Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C=O>[CH2:19]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCON=C(C(C)=O)C(=O)OCC
Yield: 97.3 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 100 g.), N,N-dimethylformamide (300 ml.), potassium carbonate (130 g.) and bromooctane (121 g.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-n-octyloxyimino-3-oxobutyrate (syn isomer, 165.5 g.), oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:39][C@@H:38]1[CH2:40][O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[N:47]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][N:34]([CH2:39][C@@H:38]([OH:37])[CH2:40][O:41][C:42]4[CH:51]=[CH:50][CH:49]=[C:48]5[C:43]=4[CH:44]=[CH:45][CH:46]=[N:47]5)[CH2:33][CH2:32]3)=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCNCC2)CC1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCN(C[C@@H](O)COc3cccc4ncccc34)CC2)CC1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
1-(Piperidine-4-carbonyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (71) (243.4 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 16 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→1 00% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (200 mg) as a white solid. ESMS: MH+ 691.6
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[S:10].Br[C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].CN(C=O)C.[OH-].[Na+]>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: S=C1Cc2ccccc2N1
Reactant: CCOC(=O)C(C)(Br)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(Sc1cc2ccccc2[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
Into a solution of 1,3-dihydroindol-2-thione (19.7 g) and ethyl 2-bromo-2-phenylpropionate (33.9 g) indimethylformamide (DMF, 200 ml), an aqueous 2 N sodium hydroxide solution (66 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and was extracted with ethyl acetate. The organic layer was washed with water, and then with saturated aqueous sodium chloride solution, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. n-Hexane was added to the evaporation residue to cause crystallization. The resulting crystalline matter was recrystallized from ethyl acetate/n-hexane to give 30.3 g (yield: 71%) of product compound as a pale yellow crystal form. The melting point was 97°-99° C.
Reaction SMILES: [F:1][C:2]1([F:13])[C:6]([F:7])=[C:5]([F:8])[C:4]([F:10])([F:9])[C:3]1([F:12])[F:11]>[Pd]>[F:8][CH:5]1[C:4]([F:9])([F:10])[C:3]([F:11])([F:12])[C:2]([F:1])([F:13])[CH:6]1[F:7]
Reactant: FC1=C(F)C(F)(F)C(F)(F)C1(F)F
Agent: [Pd]
Product: FC1C(F)C(F)(F)C(F)(F)C1(F)F
Yield: 74.3 %

Procedure:
Then a reactor was charged with 12 g of the octafluorocyclopentene and 0.24 g of a 5%-palladium/carbon catalyst and hydrogenation was conducted at a temperature of 50° C. and a hydrogenation pressure of 6 kg/cm2. When the absorption of hydrogen ceased, the reaction was completed. After the removal of the catalyst and the produced hydrogen fluoride from the reaction mixture, the reaction mixture was distilled to give 9 g of 1,2,3,3,4,4,5,5-octafluorocyclopentane (b.p., 79° C.; purity, 99%).
Reaction SMILES: [I:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C([NH:29][CH:30]([C:34](O)=[O:35])[CH:31]([CH3:33])[CH3:32])(OC(C)(C)C)=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)C>[NH2:29][CH:30]([CH:31]([CH3:33])[CH3:32])[C:34]([NH:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[CH:16]=[C:2]([I:1])[C:3]([O:20][CH3:21])=[CH:4][C:5]=2[CH:17]([CH3:19])[CH3:18])=[CH:13][N:12]=1)=[O:35]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(C(C)C)c(Oc2cnc(NC(=O)C(N)C(C)C)nc2N)cc1I
Temperature: 25 °C
Reaction time: 60 h
Yield: 9.6 %

Procedure:
To a suspension of compound 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1.0 g, 2.5 mmoles), Boc-DL-valine (1.22 g, 5.6 mmoles), and 4-dimethylaminopyridine (1.0 g, 8.2 mmoles) in dichloromethane, was added 1,3-dicyclohexylcarbodiimide (2.4 g, 11.6 mmoles). The mixture was stirred at room temperature for 60 hours, and solids were filtered off. The filtrate was evaporated and the residue was dissolved in a mixture of concentrated aqueous ammonium hydroxide and methanol (5 ml/45 ml) and stirred at room temperature for 5 hours. Solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and 0.5 N aqueous HCl. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexane) to give Boc-protected 2-Amino-N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-3-methyl-butyramide as a white foam (0.2 g), MS (M+H)=600. This Boc compound was dissolved in dichloromethane (3 ml) and 1M HCl in diethyl ether (10 ml) was added. The mixture was stirred for 4 hours at room temperature, and 10 ml of additional diethyl ether was added. The resulting solid precipitate was collected and crystallized from isopropanol and ether to give 2-amino-N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-3-methyl-butyramide as white solid (0.12 g), MS (M+H)=500.
Reaction SMILES: C(OC([NH:8][CH:9]([C:48]([OH:50])=[O:49])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:46][OH:47])[C:20]([NH:22][CH:23]2[CH2:26][N:25]([CH:27]([C:42]([OH:44])=[O:43])[C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:30][CH:29]=3)[C:24]2=[O:45])=[O:21])=[CH:15][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(OCC)C>C1C=CC=CC=1>[NH2:8][CH:9]([C:48]([OH:50])=[O:49])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[N:46][OH:47])[C:20]([NH:22][CH:23]2[CH2:26][N:25]([CH:27]([C:42]([OH:44])=[O:43])[C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:30][CH:29]=3)[C:24]2=[O:45])=[O:21])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC(CCOc1ccc(C(=NO)C(=O)NC2CN(C(C(=O)O)c3ccc(OCc4ccccc4)cc3)C2=O)cc1)C(=O)O
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(CCOc1ccc(C(=NO)C(=O)NC2CN(C(C(=O)O)c3ccc(OCc4ccccc4)cc3)C2=O)cc1)C(=O)O
Yield: 87.7 %

Procedure:
3-[2-{4-(3-tert-Butoxycarbonylamino-3-carboxypropoxy)phenyl}-2-hydroxyiminoacetamido]-1-(α-carboxy-4-benzyloxybenzyl)-2-azetidinone (240 mg) was suspended in benzene (2 ml), and to the suspension, there was added 2,2,2-trifluoroacetic acid (0.5 ml) at 7° C. with stirring. The mixture was stirred at the same temperature for 2 hours, and diethyl ether (about 25 ml) was added to the reaction mixture, and then the precipitating crystals were collected by filtration. The crystals were suspended in ethyl acetate and then the suspension was stirred at ambient temperature for half an hour. The crystals were collected by filtration and washed with diethyl ether to give 3-[2-{4-(3-amino-3-carboxypropoxy)phenyl}-2-hydroxyiminoacetamido]-1-(α-carboxy-4-benzyloxybenzyl)-2-azetidinone (180 mg), mp 164° to 167.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([NH:14][O:15][CH3:16])=[O:13].Cl[C:18]1[C:23]([CH:24]=O)=[CH:22][N:21]=[C:20]([S:26][CH3:27])[N:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[C:12](=[O:13])[N:14]([O:15][CH3:16])[C:18]2[N:19]=[C:20]([S:26][CH3:27])[N:21]=[CH:22][C:23]=2[CH:24]=1
Reactant: CSc1ncc(C=O)c(Cl)n1
Reactant: CONC(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COn1c(=O)c(-c2ccc([N+](=O)[O-])cc2Cl)cc2cnc(SC)nc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
2-(2-Chloro-4-nitrophenyl)-N-methoxyacetamide (49.3 mmol) and 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde (41.2 mmol) were dissolved in DMF (600 mL). The solution was cooled to 0° C., and K2CO3 (91 mmol) was added in one poroom temperatureion. The mixture was stirred at 0° C. for 2 h and then at room temperature for 48 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to 60 mL. Water (600 mL) was added. The precipitate was filtered, washed twice with EtOH and dried. The by-product (Z) -6-(2-chloro-4-nitrophenyl)-2-(methylthio)-7H-pyrano[2,3-d]pyrimidin-7-one O-methyl oxime was separated by reflux of the mixture for 4 h in EtOH and hot filtration of the suspension through a sintered glass funnel. Evaporation of the filtrate and drying gave 6-(2-chloro-4-nitrophenyl)-8-methoxy-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as a solid (63%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[C:33]2[CH2:34][CH2:35][N:36](C(OC(C)(C)C)=O)[CH2:37][CH:38]=2)[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C1=CCNCC1
Reaction time: 0.25 h

Procedure:
4-[2-(1-tert-Butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-cyano-phenyl]-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (example 15.10) (35 mg, 0.06 mmol) is suspended with aqueous trifluoroacetic acid (95%, 2 mL). The reaction mixture is shaken for 15 min, evaporated and the product is purified by reversed phase HPLC. Yield: 7.2 mg; ESI mass spectrum [M+H]+=525; Retention time HPLC: 0.56 min (HPLC method X018_S01).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[S:38]([C:42]1[N:43]([CH2:47][C:48](O)=[O:49])[CH:44]=[CH:45][N:46]=1)([CH3:41])(=[O:40])=[O:39]>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH:14][C:48](=[O:49])[CH2:47][N:43]2[CH:44]=[CH:45][N:46]=[C:42]2[S:38]([CH3:41])(=[O:40])=[O:39])[C:7]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)C2SC1
Reactant: CS(=O)(=O)c1nccn1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)Cn3ccnc3S(C)(=O)=O)C2SC1
Reaction time: 72 h
Yield: 83.6 %

Procedure:
3-Acetoxymethyl-7-amino-2-(tertiary butoxycarbonyl)-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (5.65 g.) and dicyclohexylcarbodiimide (3.90 g.) are added to a solution of (2-mesyl-imidazol-1-yl)-acetic acid (3.53 g) in dimethylformamide (30 cc.). The reagents are left in contact for 3 days at a temperature of about 20° C., and then the solid is filtered off. The filtrate is taken up in ethyl acetate (150 cc.) and washed successively with a saturated aqueous solution of sodium bicarbonate, with 0.5 N hydrochloric acid and then with water. The organic extracts are dried over sodium sulphate and then treated with decolorising charcoal. After concentration to dryness under reduced pressure (20 mm.Hg), the crystalline residue is washed with isopropyl ether (70 cc.). 3-Acetoxymethyl-2-(tertiary butoxycarbonyl)-7-[(2-mesyl-imidazol-1-yl)-acetamido]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (7.4 g.), which melts at 164° C., is thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si](C(C)(C)C)(C)C)[CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26]2[S:39][C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:37][C:27]=2[N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26]2[S:39][C:38]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:37][C:27]=2[N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:29]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(O[Si](C)(C)C(C)(C)C)cc3n2C(=O)OC(C)(C)C)c2sc(-c3ccccc3)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(O)cc3n2C(=O)OC(C)(C)C)c2sc(-c3ccccc3)cc21
Reaction time: 0.67 h
Yield: 99 %

Procedure:
To a solution of 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylic acid tert-butyl ester [2.44 g, 3.78 mmol, Intermediate (48)] in tetrahydrofuran (25 mL) at 0° C. was added tetrabutylammonium fluoride (4.20 mL of a 1M THF solution, 4.20 mmol) in one portion with stirring. After 40 minutes, the reaction was partitioned between ethyl acetate (75 mL) and 10% aqueous ammonium chloride (50 mL) and the layers separated. The organics were washed with water (50 mL) and brine (50 mL) successively, dried over magnesium sulfate, and the solvent removed under reduced pressure to give an amber foam. The crude product was chromatographed on silica, eluting with 10% ethyl acetate/dichloromethane, to yield 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-hydroxy-indole-1-carboxylic acid tert-butyl ester [1.99 g, 99%, Intermediate (49)] as a tan foam. TLC Rf 0.31 (silica, 10% ethyl acetate/dichloromethane); LC/MS: 532.2 (M+H), RT=4.31 minutes; 1H NMR [300 Mhz, (CD3)2SO]: δ 9.73 (s, 1H), 7.84-7.81 (m, 2H), 7.76 (s, 1H), 7.61 (d, J=2 Hz, 1H), 7.56-7.44 (m, 4H), 7.07 (s, 1H), 6.84 (dd, J=2, 8 Hz, 1H), 1.71 (s, 9H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:8]#[N:9].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CN(C)P(N(C)C)(N(C)C)=O>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]([C:8]1[NH:24][N:23]=[N:22][N:9]=1)[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: FC(F)(F)c1cccc(OC(c2ccc(Cl)cc2)c2nnn[nH]2)c1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
A mixture of (3-trifluoromethylphenoxy) (4-chlorophenyl)acetonitrile (10.68 g.), sodium azide (2.40 g.), ammonium chloride (1.98 g.) and hexamethylphosphoramide (85 ml.) is stirred at 60°-63°C. overnight (19 hours). The reaction mixture is cooled, poured into one liter of ice water containing 25 ml. of concentrated hydrochloric acid and this solution is extracted with 5 × 100 ml. of ether. The ether extracts are combined, extracted with water and dried over sodium sulfate. The ether solution is filtered, the ether is evaporated in vacuo and the residue is crystallized by trituration with methylcyclohexane. Recrystallization from a butyl chloride and methylcyclohexane mixture (about 1 to 1) affords 5-[α-(3-trifluoromethylphenoxy)-4-chlorobenzyl]tetrazole, m.p. 124.5°-126.5°C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:32])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=1[F:31])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:31][C:16]1[CH:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:28])=[O:29])[CH:19]=[CH:20][C:15]=1[NH:14][C:13]([CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2)c(F)c1

Procedure:
2-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.45 g, 0.93 mmol) was dissolved in 15 mL DCM and 15 mL trifluoroacetic acid and the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated, and the residue was redissolved in 100 mL EtOAc, washed with sat. NaCl, dried with MgSO4, filtered and concentrated to yield title compound as an oil. (0.27 g, 80%) APCI (AP−): 361.1 (M−H)−.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([Cl:31])=[N:21][C:22]([N:23]4[CH2:29][CH:28]5[O:30][CH:25]([CH2:26][CH2:27]5)[CH2:24]4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.C([O-])([O-])=O.[K+].[K+]>ClCCCl>[Cl:31][C:20]1[N:19]=[C:18]2[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:15]=[CH:16][C:17]2=[C:22]([N:23]2[CH2:24][CH:25]3[O:30][CH:28]([CH2:27][CH2:26]3)[CH2:29]2)[N:21]=1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCN(Cc4ccccc4)CC3)c2n1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCNCC3)c2n1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To 1-(1-benzyl-piperidin-4-yl)-6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (0.24 mmol) in 1,2-dichloroethane (2 mL) is added 1.9 mmol alpha-chloroethyl chloroformate (ACE-Cl) along with a small amount of K2CO3. The mixture is stirred for 5.5 h at RT. The reaction is quenched by addition of MeOH and the mixture is filtered and concentrated to dryness. The mixture is dissolved in MeOH and briefly heated to reflux. The title compound is obtained in quantitative yield by evaporation of MeOH. This material is used without further purification in the next step (reductive amination or acylation following the procedures disclosed previously, Scheme 30).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCOCC1
Solvent: CCO
Product: COc1ccc(N)cc1N1CCOCC1
Reaction time: 14 h
Yield: 70.4 %

Procedure:
4-(2-Methoxy-5-nitro-phenyl)-morpholine (w, 390 mg) was dissolved in 10 mL ethanol and reduced under 1 atm H2 using 10% Pd—C as a catalyst. After 14 hours, the catalyst was filtered off and the solvent was evaporated, affording 240 mg 4-methoxy-3-morpholin-4-yl-phenylamine (x) which was used without further purification: m/e: 208.12, MS (ES+): 209.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=NN)[CH3:8])[CH:2]=1.[OH-].[K+].[CH2:13]([N:20]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]1=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1.C(O)C.[O-2].[O-2].[Mn+4]>[CH2:13]([N:20]1[C:24](=[O:25])[CH:23]2[CH:22]([C:7]2([CH3:8])[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:21]1=[O:26])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: CC(=NN)c1cccnc1
Agent: [Mn+4]
Agent: [K+]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: CCO
Product: CC1(c2cccnc2)C2C(=O)N(Cc3ccccc3)C(=O)C21
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.7 %

Procedure:
1-(3-Pyridinyl)-1-ethanone hydrazone (Preparation 76, 5.0 g, 40.0 mmol) was dissolved in dioxan (250 ml) and manganese dioxide (6.4 g, 40.0 mmol) was added portionwise followed by a saturated solution of potassium hydroxide in ethanol (2 ml). The reaction mixture was stirred at room temperature for 4 h and then filtered through a pad of Celite®. The filtrate was added to 1-benzyl-1H-pyrrole-2,5-dione (7.5 g, 40.0 mmol) and the reaction mixture was stirred for 16 h at room temperature and was then refluxed for 72 h. The reaction mixture was concentrated in vacuo and the residue was suspended in methanol and filtered to give the title compound as a white solid (3 g, 25%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>ClCCl>[Cl:1][CH2:2][CH2:3][C:4]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCl)c1cccs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
18.1 g of 3-chloropropionyl chloride (142 mmol) are solubilized in dichloromethane (50 mL). The obtained solution is dropwise added to a suspension of AlCl3 (21.6 g; 160 mmoles) in dichloromethane (100 mL). It is left under stirring for 15 minutes at room temperature. A solution of thiophene (12.0 g; 142 mmoles) in dichloromethane (50 mL) is then slowly added while maintaining the temperature at 0° C. At the end the temperature is let to rise to room temperature while stirring for 4 hours. The reaction mixture is poured in a water/ice mixture and then extraction is carried out with diethyl ether. The organic phase is anhydrified with sodium sulphate, filtered and the solvent removed under vacuum. 23.9 g of 3-chloro-1-(thiophen-2-yl)propan-1-one are obtained (yellow oil, yield 99%). Rf=0.75 (ligroin/ethyl acetate 7/3 volume/volume); 1H NMR (CDCl3) δ (ppm): 7.66 (dd, 1H, ArH), 7.60 (dd, 1H, ArH); 7.07 (dd, 1H, ArH), 3.82 (t, 2H, CH2); 3.31 (t, 2H, CH2); 13C NMR (CDCl3) δ (ppm): 189.5, 143.6, 134.4, 132.5, 128.3, 41.8, 38.6; FT-IR (film) νmax: 3093.3, 1657.7, 1413.0, 1240.3, 850.4, 720.7 cm−1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH2:10][CH2:11][C:12]1[C:13]([O:30][CH3:31])=[C:14]2[C:18](=[C:19]([F:21])[CH:20]=1)[N:17]([CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26].O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[CH2:10][CH2:11][C:12]1[C:13]([O:30][CH3:31])=[C:14]2[C:18](=[C:19]([F:21])[CH:20]=1)[N:17]([CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26]
Reactant: CCn1cc(CC(=O)N(C)C)c2c(OC)c(CCC(=O)Nc3ccccc3N)cc(F)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCn1cc(CC(=O)N(C)C)c2c(OC)c(CCc3nc4ccccc4[nH]3)cc(F)c21
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A solution of 29-2 (230 mg, 0.52 mmol) in acetic acid (10 mL) was heated to 80° C. for 3 h. After cooled to room temperature, water (10 mL) and sat. aqueous NaHCO3 (30 mL) were added. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried with MgSO4, filtered and evaporated to afford 29-3 (150 mg, 68%) as yellow oil. LRMS: calc 422.5 and found: 423.2 [M+1].