Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:8][CH2:9][CH2:10][OH:11])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=[CH:21][C:15]=1[CH:16]=[CH:17][C:18]([OH:20])=[O:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:40]([O-:45])(=[O:44])[C:41]([O-:43])=[O:42]>C1C=CC=CC=1>[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42].[CH3:12][O:13][C:14]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=[CH:21][C:15]=1[CH:16]=[CH:17][C:18]([OH:20])=[O:19].[N:1]1([CH2:8][CH2:9][CH2:10][OH:11])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C([O-])C(=O)[O-]
Agent: COc1ccc(C=CC(=O)O)c(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OCCCN1CCCNCC1
Solvent: c1ccccc1
Product: O=C(O)C(=O)O

Procedure:
In 1.50 ml of absolute benzene there were dissolved 1.58 g of 1-homopiperazinepropanol, 3.09 g of 2,3,4-trimethoxycinnamic acid and 9.5 g of p-toluene sulfonic acid. The solution was heated for 16 hours to reflux while removing the formed water. The reaction liquid was cooled, washed with 15% potassium carbonate and then extracted with 10% hydrochloric acid. After the aqueous layer was washed with ether, the system was rendered alkaline with potassium carbonate followed by extraction with ether. After the ethereal layer was dehydrated over a Glauber's salt, the ether was distilled off. The resultant residue was subjected to chromatography using silica gel to obtain a colorless transparent liquid. The liquid was converted into the oxalate thereof in accordance with conventional manner. Upon recrystallization from methanol, 1-homopiperazinepropanol 2,3,4-trimethoxycinnamate oxalate was obtained having a melting point of 156°-158° C. The yield was 48%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:17]=1[NH2:18]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:18][C:17]2[C:16]([F:15])=[CH:22][CH:21]=[CH:20][C:19]=2[F:23])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Nc1c(F)cccc1F
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CC#N
Product: CCOC(=O)c1cnc(SC)nc1Nc1c(F)cccc1F
Temperature: 90 °C
Reaction time: 15 h
Yield: 102 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (10.0 g, 43.1 mmol) in acetonitrile (107 mL) is added 2,6-difluoroaniline (9.3 mL, 86.2 mmol). The mixture is heated to 90° C. for 4 hours. The reaction is cooled to room temperature and stored at 0° C. for 15 hours. The white precipitate which forms is filtered and washed with 20% EtOAc/hexanes to afford 14.3 g of the desired product which is used without further purification: 1H NMR (300 MHz, CDCl3/MeOH) δ 9.70 (s, 1H), 8.20 (s, 1H), 7.82 (s, 2H), 5.23 (s, 2H), 3.18 (s, 3H), 2.25 (s, 3H); ESI+ MS: m/z (rel intensity) 326.0 (100, M++H).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3)CC2)c(OC)nc1C
Yield: 86 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-phenylpiperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1([CH2:25][CH2:26][CH2:27][CH2:28]Br)[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:30]1([C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([NH:9][C:10]([C:12]1([CH2:25][CH2:26][CH2:27][CH2:28][N:33]2[CH2:34][CH2:35][N:30]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)[CH2:31][CH2:32]2)[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NCCc1ccccc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCCc1ccccc1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(phenethyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nnc(SCc2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.2 %

Procedure:
In 35 ml of water and 70 ml of ethanol, 12.8 g of 2-amino-5-mercapto-1,3,4-thiadiazol and 43 g of sodium hydroxide were added. To this mixture, 14.8 g of 4-chlorobenzyl chloride was added and the mixture was stirred at room temperature for 1 hour. Water was added and the reaction mixture was filtered. The residue was washed with water and an ethanol/n-hexane (1:1) mixture, and was dried under reduced pressure, and thus 23:1 g of 2-amino-5-(4-chlorobenzylthio)-1,3,4-thiadiazole was obtained.
Reaction SMILES: C1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2C=C1)[CH2:7]3.[CH3:11][O:12][C:13](=[O:16])C=C.C1(C=CC(O)=CC=1)O>>[CH3:11][O:12][C:13]([C:6]12[CH2:7][CH:8]([CH2:4][CH2:5]1)[CH:9]=[CH:10]2)=[O:16]
Reactant: C=CC(=O)OC
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Agent: Oc1ccc(O)cc1
Product: COC(=O)C12C=CC(CC1)C2
Temperature: 180 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
DCPD (dicyclopentadiene, Aldrich, 256.5 ml 1.9 mol), methylacrylate (Aldrich 405 ml, 4.5 mol), and hydroquinone (3.2 g, 0.03 mol) were put in a 2 L autoclave. After heating to 180° C., reaction was carried out for 5 hours while stirring at 300 rpm. After the reaction was completed, the reaction mixture was cooled down and transferred to a distillation unit. The reaction mixture was distilled at 1 torr using a vacuum pump at 50° C. to obtain the product (yield: 85%). The mole ratio (mol %) of exo-isomers to endo-isomers of the product was 41.1:58.9.
Reaction SMILES: [CH:1](=[O:3])[CH3:2].C(OC)=O.[S:8](=[O:11])([OH:10])[O-:9].[Na+:12].[OH-].[Na+].[CH2:15]1[CH2:20][CH2:19]C[CH2:17][CH2:16]1>O>[CH:2]1([CH:1]=[O:3])[CH2:19][CH2:20][CH2:15][CH2:16][CH2:17]1.[S:8](=[O:9])([OH:11])[O-:10].[Na+:12]
Reactant: C1CCCCC1
Reactant: CC=O
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: COC=O
Solvent: O
Product: O=CC1CCCCC1

Procedure:
A solution of cyclohexane with 1000 ppm acetaldehyde and 500 ppm methyl formate impurities was prepared and a partitioning run was carried out in a 500 mL separatory funnel, reacting this mixture with aqueous sodium bisulfite as the reducing agent and aqueous sodium hydroxide as the base. The cyclohexane-aldehyde solution was prepared by mixing 1000 g cyclohexane, 1.0 g acetaldehyde, and 0.5 g methyl formate in a large flask. After mixing, a portion was decanted into a labeled vial for analysis. Sodium bisulfite solution was prepared by mixing 9.66 g water and 2.16 g Na2S2O5 in a flask with shaking until complete dissolution had occurred. Sodium hydroxide solution was drawn from 0.2 N sodium hydroxide laboratory stock solution.
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4].CCN(C(C)C)C(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C1COCC1>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][N:22]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCNC3)n(C)c2n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(S(C)(=O)=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-3-ol dihydrochloride from Example 746 (150 mg, 0.28 mmol) and DIPEA (192 μL, 1.12 mmol) in THF (3 mL) was stirred for 5 min before the addition of methanesulfonyl chloride (22 μL, 0.28 mmol). The resulting mixture was stirred at r.t. for 4 h then partitioned between H2O and DCM. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) affording 765 (67 mg, 44%). LCMS (method I): RT 3.30 min, [M+H]+ 541.2. 1H NMR (DMSO, 400 MHz): δ 8.02-8.01 (1 H, m), 7.64-7.64 (1 H, m), 7.25-7.24 (2 H, m), 6.05 (1 H, s), 4.26 (4 H, brd s), 3.96 (3 H, s), 3.78 (4 H, t, J=4.60 Hz), 3.61 (2 H, s), 3.44-3.41 (1 H, m), 3.28-3.26 (2 H, m), 3.06-3.03 (1 H, m), 2.95 (3 H, s), 2.17-2.14 (1 H, m), 2.09-1.92 (2 H, m), 1.80-1.70 (1 H, m), 1.33 (3 H, t, J=7.43 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[C:4]([F:12])[C:3]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[C:15]1=[O:33].Cl.C(Cl)[Cl:36]>CO>[ClH:36].[F:12][C:4]1[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[C:15]1=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Nc3c(F)cc(S(C)(=O)=O)cc3F)C2=O)CC1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCNCC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
A flask was charged with (S)-tert-butyl 3-(2,6-difluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (1.2 g, 2.46 mmol), HCl (6.15 mL, 24.6 mmol), DCM (25 mL), and methanol (1 mL). The reaction mixture was stirred at ambient temperature overnight. The organic solvents were removed under reduced pressure to afford (S)-3-(2,6-difluoro-4-(methylsulfonyl)phenylamino)-[1,4′-bipiperidin]-2-one hydrochloride (0.986 g, 94.5% yield). Mass spectrum (apci) m/z=388.2 (M+H).
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][CH2:11][NH2:12])([O-:7])=[O:6].[O:13]=[C:14]1[NH:18][CH:17]([C:19](O)=[O:20])[CH2:16][S:15]1>>[N+:5]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:19]([CH:17]1[CH2:16][S:15][C:14](=[O:13])[NH:18]1)=[O:20])([O-:7])=[O:6]
Reactant: O=C1NC(C(=O)O)CS1
Reactant: NCCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCCO[N+](=O)[O-])CS1
Yield: 35.4 %

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 1.25 g of N-(3-nitrooxypropyl)amine nitrate and 1.0 g of 2-oxothiazolidine-4-carboxylic acid, to obtain 0.60 g of the title compound as pale yellow crystals, melting at 83°-850° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([S:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@@H:18]3[CH3:30])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[F:31][C:32]1[CH:33]=[C:34]([CH2:38][CH2:39][NH2:40])[CH:35]=[CH:36][CH:37]=1>>[F:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[CH2:38][CH2:39][NH:40][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH3:30])(=[O:15])=[O:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCCc1cccc(F)c1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1cccc(-c2ccnc(Cl)n2)c1
Product: C[C@H]1CNCCN1S(=O)(=O)c1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 153 from above was coupled with 2-(3-fluorophenyl)ethanamine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 456. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.6 (d, 1H) 8.5 (d, 1H) 8.4 (d, 1H), 8.1 (d, 1H), 7.8 (t, 1H), 7.6 (d, 1H), 7.2 (t, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 3.9 (m, 3H), 3.4 (m, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 3.1 (m, 1H), 3.0 (t, 2H), 1.2 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)=[N:4][N:3]=1.C([Sn](=O)CCCC)CCC.[N:51]([Si](C)(C)C)=[N+:52]=[N-:53].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C@H:7]2[CH2:8][CH2:9][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]5[NH:53][N:52]=[N:51][N:34]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:11][CH2:12]2)=[N:4][N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3nnc(C)o3)CC2)c2ncnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](c3nnc(C)o3)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-({4-[trans-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.15 g), dibutyltin oxide (0.035 g), azidotrimethylsilane (0.97 g) and toluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.023 g, 14%).
Reaction SMILES: C([O:4][C:5]1[C:10](=[O:11])[N:9]([CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[N:7]2[CH:16]([CH2:29][CH2:30][NH:31][CH3:32])[CH2:17][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19](=[O:20])[C:6]=12)(=O)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:18]2[CH2:17][CH:16]([CH2:29][CH2:30][N:31]([CH3:32])[S:34]([CH3:33])(=[O:36])=[O:35])[N:7]3[C:8](=[O:15])[N:9]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:11])[C:5]([OH:4])=[C:6]3[C:19]2=[O:20])=[CH:23][CH:24]=1
Reactant: CNCCC1CN(Cc2ccc(F)cc2)C(=O)c2c(OC(C)=O)c(=O)n(C(C)C)c(=O)n21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1c(=O)c(O)c2n(c1=O)C(CCN(C)S(C)(=O)=O)CN(Cc1ccc(F)cc1)C2=O

Procedure:
2-(4-Fluorobenzyl)-7-isopropyl-4-[2-(methylamino)ethyl]-1,6,8-trioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidin-9-yl acetate (Example 67, Step 2, 37 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was treated with a large excess of reagents (70 μL MsCl, 270 μL triethylamine and 20 mg DMAP). Stirring the reaction at ambient temperature over night gave complete conversion to the sulfonamide with exchange of the 9-acetate to the 9-mesylate. The solvent was removed under a steady nitrogen stream at 50° C. and the residue dissolved in MeOH (1 mL) and treated with a solution of sodium methoxide in MeOH (25 wt %, 2.5 mL). After four days of stirring at ambient temperature, cleavage of the 9-mesylate to the 9-hydroxy was complete. The mixture was quenched by the addition of TFA and water and was then concentrated under a steady stream of nitrogen at 50° C. The crude material was purified by reverse phase preparative HPLC to afford the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 11.73 (s, 1 H), 7.38-7.27 (m, 2 H), 7.09-7.05 (m, 2 H), 5.22-5.15 (m, 1 H), 4.96 (d, J=14.5 Hz, 1 H), 4.78-4.76 (m, 1 H), 4.37 (d, J=14.0 Hz, 1 H), 3.72 (dd, J=1.5, 14.0 Hz, 1 H), 3.62 (dd, J=3.8, 14.0 Hz, 1 H), 2.83 (s, 3 H), 2.80-2.66 (m, 5 H), 1.90-1.83 (m, 1 H), 1.56-1.49 (m, 1 H), 1.47 (d, J=7.0 Hz, 6 H). HRMS (APCI) M+H: calcd for (C21H28FN4O6S)+ 483.1708. found 483.1729.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19].O>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5 g, 32.6 mmol) in THF (50 mL) was added NaH (30%, 4 g, 50.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour before the addition of (2-(chloromethoxy)ethyl)-trimethylsilane (15 g, 90.0 mmol). The reaction was stirred at ambient temperature for 3 hours. It was then treated with water (5 mL) and extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by chromatography to give the title compound. MS (m/z): 284 (M+H)+ (35Cl), 286 (M+H)+ (37Cl).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([CH3:13])[CH:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][CH2:24][C:25](=O)[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:18][CH:17]=1>CCO.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2]>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:12]=[CH:11][C:9]([N:10]2[C:22]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[CH:23][CH:24]=[C:25]2[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:8]([CH3:13])[CH:7]=1
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(OC)cc1
Reactant: Cc1cc(-c2ncc[nH]2)ccc1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(-c2ncc[nH]2)cc1C
Temperature: 120 °C
Yield: 30.5 %

Procedure:
To a solution of 4-(1H-imidazol-2-yl)-2-methylaniline (Method #3) (1.0 g, 5.76 mmol) and ethyl 7-(4-methoxyphenyl)-4,7-dioxoheptanoate (25C) (2.03 g, 6.93 mmol) in EtOH (12 mL) was added Zn(OTf)2 (6.30 g, 17.34 mmol). The mixture was heated by microwave at 120° C. for 5 h. The solvent was removed under reduced pressure and the residue was dissolved in EA, washed with water and brine, dried over MgSO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=1:1) to afford ethyl 3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoate as a brown solid (755 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[N:5]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH2:3]1.[Li+].[OH-].CC1(C)C2C(=CC=C(C#CC3C=CC(C(O)=O)=CC=3)C=2)NC(OC(C)C)C1>C1COCC1.CCO>[CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)[CH:10]=2)[N:5]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:4](=[O:32])[CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(=O)N3Cc2ccccc2)cc1
Agent: CC(C)OC1CC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc2N1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=O)N(Cc2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
163 mg (0.39 mmol) of ethyl 4-[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-1-benzyl-6-quinolinyl)ethynyl]benzoate (Compound 37) in 2 ml of THF, 2 ml of EtOH, and 2 ml of 1N LiOH were reacted substantially in accordance with the procedure used for the preparation of 4-[(4,4-dimethyl-2-iso-propoxy-3,4-dihydro-6-quinolinyl)ethynyl]benzoic acid (Compound 11) to give the title compound as a white flaky solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:29][C:10]=1[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:15]=1)=[O:12])=[O:7].[SH:42][C:43]1[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:33]1([C:30]2[CH:31]=[CH:32][C:9]([NH:8][C:6]([C:5]3[CH:4]=[C:3]([CH:41]=[CH:40][CH:39]=3)[CH2:2][S:42][C:43]3[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=3)=[O:7])=[C:10]([C:11](=[O:12])[NH:13][C:14]3[CH:18]=[CH:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=4)[N:15]=3)[CH:29]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: O=C(O)c1ccc(S)cc1
Reactant: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3ccn(-c4cccc(C(F)(F)F)c4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Into a round bottom flask was placed a solution of intermediate 21a (0.0580 mmol, 1 equiv), 4-mercaptobenzoic acid (11 mg, 0.0696 mmol, 1.2 equiv), potassium carbonate (24 mg, 3 equiv), and DMF (1 mL). The solution was stirred at room temperature overnight. The solvent was evaporated at reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was dried (Na2SO4). The solvent was evaporated and the residue was purified by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient to give 34 mg of product. 1H-NMR (400 MHz, DMSO, ppm): δ 11.55 (s, 1H), 11.48 (s, 1H), 8.67 (d, J=2.6 Hz, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.19 (S, 1H), 8.16 (d, J=7.8 Hz, 1H), 8.01 (s, 1H), 7.85-7.71 (m, 5H), 7.65 (d, J=7.5 Hz, 3H), 7.52 (t, J=7.7 Hz, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.04 (d, J=2.7 Hz, 1H), 4.46 (s, 2H), 3.30 (s, 4H), 1.70 (s, 4H), 1.59 (s, 2H). MS (ES, m/z) 700 [M+H]+.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[C:9]([Cl:30])[CH:8]=1)C.Cl.C(O)(=O)C>O>[F:29][C:26]([F:27])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[C:9]([Cl:30])=[CH:8][C:7]([O:6][CH2:5][CH:4]=[O:3])=[CH:12][C:11]=2[Cl:13])=[CH:21][CH:22]=1
Reactant: CCOC(COc1cc(Cl)c(OCCCCOc2ccc(C(F)(F)F)cc2)c(Cl)c1)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=CCOc1cc(Cl)c(OCCCCOc2ccc(C(F)(F)F)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
4-(4-(4-(Trifluoromethyl)phenoxy)butyloxy)-3,5-dichlorophenoxyacetaldehyde diethylacetal (manufactured in Production Example 1 of intermediate described hereinafter) (1.0 g) was added dropwise to a mixed solution of 1 ml of hydrochloric acid and 9 ml of acetic acid with stirring at room temperature. After stirring at room temperature for 20 minutes, the reaction solution was poured into iced water and extracted twice with 100 ml of diethyl ether. The ether layers were combined, washed with water, washed twice with aqueous 5% sodium hydrogencarbonate, washed with water, dried over anhydrous magnesium sulfate and then concentrated to obtain 0.7 g of 4-(4-(4-(trifluoromethyl)phenoxy)butyloxy)-3,5-dichlorophenoxyacetaldehyde as a crude product.