Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)#[N:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O.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>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:30]5[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)cc1
Temperature: 110 °C
Yield: 28.3 %

Procedure:
A vial was charged with a slurry of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.256 mmol), (4-cyanophenyl)boronic acid (75 mg, 0.511 mmol), tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 0.026 mmol) and tripotassium phosphate (217 mg, 1.022 mmol) in ethanol (4.0 mL) and water (4.00 mL) then purged with nitrogen and sealed with a standard teflon septa (crimped aluminum seal). The reaction was then heated in an aluminum block at 110° C. for 2 h. The resulting yellow slurry was diluted with ethanol, treated with silica powder (2 g) then evaporated under reduced pressure. The dried powder was placed in a column adaptor (Analogix Dasi adapter) attached to a standard stock silica column (Analogix SF25-40 g) and eluted with ethyl acetate for 10 min and then with 7% methanol in dichloromethane. The combined desired fractions were evaporated to a colorless oil that was crystallized from hexanes/ethyl acetate to afford the title compound as a white solid (30 mg, 28.1%). MS(ES)+ m/e 414.2 [M+H]+.
Reaction SMILES: B(F)(F)F.CCOCC.[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([C:19]2([C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)[CH2:21][O:20]2)[CH:16]=[CH:17][CH:18]=1.[CH3:35][O:36][CH2:37][CH2:38][OH:39]>>[Cl:12][C:13]1[CH:14]=[C:15]([C@:19]([C@@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23]2)([OH:20])[CH2:21][O:39][CH2:38][CH2:37][O:36][CH3:35])[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C2(c3cccc(Cl)c3)CO2)C1
Reactant: COCCO
Agent: FB(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COCCOC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
A stirred solution of BF3.Et2O (12.9 mg, 0.0592 mmol) and NaH (22.6 mg, 0.296 mmol) in 2-methoxyethanol (10 mL) was warmed to 55-60° C. and (3R)-tert-butyl 3-(2-(3-chlorophenyl)oxiran-2-yl)piperidine-1-carboxylate (100 mg, 0.296 mmol) was added dropwise. After addition, the reaction mixture was stirred at the same temperature overnight. The reaction mixture was concentrated and the residue was partitioned between H2O and EtOAc. The organic layer washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. LC-MS analysis of the crude product indicated the presence of two isomers. The crude product was purified by preparative HPLC to give the major isomer (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-2-(2-methoxyethoxy)ethyl)piperidine-1-carboxylate (30 mg, 0.073 mmol); 1H NMR (400 MHz, CDCl3): 1.33 (s, 9H), 1.65 (m, 1H), 1.74 (m, 1H), 1.96 (m, 1H), 2.47 (m, 2H), 3.26 (m, 2H), 3.33 (s, 3H), 3.46 (m, 2H), 3.61 (m, 2H), 3.79 (m, 1H), 3.84 (m, 1H), 3.99 (m, 1H), (m, 1H), 7.22 (m, 3H), 7.42 (s, 1H); MS (E/Z): 414 (M+H+)
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[C:13](=[O:15])[CH3:14].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:31]1([CH2:37][S:38][CH:39]([C:43](O)=[O:44])[C:40](O)=[O:41])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[OH:44][C:43]1[CH:14]=[C:13]([C:4]2[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])[O:15][C:40](=[O:41])[C:39]=1[S:38][CH2:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(C(C)=O)c(OC)c1OC
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)c(OC)c1OC

Procedure:
The title compound was prepared by Method A using 2',3', 4'-trimethoxyacetophenone (1.5 g, 7.13 mmol), lithium bis(trimethylsilyl)amide (1.43 g, 8.56 mmol), chlorotrimethylsilane (1.8 mL, 10.67 mmol) and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol).
Reaction SMILES: [CH3:1][C:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][Si](C)(C)C)=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[C:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][C:2]([CH3:1])([S:21]([CH3:24])(=[O:22])=[O:23])[C:3]([O:5][CH3:6])=[O:4])=[CH:14][CH:13]=1)#[CH:16]
Reactant: COC(=O)C(C)(CCc1ccc(C#C[Si](C)(C)C)cc1)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc(CCC(C)(C(=O)OC)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a stirring solution of methyl 2-methyl-2-(methylsulfonyl)-4-(4-((trimethylsilyl)ethynyl)phenyl)butanoate (9.4, 4.4 g, 12.0 mmol) in methanol (80 mL) was added K2CO3 (100 mg, 0.720 mmol) and the reaction was stirred at room temperature for 3 hr. The reaction mixture was filtered through celite, concentrated under reduced pressure to give a residue, which was dissolved in DCM, filtered and concentrated under reduced pressure to yield methyl 4-(4-ethynylphenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.5, 2.49 g, 70.5%). MS: m/z calcd for C15H18O4S 294.09. found [M+H]+ 295.2.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@H:12]([NH:14][CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]1([N:42]=[C:43]=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:43](=[O:44])[NH:42][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@@H](NCc2ccnc3ccccc23)C[C@@H]1Cc1ccccc1
Reactant: O=C=NC1CCCCC1
Product: O=C(NC1CCCCC1)N(Cc1ccnc2ccccc12)[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1

Procedure:
200 mg (0.396 mmol) of (2S*,4R*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine are reacted with 66 μl (0.515 mmol) of cyclohexyl isocyanate in analogy to Example 16a. The title compound ##STR79## is obtained as white crystals (165 mg, 66%) of melting point 229° C. (decomposition). TLC:methylene chloride/methanol/conc. ammonia (700:50: 1) Rf =0.44, FD-MS:M+ =628, 630.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[O:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].O1CCCC1.Cl>N1C=CC=CC=1>[Cl:22][C:5]1[CH:4]=[C:3]([F:23])[C:2]([NH:1][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][C:6]=1[O:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)COc1ccccc1Oc1cc(N)c(F)cc1Cl
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccccc1Oc1cc(NC(=O)OCC)c(F)cc1Cl
Temperature: 25 °C

Procedure:
Into a mixture of ethyl [2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acetate [Intermediate compound A3-23], ethyl chloroformate and tetrahydrofuran is added dropwise pyridine, and the mixture is stirred at room temperature. Dilute hydrochloric acid is added to the reaction solution, and this is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain ethyl [2-(2-chloro-4-fluoro-5-ethoxycarbonylaminophenoxy)phenoxy]acetate [Intermediate compound A8-23].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:18]([OH:20])=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:18]([O:20][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)OCc2ccccc2)CCc2ccccc21
Reaction time: 0.5 h

Procedure:
To 0.140 mol of 1-[(tert-butyloxycarbonyl)amino]-1-indancarboxylic acid there are added 750 ml of dimethylformamide and then 0.147 mol of caesium carbonate. Stirring is then carried out for 2 hours 30 minutes at ambient temperature and there is then poured in, dropwise, over ½ hour, 0.145 mol of benzyl bromide dissolved in 150 ml of dimethyl-formamide, and stirring is carried out for 20 hours at ambient temperature.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]([C:10]2[N:15]=[C:14](C(O)=O)[C:13]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:12][C:11]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:4]1)[CH3:2]>ClC1C=CC=CC=1Cl>[CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]([C:10]2[C:11]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:12][C:13]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:14][N:15]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2nc(C(=O)O)c(NCc3ccc(OC)cc3)nc2-c2ccccc2)ccc1=O
Solvent: Clc1ccccc1Cl
Product: CCn1nc(-c2ncc(NCc3ccc(OC)cc3)nc2-c2ccccc2)ccc1=O
Yield: 84.9 %

Procedure:
A mixture of 6-(1-ethyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-[(4-methoxybenzyl)amino]-5-phenyl-2-pyrazinecarboxylic acid (1.02 g) in 1,2-dichlorobenzene (20 ml) was refluxed for 3 hours. The mixture was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give 2-ethyl-6-{5-[(4-methoxybenzyl)amino]-3-phenyl-2-pyrazinyl}-3(2H)-pyridazinone as a solid (783 mg).
Reaction SMILES: [C:1]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:32]C(OC(C)(C)C)=O)[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:32][CH:27]([CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:13]2[C:12]3[CH:40]=[CH:41][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[S:15][C:14]2=[O:16])=[CH:25][CH:24]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4 g of the compound obtained in Step C of Example 10 are dissolved in 200 ml of dichloromethane and the temperature is lowered to 0° C. 12.47 ml of trifluoroacetic acid are then added and the reaction mixture is stirred at ambient temperature for 4 hours.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O>[NH2:2][C:3]1[CH:8]=[C:7]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11]
Reactant: Cc1cc(Cl)cc(N)[n+]1[O-]
Reactant: C1COCCN1
Agent: Cl
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(N)[n+]1[O-]
Temperature: 180 °C
Yield: 27 %

Procedure:
A quantity (4.88 g., 0.025 mole) of 2amino-4-chloro-6-methylpyridine-1-oxide hydrochloride (prepared in Part B, Example 1, above) with 20.0 ml. morpholine, and 20.0 ml. water was sealed in a reinforced bottle and heated in an oil bath at the temperature 180° C. for 6 hrs. The aqueous reaction mixture was cooled to 25° C. and then reheated to effect removal of excess morpholine and about one-half the water was removed by evaporation. This concentrate was then diluted with 50 ml. water and extracted with three 50-ml. portions of chloroform. The chloroform extracts were combined, dried over anhydrous sodium sulfate, treated with charcoal, and filtered. The chloroform was removed from the filtrate by evaporation under reduced pressure and the solid residue was triturated with acetone. The insolubles were collected on a filter. Testing via thin layer chromatography showed that there were three components. The components were separated by chromatography on a column of silica gel using a solvent mixture consisting of 1 part methanol and 9 parts methylene chloride. The fractions having the most rapidly moving component were collected and combined. The solvents were removed by evaporation. Chloroformic extraction of the original water-diluted reaction mixture was repeated followed by drying, treating with charcoal, filtration, and removal of chloroform was effected as before. This residue was combined with the residue from the chromatographic separation, and a crystallization and recrystallization from acetonitrile was effected. There was thus obtained 1.40 g. (27% yield) of 2-amino-6-methyl-4-morpholinopyridine-1-oxide as colorless needles having a melting point at 292° C. (with decomposition).
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C:19](=O)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)C>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C:19](=[N:2][OH:3])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(=NO)C1
Yield: 68.5 %

Procedure:
1.87 g of hydroxylamine hydrochloride and 3.3 ml of pyridine were added to a solution of 2.0 g of 1-(t-butoxycarbonyl)-3-pyrrolidone in 9 ml of ethanol, and the mixture was refluxed for 2 hours. The solvent was then distilled off from the reaction mixture, saturated aqueous sodium bicarbonate solution was added to the residue, and it was extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel column, using a 2/1 mixture of benzene and ethyl acetate as eluent, giving 1.482 g of 1-(t-butoxycarbonyl)-3-hydroxyiminopyrrolidine as a mixture of syn- and anti-isomers.
Reaction SMILES: C(N1C(C2SC3CCO[C:15]4C=C(C5CN(C(C)(C)C#N)C5)C=[CH:19][C:16]=4[C:17]=3[N:18]=2)=NC=N1)(C)C.OC(C(F)(F)F)=O.[CH:39]([N:42]1[C:46]([C:47]2[S:48][C:49]3[CH2:50][CH2:51][O:52][C:53]4[CH:60]=[C:59]([CH:61]5[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]5)[CH:58]=[CH:57][C:54]=4[C:55]=3[N:56]=2)=[N:45][CH:44]=[N:43]1)([CH3:41])[CH3:40]>>[CH:39]([N:42]1[C:46]([C:47]2[S:48][C:49]3[CH2:50][CH2:51][O:52][C:53]4[CH:60]=[C:59]([CH:61]5[CH2:66][CH2:65][N:64]([C:16]([CH3:19])([CH3:15])[C:17]#[N:18])[CH2:63][CH2:62]5)[CH:58]=[CH:57][C:54]=4[C:55]=3[N:56]=2)=[N:45][CH:44]=[N:43]1)([CH3:41])[CH3:40]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(C)(C)C#N)C3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(C(C)(C)C#N)CC3)ccc1-2

Procedure:
The title compound was prepared by a similar procedure to 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile using 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt to give 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile isolated as an orange oil (346 mg) as a roughly 1:1 mixture with 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and was used without further purification. LCMS: RT=4.71 min, [M+H]+=463
Reaction SMILES: Cl[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Mg].II.[Cl:13][Si:14](Cl)([CH3:16])[CH3:15]>O1CCCC1.C(OCC)C>[Cl:13][Si:14]([CH3:16])([CH3:15])[C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[CH2:2])=[CH:5][CH:6]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: ClC=Cc1ccccc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=Cc1ccc([Si](C)(C)Cl)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
Two milliliters of chlorostyrene was added to 0.97 gram of magnesium turnings in 20 milliliters (ml) of dry tetrahydrofuran under argon. A crystal, about 5 milligrams of iodine, was then added, and the reaction mixture was heated at 65° C. with an air gun until the reaction started (approximately 15 minutes). Thereafter, an additional 2.33 milliliters of chlorostyrene was added slowly to the reaction mixture with a syringe over a period of 15 minutes. The reaction mixture was then refluxed for about 5 minutes at 67° C., and then allowed to cool to room temperature. Dichlorodimethylsilane (9.7 milliliters) was then carefully added with a syringe, (the reaction was exothermic) followed by stirring at 60° C. in an oil bath for 30 minutes. The reaction mixture was then cooled to room temperature, diluted with anhydrous diethylether (approximately 75 ml), and filtered to remove the insoluble magnesium salts. Subsequently, the solvent tetrahydrofuran was removed under reduced pressure and the resulting oil was distilled to yield 3.9 grams (55 percent) of the above product, which was characterized by NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[CH2:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:30][CH2:29][C:28]2[C:31]3[CH:21]1[CH2:22][CH2:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)[CH3:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[ClH:11].[CH2:14]([N:16]([CH2:17][CH2:18][CH2:19][N:20]1[CH2:30][CH2:29][C:28]2[C:31]3[CH:21]1[CH2:22][CH2:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:15]
Reactant: CCNCCCN1CCc2cccc3c2C1CC3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CCCN1CCc2cccc3c2C1CC3)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
4-Methylbenzenesulfonyl chloride (20.9 mg, 0.11 mmol) was added to a solution of Ethyl-[3-(2,2a,4,5-tetrahydro-1H-3-aza-acenaphthyl en-3-yl)-propyl]-amine dihydrochloride (31.7 mg, 0.1 mmol) and N,N′-diisopropylethylamine (64.6 mg, 0.5 mmol) in CH2Cl2 (10 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 mL), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (18.0 mg, 41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][C:12](=[O:21])[CH2:13]4.C([O-])([O-])=O.[K+].[K+].[N:28]#CBr>C(Cl)(Cl)Cl>[C:20]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@@H:9]2[CH2:10][CH2:11][C:12](=[O:21])[CH2:13]3)#[N:28]
Reactant: N#CBr
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@@H]1CCC(=O)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@@H]1CCC(=O)C3

Procedure:
An 8.4 g sample of 3-methoxy-17-methylmorphinan-6-one (prepared as in Part 6A) in 85 ml of chloroform containing 6.09 g of dry K2CO3 was reacted with 3.8 g of cyanogen bromide and the product isolated as described in Example 1B. The product was crystallized from ethanol; yield 6.96 g (80%), mp 211°-214° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl[C:13]([O:15][CH3:16])=[O:14].CC(N(C)C)=O>O1CCOCC1>[C:13]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cl
Reactant: NCc1ccc(C(=O)O)cc1
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COC(=O)NCc1ccc(C(=O)O)cc1
Temperature: 65 °C

Procedure:
To suspension of the 4-aminomethylbenzoic acid (10 g, 66.2 mmol) in 1,4-dioxane (100 mL) were added methyl chloroformate (5.4 mL, 69.5 mmol) and dimethyl acetamide (3.4 mL). The reaction mixture was then heated to 65° C. overnight. Reaction mixture was evaporated to dryness and the residue was triturated with water. The solids were filtered and dried to give pure product as white solid. 1H NMR (600 MHz, DMSO) δ 12.84 (bs, 1H), 7.85 (d, J=7.8 Hz, 2H), 7.73 (t, J=6 Hz, 1H), 7.32 (d, J=7.8 Hz, 2H), 4.20 (bd, J=6 Hz, 2H), 3.52 (s, 3H); MS: (MH+), (MH+).
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[N:12]([CH2:15][C:16](OCC)=[O:17])=[C:13]=[O:14]>C(Cl)Cl>[O:14]=[C:13]1[NH:12][CH2:15][C:16](=[O:17])[N:10]1[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:2])=[O:11]
Reactant: CCOC(=O)CN=C=O
Reactant: COC(=O)c1cccc(N)c1
Solvent: ClCCl
Product: O=C(O)c1cccc(N2C(=O)CNC2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13 mmol of methyl-3-aminobenzoate were dissolved in 20 ml DCM and 1.7 ml of ethyl isocyanatoacetate added. The reaction mixture was stirred at rt for 1 h. The solvent was evaporated and the resulting crude taken up in 50 ml acetone. 50 ml of aq. HCl (25%) were added and heated to reflux for 8 h. After evaporation of the organic layer the resulting solid was filtered off, washed with water and dried under vacuum. MS(ISO): 219.2 (M−H+)
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][N:7]=1)=O.[CH3:15][C:16]([S@@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(Cl)Cl>[C:16]([S@@:19](/[N:21]=[CH:1]/[C:3]1[S:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][N:7]=1)=[O:20])([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(C)(C)OC(=O)c1cnc(C=O)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)c1cnc(/C=N/[S@@](=O)C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of tert-butyl 2-formylthiazole-5-carboxylate (15.7 g, 74 mmol) and (S)-2-methylpropane-2-sulfinamide (10.7 g, 88 mmol) in DCM (750 mL) at 0° C. was added cesium carbonate (48.2 g, 148 mmol). The mixture was warmed to rt and stirred for 8 h. To the solution was added water (200 mL). After separation, the aqueous phase was extracted with DCM (3×200 mL). The combined organic phases were dried (Na2SO4), and concentrated. Flash column chromatography (petroleum ether:EtOAc, 100:1 to 10:1) afforded (S,E)-tert-butyl 2-((tert-butylsulfinylimino)methyl)thiazole-5-carboxylate (18.9 g, 81%). 1H NMR (CDCl3, 400 MHz) δ 8.67 (s, 1H), 8.39 (s, 1H), 1.52 (s, 9H), 1.22 (s, 9H).