Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][S:5]1(=[O:16])=[O:15])[CH3:3].CC(C)([O-])C.[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(#N)C>[CH3:3][CH:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([S:24]([CH3:23])(=[O:26])=[O:25])[S:5]1(=[O:16])=[O:15])[CH3:1]
Reactant: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1C(=O)c2ccccc2N(S(C)(=O)=O)S1(=O)=O
Reaction time: 64 h

Procedure:
To 200 ml of acetonitrile was added with stirring 24 g(0.1 mole) of 3-(1-methylethyl)-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide and 11.8 g (0.105 mole) of potassium t-butoxide. The resultant mixture was heated to reflux, cooled, and 8.0 ml (0.105 mole of methanesulfonyl chloride in 100 ml of acetonitrile was added dropwise over a 0.5 hr period. The mixture was stirred 64 hours, filtered, and the solvent removed from the filtrate in vacuo. The crude product, 31.5 g, was washed with 2-50 ml-portions of methanol to afford 18.8 g of analytically pure 3-(1-methylethyl)-1-methylsulfonyl-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide. m.p. 156°-158° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([OH:27])=[N:18][C:19](SC)=[N:20][C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].O.[NH2:29][NH2:30]>COCCO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([OH:27])=[N:18][C:19]([NH:29][NH2:30])=[N:20][C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: NN
Reactant: CCCc1nc(SC)nc(O)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: COCCO
Solvent: O
Product: CCCc1nc(NN)nc(O)c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
12.4 g of the 5-[(2'-cyanobiphenyl-4-yl)-methyl]-4-hydroxy-2-methylmercapto-6-propylpyrimidine prepared above are dissolved in 370 ml of 2-methoxyethanol. 33 ml of hydrazine hydrate are added and the mixture is then refluxed for 3 h. It is concentrated under vacuum, taken up in acetonitrile and triturated. The solid obtained is filtered off and washed with ether and isopropyl ether to give 9.9 g of 5-[(2'-cyanobiphenyl- 4-yl)methyl]-2-hydrazino-4-hydroxy-6-propylpyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].CC(O)=O.[O:29]1[CH2:33][CH2:32][C:31](=O)[CH2:30]1.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:31]2[CH2:32][CH2:33][O:29][CH2:30]2)[CH:3]=1
Reactant: O=C1CCOC1
Reactant: Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(NC2CCOC2)c1
Temperature: 22 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (100 mg, 0.31 mmol) in MeOH (5 mL) was added AcOH (0.05 mL) and dihydrofuran-3(2H)-one (27 mg, 0.31 mmol). The mixture was stirred at 22° C. for 2 h. NaBH3CN (98 mg, 1.55 mmol) was added and the resulting mixture was stirred at 22° C. for 2 h. The reaction solution was concentrated, and the residue was washed with water, extracted with EA, the organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (22 mg, Yield 18.0%). 1H NMR (CD3OD, 400 MHz): δ 7.14-6.95 (m, 7H), 6.80-6.71 (m, 1H), 4.14-4.03 (m, 2H), 3.99-3.89 (m, 2H), 3.87-3.78 (m, 1H), 3.75-3.69 (m, 2H), 3.67-3.61 (m, 1H), 3.55-3.41 (m, 2H), 2.91-2.79 (m, 4H), 2.71-2.57 (m, 2H), 2.32-2.19 (m, 1H), 1.91-1.79 (m, 1H). LCMS (m/z): 396.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]([O:22]CC)=O)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[CH:10]1[C:20](=[O:22])[C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[NH:13][C:11]1=[O:12]
Reactant: CCOC(=O)c1ccncc1NC(=O)Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2cnccc2C(=O)C1c1c(F)cc(F)cc1F
Yield: 77.2 %

Procedure:
The product from Step 2 (3.0 g) and potassium carbonate (1.6 g) were stirred in dry DMF (100 ml) at 100° C. for 3 hours. The reaction was cooled and the excess DMF evaporated to give a black oil. Water (100 ml) was added and then washed with ethyl acetate. The aqueous fraction was filtered and acidified with 2M aqueous hydrochloric acid to neutral pH, and the water was evaporated to give a solid, which was then extracted with methanol. The methanol extract was evaporated to give the crude 3-(2,4,6-trifluorophenyl)-1H-[1,7]naphthyridine-2,4-dione as a dark brown crystalline solid (2.0 g), which was used for the next reaction without further purification.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C@@H:3]1[O:8][C:7](=[O:9])[C@@H:6]([CH3:10])[C@H:5]([CH3:11])[O:4]1.S(=O)(=O)(O)O.[CH3:19]C(O)C>O>[CH3:10][C@H:6]([C@@H:5]([OH:4])[CH3:11])[C:7]([O:8][CH:3]([CH3:19])[CH3:2])=[O:9]
Reactant: CC(C)O
Reactant: C[C@@H]1O[C@H](C(Cl)(Cl)Cl)OC(=O)[C@H]1C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)[C@H](C)[C@H](C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.0 g of (2S, 5S,6S)-2-trichloromethyl-5,6-dimethyl-1,3-dioxan-4-one produced by a procedure similar to Example 1-(7) were added 0.1 ml of concentrated sulfuric acid and 10 ml of 2-propanol, stirred at room temperature for one hour, and 20 ml of water was added to effect ether extraction. The ether phase was dried over anhydrous sodium sulfate and ether was distilled off followed by distilling the residue to obtain 0.4 g of isopropyl (2R, 3S)-2-methyl-3-hydroxybutanoate of the following formula. ##STR61## (2) Repeating the procedure of Example 5-(1) except that 2-propanol was replaced with 2-butanol, 0.5 g of 1-methylpropyl (2R, 3S)-2-methyl-3-hydroxybutanoate of the following formula was obtained.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1.[CH:19]1([C:22](N2C3C=CC=CC=3N=N2)=[O:23])[CH2:21][CH2:20]1.O>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH2:17][C:22]([CH:19]2[CH2:21][CH2:20]2)=[O:23])=[CH:12][CH:11]=1
Reactant: O=C(C1CC1)n1nnc2ccccc21
Reactant: CC(=O)c1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(=O)C1CC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a −78C solution of LDA (generated from 8 ml of 2.5 M nBuLi and 2.1 ml of diisopropylamine) in THF (120 ml) was added dropwise, over 80 min, a solution a 4′-bromoacetophenone (2.98 g, 14.97 mmol) in THF (45 ml). The mixture continued to stir at −78C for 1 h, followed by addition of 1-(cyclopropylcarbonyl)-1H-1,2,3-benzotriazole (2.56 g, 13.65 mmol) in THF (45 ml). The mixture was warmed to rt overnight. The yellow mixture was poured into water and extracted with Et2O (2×300 ml). The combined organic phases were washed with water, dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (CH2Cl2/hexanes, 10:90 to 30:70) to yield 1-(4-bromophenyl)-3-cyclopropyl-1,3-propanedione as an orange solid (1.60 g, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:16][N:17]=[C:18]=[O:19]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[NH:10][C:18]([NH:17][CH3:16])=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: CN=C=O
Reactant: COC(=O)CN(N)c1cccc(OC)c1
Solvent: CC#N
Product: CNC(=O)NN(CC(=O)OC)c1cccc(OC)c1

Procedure:
A solution of methyl [1-(3-methoxyphenyl)hydrazino]acetate (1.6 g) and methyl isocyanate (0.9 ml) in acetonitrile (20 ml) was heated under reflux for 1 h. The solvent was removed in vacuo and the residue was treated with ether to give the title compound (1.8 g) as a solid, m.p. 145°-146°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH:8]([CH:11]=[CH2:12])[N:7]1C(OC(C)(C)C)=O)=[O:5])[CH3:2].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C([O-])(O)=O.[Na+].O>C(Cl)Cl.CCOCC>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH:8]([CH:11]=[CH2:12])[NH:7]1)=[O:5])[CH3:2]
Reactant: C=CC1CC[C@@H](C(=O)OCC)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: C=CC1CC[C@@H](C(=O)OCC)N1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
130 mg of 172 (0.46 mmol) was dissolved in 3 ml of anhydrous CH2Cl2, cooled to 0° C. and added dropwise with 90 ml of TMSOTf (0.466 mmol, 1.01 eq.). After 15 min, this was added with 0.5 ml of saturated NaHCO3 solution, 0.5 ml of H2O and 10 ml of Et2O, and the batch was allowed to come to RT. Following phase separation, the organic phase was dried over MgSO4, filtered and concentrated. The resulting crude product was purified using silica gel column chromatography (DCM/MeOH 25:1) to isolate 54 mg of amine 174 (0.32 mmol, 70%) as a slightly yellowish oil (mixture of diastereomers, cis/trans=4:1).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1([C:22]2[N:27]=[CH:26][C:25]([C@H:28]3[C@H:30]([C:31]([O-:33])=[O:32])[C:29]3([CH3:35])[CH3:34])=[CH:24][N:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[C:36]([CH:38]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:41]=1)O)#[N:37]>CN(C)C1C=CN=CC=1.ClCCl>[CH:16]1([C:22]2[N:27]=[CH:26][C:25]([C@H:28]3[C@H:30]([C:31]([O:33][CH:38]([C:36]#[N:37])[C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[N:41]=4)=[O:32])[C:29]3([CH3:35])[CH3:34])=[CH:24][N:23]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CC1(C)[C@@H](C(=O)[O-])[C@@H]1c1cnc(C2CCCCC2)nc1
Reactant: N#CC(O)c1cccc(Oc2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)n2)[C@@H]1c1cnc(C2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.7 %

Procedure:
Dicyclohexylcarbodimide (118 mg) was added to a stirred mixture of (±)-trans-3-(2-cyclohexylpyrimidin-5-yl)-2,2-dimethylcyclopropane carboxylate (150 mg), 1-cyano-1-(6-phenoxypyrid-2-yl)methanol (130 mg), 4-dimethylaminopyridine (5 mg) and dichloromethane (5 cm3) and the mixture stirred at the ambient temperature for 7 hours, and kept for a further 16 hours without stirring. The product was isolated by filtering through a silica column, eluting first with dichloromethane and then with a mixture of dichloromethane (20 parts by volume) and ethyl acetate (1 part by volume) to yield (RS)-1-cyano-1-(6-phenoxypyrid-2-yl)methyl (1RS, trans)-3-(2-cyclohexylpyrimidine-5-yl)-2,2-dimethylcyclopropane carboxylate, (248 mg) identified by n.m.r. as a 1:1 mixture of the two pairs of enantiomeric diastereomers.
Reaction SMILES: CO[C:3]1[CH:4]=C2C(=C[CH:12]=1)C=NC(C(O)=O)=C2.C[O:17][C:18]([CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:30])[CH:27]=2)[CH2:22][N:21]1C(OC(C)(C)C)=O)=[O:19]>>[CH:3]([O:30][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[CH2:22][NH:21][CH:20]([C:18]([OH:17])=[O:19])[CH2:29]2)([CH3:4])[CH3:12]
Reactant: COC(=O)C1Cc2cc(O)ccc2CN1C(=O)OC(C)(C)C
Reactant: COc1ccc2cnc(C(=O)O)cc2c1
Product: CC(C)Oc1ccc2c(c1)CC(C(=O)O)NC2
Yield: 9.1 %

Procedure:
0.2 g (9.1%, 4 steps) of the 6-isopropoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid was prepared according to procedure described for the synthesis of 6-methoxy-isoquinoline-3-carboxylic acid (in Example 294) starting from 0.67 g (2.18 mmol) of 6-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester. LCMS: 232 (M+1)+.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([N:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:6]([OH:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:23]([N:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:5]([CH:6]([OH:14])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:4]([OH:30])=[O:3])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(C(O)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(C(O)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 4.12 g (10.2 mmol) racemic (2R,3R and 2S,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid ethyl ester in 57 ml tetrahydrofurane were added 1.73 g (40.8 mmol) lithium hydroxide monohydrate dissolved in 10 ml water. The mixture was stirred at 60° C. overnight. Water was added followed by extraction with ethyl acetate. The waterphase was adjusted to pH 1 with 1 N aqueous hydrochloric acid. Extraction with ethylacetate and chromatography on silicagel with dichloromethane/methanol 9/1 yielded 3.40 g (89%) racemic (2R,3R and 2S,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid, MS m/e (%): 376.5 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH3:11])[CH:6]=[C:5]([C:12]([CH3:20])([CH3:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:4]=1.C([Li])CCC.[CH2:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=[O:32].[Cl-].[NH4+]>CCOCC.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([CH3:19])([CH3:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:6]=[C:7]([O:9][CH2:10][CH3:11])[C:8]=1[CH:31]1[CH2:30][CH2:29][CH2:28][C:27](=[O:32])[CH2:26]1
Reactant: O=C1CCCCC1
Reactant: CCCCCCC(C)(C)c1cc(OC)cc(OCC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCC(C)(C)c1cc(OC)c(C2CCCC(=O)C2)c(OCC)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1-Methoxy-3-(1,1-dimethylheptyl)-5-ethoxybenzene (IIa) (1500 mg, 5.4 mmol) was dissolved in dry ether (25 ml) and the solution was cooled to 0° C. The reaction was placed under nitrogen and butyl lithium (5.94 mmol, 3.6 ml of a solution in hexane) was injected into the reaction. The reaction mixture was brought to room temperature, and was stirred for 4 hrs. Cuprous bromide (360 mg, 2.5 mmol) was added in one portion. The reaction mixture turned dark and became homogeneous. After stirring for 5 min, 2-cyclohexanone (240 mg, 2.5 mmol) was injected into the solution, and the reaction mixture was stirred for 15 min at 0°. Ether (50 ml) and a saturated ammonium chloride solution (150 ml) were added. The organic layer was washed with brine, dried and evaporated to dryness. The oil obtained was purified by medium pressure liquid chromatography (230-400 mesh ASTM, silica gel 60" for column chromatography; elution with petroleum ether, b.p. 60°-80°) to yield the title compound, IIIa (66%).
Reaction SMILES: Cl[C:2]1[C:3]([S:9][CH:10]([CH3:12])[CH3:11])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C-:13]#[N:14].[K+]>O.O.[Ni](Cl)Cl.[Mn].CN(C)C=O>[NH2:5][C:4]1[C:3]([S:9][CH:10]([CH3:12])[CH3:11])=[C:2]([CH:8]=[CH:7][CH:6]=1)[C:13]#[N:14]
Reactant: CC(C)Sc1c(N)cccc1Cl
Reactant: [C-]#N
Agent: Cl[Ni]Cl
Agent: [Mn]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1c(N)cccc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
6 liters of dimethylformamide are added to 50 g of nickel chloride dihydrate, 200 g of BPPFA (1,1'-bisdiphenylphosphine-1-(dimethylaminoethyl)ferrocene) and 49 g of manganese powder, and the mixture is stirred at 50° C. for 2 hours under an inert atmosphere. A brown suspension forms. 1,200 g of 3-chloro-2-isopropylthioaniline and 430 g of KCN are added to the suspension and the mixture is stirred for 16 hours at 50° C. After working up, white crystals of m.p. 82° C. are obtained in a yield of approximately 90%.
Reaction SMILES: C([Sn]1(CCCC)[O:10][CH2:9][C:8]2([CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]2)[CH2:7][O:6]1)CCC.[CH2:20]([C:22]1([CH2:29][CH3:30])[CH2:27][O:26][C:25](=S)[O:24][CH2:23]1)[CH3:21]>>[CH2:20]([C:22]1([CH2:29][CH3:30])[CH2:27][O:26][C:25]2([O:6][CH2:7][C:8]3([CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]3)[CH2:9][O:10]2)[O:24][CH2:23]1)[CH3:21]
Reactant: CCCC[Sn]1(CCCC)OCC2(CC=CCC2)CO1
Reactant: CCC1(CC)COC(=S)OC1
Product: CCC1(CC)COC2(OC1)OCC1(CC=CCC1)CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To the above solution of 3,3-dibutyl-2,4-dioxa-3-stannaspiro[5.5]undec-8-ene 2 was added 5,5-diethyl-1,3-dioxane-2-thione 1 (10.39 g, 59.6 mmol) in several small portions at room temperature over a period of 20 min. The resulting mixture was allowed to stir at room temperature for 24 hours. The reaction was monitored by TLC (silica gel, 25% ether/hexanes). The reaction mixture was then concentrated under reduced pressure and the residue taken up with ethyl ether (white suspension formed upon standing). The ether solution was filtered and concentrated under reduced pressure to give light yellowish oil. The crude material was purified by column chromatography (silica gel, 10-15% ethyl ether/hexanes). The desired 3,3-diethyl-1,5,7,16-tetraoxadispiro[5.2.5.2]hexadec-11-ene (DECH 3) was obtained as colorless oil in 94% yield. 1H-NMR (CDCl3, 300 MHz) δ5.68-5.58 (m, 2H), 3.74-3.68 (4s, 8H), 2.08-1.94 (m, 4H), 1.63-1.56 t, 2H, J=6.6 Hz), 1.46-1.37 (q, 4H, J=7.5 Hz), 0.84-0.76 (t, 6H, J=7.5 Hz); —C-NMR (CDCl3, 75 MHz) δ126.03, 124.16, 114.68, 70.03, 69.32, 34.27, 30.50, 26.44, 23.14, 21.30, 13.92, 7.01; IR (neat) (cm−1) 3020, 2960, 2880, 1640, 1450, 1360, 1250, 1220, 1200, 1185, 1160, 1105, 1020, 995, 920, 730, 655; Anal. Calcd for C16H26O4: C, 68.06%; H, 9.28%; Found: C, 68.20%; H, 9.59%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C)=[O:8])[CH2:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:3]1=[O:17].[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:3]1=[O:17]
Reactant: COC(=O)C1CN(c2cccnc2)C(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)N(c2cccnc2)CC1C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-bromopyridine (316 mg, 2. mmol) and methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (316 mg, 2 mmol) (prepared as described in step (ii) of Example 8) in 1,4-dioxane (10 ml) was treated with cesium carbonate (977 mg, 3 mmol), Xantphos™ (87 mg, 0.15 mmol) (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, e.g. available from Aldrich, CAS no. 161265-03-8) and tris(dibenzylideneacetone)dipalladium(0) (45.8 mg, 0.05 mmol) and the mixture was heated under reflux under argon for 22 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give methyl 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylate (273 mg, 58%). LC/MS [M+H]+=236. (ii) A solution of methyl 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylate (0.27 g, 1.15 mmol) in tetrahydrofuran (3 ml) at 0° C. was treated with a solution of lithium hydroxide (0.030 g, 1.26 mmol) in water (2 ml) and the mixture was stirred at 0° C. for 90 minutes. Hydrochloric acid (2M) was added to adjust the pH of the reaction mixture to pH 2 and the solvent was evaporated. The residue was dried over phosphorus pentoxide to give crude 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylic acid which was used in the next step. LC/MS [M+H]+=222.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]2[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH:20]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(Br)ccc(N)c2C1=O
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1Cc2c(C3=CCC4(CC3)OCCO4)ccc(N)c2C1=O

Procedure:
A mixture of 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (1.7 g, 7.0 mmol), 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid pinacol ester (2.2 g, 8.5 mmol) (preparation: WO 2007/141517), potassium carbonate (2.9 g, 21 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.57 g, 0.69 mmol) in 1,4-dioxane (40 mL) and H2O (10 mL) was evacuated and refilled with nitrogen (3×) and irradiated in the microwave at 100° C. for 30 min. The reaction mixture was partitioned between EtOAc and brine and separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated. The compound was purified on an Isco Combiflash eluting with 30 to 100% EtOAc in heptane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, J=8.34 Hz, 1H), 6.55 (d, J=8.59 Hz, 1H), 6.08 (s, 2H), 5.60-5.66 (m, 1H), 4.39 (s, 2H), 3.91 (s, 4H), 2.98 (s, 3H), 2.50 (td, J=1.86, 3.60 Hz, 1H), 2.42-2.48 (m, 2H), 2.31-2.37 (m, 2H), 1.77 (t, J=6.44 Hz, 2H); MS (ES+): m/z: 302.1621 [MH+]. HPLC: tR=1.21 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12]([N:15]=[C:16]=[S:17])[CH:13]=[CH2:14].CCOCC>C(Cl)Cl>[SH:17][C:16]1[N:15]([CH2:12][CH:13]=[CH2:14])[C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: COC(=O)c1ccccc1N
Reactant: C=CCN=C=S
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCn1c(S)nc2ccccc2c1=O
Temperature: 40 °C

Procedure:
To a stirred mixture of 50 g (0.33 mole) methyl anthranilate in 100 ml methylene chloride, 32.7 g (0.33 mole) allyl isothiocyanate in 50 ml methylene chloride was added dropwise. The reaction mixture was refluxed at 40° C. one hour, stirred over the weekend at ambient temperature, and refluxed at 40° C. for one hour. The reaction mixture was stripped. Additional methylene chloride (200 ml) was added; the resulting mixture was refluxed at 40° C. for 7 hours, and then stirred about 11/2 days at ambient temperature. The reaction mixture was stripped. Ether was added; a precipitate formed. The above-identified product was isolated by suction filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][NH:25][CH3:26])[C:18]4=[O:27])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][CH2:24][N:25]([CH3:26])[S:35]([CH3:34])(=[O:37])=[O:36])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:31])([F:33])[F:32])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNCCN1C(=O)SC(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: CN(CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O)S(C)(=O)=O

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-N-methylmethane sulfonamide was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-3-(2-methylaminoethyl)thiazolidine-2,4-dione (from Example 394) and methanesulfonyl chloride following General Procedure U.