Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[C:6]2[C:29](=[CH:30][CH:31]=1)[C:10]1=[N:11][O:12][C:13]([C:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:16][N:15]=3)=[C:9]1[CH2:8][CH2:7]2.[NH:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:33]1>CC(O)C>[OH:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:29](=[CH:30][CH:31]=1)[C:10]1=[N:11][O:12][C:13]([C:14]3[C:18]([C:19]([F:22])([F:20])[F:21])=[C:17]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:16][N:15]=3)=[C:9]1[CH2:8][CH2:7]2)[CH2:3][N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:33]1
Reactant: CCOC(=O)C[C@H]1CCCNC1
Reactant: FC(F)(F)c1c(-c2onc3c2CCc2cc(C4CO4)ccc2-3)noc1-c1ccccc1
Solvent: CC(C)O
Product: CCOC(=O)C[C@H]1CCCN(CC(O)c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 85 °C
Reaction time: 5 h
Yield: 59.5 %

Procedure:
A mixture of 7-(oxiran-2-yl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 13A, 150 mg, 0.353 mmol) and (R)-ethyl 2-(piperidin-3-yl)acetate (90 mg, 0.526 mmol) in 2-propanol (5 mL) was stirred at 85° C. under a nitrogen atmosphere for 5 hr. The reaction mixture was concentrated and purified by silica gel column chromatography using ethyl acetate/heptane followed by 10% methanol in ethyl acetate to afford ethyl 2-((3R)-1-(2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethyl)piperidin-3-yl)acetate (125 mg, 0.210 mmol, 59.4% yield) as a yellow solid. LC/MS M+1=596.3.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([S:10][C:11]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][C:12]=1[CH:13]=[CH:14][C:15]1=[N:16][CH2:17][CH2:18][N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Sn](Cl)[Cl:35].Cl>O1CCCC1.C(O)C>[ClH:35].[ClH:1].[CH2:3]([S:10][C:11]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:12]=1/[CH:13]=[CH:14]/[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]([CH3:26])[CH2:18][CH2:17][N:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cl[Sn]Cl
Reactant: CN1CCN=C(C=Cc2cc([N+](=O)[O-])ccc2SCc2ccccc2)c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN=C(/C=C/c2cc(N)ccc2SCc2ccccc2)c2ccccc21
Temperature: 60 °C
Yield: 19.5 %

Procedure:
To 215 mg (0.50 mmol) of (E)-5-(2-benzylthio-5-nitrostyryl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepine dihydrochloride (prepared as described in Example 15) in 8 ml of tetrahydrofuran and 8 ml of ethanol was added 380 mg (0.90 mmol) of tin (II) chloride and 0.48 ml of concentrated hydrochloric acid. The mixture was heated at 60° C. for 7 hours. The solution was reduced to half volume and partitioned between 50 ml of saturated sodium hydrogen carbonate solution and 100 ml and 50 ml of dichloromethane. The combined organic phases were dried (magnesium sulphate), filtered and evaporated. The residue was purified by column chromatography eluting with 2-5% methanol/dichloromethane and treated with 0.30 ml of 4M hydrogen chloride in dioxan. The solvent was evaporated and the residue was recrystallised from methanol/ether to give 46 mg of (E)-4-benzylthio-3-[2-(2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-5-yl)vinyl]aniline dihydrochloride as dark red crystals; MS: m/e 400 [M+H]+.
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[N:16]([CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22])=[C:17]=[S:18].[OH-].[Na+]>CO>[CH3:22][O:21][CH:20]([O:23][CH3:24])[CH2:19][NH:16][C:17]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[S:18]
Reactant: COC(CN=C=S)OC
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(CNC(=S)N1CCN(c2ccc(O)cc2)CC1)OC

Procedure:
A mixture of 10.8 parts of 4-(1-piperazinyl)phenol dihydrobromide, 2.6 parts of 2-isothiocyanato-1,1-dimethoxyethane and 54 parts of methanol is stirred and refluxed for 30 minutes. Then there are added 4.7 parts of sodium hydroxide and the whole is stirred overnight at room temperature. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 4.9 parts of N-(2,2-dimethoxyethyl)-4-(4-hydroxyphenyl)-1-piperazinecarbothioamide; mp. 161.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:7]1[N:12]=[C:11](SC)[N:10]=[C:9]([NH2:15])[N:8]=1)[CH3:6]>C(O)C.[Ni]>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH2:15])[N:8]=1)[CH3:6]
Reactant: CSc1nc(N)nc(C(C)Oc2ccccc2Cl)n1
Agent: [Ni]
Solvent: CCO
Product: CC(Oc1ccccc1Cl)c1ncnc(N)n1
Temperature: 85 °C
Yield: 16.4 %

Procedure:
To a solution of 4-(1-(2-chlorophenoxy)ethyl)-6-(methylthio)-1,3,5-triazin-2-amine (16a) (181 mg) in ethanol (10 mL) was added. Raney-nickel was added via a syringe (2.0 mL) and the reaction mixture was heated at 85° C. for 40 minutes then cooled to room temperature and the mixture was filtered over Celite and washed with ethanol/water (1/1 v/v) and methanol. The filtrate was concentrated in vacuo and further purified by column chromatography (eluting with 1% acetontrile in dichloromethane) to give the title compound (25 mg), MS (ES): m/z 251 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([CH:14]=[CH:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.CN(C)[CH:34]=[O:35].C(Cl)(Cl)Cl>O1CCCC1>[CH2:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:7]=[C:8]([O:21][CH3:22])[C:9]([CH:14]=[CH:15][C:16]2[S:17][C:18]([CH:34]=[O:35])=[CH:19][CH:20]=2)=[C:10]([O:12][CH3:13])[CH:11]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CN(C)C=O
Reactant: CCCCN(CCCC)c1cc(OC)c(C=Cc2cccs2)c(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCN(CCCC)c1cc(OC)c(C=Cc2ccc(C=O)s2)c(OC)c1
Temperature: 0 °C
Yield: 100 %

Procedure:
In a stream of argon, in 10 ml of tetrahydrofuran was dissolved 0.75 g (2.00 mmol) of 2-[2-(4-dibutylamino-2,6-dimethoxyphenyl)vinyl]thiophene, and 1.27 ml of n-butyllithium (1.6 M solution in hexane) (2.03 mmol) was added dropwise thereto under cooling. The mixture was stirred for hour. To this mixture, 0.20 ml (1.20 mmol) of N,N-dimethylformamide was added dropwise and reacted. The temperature was then allowed to rise gradually, and the mixture was allowed to react at room temperature for 12 hours. After the mixture was poured into 100 ml of ice water, extraction with 200 ml of chloroform, washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 482 mg (yield: 60%) of 5-[2-(4-dibutylamino-2,6-dimethoxyphenyl)vinyl]thiophene-2-carboaldehyde as a dark purple crystal (mp: 105-106° C.).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=O.CC(C[AlH]CC(C)C)C.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:14]([O:13][C:11]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:5]1[CH:3]=[O:2])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C=O
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To the title compound of Example 1.1 (5.4 g, 22.1 mmol) in toluene (50 mL) at −78° C. was added 1.5 M DIBAL in toluene (33.8 mL, 50.7 mmol) drop-wise over 40 minutes. Methanol (120 mL) was then added drop-wise at −78° C. over 10 minutes. The reaction mixture was moved to an ice-bath where 10% wt citric acid (500 mL) was added and then mixture was stirred for an additional 1 hour. After the resulting mixture was extracted with ethyl acetate (2 times), the organic layer washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product as a colorless oil (3.0 g, 64%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][C:4](=[S:13])[NH:3]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=2)=[CH:17][C:16]=1[C:30]([F:33])([F:32])[F:31].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][S:13][C:4]3[NH:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2](=[O:1])[N:3]=3)=[CH:26][CH:27]=2)=[CH:17][C:16]=1[C:30]([F:31])([F:32])[F:33]
Reactant: CCOC(=O)c1c[nH]c(=S)[nH]c1=O
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c[nH]c(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of ethyl 4-oxo-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (1.016 g, 5.07 mmol), 1-chloro-4-{[4-(chloromethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (1.793 g, 5.58 mmol) and K2CO3 (0.771 g, 5.58 mmol) in DMF (15 mL) was heated with a microwave reactor at 80° C. for 0.5 h. The mixture was poured into 100 mL water and extracted with EA. The organic phase was dried over sodium sulfate, filtered, and concentrated to afford the title compound (2.461 g, 5.07 mmol, 100% yield). LCMS: rt=3.64 min, [M+H]=485
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[Cu](C#N)[C:14]#[N:15]>CN(C=O)C>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:14]#[N:15])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)c2ccccc12
Temperature: 125 °C
Yield: 33 %

Procedure:
A mixture of 1,4-dibromonaphthalene (24.06 g, 84 mmol) and copper cyanide (6.02 g, 67 mmol) in DMF (85 mL) was heated to 125° C. overnight. The mixture was partially concentrated to remove DMF and the resulting residue washed with aqueous ammonium hydroxide and extracted with ethyl acetate. The organic layer was concentrated and purified by chromatography to yield 4-bromo-1-naphthonitrile (5.13 g, 26%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][NH:21][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(CN)c1ccc(F)cc1
Reactant: COC(=O)c1cnc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(NCC(C)(C)c2ccc(F)cc2)nc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 76.5 %

Procedure:
To a 20 dram vial was added methyl 2-chloropyrimidine-5-carboxylate (250 mg, 1.4 mmol, 1.0 equiv), 2-(4-fluorophenyl)-2-methylpropan-1-amine (468 mg, 2.8 mmol, 2.0 equiv), DIPEA (1.0 mL, 5.6 mmol, 4.0 equiv), and toluene (5 mL). The vial was heated in an oil bath to 60° C. and stirred for 20 min, concentrated, and purified by silica gel column chromatography (0-50% EtOAc/hexanes) to give 325 mg (77%) of methyl 2-(2-(4-fluorophenyl)-2-methylpropylamino)pyrimidine-5-carboxylate as a white solid (m/z [M+H]=304.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26]([NH:28][NH2:29])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:30]2[CH2:34][C@H:33]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:32]([OH:40])[C@H:31]2[OH:41])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH2:42]([O:44][C:45](=[O:51])[CH:46]([CH:49]=O)[CH:47]=O)[CH3:43]>C(O)C>[CH2:42]([O:44][C:45]([C:46]1[CH:47]=[N:29][N:28]([C:26]2[N:25]=[C:24]3[C:20]([N:21]=[CH:22][N:23]3[C@@H:30]3[CH2:34][C@H:33]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:32]([OH:40])[C@H:31]3[OH:41])=[C:19]([NH:18][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:27]=2)[CH:49]=1)=[O:51])[CH3:43]
Reactant: CCOC(=O)C(C=O)C=O
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(NN)nc32)[C@H](O)[C@@H]1O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc(NC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
To a solution of N-[(1S,2R,3S,4R)-4-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-hydrazino-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (0.1 g, 0.177 mmol) in dry ethyl alcohol (5 ml) is added 2-formyl-3-oxo-propionic acid ethyl ester (synthesised from ethyl-3,3-diethoxy-propionate, as described in: Bertz S. H., Dabbagh G. and Cotte P.; J. Org. Chem. (1982) 47, pp 2216-2217) (0.033 g, 0.231 mmol). The reaction mixture is heated at reflux for 8 hours then concentrated in vacuo. The crude residue is purified by chromatography on silica (60-120 mesh) eluting with 3% methanol in chloroform to afford the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH+ 671).
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].C([NH:11][C:12]1[N:13]=[C:14]([OH:33])[C:15]2[CH2:21][CH:20]([CH2:22][CH2:23][C:24]3[S:28][C:27]([C:29](OC)=[O:30])=[CH:26][CH:25]=3)[CH2:19][NH:18][C:16]=2[N:17]=1)(=O)C(C)(C)C>CO>[NH2:11][C:12]1[N:13]=[C:14]([OH:33])[C:15]2[CH2:21][CH:20]([CH2:22][CH2:23][C:24]3[S:28][C:27]([C:29]([NH:3][OH:4])=[O:30])=[CH:26][CH:25]=3)[CH2:19][NH:18][C:16]=2[N:17]=1
Reactant: COC(=O)c1ccc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)s1
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)NO)s1)C2
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
To 10 mL of anhydrous methanol was added 0.33 g (14.4 mmol) of sodium metal and a solution of 0.050 g (0.72 mmol) of hydroxylamine hydrochloride in 7 mL of methanol was then added. The resulting reaction mixture was stirred for 15 minutes and 0.23 g (0.5 mmol) of methyl 5-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarboxylate was added under nitrogen. The reaction mixture was stirred for 30 minutes, 0.011 g (0.16 mmol) of hydroxylamine hydrochloride was added, and the reaction was stirred a total of 4.5 hours, and then filtered. The filtrate was then treated with diethyl ether and the solid collected and dried in vacuo to give 0.13 g (71%) of N-{5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarbonyl}hydroxylamine as a tan colored solid. Rf=0.09 (10% CH3OH/CHCl3); 1H NMR (300 MHz, DMSOd6 /TFAd4) δ1.55-1.70 (m, 4H), 1.83; 1.91 (m, 1H), 2.82-2.87 (m, 4H), 3.29-3.33 (m, 1H), 6.82 (d, J=3.6 Hz, 1H), 7.43 (d, J=1.4 Hz, 1H);
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:24])[CH2:11][CH2:12][C:13](C2C=CC([N+]([O-])=O)=CC=2)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].O>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:24])[CH2:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C(O)CCCO)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 127.3 %

Procedure:
To a solution of the product from Example 1A (1.0 g, 3.05 mmol) in anhydrous THF (30 ml) at 0° C. was added sodium borohydride (0.357 g, 9.44 mmol). The resulting mixture was stirred at 50° C. overnight. The cooled mixture was poured into water, extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo. The resulting solid was triturated with dichloromethane to give a tan solid that was collected by filtration and dried to give the title compound (0.82 gm, 81% yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:17][C:18](=[O:22])[C:19](=[O:21])[CH3:20]>CCCCCC>[OH:21][C:19]([C:2]([CH3:1])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:20])[C:18](=[O:22])[CH3:17]
Reactant: CC(=O)C(C)=O
Reactant: CCCCCCCCCC(C)C(=O)OCC
Solvent: CCCCCC
Product: CCCCCCCCCC(C)(C(=O)OCC)C(C)(O)C(C)=O
Yield: 58.5 %

Procedure:
The reaction of ethyl 2-methylundecanoate (11.4 g, 0.05 mole) with 2,3-butanedione (4.73 g, 0.055 mole) is conducted in the manner described in Example I, and 16.6 g of a crude oil is obtained. The crude oil product is subjected to high pressure liquid chromatography on silica gel using 5% ethyl acetate in hexane as the eluant, yielding a pure product (9.2 g, 59%), b.p. 100° C. (Kugelrohr air bath temperature) at 0.01 mm Hg.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:15][OH:16].C[O-].[Na+].Cl>CCOC(C)=O>[CH3:15][O:16][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 23 h
Yield: 90.4 %

Procedure:
To a solution of 2-chloro-6-(trifluoromethyl)isonicotinic acid (0.15 g, 665 μmol, prepared according to F. Cottet, M. Schlosser, Eur. J. Org. Chem. 2004, 18, 3793-3798) in methanol (2 mL) sodium methoxide (79.0 mg, 1.46 mmol) was added and the reaction refluxed for 5 hours. Another 287 mg (5.32 mmol) sodium methoxide was added and the white suspension was stirred at reflux temperature overnight. After 23 hours the suspension was allowed to cool to room temperature and was poured on saturated 1M HCl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered and evaporated to give the desired compound as a colorless solid (0.133 g; 90%). MS (ESI): m/z=220.02 [M−H]−.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][S:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])(=O)=O>ClCCl>[Cl:16][CH:10]1[S:9][CH2:8][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]1=[O:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C1CSCN1c1ccccc1
Solvent: ClCCl
Product: O=C1C(Cl)SCN1c1ccccc1

Procedure:
This compound was prepared by a procedure similar to that described in Preparative Example 2, Step 2 above, but using 3-phenyl-4-thiazolidinone (prepared as in Step 1 above) (0.38 g), sulphuryl chloride (0.29 g), and dichloromethane (5 ml). This product was used directly in Step 3.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](/[C:23](/[CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24]\[C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.[H][H]>[Pd]>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([CH:23]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(/C(=C\C(N)=O)C4CCCC4)c3)ncnc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC(N)=O)C4CCCC4)c3)ncnc21
Reaction time: 17 h
Yield: 99.7 %

Procedure:
To a 25 ml round bottom flask equipped with a stir bar was charged (Z)-(4-(1-(3-amino-1-cyclopentyl-3-oxoprop-1-enyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (10, 1.15 g, 2.63 mmol), tetrahydrofuran (THF, 20.0 ml, 246 mmol) and 10% palladium on carbon (50% wet, 130 mg) at room temperature. The resulting reaction mixture was degassed three times back filling with hydrogen gas each time before the hydrogenation reaction was conducted under a steady stream of hydrogen gas released by a hydrogen balloon. The reaction was checked after 17 h and was found to be complete. The reaction mixture was then filtered through a Celite bed to remove the catalyst and the Celite bed was rinsed with a small volume of tetrahydrofuran (THF). The combined filtrates were concentrated under reduced pressure to afford the crude (4-(1-(3-amino-1-cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (11, 1.15 g, 1.153 g theoretical, 99% yield) as a yellow to brown oil, which solidified upon standing in vacuum at room temperature. This crude product (11) was found to be pure enough (>98% by HPLC) to do the following reaction without further purification. For 11: 1H NMR (DMSO-d6, 300 MHz) δ ppm 8.73 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.70 (d, 1H, J=3.8 Hz), 7.32 (bs, 1H), 7.09 (d, 1H, J=3.8 Hz), 6.75 (bs, 1H), 6.21 (s, 2H), 4.56 (td, 1H, J=4.0, 9.8 Hz), 2.86 (dd, 1H, J=10.5, 5.6 Hz), 2.63 (dd, 1H, J=4.0, 15.3 Hz), 2.32 (m, 1H), 1.77 (m, 1H), 1.56-1.19 (m, 7H), 1.06 (s, 9H); LCMS (EI) m/e 439 (M++H); C23H30N6O3 (MW, 438.52), LCMS (EI) m/e 439 (M++H).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:16]3[N:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=3)=[CH:14][CH:15]=2)=[C:7]([CH3:32])[CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:17]1[CH:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[N:20]=[C:16]1[C:13]1[S:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:6][C:7]=2[CH3:32])=[CH:15][CH:14]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3-c3ccccc3Cl)s2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CC(=O)O)ccc1-c1ccc(-c2nc(C(F)(F)F)cn2-c2ccccc2Cl)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
(4-{5-[1-(2-Chloro-phenyl)-4-trifluoromethyl-1H-imidazol-2-yl]-thiophen-2-yl}-3-methyl-phenyl)-acetic acid methyl ester (123 mg, 0.25 mmol) was dissolved in 6 mL mixture of THF and water (3:1, V/V). Lithium hydroxide monohydrate (2.3 mg, 0.55 mmol) was added then. The mixture was stirred at room temperature for 3 hrs. The mixture was neutralized to pH 7 by 1N HCl, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0→5% MeOH/DCM) to give a white solid (47 mg, 39% yield). 1H-NMR (400 MHz, CDCl3): δ 2.35 (s, 3H), 3.64 (s, 2H), 6.83 (s, 2H), 7.13-7.10 (m, 1H), 7.16 (m, 1H), 7.29-7.27 (m, 1H), 7.35 (m, 1H), 7.47-7.46 (m, 2H), 7.57-7.52 (m, 1H), 7.64-7.62 (m, 1H). MS (ES): 477.1, [M+H]+
Reaction SMILES: [C:1](=[O:18])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]([NH:22][C:23]1[C:24]([I:39])=[C:25]([N:34]([C:36](=[O:38])[CH3:37])[CH3:35])[C:26]([I:33])=[C:27]([C:30]([O-:32])=[O:31])[C:28]=1[I:29])(=[O:21])[CH3:20].[K+].[I-].[Na+]>CN(C=O)C>[C:19]([NH:22][C:23]1[C:24]([I:39])=[C:25]([N:34]([C:36](=[O:38])[CH3:37])[CH3:35])[C:26]([I:33])=[C:27]([C:30]([O:32][CH:3]([O:2][C:1]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:18])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:31])[C:28]=1[I:29])(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: O=C(Oc1ccccc1)OC(Cl)c1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(OC(=O)Oc2ccccc2)c2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1-Chloro-1-phenylmethyl phenyl carbonate (0.63 g, 2.4 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (1.44 g, 2.2 mmol) and sodium iodide (0. 034 g, 0.23 mmol) in dry DMF (12 ml). After stirring at 60° C. for 2 hours and at room temperature for 18 hours the solvent was removed at reduced pressure. The residue was suspended in chloroform (20 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 0.90 g. Purity by HPLC: 96.6 % 1H-NMR (DMSO-d6): delta=1.67 (NCH3COCH3); 2.05 (NHCOCH3); 2.96 (NCH3); 7.29-7.54 phenyl); 7.71 (CH); 10.13 ppm (NH) . FAB/MS: 854 (M+) .