Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH:28]([C@@H:31]1[C:35]([CH3:37])([CH3:36])[O:34][C:33](=[O:38])[NH:32]1)([CH3:30])[CH3:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:32]4[C@H:31]([CH:28]([CH3:29])[CH3:30])[C:35]([CH3:36])([CH3:37])[O:34][C:33]4=[O:38])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC(C)[C@H]1NC(=O)OC1(C)C
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC(C)(C)[C@H]4C(C)C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 4.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (890 mg) described in Preparation Example 61 and (R)-(+)-4-isopropyl-5,5-dimethyloxazolidin-2-one (409 mg), the title compound (51 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15](=[S:18])[NH:16][NH2:17])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=O>>[Br:23][CH2:24][CH2:25][CH2:26][C:27]1[S:18][C:15]([NH:14][C:13]2[C:8]([O:7][C:6]3[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=3[C:1]([CH3:4])([CH3:2])[CH3:3])=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:16][N:17]=1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1NC(=S)NN
Reactant: O=C(Cl)CCCBr
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nnc(CCCBr)s1

Procedure:
Example 102a was synthesized following the procedure for Example 1 using 4-(2-(2-tert-butylphenoxy)pyridin-3-yl)thiosemicarbazide (Example 1b) with 4-bromobutanoyl chloride.
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[C:10]1([C:16]([CH3:22])([CH3:21])[CH2:17][CH:18]([NH2:20])[CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(O)(=O)C>[C:10]1([C:16]([CH3:21])([CH3:22])[CH2:17][CH:18]([N:20]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8])[CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: CC(N)CC(C)(C)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(CC(C)(C)c1ccccc1)N=C(O)/C(Cl)=C(/Cl)C(=O)O
Temperature: 20 °C
Yield: 682.7 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 17.7 g (0.01 mol) of 3-phenyl-1,3,3-trimethylpropylamine are stirred in 100 ml of glacial acetic acid under reflux for 4 hours. 50 ml of water are added and the mixture is cooled to 20° C. The product is filtered off with suction and dried. 23.5 g (72% of theory) of dichloromaleic acid N-(3-phenyl-1,3,3-trimethylpropyl)-imide of melting point 106°-109° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[S:13](Cl)(=[O:15])=[O:14].[NH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(OCC)C>C(Cl)Cl>[OH:21][CH2:20][CH2:19][CH2:18][NH:17][S:13]([C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])(=[O:15])=[O:14]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1OC
Reactant: NCCCO
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCCCO)c(OC)c1OC
Reaction time: 8 h

Procedure:
2,3,4-Trimethoxybenzene sulfonyl chloride (20.4 g, 0.765 m) in methylene chloride (100 ml) was added dropwise to 3-aminopropanol (17.2 g) in methylene chloride (300 ml). After stirring overnight the reaction was washed with dilute aqueous HCl, dried and stripped to provide a solid. Trituration with diethyl ether provided the product N-(3-hydroxypropyl)-2,3,4-trimethoxy-benzenesulfonamide, m.p. 95°-97° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.[N:19]1([NH2:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([NH:25][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:11])[CH2:2][CH2:3]1
Reactant: NN1CCOCC1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Product: O=C(NN1CCOCC1)c1cnc(OCC(F)(F)F)c(C2CC2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 34 c), using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (example 34b) and morpholin-4-ylamine as starting materials (CAN 4319-49-7); MS (ESI) 346.4 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([O:20]C)=O.[NH3:22]>>[O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([NH2:22])=[O:20]
Reactant: N
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Product: NC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 100 °C
Yield: 64 %

Procedure:
A solution of methyl 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (1.007 g, 3.38 mmol) in ammonia (7 N in MeOH, 12 mL, 84 mmol) was heated under microwave heating conditions at 100° C. for 5 min. After that time the reaction was cooled to room temperature and concentrated to give a yellow solid. This was recrystallized from EtOAc to give 0.613 g (64%) of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]([N:16]=CN(C(C)C)C(C)C)[N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH3:33]>C(O)C>[NH2:16][C:4]1[N:3]=[C:2]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=2[CH3:33])[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:6][N:5]=1
Reactant: CC(C)N(C=Nc1ncc(Oc2ccc(Cl)cc2)c(Cl)n1)C(C)C
Reactant: Cc1cc(O)ccc1N
Solvent: CCO
Product: Cc1cc(O)ccc1Nc1nc(N)ncc1Oc1ccc(Cl)cc1
Temperature: 24 °C
Reaction time: 20 h
Yield: 6.2 %

Procedure:
Nitrogen was bubbled through a suspension of 2 g (9 mmol) of 4-chloro-5-(4-chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidine (see Example 2) in 20 ml of ethanol for 10 minutes. Then 1.15 g (9.34 mmol) of 4-amino-3-methylphenol was added and nitrogen bubbled through the suspension for 5 minutes. The solution was then tightly sealed and stirred at 24° C. for 20 hours. Then 5 ml of concentrated hydrochloric acid was added to the mixture and refluxed for 60 minutes. The mixture was cooled and spin evaporated. The residue was suspended in 100 mL CH2Cl2 and 400 mL water. The pH was adjusted to 12 with 3N NaOH. The organic phase was washed with water (400 mL) twice, brine (200 mL) and then dried over Na2SO4. The salt was removed by filtration and the filtrate applied to a Silica Gel 60 column (2.5×10 cm) preequilibrated with CH2Cl2. The column was eluted with 800 mL CH2Cl2 and then with mixtures of ethylacetate and CH2Cl2. The fractions showing one spot on TLC (EtOAc; Rf0.45) were pooled and concentrated by spin evaporation. The liquor formed crystals on standing. 0.19 g (6% yield) of product, a white solid, was obtained after drying in vacuo at 105° C. for 16 hours, mp 199-201° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)C.C[O-].[Na+].CO.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=O)[C:29]([CH3:35])([CH3:34])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH:31]=[C:30]([CH2:5][C:4]([O:3][CH3:1])=[O:14])[C:29]([CH3:35])([CH3:34])[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC1=CCN(C(=O)OC(C)(C)C)CC1(C)C
Yield: 52.9 %

Procedure:
To a cooled (0° C.) solution of diethylphosphonoacetic acid ethyl ester (4.4 mL, 24.2 mmol) in tetrahydrofuran (50 mL) under an atmosphere of nitrogen were added a solution of 28% sodium methoxide in methanol (4.6 mL, 26.4 mmol), and then a solution of 3,3-dimethyl-4-oxopiperidine-1-carboxylic acid t-butyl ester (5.0 g, 22.0 mmol) in tetrahydrofuran (10 mL) and stirred for 3 hours at room temperature. After the reaction was completed, the solvent was removed under a reduced pressure and water was added to the residue. The mixture was extracted with ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After drying, the extract was filtered and the filtrate was concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, hexane:ethyl acetate=6:1) to obtain 1.8 g (yield 32.1%) of 4-methoxycarbonylmethylene-3,3-dimethylpiperidine-1-carbxylic acid t-butyl ester (A) and 3.3 g (yield 58.9%) of 4-methoxycarbonylmethyl-3,3-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (B). Each of their physical properties is shown below.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[CH3:21][S:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:32]4[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: Nc1ncc(B(O)O)cn1
Product: CS(=O)(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica gave 283. NMR (400 MHz, CDCl3): 1.88-2.00 (2H, m), 2.04-2.20 (4H, m), 2.83-2.86 (4H, m), 3.13-3.20 (2H, m), 3.81 (2H, s), 3.88-3.90 (4H, m), 3.92-3.96 (4H, m), 5.25 (2H, br, s), 7.18 (1H, s),9.37 (1H, s). (M+H)+ 490
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@:11]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][N:28]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[C:25]2=[N:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[Cl:21][C:22]1[CH:23]=[C:24]2[C:30]([C:2]3[N:7]=[C:6]([NH:8][C@H:9]4[CH2:14][CH2:13][CH2:12][C@@:11]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:10]4)[C:5]([F:20])=[CH:4][N:3]=3)=[CH:29][N:28]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:41])=[O:42])[C:25]2=[N:26][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1

Procedure:
In a 25 mL round-bottomed flask were combined (1R,3S)-methyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate, 52h, (0.061 g, 0.202 mmol), 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.096 g, 0.222 mmol), disodium carbonate (0.064 g, 0.607 mmol) in 5 mL of THF and 1 ml of water. The reaction mixture was degassed via a stream of nitrogen. To the reaction was added tetrakis triphenyl phosphine palladium (0) (0.021 g, 0.202 mmol) and the reaction was stirred at reflux overnight. The reaction was concentrated in vacuo and purified by silica gel chromatography (4:1 Hexanes:EtOAc), yielding 85 mg of desired product, 52i.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]=[CH:10][C@@H:11]([C@H:13]([C@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])O)[OH:14])[OH:12]>[Cl-].[Cl-].[Zn+2]>[CH2:19]1[O:20][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][C@H:15]([C@H:13]([OH:14])[C@@H:11]([OH:12])[CH:10]=[O:9])[C@@H:17]1[OH:18]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C[C@H](O)[C@@H](O)[C@H]1OC(c2ccccc2)OC[C@H]1O
Reaction time: 0.5 h

Procedure:
A portion of ZnCl2 (23 kg, 171 mol) was placed into a reactor, taking measures to exclude moisture. Benzaldehyde (70 L, 680 mol) was poured into the reactor, and the mixture was stirred for about 30 minutes using a powerful mechanical stirrer. After initial dissolution of zinc chloride, a thick slurry of a benzaldehyde-ZnCl2 complex forms. Anhydrous D-galactose (30 kg, 164 mol) and more benzaldehyde (60 L, 570 mol) were added to the warm slurry, and the mixture was allowed to react at RT for 24 hours with vigorous stirring. The precipitate was filtered off and washed portionwise with benzaldehyde (10-15 L total) and then with acetone, to give, after air-drying, 6-7 kg of unreacted D-galactose, probably as the monohydrate. The combined filtrate and benzaldehyde washings were diluted with ether (70 L) and petroleum ether (80 L), and the mixture was extracted with ice-cold water (140 L) . The organic layer was washed 3 times with ice water (70 L each time), and the combined aqueous layers were neutralized by rapid addition of a solution of potassium carbonate (38 kg of anhydrous carbonate in approximately 45-50 L of water). The resulting thick suspension of zinc salts was filtered, and the precipitate was washed thoroughly with water until 500-600 L of filtrate were collected. After extraction with chloroform (70 L) and with petroleum ether (70 L), the filtrate, containing 4,6-O-benzylidene-D-galactose (2) and a mixture of KCl and KHCO3, and having a pH of about 8.7, was used directly for the following oxidation.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5].[CH3:16][Mg]Br.O.[Cl-].[NH4+]>O1CCCC1>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:4](=[O:5])[CH3:16])=[N:7]1
Reactant: CON(C)C(=O)c1n[nH]c2ccccc12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1n[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 20 h

Procedure:
In a round-bottomed flask, 2.4 g of N-methoxy-N-methyl-1H-indazole-3-carboxamide are placed in 140 ml of tetrahydrofuran at 0° C. and under argon. 19 ml of methylmagnesium bromide (3M in ethyl ether) are added dropwise. The mixture is stirred for one hour at 0° C. and 20 h at ambient temperature. It is cooled to 0° C. and 80 ml of water and 40 ml of a saturated solution of ammonium chloride are added. The mixture is extracted with 40 ml of ethyl acetate. The organic phase is washed with 40 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 1.6 g of compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([C:18]1[S:19][C:20](Br)=[CH:21][C:22]=1[NH:23][S:24]([C:27]1[C:28]([CH3:33])=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25])=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(C)C=CC=CC=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:11]([O:15][C:16]([C:18]1[S:19][C:20]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:21][C:22]=1[NH:23][S:24]([C:27]1[C:28]([CH3:33])=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(Br)sc1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(-c2cc(NS(=O)(=O)c3ccccc3C)c(C(=O)OC(C)(C)C)s2)cc1
Temperature: 70 °C
Yield: 87.7 %

Procedure:
To the mixture of 4-methylbenzeneboronic acid (38.0 mg, 0.279 mmol) and 5-Bromo-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (40 mg, 0.0925 mmol) in 5:1 mixture of toluene/MeOH (2.0 mL) was added a solution of Pd(PPh3)4 (12.0 mg, 0.01 mmol, 10 mol %) in toluene (1.0 mL) followed by aqueous 2M Na2CO3 solution (0.1 mL, 0.2 mmol). The resultant reaction mixture was heated at 70° C. for 16 h, cooled to room temperature, filtered off through MgSO4 and washed with EtOAc. Evaporation of the solvent and purification of the residue over preparative TLC (1 mm, 60 A°) using ethyl acetate/hexane (1:10) as an eluent furnished 3-(Toluene-2-sulfonylamino)-5-p-tolyl-thiophene-2-carboxylic acid tert-butyl ester (36.0 mg, 81% yield). 1H NMR (CDCl3, 300 MHz) 9.94 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.44-7.25 (m, 6H), 7.18 (d, J=8.1 Hz, 2H), 2.71 (s, 3H), 2.36 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Reactant: OB(O)c1cccnc1
Product: COc1cccc(Nc2nc(-c3cccnc3)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6, from Example 4, was reacted with pyridine-3-boronic acid using General Procedure A. Purification on silica yielded 124. NMR: (CDCl3): 3.88 (s, 3H, CH3), 4.13 (s, 3H, CH3), 6.88-6.90 (m, H, ArH), 7.16 (m, H, ArH), 7.30 (s, H, ArH), 7.38-7.46 (m, 2H, 2×ArH), 7.50 (sbr, H, NH), 8.72 (m, H, ArH), 8.79-8.82 (m, H, ArH) 9.76 (m, H, ArH). MS: (ESI+) MH+=333.24
Reaction SMILES: [CH2:1]([OH:10])[C@H:2]([C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].[OH-].[Na+].[H][H]>[Ni]>[CH2:8]([OH:9])[CH:6]([OH:7])[CH:4]([OH:5])[CH:2]([OH:3])[CH2:1][OH:10]
Reactant: [H][H]
Reactant: OC[C@@H](O)C(O)[C@H](O)CO
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: OCC(O)C(O)C(O)CO
Reaction time: 4 h

Procedure:
Fermentation of glucose to arabinitol is performed by using a culture medium of 10% (w/v) glucose, 0.5% (w/v) yeast extract and 0.1% (w/v) urea. The medium is inoculated with a yeast strain of the genus Endomycopsis chodati. After 72 hours fermentation time 56% arabinitol was obtained without considerable amounts of glycerol (below 4%). After demineralisation and refining the arabinitol syrup is directly used for polyol isomerisation in the presence of Raney-nickel (5% catalyst slurry on total dry substance). The pH is increased to 11, by the addition of 0.5 M NaOH. A hydrogen pressure of 4 MPa is applied at a temperature of 170° C. and the isomerisation reaction is stopped after 4 hours, resulting in a pentitol mixture of the following composition: arabinitol (90%), xylitol (6%), ribitol (4%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.O.O.C([O-])(=O)C.[Na+]>O.C(O)C>[C:10]1([N:16]([C:6]2[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=2)[NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccccc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NN(c1ccccc1)c1cc(Cl)nc(Cl)n1
Reaction time: 72 h

Procedure:
A mixture of 2,4,6-trichloropyrimidine (50ml.) and phenylhydrazine (45ml.) was added to a solution of sodium acetate trihydrate (100g.) in water (270ml.) and ethanol (720ml.). The resulting mixture was kept at room temperature for 3 days. The resulting crystalline precipitate was collected by filtration, washed with ethanol (100ml.) and dried at 60° C. to give N-phenyl-N-(2,6-dichloropyrimidin-4-yl)hydrazine, m.p. 114°-116° C.
Reaction SMILES: [CH2:1]([C:6]1[S:7][C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH:18]C(=O)C(Cl)(Cl)Cl)[C:9]=2[N:25]=1)[CH2:2][CH2:3][CH2:4][CH3:5].N.ClCCl>CO>[CH2:1]([C:6]1[S:7][C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:18])[C:9]=2[N:25]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1nc2c(NC(=O)C(Cl)(Cl)Cl)nc3ccccc3c2s1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCCCCc1nc2c(N)nc3ccccc3c2s1

Procedure:
Trichloroacetyl isocyanate (0.51 mL) was added to a solution of 2-pentylthiazolo[4,5-c]quinoline-5N-oxide (0.78 g) in dichloromethane (50 mL). The reaction mixture was stirred at ambient temperature for about 75 minutes and then concentrated under vacuum to provide crude N-(2-pentylthiazolo[4,5-c]quinolin-4-yl)trichloroacetamide. The amide was combined with a solution of ammonia in methanol (40 mL of 2M). Dichloromethane was added to bring all of the material into solution. When the reaction was completed as indicated by thin layer chromatography, the reaction mixture was concentrated under vacuum. The residue was mixed with dichiloromethane and sodium bicarbonate. The organic layer was separated, washed with sodium bicarbonate then with water, dried over magnesium sulfate and then concentrated under vacuum to provide a white solid. This material was recrystallized from ethyl acetate to provide 2-pentylthiazolo[4,5-c]quinolin-4-amine as an off-white crystalline solid, m.p. 119-121° C. Analysis: Calculated for C15H17N3S: %C, 66.39; %H, 6.3 1; %N, 15.48; Found: %C, 66.21; %H, 6.35; %N, 15.39.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[I:9].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.CCOC(C)=O>CC1CCCO1>[C:13]([Si:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([I:9])[CH:4]=1)([CH3:12])[CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1ccc(Cl)c(I)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)c(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a solution of 4-chloro-3-iodophenol (2 g. 7.86 mmol) in anhydrous 2-methyltetrahydrofuran (10 mL) was added tert-butyldimethylsilyl chloride (1.25 g, 8.28 mmol) followed by imidazole (642 mg, 68.1 mmol) The resulting mixture was stirred at room temperature for 3 hours. EtOAc (10 mL) was added and the mixture washed with aqueous sodium hydroxide solution (2M, 3×10 mL), water (10 mL), and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with heptane:EtOAc 90:10 to afford the title compound as colourless oil in 30% yield, 870 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([CH2:30][NH:31][C:32]2[S:36][N:35]=[C:34]([C:37]3[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=3)[CH:33]=2)[CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:42][CH2:41][C:40]1[CH:39]=[CH:38][C:37]([C:34]2[CH:33]=[C:32]([NH:31][CH2:30][CH:27]3[CH2:29][CH2:28]3)[S:36][N:35]=2)=[CH:44][CH:43]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(-c2cc(NCC3CC3)sn2)cc1
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(-c4cc(NCC5CC5)sn4)cc3)c2CC1)C(F)(F)F
Yield: 39.5 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (75 mg, 0.18 mmol) with 4-[5-(cyclopropylmethyl-amino)-isothiazol-3-yl]-benzylamine (68 mg, 0.26 mmol) in toluene (3 mL). Purify the crude mixture by chromatography on silica gel (4 g) eluting with hexane/EtOAc with 2% methanol (9:1 to 4:1 gradient) to obtain 7-chloro-6-{4-[5-(cyclopropylmethyl-amino)-isothiazol-3-yl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (38 mg, 40%). MS (ES+) m/z: 535.3 (M+H)4.