Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:9][O:10][CH3:11])[C:5]([O:7][CH3:8])=[O:6].O.O.O.C([O-])(=O)C.[Na+].[NH2:21][C:22]([NH2:24])=[S:23].C(=O)([O-])O.[Na+]>O1CCCC1.O>[NH2:24][C:22]1[S:23][CH:2]=[C:3]([C:4](=[N:9][O:10][CH3:11])[C:5]([O:7][CH3:8])=[O:6])[N:21]=1
Reactant: NC(N)=S
Reactant: CON=C(C(=O)CBr)C(=O)OC
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)OC)c1csc(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
In 350 ml of tetrahydrofuran is dissolved 52 g of methyl 4-bromo-3-oxo-2-methoxyiminobutyrate, followed by addition of 250 ml of water. Then, 89.1 g of sodium acetate trihydrate and 33.2 g of thiourea are added and the mixture is reacted with stirring at room temperature for 18 hours. To this reaction mixture is added 200 ml of a 5% aqueous solution of sodium hydrogen carbonate and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and distilled under reduced pressure to remove the solvent. To the residue is added 200 ml of ether and the resultant crystals are collected by filtration. By the above procedure is obtained 24.8 g of methyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (syn-isomer) as crystals melting at 164.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[C:23][C:25]4[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 3-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (13 mg, 10%). MS (ISP) 511.5 [(M+H)+]; mp 230–231° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.C([O-])(O)=O.[Na+].[CH3:24][C:25](=[CH2:28])[CH2:26][OH:27]>ClC(Cl)C.CN(C)C=O>[CH3:24][C:25]1([CH2:26][OH:27])[O:6][N:5]=[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[CH2:28]1
Reactant: Cc1ccccc1C=NO
Reactant: C=C(C)CO
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Cc1ccccc1C1=NOC(C)(CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60 g of 2-methylbenzaldehyde oxime was dissolved in 1 L of dichloroethane, and then, 65 g of N-chlorosuccinimide and 100 mL of dimethylformamide were slowly added thereto at a temperature of 0° C. The reaction mixture was stirred at room temperature for 1 hour, and then, the reaction state was confirmed by thin layer chromatography (TLC). When 2-methylbenzaldehyde oxime, which was a starting material, disappeared, the reaction mixture was cooled to a temperature of 0° C., and then 56 g of NaHCO3 and 41 mL of 2-methyl-2-propene-1-ol were sequentially added thereto. The reaction mixture was stirred at room temperature overnight, and then washed with water, and then, an separated organic layer was dried and concentrated by using magnesium sulfate, and then, purified by column chromatography to obtain 70 g of (5-methyl-3-o-tolyl-4,5-dihydroisoxazole-5-yl)methanol. The obtained compound was dissolved in 1 L of toluene, and then, 1 L of water, 90 g of NaOH, and 4.5 g of tetrabutylammonium hydrogensulfate were added thereto. After the reaction mixture was stirred for 30 minutes at room temperature, 77 g of 2,6-difluorobenzyl chloride was slowly dropped thereto. The reaction mixture was stirred at a temperature of 60° C. for 5 hours and cooled, and then, a separated organic layer was washed with water and then dried by using magnesium sulfate and concentrated, and the concentrate was separated by silicagel column chromatography to obtain 88 g of 5-((2,6-difluorobenzyloxy)methyl)-5-methyl-3-o-tolyl-4,5-dihydroisoxazole.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH2:25][CH3:26])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([CH:43]=1)[C:40](O)=[O:41])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([C:40]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH2:25][CH3:26])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:41])[CH:43]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Agent: Cl
Product: CCC1(C)C(=O)N(C2CCN(C(=O)c3cc(OCc4ccccc4)ccc3C)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B9) and (benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by a second chromatography (silica gel and cyclo hexane/EA=6:4) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[C:9]([CH:16]=1)[O:10][CH:11]([CH3:15])[C:12](Cl)=[O:13].[OH:28][CH2:29][N:30]1[CH:34]=[CH:33][CH:32]=[N:31]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[C:9]([CH:16]=1)[O:10][CH:11]([CH3:15])[C:12]([O:28][CH2:29][N:30]1[CH:34]=[CH:33][CH:32]=[N:31]1)=[O:13]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: OCn1cccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)OCn1cccn1
Temperature: 20 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
A solution of 21.2 g (0.05 mol) of α-(5-(2-chloro-4-trifluoromethylphenoxy)-2-nitro-phenoxy)-propionic acid-chloride in 30 ml of toluene was added to a mixture, cooled to from 0° to 5° C., of 5.4 g (0.055 mol) of 1-hydroxymethylpyrazole, 6 g (0.06 mol) of triethylamine and 70 ml of toluene. The reaction mixture was stirred overnight (approx. 15 hours) at room temperature (approx. 20° C.). To work up the mixture, it was diluted with toluene and then washed with water, dilute sodium hydroxide solution and again with water, and the organic phase was dried, filtered and concentrated. 17.0 g (70% of theory) of pyrazol-1-yl-methyl α-(5-(2-chloro-4-trifluoromethyl-phenoxy)-2-nitrophenoxy)-propionate were obtained in the form of beige-colored crystals of melting point 75° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.CO.O.N>>[CH3:1][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: N
Solvent: CO
Solvent: O
Product: C=Cc1ccc(OC)cc1

Procedure:
p-Methoxystyrene was polymerized in the same manner as in Example 10, and 25 ml (0.26 mole/1) of p-tert-butoxystyrene was thereafter added to the reaction mixture and further polymerized therewith at an elevated temperature of 25° C. Subsequently, methanol (330 mmoles/1) containing a small amount of ammonia water was added to the reaction system to terminate the polymerization and obtain a mixture containing a polymer. The mixture was washed first with a hydrochloric acid aqueous solution (8 vol. %) and then with water, followed by evaporation for the removal of the solvent, etc. to collect the polymer.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1[CH2:40][NH2:41]>>[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1[CH2:40][NH:41][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: Cc1ccc(CN)c(C)c1
Product: Cc1ccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)c(C)c1

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 2,4-dimethylbenzylamine, m.p. 159-161° C. MS [(+)ESI, m/z]: 552 [M+H]+ Anal. Calcd for C37H35N3O2: C, 80.26; H, 6.37; N, 7.59. Found: C, 79.84; H, 6.12; N, 7.41.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]([O:34]CC)=[CH2:33])CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([C:32](=[O:34])[CH3:33])=[CH:3][N:4]=5)[CH:7]=4)=[CH:13][N:14]=3)[N:17]=2)[CH:22]=[N:23]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1cnc2ccc(Cc3cnc4ccc(-c5cnn(C)c5)nn34)cn12
Temperature: 150 °C

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 296, 100 mg, 0.245 mmol) was dissolved in dioxane (0.98 mL) in a microwave reactor. Then tributyl(1-ethoxyvinyl)tin (85 μL, 0.245 mmol) and tetrakis(triphenylphosphine)palladium (2.8 mg, 0.002 mmol) were introduced. The RM was heated at 150° C. for 1 h under microwave irradiations. The solvent was removed and the residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM). Combined fractions were concentrated and the residue was triturated with Et2O. The precipitate was filtered off and dried to afford the title compound as a white solid (tR 0.7 min (conditions 2), MH+=372).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][CH:18]([F:29])[O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=O>>[F:17][CH:18]([F:29])[O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: O=C(O)c1ccccc1OC(F)F
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2OC(F)F)o1
Yield: 86 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-(difluoromethoxy)-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 294 mg, 86%) which was obtained as a white solid. MS: m/e=370.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[N:13]1[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:2].[C:26](#[N:30])[CH2:27][C:28]#[N:29]>CCO.N1CCCCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=[C:27]([C:26]#[N:30])[C:28]#[N:29])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[N:13]1[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:2]
Reactant: N#CCC#N
Reactant: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCc1cc(C=C(C#N)C#N)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Reaction time: 2 h
Yield: 28.5 %

Procedure:
To a solution of 2-(2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane (Method D11a; 0.037 g, 0.104 mmol) in EtOH (10 mL) was added malononitrile (0.007 g, 0.104 mmol) and piperidine (4 drops). The reaction mixture was stirred at room temp. for 2 h, then concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc/hex) to give 2-(2-ethyl-4-(2,2-dicyanovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane as a yellow solid (0.012 g, 28%): mp 135-136° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[C:11]1([O:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)CCC>[C:11]1([O:21][CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2c(OCC3CCCN3)cccc2c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: c1ccc2c(OC[C@H]3CCCN3c3ncnc4[nH]cnc34)cccc2c1

Procedure:
1.6 235 mg of 6-chloropurine, 400 mg of 2(-naphthalen-1-yloxymethyl)pyrrolidine and 0.8 ml of triethylamine are dissolved in 30 ml of 1-butanol and irradiated in the microwave at 120° C. for 6 h. After removal of the solvent in vacuo, the residue is taken up in 10 ml of methanol, the crystals which precipitate in the process are filtered off with suction and washed with methanol, giving 340 mg of colourless crystals 6-[(R)-2-(naphthalen-1-yloxymethyl)pyrrolidin-1-yl]-9H-purine (“A1”); Rt.: 1.806 min; [M+H]+346; m.p. 207-208°;
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[O:24])=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:14]2[N:15]([C:39]3[CH:38]=[CH:37][N:36]=[C:35]([Cl:34])[CH:40]=3)[C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]2)=[O:24])=[CH:18][CH:17]=3)=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Product: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2ccnc(Cl)c2)CC1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 5, from 4-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-piperazine-1-carboxylic acid ethyl ester (example 43) and 2-chloropyridine-4-boronic acid to give the desired product as a light-yellow foam (60%). MS (ISP): 567.4 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:11].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:11][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=1[CH2:2][S:19][C:17]1[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: COc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(Cl)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
2-(bromomethyl)-1-chloro-3-methoxybenzene (470 mg, 2 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (270 mg, 1.9 mmol), and potassium carbonate (263 mg, 1.9 mmol) were mixed in DMF (10 mL). The mixture was stirred at room temperature for 2 hours. To the mixture, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide pure titled product (400 mg, 70% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.82 (s, 3H), 4.50 (s, 2H), 6.00 (s, 1H), 7.05 (m, 2H), 7.31 (t, 1H); M+297.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:22][NH:23][O:24][CH3:25].CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:9][C:10]([N:23]([O:24][CH3:25])[CH3:22])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)CN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 66 h

Procedure:
To a stirred solution of N-(tert-butoxycarbonyl)-N-(4-fluorobenzyl)glycine (10.5 g, 37.2 mmol) in CH2Cl2 (37 mL) was added N,O-dimethylhydroxylamine hydrochloride (3.62 g, 37.2 mmol). The resulting suspension was treated with N-methylmorpholine (4.08 mL, 37.2 mmol) and cooled to 0° C. The mixture was then treated with a 1 M solution of N,N′-dicyclohexylcarbodiimide in CH2Cl2 (37.2 mL, 37.2 mmol) and was then allowed to warm to ambient temperature under inert atmosphere. After stirring for 66 h, the mixture was filtered, washing the solid residue with excess CH2Cl2. The filtrate was concentrated in vacuo and resuspended in EtOAc. After stirring for 1 h, the mixture was filtered, washing the solids with excess EtOAc. The filtrate was again concentrated in vacuo to give an orange oil. Purification by silica gel chromatography (20% to 60% EtOAc/hexanes) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.27-7.20 (m, 2H), 7.03-7.01 (m, 2H), 4.52 (d, J=13.6 Hz, 2H), 4.09 (s, 1H), 3.95 (s, 1H), 3.63 (d, J=20.4 Hz, 3H), 3.18 (s, 3H), 1.47 (s, 9H). ES MS (M+1)=327.17.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1.S(Cl)(Cl)=O>N1C=CC=CC=1.Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1)=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(OCc2ccccc2C(=O)O)cc(C(C)(C)C)c1
Reactant: Nc1nnn[nH]1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1cc(OCc2ccccc2C(=O)Nc2nnn[nH]2)cc(C(C)(C)C)c1
Yield: 31.9 %

Procedure:
A solution of 3.40 g (0.01 mole) of 2-(3,5-di-t-butylphenoxymethyl)benzoic acid and 1.03 g (0.01 mole) of 5-aminotetrazole in 30 ml of pyridine was treated with a dropwise addition of 2.36 g (0.02 mole) of thionyl chloride. The resulting solution was stirred for forty minutes before being diluted with 300 ml of 5% hydrochloric acid to give a gum which slowly crystallized. The solid was collected, rinsed with water and recrystallized from aqueous dimethylformamide to give 1.3 g of white solid 2-(3,5-di-t-butylphenoxymethyl)-N-(tetrazol-5-yl)benzamide, m.p. 251°-254° C.. Analysis: Calculated for C23H29N5O2 : %C, 67.8; %H, 7.2; %N, 17.2; Found: %C, 67.7; %H, 7.1; %N, 17.2.
Reaction SMILES: CCCCCC.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][C:9]=1[CH3:17].[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[S:29][C:27]1([C:58]1[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([CH:65]=[O:66])[CH:59]=1)[OH:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[S:29][C:27]1([C:58]1[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([CH:65]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][C:9]=2[CH3:17])[OH:66])[CH:59]=1)[OH:28])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOc1ccc(Br)c(C)c1
Reactant: O=Cc1cc(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(C(O)c2cc(C3(O)S[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Then, 2.6 M n-butylithium hexane solution (1.6 mL) was added to a mixture of 1-bromo-4-ethoxy-2-methylbenzene (0.94 g, 4.37 mmol) and tetrahydrofuran (12 mL) at −78° C. After stirred for one hour, the mixture was added with a tetrahydrofuran (10 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-(4-chloro-3-formylphenyl)-5-thio-D-glucopyranose (1.52 g, 2.18 mmol), and, further stirred for 20 minutes, and the reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 2,3,4,6-tetra-O-benzyl-1-C-{4-chloro-3-[(4-ethoxy-2-methylphenyl)(hydroxy)methyl]phenyl}-5-thio-D-glucopyranose (1.72 g, 95%) as a yellow amorphous diastereomer mixture.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C(N(CC)CC)C>O1CCOCC1>[CH3:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:3]3[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CSc1ncc2ncnc(Cl)c2n1
Reactant: Cc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSc1ncc2ncnc(Nc3cccc(C)c3)c2n1

Procedure:
4.9 g of 4-chloro-6-methylthio-pyrimido[5,4-d]pyrimidine, 2.0 g of 3-methylaniline, 2.4 ml of triethylamine and 100 ml of dioxane are heated at 100° C. for 3 hours. After cooling, the reaction mixture is concentrated and partitioned between water and methylene chloride. The organic phase is separated off, dried and concentrated and the residue is purified by chromatography over a silica gel column (petroleum ether/ethyl acetate=2:1). The solid is triturated with diethyl ether, filtered off with suction and dried.
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[N:12]2[N:13]=[C:14]([CH2:17][CH2:18][CH3:19])[CH:15]=[CH:16][C:11]2=[N:10][C:9]=1[C:20]([F:23])([F:22])[F:21])(=[O:7])=[O:6].Cl>O1CCOCC1>[CH2:17]([C:14]1[CH:15]=[CH:16][C:11]2[N:12]([C:8]([S:5]([NH2:4])(=[O:6])=[O:7])=[C:9]([C:20]([F:23])([F:21])[F:22])[N:10]=2)[N:13]=1)[CH2:18][CH3:19]
Reactant: CCCc1ccc2nc(C(F)(F)F)c(S(=O)(=O)N=CN(C)C)n2n1
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1ccc2nc(C(F)(F)F)c(S(N)(=O)=O)n2n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
N,N-dimethyl-N′-(6-n-propyl-2-trifluoromethylimidazo[1,2-b]pyridazin-3-ylsulfonyl)formamidine (0.30 g, 0.83 mmol) was dissolved in dioxane (10.0 ml), and to the solution was added concentrated hydrochloric acid (5.0 ml) and stirred at 60° C. for 2 hours, 80° C. for 2 hours and 90° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residues was added water, and adjusted pH to 3 with aqueous 1N sodium hydroxide solution. The precipitated solid was collected by filtration, and washed with water to give the title compound as white crystals. The yield was 0.24 g (94.3%).