Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:12]=[C:11]([C:13]([O-])=[O:14])[CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8])#[N:2].[Cl-].[Cl-].[Ca+2].[BH4-].[Na+].Cl>CCO.C1COCC1>[OH:14][CH2:13][C:11]1[CH:10]=[CH:9][C:6]2[C:7]([CH3:8])=[C:3]([C:1]#[N:2])[O:4][C:5]=2[CH:12]=1
Reactant: Cc1c(C#N)oc2cc(C(=O)[O-])ccc12
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C#N)oc2cc(CO)ccc12
Temperature: 0 °C
Yield: 49.6 %

Procedure:
2-Cyano-3-methylbenzofuran-6-carboxylate (540 mg, 2.51 mmol) was dissolved in 17 mL of EtOH, and CaCl2 (557 mg, 5.02 mmol) was added and the mixture was briefly stirred in the ultrasound bath. Then the mixture was cooled to 0° C. and a solution of NaBH4 (380 mg, 10.04 mmol) in 17 mL of THF was added. The mixture was stirred at 0° C. for 1.5 hr, and then 1N HCl was carefully added. The organic layer was separated, and the aqueous phase was extracted with DCM (4×7 mL), the combined organic phases were dried over Na2SO4, filtered off and evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography 100% DCM-7% MeOH/93% DCM to give 6-(hydroxymethyl)-3-methylbenzofuran-2-carbonitrile (233 mg). 1H NMR (400 MHz, DMSO-d6) δ 2.44 (s, 3H), 4.65 (d, J=5.8 Hz, 2H), 5.42 (t, J=5.8 Hz, 1H), 7.35-7.42 (m, 1H), 7.60 (s, 1H), 7.77 (d, J=8.2 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.C(=O)(O)[O-:19].[Na+].ClC1C=CC=C(C(OO)=O)C=1>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)=[O:19]
Reactant: O=C([O-])O
Reactant: c1cnc(Sc2cccc3cccnc23)nc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(c1ncccn1)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5 ml. of tetrahydrofuran containing 170 mg. (0.71 m mole) of 8-(2-pyrimidylthio)quinoline was added 300 mg. of sodium bicarbonate and the mixture cooled to 0° C. m-Chloroperbenzoic acid (153 mg., 1.0 eg) in 5 ml. of the same solvent was added dropwise. After the addition was complete the reaction was allowed to warm to 25° C. and was stirred overnight. The reaction mixture was poured into a sodium bicarbonate solution and the product extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was triturated with a small amount of ethyl acetate and filtered, 84 mg., m.p. 152°-155° C.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10]O)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:7][CH:6]1[I:18])[CH2:2][CH2:3][CH3:4].O=S(Cl)Cl.C(N1C(C[N:33](CC2C=CC3OCCOC=3C=2)[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:42][CH3:43])[CH:36]=2)=C(Cl)N=C1N1CCOCC1)CCC.C(ONCC1C=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:5]1[C:9]([CH2:10][NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:42][CH3:43])[CH:36]=2)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:7][CH:6]1[I:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(N2CCOCC2)nc(Cl)c1CN(Cc1cccc(OCC)c1)Cc1ccc2c(c1)OCCO2
Reactant: CCCCN1C(CO)=C(c2ccccc2)NC1I
Agent: CCONCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCN1C(CNCc2cccc(OCC)c2)=C(c2ccccc2)NC1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(1-Butyl-2-iodo-4-phenyl-3H-imidazol-5-yl)-methanol (1.96 g), prepared by the method given in Example 2, step 2, is dissolved in 20 mL CH2Cl2. The solution is cooled to 0° C. and 3 equivalents of SOCl2 are added. The resulting solution is stirred at room temperature for 2 hours and then evaporated to dryness. The residue is dissolved in 5 mL of DMF and added to an ice cooled solution of 2 equivalents of 3 ethoxybenzylamine and 2 equivalents K2CO3 in 10 mL DMF. The mixture is stirred overnight at room temperature. The reaction is quenched with 20 mL water, extracted with EtOAc (3×30 mL), washed with water and brine, and dried over Na2SO4. Concentration and purification via silica gel chromatography provides (1-Butyl-2-iodo-4-phenyl-3H-imidazol-5-ylmethyl)-(3-ethoxy-benzyl)-amine.
Reaction SMILES: [Cl-].C(CC[N+:7]1[CH:12]=[CH:11][C:10](C#N)=[CH:9][CH:8]=1)(=O)N.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH-].[Na+].[OH-].[Na+]>O>[N:15]1([C:10]2[CH:9]=[CH:8][N:7]=[CH:12][CH:11]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#Cc1cc[n+](CCC(N)=O)cc1
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(N2CCCC2)ccn1

Procedure:
A solution of 1-(2-carbamoylethyl)-4-cyanopyridinium chloride (21.2 g; 0.1 mole) dissolved in 15 ml of deionized water was prepared and charged to the dropping funnel. This solution was then added to the pyrrolidine/sodium hydroxide solution at a rate which permitted maintenance of the reaction temperature with stirring at below 5° C. It was held there for an additional hour, after which 14 g (0.175 mole) of a 50% (w/w) sodium hydroxide solution was added dropwise with continued maintenance of the reaction temperature below 5° C. (approximately 45 minutes). The mixture was then heated to reflux and maintained for two hours and then allowed to cool.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[C@@H:14]([CH:15]2[CH2:17][CH2:16]2)[CH:13]([C:18]([O:20]CC)=[O:19])[O:12][CH:11]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O>[C:3]([O:7][C:8]([N:10]1[C@@H:14]([CH:15]2[CH2:17][CH2:16]2)[CH:13]([C:18]([OH:20])=[O:19])[O:12][CH:11]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(=O)C1OC(c2ccc(OC)cc2)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C2OC(C(=O)O)[C@H](C3CC3)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 125.5 %

Procedure:
(1)Ethyl (45, 5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate (diastereomeric mixture) obtained in Example 6(1) is purified by column chromatography to give ethyl (4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate. A 87 mg of lithium hydroxide is added under ice-cooling to a solution of 1.03 g of ethyl (4S,SR)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate in a mixture of 20 ml of methanol and 10 ml of water. The mixture is stirred at room temperature for 30 minutes. The reaction n-tixture is evaporated under reduced pressure to remove methanol. The pH of the solution of the residue in ethyl acetate is adjusted to pH 2 with 1N hydrochloric acid under ice-cooling. After the mixture is extracted with ethyl acetate, the extract is washed with brine, dried and evaporated to remove the solvent to give 1.20 g of (4S,SR)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylic acid quantitatively.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(OC(=O)c2ccc(N)cc2)cc1
Yield: 100 %

Procedure:
11.0 g of 4-nitrophenyl 4-nitrobenzoate (38.2 mM) were dissolved in 350 ml of ethyl acetate and 1.0 g of palladium on charcoal (10%) was added. The resulting mixture was hydrogenated at atmospheric pressure until the theoretical amount of hydrogen was consumed. The mixture was then filtered, the cake was washed with ethyl acetate and the filtrate was evaporated to dryness to give 8.71 g (38.2 mM, 99%) of 4-aminophenyl 4-aminobenzoate as slightly beige crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCC(Nc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine (3-aminophenyl)carbamic acid tert-butyl ester (0.156 g, 0.756 mmol), 1-methylpiperidin-4-one (0.093 mL, 0.756 mmol), sodium triacetoxyborohydride (208 mg, 0.982 mmol), acetic acid (0.043 mL, 0.756 mmol) and dichloromethane (8 mL). Stir at room temperature overnight. Dilute with dichloromethane (5 mL) and wash twice with sodium hydroxide (10 mL 1N aq.). Combine the organic layers and wash with saturated aqueous NaCl (10 mL). Dry over magnesium sulfate, filter under reduced pressure and concentrate to dryness. Purify by flash chromatography on a Biotage® silica cartridge eluting with a 20/1 mixture of dichloromethane and 2N ammonia in methanol to give the free base of the title compound. Dissolve the residue in diethyl ether and treat with ethereal hydrogen chloride. Triturate the resulting gum with ether to give the title compound as a white solid: mp 124-5° C.; mass spectrum (ion spray): m/z=306.2 (M+1), 1H NMR (CDCl3): 7.06 (t, J=8.0 Hz, 1H), 6.86 (bs, 1H), 6.51-6.48 (m, 1H), 6.42 (bs, 1H), 6.30-6.27 (m, 1H), 3.60 (bs, 1H), 3.30 (bs, 1H), 2.80 (bd, J=11.8 Hz, 2H), 2.31 (s, 3H), 2.19-2.02 (m, 4H), 1.89 (bs, 2H), 1.52 (s, 9H).
Reaction SMILES: ClC(OCC)=O.[NH2:7][C:8]1[CH:9]=[C:10]([C:15](=[O:21])[CH2:16][CH2:17][C:18](O)=[O:19])[CH:11]=[CH:12][C:13]=1[Cl:14].[CH2:22]([N:24](CC)CC)C.CN>O1CCCC1>[NH2:7][C:8]1[CH:9]=[C:10]([C:15]2([OH:21])[N:24]([CH3:22])[C:18](=[O:19])[CH2:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: Nc1cc(C(=O)CCC(=O)O)ccc1Cl
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Product: CN1C(=O)CCC1(O)c1ccc(Cl)c(N)c1
Reaction time: 0.17 h

Procedure:
42.8 g of ethyl chloroformate are metered into a solution of 60 g of 4-(3-amino-4-chlorophenyl)-4-oxobutyric acid and 27.8 g of triethylamine in 500 ml of tetrahydrofuran in such a way that the temperature does not exceed 10° C. The mixture is stirred in the icebath for a further 10 min and then, while maintaining the cooling, a solution of 35 g of gaseous methylamine in 250 ml of tetrahydrofuran is added, during which a temperature of 25° C. should not be exceeded. After stirring for a further 45 minutes in the icebath, the solvent is removed by distillation, water is added to the residue, and the crystalline precipitate is filtered off. Crystals of melting point 154° C. (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][C:18]([N:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:24])=[O:20])[C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=2)=[O:7])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CNC
Reactant: COc1ccc(N(CC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)CN(C)C(=O)CN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(p-anisidino) acetic acid and ethyl sarcosinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]sarcosinate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]sarcosine (M.P. 146° to 148°).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[Cl:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[CH:19]=[CH:18][N:17]=1
Reactant: Clc1cc(I)ccn1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccnc(Cl)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
A mixture of 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol), 2-chloro-4-iodopyridine (172 mg, 0.72 mmol), triethylamine (209 μl, 1.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (13 mg, 0.02 mmol) in N,N-dimethylformamide (1.2 mL) was evaporated and flushed with argon. Cuprous iodide (2 mg, 0.01 mmol) was added and the reaction mixture was stirred for 1.5 h at 90° C. before it was cooled to ambient temperature and separated between aqueous sodium hydroxide (1 M, 20 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL) and the combined organic layers were washed with aqueous sodium hydroxide (1 M, 20 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (160 mg, 91%) as a colorless oil. MS: m/e=295.0/297.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1([CH3:22])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[C:6]([Cl:20])[C:7]([Cl:19])=[C:8]([OH:18])[CH:9]=2)[C:4]1=[O:21])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33]CC)=[O:32].[OH-].[Na+].Cl>CN(C)C=O.O>[O:21]=[C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:18][CH2:30][C:31]([OH:33])=[O:32])=[C:7]([Cl:19])[C:6]=2[Cl:20])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]1([CH2:1][CH3:2])[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CCC1(C)C(=O)c2c(cc(O)c(Cl)c2Cl)C1c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(C)C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1c1ccccc1
Temperature: 80 °C

Procedure:
A stirred mixture of 2-ethyl-2-methyl-3-phenyl-6,7-dichloro-5-hydroxy-1-indanone (6.24 g., 0.0186 mole), potassium carbonate (5.15 g., 0.0372 mole) and ethyl bromoacetate (6.22 g., 0.0372 mole) in dimethylformamide (60 ml.) is warmed at 55°-60° C. for 3 hours, then treated with water (60 ml.) and 10N sodium hydroxide solution (5 ml., 0.05 mole) and heated at 80°C. for one hour. The reaction mixture is added slowly to water (800 ml.)-6N hydrochloric acid (20 ml.) to precipitate (1-oxo-2-ethyl-2-methyl-3-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (3.7 g.) which melts at 192° C. on crystallization from
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Li]CCCC.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].O>C1COCC1>[CH2:26]([Sn:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[C:5]1[S:1][C:2]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:3][CH:4]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1cncc(-c2nccs2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(-c2cccnc2)s1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 37.1 %

Procedure:
To a stirred solution of 3-thiazol-2-yl-pyridine (J. Med. Chem. 2005, 48, 224) (927 mg, 5.71 mmol) in dry THF (30 mL) cooled at −78° C. under an inert atmosphere was added n-BuLi (2.5M in hexanes) (2.75 mL, 6.87 mmol) dropwise. After stirring at −78° C. for 45 mins, tributyltin chloride (1.86 mL, 6.87 mmol) was added. The mixture was allowed to warm to 0° C. over 90 mins, then treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2 using combiflash Companion®, eluting with cyclohexane/ethyl acetate 100/0 to 82/18 to afford 3-(5-tributylstannanyl-thiazol-2-yl)-pyridine as a colourless oil (955 mg, 37%). 1H NMR (DMSO-d6, 300 MHz) δ=9.11 (m, 1H), 8.62 (dd, J=4.77-1.52 Hz, 1H), 8.28 (m, 1H), 7.90 (s, 1H), 7.50 (dd, J=8.0-4.8 Hz, 1H), 1.52 (m, 6H), 1.28 (m, 6H), 1.13 (m, 6H), 0.84 (t, J=7.2 Hz, 9H).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][CH3:8].Cl.[OH:10][C:11]1[C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[C:23]([CH3:26])([CH3:25])[CH3:24]>CO>[OH:10][C:11]1[C:18]([C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:17][C:14]([CH:15]=[N:1][N:2]2[CH:6]=[CH:5][N:4]=[C:3]2[S:7][CH3:8])=[CH:13][C:12]=1[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CSc1nccn1N
Agent: Cl
Solvent: CO
Product: CSc1nccn1N=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.65 g of 1-amino-2-methylmercaptoimidazole are dissolved in 50 ml of methanol and treated with 3 ml of 2N hydrochloric acid. After the addition of 1.05 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde, the reaction mixture is stirred at room temperature overnight. Subsequently, the solvent is removed by evaporation in a vacuum. The residue is suspended in 30 ml of water and treated with saturated sodium carbonate solution up to an alkaline reaction. The mixture is extracted three times with 20 ml of methylene chloride each time, the combined organic phases are dried over sodium sulfate, filtered and evaporated. The crystalline residue is recrystallized from water/methanol, and there is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-2-methylmercaptoimidazole of m.p. 181°-183°.
Reaction SMILES: [CH3:1][N:2]1[C:9]([C:10]([NH2:12])=O)=[C:8]2[C:4]([N:5]=[N:6][S:7]2)=[N:3]1.S(Cl)(Cl)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:10]([C:9]1[N:2]([CH3:1])[N:3]=[C:4]2[C:8]=1[S:7][N:6]=[N:5]2)#[N:12]
Reactant: Cn1nc2nnsc2c1C(N)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Cn1nc2nnsc2c1C#N
Temperature: 80 °C
Reaction time: 55 h
Yield: 24.6 %

Procedure:
The compound, 5-methylpyrazolo-1,2,3-thiadiazole-6-carboxamide (0.9 g, 4.92 mmol) was slurried in toluene (10 mL) and thionyl chloride (0.5 mL) was added. The mixture was heated to 80° C. and then to 105° C. with no reaction. The mixture was cooled to 70° C. and ethyl acetate (10 mL) was added. The slurry was stirred at 70° to 80° C. for 55 h, cooled and concentrated onto Silica Woelm®TSC and chromatographed on 50 g of the same silica (25% ether-hexane) to give after a 300 mL forerun 0.2 g of 6-cyano-5-methylpyrazolo-1,2,3-thiadiazole as a light yellow solid; mp 111° to 114° C.; 1H-NMR (CDCl3) σ 4.41 (s, 3H); IR (KBr) 2230, 1332, 679 cm-1 ; Mass spec. m/e 165.0109; m/e calcd. for C5H3N5S 165.0109.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Si:26]([O:1][CH2:2][C@@H:3]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:7][CH:6]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1N[C@H](CO)Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H](Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 40 °C
Reaction time: 60 h
Yield: 68.9 %

Procedure:
4-{(2S)-3-Hydroxy-2-[(3-nitroquinolin-4-yl)amino]propyl}phenol (21.69 g, 64.5 mmol) was dissolved in 100 mL of dry pyridine and treated with tert-butyldimethylsilyl chloride (22.4 g, 148 mmol) and a catalytic amount of DMAP (0.79 g, 6.45 mmol). The reaction mixture was stirred under N2 and heated to 40° C. After 2.5 days, the reaction mixture was concentrated under reduced pressure. The resulting orange residue was partitioned between 200 mL of ethyl acetate and 200 mL of H2O. The layers were separated and the organic portion was washed sequentially with H2O and brine. The organic layer was then dried over Na2SO4, filtered, and concentrated under reduced pressure to give N-[(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-{[tert-butyl(dimethyl)silyl]oxy}benzyl)ethyl]-3-nitroquinolin-4-amine (25.24 g) as an orange solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)(O)[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(N(S(F)(F)[F:32])CC)C>C(Cl)Cl>[F:32][C:15]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:25][CH2:24][C:5]1=2
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)C1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(C)(F)c2cccnc2)CCN(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
1-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol (500 mg, 1.492 mmol) was dissolved in 20 mL DCM, cooled to 0° C. and diethylaminosulfur trifluoride (720 mg, 4.477 mmol) in DCM (5 mL) was added dropwise at the same temperature and stirred for 1 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with saturated bicarbonate and extracted with DCM. The organic layer was washed with bicarbonate and brine solution, dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 60 mg of 5-(2-Fluoro-2-pyridin-3-yl-propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 8.61 (s, 1H), 8.56 (d, 1H), 7.55 (d, 1H), 7.23 (d, 1H), 7.16 (s, 1H), 7.05 (d, 1H), 6.93 (d, 1H), 4.3 (m, 2H), 3.8 (dd, 2H), 2.96 (m, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 2.6 (m, 1H), 2.58 (s, 3H), 2.41 (s, 3H), 1.75 (d, 3H). Separation by chiral HPLC provided enantiomers II-212a-b.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:35]([O:36][CH3:37])=[CH:34][C:6]2[S:7][C:8](/[CH:23]=[C:24](\[C:28]3[CH:33]=[CH:32]N=[CH:30][CH:29]=3)/[C:25]([O-:27])=[O:26])=[C:9]([O:10][C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=4)[CH:12]=3)[C:5]=2[CH:4]=1.[Na+].[CH3:39]OC1C(OC)=CC2SC(/C=C(\C3C=CC=CC=3)/C([O-])=O)=C(OC3C=CC(OC)=CC=3)C=2C=1.[Na+]>>[CH3:1][O:2][C:3]1[C:35]([O:36][CH3:37])=[CH:34][C:6]2[S:7][C:8](/[CH:23]=[C:24](\[C:28]3[CH:33]=[CH:32][CH:39]=[CH:30][CH:29]=3)/[C:25]([OH:27])=[O:26])=[C:9]([O:10][C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=4)[CH:12]=3)[C:5]=2[CH:4]=1
Reactant: COc1ccc(Oc2c(/C=C(/C(=O)[O-])c3ccccc3)sc3cc(OC)c(OC)cc23)cc1
Reactant: COc1ccc2cc(Oc3c(/C=C(/C(=O)[O-])c4ccncc4)sc4cc(OC)c(OC)cc34)ccc2c1
Agent: [Na+]
Product: COc1ccc2cc(Oc3c(/C=C(/C(=O)O)c4ccccc4)sc4cc(OC)c(OC)cc34)ccc2c1

Procedure:
The procedure is as for Example 1 using the reagent of Example 5 in Step E, and the reagent of Example 6 in Step F.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14][C:15]([F:31])([F:30])[C:16]1[CH:17]=[C:18]([S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=1>>[OH:28][C:27]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:24](=[O:25])[C:23]=1[S:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:31])([F:14])[F:30])[CH:17]=1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: O=C(O)C(Sc1cccc(C(F)(F)F)c1)C(=O)O
Product: O=c1oc(-c2ccccc2)cc(O)c1Sc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.72 g, 8.92 mmol) and diethyl ester of [[3-(trifluoromethyl)phenyl]thio]propanedioic acid (1.5 g, 4.46 mmol). m.p. 228-229° C.; 1H NMR (400 MHz, DMSO-d6) δ6.89 (s, 1H), 7.4-7.61 (m, 7H), 7.89 (m, 2H).