Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])OC.[Mg+2].COC(=O)[O-].[CH2:12]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:29]1[CH2:33][CH2:32][CH2:31][CH:30]=1.Cl>CO>[CH2:12]([C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:28])[CH2:27][CH:30]2[CH2:31][CH2:32][CH2:33][NH:29]2)=[CH:24][CH:25]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)c1ccc(CCc2ccccc2)cc1
Reactant: C1=NCCC1
Agent: COC(=O)[O-]
Agent: Cl
Agent: [Mg+2]
Solvent: CO
Product: O=C(CC1CCCN1)c1ccc(CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 63 %

Procedure:
Magnesium methyl carbonate (0.4 mole, 2 M in dimethylformamide) is heated to 120°C. under carbon dioxide. The compound 4'-phenethylacetophenone, 22.4 g (0.1 mole), is added and the mixture is stirred at 120°C. for 4 hours under a stream of nitrogen allowing the methanol that forms to escape. The reaction mixture is allowed to cool to room temperature under an atmosphere of carbon dioxide and 8.3 g (0.12 mole) of 1-pyrroline (as the trimer) added and stirred at room temperature under carbon dioxide for a period of 40 hours. The solution is poured into a mixture of 200 ml of concentrated HCl and 800 g of ice and the product removed by filtration. The 4'-phenethyl-2-(2-pyrrolidinyl)-acetophenone when twice recrystallized in the form of its hydrochloride salt from an aqueous isopropanol solution is obtained in 63% yield (20.1 g) and has a M.P. of 200-1°C. (dec).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CN(C)C=O.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:19])=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1CCC(C(=O)O)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)Cl)CC1
Temperature: 20 °C

Procedure:
A flask was flame dried and placed under a nitrogen atmosphere. 1-methylpiperidine-4-carboxylic acid (1 eq) in anhydrous methylene chloride added to flask and cooled to 20° C. in a water bath. Dimethylformamide added, then oxalyl chloride (1.4 eq) in methylene chloride. Reaction refluxed for 2 hours, brought to room temperature, concentrated and azeotroped with toluene to yield 1-methylpiperidine-4-carbonyl chloride as a light yellow fluffy solid. MS: MH+=162.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][C@@H:5]1[CH3:25])=[N+]=[N-].[N:26]([C@@H:29]1[CH2:34][CH2:33][C@@H:32]([N:35]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:31][C@H:30]1[CH3:50])=[N+]=[N-]>C(O)(=O)C.Cl.C(OCC)C.[Zn]>[CH2:18]([N:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:7]1[CH2:8][CH2:9][C@H:4]([NH2:1])[C@@H:5]([CH3:25])[CH2:6]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1.[CH2:43]([N:35]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:32]1[CH2:33][CH2:34][C@@H:29]([NH2:26])[C@H:30]([CH3:50])[CH2:31]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: C[C@H]1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CC[C@@H]1N=[N+]=[N-]
Reactant: C[C@@H]1C[C@H](N(Cc2ccccc2)Cc2ccccc2)CC[C@H]1N=[N+]=[N-]
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: C[C@@H]1C[C@H](N(Cc2ccccc2)Cc2ccccc2)CC[C@H]1N
Product: C[C@H]1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CC[C@@H]1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,3S,4S)-4-azido-N,N-dibenzyl-3-methylcyclohexanamine/(1R,3R,4R)-4-azido-N,N-dibenzyl-3-methylcyclohexanamine (2.174 g, 6.5 mmol) in acetic acid (50 mL) was added slowly Zn-dust (0.638 g, 9.75 mmol). The mixture was stirred for 30 min at ambient temperature. Additional Zn-dust was added (150 mg) and stirring was continued for ˜15 min. The mixture was diluted carefully with 1N aqueous HCl and diethylether. The separated aqueous layer was extracted with diethylether (5×˜100 mL). The aqueous layer was partially lyophilized and concentrated to dryness in vacuo. The resulting residue was diluted with 1N aqueous HCl and concentration to dryness was repeated. Dilution with 1N HCl and concentration was repeated. The resulting residue was dissolved in water/acetonitrile and lyophilized to provide crude (1S,3S,4S)—N1,N1-dibenzyl-3-methylcyclohexane-1,4-diamine/(1R,3R,4R)—N1,N1-dibenzyl-3-methylcyclohexane-1,4-diamine as fluffy white solid. The crude material was directly used in the next step without further purification. Yield: 2.292 g. LCMS (m/z): 309.3 [M+H]+; Retention time=0.50 min.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:8][CH:7]=[CH:6]2)=[O:2].[BH4-].[Na+].O>O1CCCC1.CO>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:13][C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[N:8][CH:7]=[CH:6]2
Reactant: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1nccc2cc(CO)ccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 102.5 %

Procedure:
To a stirred suspension of 1.23 g of 1f in 40 mL of tetrahydrofuran and 15 mL of methanol was added 217 mg sodium borohydride in small portions. After stirring the mixture at ambient temperature for 5 min, 50 mL of water was added and tetrahydrofuran and methanol were removed in vacuo. Brine was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried (MgSO4) and concentrated under reduced pressure giving 1.27 g of 1g. 1H-NMR 200 MHz (CDCl3) δ: 4.75 (2H, s), 6.95 (1H, br.s), 7.30-7.55 (7H, m), 8.25-8.38 (2H, m), 8.69 (1H, br.s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH2:31])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2].[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH:31][C:32](=[O:34])[CH3:33])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1N
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1NC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
1-Amino-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carboxylic acid ethyl ester (30 mg, 0.07 mmol) prepared in Example 21 was dissolved in dichloromethane (10 mL), and acetyl chloride (30.15 mg, 0.37 mmol) and triethylamine (40 mg, 0.37 mmol) were added thereto in order at 0° C. The mixture was stirred for 24 hrs at RT, washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 15 mg of the titled compound (yield: 45%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[C:11]1[C:21]([NH2:22])=[N:20][C:14]2[N:15]=[C:16]([NH2:19])[N:17]=[CH:18][C:13]=2[CH:12]=1.[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[NH2:19][C:16]1[N:17]=[CH:18][C:13]2[CH:12]=[C:11]([C:3]3[C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=[C:5]([CH3:9])[C:4]=3[CH3:10])[C:21]([NH:22][C:28]([NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[N:20][C:14]=2[N:15]=1
Reactant: Cc1cc(C)c(C)c(-c2cc3cnc(N)nc3nc2N)c1C
Reactant: CC(C)(C)N=C=O
Product: Cc1cc(C)c(C)c(-c2cc3cnc(N)nc3nc2NC(=O)NC(C)(C)C)c1C

Procedure:
The title compound was prepared from 0.3 g of 6-(2,3,5,6-tetramethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 98 and 0.125 mL of tert-butyl isocyanate according to Example 2. The product was purified by medium pressure liquid chromatography eluting with 1:1CHCl3 :EtOAc; mp >300° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 393 (MH+, 55), 394 (MH+ +1, 13), 84 (100).
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:6]=1[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O.CO.[Pd]>[C:1]([C:5]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:6]=1[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1cc([N+](=O)[O-])ccc1C(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cc(N)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-tert-butyl-5-nitrobenzylcarbamate (20 mg, 0.065 mmol) in 5% AcOH-MeOH (1 mL) was added 10% Pd—C (14 mg) under nitrogen atmosphere. The mixture was stirred under H2 (1 atm) at room temperature for 1 h. The catalyst was removed via filtration through Celite, and the filtrate was concentrated to give tert-butyl 2-tert-butyl-5-aminobenzylcarbamate (E-4), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J=8.5 Hz, 1H), 6.62 (d, J=2.6 Hz, 1H), 6.47 (dd, J=8.5, 2.6 Hz, 1H), 4.61 (br s, 1H), 4.40 (d, J=5.1 Hz, 2H), 4.15 (br s, 2H), 1.39 (s, 9H), 1.29 (s, 9H); HPLC ret. time 2.47 min, 10-100% CH3CN, 5 min gradient; ESI-MS 279.3 m/z (MH+).
Reaction SMILES: BrC1C(CSCCN)=NC=CC=1.C([NH:21][C:22]([NH:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[C:45]([Br:46])=[CH:44][CH:43]=[CH:42][N:41]=1)=[N:23][CH2:24][CH2:25][S:26][CH2:27][C:28]1[C:33]([Br:34])=[CH:32][CH:31]=[CH:30][N:29]=1)(=O)C1C=CC=CC=1>N1C=CC=CC=1>[Br:46][C:45]1[C:40]([CH2:39][S:38][CH2:37][CH2:36][NH:35][C:22]([NH:23][CH2:24][CH2:25][S:26][CH2:27][C:28]2[C:33]([Br:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[NH:21])=[N:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(NC(=NCCSCc1ncccc1Br)NCCSCc1ncccc1Br)c1ccccc1
Agent: NCCSCc1ncccc1Br
Solvent: c1ccncc1
Product: N=C(NCCSCc1ncccc1Br)NCCSCc1ncccc1Br

Procedure:
The reaction of 3-bromo-2-[(2-aminoethyl)thiomethyl]-pyridine with N-benzoyl-bis-dimethylthiomidocarbonate in pyridine by the method described in Example 12 yielded N-benzoyl-N',N"-bis-[2-((3-bromo-2-pyridyl)-methylthio)ethyl]guanidine which, on acid hydrolysis, yielded the title compound.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[C:15]([Br:16])=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:17])C)(C)(C)C.Cl.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(O)C>[Br:16][C:15]1[C:10]([CH2:9][NH:7][CH3:6])=[C:11]([NH2:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c(N)cccc1Br)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1c(N)cccc1Br
Temperature: 100 °C
Yield: 765.5 %

Procedure:
(2-Amino-6-bromo-benzyl)-methyl-carbamic acid tert-butyl ester (371 mg) was dissolved in 50 ml ethanol. To this solution was added 2M ethanolic hydrochloride acid solution (10 ml). The reaction mixture was heated at 100° C. for 30 minutes, at which time the deprotection was completed. The solution was allowed to cool to room temperature and poured into the mixture of saturated NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with EtOAc three times and the organic fractions were concentrated to give 3-bromo-2-methylaminomethyl-phenylamine as a brown oil (1.938 g, 76%). MS: (M+H)+ 217.1.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:11][N:12]([CH3:14])[NH2:13]>C1(C)C=CC=CC=1>[CH3:11][N:12]([CH3:14])[NH:13][C:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10])=[O:9]
Reactant: Cc1ccccc1N=C=O
Reactant: CN(C)N
Solvent: Cc1ccccc1
Product: Cc1ccccc1NC(=O)NN(C)C
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
o-Tolyl isocyanate (10.0 g) was dissolved in 75 mL of toluene under nitrogen. The solution was cooled to 5° C. and to this was slowly added a solution of 1,1-dimethylhydrazine (5.7 mL) in toluene. After addition, the ice-bath was removed and the resulting slurry was allowed to stir an additional 10 minutes. The solid was filtered off and rinsed successively with hexane, a small amount of 20% diethyl ether/hexane, and then hexanes again. This afforded 11.1 g (77%) of the title compound of Step A. 1H NMR (CDCl3): δ 8.1 (br s,1H), 7.94 (d,1H), 7.21-7.15 (m,3H), 6.99 (t,1H), 5.23 (br s,1H), 2.63 (s,6H), 2.27 (s,3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[N:4][CH:3]=1.C([Li])CCC.[I:16]I>C1COCC1>[I:16][N:4]1[CH:5]=[C:6]2[S:10][CH2:9][CH:8]=[C:7]2[C:2]([Cl:1])=[CH:3]1
Reactant: II
Reactant: Clc1cncc2sccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: ClC1=CN(I)C=C2SCC=C12
Temperature: 25 °C
Yield: 51.8 %

Procedure:
In a 500 mL round-bottomed flask 120 mL of tetrahydrofuran and with 13 grams of 4-chloro-thieno[3,2-d]pyridine (76.6 mmol) were cooled to −78° C. To the stirring solution was added n-butyllithium (191.6 mmol, 2.5M in hexane) was added dropwise over a 20 minute period. After stirring an additional 20 minutes iodine (48.3 g, 191.6 mmol) in 80 mL of THF was added dropwise such that the internal temperature did not exceed −78° C. After the addition was complete the reaction was allowed to slowly warm to room temperature. The reaction mixture was quenched by diluting with chloroform and extracting with H2O (2×250 mL), followed by extraction of the combined aqueous material with CHCl3 (1×100 mL). The organic portions were then washed with Na2S2O3 (2×200 mL), H2O (2×200 mL), dried over MgSO4, filtered and dried. The resulting residue was suspended in a minimal amount of chloroform and an excess of ether was added. The solid obtained was filtered and washed with ether. The mother liquor was concentrated and another crop of material was isolated in the same fashion. The two crops of crystals were combined to afford 11.8 g (52%) of 6-iodo-4-chloro-thieno[3,2-d]pyridine that was greater than 90% pure. 1H NMR (400 MHz, CDCl3) δ8.51 (d, 1H), 7.83 (s, 1H), 7.24 (d, 1H). LC-MS: 295.9, 297.9 (MH+); HPLC RT: 6.45 min.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8](=O)[CH:7](C(OCC)=O)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[NH2:17][C:18]1[N:22]([CH2:23][CH2:24][C:25]#[C:26][CH3:27])[N:21]=[CH:20][C:19]=1[C:28]#[N:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.C1(C)C=CC=CC=1>[NH2:29][C:28]1[C:7]2[C:6](=[O:16])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:9][C:8]=2[N:17]=[C:18]2[N:22]([CH2:23][CH2:24][C:25]#[C:26][CH3:27])[N:21]=[CH:20][C:19]=12
Reactant: CC#CCCn1ncc(C#N)c1N
Reactant: CCCCN1CC(=O)C(C(=O)OCC)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC#CCCn1ncc2c(N)c3c(nc21)CN(CCCC)C3=O

Procedure:
A solution of 1-(n-butyl)-3-ethoxycarbonyl-pyrrolidin-2,4-dione (1.02 g.) in wet acetonitrile (23 ml.) was heated under reflux for 1.5 hours. The acetonitrile was evaporated under reduced pressure, leaving a clear oil which was immediately dissolved in toluene (28 ml.). To this solution was added 5-amino-1-(pent-3-ynyl)-4-cyanopyrazole (0.6 g.) and a catalytic amount of toluene-p-sulphonic acid (0.05 g.). The mixture was heated under reflux overnight, collecting water in a Dean-Stark trap. The reaction mixture was cooled to 0° and diluted with ether. The resulting precipitate was collected by filtration, giving 0.89 g. of 5-[N-(n-butyl)-2-oxo-3-pyrrolin-4-yl]amino-1-(pent-3-ynyl)-4-cyanopyrazole, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH2:9][CH2:10][C:11]2=[O:12]
Reactant: O=C(Cl)CCc1ccc(F)cc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2c(F)cc(F)cc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2,4-difluorophenyl) propanoic acid (28.7 g, 0.15 mol) and dimethylformamide (5 drops) at ambient temperature was added dropwise oxalyl chloride (50 mL, Aldrich). The mixture was stirred at ambient temperature for 18 h. The excess oxalyl chloride was removed by distillation in vacuo to give 3-(2,4-difluorophenyl)propionyl chloride. A solution of the 3-(2,4-difluorophenyl)propionyl chloride in dichloromethane (300 mL) was added dropwise to a mixture of aluminum chloride (23.4 g, 0.18 mol, Aldrich) in dichloromethane (300 mL) at ice bath temperature. After the addition was completed, the mixture was refluxed for 3.5 h and allowed to come to ambient temperature overnight. The reaction mixture was poured into ice water (1500 mL), the two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed successively with 0.1N aqueous sodium hydroxide and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to give 21.7 g of crude 4.6-difluoro-1-indanone. Chromatography on silica gel with hexanes: dichloromethane (3:1) as eluent gave 10.1 g of a light yellow solid. Recrystallization of 0.5 g from acetone: water mixture gave 0.2 g of 4,6-difluoro-1-indanone as a white solid: mp 97-99° C.; NMR (CDCl3): d 7.02-7.27 (m, 2H), 3.12 (t, 2H), 2.76 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:26](=[O:30])[C:27]([NH2:29])=[O:28])=[C:11]([CH2:24][CH3:25])[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:26](=[O:30])[C:27]([NH2:29])=[O:28])=[C:11]([CH2:24][CH3:25])[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CBr
Reactant: CCc1c(C(=O)C(N)=O)c2c(N)cccc2n1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C(=O)C(N)=O)c2c(NCC(=O)OC)cccc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
Methyl bromoacetate (0.07 ml, 0.78 mmol) was added to 250 mg (0.78 mmol) of 4-Amino-2-Ethyl-α-oxo-1-(phenylmethyl)-1H-indole-3-Acetamide in 4 ml of DMF, stirred at 60° C. for 0.5 hour, and then at room temperature for 20 hours. The mixture was diluted with water and extracted with EtOAc. The EtOAC solution was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel eluting with Hexane/50 to 100% EtOAc to give 196 mg (64%) of [[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]amino]acetic acid methyl ester melting at 188°-193° C.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][SH:9])[CH3:2].[H-].[Na+].I[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[C:17]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][S:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][S:3][CH2:1][CH3:2]
Reactant: CCSCCCCCS
Reactant: CCOC(=O)CCCCI
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCCSCCCCCSCC

Procedure:
To illustrate the preparation of the dithia-substituted fatty acid ethers, 5-ethylthiopentane thiol can be reacted with sodium hydride and the resulting product reacted with ethyl 5-iodovalerate to yield ethyl 6,12-dithiatetradecanoate. The ester group can then be removed by treatment with alkali metal hydroxide, e.g. NaOH, to produce the desired 6,12-dithiatetradecanoic acid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[SH:30][CH2:31][CH2:32][OH:33]>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:28][CH3:29])=[N:3][C:2]([S:30][CH2:31][CH2:32][OH:33])=[CH:7][N:6]=1)(=[O:10])=[O:11]
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: OCCS
Product: COc1nc(SCCO)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.2 g) and 2-mercaptoethanol (0.2 g). After removal of the SEM (2-[trimethylsilyl]ethoxymethyl) group the title compound was purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.015 g
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].C(N(CC)CC)C.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH:26]([CH2:28][NH:29][C:30]([C:32]3[S:33][C:34]([Cl:37])=[CH:35][CH:36]=3)=[O:31])[O:25][C:24]2=[O:38])=[CH:19][CH:18]=1>ClCCl>[Cl:37][C:34]1[S:33][C:32]([C:30]([NH:29][CH2:28][CH:26]2[O:25][C:24](=[O:38])[N:23]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[CH:22][CH:21]=3)[CH2:27]2)=[O:31])=[CH:36][CH:35]=1
Reactant: Nc1ccc(N2CC(CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CN(c2ccc(NS(=O)(=O)CCCCl)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An ice-cooled solution of 26.4 mg (0.15 mmol) of 3-chloro-1-propanesulphonyl chloride and 0.03 ml (0.2 mmol) of triethylamine in 3.5 ml of absolute dichloromethane is admixed with 35 mg (0.1 mmol) of N-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl}-5-chloro-2-thiophene-carboxamide (from Example 149). After 30 min, ice-cooling is removed and the mixture is stirred at room temperature overnight, and 150 mg (about 5.5 eq.) of PS-trisamine (Argonaut Technologies) and 0.5 ml of dichloromethane are then added. The suspension is stirred gently for 2 h and filtered (the resin is washed with dichloromethane/methanol), and the filtrate is concentrated. The product is purified by preparative RP-HPLC. Yield: 19.6 mg (40% of theory),
Reaction SMILES: [OH:1]C1CCN(C)CC1.FC1C=C(C=CC=1F)C#N.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)[C:23]#N>>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)[CH:23]=[O:1]
Reactant: CN1CCC(Oc2ccc(C#N)cc2F)CC1
Reactant: CN1CCC(O)CC1
Agent: N#Cc1ccc(F)c(F)c1
Product: CN1CCC(Oc2ccc(C=O)cc2F)CC1

Procedure:
Synthesized from 4-hydroxy-1-methylpiperidine and 3,4-difluorobenzonitrile according to an analogous synthetic method to Preparation Example 15, 3-fluoro-4-(1-methylpiperidin-4-yloxy)benzonitrile (1.1 g) was used according to an analogous synthetic method to Preparation Example 16 to provide the title compound (1.1 g).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][C:31]#[C:32][CH2:33][OH:34])[N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[N:42]=[C:41](S(C)(=O)=O)[N:40]=1>C1COCC1>[NH3:8].[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][C:31]#[C:32][CH2:33][O:34][C:41]3[N:42]=[C:43]([O:45][CH3:46])[CH:44]=[C:39]([O:38][CH3:37])[N:40]=3)[N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)ncnc1OCC#CCO
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(OCC#CCOc2ncnc(NS(=O)(=O)c3ccc(C(C)C)cn3)c2Oc2ccccc2OC)n1
Product: N
Reaction time: 16 h
Yield: 44.2 %

Procedure:
To a solution of 250 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 13) in 15 ml of THF was added 48 mg of NaH. The mixture was stirred for 2 h at room temperature before 120 mg of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added. Stirring was continued for 16 h at reflux. Eventually, the solvent was evaporated and the remaining residue was partitioned between 50 ml of 10% aqueous citric acid and 50 ml of ethyl acetate. The organic layer was separated and the aqueous layer was extracted two more times with 50 ml of ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The crude product was purified by chromatography on prep. tlc-plates coated with silica gel with ethyl acetate:methanol: sat. aqueous ammonia 8:2:1 to give 71 mg of 5-isopropyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as a beige foam. LC-MS: tR=5.50 min, [M+1]+=623.29, [M−1]+=621.40.