Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Li].[Si:3]([O:10][C@H:11]1[CH2:16][CH2:15][O:14][C:12]1=[O:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[C:17](O)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)C.C1COCC1>[Si:3]([O:10][C@H:11]1[CH2:16][CH2:15][O:14][C:12]1([OH:13])[CH3:17])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCOC1=O
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Li]C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)OCC[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Methyl lithium (670 μl [1.11 mmol, 1.1 equiv] of a 1.65 M solution in diethyl ether) is added dropwise to a stirred solution of (S)-2-(tertbutyidimethylsilyloxy)-γ-butyrolactone 12 (218 mg, 1.01 mmol) in THF (4.0 ml) cooled to −78° C. is added dropwise. After stirring at −78° C. for 3 h, the reaction is quenched by the addition of glacial acetic acid (72 μl, 1.26 mmol, 1.25 equiv). Diethyl ether (20 ml) and saturated aqueous sodium bicarbonate solution (10 ml) are added. After stirring for 5 min the organic layer is separated and the aqueous layer is extracted with diethyl ether (2×20 ml). The combined organic extracts are dried over magnesium sulfate and concentrated in vacua. Crude (3S)-3-(tertbutyidimethylsilyloxy)-2-hydroxy-2-methyl-tetrahydrofurane 13 (235 mg, 93%) is obtained as a colourless crystalline solid (mixture of diastereomers) which is used for the synthesis of (S)-3,5-di-(tert-butyldimethylsilyloxy)-pentan-2-one 14 without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].Br[CH:39]([CH3:43])[C:40](=[O:42])[CH3:41].C(N(CC)CC)C>CC(=O)CC>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:40]([CH3:41])([OH:42])[CH:39]([CH3:43])[S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)C(C)Br
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CC(C)c1ccccc1N1/C(=N\N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SC(C)C1(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (114 mg, 0.22 mmol) in butanone (2.2 mL) was added 3-bromo-2-butanone (0.03 mL, 0.28 mmol) and triethylamine (0.06 mL, 0.44 mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was directly applied to a silica gel cartridge and purified by flash chromatography (0-30% ethyl acetate/B, where B=1:1 dichloromethane/hexanes) to provide the title compound as a yellow solid (108 mg, 84% yield): mp 140° C. (dec); 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.22-8.16 (m, 3H), 7.82-7.74 (m, 4H), 7.55-7.47 (m, 1H), 7.42-7.35 (m, 4H), 7.29-7.24 (m, 1H), 3.92-2.96 (m, 3H), 1.57 (s, 1H), 1.57-1.50 (m, 3H), 1.35-1.17 (m, 9H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 595 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:20]O.C[O-].[Na+]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:3]=1[C:4]([O:6][CH3:20])=[O:5]
Reactant: O=C(O)c1c(C(F)(F)F)ccc(Cl)c1Cl
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1c(C(F)(F)F)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.04 g of 2,3-dichloro-6-trifluoromethylbenzoic acid in 10 ml of toluene was added 0.71 g of thionyl chloride and 1 drop of pyridine and the mixture was heated at reflux for 3 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and 2,3-dichloro-6-trifluoromethylbenzoyl chloride obtained was added to a solution which is prepared by dissolving 28% methanol solution of 0.77 g of sodium methoxide into 10 ml of methanol at a temperature of from 5 to 10° C., and the solution was stirred for 2 hours at room temperature. After condensing the reaction mixture, it was extracted with ether. The extract was washed with IN-aqueous hydrochloric acid, water and saturated saline solution in series and then dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the oily substance obtained was purified by using silica gel column chromatography to obtain 0.89 g of the title compound (nD 23.3-1.4801).
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH2:16][CH2:15][C:14](OC)([O:21]C)[CH2:13][C:12]=1[CH2:11][CH2:10]3)#[N:2].O.Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl.C(O)(C)(C)C>[C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH2:16][CH2:15][C:14](=[O:21])[CH2:13][C:12]=1[CH2:11][CH2:10]3)#[N:2]
Reactant: COC1(OC)CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C#N)CC[C@@H]32)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: C[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2C#N)CC(=O)CC4

Procedure:
3 g of 17β-cyano-3,3-dimethoxyestr-5(10)-ene are suspended in a mixture of 24 ml of dichloromethane and 70 ml of t-butanol. After addition of 28 ml of water and 0.11 ml of 60% perchloric acid, the batch is stirred until fully reacted, admixed with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered and the filtrate is evaporated to dryness to leave 17β-cyanoestr-5(10)-en-3-one which is further processed without purification.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][O:9][C:10]=1[CH3:11])C.O.[NH2:15][NH2:16]>C(O)CCC>[CH3:12][C:7]1[C:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CCOC(=O)Cc1c(C)noc1C
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1noc(C)c1CC(=O)NN
Yield: 87 %

Procedure:
As described for example 112a, (3,5-dimethyl-isoxazol-4-yl)-acetic acid ethyl ester (Bacon, Edward R.; Daum, Sol J.; Singh, Baldev. 6-Substituted pyrazolo[3,4-d]pyrimidin-4-ones and compositions and methods of use as c-GMP phosphodiesterase inhibitors. PCT Int. Appl. (1996), WO 9628429 A1) in butanol was reacted with hydrazine hydrate (3.2 equivalents) and the resulting mixture was heated under reflux for 24 h. Evaporation of all volatiles and crystallization from n-butanol/toluene afforded the title compound as a white solid (yield: 87%). MS: m/e=170.2 [M+H]+.
Reaction SMILES: [CH3:1]/[C:2](/[OH:19])=[C:3](/[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)=[O:7])\C#N.C(OC(=O)CC(C)=O)C.FC(F)(F)C1C=CC(N)=CC=1.[N+](C1C=CC=CC=1)([O-])=O>C1C=CC=CC=1.C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[O:19]=[C:2]([CH3:1])[CH2:3][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)=[O:7]
Reactant: C/C(O)=C(\C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: Nc1ccc(C(F)(F)F)cc1
Solvent: CCOC(=O)CC(C)=O
Solvent: c1ccccc1
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
The present invention provides a process for preparation of Teriflunomide. Ethylacetoacetate (II) and 4-trifluoromethyl aniline (III) is refluxed in a solvent. The solvent is selected from aromatic hydrocarbon such as toluene, xylene, nitrobenzene, benzene and the like or mixtures thereof. The reaction mixture is refluxed for about 48 hours. The Reaction mixture is concentrated and purified by column chromatography to give pure 3-oxo-N-(4-trifluoromethylphenyl)butanamide (IV).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[C:20]([O:24][C:25]([N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][C:31]([C:37](O)=[O:38])=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[C:20]([O:24][C:25]([N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][C:31]([C:37](=[O:38])[NH:1][CH:2]3[C:8]4=[N:9][C:10]([C:14]5[CH:19]=[CH:18][N:17]=[CH:16][N:15]=5)=[CH:11][C:12](=[O:13])[N:7]4[CH2:6][CH2:5][O:4][CH2:3]3)=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: NC1COCCn2c1nc(-c1ccncn1)cc2=O
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc2C1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)NC3COCCn4c3nc(-c3ccncn3)cc4=O)cc2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.6 %

Procedure:
To a solution of 0.080 g (0.31 mmol) of (+/−)-9-Amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one dissolved in 2.60 mL of dimethylformamide was added 0.086 g (0.31 mmol) of 3,4-dihydro-1H-isoquinoline-2,7-dicarboxylic acid 2-tert-butyl ester. To the resulting mixture was added 60 μL (0.37 mmol) of diethyl cyanophosphonate and 40 μL (0.31 mmol) of triethylamine at 0° C. The resulting mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added and the mixture was stirred. The resulting residue was filtered, washed with water, ethyl acetate and diethyl ether to afford 0.062 g (38%) of the pure product as a white powder.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:30])[CH2:15][CH2:16][C:17]2[N:21](CCC#N)[C:20]3[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=3[N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)(C)C.CC(C)([O-])C.[K+].C(OCC)(=O)C>C(=O)(O)[O-].[Na+].C(N(CC)CC)C.CO>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH3:30])[CH2:15][CH2:16][C:17]2[NH:18][C:19]3[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=3[N:21]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CCc1nc2ccccc2n1CCC#N)N1CCC(Cc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(CCc1nc2ccccc2[nH]1)N1CCC(Cc2ccccc2)CC1

Procedure:
A mixture of 0.32 g of 3-{2-[3-(4-benzyl-piperidin-1-yl)-butyl]-benzimidazol-1-yl}-propionitrile, 100 mL of tert-butanol and 1 g of potassium tert-butoxide was heated to reflux for 10 min. Conversion was complete by TLC (80:20:1 ethyl acetate:methanol:triethylamine). The mixture was cooled, diluted with 10 mL of saturated sodium bicarbonate and concentrated. The residue was partitioned between 3×100 mL of chloroform and 50 mL of water. After drying over magnesium sulfate and concentration under reduced pressure, the residue was purified by preparative TLC eluting with 90:10:2 chloroform:methanol:ammonium hydroxide. The major band (UV visualization) was 2-[3-(4-benzyl-piperidin-1-yl)-butyl]-1H-benzimidazole (250 mg): MS (m+1)=348.5; 1H NMR (400 MHz, CDCl3) 7.42 (s, 2H), 7.3 (m, 2H), 7.25 (m, 1H), 7.2 (m, 4H), 3.25 (m, 1H), 3.0 (m, 2H), 2.8 (d, 2H), 2.65 (m, 2H), 2.5 (m, 2H), 2.1 (m, 2H), 1.6 (d, 2H), 1.3 (m, 1H), 1.2 (d, 3H), 1.0 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9](I)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH3:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[N:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=2)[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=1.C(OCC)(=O)C>O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:24]2[CH:23]=[C:22]([NH:35][C:36]3[N:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=3)[CH:21]=[C:20]([CH3:19])[CH:25]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1cc(I)ccc1O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)ccc1O
Temperature: 80 °C

Procedure:
A mixture of methyl 2-hydroxy-5-iodobenzoate (11.6 g, 41.5 mmol) in 2-methyl-THF (180 mL) and water (82.5 mL) was purged with N2 for 30 minutes. Sodium carbonate (12.6 g, 119 mmol), N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (15.0 g, 39.6 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.61 g, 1.98 mmol) were added to the reaction mixture at rt under N2 and then the mixture was heated to 80° C. for 14 hours. The reaction mixture was poured into a 1:1 solution of ethyl acetate/2N HCl (800 mL) and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) to afford methyl 4-hydroxy-3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carboxylate. MS ESI calcd. for C20H12F3N3O3 [M+H]+ 404, found 404.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].C[O:10][C:11](=O)[C:12]#[C:13][CH3:14].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[CH3:14][C:13]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[NH:8][C:11](=[O:10])[CH:12]=1
Reactant: CC#CC(=O)OC
Reactant: NNc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(=O)[nH]n1-c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.7 %

Procedure:
To a solution of pyridin-2-yl-hydrazine (1 g) in tert-butanol (15 mL) at 30° C. was added but-2-ynoic acid methyl ester (1 g). The reaction vessel was then cooled in an ice bath was treated with potassium tert butoxide (2 g) portionwise. The resulting suspension was stirred at ambient temperature for 16 hours. The tert-butanol was reduced in vacuo and the residue was taken up in water. The aqueous layer was extracted once with DCM. The aqueous layer was then acidified with AcOH to pH=3 and the resulting precipitate was collected by filtration and washed with water. The solid was collected and dried over P2O5 in a dessicator to give 5-methyl-1-pyridin-2-yl-1,2-dihydro-pyrazol-3-one (0.3 g) as a white solid. MS (ESI+): 176.3 [M+H]+).
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C@:14]2([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31]>O1CCOCC1>[ClH:31].[S:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[C@:14]12[CH2:16][NH:17][CH2:18][C@H:13]1[CH2:12][S:11][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N:15]2
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccs2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1=N[C@@]2(c3cccs3)CNC[C@H]2CS1)c1ccccc1
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of tert-butyl (4aR,7aR)-2-benzamido-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (1.3 g, 2.93 mmol) in 1,4 dioxane (60 mL) is added drop wise 4 N hydrogen chloride in 1,4 dioxane (14.6 mL, 58.6 mmol). The reaction is stirred for 4 hours. The solution is concentrated to give the title compound (1.1 g, 99%). ES/MS (m/e): 344 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH3:15].[BH4-].[Na+]>CCO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 44 %

Procedure:
A mixture of 1-BOC-piperidone (2 g, 10 mmol), titanium(IV) isopropoxide and ammonia in EtOH was stirred under argon in a capped flask at room temperature for 6 h. Sodium borohydride was then added and the resulting mixture was stirred at room temperature for an additional 3 h. The reaction was then quenched by pouring it into ammonium hydroxide (2M, 25 mL). The resulting inorganic precipitate was filtered off, and washed with EtOAc (2×25 mL). The organic layer was separated and the remaining aqueous layer was extracted with EtOAc (2×25 mL). The combined organic fractions were next extracted with HCl (1M, 30 mL) to separate the neutral materials. The acidic extracts were washed with EtOAc (50 mL), then treated with aqueous NaOH 2M to pH 10-12, and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to afford 4-aminopiperidine-1-carboxylic acid tert-butyl ester as a white solid (882 mg, 44%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 1.12-1.27 (3H, m), 1.42 (9H, s, 3CH3), 1.97 (2H, m), 1.73 (2H, m), 2.76 (3H, m) and 4.01 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:21])[C:6](=[O:22])[NH:5]2.[CH3:23][O:24][C:25]([C:27]1(OC)[CH2:31][CH2:30][CH:29](OC)O1)=[O:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH:15]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([N:1]4[CH:29]=[CH:30][CH:31]=[C:27]4[C:25]([O:24][CH3:23])=[O:26])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=3)[NH:5][C:6](=[O:22])[C:7]2=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Reactant: COC(=O)C1(OC)CCC(OC)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccn1-c1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Yield: 80.8 %

Procedure:
10 g (33 mmol) of 6-amino-1-cyclohexyl-7-nitro-2,3(1H,4H)-quinoxalinedione (Example 28e), 6.9 g (36 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran and a spatula tip of p-toluenesulfonic acid were refluxed in a mixture of 50 ml of dimethylformamide and 50 ml of toluene with a water trap. After reaction was complete, the mixture was concentrated under reduced pressure, and the residue was treated with water. The precipitate was filtered off with suction to yield 11 g (79%) of the product. Melting point 211°-212° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:11]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: Cc1ccc(F)cc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(F)ccc1CBr
Temperature: 25 °C
Yield: 101.7 %

Procedure:
A mixture of 5-fluoro-2-methylbenzonitrile (10.0 g, 74.0 mmol), N-bromosuccinimide (NMS, 13.2 g, 74.0 mmol), benzoyl peroxide (0.2 g, 0.82 mmol), and carbon tetrachloride (100 mL) was refluxed for 18 h. The reaction mixture was then cooled to room temperature and filtered through fritted glass. The solid in the funnel was washed with carbon tetrachloride (3×50 mL) and evaporated to dryness under vacuum to provide 16.1 g, 102% yield of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([F:11])=[C:6]([CH2:12][NH:13]C(OC(C)(C)C)=O)[CH:5]=1.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([F:11])=[C:6]([CH2:12][NH2:13])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)c(F)c(CN)c1
Reaction time: 8 h

Procedure:
To a solution of 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid methyl ester (4.25 g, 13.4 mmol) in CH2Cl2 (70 mL) was added TFA (10.3 mL, 134 mmol), and stirring was continued at RT overnight. Methanol was then added to the reaction mixture, and volatiles were removed in vacuo. The residue was taken up in methanol and concentrated again under reduced pressure to afford the title compound as a beige solid. MS (LC/MS): 218.0 [M+H]+; tR (HPLC conditions c): 3.10 min. The material thus obtained was used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[O:6][C@@H:5]2[O:7][C@H:8](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)=[CH:27][CH:26]=3)[C@H:9]([CH2:10][CH2:11][N:12]3[C:17](=[O:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=[N:13]3)[C@@H:4]2[O:3]1.O1CCCC1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:37])[O:6][C@@H:5]2[O:7][C@H:8]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)=[CH:29][CH:30]=3)[C@H:9]([CH2:10][CH2:11][N:12]3[C:17](=[O:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=[N:13]3)[C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(-c4cncnc4)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)O[C@@H]2O[C@H](CCc3ccc(-c4cncnc4)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1

Procedure:
To the solution of the compound obtained from step k above (0.3 g) in a solvent mixture of tetrahydrofuran: methanol (10 mL, 1:1), 10% palladium on charcoal (0.15 g) was added at room temperature and the reaction mixture was hydrogenated with hydrogen at 35 psi for 4 hours in a Paar apparatus. The reaction mixture was filtered through a celite pad and the residue was washed with methanol. The filtrate was concentrated to afford the title compound (0.3 g).
Reaction SMILES: [NH:1]([C:3]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)=[O:4])[NH2:2].[CH3:10]OC(OC)N(C)C.C(OCC)C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[N:6]1[CH:7]=[CH:8][N:9]2[C:5]=1[C:3](=[O:4])[NH:1][N:2]=[CH:10]2
Reactant: COC(OC)N(C)C
Reactant: NNC(=O)c1ncc[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=c1[nH]ncn2ccnc12
Temperature: 100 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
2-Hydrazinocarbonylimidazole (prepared according to the procedure described in EP-A-0713876) (1.00 g, 7.93 mmol) was suspended in Dowtherm A (6 ml), N,N-dimethylformamide dimethyl acetal (1.89 g, 15.9 mmol) added and the mixture heated at 100° C. for 1.5 h then at 210° C. for 18 h. The mixture was allowed to cool to room temperature, diethyl ether (100 ml) added and the precipitated solid was filtered. The brown solid was purified by dry flash column chromatography on silica eluting with dichloromethane (+0.1% 0.880 ammonia) on a gradient of methanol (5-12%). Collecting appropriate fractions gave 7H-imidazo[1,2-d][1,2,4]triazin-8-one (216 mg, 20%) as an off-white solid: δH (400 MHz, CDCl3) 7.59 (1H, d, J 1), 7.91 (1H, d, J 1), 8.74 (1H, s), 12.39 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10]Br)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C1COCCN1
Reactant: N#Cc1cc(Br)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1CN1CCOCC1

Procedure:
A mixture of 5-bromo-2-bromomethyl-benzonitrile (2.0 g, 7.3 mmol), morpholine (0.76 g, 8.7 mmol) and K2CO3 (1.0 g, 7.3 mmol) is stirred in 50 DMF at room temperature for 72 hours. The reaction mixture is filtered and the filtrate is dried under vacuum to yield the title compound. 1H-NMR (400 MHz; DMSO-d6): 8.11 (d, 1H), 7.90 (dd, 1H), 7.53 (d, 1H), 3.60 (s, 2H), 3.56 (t, 4H), 2.39 (t, 4H). LC-MS (m/z, ES+): 281 (MH+), Retention time: 1.79 mins (LC-MS method 2)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]#[N:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[SH2:26]>N1C=CC=CC=1>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][C:17]([NH2:18])=[S:26])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: S
Reactant: CC(C)(C)c1cc(CC#N)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(CC(N)=S)cc(C(C)(C)C)c1O

Procedure:
3,5-Di-tert-butyl-4-hydroxyphenylacetonitrile (20.0 g) and 11.4 ml of triethylamine were dissolved in 40 ml of pyridine, and hydrogen sulfide was blown into the solution at room temperature over 13 hours. The reaction mixture was concentrated, and the crude product thus obtained was purified by silica gel column chromatography (diethyl ether-hexane =3:7) to give 4.9 g of the desired compound as a colorless solid.