Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N:12]2[C@H:16]([CH3:17])[CH2:15][O:14][C:13]2=[O:18])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[ClH:19].[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[ClH:19].[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:5]([C:4]3[CH:8]=[CH:9][C:10]([N:12]4[C@H:16]([CH3:17])[CH2:15][O:14][C:13]4=[O:18])=[CH:11][C:3]=3[O:2][CH3:1])=[O:7])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: COc1cc(N2C(=O)OC[C@H]2C)ccc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: Cl
Product: COc1cc(N2C(=O)OC[C@H]2C)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Yield: 37.8 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-2-methoxy-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (1.1 g) described in Preparation Example 45 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (956 mg) described in Preparation Example 64, the title compound (731 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23]C)[CH2:5][C:6]1[N:15]2[N:16]=[C:17]([NH2:19])[N:18]=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.COC1C=C(C=C(OC)C=1)CC1N2N=C(N)N=C2C2C=CC=CC=2N=1>>[NH2:19][C:17]1[N:18]=[C:14]2[N:15]([C:6]([CH2:5][C:4]3[CH:20]=[CH:21][C:22]([OH:23])=[C:2]([Br:1])[CH:3]=3)=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:16]=1
Reactant: COc1ccc(Cc2nc3ccccc3c3nc(N)nn23)cc1Br
Agent: COc1cc(Cc2nc3ccccc3c3nc(N)nn23)cc(OC)c1
Product: Nc1nc2c3ccccc3nc(Cc3ccc(O)c(Br)c3)n2n1
Yield: 68 %

Procedure:
Operating as in Example 39, but employing 5-(3-bromo-4-methoxy-benzyl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, prepared as described in Example 11, instead of 5-(3,5-dimethoxy-benzyl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, the title compound was obtained in 68% yield.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[C:7]([O:6][C:4]([C:3]1[C:2]([NH:1][C:48](=[O:49])[C:47]2[CH:51]=[C:43]([CH2:42][C:36]3[C:37](=[O:41])[C:38]([O:39][CH3:40])=[C:33]([O:32][CH3:31])[C:34](=[O:57])[C:35]=3[CH3:56])[CH:44]=[CH:45][C:46]=2[O:52][C:53](=[O:55])[CH3:54])=[N:14][CH:13]=[CH:12][CH:11]=1)=[O:5])([CH3:10])([CH3:8])[CH3:9]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: CC(C)(C)OC(=O)c1cccnc1N
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ncccc3C(=O)OC(C)(C)C)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 53.3 %

Procedure:
tert-Butyl 2-aminonicotinate (0.311 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=15:1) to obtain the titled compound (0.157 g, 0.285 mmol, 53%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]([CH:26]=[O:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[C:12]([C@H:26]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[OH:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Product: CC1(C)Cc2nc(C3CCCC3)c([C@@H](O)c3ccc(F)cc3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-2-cyclopentyl-4-iodo-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-fluorophenylmagnesium bromide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:24]=[C:23]3[C:15]([C:16]4[CH:17]=[CH:18][C:19]([S:26]([NH:29][C:30]5[CH:31]=[C:32]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[CH:34][CH:35]=5)(=[O:28])=[O:27])=[CH:20][C:21]=4[C:22]3=O)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:41][OH:42]>N1C=CC=CC=1>[OH:42][N:41]=[C:22]1[C:21]2[CH:20]=[C:19]([S:26]([NH:29][C:30]3[CH:31]=[C:32]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[CH:34][CH:35]=3)(=[O:27])=[O:28])[CH:18]=[CH:17][C:16]=2[C:15]2[C:23]1=[CH:24][C:12]([S:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)(=[O:11])=[O:10])=[CH:13][CH:14]=2
Reactant: CC(=O)Nc1cccc(NS(=O)(=O)c2ccc3c(c2)C(=O)c2cc(S(=O)(=O)Nc4cccc(O)c4)ccc2-3)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(NS(=O)(=O)c2ccc3c(c2)C(=NO)c2cc(S(=O)(=O)Nc4cccc(O)c4)ccc2-3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
The product from Example 6A (223 mg, 0.396 mmol) in pyridine (3 mL) was treated with hydroxylamine hydrochloride (30 mg, 0.435 mmol) and heated at reflux. After 30 minutes, the mixture was allowed to cool to ambient temperature and partitioned between ethyl acetate and H2O. The separated organic phase was washed with 1 N HCl, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (75% ethyl acetate/hexanes) to provide the title compound as a light yellow solid (91 mg, 40% yield). 1H NMR (300 MHz, DMSO-d6) δ 13.32 (bs, 1H), 10.2-10.4 (bs, 2H), 9.89 (s, 1H), 9.43 (d, 1H), 8.75 (m, 1H), 8.03-8.17 (m, 3H), 7.8-7.95 (m, 2H), 7.45 (m, 1H), 7.25 (m, 1H), 7.1 (m, 1H), 6.98 (m, 1H), 6.75 (m, 1H), 6.58 (m, 1H), 6.52 (m, 1H), 6.4 (m, 1H), 1.98 (s, 3H); MS (ESI) 577 (M−H)−.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[NH:8].C1C=CC=CC=1.[OH-].[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>O>[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[N:8][C:24]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=1)=[O:25]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CN1CCCC1=N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(NC(=O)N=C2CCCN2C)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of 6.73 g. (0.05 mole) of 1-methyl-2-iminopyrrolidine hydrochloride in 100 ml. of benzene is added 2 ml. of water followed by 5 ml. of 50% NaOH. After stirring for 5 min., the benzene layer is decanted onto anhydrous potassium carbonate. The extraction is repeated twice with 75 ml. portions of fresh benzene. The combined extracts are filtered from drying agent (dicalite pad and suction). To the filtrate is added in one portion with stirring 6.66 g. (0.05 mole) of p-tolylisocyanate. After stirring for 5 hours, the solution is taken to dryness in vacuo and the resulting solid is recrystallized from ethyl acetate to give 1-(1-methyl-2-pyrrolidylidene)-3-p-tolylurea, m.p. = 136°-137° C. A final recrystallization from acetone shows the product melting at 140°-150° C. Thin layer chromatography (TLC) indicates both samples to be identical in purity. Apparently the two melting points represent polymorphic forms.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-])=O)[CH:33]=2)=[C:4]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:5]=[C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])[CH:7]=1.[S-2].[Na+].[Na+]>C(O)C.O.C(OCC)(=O)C>[NH2:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][O:30][C:3]1[C:2]([Br:1])=[CH:7][C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])=[CH:5][C:4]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc([N+](=O)[O-])c2)c(NS(C)(=O)=O)c1
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(N)c2)c(NS(C)(=O)=O)c1

Procedure:
A mixture of N-[3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-2-(3-nitro-benzyloxy)-phenyl]-methanesulfonamide (950 mg) and sodium sulfide (350 mg) in ethanol (12 ml) and water (250 μl) was heated at reflux for 2 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([CH3:24])[N:12]=[C:11]2[C:25](=[O:28])[NH:26][CH2:27][C:10]=12.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.CCN(CC)CC.N1C=CC=CC=1.ClC(Cl)C>CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:26]2[CH2:27][C:10]3[C:11](=[N:12][C:13]([CH3:24])=[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]=3[C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:25]2=[O:28])=[CH:32][CH:31]=1
Reactant: Cc1nc2c(c(-c3ccc(Cl)cc3Cl)c1CNC(=O)OC(C)(C)C)CNC2=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc2c(c(-c3ccc(Cl)cc3Cl)c1CNC(=O)OC(C)(C)C)CN(c1ccc(Cl)cc1)C2=O
Yield: 61 %

Procedure:
A mixture of Example 11B (29.8 mg, 0.071 mmol), 4-chlorophenylboronic acid (45 mg, 0.288 mmol), Cu(OAc)2 (24 mg, 0.132 mmol), Et3N (45 μL, 0.324 mmol), pyridine (60 μL, 0.743 mmol), and dichloroethane (1 mL) was heated at 75° C. for 1.5 h. Concentration in vacuo followed by flash chromatography (50% to 100% EtOAc/Hexanes) to yield a Example 11C which was further purified by recrystallization fom MeOH to give 23 mg (61%) of a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28]CC(O)=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[NH2:35][C@@H:36]([C:38]([O:40]C(C)(C)C)=[O:39])[CH3:37].CN1CC[O:49][CH2:48][CH2:47]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:47][C:48]([NH:35][C@@H:36]([C:38]([OH:40])=[O:39])[CH3:37])=[O:49])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.2 %

Procedure:
[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid (50 mg, 0.1 mmol), tert-butyl D-alaninate (23 mg, 0.12 mmol) and 4-methylmorpholine (31 mg, 0.31 mmol) were dissolved in DCM (1.5 ml) and stirred at room temperature for 5 minutes. TBTU (40 mg, 0.12 mmol) was added and the reaction mixture was stirred for 2 h. TFA (0.7 ml) was added and the solution was stirred for 90 minutes. TFA and DCM were removed under reduced pressure and the residue was dissolved in DCM and washed with water. The organic layer was dried over sodium sulphate and the solvent was removed under reduced pressure giving 55 mg (95%) of the title product. M/z: 553.0 (M−1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3]1.S(=O)(=O)(O)O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C.C(O)C>[CH2:6]1[C:7]2[NH:29][C:23]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:2]=2[CH2:3][CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1CCC(=O)CC1C(=O)OCC
Reactant: NNc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1Cc2[nH]c3ccccc3c2CC1C(=O)OCC
Temperature: 25 °C
Yield: 59.4 %

Procedure:
To 20 ml of ethanol were added 2.66 g of diethyl 4-oxocyclohexane-1,2-dicarboxylate, 2.45 g of concentrated sulfuric acid and 1.08 g of phenylhydrazine. The mixture was refluxed for 2 hours and then cooled to room temperature. Thereto were added 50 ml of ethyl acetate and 50 ml of water. The mixture was adjusted to pH 7.5 with an aqueous saturated sodium hydrogencarbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethanol to obtain 1.87 g (yield: 59%) of diethyl 1,2,3,4-tetrahydrocarbazole-2,3-dicarboxylate as colorless needles.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1([F:24])[CH2:12][C:11]1([C:14]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:15])[CH3:13]>CS(C)=O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:14]2([C:11]3([CH3:13])[CH2:12][C:10]3([F:9])[F:24])[CH2:2][O:15]2)=[CH:22][CH:21]=1
Reactant: C[S+](C)(C)=O
Reactant: CC1(C(=O)Cc2ccc(F)cc2)CC1(F)F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C2(Cc3ccc(F)cc3)CO2)CC1(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 118.8 %

Procedure:
20 ml of absolute dimethyl sulphoxide are added dropwise to a mixture of 5.31 g (0.0241 mol) of trimethylsulphoxonium iodide and 0.79 g (0.0329 mol) of sodium hydride (80%) at 10° C. under a nitrogen atmosphere. When the addition is complete, the mixture is allowed to warm to room temperature in the course of 10 minutes, and a solution of 5 g (0.0219 mol) of 4-fluorobenzyl 2,2-difluoro-1-methyl-cyclopropyl ketone in 10 ml of absolute dimethyl sulphoxide is then added dropwise with stirring. Stirring is continued for 4 hours at 40° C. The reaction mixture is then poured onto ice-water. The mixture which forms is extracted three times using cyclohexane. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. In this manner, 6.3 g of 2-(4-fluoro-benzyl)-2-(2,2-difluoro-1-methyl-cyclopropyl)-oxirane are obtained, which is used for further reaction without additional purification. ##STR31##
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].Br[CH2:6][CH:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10]>CS(C)=O>[N+:1]([CH2:6][CH:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])([O-:3])=[O:2]
Reactant: CCCC(CBr)CCC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCC(CCC)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of sodium nitrite (30.6 g, 0.43 mol) in DMSO (700 ml) was added 1-bromo-2-propylpentane (49 g, 0.254 mol). The mixture was stirred overnight at room temperature and poured into ice water (700 g). The mixture was extracted with ether (4×250 ml), the organic layers were combined, washed with water (2×500 ml), brine (500 ml), dried and concentrated in vacuo to furnish 37.4 g (93%) of 1-nitro-2-propylpentane which was 85% pure based on 1H NMR data.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH:4]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([NH:19][C:20]([NH:22][C:23]2[N:28]=[C:27](Cl)[CH:26]=[C:25](Cl)[N:24]=2)=[O:21])(=[O:18])=[O:17])=[O:8])[CH2:6][CH2:5]1.[CH3:31][OH:32]>>[CH:4]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([NH:19][C:20]([NH:22][C:23]2[N:28]=[C:27]([O:2][CH3:1])[CH:26]=[C:25]([O:32][CH3:31])[N:24]=2)=[O:21])(=[O:18])=[O:17])=[O:8])[CH2:6][CH2:5]1
Reactant: CO
Reactant: O=C(Nc1nc(Cl)cc(Cl)n1)NS(=O)(=O)Nc1ccccc1C(=O)C1CC1
Reactant: C[O-]
Agent: [Na+]
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Nc2ccccc2C(=O)C2CC2)n1
Temperature: 60 °C
Yield: 70 %

Procedure:
A mixture of sodium methoxide (1.08 g, 0.02 mol) in methanol is added slowly to a mixture of 1-{[o-(cyclopropyl)phenyl]sulfamoyl}-3-(4,6-dichloro-2-pyrimidinyl)urea from Example 1 (4.30 g, 0.01 mol) in methanol at 60° C. The reaction mixture is heated at 60° C. for two hours, cooled, treated with additional sodium methoxide (0.54 g), refluxed overnight, cooled, acidified and concentrated in vacuo to obtain a residue. The residue is slurried in methanol, filtered, washed sequentially with methanol and water, and dried in a vacuum oven at 55°-60° C. to give the title product as a cream colored solid (2.2 g, 98.6% real by HPLC analysis, 70% yield, mp 168.5°-169.5° C.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]3([C:18]([F:21])([F:20])[F:19])[CH2:17][CH2:16]3)=[O:13])[CH:9]=[CH:8][C:7]=2[N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)[CH2:3][CH2:2]1.Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>>[CH2:29]([N:14]([C:15]1([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:17]1)[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:11]=1)=[O:13])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: ClCc1ccccc1
Reactant: O=C(NC1(C(F)(F)F)CC1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: [H-]
Agent: [Na+]
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N(Cc1ccccc1)C1(C(F)(F)F)CC1

Procedure:
In analogy to the procedure described in Example 16 b), 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(1-(trifluoromethyl)cyclopropyl)picolinamide (Example 16 a) was reacted with (chloromethyl)benzene (CAN 27987-13-9) in the presence of sodium hydride to give the title compound as colorless oil; MS (EI): m/e=482.4 [MH]+.
Reaction SMILES: [CH:1]1[C:2]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[C:13]([O:19][C@@H:20]4[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]([OH:29])[C@H:21]4[OH:30])[C:12]([OH:31])=[CH:11][C:10]=3[O:9][C:3]=2[CH:4]=[C:5]([OH:8])[C:6]=1[OH:7].CS(C)=O.[OH-].[Ca+2:37].[OH-].C(O)C>OCC(CO)O>[CH:1]1[C:2]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[C:13]([O:19][C@@H:20]4[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]([OH:29])[C@H:21]4[OH:30])[C:12]([OH:31])=[CH:11][C:10]=3[O:9][C:3]=2[CH:4]=[C:5]([OH:8])[C:6]=1[OH:7].[Ca:37]
Reactant: [Ca+2]
Agent: O=c1c2cc(O)c(O)cc2oc2cc(O)c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(O)c12
Agent: [OH-]
Solvent: CS(C)=O
Solvent: OCC(O)CO
Solvent: CCO
Product: [Ca]
Temperature: 60 °C

Procedure:
mangiferin 4.2 g (0.01 mol) is dissolved into 50 ml DMSO, calcium hydroxide 0.37 g (0.005 mol) is dissolved in 80 g glycerol, calcium hydroxide solution is added slowly into mangiferin solution while mixing round, mixing round until it react completely. Appropriate quantity ethanol is added into the reaction solution, mixing round adequately. A lot of deposition is come into being in solution. The reaction solution is filtrated to get the deposition. This deposition is heated up no excess 60° C. to dry. The yellow green solid substance is mangiferin calcium. Its weight is 3.8 g, the productivity is 90.4%. The purity of mangiferin monopotassium is 71.2% detected by HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]OS(C)(=O)=O)[CH:5]=[CH:4][N:3]=1.[C-:14]#[N:15].[K+].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:14]#[N:15])[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)OCc1ccnc(Br)c1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCc1ccnc(Br)c1
Reaction time: 72 h

Procedure:
Methanesulfonic acid 2-bromo-pyridin-4-ylmethyl ester (4.24 g, 15.9 mmol) is added to a stirred solution of potassium cyanide (1.02 g, 15.1 mmol) in a mixture of ethanol (30 mL) and water (6 mL) at room temperature. After 72 hours, ethyl acetate (80 mL) and saturated aqueous sodium bicarbonate (40 mL) are added and phases are separated. The organic layer is washed with water (3×40 mL), dried over MgSO4, filtered and concentrated. The resulting residue is purified by silica gel chromatography eluting with a gradient of 0-60% ethyl acetate in heptane to afford (2-bromo-pyridin-4-yl)-acetonitrile (ES+ m/z 197.41; 199.40).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][NH:8]C(OC(C)(C)C)=O)[CH2:2]1.C(OCC)(=O)C.[ClH:22]>ClCCl>[ClH:22].[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][NH2:8])[CH2:2]1
Reactant: CC(C)(C)OC(=O)NNC1CCCOC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NNC1CCCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 2-(tetrahydro-2H-pyran-3-yl)hydrazinecarboxylate (216 mg, 1.00 mmol) was dissolved in dichloromethane (10 mL) and ethyl acetate (10 mL) and cooled to 0° C. The mixture was saturated with gaseous hydrogen chloride, warmed to ambient temperature and stirred for 1 hour. The mixture was concentrated in vacuo and the residue was concentrated with toluene (2×20 mL) to afford the titled compound.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[OH:13][C:14]([CH3:44])([CH3:43])[CH2:15][C@@:16]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH3:24])[CH2:18][CH2:17]1>ClCCl>[CH3:12][O:11][C:9]([N:34]1[CH2:35][CH2:36][CH:31]([C:28]2[CH:27]=[CH:26][C:25]([C@@H:23]([N:19]3[CH2:18][CH2:17][C@:16]([CH2:15][C:14]([OH:13])([CH3:43])[CH3:44])([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[O:21][C:20]3=[O:22])[CH3:24])=[CH:30][CH:29]=2)[CH2:32][CH2:33]1)=[O:10]
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.10 mL) and methyl chloroformate (24 μL) were added consecutively to (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (0.12 g) dissolved in dichloromethane (5 mL) at room temperature. The resulting solution was stirred at room temperature overnight and then diluted with dichloromethane. The resulting solution was washed with water and brine and dried (Na2SO4). After removal of the solvent, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 99:1→90:10) to afford the title compound as a foam-like solid.
Reaction SMILES: Cl.[CH3:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=[O:4].Cl.[CH3:18][NH:19][CH3:20].[CH2:21]=O>C(O)C.CC(C)=O>[CH3:18][N:19]([CH2:21][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=1)=[O:4])[CH3:20]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: CNC
Reactant: C=O
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc(C(=O)CCN(C)C)cc(OC)c1OC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Concentrated hydrochloric acid (1 mL) was added to a stirred mixture of 3,4,5-trimethoxyacetophenone (210 g, 1 mole), dimethylamine hydrochloride (81 g, 1 mole) and paraformaldehyde (45 g, 1.5 mole) in ethanol (300 mL). The reaction mixture was heated under reflux for 1 hour. Another portion of paraformaldehyde (30 g, 1 mole) was added, and the heating was continued for another 2 hours. The warm reaction mixture was poured with vigorous stirring into acetone (2.4 L). The slurry was heated at 60° C. for 15 minutes, cooled, and filtered. The solid was washed with acetone and dried to provide the hydrochloride salt of 3-(N,N-dimethylamino)-1-(3,4,5-trimethoxyphenyl)propan-1-one, R, 0.05 (SiO2, 2:1 [v/v] hexane-ethyl acetate); m.p. 175° C. A mixture of the above hydrochloride (147.5 g, 0.48 mole) in 1 N NaOH (750 mL) was shaken with ethyl acetate (4×100 mL). The combined organic extracts were washed with brine, dried, and evaporated in vacuo to provide 3-(N,N-dimethylamino)-1-(3,4,5-trimethoxyphenyl)propan-1-one.