Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH3:30][C:31](=[O:34])[CH:32]=[CH2:33]>C1C=CC=CC=1>[O:34]=[C:31]1[CH2:32][CH2:33][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:30]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 70 °C
Yield: 62.5 %

Procedure:
To a benzene (700 mL) solution of benzyl 4-formylpiperidine-1-carboxylate (90.0 g, 363.9 mmol) stirring in a 2 L 3-neck flask fitted with a Dean-Stark trap was added p toluenesulfonic acid (6.92 g, 36.4 mmol). The reaction was heated to 70° C. 3-buten-2-one (61.8 mL, 753 mmol) was added and mixture was heated at reflux for 24 hours collecting expelled water in the trap. The reaction was coded to room temperature and washed with 500 mL saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated. The resultant dark brown oil was taken up in 200 mL dichloromethane and filtered through a silica pad (600 mL silica), eluting with 2 L heptane followed by 3 L 50% ethyl acetate/heptane and then 3 L ethyl acetate, collecting by 1 L fractions. Fractions containing clean product were combined and concentrated to yield 68.1 g of the title compound as a thick brown oil. The fractions containing impure product were combined and concentrated and purified by flash chromatography (10-60% ethyl acetate/heptane, 340 g silica gel) to yield an additional 23.6 g of the title compound as a thick brown oil. Combined yield of 91.7 g, (94.1%) was realized. 1H NMR (400 MHz, CDCl3) δ ppm 7.27-7.43 (m, 5H), 6.79 (d, J=10.3 Hz, 1H), 5.95 (d, J=10.3 Hz, 1H), 5.13 (s, 2H), 3.58-3.71 (m, 2H), 3.39-3.55 (m, 2H), 2.38-2.50 (m, 2H), 1.96 (t, J=6.7 Hz, 2H), 1.70-1.52 (m, 4H).
Reaction SMILES: [S].[S:2](=O)=[O:3].[NH3:5].[S:6]([O-:10])([O-])(=[O:8])=[O:7].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O>[S:6]([O-:10])([O-:8])(=[O:7])=[S:2].[NH4+:5].[NH4+:5].[OH-:3].[NH3:5]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=S=O
Agent: N
Agent: [NH4+]
Agent: [S]
Solvent: O
Product: O=S([O-])([O-])=S
Product: [OH-]

Procedure:
The present invention accomplishes its desired objects by broadly providing an improved process of preparing a metallic sulphate from mixing of the corresponding metallic sulphide concentrates with ammonium sulphate and heating the mixture to yield the metallic sulphate, evolved sulphur, sulphur dioxide, ammonia, and water. The improvement comprises heating the mixture by directly contacting the mixture with products of combustion of a heating fuel. The metallic sulphate may initially be added before heating to the mixture of the corresponding metallic sulphide and ammonium sulphate to inhibit the development of semi-fluid conditions in the reaction of the metallic sulphide concentrates with the ammonium sulphate. Heating may be done at a temperature between about 150° C. and 480° C., and a diluent gas may additionally be added to the products of combustion. A raw fuel gas may be also added above the mixture being heated and the volatile sulphur, sulphur dioxide and ammonia may be subsequently dissolved in water in an absorption tower to produce solutions of ammonium thiosulphate and ammonia hydroxide.
Reaction SMILES: F[C:2]1C=C([C@H]2N(CC(OCC)=O)C(=O)C3(CCCC3)NC2)C=C(F)C=1.[ClH:26].[NH2:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.NC1(C(O)=O)CCCCC1>>[ClH:26].[NH2:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:2]1
Reactant: COC(=O)C1(N)CCCC1
Reactant: CCOC(=O)CN1C(=O)C2(CCCC2)NC[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Agent: NC1(C(=O)O)CCCCC1
Product: COC(=O)C1(N)CCCCC1

Procedure:
Essentially following the procedures described in Intermediate 25 for methyl 1-aminocyclopentanecarboxylate hydrochloride, but using 1-aminocyclohexanecarboxylic acid in place of 1-aminocyclopentanecarboxylic acid, the title compound was obtained. MS: m/z=158 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:14]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1cc(F)ccc1[N+](=O)[O-]

Procedure:
To a mixture of 2,4-difluoronitrobenzene (VII, 19.20 g), glycine ethyl ester hydrochloride (XII, 16.52 g), and acetonitrile (50 ml) is added diisopropylethylamine (42 ml). A mild exotherm ensues. The reaction is stirred (without cooling) for two hours. The acetonitrile is removed under reduced pressure and the residue is partitioned between dichloromethane and water. The organic layers are dried over sodium sulfate and concentrated to give the produce as a solid (single spot by TLC), mp 194°-195°; NMR (CDCl3) 1.33, 4.05, 4.30, 6.35, 6.45, 8.26 and 8.56 β.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[C:11]#[N:12].[CH2:17]([NH:19][CH2:20]C)C.C(N(CC)CC)C>C1C=CC=CC=1>[C:11]([C:10]1[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][S:7][C:6]=1[NH:5][C:1]([N:19]([CH3:20])[CH3:17])=[O:2])#[N:12]
Reactant: CCNCC
Reactant: CC(C)(C)c1csc(N)c1C#N
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1scc(C(C)(C)C)c1C#N
Temperature: 25 °C

Procedure:
A solution of 3.04 g phosgene in about 25 ml benzene was added to a cooled (0°C.) solution of 5 g 2-amino-3-cyano-4-t-butylthiophene, 5 g diethylamine and 8.4 g triethylamine in 100 ml benzene. The reaction mixture was warmed to about 25°C. and maintained at this temperature for about 16 hours. The reaction mixture was filtered and the filtrate was evaporated to give a black oil. The oil was chromatographed on silica gel. The product, a brown solid melting at 120°-125°C., was eluted from the silica gel with 1:1 ether-hexane. The infrared spectrum of the product showed strong cyano absorption at 4.6 microns and strong carbonyl absorption at 6.0 microns. Sulfur analysis for the product is tabulated in Table I.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH2:15]([NH2:18])[CH2:16][NH2:17].Cl>O>[NH2:17][CH2:16][CH2:15][NH:18][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9]
Reactant: NCCN
Reactant: S=C=Nc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: NCCNC(=S)Nc1ccccc1

Procedure:
A solution of phenyl isothiocyanate (500 mg) in abs. THF (6 ml) was added dropwise over 20 minutes under argon to a solution of ethylenediamine (5.56 g) in abs. THF (6 ml). Afterwards, the reaction mixture was added to water, acidified with 10% HCl and extracted with ethyl acetate. The aqueous phase was then basified with potassium carbonate and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. Subsequently, co-evaporation with toluene was effected twice. 650 mg of the desired product remained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[Cl:27][C:28]1[C:36]2[N:35]=[N:34][N:33]([CH2:37][CH:38]3[CH2:40][CH2:39]3)[C:32]=2[CH:31]=[CH:30][C:29]=1[C:41]1[CH2:46][CH2:45][CH:44]([CH2:47]O)[CH2:43][CH:42]=1>O1CCCC1>[Cl:27][C:28]1[C:36]2[N:35]=[N:34][N:33]([CH2:37][CH:38]3[CH2:40][CH2:39]3)[C:32]=2[CH:31]=[CH:30][C:29]=1[C:41]1[CH2:46][CH2:45][CH:44]([CH2:47][I:25])[CH2:43][CH:42]=1
Reactant: II
Reactant: OCC1CC=C(c2ccc3c(nnn3CC3CC3)c2Cl)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1c(C2=CCC(CI)CC2)ccc2c1nnn2CC1CC1
Reaction time: 0.17 h

Procedure:
To a tetrahydrofuran solution (2 mL) of triphenylphosphine (94 mg, 0.36 mmol, 1.1 equiv) was added imidazole (0.11 g, 1.6 mmol, 5 equiv) and iodine (86 mg, 0.34 mmol, 1.05 equiv). After stirring for 10 minutes, a tetrahydrofuran solution (1.5 mL) of {4-[4-chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]cyclohex-3-en-1-yl}methanol (Example 2, 0.10 g, 0.32 mmol) was added and the mixture was stirred for 1 hour. In a separate flask, a tetrahydrofuran solution (2 mL) was prepared containing triphenylphosphine (94 mg, 0.36 mmol, 1.1 equiv), imidazole (0.11 g, 1.6 mmol, 5 equiv) and iodine (86 mg, 0.34 mmol, 1.05 equiv), which was added to the reaction mixture after stirring for 10 minutes. After stirring for an additional 1 hour, an additional tetrahydrofuran solution (2 mL) containing triphenylphosphine (94 mg, 0.36 mmol, 1.1 equiv), imidazole (0.11 g, 1.6 mmol, 5 equiv) and iodine (86 mg, 0.34 mmol, 1.05 equiv) was added to the reaction mixture. After stirring for an additional 30 minutes, the mixture was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethly acetate), providing the titled compound as a light yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([N+:29]([O-:31])=[O:30])[CH:22]=2)[CH:16]=1.O>O1CCCC1>[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[CH:5][C:3]#[N:4])=[C:23]([N+:29]([O-:31])=[O:30])[CH:22]=2)[CH:16]=1
Reactant: Cc1ccnc(-c2ccc(C=O)c([N+](=O)[O-])c2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(-c2ccc(C=CC#N)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 240 mg) in tetrahydrofuran (10 ml) was added a solution of diethyl cyanomethylphosphonate (0.971 ml) dropwise at 0° C., and the mixture was stirred at ambient temperature for 30 minutes. Then to the resultant mixture was added a solution of 4-(4-methylpyridin-2-yl)-2-nitrobenzaldehyde (1.21 g) in tetrahydrofuran (15 ml) dropwise at 0° C., and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered and dried to give 4-(4-methylpyridin-2-yl)-2-nitrocinnamonitrile (1.22 g) as a mixture of regioisomers.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]([NH:26][C:27]([CH3:31])([CH3:30])[CH:28]=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]([NH:26][C:27]([CH3:31])([CH3:30])[CH2:28][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CC(C)(C=O)NC(=O)OCc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NCC(C)(C)NC(=O)OCc2ccccc2)cc1

Procedure:
By treating 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone and 2-(benzyloxycarbonylamino)-2-methylpropanal obtained in 2-a above in the same way as in Example 1, (1-c), 6-[4-(2-benzyloxycarbonylamino-2-methylpropylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:7]([C:22]([O:24][CH3:25])=[O:23])=[C:6]2[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34]C)=[C:28]([O:36][CH3:37])[CH:27]=1.Cl.O1CCOCC1.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:7]([C:22]([O:24][CH3:25])=[O:23])=[C:6]2[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([OH:34])=[C:28]([O:36][CH3:37])[CH:27]=1
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1c(-c2cc(OC)c(O)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1N1CCOCC1
Temperature: 25 °C
Yield: 41.9 %

Procedure:
A mixture of the compound obtained in Example 118 (1.3 g), conc.hydrochloric acid (15 ml) and dioxane (15 ml) is heated under reflux overnight. The reaction mixture is cooled to room temperature, and thereto are added water and chloroform. The extract is washed, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform:acetone=50:1) to give 6,7-dimethoxy-4-(3,5-dimethoxy-4-hydroxyphenyl)-3-methoxycarbonyl-2-morpholino-1(2H)-isoquinolinone (530 mg) as listed in Table 10.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([CH3:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CN(C)[CH:34]=[O:35]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:34]=[O:35])=[N:3][CH:4]=[C:5]([CH3:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CN(C)C=O
Reactant: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a solution of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (750 mg, 1.59 mmol) in THF (3 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF). The mixture was then stirred for 30 min at 0° C. followed by the addition of N,N-dimethylformamide (1.19 mL, excess) at 0° C. The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). Combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. Obtained residue was column purified (SiO2, 30% EtOAc-hexanes) to obtain 4-chloro-N-(2-formyl-5-methyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (300 mg) in 44.7% yield. ESMS m/z (relative intensity): 390.9 (M−32+H)+ (40), 423 (M+H)+ (40), 444.9 (M+Na)+ (40).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2.[OH-].[Na+].CC(O)=O>CO.O>[CH3:1][N:2]([CH3:34])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(N(C)C)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)c1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
To a solution of methyl 3-[6-(dimethylamino)-1,2,3,4-tetrahydroquinolin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylate (30 mg, 0.07 mmol) in methanol (20 ml) and water (2 ml) was added sodium hydroxide (10 mg, 0.25 mmol) and the reaction was stirred overnight at room temperature. The resulting solution was diluted with water (100 ml), adjusted pH to 5 with AcOH, extracted with ethyl acetate (3×20 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3-[6-(dimethylamino)-1,2,3,4-tetrahydroquinolin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a red solid (3 mg, 10%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:10][C:11]([F:16])([F:15])[C:12]([NH2:14])=[S:13]>C(O)C>[F:10][C:11]([F:16])([F:15])[C:12]1[S:13][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:14]=1
Reactant: NC(=S)C(F)(F)F
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(C(F)(F)F)n1
Yield: 27.9 %

Procedure:
A mixture of ethyl bromopyruvate (6.82 g), 2,2,2-trifluorothioacetamide (4.52 g) and ethanol (30 ml) was refluxed for 3 hours. The reaction mixture was cooled, then ethanol was distilled off under reduced pressure. To the residue was added water (40 ml), which was subjected to extraction with ethyl acetate (60 ml×2). The extract solution was washed with water (40 ml) and dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel chromatography (2.5×45 cm), eluting with ethyl acetate-hexane (1:5). The desired fraction was concentrated to give ethyl 2-trifluoromethyl-4-thiazolecarboxylate (2.2 g) as pale yellow needles.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[S-:11][C:12]#[N:13].[NH4+]>CO>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:10])[C:4]([CH3:9])=[CH:5][C:6]=1[S:11][C:12]#[N:13]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(SC#N)c(C)c(C)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
2,3,6-trimethylphenol (1.6 g, 11.8 mmol) was disolved in 50 mL of anhydrous methanol which had been deoxygenated by bubbling with nitrogen. Ammonium thiocyanate (2.2 g, 28,9 mmol) was added to this solution which was then cooled to 0° C. and bubbled with chlorine gas. The initially colorless homogeneous solution becomes pink and then green with the formation of a white precipitate. The solution was stirred for 1 h at 0° C. and then for a further hour at 20° C. The dissolved chlorine was removed by bubbling with nitrogen and the precipitate removed by filtration. Evaporation of the filtrate under reduced pressure followed by drying under high vacuum (0.1 torr) yielded 2.20 g (97%) of 2,3,5-Trimethyl-4-hydroxyphenylthiocyanate in a form pure enough for the next step in the synthesis. An analytical sample was recrystallized from hexanes : white crystals, mp 100.3° C. 1H NMR (CDCl3) δ 7.2 (s, 1 H), 5.0 (s, 1 H) 2.4 (s, 3 H), 2.2 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:22])[C:11](=[O:23])[CH2:10][N:9]=1.O1CCCC1.O.O.O.C([O-])(=O)C.[Na+].N>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][OH:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:22])[C:11](=[O:23])[CH2:10][N:9]=1
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NO)ccc21

Procedure:
A mixture of 16 g. (0.05 mol) of 1,3-dihydro-5-(2-fluorophenyl)-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one, 500 ml. of tetrahydrofuran, 250 ml. of methanol, 68 g. of sodium acetate trihydrate and 56 g. of stannous chloride dihydrate was stirred under nitrogen for 6 hours. 25 ml. of concentrated ammonia was added and the inorganic salts were removed by filtration through celite. The filtrate was washed well with 2 l. of tetrahydrofuran. The filtrate was evaporated and the solid residue was dissolved in ethanol/tetrahydrofuran. The solution was again filtered with celite and concentrated. The separated crystals were collected to leave light yellow product. For analysis it was recrystallized from ethanol/tetrahydrofuran, m.p. 228°-230° dec.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][C:2]1[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: Cc1cc(C(F)(F)F)ccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(F)(F)F)ccc1Oc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-{4-[2-methyl-4-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (315 mg) in THF (dry) (10 mL) and MeOH (10 mL) and the mixture was stirred at room temperature under hydrogen for 4 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (206.1 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][O:18][C:17]3=[O:22])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:23][NH2:24]>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][NH:16][C:17](=[O:22])[O:18][CH2:19][C:20]([NH:24][CH3:23])=[O:21])[CH2:12][CH2:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1cccc(N2CCC(CCN3C(=O)COC3=O)CC2)n1
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCC1CCN(c2cccc(C)n2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.5). Starting with 0.841 g (2.77 mmol) of 3-{2-[1-(6-methyl-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in step 4.3, and 6.9 ml (13.86 mmol) of a solution (2M) of methylamine in tetrahydrofuran, 0.598 g of pure product is obtained in the form of an oil, after chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol. This oily residue is then taken up with a solution of hydrochloric acid (5N) in isopropanol and the salt formed is filtered off and then washed successively with acetone and then with ether.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[S:23][C:22]([CH3:24])=[N:21][C:20]=3[CH3:25])[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)=[O:4].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:24][C:22]1[S:23][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:7][CH:8]=3)[N:18]=2)=[C:20]([CH3:25])[N:21]=1
Reactant: C1COCCN1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CCl)cc3)n2)s1
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CN4CCOCC4)cc3)n2)s1

Procedure:
By treatment of 2-chloro-N-{4-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-acetamide with morpholine. 1H-NMR (DMSO-D6) δ: 2.61 (s, 3H, CH3), 2.64 (s, 3H, CH3), 3.09 (s, 2H, CH2), 3.27-3.31 (m, 4H, CH2), 3.62-3.64 (m, 4H, CH2), 7.04 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.54 (d, 2H, J=8.8 Hz, Ph-H), 7.67 (d, 2H, J=8.8 Hz, Ph-H), 8.48 (d, 1H, J=4.9 Hz, pyrimidinyl-H), 9.59 (s, 1H, NH). MS (ESI+) m/z 425.01 [M+H]+ (C21H24N6O2S requires 424.52).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:13]([O-:15])=[O:14].[Na+].[F:17][B-](F)(F)F.[Na+]>O>[F:17][C:8]1[CH:10]=[CH:11][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=N[O-]
Reactant: F[B-](F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 6.5 °C

Procedure:
To a cold (5° C.) suspension of 4-t-butylaniline in a mixture of conc. hydrochloric acid (25 ml) and water (25 ml) was added a solution of sodium nitrite (7.6 g, 0.11 mol) in water (10 ml) keeping the temperature at 5-7° C. At the end of the addition, the mixture was stirred for additionally 15 min, whereafter a solution of sodium tetrafluoroborate (15.4 g, 0.14 mol) in water (30 ml) was added dropwise, maintaining the temperature at 5-8° C. After another 15 min at 5° C. the diazonium salt was filtered off, dried with suction and washed with diethyl ether (yield: 21 g). The diazonium salt was decomposed by gentle heating to 120° C. on an oil-bath. The product was distilled off and collected to yield if (11.2, 73.5%).