Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.N1C=CC=CC=1.[C:32]1([CH3:42])[CH:37]=[CH:36]C(S(Cl)(=O)=O)=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:21][S:22]([C:25]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:24])=[O:23])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: COC(=O)C1CN2c3c(cc(F)c(OS(C)(=O)=O)c3CCN2C)C1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cn2c3c(c(OS(=O)(=O)c4ccc(C)cc4)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
304 mg of the compound (168) obtained in Example 45 was added to 2 ml of pyridine, and 260 mg of p-toluene-sulfonyl chloride was added to the solution. The solution was stirred for 2 hours at room temperature. 50 ml of chloroform was added to the solution, and the solution was washed with water and aqueous 5% citric acid solution. The organic layer was separated, and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and washed with isopropyl ether to obtain mg of the subject compound (169).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[N:8]([C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:7][CH2:6]1)C.C[NH:29]N>CO>[CH3:1][N:2]1[CH:4]=[C:5]2[CH2:6][CH2:7][N:8]([C:17](=[O:27])[C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]2=[N:29]1
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2C1=O
Reactant: CNN
Solvent: CO
Product: Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2

Procedure:
A solution of 0.150 g of 4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one and 44 μl of methylhydrazine in 5 ml of methyl alcohol is heated at reflux for 18 hours. A precipitate forms on standing. The volatiles are evaporated to a residue which is purified by column chromatography on silica gel by elution with 5% ethyl acetate-methylene chloride. The product fractions are combined and the volatiles evaporated to a residue which is dissolved in chloroform-methanol, filtered through glass wool and the filtrate evaporated in vacuo to give 0.110 g of the desired product as pale yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][CH2:4][O:5][C:6](=[O:22])[CH:7]=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[OH:21])[CH3:9].C(OC(=O)C=C(C1C=CC(N(CC)CC)=CC=1O)C)C.CC(CCC1C=CC=CC=1)CCO>>[CH3:1][CH:2]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][CH2:4][O:5][C:6](=[O:22])/[CH:7]=[C:8](/[C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:12][C:11]=1[OH:21])\[CH3:9]
Reactant: CCN(CC)c1ccc(C(C)=CC(=O)OCCC(C)CCc2ccccc2)c(O)c1
Agent: CC(CCO)CCc1ccccc1
Agent: CCOC(=O)C=C(C)c1ccc(N(CC)CC)cc1O
Product: CCN(CC)c1ccc(/C(C)=C/C(=O)OCCC(C)CCc2ccccc2)c(O)c1

Procedure:
According to the same procedure, 3-(4-diethylamino-2-hydroxy-phenyl)-but-2-enoic acid 3-methyl-5-phenyl-pentyl ester was prepared from 3-(4-diethylamino-2-hydroxy-phenyl)-but-2-enoic acid ethyl ester, 3-methyl-5-phenyl-pentanol and tetraisopropyl-o-titanate.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:19](Cl)[N:18]2[N:25]=[CH:26][N:27]=[C:17]2[N:16]=1>C(Cl)Cl>[Cl:14][C:15]1[C:20]([CH:21]([CH3:22])[CH3:23])=[C:19]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:18]2[N:25]=[CH:26][N:27]=[C:17]2[N:16]=1
Reactant: NC1CCCC1
Reactant: CC(C)c1c(Cl)nc2ncnn2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1c(Cl)nc2ncnn2c1NC1CCCC1
Yield: 76 %

Procedure:
With stirring, a mixture of 0.13 g (1.5 mmol) of cyclopentylamine and 0.15 g (1.5 mmol) of triethylamine in 10 ml of methylene chloride was added to a mixture of 0.34 g (1.5 mmol) of 5,7-dichloro-6-isopropyl-[1,2,4]-triazolo-[1,5-α]-pyrimidine (cf. Ex. 2) in 20 ml of methylene chloride. The reaction mixture was stirred at room temperature for 16 h and then washed with 5% strength hydrochloric acid. The organic phase was separated off, dried over sodium sulfate and filtered. The filtrate was freed from the solvent and the residue was purified chromatographically. This gave 0.32 g (1.14 mmol) of the title compound (melting point 139° C.).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][CH:17]=1)#[N:15]>>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[N:11]=[C:20]([C:19]4[CH:23]=[CH:24][C:16]([C:14]#[N:15])=[CH:17][CH:18]=4)[O:13][N:12]=3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: N=C(NO)C1CCN(C2CC2)CC1
Product: N#Cc1ccc(-c2nc(C3CCN(C4CC4)CC3)no2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 35a, starting from 1-cyclopropyl-N-hydroxypiperidine-4-carboxamidine and 4-cyanobenzoyl chloride.
Reaction SMILES: CS(O)(=O)=O.[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:37])[C:13]2[C:28]([CH2:29][Br:30])=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[S:26][C:14]=2[N:15]([CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[CH:16]=1)=[O:10])[CH3:7].[N+:38]([O-])([O-:40])=[O:39].[Na+]>>[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:37])[C:13]2[C:28]([CH2:29][Br:30])=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([N+:38]([O-:40])=[O:39])=[CH:33][CH:32]=3)[S:26][C:14]=2[N:15]([CH2:17][C:18]2[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=2[F:24])[CH:16]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccccc3)c(CBr)c2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Product: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CBr)c2c1=O
Temperature: 0 °C
Yield: 75 %

Procedure:
To methanesulfonic acid (4.5 L), 900 g of the compound obtained in Example 1 described above was added over a period of 30 minutes (internal temperature 19 to 23° C.). After cooling on ice with stirring, sodium nitrate (147 g)/methanesulfonic acid (1.98 L) was added dropwise over a period of 2 hours (internal temperature 12 to 14° C.). Subsequently, the reaction mixture was stirred for 1.5 hours at 11 to 12° C., and was added to 155 L of an ice-water, and the precipitated crystal was recovered by a filtration, washed with water and then dried. 1The crystal was dried in vacuo for 26 hours at 50° C. to obtain 944 g of a crude product of the title compound (yield: 75%, HPLC). The crystal was suspended in ethyl acetate (2.9 L), and the mixture was stirred under reflux for 30 minutes, at room temperature for 30 minutes, and then stirred with cooling on ice for 1 hour and 20 minutes. The crystal was recovered by a filtration, washed with cool ethyl acetate (0.8 L), dried under reduced pressure for 8 hours at 50° C. to obtain 837 g of the title compound (yield: 86%).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl-].[CH3:12][O:13]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N:34]1[CH:39]=[CH:38][CH:37]=[N:36][C:35]=1[C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[N:34]1[CH:39]=[CH:38][CH:37]=[N:36][C:35]=1[C:40]1[CH:47]=[CH:46][C:43]([CH2:44][CH:12]=[O:13])=[CH:42][CH:41]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(-c2ncccn2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: O=CCc1ccc(-c2ncccn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
Sodium hexamethyldisilazide (1.0M in THF, 2.65 mL, 2.65 mmol) was added to a suspension of methoxymethyltriphenylphosphonium chloride (0.93 g, 2.71 mmol) in THF (13 mL) at 0° C., and the red-orange mixture was stirred for 15 min at 0° C. A solution of 4-(2-pyrimidinyl)benzaldehyde (250 mg, 1.36 mmol, prepared as described in WO 9828264) in THF (5 mL) was added, and stirring was continued at 0° C. for 1 h. 10% aq. HCl (13 mL) was added and the mixture was heated to 50° C. for 1 h. The reaction mixture was then cooled to 0° C. and solid Na2CO3 was added cautiously until the solution was basic. The mixture was extracted with ethyl acetate (2×25 mL) and the combined organic extracts were washed with brine (2×25 mL), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 2:1 hexane/ethyl acetate) yielded 141 mg (52%) of the title compound. MS 199 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B#B>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCc1ccccc1
Agent: B#B
Solvent: C1CCOC1
Product: OCCCCCCc1ccccc1

Procedure:
A solution of 6-phenylhexanoic acid (19.8 mmoles in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmoles) at 0° C. for 4 hours to give 6-phenylhexanol. To an ice cold solution of the hexanol (ca. 19.8 mmoles) and carbon tetrabromide (21.98 mmoles) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmoles) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 6-phenylhexyl bromide as an oil.
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[B:4]([OH:7])([OH:6])[OH:5].C1(C)C(C)=CC=CC=1.CO>CCCCCC>[B:4]([O-:7])([O-:6])[O-:5].[Ca+2:2].[B:4]([O-:7])([O-:6])[O-:5].[Ca+2:2].[Ca+2:2]
Reactant: OB(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Solvent: Cc1ccccc1C
Product: [O-]B([O-])[O-]
Temperature: 60 °C

Procedure:
200 g of the same neutral calcium alkylsalicylate (A) as used in Example 1, 26 g of calcium hydroxide (B), 43.4 g (2.0 moles per mole of the calcium hydroxide) of orthoboric acid (C) and 400 g of xylene (F) were put in a 1000-ml four-necked flask fitted with a condenser and heated to 60° C. while agitating. To this mixture was added 120 g of methanol, and the resulting mixture was heated up to a refluxing temperature (66° C.) under agitation and reacted for 4 hours to obtain a reaction product. The reaction product was further heated to 140° C. for 1.5 hours to distill out the methanol, reaction water and xylene. Finally the reaction product was diluted twofold with hexane and filtered to remove any residual solids present, and the hexane was distilled out to obtain a calcium borate overbased alkylsalicylate. However, the thus obtained calcium borate overbased alkylsalicylate caused its gelation and was found generally unusable as an additive for petroleum products.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:18][CH:17]4[CH2:19][CH:15]3[CH2:16]4)[N:11]=[C:10]([N:20]3[CH2:25][C@@H:24]4[CH2:26][C@H:21]3[CH2:22][N:23]4C(OC(C)(C)C)=O)[CH:9]=2)=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].FC(F)(F)C(O)=O>ClCCl>[CH:15]12[CH2:16][CH:17]([CH2:19]1)[CH2:18][N:14]2[C:12]1[N:13]=[C:8]([C:5]2[CH:4]=[C:3]([C:34]([F:37])([F:36])[F:35])[C:2]([NH2:1])=[N:7][CH:6]=2)[CH:9]=[C:10]([N:20]2[CH2:25][C@@H:24]3[CH2:26][C@H:21]2[CH2:22][NH:23]3)[N:11]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(-c2cnc(N)c(C(F)(F)F)c2)nc(N2CC3CC2C3)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(-c2cc(N3C[C@@H]4C[C@H]3CN4)nc(N3CC4CC3C4)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
To an ice-cooled solution of (1S,4S)-tert-butyl 5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (130 mg, 0.25 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 0.5 h. After removal of the solvent, the residue was dissolved with water (30 mL), basified and extracted with dichloromethane (3×30 mL). The organic layer was dried over sodium sulfate, concentrated to provide 5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine (80 mg, 75.0% yield). LCMS (ESI): [MH]+=417.9.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[CH:6][N:7](C(OCC)C)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3].CN(C)CCN(C)C.C([Li])CCC.[F:33][C:34]([F:42])([F:41])[C:35]([C:37]([F:40])([F:39])[F:38])=[O:36].C(=O)(O)[O-].[Na+]>O1CCCC1.CCCCCC>[CH3:3][CH:2]([C:4]1[N:5]=[C:6]([C:35]([C:37]([F:40])([F:39])[F:38])([C:34]([F:42])([F:41])[F:33])[OH:36])[NH:7][C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:1]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: CCOC(C)n1cnc(C(C)C)c1-c1ccccc1
Agent: CN(C)CCN(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)c1nc(C(O)(C(F)(F)F)C(F)(F)F)[nH]c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
To a stirred solution of 4-(1-methylethyl)-5-phenyl-1-(α-ethoxyethyl)imidazole (13.9 g, 0.054 mole) in 210 ml of dry tetrahydrofuran was added 9.45 ml of tetramethylethylenediamine (0.06 moles). The reaction was cooled to -78° C. and 56.15 ml of 1.66M n-butyl lithium in hexane was added dropwise. After stirring the mixture for 20 minutes, hexafluoroacetone (14.0 ml) was condensed and added dropwise. The reaction was stirred an additional hour at -78° C. and then 275 ml of saturated aqueous sodium bicarbonate solution was added dropwise. After warming to room temperature, the layers were separated and the aqueous was extracted with ethyl acetate. The organic layers were combined and concentrated in vacuo. The residue was stirred overnight in 350 ml of ethanol and 350 ml of 2N aqueous hydrochloric acid. The ethanol was evaporated and the reaction mixture was basified to a pH of 8 with saturated aqueous potassium carbonate. The mixture was extracted with ether, washed with 10% aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The residue was purified via flash chromatography on silica gel (98:2 hexane/ethyl acetate) to afford 13.19 g (70%) of the product which was recrystallized from hexane to give a white crystalline solid, m.p. 80°-81° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:11]O>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:11])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CO
Product: COC(=O)c1cncc(Br)c1
Yield: 94 %

Procedure:
5-Bromonicotinic acid (10 g) and methanol were treated as in the above Production Example 3-3 to give the title compound (10.052 g) as colorless crystals (yield: 94.0%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1C(=O)N([Br:22])C(=O)C1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[N:6][C:7]=1[Br:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cnc(C2CCC(=O)NC2)cn1
Product: Nc1ncc(C2CCC(=O)NC2)nc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-(5-aminopyrazin-2-yl)piperidin-2-one (25 mg, 0.13 mmol) acetonitrile (10 mL) solution at 0° C. was added NBS (23.2 mg, 0.13 mmol) and the reaction mixture was stirred at 0° C. for 30 min, then at room temperature for 4 h. The reaction mixture was concentrated, and the residue was basified by 1 N NaOH (140 ul), diluted with methanol (2 mL), concentrated. The residue was triturated with EtOAc (3×1 mL), and the EtOAc supernatants were collected, combined and concentrated and a light solid was obtained as crude 5-(5-amino-6-bromopyrazin-2-yl)piperidin-2-one which was used in next step without further purification. LCMS (m/z): 241/243 (MH+), 0.41 min.
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.[NH:12]([C:16]1[O:17][CH:18]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[N:20]=1)[C:13]([NH2:15])=[NH:14].N(C1OC=C(CCC[CH2:38][NH:39][C:40]2(OC)[NH:44][S:43](=[O:46])(=[O:45])[N:42]=[CH:41]2)N=1)C(N)=N.CN>>[NH:12]([C:16]1[O:17][CH:18]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:40]2([NH:39][CH3:38])[NH:44][S:43](=[O:46])(=[O:45])[N:42]=[CH:41]2)[N:20]=1)[C:13]([NH2:15])=[NH:14]
Reactant: COC1(NCCCCc2coc(NC(=N)N)n2)C=NS(=O)(=O)N1
Reactant: N=C(N)Nc1nc(CCCCN)co1
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: CNC1(NCCCCc2coc(NC(=N)N)n2)C=NS(=O)(=O)N1

Procedure:
When a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with an equimolar amount of 4-[(2-guanidino-4-oxazolyl]butylamine [prepared according to the procedure described in Belgian Pat. No. 866,155] and the resultant 3-{4-[(2-guanidino-4-oxazolyl]butylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with excess methylamine, the title compound is thereby produced.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CCN(S(C)(=O)=O)CC3)=[CH:8][C:6]=2[N:7]=1.ClC1N=C(N2CC[O:41]CC2)C2SC=CC=2N=1.[Li]CCCC>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH:11]=[O:41])=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
Scheme 4 shows the synthesis of 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine 9 starting with formylation at the 7-position of 4-(2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine 4 (1.0 equiv.) in THF with n-BuLi in hexanes to give 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 5 after acidification. Reductive amination of aldehyde 5 was accomplished with 4-(methylsulfonyl)piperazin-1-ium chloride 8 and sodium acetate (anhydrous powder) in 1,2-dichloroethane. Trimethyl orthoformate was added and stirred for 6 hours, followed by the addition of sodium triacetoxyborohydride to give 9.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C@@H:3]([C:14]([OH:16])=[O:15])[NH:4][C:5]([N:7]([CH3:13])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6].[C:19](Cl)(=O)CCCC=C>>[CH3:1][C:2]([CH3:18])([CH3:17])[C@@H:3]([C:14]([OH:16])=[O:15])[NH:4][C:5]([N:7]([CH3:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:19])=[O:6]
Reactant: C=CCCCC(=O)Cl
Reactant: C=CCCCN(C)C(=O)N[C@H](C(=O)O)C(C)(C)C
Product: C=CCCCCN(C)C(=O)N[C@H](C(=O)O)C(C)(C)C

Procedure:
3-Methyl-N-{[methyl(hex-5-enyl)amino]carbonyl}-L-valine was prepared according to the procedure for 3-methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valine (Steps 1-5) by using 5-hexenoyl chloride instead of 4-pentenoyl chloride in Step 1. LRMS (ESI) m/z 271 [(M+H)+; calcd for C14H27N2O3: 271].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](F)[N:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[N:18]=1
Reactant: Fc1cccc(F)n1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(F)n1

Procedure:
The title compound, off-white cristalline solid, MS: m/e=313.2, 315.1 (M+H+) was prepared in accordance with the general method of example 1b from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2,6-difluoropyridine.
Reaction SMILES: [O-:1]CC.[Na+].[CH2:5]([O:7][C:8]([C:10]1[C:15](=[O:16])[N:14](CC2C=CC=C(F)C=2)[C:13]2[CH:25]=[CH:26][S:27][C:12]=2[C:11]=1N1CCNCC1)=[O:9])[CH3:6]>C(O)C>[CH2:5]([O:7][C:8]([C:10]1[C:15](=[O:16])[NH:14][C:13]2[C:25]([C:11]=1[OH:1])=[CH:26][S:27][CH:12]=2)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1c(N2CCNCC2)c2sccc2n(Cc2cccc(F)c2)c1=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cscc2[nH]c1=O
Yield: 56.9 %

Procedure:
Sodium ethoxide (4.75 g, 66.34 mmol) was added to a solution of 4-(2-ethoxycarbonyl-acetylamino)-thiophene-3-carboxylic acid methyl ester (19) (8.57 g, 31.59 mmol) in anhydrous ethanol and refluxed overnight. The solution was cooled and excess solvent was distilled off The residue was dissolved in water and acidified by cold diluted HCl solution. The solids formed were filtered, washed by water and dried under vacuum at room temperature to get 4.3 g (57%) of 7-hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester as white solid. MP 193° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.27 (t, J=7.2 Hz, 3H), 4.28 (q, J=7.2 Hz, 2H), 6.83 (d, J=3.2 Hz, 1H), 8.24 (d, J=3.6 Hz, 1H), 11.10 (s, 1H), 12.90 (s, 1H) ppm; MS m/z=240 amu (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH3:7][Si:8]([CH3:20])([CH3:19])[N:9]1[CH:14]=[CH:13][CH:12]([Si](C)(C)C)[CH:11]=[CH:10]1>O1CCCC1>[CH3:7][Si:8]([N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[CH:4]([C:3]([O:2][CH3:1])=[O:6])[CH3:5])([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)C1C=CN([Si](C)(C)C)C=C1
Reactant: C=CC(=O)OC
Solvent: C1CCOC1
Product: COC(=O)C(C)C1C=CC=CN1[Si](C)(C)C
Temperature: 50 °C
Reaction time: 70 h

Procedure:
Following the procedure of Example 1, 8.6 g (0.1 mol) of acrylic acid methyl ester are brought to reaction with 22.6 g (0.1 mol) of 1,4-bis-(trimethylsilyl)-1,4-dihydropyridine. Upon addition of 20 ml of tetrahydrofuran the mixture is stirred at 50°C for 70 hours. The distillation in high vacuum yields 21.1 g (68%) of 1,4-bis-(trimethylsilyl-2-(1-carbomethoxyethyl)-1,2-dihydropyridine.
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[NH:3]1.[OH-].[Na+]>CCO>[O:35]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:5][C:4]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[NH:3]1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)OCC)cc2S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)N1
Reaction time: 8 h

Procedure:
To a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Method 1; 0.184 g, 3.24*10−4 mol) in EtOH (7 ml) was added NaOH (0.052 g, 1.30 mmol) and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and 0.5 M HCl. The aqueous layer was extracted twice more with EtOAc and the combined organic extracts were washed with brine and concentrated. The crude product was purified by preparative HPLC using an MeCN/ammonium acetate buffer as eluent and freeze-dried to give the title compound in 0.173 g (99%) as a white solid. NMR (400 MHz, CD3OD) 0.70–0.85 (m, 6H), 0.95–1.70 (m, 12H), 3.90 (brs, 2H), 4.50 (s, 2H), 6.90–7.40 (m, 7H).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].[C:15]([NH2:21])(=[O:20])[CH2:16][C:17]([NH2:19])=[O:18].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:1][Si:2]([CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[C:16]([C:15]([NH2:21])=[O:20])[C:17]([NH2:19])=[O:18])=[CH:9][CH:8]=1)([CH3:4])[CH3:3]
Reactant: NC(=O)CC(N)=O
Reactant: C[Si](C)(C)COc1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: O
Product: C[Si](C)(C)COc1ccc(C=C(C(N)=O)C(N)=O)cc1
Yield: 49 %

Procedure:
4-(Trimethylsilanylmethoxy)benzaldehyde (obtained in step 1 of Example 1) (10.4 g, 0.005 mol) and malonamide (5.5 g, 0.055 mol) in 20 ml of dry toluene in the presence of 0.5 ml of piperidine and 0.3 g of acetic acid are refluxed for 3 hours in a reactor equipped with Dean-Stark apparatus. The water formed is removed azeotropically. The mixture is cooled and the organic phase is washed twice with water. The organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off under vacuum. After recrystallization from ethanol, 7.2 g (yield: 49%) of the derivative of Example 10 are obtained in the form of an off-white powder: