Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>CC(=O)CCC>[S:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)([C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC(C)=O
Product: COC(=O)c1ccc2ccn(S(=O)(=O)c3ccc(C)cc3)c2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
To a solution of methyl indole-6-carboxylate (2.1 g) of 2-pentanone (40 mL), potassium carbonate (6.5 g) and 4-methylbenzenesulfonyl chloride (4.4 g) were added at room temperature, and then the reaction mixture was stirred at 80° C. for 16 hours. After cooling to room temperature, the insoluble materials were filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, a mixed solvent of ethyl acetate-hexane was added, and the obtained solid was filtered, and washed with hexane to give the titled compound (3.6 g) as a white solid.
Reaction SMILES: Br[CH:2]([CH:7](Br)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[C:3]([O:5][CH3:6])=[O:4].[OH-].[K+].[CH2:27](O)C>>[N:21]1[CH:22]=[CH:23][C:18]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([C:7]#[C:2][C:3]([O:5][CH2:6][CH3:27])=[O:4])[CH:9]=3)[N:14]=[CH:13][CH:12]=2)=[CH:19][CH:20]=1
Reactant: CCO
Reactant: COC(=O)C(Br)C(Br)c1ccc2nccc(-c3ccncc3)c2c1
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C#Cc1ccc2nccc(-c3ccncc3)c2c1
Temperature: 95 °C
Yield: 60 %

Procedure:
A slurry of methyl 2,3-dibromo-3-[4-(4-pyridinyl)-6-quinolinyl]propanoate (4.20 g, 9.33 mmol) in ethanol (120 ml) was treated with solid potassium hydroxide pellets in one portion then heated at 95° C. for 2 hours. The reaction was cooled to room temperature then evaporated under reduced pressure. The resulting residue was diluted with ethanol (90 ml) and concentrated H2SO4 (3 ml) then heated at 95° C. for 3.5 hours. Cooled to room temperature then concentrated under reduced pressure. The resulting wet residue was taken into a minimum of water then made neutral with the addition of saturated aqueous NaHCO3 solution. This solution was extracted with EtOAc and the extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc) to give the title compound (1.68 g, 60%) as a pale yellow solid. MS(ES)+ m/e 303 [M+H]+.
Reaction SMILES: BrC([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)C.[C:18]([O:24]CC)(=[O:23])[CH2:19][C:20]([CH3:22])=O.[OH-].[K+].Cl>O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([CH:20]([CH3:22])[CH2:19][C:18]([OH:24])=[O:23])=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(Br)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of 2-[1-(2',4'-difluoro-4-biphenylyl)ethyl]-butan-3-one acid ethyl ester, obtained by reacting 4-(1-bromoethyl)-2',4'-difluorobiphenyl with ethyl acetoacetate, and 15 ml. of 50% KOH are stirred for 45 minutes at 90° under N2. The mixture is cooled, diluted with water and brought to pH 10 with HCl. The reaction mixture is washed with ether and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: C(OCCNC(C(N)=S)=S)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].OCC[NH:26][C:27]([C:29]([NH2:31])=[S:30])=[S:28].C(Cl)(=O)CCCCCCCCCCC.C(OCCNC(C(N)=S)=S)(=O)CCCCCCCCC.C(Cl)(=O)CCCCCCCCC>>[C:3]1([CH2:2][NH:26][C:27]([C:29]([NH2:31])=[S:30])=[S:28])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: NC(=S)C(=S)NCCO
Reactant: CCCCCCCCCCCC(=O)OCCNC(=S)C(N)=S
Agent: CCCCCCCCCC(=O)Cl
Agent: CCCCCCCCCC(=O)OCCNC(=S)C(N)=S
Agent: CCCCCCCCCCCC(=O)Cl
Product: NC(=S)C(=S)NCc1cccc2ccccc12

Procedure:
Using the general procedure outlined in Experiment 2, N-(2-dodecanoyloxyethyl)dithiooxamide was synthesized from N-(2-hydroxyethyl)dithiooxamide and dodecanoyl chloride, and N-(2-decanoyloxyethyl)dithiooxamide was synthesized from N-(2-hydroxyethyl)dithiooxamide and decanoyl chloride.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[Si](C)(C)[N:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[C:57]([O:59][Si](C)(C)C)=[O:58]>C1COCC1.C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([N:52]3[CH2:56][CH2:55][CH2:54][C@H:53]3[C:57]([OH:59])=[O:58])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)OC(=O)[C@@H]1CCCN1[Si](C)(C)C
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)N3CCC[C@H]3C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (15 mg, 0.044 mmol), TEA (0.019 mL, 0.133 mmol), and HATU (25.4 mg, 0.067 mmol) in THF (0.5 mL) and DCM (0.500 mL) was added (S)-trimethylsilyl 1-(trimethylsilyl)pyrrolidine-2-carboxylate (23.07 mg, 0.089 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue purified by HPLC to give the title compound. LCMS m/z=435.4 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:21])[C:18](O)=[O:19])[CH:11]=[CH:10]2>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:21])[C:18]([Cl:3])=[O:19])[CH:11]=[CH:10]2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc(C(C)C(=O)Cl)ccc2c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
7 ml of thionyl chloride were cautiously added to a solution of 2.3 g of 2-(6-methoxy-2-naphtyl)propionic acid in 15 ml of anhydrous chloroform. The reaction mixture was stirred for 40 minutes at room temperature and then the solvent was evaporated at a reduced pressure, obtaining 2.23 g of 2-(6-methoxy-2-naphtyl)propionylchloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([S:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:41])=[O:40])[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(S(=O)(=O)c3ccccc3)CC2)cc1
Reaction time: 20 h
Yield: 71.8 %

Procedure:
A solution of N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (41 mg, 0.12 mmol) and pyridine (0.05 mL) in methylene chloride (3 mL) was treated with benzenesulfonyl chloride (0.014 mL, 0.11 mmol). After 20 h, the mixture was treated with silica gel (3 cm3) and concentrated in vacuo. The residue was chromatographed (silica gel, 50% hexanes/50% ethyl acetate to 30% hexanes/70% ethyl acetate). Recrystallization of the residue from hexanes/ethyl acetate yielded 39 mg (68%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>>[Cl-:17].[CH2:1]([NH+:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCCN1Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: ClCC1CCC[NH+]1Cc1ccccc1
Product: [Cl-]
Temperature: 35 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
(1-benzylpyrrolidin-2-yl)methanol was slowly added to thionyl chloride (45 eq) and the resulting mixture was stirred for 15 h at 35° C. All the volatiles were removed in vacuo. The yellow oil residue was treated with Et2O and re-evaporated to drive off excess thionyl chloride. The crude material was then dried at the high vacuum pump for 2 h to afford the product (100%). 1H NMR (400 MHz, CDCl3) 1.85-2.01 (m, 1H), 2.15-2.32 (m, 3H), 2.85-3.05 (m, 1H), 3.43-3.54 (m, 1H), 3.65-3.79 (m, 1H), 3.92-4.02 (m, 2H), 4.20-4.22 (m, 1H), 4.41-4.43 (m, 1H), 7.44-7.62 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.O.[C:15]([OH:19])(=[O:18])[CH:16]=[O:17]>CCOC(C)=O>[OH:17][CH:16]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[C:15]([OH:19])=[O:18]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: O=CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCC(C(O)C(=O)O)C2=O
Temperature: 120 °C
Yield: 29.8 %

Procedure:
A mixture of 6-methoxy-1-tetralone (20 g, 114 mmol) and glyoxylic acid monohydrate (10.5 g, 114 mmol) was heated at 120° C. in a melt for 5 min. After slight cooling, EtOAc (100 mL) was carefully added. The solid which precipitated was collected to afford 8.5 g (30%) of hydroxyl-(6-methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-acetic acid; Mp 212-214° C., MS m/z 251 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:15][CH2:16][CH3:17])[CH2:7][C:6]=2[N:18]=1.[C:19]([Cl:27])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[ClH:27].[ClH:27].[C:19]([NH:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:15][CH2:16][CH3:17])[CH2:7][C:6]=2[N:18]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCN1CCC[C@H]2Cc3nc(N)ncc3C[C@@H]21
Solvent: c1ccncc1
Product: CCCN1CCC[C@H]2Cc3nc(NC(=O)c4ccccc4)ncc3C[C@@H]21
Product: Cl

Procedure:
Following the above procedure, trans-(±)-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline was reacted with benzoyl chloride in pyridine solution. The residue obtained after working up the reaction mixture as indicated above was chromatographed over florisil using chloroform with increasing amounts (0-10%) of methanol as the eluant. Fraction ten contained the desired 2-benzoylamino compound (by TLC). The solvent was removed therefrom in vacuo. The resulting residue was dissolved in ethanol and gaseous hydrogen chloride passed into the ethanol solution. Addition of ether to the point of incipient precipitation yielded trans-(±)-2-benzoylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline dihydrochloride; molecular ion at 350.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[CH:41]=2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[CH:41]=2)[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(2-methoxy-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J32) (263 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (351 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>>[CH2:21]([N:13]1[C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][S:16][C:12]1=[N:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1CC(C)C

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(OC(=O)C)(=O)C.O>ClCCl>[N:23]1[CH:24]=[CH:25][C:20]([CH:19]=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(OCc2ccc(C=O)cc2)cc1
Reactant: Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(OCc2ccc(C=Cc3ccncc3)cc2)cc1
Yield: 48.8 %

Procedure:
A solution of 9.8 g (40 mmol) 4-(4-formylphenylmethoxy)-benzonitrile, 4 ml (40 mmol) 4-methylpyridine and 4 ml acetic acid anhydride is heated to 120° C. for 18 h. One mixes with water, extracts with dichloromethane, dries the extract, evaporates and triturates with ether. One isolates 6.1 g of title compound (49% of theory) of the m.p. 149°-150° C.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:13]Br.Cl>C(Cl)(Cl)Cl>[Br:13][C:7]1[CH:8]=[C:4]([C:1](=[O:3])[CH3:2])[S:5][CH:6]=1
Reactant: CC(=O)c1cccs1
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(Br)cs1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
2-Acetylthiophene (21.6 ml, 0.20 mol) was dissolved in 200 ml CHCl3 at 0° C. AlCl3 (40 g, 0.30 mol) was added in small portions at such a rate as to maintain the temperature at 5-10° C. The reaction mixture was then cooled to 0° C. and bromine, Br2 (11.34 ml, 0.22 mol) was added quickly. The reaction mixture was refluxed for two hours, then was allowed to cool and was poured into a mixture of 400 ml ice water and 50 ml concentrated HCl and stirred for 30 minutes. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum. The crude product was distilled under vacuum to yield pure 4-bromo-2-acetylthiophene (27.6 g, 67%). MS (M−H)−: 204.85; 1H NMR (300 MHz, CDCl3) δ7.58 (1H, d, J=1.3 Hz), 7.53 (1H, d, J=1.3 Hz), 2.55 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=2)[C:22]#[N:23])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]12[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([O-])=O.O.O.[Sn](Cl)Cl.CCOCC>C(O)(=O)C.Cl>[NH2:1][C:4]1[CH:5]=[C:6]([C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=2)[C:22]#[N:23])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]12[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: N#Cc1cc(F)cc(-c2cc([N+](=O)[O-])c3c(c2)C2(CCCCC2)C(=O)N3)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: N#Cc1cc(F)cc(-c2cc(N)c3c(c2)C2(CCCCC2)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a solution of 3-(7′-nitro-1′,2′-dihydro-2′-oxospiro-[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile (1.0 eq, 0. 16 g, 0.4 mmol) in glacial acetic acid (4 mL) at room temperature was added a solution of tin (II) chloride dihydrate (0.25 g, 1.1 mmol) in hydrochloric acid (2 mL). The yellow mixture was boiled for 30 min at which point the yellow color disappeared. After cooling to room temperature, 1N HCl (10 mL) and ether (20 mL) were added. The layers were separated and the aqueous phase was extracted with ether (2×20 mL). The organic layers were combined, washed sequentially with water (2×20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 40% EtOAc/hexane) to give the title compound (70 mg, 50%) as an oil which crystallized upon addition of 10% EtOAc/hexanes; mp 241-3° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.50-1.75 (m, 8H), 1.82-1.95 (m, 2H), 4.98 (s, 2H), 6.90 (d, 1H, J=1.8 Hz), 7.09 (d, 1H, J=1.5 Hz), 7.75 (m, 2H), 7.90 (‘s’, 1H), 9.96 (bs, 1H). MS ((+)-APCI) m/z 336 [(M+H)+]. Anal. Calcd for C20H18FN3O: C, 71.63; H, 5.41; N, 12.18. Found: C, 71.16; H, 5.58; N, 12.18.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH3:44])=[C:38]([O:45][CH2:46][CH3:47])[CH:37]=3)[S:34][CH:35]=2)=[CH:27][CH:26]=1)(=O)C.C[O-].[Na+]>CO.ClCCl>[C@@H:6]1([O:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[N:32]=[C:33]([C:36]4[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH3:44])=[C:38]([O:45][CH2:46][CH3:47])[CH:37]=4)[S:34][CH:35]=3)=[CH:29][CH:30]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CCOc1ccc(-c2nc(-c3ccc(O[C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)cc3)cs2)cc1OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccc(-c2nc(-c3ccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)cc3)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
In 6 ml of a methanol-dichloromethane (2:1) mixed solvent was suspended 0.15 g of 4-[4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)phenyl]-2-(3,4-diethoxyphenyl)thiazole. Thereto was added a catalytic amount of sodium methylate. The mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation. The residue was recrystallized from methanol to obtain 71 mg of 4-[4-(β-D-glucopyranosyloxy)-phenyl]-2-(3,4-diethoxyphenyl)thiazole.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([NH:11][C:12]2[NH:13][CH2:14][CH2:15][N:16]=2)[CH:3]=1.[Br:17]Br.N.CO.CCOC(C)=O>CC(O)=O>[Br:17][C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[C:2]([Br:1])=[CH:3][C:4]=1[NH:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1
Reactant: BrBr
Reactant: Brc1cc(NC2=NCCN2)cc2[nH]cnc12
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: Brc1cc(NC2=NCCN2)c(Br)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.4 %

Procedure:
To a solution of 7-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (0.6 g, 2.1 mmol) in 10 ml of AcOH was added Br2 (0.057 ml, 1.1 mmol) in a portion. The resulting reaction mixture was stirred for 1 h at 25° C. Concentration of reaction mixture in vacuo yields a brown oil which was subjected to column chromatography (30% NH3 sat'd MeOH/EtOAc) to provides 0.28 g (1.5 mmol, 71%) of the desired product. The product obtained was recrystallized from MeOH to afford 0.22 g (56%) of the product as a light brown solid: mp 320-321° C.; Anal. Calc. for C10H9N5Br2 requires C, 33.45; H, 2.53; N, 19.51. Found: C, 33.93; H, 4.05; N, 19.01.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH:4]([C:6]1([OH:18])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5].[CH3:20][I:21]>CCOCC.O1CCCC1>[I-:21].[OH:18][C:6]1([CH:4]([CH3:5])[CH2:3][N+:2]([CH3:20])([CH3:1])[CH3:19])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CI
Reactant: CC(CN(C)C)C1(O)CCCCC1c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C[N+](C)(C)C)C1(O)CCCCC1c1ccccc1
Product: [I-]
Reaction time: 168 h

Procedure:
A solution of 3.5 grams of 1-(2-dimethylamino-1-methylethyl)-2-phenyl-cyclohexanol in 250 ml ether and 10 ml tetrahydrofuran is treated with 6 ml methyl iodide and allowed to stand for 7 days. The crystalline product is filtered and washed with ether and recrystallized from water giving 2.1 grams melting at 155°-159°C.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:15]1[C:14]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17]
Reactant: Clc1cccc(CBr)c1
Reactant: Cc1ccc2c(c1)OC(CCO[Si](C)(C)C(C)(C)C)C(=O)N2
Product: Cc1ccc2c(c1)OC(CCO)C(=O)N2Cc1cccc(Cl)c1
Yield: 76 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-7-methyl-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 3-chlorobenzyl bromide, in 76% yield as a white solid after crystallization from ether/hexane, mp 72°-74° C.; IR (KBr) 3418, 1679, 1512, 1402, 1292, 1061, 763 cm-1 ; 1H NMR (CDCl3) δ 2.20-2.36 (m, 3H), 2.27 (s, 3H), 3.92 (q, J=5.6 Hz, 2H), 4.83 (dd, J=7.6, 5.5 Hz, 1H), 5.10 (ABq, JAB =17.0 Hz, 2H), 6.68-6.75 (m, 2H), 6.84 (s, 1H), 7.10-7.14 (m, 1H), 7.22-7.29 (m, 3H); MH+ at m/z=332; Anal. Calc'd for C18 H18ClNO3.0.2H2O: C, 64.46; H, 5.53; N, 4.18. Found: C, 64.48; H, 5.51; N, 4.06.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([NH:15]C(OC(C)(C)C)=O)=[CH:13][C:12]([S:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[C:11]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:10]=1)=O)(C)(C)C.Cl>C(Cl)Cl>[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][C:12]([S:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[C:11]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc2C(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Sc2cc(N)c(N)cc2C(C)(C)C)cc1

Procedure:
The title compound was prepared as described in Example VV-1 from toluene-4-thiosulfonic acid S-(4,5-bis-tert-butoxycarbonylamino-2-tert-butyl-phenyl)ester (prepared in Example UU-2; 15 g, 28 mmol), CH2Cl2 (100 mL), and HCl gas. MS(APCI): 351 (M+H).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[NH2:38])=[CH:31][CH:30]=1)[CH3:21]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([N:35]2[C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[NH:38][C:9]2=[O:11])=[CH:31][CH:30]=1)[CH3:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)N)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccc(N2C(=O)NC(C)(C)C2=O)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 171.7 %

Procedure:
In a 50 mL round-bottomed flask N-{6-[(2-ethylphenyl)oxy]-3-pyridinyl}-2-methylalaninamide (Intermediate 78, 67.1 mg) was dissolved in dichloromethane (5 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. N,N-dimethyl-4-pyridinamine (13.28 mg, 0.109 mmol), triethylamine (0.076 mL, 0.544 mmol) and triphosgene (32.3 mg, 0.109 mmol) were added. The reaction mixture was stirred at 0° C. After 20 minutes, the reaction mixture was evaporated under vacuum to afford a yellow solid which was purified by silica gel chromatography (Biotage system, 10 g SNAP column) eluting with a gradient Cyclohexane/EtOAc from 2:1 to 1:3 in 20 CV; then 1:3 for 5 CV. The collected fractions afforded the title compound as a white solid (60.9 mg).