Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:24][CH2:25][CH2:26]O>CC(=O)OCC>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:26][CH2:25][Br:24])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: OCCBr
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCBr)o1

Procedure:
The title compound was prepared as described in Example 1 starting from 0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.150 mL (2.1 mmol) of 2-bromoethanol. MS (m/z, ES+): 446.30 (79BrM+1, 100%), 448.30 (81BrM+1, 80%); 1H NMR (400 MHz, DMSO-d6) δ: 7.30 (d, 1H), 5.67 (d, 1H), 4.49 (t, 2H), 4.16 (t, 2H), 3.73 (t, 2H), 1.72 (p, 2H), 1.3-1.45 (m, 2H), 1.25 (s, 20H), 0.85 (t, 3H); EA found for C21H35BrO4: C, 58.93: H, 8.52; calcd: C, 58.47; H, 8.18.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[CH2:32][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:4]2[S:3][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=2)=[CH:18][CH:17]=1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Oc1ccc(Cc2nc3ccccc3s2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a 25 mL vial which contained a suspension of NaH (60% in mineral oil, 60 mg, 1.5 mmol) in DMF (10 mL) was added the product from step 1 (241 mg, 1 mmol) at 0° C. The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (355 mg, 1 mmol) at 0° C. The resulting mixture was allowed warm to rt and stir at rt for 30 min and then was heated to 95° C. and stirred at 95° C. for 16 h. After cooling to rt, the mixture was poured onto 200 mL ice-water solution and this solution was allowed to stir at 0° C. for 30 min. The solid which formed was filtered out, dried through air to afford the title product (320 mg, 70%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.81-2.11 (m, 4H), 3.32-3.47 (m, 2H), 3.70-4.20 (m, 3H), 4.37 (s, 2H), 6.84-6.97 (m, 4H), 7.33 (t, J=7.6, 1H), 7.45 (t, J=7.6, 1H), 7.78 (d, J=8.0, 1H), 7.98 (d, J=8.4, 1H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].N1C=CC=CC=1.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[S:37]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])([C:34]1[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCCCCCCCCCCS(=O)(=O)c1ccc(C)cc1
Reaction time: 14 h
Yield: 94 %

Procedure:
In 90 ml of methylene chloride was dissolved methyl 20-hydroxyeicosanoate (8.0 g, 23.4 mmoles). To the obtained solution were added pyridine (7.93 g, 93.4 mmoles) and then, under ice-cooling, p-toluenesulfonyl chloride (8.90 g, 46.7 mmoles) gradually over a period of 1 hour. The mixture was stirred for 14 hours in a refrigerator. After the completion of the reaction, the reaction mixture was subjected to the same after-treatment steps as in Reference Example 1, to give methyl 20-tosyleicosanoate (10.57 g, 91%) having the following properties.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(#N)C>[N+:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:3][CH:4]=1)([O-:14])=[O:13]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)c2ccccc12
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(N2CCNCC2)c2ccccc12
Temperature: 60 °C

Procedure:
Treat a slurry of 1-chloro-4-nitro-isoquinoline (2.5 g, 12 mmol) in acetonitrile (100 mL) with solid piperazine (5.2 g, 60 mmol). Heat the resulting yellow mixture overnight at 60° C. After cooling to ambient temperature, partition the reaction mixture between ethyl acetate and a saturated aqueous sodium bicarbonate solution. Add MeOH, dichloromethane and ethyl acetate, and filter the entire mixture to give a bright yellow solid. (2.15 g, 69%; LCMS ES+ (m/z) 259 [M+H]).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][C:32](OC)=[O:33])[C:6]=2[CH:36]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][OH:33])[C:6]=2[CH:36]=1
Reactant: COC(=O)COC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc21
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCO)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of 7-chloro-5-methoxycarbonylmethoxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.2 g) in tetrahydrofuran (15 ml) is added with stirring lithium borohydride (0.1 g) under ice-cooling, and the mixture is stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-hydroxyethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.73 g) as colorless amorphous.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:25]1[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COc1ccc2c(-c3ccc(C(F)(F)F)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-trifluoromethyl-phenylboronic acid to give [6-methoxy-1-(4-trifluoromethyl-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 385(MH+).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]#[C:6][C@@H:7]([O:13]C1CCCCO1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C.O1CCCC1.S(=O)(=O)(O)O>O>[OH:13][C@@H:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6]#[C:5][CH:4]=[O:3]
Reactant: CCCCC[C@@H](C#CC(OCC)OCC)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCC[C@H](O)C#CC=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of (4S)-1,1-diethoxy-4-(2-tetrahydropyranyloxy)-2-nonyne (96.0 g., 0.31 mole), tetrahydrofuran (500 ml.), and 30% aqueous sulfuric acid (100 ml.) is stirred at room temperature for 17 hours. The solution is diluted with water and the oily product is extracted with ether. The ether extract is washed with sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of the ether leaves (4S)-4-hydroxy-2-nonynal as a colorless residual oil which is used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@@H:11]2[CH2:13][O:12]2)=[CH:5][C:4]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32]>C(O)(C)C.C(N)(C)C>[CH:15]([N:14]([CH:10]([CH3:11])[CH3:9])[CH2:13][C@@H:11]([C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:9][C@H:8]([CH2:7][C:6]1[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[C:4]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:5]=1)[CH:22]([CH3:24])[CH3:23])[OH:12])=[O:16]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO2)C(C)C)ccc1OC
Solvent: CC(C)N
Solvent: CC(C)O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN(C=O)C(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.030 g of tert-butyl {3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methyl-1(S)-(R)-oxiranylpentyl}carbamate (Example 1b) in 1.0 ml of isopropanol and 0.165 ml of isopropylamine is stirred at 60° C. over 2 hours. The reaction mixture is concentrated by evaporation to dryness. The residue is dissolved in 1.22 ml of dichloromethane, admixed successively with 0.006 ml of pyridine and 0.013 g of 4-nitrophenyl formate and stirred at room temperature over 1 hour. The reaction solution is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with 1M HCl, water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly yellowish oil. Rf=0.51 (95:5 dichloromethane-methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:12])[CH:10]=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:22][C:23]1([C:29]([O:31][CH3:32])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[C:16]([O:15][C:14]([NH:13][C:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)([CH3:12])[CH2:10][NH:22][C:23]1([C:29]([O:31][CH3:32])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1cc(F)cc(F)c1
Reactant: COC(=O)C1(N)CCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1(NCC(C)(NC(=O)OC(C)(C)C)c2cc(F)cc(F)c2)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl [1-(3,5-difluorophenyl)-1-methyl-2-oxoethyl] carbamate from Step C (500 mg, 1.75 mmol), methyl 1-aminocyclohexanecarboxylate hydrochloride from Step D (1.38 g, 8.76 mmol), and AcOH (0.301 mL, 5.26 mmol) in MeOH (15 mL) was stirred at ambient temperature for 30 min. NaCNBH3 (165 mg, 2.63 mmol) was added and the pH of the mixture was checked and adjusted to pH˜5 as necessary by addition of AcOH. The reaction mixture was stirred at ambient temperature for 1 h, then quenched with saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc-100:0 to 80:20, to give the title compound.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:12][C:13](=[O:20])[CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:7][CH:8]=2)[C:3]1=[O:21].N1C(C)=CC(C)=CC=1C>O1CCCC1>[CH:15]1([CH2:14][C:13]([NH:12][C:6]2[CH:5]=[C:4]3[C:9]([CH:10]=[CH:11][CH:2]=[C:3]3[OH:21])=[CH:8][CH:7]=2)=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(CC1CCCC1)Nc1ccc2c(c1)C(=O)C(Br)CC2
Solvent: Cc1cc(C)nc(C)c1
Solvent: C1CCOC1
Product: O=C(CC1CCCC1)Nc1ccc2cccc(O)c2c1
Temperature: 160 °C

Procedure:
A mixture of 2-bromo-7-cyclopentylacetamido-1-tetralone (1.1 g) and collidine (12 ml) was heated at 160° C. for 2 h. After cooling, the reaction mixture was diluted with 1:9 tetrahydrofuran:ethyl acetate, washed (1N HCl (4 times), brine), dried (MgSO4) and evaporated to give 7-cyclopentylacetamido-1-napthol (quantitative) as a brown glassy solid which was used without further purification.
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][NH2:16])[CH:11]=1.FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59](O)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59]([NH:16][CH2:15][C:12]4[CH:11]=[C:10]([CH3:9])[O:14][N:13]=4)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)O
Reactant: Cc1cc(CN)no1
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cc(CNC(=O)c2sc(N3C(=O)N(Cc4ccc(F)cc4)C[C@@H]3C)nc2C)no1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (5-methylisoxazol-3-yl)methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (S)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid (70%): mp 174-175° C. (N,N-dimethylformamide/water); 1H NMR (300 MHz, DMSO-d6) δ 8.48 (t, J=5.8 Hz, 1H), 7.37-7.32 (m, 2H), 7.23-7.17 (m, 2H), 6.13 (d, J=0.7 Hz, 1H), 4.58-4.52 (m, 1H), 4.43 (d, J=4.3 Hz, 2H), 4.36 (d, J=5.8 Hz, 2H), 3.64-3.58 (m, 1H), 3.04 (dd, J=9.0, 3.4 Hz, 1H), 2.48 (s, 3H), 2.37 (d, J=0.7 Hz, 3H), 1.39 (d, J=6.0 Hz, 3H); MS (ES+) m/z 443.8 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:24]([CH3:26])[CH3:25])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:8])=[O:4].C1COCC1>CCCCCCC>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:24]([CH3:26])[CH3:25])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=[O:15])=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(C)C
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(S)-Benzyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylate (40 g) and 5% Pd/alumina were charged to a Parr® reactor followed by THF (160 mL). The reactor was sealed and purged with nitrogen (6×20 psig) followed by a hydrogen purge (6×30 psig). The reactor was pressurized to 30 psig with hydrogen and agitated at room temperature for approximately 15 hours. The resulting slurry was filtered through a GF/F filter and concentrated to approximately 135 g solution. Heptane (120 mL) was added, and the solution was stirred until solids formed. After an addition 2-3 hours, additional heptane (240 mL) was added drop-wise, the slurry was stirred for approximately 1 hour, then filtered. The solids were dried to afford the title compound (S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][Si:48]([C:51]#[CH:52])([CH3:50])[CH3:49]>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([C:52]#[C:51][Si:48]([CH3:50])([CH3:49])[CH3:47])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCC(CC)COc1ccc(Br)cc1Cn1nc(CCC(=O)OC)cc1C
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCC(CC)COc1ccc(C#C[Si](C)(C)C)cc1Cn1nc(CCC(=O)OC)cc1C
Temperature: 120 °C
Yield: 48.4 %

Procedure:
A mixture of 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.0774 g, 0.18 mmol), [PdCl2(PPh3)]2 (0.007 g, 0.01 mmol), PPh3 (0.0094 g, 0.018 mmol) mmol), CuI (2 mg, 0.01 mmol), trimethylsilylacetylene (0.0196 g, 0.2 mmol), Et2N (0.07314 g, 2.72 mmol in DMF (1 ml) heated at 120° C. in a microwave reactor under a N2 atmosphere for 50 min. The mixture was partitioned between 0.1M HCl and EtOAc. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by MPLC (20 g SiO2 cartridge, eluent 90% iso-hexane-10% EtOAc) yielding 3-{1-[5-trimethylsilanylethynyl-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.0396 g). This was dissolved in THF (20 ml), MeOH (20 ml), glacial acetic acid (8 ml) and Bu4NF solution (24 ml, 1M) was added. The mixture was stirred at RT overnight then heated at 60° C. for 3 hours, thereafter cooled to RT and partitioned between sat. NH4Cl solution and EtOAc, the organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by MPLC (20 g SiO2 cartridge, eluent 85% iso-hexane-15% EtOAc) yielding 3-{1-[5-Ethynyl-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.0078 g) which was converted to the title compound following the method in Example 1, Step 8.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:7][CH:6]=1.[CH:27]([NH:30][CH3:31])([CH3:29])[CH3:28].CN(C=O)C>O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:30]([CH:27]([CH3:29])[CH3:28])[CH3:31])=[CH:6][CH:7]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: CNC(C)C
Reactant: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OCCBr)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(C)CCOc1ccc(-n2ccc(OCc3ccc(Cl)cn3)cc2=O)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
A mixture of 1-[4-(2-bromoethoxy)phenyl]-4-[(5-chloro-2-pyridinyl)methoxy]-1H-pyridin-2-one (1.1 g, 2.6 mmols, Step (1) of Example 109), isopropyl(methyl)amine (0.811 mL, 7.8 mmols) and DMF (2.6 mL) was stirred at 60° C. for 2 days. Water was added to the reaction liquid and filtered. So obtained crude title compound was purified on silica gel column chromatography (KP-Sil FLASH 25+M, chloroform:methanol=1:0→5:1) to provide the title compound (1.1 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[CH:4][C:5]([F:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)[CH:7]=1.CCO[C:23]([S-:25])=[S:24].[K+].Cl>CN(C)C=O>[F:18][C:5]1[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[CH:7][C:2]2[N:1]=[C:23]([SH:25])[S:24][C:3]=2[CH:4]=1
Reactant: CCOC(=S)[S-]
Reactant: Cc1nn(-c2cc(N)c(Br)cc2F)c(=O)n1C(F)F
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc3nc(S)sc3cc2F)c(=O)n1C(F)F
Temperature: 140 °C
Yield: 73 %

Procedure:
30 mL N,N-dimethylformamide was charged with 0.01 mol 1-(5-amino-4-bromo-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred until it became clear. Then, 0.02 mol potassium ethyl xanthogenate was added to the mixture in two portions. The mixture was refluxed at 140° C. for 5 h, cooled, and poured into 100 mL ice water slurry. Then, the mixture was acidified with 6 mol/L hydrochloric acid, and a large amount of solids crushed out. The title compound was obtained in a 73% yield as a white solid after filtration.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:11]([Cl:14])=[N:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.[CH2:25]([O:32][CH2:33][C:34](Cl)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:19]1([S:16]([NH:15][C:10]2[CH:9]=[C:8]([C:4]3[S:3][C:2]([NH:1][C:34](=[O:35])[CH2:33][O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:6][C:5]=3[CH3:7])[CH:13]=[N:12][C:11]=2[Cl:14])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1nc(N)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1
Reactant: O=C(Cl)COCc1ccccc1
Product: Cc1nc(NC(=O)COCc2ccccc2)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1

Procedure:
Using an analogous method to that described in Example 51, N-[5-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]benzenesulfonamide was reacted with 2-benzyloxyacetyl chloride. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 9.6 minutes); 1H NMR Spectrum: (DMSOd6+D2O) 8.56 (1H, d); 8.09 (1H, d); 8.03 (2H, br d); 7.83 (1H, t); 7.70 (2H, t); 7.31-7.26 (3H); 7.26-7.24 (2H); 4.41 (2H, AB system); 4.12 (1H, d); 3.86 (1H, d); 2.24 (3H, s); Mass Spectrum: M+H+ 529.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10](C)[C:11]2=[O:14])=[CH:6][CH:5]=1.O>C(O)(=O)C>[Br:1][C:8]1[C:7]2[C:12](=[CH:13][C:4]([F:3])=[CH:5][CH:6]=2)[C:11](=[O:14])[NH:10][CH:9]=1
Reactant: BrBr
Reactant: Cn1ccc2ccc(F)cc2c1=O
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]cc(Br)c2ccc(F)cc12
Temperature: 26 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
Bromine (3.8 g, 24 mmol) in acetic acid (6 mL) was added slowly to a mixture of 7-fluoro-2-methylisoquinolin-1-one (4 g, 22.4 mmol) in acetic acid (8 mL) at 0° C. After stirring at 26° C. for 2 h, the mixture was poured into water (100 mL) and the solid was collected by filtration. Purification by silica gel chromatography (PE:EA=20:1) gave the title compound (1.4 g, 44%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 8.11 (d, J=9.2 Hz, 1H), 7.84 (dd, J1=9.6 Hz, J2=4.8 Hz, 1H), 7.49-7.45 (m, 1H), 7.34 (s, 1H), 3.62 (3H, s). LCMS: 255.9 [M+H]+
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([Cl:17])[C:15]=1[Cl:16])[C:12](=[O:18])[C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:19])[CH2:10]2)C.[Pb]=O.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:32]>FC(F)(F)C(O)=O>[O:18]=[C:12]1[C:13]2[C:9](=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:26])=[C:15]([Cl:16])[C:14]=2[Cl:17])[CH2:10][C:11]1([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([OH:32])[CH:25]=1)[CH3:19]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Agent: O=[Pb]
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2cccc(O)c2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
Ethyl(1-oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)acetate (18.95 g., 0.05 mole) dissolved in trifluoroacetic acid (100 ml.) is added portionwise at less than 10° C. to a stirred mixture of lead tetrakistrifluoroacetate (0.055 mole) prepared by stirring lead oxide (37.5 g.), trifluoroacetic acid (85 ml.) and trifluoroaceticanhydride (75 g.) at 25° C. for 96 hrs. After stirring the reaction mixture at 25° C. for 6 hours it is poured into crushed ice-water (1 l.) to precipitate 19.7 g. of a mixture of esters which is hydrolyzed by heating at reflux with ethanol (400 ml.) -water (250 ml.)-10 N sodium hydroxide solution (40 ml.) for 3/4 hr. On addition to crushed ice-water (1 l.)-12 N hydrochloric acid (50 ml.) a gummy product precipitates, is extracted with ether then concentrated to give 60% of [1-oxo-2-(3-hydroxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid and 20% of the 4-hydroxyphenyl derivative. Crystallization from acetic acid gives 2.6 g. of [1-oxo-2-(3-hydroxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid, m.p. 248°-255° C.