
Reactant: FC(F)=C(F)C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Br)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 70 °C

Procedure:
Potassium fluoride (23 grams; 0.4 mole) which was dried by heating strongly with a bunsen burner in a porcelain crucible and subsequently powdered, was added to 200 ml of a DMF solution of 2-bromo-4-nitrophenyl isocyanate (6 grams; 0.025 mole). The mixture was placed in a pressure vessel, purged with a small stream of hexafluoropropene, and heated to 70° C. while adding hexafluoropropene from a pre-weighed supply cylinder at 10-20 psig. A pressure drop occurred as the gas reacted, and the remaining hexafluoropropene was added intermittently until the supply cylinder was empty; heating was continued at 65°-70° C. for 21/2 hours with pressure stabilized at 5 psig. The reaction vessel was then cooled and the solution poured off and extracted with hexane.. The DMF solution was poured into water and filtered. The solid products were taken up in chloroform, dried over sodium sulfate, filtered, evaporated, and chromatographed on silica gel with ethyl acetate/hexane (1:5). The front-running product was collected; H-NMR of this product indicated the desired product The material was then chromatographed on silica gel with gradient elution from 100% hexane to 100% ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[Cl:12]N1C(=O)CCC1=O.O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:9]([Cl:12])[CH:10]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: O=C1CCC(=O)N1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(Cl)c1C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-2-methyl-benzoic acid (6.45 g, 30 mmol,), N-chlorosuccinimide (4.67 g, 35 mmol), and palladium (II) acetate (0.675 g, 3 mmol) in dry DMF (35 mL) was heated under a nitrogen atmosphere at 100° C. for 36 h. After this time, the reaction mixture was cooled to ambient temperature and poured into water. The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic extracts washed with aqueous sodium thiosulphate (30 mL) and then brine (30 mL). The remaining organic solution was dried over anhydrous MgSO4, filtered, and concentrated to give 4-bromo-2-chloro-6-methyl-benzoic acid. The product was used without further purification.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([N:12]2[C:17]3[N:18]=[C:19](S(C)(=O)=O)[N:20]=[CH:21][C:16]=3[CH:15]=[C:14]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])[C:13]2=[O:34])[CH2:11][CH2:10][CH2:9][CH2:8]1.[N:35]1[S:36][N:37]=[C:38]2[CH:43]=[C:42]([NH2:44])[CH:41]=[CH:40][C:39]=12>CS(C)=O.O.C(OCC)(=O)C>[N:35]1[S:36][N:37]=[C:38]2[CH:43]=[C:42]([NH:44][C:19]3[N:20]=[CH:21][C:16]4[CH:15]=[C:14]([C:26]5[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=5[Cl:33])[C:13](=[O:34])[N:12]([CH:7]5[CH2:11][CH2:10][CH2:9][CH2:8]5)[C:17]=4[N:18]=3)[CH:41]=[CH:40][C:39]=12
Reactant: CS(=O)(=O)c1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C3CCCC3)c2n1
Reactant: Nc1ccc2nsnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=c1c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc4nsnc4c3)nc2n1C1CCCC1

Procedure:
202 mg of potassium tert-butoxide are added in 3 installments, at ambient temperature under argon, to 500 mg of compound of formula (II), 8-cyclopentyl-6-(2,6-dichlorophenyl)-2-methylsulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and 249 mg of the compound of formula (III), 2,1,3-benzothiadiazol-5-ylamine, in suspension in 18 ml of DMSO. After a contact time of 45 min, the reaction medium is diluted with a mixture of water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are then washed with water and then with a saturated NaCl solution. After drying over sodium sulfate and filtering, the residue is chromatographed on silica (gradient: heptane 100 to heptane/ethyl acetate 60:40) and precipitated from diethyl ether to give 283 mg of the expected product in the form of a yellow solid.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([C:15]1[S:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=1)[CH3:14].[CH3:23][C:24]12[CH2:31][CH:28]([NH:29][CH2:30]1)[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2.O>C(Cl)Cl>[CH2:13]([C:15]1[S:19][CH:18]=[C:17]([C:20]([N:29]2[CH2:30][C:24]3([CH3:23])[CH2:31][CH:28]2[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]3)=[O:22])[CH:16]=1)[CH3:14]
Reactant: CC1(C)CC2CC(C)(CN2)C1
Reactant: CCc1cc(C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCc1cc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.06 g; 1.2 eq) was added to a solution of 5-ethyl-thiophene-3-carboxylic acid (0.04 g; 1 eq.) in DCM (1 mL/100 mg of starting material). This mixture was stirred at room temperature for 5 minutes, then 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (0.043 g; 1.1 eq.) added and the mixture allowed to stir for 18 hours. Water (1 mL/100 mg of starting material) was then added and the organic layer separated, dried and evaporated to give the crude product which was purified by column chromatography (EtOAc/iso-hexane) to give the title compound (0.046 g). LCMS m/z 292 [M+H]+ RT=4.28 min (Analytical Method 3).
Reaction SMILES: C1(O)C=CC=CC=1.[C:8](C1C=CC=CC=1O)([CH2:11][CH3:12])([CH3:10])[CH3:9].C(C1C=CC(O)=CC=1)(CC)(C)C.[C:32]([C:37]1[CH:42]=[C:41]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:38]=1[OH:48])([CH2:35][CH3:36])([CH3:34])[CH3:33]>>[C:32]([C:37]1[CH:42]=[C:41]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])[CH:40]=[C:39]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])[C:38]=1[OH:48])([CH2:35][CH3:36])([CH3:34])[CH3:33]
Reactant: CCC(C)(C)c1ccc(O)c(C(C)(C)CC)c1
Reactant: CCC(C)(C)c1ccccc1O
Agent: CCC(C)(C)c1ccc(O)cc1
Solvent: Oc1ccccc1
Product: CCC(C)(C)c1cc(C(C)(C)CC)c(O)c(C(C)(C)CC)c1
Reaction time: 10 h
Yield: 10.8 %

Procedure:
The procedure of Example 1 was repeated except that 1.00 g (10.6 millimoles) of phenol, 11.4 g of the same C5 fraction as used in Example 1, and 1.00 g of Silica-Alumina "IS-28" (produced by Shokubai Kasei Kogyo Co., Ltd.) which had been burned at 500° C. for 10 hours were used. The acid strength of the silica alumina (as determined in the same manner as in Example 1) was as follows: H0 ≤- 8.2. The proportion of the unreacted phenol was 5.0%, and 0.05 g (2.9%) of o-tert-amylphenol, 0.22 g (12.6%) of p-tertamylphenol, 1.73 g (69.6%) of 2,4-di-tert-amylphenol, and 0.01 g (0.3%) of 2,4,6-tri-tert-amylphenol were formed.