Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].[CH2:16]([NH:24][CH2:25][C@@H:26]([C@H:28]([C@@H:30]([C@@H:32]([CH2:34][OH:35])[OH:33])[OH:31])[OH:29])[OH:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH2:16]([NH:24][CH2:25][C@@H:26]([C@H:28]([C@@H:30]([C@@H:32]([CH2:34][OH:35])[OH:33])[OH:31])[OH:29])[OH:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH:3][C:2]([C@H:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: CCCCCCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
Racemic ibuprofen (18.03 g, 87.4 mmol), N-octyl-D-glucamine (12.12 g, 41.3 mmol), triethylamine (4.4 g, 43.5 mmol), water (0.5 mL), and toluene (150 mL) were heated to 80° C., forming a clear solution. The solution was cooled to 25° C. over 2 1/2 hours, then cooled in an ice bath to 15° C. The resulting crystalline precipitate was recovered by filtration, washed with toluene, and dried to give (S)-ibuprofen N-octyl-D-glucamine salt (17.2 g, 78.8% yield, 94.8% ee).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:23])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=1.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:24][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:23])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=CCOc1cccc(C=CC(=O)c2c(O)cc(C)oc2=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOc1cccc(C=CC(=O)c2c(OC)cc(C)oc2=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 5.7 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.00 g of 4-hydroxy-3-[3-(3-allyloxyphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one, 1.85 g of triphenylphosphine and 0.23 g of methanol, and to the mixture was added dropwise a solution of 1.23 g of diethyl azodicarboxylate in 12 ml of tetrahydrofuran. The mixture was stirred at room temperature for 18 hours, and the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.12 g of 4-methoxy-3-[3-(3-allyloxyphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (5a)] as a yellow oil.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:8]([SH:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>[OH-].[Na+].C1COCC1>[CH2:8]([S:24][CH:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C1C=CCCC1
Reactant: CCCCCCCCCCCCCCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCSC1CCCC(=O)C1
Yield: 70 %

Procedure:
2-Cyclohexenone (0.14 mol, 13.4 mL) was dissolved in 10 mL of 10 percent sodium hydroxide and 50 mL of THF. An equimolar amount of hexadecyl mercaptan (0.14 mol, 42.9 mL) was added to the unsaturated ketone and the mixture refluxed to produce 3-hexadecylthiocyclo-hexanone (70 percent yield). This product (5.23 mmol, 1.851 g) was dissolved in methanol and reduced with sodium borohydride (5.23 mmol, 0.199 g) to give a racemic mixture of 3-hexadecylthiocyclo-hexanol (yield 62 percent; cis:trans ratio 4:1). The phosphorylating agent was prepared by refluxing phosphorus oxychloride (0.65 mol, 60.8 mL) and 2-bromoethanol (0.38 mol, 27.0 mL) in 25 mL of trichloroethylene to produce 2-bromoethyl dichlorophosphate (yield 53 percent). The 3-hexadecylthiocyclohexanol (0.56 mmol, 0.200 g) was dissolved in diethyl ether:THF (2:1) and refluxed with the 2-bromoethyl dichlorophosphate (222 mmol, 0.3 mL) to produce 3-hexadecylthio-cyclohexyl phosphoethyl bromide (yield 54 percent). The latter (0.276 mmol, 0.150 g) was dissolved in isopropyl alcohol chloroform:DMF (5:3:5) and heated at 65° C. with trimethylamine (0.042 mol, 2 mL) to produce the desired product, 3-hexadecylthiocyclohexyl-phosphocholine (yield 38 percent).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22].[NH2:23][C:24]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:35])=[N:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:23][C:24]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:35])=[N:29]3)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22]
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(C)c1OC
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1ccc(F)c2nc(C)ncc12)C(F)(F)F)c1ccc(F)c(C)c1OC

Procedure:
In the same way as in Example 130, 300 mg (0.93 mmol) of (2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 183 mg (1.03 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 0.58 ml (1.86 mmol) of titanium tert-butoxide is reacted to give 5-{[(2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-1-[(8-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol. 450 mg of crude imine are cyclized in the same way as in Example 130 at −30° C. with 7.6 ml (7.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-65%) yields 77 mg of desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[C:11](C(O)=O)[S:10][N:9]=2)=[CH:4][CH:3]=1>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1snc(-c2ccc(Cl)cc2)c1C(=O)O
Solvent: Clc1ccccc1Cl
Product: O=C(O)c1csnc1-c1ccc(Cl)cc1
Temperature: 200 °C
Reaction time: 0.33 h

Procedure:
Into a 50-mL round-bottom flask, was placed 3-(4-chlorophenyl)-1,2-thiazole-4,5-dicarboxylic acid (1.8697 g, 6.74 mmol, 1.00 equiv), 1,2-dichlorobenzene (20 mL). The resulting solution was stirred for 20 min at 200° C. The resulting mixture was concentrated, and then added 30 mL of petroleum ether slowly when it is hot. The solids were collected by filtration, washed with petroleum ether. This resulted in 1.35 g (86%) of 3-(4-chlorophenyl)-1,2-thiazole-4-carboxylic acid as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9]>>[CH:6]1[C:1]([OH:7])=[CH:2][CH:3]=[CH:4][C:5]=1[CH3:8].[CH2:8]=[O:9]
Reactant: Oc1ccccc1
Agent: C=O
Product: Cc1cccc(O)c1

Procedure:
Among these, for example, a novolak resin obtained from phenol and formaldehyde, a novolak resin obtained from m-cresol n and formaldehyde, a novolak resin obtained from p-cresol and formaldehyde, a novolak resin obtained from o-cresol and formaldehyde, a novolak resin obtained from octylphenol and formaldehyde, a novolak resin obtained from an m-/p-cresol mixture and formaldehyde, a novolak resin obtained from a phenol/cresol (any one of m-, p-, o- or m-/p-, m-/o-, o-/p-mixture) mixture and formaldehyde, and the like are preferable.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][NH2:25])=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>CN(C=O)C>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][NH:25][C:35]5[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:28][CH:29]([CH3:30])[CH3:31])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)Cc1nc(-c2ccc(OCCN)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Clc1ccncc1
Solvent: CN(C)C=O
Product: CC(C)Cc1nc(-c2ccc(OCCNc3ccncc3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 100 °C

Procedure:
2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethylamine, the product of Example 512, was treated with 4-chloropyridine in DMF and was heated at 100° C. Aqueous workup and chromatography on silica gel afforded Example 519. (Yield: 80 mg)
Reaction SMILES: Br[CH2:2][CH2:3]Br.C([O-])([O-])=O.[K+].[K+].[CH3:11][O:12][C:13](=[O:46])[CH:14]([NH:26][C:27](=[O:45])[CH:28]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N+:42]([O-:44])=[O:43])(=[O:35])=[O:34])[CH2:29][O:30][CH3:31])[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH3:11][O:12][C:13](=[O:46])[CH:14]([N:26]1[CH2:3][CH2:2][N:32]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[N+:42]([O-:44])=[O:43])(=[O:34])=[O:35])[CH:28]([CH2:29][O:30][CH3:31])[C:27]1=[O:45])[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1
Reactant: COCC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)NC(Cc1ccc2ccccc2c1)C(=O)OC
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC1C(=O)N(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
1,2-Dibromoethane (11 mL, 125 mmol) and K2CO3 (15.5 g, 112.3 mmol) are added to a 2-[3-methoxy-2-(2-nitro-benzenesulfonylamino)-propionylamino]-3-naphthalen-2-yl-propionic acid methyl ester, 59, (6.4 g, 12.4 mmol) solution in anhydrous DMF (30 mL). The reaction mixture is stirred at 60° C. overnight. The reaction mixture is cooled to room temperature and the pH is adjusted to 3 with 1M KHSO4. The solution is extracted with EtOAc (3×100 mL) and the organic layers are combined and dried over Na2SO4. The solvent is removed in vacuo to afford 5.6 g (85% yield) of the desired product. 1H NMR (300 MHz, CDCl3, δ): 7.89 (m, 1H), 7.70 (m, 3H), 7.57 (m, 3H), 7.47 (m, 1H), 7.41 (m, 2H), 7.30 (d, J=8.6 Hz, 1H), 5.39 (m, 1H), 4.37 (s, 3H), 3.62 (m, 4H), 3.46 (m, 2H), 3.35 (m, 1H), 3.20 (m, 2H), 3.13 (s, 3H); 13C NMR, δ 170.4, 165.7, 156.5, 147.9, 134.2, 134.1, 133.6, 133.4, 132.6, 132.4, 130.8, 128.4, 127.8, 127.7, 127.2, 126.4, 126.0, 124.6, 74.1, 65.0, 58.9, 58.1, 52.7, 44.3, 41.8, 34.3.
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10](=S)[NH:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH2:17]([NH2:19])[CH3:18]>O>[CH:1]1([C:4]2[NH:12][C:11]3[C:10]([NH:19][CH2:17][CH3:18])=[N:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCn1c(=O)[nH]c(=S)c2[nH]c(C3CC3)nc21
Reactant: CCN
Solvent: O
Product: CCNc1nc(=O)n(CC)c2nc(C3CC3)[nH]c12

Procedure:
5.91 g of 8-cyclopropyl-3-ethyl-6-thioxanthine and 100 ml of 70% ethylamine in water were heated in a 450 ml reactor to 150° C. After 6 hours the solution was filtered and evaporated to dryness. The residue was suspended in methanol, collected, washed and dried to give the title compound (5.67 g) as an off-white solid mp 260° subl./301-5° C. The hydrochloride salt was also obtained as an off-white solid mp 205-50° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[N+:24]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][S:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (2-nitro-5-thiomorpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example B2) (1.2 g, 2.95 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a yellow solid (978 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.S(=O)(=O)(O)O>O>[CH2:1]([N:3]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: CCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCN(CC(F)(F)F)c1ccccc1

Procedure:
484 parts of N-ethylaniline, 106 parts of sodium carbonate and 254 parts of 2,2,2-trifluoro-ethyl tosylate are heated for 48 hours at 190°-200° C. The cooled reaction mixture is diluted with 1000 parts by volume of distilled water and acidified with sulphuric acid until it is distinctly acid to Congo red paper. The N-ethyl-N-(2,2,2-trifluoro-ethyl)-aniline which is formed is then steam distilled. The lower organic layer of the distillate is separated and subjected to distillation under reduced pressure. 182 parts of N-ethyl-N-(2,2,2-trifluoro-ethyl)-aniline are thus obtained, distilling at 53°-54° C. under 1 mm of mercury, of which the elementary analysis is as follows:
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:11]([OH:16])[CH2:12][CH2:13][C:14]#[CH:15]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I.C(OCC)(=O)C>[N:6]1[CH:7]=[CH:8][C:3]([C:15]#[C:14][CH2:13][CH2:12][CH2:11][OH:16])=[CH:4][CH:5]=1
Reactant: Brc1ccncc1
Reactant: C#CCCCO
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: Cl
Solvent: CCOC(C)=O
Product: OCCCC#Cc1ccncc1
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
4-Bromopyridine hydrochloride (5 g, 0.031 mol) was partitioned between 2N NaOH (50 ml) and ethyl acetate (250 ml). The organic layer was collected, dried over MgSO4 and evaporated in vacuo. The resulting oil was dissolved in triethylamine (10 ml) and degassed with nitrogen. Pent-4-yn-1-ol (3 g, 0.035 mol) was added, followed by bis(triphenylphosphine)palladium (II) chloride (200 mg) and copper iodide (100 mg). The reaction was heated to reflux and stirred for 15 min. The reaction was partitioned between ethyl acetate (250 ml) and water (50 ml). The organic layer was collected, dried over MgSO4 and evaporated. The residue was chromatographed on silica eluting with ethyl acetate to afford the title compound as a yellow solid (3.14 g). 1H NMR (250 MHz, CDCl3) 1.8 (1H, br s), 1.87 (2H, q), 2.57 (2H, t), 3.81 (2H, br t), 7.24 (2H, dd), 8.78 (2H, dd).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]2[C:8]3[C:13](S(=O)(=O)[C:5]2=[CH:4][C:3]=1[NH2:19])=[CH:12][C:11]([NH2:17])=[C:10]([CH3:18])[CH:9]=3.C(C1C=C(CC)C(N)=C(CC)C=1)C1C=C(CC)C(N)=C(CC)C=1>>[CH3:18][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][C:3]([NH2:19])=[C:2]([CH3:1])[CH:7]=2)[CH:13]=[CH:12][C:11]=1[NH2:17]
Reactant: Cc1cc2c(cc1N)S(=O)(=O)c1cc(N)c(C)cc1-2
Agent: CCc1cc(Cc2cc(CC)c(N)c(CC)c2)cc(CC)c1N
Product: Cc1cc(-c2ccc(N)c(C)c2)ccc1N

Procedure:
o-tolidine sulfone; 4,4′-methylene-bis-(2,6-diethyl aniline);
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]([NH2:33])=[S:32])[CH:26]=[C:27]([Cl:29])[CH:28]=1.C(CC(C)(C)C)(C)C>C(O)C.C(OCC)(=O)C.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:33]=[C:31]([NH:30][C:25]3[CH:24]=[C:23]([Cl:22])[CH:28]=[C:27]([Cl:29])[CH:26]=3)[S:32][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1cc(Cl)cc(Cl)c1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(C)CC(C)(C)C
Product: CS(=O)(=O)c1ccc(-c2sc(Nc3cc(Cl)cc(Cl)c3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.312, 0.841 mmol) in ethanol (10 mL) in a 25 mL round bottom flask was added N-(3,5-dichlorophenyl)thiourea (0.195 g, 0.882 mmol). The solution was heated to reflux (14 hours) and the reaction was cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in ethyl acetate (100 mL) and washed with sodium carbonate solution (10%, 3×20 mL), brine (1×20 mL), dried over sodium sulfate, filtered and concentrated, yielding a powdery solid. This solid was dissolved in ethyl acetate/methylene chloride. Addition of isooctane resulted in the precipitation of 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(3,5-dichlorophenylamino)thiazole (0.261 g, 63%) as a pale yellow powder: mp 287°-288° C.; 1HNMR (DMSO d6) 400 mHz 10.84 (s, 1 H), 7.86 (d, J=8.79 Hz, 2 H), 7.73 (s, 2 H), 7.54-7.45 (m, 4 H), 7.22 (t, J=8.79 Hz, 2 H), 7.15 (s, 1 H), 3.22 (s, 3 H); MS m/z 492 (M+). HRMS Δ=4.8 mmu.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][N:16]=1.Cl>CC(OC)(C)C.C(O)C.O>[ClH:14].[Cl:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:6][CH2:7]2)=[O:20])=[CH:22][CH:23]=1
Reactant: C1CC(N2CCCNCC2)C1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCO
Product: O=C(c1ccc(Cl)nc1)N1CCCN(C2CCC2)CC1
Temperature: 12.5 °C
Reaction time: 0.62 h

Procedure:
A mixture of 1-cyclobutyl-[1,4]diazepane (prepared e.g. as in Example 13 above, 20.0 g, 129.7 mmol, 1.00 eq), water (95.2 g) and NaOH 30% aq. (34.6 g, 259.5 mmol, 2.00 eq) was cooled to 10-15° C. To the resulting mixture was added a solution of 6-chloronicotinic acid chloride (24.0 g, 136.4 mmol, 1.05 eq) in MTBE (250.0 g) at 10-15° C., over about 30-45 min, while stirring vigorously. The resulting emulsion was maintained at 10-20° C. for 45-60° C., before the layers were allowed to separate. The aqueous layer was removed and the organic layer washed with water (25.0 g). After removal of the aqueous layer, the organic layer was concentrated by distillation (140 g solvent are distilled off), ethanol (120 g) was added and additional solvent was distilled off (170 g solvent). The resulting solution was then heated to about 50-60° C. and HCl (gas, 4.8 g, 130.2 mmol) in ethanol (9.1 g) was added dropwise. The resulting solution was cooled to 43-45° C. and seeded crystals of the title compound. The product crystallized slowly at 43-45° C. when stirred for about 4-6 h. MTBE (60 g over 1.5-2 h, 120 g over 0.5-1 h) was added, the resulting mixture was then cooled to room temperature over 1-2 h and maintained for 1-2 h, before the title compound was isolated by filtration, washed with MTBE (2×40 g) and dried in vacuo at 65-75° C. for 2 days, to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28][C:29]([O:31]C)=[O:30])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:25][CH2:26]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)CC[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from compound 240 of Example 1 by reaction with sodium hydroxide in a methanol/tetrahydrofuran mixture.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([OH:11])[CH2:9]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(OCCCCO)(=[O:16])C(C)=C>>[C:1]([O:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCCCO
Reactant: C=C(C)C(=O)OCC(O)CC
Product: C=C(C)C(=O)OCC(O)CO

Procedure:
2-hydroxybutyl methacrylate; 4-hydroxybutyl methacrylate;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[OH:13].[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cccc(OC)c1O
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OC)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a solution of methyl 3-methoxysalicylate (1.0 g, 5.49 mmol) in 5 ml tetrahydrofuran and 5 ml dimethylformamide was added sequentially at room temperature, benzyl alcohol (0.71 ml, 6.86 mmol), triphenylphosphine (2.16 g, 8.23 mmol) and diethyl azodicarboxylate (1.3 ml, 8.23 mmol). The reaction solution was stirred at room temperature overnight, then ethyl acetate was added and the resulting solution was washed sequentially with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was triturated with diethyl ether and filtered to remove triphenylphosphine oxide. The ether solution was concentrated to dryness in vacuo and the residue was purified by column chromatography on silica gel, eluting with 95:5 hexane/ethyl acetate, yielding the title compound as an oil (870 mg 58% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[NH:16][N:15]=[CH:14][CH:13]=1>CO>[N:15]1[N:16]2[C:8](=[O:10])[C:7]3[CH:6]=[CH:5][CH:4]=[N:3][C:2]=3[NH:11][C:12]2=[CH:13][CH:14]=1
Reactant: Nc1ccn[nH]1
Reactant: O=C(O)c1cccnc1Cl
Solvent: CO
Product: O=c1c2cccnc2[nH]c2ccnn12
Temperature: 25 °C

Procedure:
15.7 g. of 2-chloropyridine-3-carboxylic acid and 16.6 g. of 5-aminopyrazole are heated carefully to about 180°. At this point, the reaction starts and the temperature rises to about 230°-240°. The mixture is allowed to cool to room temperature and is then treated with methanol. The undissolved pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-one is filtered off and recrystallized from dimethylformamide, yield: 10.5 g. (56%); m.p. >300°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:32][CH3:33].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)CCCC>[NH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[N:7]=[C:6]([C:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[NH:10][CH:9]=4)[C:5]([Cl:17])=[CH:4][N:3]=3)=[C:20]([O:32][CH3:33])[CH:21]=2)[CH2:26][CH2:27]1
Reactant: COc1cc(N2CCC(N)CC2)ccc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCO
Product: COc1cc(N2CCC(N)CC2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Temperature: 140 °C
Reaction time: 72 h
Yield: 36.2 %

Procedure:
A solution of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (5.28 g, 20 mmol), 1-(4-amino-3-methoxyphenyl)piperidin-4-amine (4.43 g, 20.00 mmol), and tosic acid (5.71 g, 30.00 mmol) in n-pentanol (40.0 ml) was placed in a round-bottomed flask. The solution was heated at 140° C., and stirred at that temperature for three days. The solvent was removed by concentration in vacuo, and to the residue was added sat. NaHCO3 solution and dichloromethane. The mixture was filtered and the obtained solid was dissolved in a mixture of THF and methanol and pre-absorbed on silica gel (120 g). The mixture was loaded onto silica gel column and eluted with 10% MeOH, 1% NH4OH in DCM. The collected fractions were concentrated, and the residue was triturated in diethyl ether. The collected solid after filtration was triturated in ethanol. Filtration afforded the title compound (3.25 g, 36.2% yield).