Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(N=C=NC2CCCCC2)CCCCC1.[F:39][C:40]([F:44])([F:43])[CH2:41]O.CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCC(F)(F)F
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCC(F)(F)F)o1
Yield: 69.5 %

Procedure:
To a stirred, room temperature suspension of 5-(tetradecyloxy)furan-2-carboxylic acid (1.3 g, 4.0 mmol) in CH2Cl2 (40 mL) was added N,N′-dicyclohexylcarbodiimide (0.990 g, 4.8 mmol), N,N-dimethylaminopyridine (0.488 g, 4.0 mmol) and 2,2,2-trifluoroethanol (0.875 mL, 12.0 mmol). The flask was capped and stirring was continued for 16 hrs at which time TLC (10% EtOAc in Hexanes Rf=0.05 (SM) and 0.25 (Prod)) indicated complete consumption of the starting material. The resulting suspension was diluted with CH2Cl2 (40 mL), filtered and concentrated. This crude material was purified by flash chromatography eluting with 5-20% EtOAc in Hexanes. The resulting solid was further purified by recrystallization in 30 mL of hot 2-propanol with the addition of a minimum amount of water to yield 1.13 g (70%) of the title compound as white needles. MS (m/z, ES−): 406.0 (M−1, 100%); EA found for C23H36F3NO2: C, 62.20; H, 8.18; calcd: C, 62.05; H, 8.18; 1H NMR (400 MHz, DMSO-d6) δ: 7.4 (d, 1H), 5.7 (d, 1H), 4.9 (q, 2H), 4.2 (t, 2H), 1.50-1.57 (m, 2H), 1.10-1.20 (m, 22H), 0.85 (t, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CN(C)c1ccc(C=O)cc1
Product: CN(C)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-dimethylaminobenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N,N-dimethyl-4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]aniline.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1)=[O:2].S(C1C=CC(C)=CC=1)(O[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)(=O)=O>>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:11][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:10][C:7]=2[CH:8]=[O:9])=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(O)c(C=O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCc2ccc(-c3ccccc3)cc2)cc1
Product: O=Cc1ccc(OCCCCCCc2ccc(-c3ccccc3)cc2)c(C=O)c1

Procedure:
4-[6-(biphenyl-4-yl)hexyloxy]-1,3-benzenedicarboxaldehyde (MS: M+NH4+ =400) was prepared from 5-formyl salicylaldehyde and 6-(biphenyl-4-yl)hexyl tosylate at a temperature of 150° C. using the method in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[C:9](=O)([O:13]CC)[O:10][CH2:11][CH3:12]>>[Br:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:1][C:9]([O:10][CH2:11][CH3:12])=[O:13])[CH:7]=1
Reactant: CCOC(=O)OCC
Reactant: Cc1cc(Br)ccn1
Product: CCOC(=O)Cc1cc(Br)ccn1

Procedure:
Scheme 15 illustrates a synthesis of the indolizine-1-carboxylate ring system. In a similar manner to that in the literature (Parrick J, et al. J. Chem. Research (Synopses) 1990; 64-65), 2-methyl-4-bromopyridine may be deprotonated and treated with diethyl carbonate to give ethyl 2-(4-bromopyridin-2-yl)acetate (84). The ester (84) may then be treated with a bromoacetophenone (e.g. 2-bromo-1-(4-methoxyphenyl)ethanone) to give the indolizine ring system (85). The ester may be converted to the carboxaldehyde (86) by methods known to those skilled in the art. The aldehyde may be manipulated to the nitrile (87); and (86) and (87) both further transformed as described hereinabove.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:20])[CH:11]([N:21]3[C:25](=[O:26])[C:24]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]4[C:22]3=[O:31])[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I-].[Na+].Cl[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][N:37]=1>CN(C)C=O>[C:36]1([CH2:35][N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[N:10][CH:11]([N:21]3[C:22](=[O:31])[C:23]4=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]4[C:25]3=[O:26])[C:12]2=[O:20])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][N:37]=1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=NC1N1C(=O)c2ccccc2C1=O
Reactant: ClCc1nccc2ccccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1Cc1nccc2ccccc12
Reaction time: 2 h
Yield: 39.4 %

Procedure:
To a suspension of sodium hydride (0.11 g in a 64% dispersion of mineral oil) in dry N,N-dimethylformamide (20 ml) was added slowly (3RS)-2,3-dihydro-5-phenyl-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.00 g) at ambient temperature, and stirred for 2 hours. To the mixture was added sodium iodide (0.413 g) and followed dropwise a solution of 1-chloromethylisoquinoline (0.695 g) in dry N.N-dimethylformamide (5 ml) at ambient temperature and stirred overnight. The mixture was concentrated in vacuo and the residue was taken up with ethyl acetate. The organic layer was washed with saturated sodium carbonate aqueous solution, and dried over sodium sulfate, filtered and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography with chloroform as an eluent to give (3RS)-2,3-dihydro-1-(isoquinolin-1-yl)methyl-5-phenyl-3-phthalimido-1H-1,4-benzodiazepin-2-one (0.54 g) as a colorless form.
Reaction SMILES: Br[C:2]1[CH:27]=[C:26]([O:28][CH3:29])[C:5]2[NH:6][C:7](=[O:25])[CH:8]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C[C:31]([N:33](C)C)=O>[C-]#N.[Zn+2].[C-]#N.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:31]([C:2]1[CH:27]=[C:26]([O:28][CH3:29])[C:5]2[NH:6][C:7](=[O:25])[CH:8]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1)#[N:33]
Reactant: COc1cc(Br)cc2c1NC(=O)C(NC(=O)OC(C)(C)C)N=C2c1ccccc1
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C#N)cc2c1NC(=O)C(NC(=O)OC(C)(C)C)N=C2c1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
tert-Butyl (7-bromo-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate (0.050 g, 0.109 mmol), zinc cyanide (0.013 g, 0.109 mmol), and Pd(Ph3P)4 (0.013 g, 10.86 μmol) were dissolved in DMA (0.543 ml) and heated to 90° C. After 1 h, the reaction was quenched with saturated NaHCO3. The reaction mixture was extracted three times with EtOAc. The combined organic layers were dried with MgSO4 and evaporated. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give tert-butyl 7-cyano-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate (41 mg, 93%): HPLC RT=1.948 min (H2O/MeOH with TFA, SunFire C18, 5.0 μm, 2.1 mm×30 mm, 4 min gradient, monitored at 220 nm). [M+H+]=407.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[C:21]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=3)=[N:20]2)[CH2:15][CH2:14]1)=[O:12])(=O)C.[OH-].[Na+].Cl>C1COCC1>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([C:21]2[C:22]([CH3:26])([CH3:25])[C:23](=[O:24])[N:19]([CH:16]3[CH2:17][CH2:18][N:13]([C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[OH:4])=[O:12])[CH2:14][CH2:15]3)[N:20]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH3:34]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4OC(C)=O)CC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4O)CC3)C(=O)C2(C)C)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
17 g 2-({4-[3-(3,4-Dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}carbonyl)phenyl acetate (compound described in example 93) are dissolved in 200 ml THF, 200 ml of 2 M methanolic sodium hydroxide solution are added, and the reaction mixture is stirred at RT for 1 h until the reaction is completed according to TLC analysis. The reaction mixture is acidified with concentrated aqueous hydrochloric acid, and the solvents are largely removed under reduced pressure, while the crude product is precipitating. The solids are collected and washed with water to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25].C(N(CC)CC)C>C(#N)C>[C:19]([NH:18][C:10]([NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[N:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[Cl:21])#[N:20]
Reactant: N#CN=C(Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Reactant: NCc1ccccc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#CNC(=NCc1ccccc1Cl)Nc1cc(Cl)cc(Cl)c1
Temperature: 82 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a solution of N-(3,5-dichlorophenyl)-N'-cyano-O-phenylisourea (0.8 mmol, 250 mg) in dry acetonitrile (2 ml), 2-chlorobenzylamine (0.9 mmol, 0.108 ml) and triethylamine (0.125 ml) were added. The mixture was stirred for 21/2 h at 82° C. under nitrogen. After concentration the residue was recrystallized from ethyl acetate to give the title compound (208 mg, 72%). Mp 186-187.5° C.; 1H-NMR (CDCl3): δ 4.54 (d, 2H), 5.53 (br, 1H), 7.15 (m, 2H), 7.3 (m, 3H), 7.4 (m, 2H), 7.75 ppm (br, 1H); EI SP/MS: 394 (M+). MA calc for C15H11C13N4 : C, 50.95%; H, 3.14%; N, 15.84%. Found: C, 50.68%; H, 3.10%; N, 15.49%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[S:5][CH:6]=1.[CH3:17][S-:18].[Na+]>CN(C=O)C.[Cu](I)I>[CH3:17][S:18][C:2]1[N:3]=[C:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[S:5][CH:6]=1
Reactant: O=c1[nH]c2ccccc2n1-c1nc(Br)cs1
Reactant: C[S-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1csc(-n2c(=O)[nH]c3ccccc32)n1
Temperature: 140 °C
Reaction time: 20 h

Procedure:
A mixture of 1-(4-bromo-1,3-thiazol-2-yl)-1,3-dihydro-2H-benzimidazol-2-one from Step A (1.0 g, 3.38 mmol), sodium methanethiolate (710 mg, 10.13 mmol), and copper iodide (643 mg, 3.38 mmol) in DMF (6 mL) were heated at 140° C. An additional amount of sodium methanethiolate (474 mg, 6.76 mmol) was added to the mixture after 3 h and 16 h and the reaction continued stirring at 140° C. After 20 h, the cooled mixture was partitioned between saturated aqueous NaHCO3 (30 mL) and CHCl3 (50 mL). The aqueous phase was extracted further with CHCl3 (50 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=264 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:28][C:29]#[C:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:28]([N:9]1[CH2:8][CH2:7][C:6]([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:20][CH:21]=2)(=[O:15])=[O:14])([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1)[C:29]#[C:30][CH3:31]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(CC#CC)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
A mixture of 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (0.208 g, 0.5 mmol), 1-bromo-2-butyne (0.044 mL 0.53 mmol) and K2CO3 (0.138 g, 1.0 mmol)in 5.0 mL of DMF was stirred at room temperature for 6 h. The reaction was diluted with EtOAc and washed with H2O, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc:hexanes (1:1) to provide 0.183 g (85%) of the desired product as a pale yellow gum. Electrospray Mass Spec: 432.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=[O:4].[C:13]([O:17][C:18](=[O:21])[CH:19]=[CH2:20])([CH3:16])([CH3:15])[CH3:14].N12CCN(CC1)CC2>C(OCC)(=O)C.CCCCCC>[C:13]([O:17][C:18](=[O:21])[C:19](=[CH2:20])[CH:9]([OH:10])[C:8]1[CH:11]=[CH:12][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C1CN2CCN1CC2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C(C(=O)OC(C)(C)C)C(O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 73 %

Procedure:
4-(methoxycarbonyl)benzaldehyde (3.3 g, 20 mM), t-butylacrylate (3.5 ml, 24 mM) and 1,4-diazabicyclo[2,2,2]octane (449 mg, 4 mM) were mixed and stirred in a vessel at room temperature for 5 days. The resulting mixture was extracted with ethyl ether. The organic layer was separated, washed with 2N hydrochloric acid, water and an aqueous sodium bicarbonate solution in order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/19), to obtain 4.1 g of the title compound as a white solid (yield 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2.[Cl:18]N1C(=O)CCC1=O>CC(O)=O>[NH2:1][C:2]1[C:3]([Cl:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2
Reactant: CN1C(=O)NC(=O)C12Cc1ccc(N)cc1C2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CN1C(=O)NC(=O)C12Cc1ccc(N)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(−)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (265 mg, 1.15 mmol, described in Intermediate 47) was dissolved in AcOH (7 mL) and N-chlorosuccinimide (145 mg, 1.09 mmol) was added in one portion. The mixture was stirred at ambient temperature for 5 h, then the solvent was removed in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (70 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2::EtOAc—100:0 to 0:100, to give 5′-amino-4′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, which eluted first, and the title compound, which eluted second. MS: m/z=266 (M+1).
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]#[N:13])=[CH:10][C:4]=2[O:3]1.Br[CH2:16][CH2:17]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:14][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:12]#[N:13])[CH2:17][CH2:16]3)=[CH:10][C:4]=2[O:3]1
Reactant: ClCCBr
Reactant: N#CCc1ccc2c(c1)OC(F)(F)O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: N#CC1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A stock solution of 50% w/w NaOH was degassed via nitrogen sparge for no less than 16 h. An appropriate amount of MTBE was similarly degassed for several hours. To a reactor purged with nitrogen was charged degassed MTBE (143 mL) followed by (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (40.95 g, 207.7 mmol) and tetrabutylammonium bromide (2.25 g, 10.38 mmol). The volume of the mixture was noted and the mixture was degassed via nitrogen sparge for 30 min. Enough degassed MTBE is charged to return the mixture to the original volume prior to degassing. To the stirring mixture at 23.0° C. was charged degassed 50% w/w NaOH (143 mL) over 10 min followed by 1-bromo-2-chloroethane (44.7 g, 311.6 mmol) over 30 min. The reaction was analyzed by HPLC in 1 h intervals for % conversion. Before sampling, stirring was stopped and the phases allowed to separate. The top organic phase was sampled for analysis. When a conversion>99% was observed (typically after 2.5-3 h), the reaction mixture was cooled to 10° C. and was charged with water (461 mL) at such a rate as to maintain a temperature <25° C. The temperature was adjusted to 20-25° C. and the phases separated. Note: sufficient time should be allowed for complete phase separation. The aqueous phase was extracted with MTBE (123 mL), and the combined organic phase was washed with 1 N HCl (163 mL) and 5% NaCl (163 mL). The solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in MTBE was concentrated to 164 mL under vacuum at 40-50° C. The solution was charged with ethanol (256 mL) and again concentrated to 164 mL under vacuum at 50-60° C. Ethanol (256 mL) was charged and the mixture concentrated to 164 mL under vacuum at 50-60° C. The resulting mixture was cooled to 20-25° C. and diluted with ethanol to 266 mL in preparation for the next step. 1H NMR (500 MHz, DMSO) δ 7.43 (d, J=8.4 Hz, 1H), 7.40 (d, J=1.9 Hz, 1H), 7.30 (dd, J=8.4, 1.9 Hz, 1H), 1.75 (m, 2H), 1.53 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])([CH2:8]CCC)[C:6]#[N:7])[CH2:2][CH2:3][CH3:4].C(Br)[Br:21].[OH-].[Na+]>CS(C)=O>[Br:21][CH2:8][C:5]([C:6]#[N:7])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: BrCBr
Reactant: CCCCC(C#N)(CCCC)c1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCC(C#N)(CBr)c1ccccc1OC
Yield: 65.6 %

Procedure:
A 5 liter three neck round bottom flask equipped with mechanical stirrer was charged with 500 grams (2.46 moles, 1.0 ec.) of alpha-n-butyl-alpha-(2-methoxyphenyl) hexanenitrile and 2500 ml of DMSO and 513 grams of CH2Br2 (2.95 moles, 1.20 ec.). To the reaction was added dropwise over 3 hours 394 grams (4.92 moles, 2.0 eq.) of 50% NaOH. Upon addition of the base the reaction exothermed to 55° C. and was maintained at that temperature during the addition and for two hours following the completion of the addition. The reaction was 90% complete and was quenched by the addition of water. The product was isolated with ether and washed with water and brine. Distillation of the crude material gave 478 grams of product (66% yield, 90% pure) as a colorless liquid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Li+].Cl[CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][O:20][C:21](=[O:23])[CH3:22]>CN(C)C=O>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: O=S([O-])c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OCC=C(C)CCl
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)OCC=C(C)CS(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of the sulfinic acid salt (26.0 g.) and 1-chloro-2-methyl-4-acetoxy-but-2-ene (9.75 g.) in 125 ml. of dimethylformamide was heated to 60°C. for 33/4 hours, cooled, poured into 1.21. of water and extracted with ethyl acetate. The extracts were washed with water and brine and dried. Removal of the solvent afforded 18.72 g. of the desired product. Chromatography of a 3.5 g. portion on silica gel gave 3.25 g. of the 1-(p-trifluoromethylphenylsulfonyl)-2-methyl-4-acetoxy-but-2-ene as a colorless oil. Anal. calcd. for C14H15F3O4S: C 50.00, H 4.50, S 9.53; found C 49.77, H 4.68, S 9.71%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[N:4][S:5][N:6]=1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[OH:17][N:16]=[C:7]([C:3]1[C:2]([CH3:1])=[N:6][S:5][N:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: Cc1nsnc1C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nsnc1C(=NO)c1ccccc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a stirred solution of (4-Methyl-[1,2,5]thiadiazol-3-yl)-phenyl-methanone (20 g, 98 mmol) in dry pyridine (70 mL) was added hydroxylamine hydrochloride (17 g, 245 mmol). The reaction mixture was stirred at 70° C. for 3 h, then concentrated in vacuo and diluted with ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with water (2×100 mL) and dried over MgSO4. Evaporation of the solvent in vacuo afforded N-hydroxy-1-(4-methyl-1,2,5-thiadiazol-3-yl)-1-phenylmethanimine as an orange oil [24.3 g, yield 99.6%; HPLC/MS: m/z=220 (M+H); log P(HCOOH)=2.26].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]#[N:25].[CH3:26][S:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].Cl.N1C=CC=CC=1.C(OCCO)C>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][C:3]([C:24]#[N:25])=[C:2]2[NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=1[S:27][CH3:26]
Reactant: CSc1ccccc1N
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCOCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccccc3SC)c(C#N)cnc2cc1OCCCN1CCOCC1

Procedure:
The method of Example 312 was used as well as 0.3 g of 4-chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline-3-carbonitrile, 0.14 ml of 2-(methyl mercapto) aniline, 0.1 g of pyridine hydrochloride and 4.0 ml of 2-ethoxy ethanol. This afforded an oil which was purified by silica gel flash chromatography [methylene chloride/methanol (96:4) ] to give 0.16 g of the title compound as an off white solid, mp 179-180 C; mass spectrum (ES, m/e):M+H465.