Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([NH:25][CH2:26][C:27]([OH:29])=O)=[O:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:32])=O>>[C:1]1([CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([NH:25][CH2:26][C:27]([Cl:32])=[O:29])=[O:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CNC(=O)c1ccc2c(c1)C(CCNC(=O)Cc1ccccc1)CCO2
Product: O=C(Cl)CNC(=O)c1ccc2c(c1)C(CCNC(=O)Cc1ccccc1)CCO2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The product obtained in Step A (3 mmol), dissolved in thionyl chloride, is stirred at 60° C. under a current of nitrogen for one hour. The thionyl chloride is evaporated off under reduced pressure and the residue is dried with the aid of a vane pump to yield the title product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][N:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].O.[OH-].[Li+]>CS(C)=O>[CH:7]([N:5]1[N:4]=[C:3]([C:10]#[N:11])[C:2]([NH:1][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[N:6]1)([CH3:9])[CH3:8]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)n1nc(N)c(C#N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)n1nc(C#N)c(Nc2ccccc2[N+](=O)[O-])n1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Combine 5-amino-2-isopropyl-2H-1,2,3-triazole-4-carbonitrile (44.2 g, 0.292 mol) and 2-fluoronitrobenzene (41.25 g, 0.292 mol) in dimethylsulphoxide (590 ml) and stir in the presence of lithium hydroxide monohydrate (24.56 g;0.584 mol) for eighteen hours at 55° C. Pour the reaction mixture onto ice-water, stir for one hour, filter and wash the filter pad well with water to leave a yellow crystalline solid to give 2-isopropyl-5-(2-nitroanilino)-2H-1,2,3-triazole4-carbonitrile (73.7 g, 93% yield): 1HNMR/c: 1.6 ppm (d, 6H), 4.8 ppm (m, 1H), 7.05 ppm (tr, 1H), 7.64 ppm (tr, 1H), 8.2 ppm (dd, 1H), 8.28 ppm (dd, 1H), 10.25 ppm (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]([OH:18])=[O:17])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[N+](=[CH2:21])=[N-]>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]([O:18][CH3:21])=[O:17])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=C(O)c1c2ccccc2nc2ccc(Cl)cc12
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)c1c2ccccc2nc2ccc(Cl)cc12
Reaction time: 1.5 h

Procedure:
4.9 gm of 2-chloro-9-carboxy-acridine were suspended in 5 cc of methylene chloride at room temperature and then 60 cc of a methylene chloride solution of diazomethane titrating 17.9 gm per liter was added thereto. The reaction mixture was then stirred for 90 minutes while bubbling nitrogen therethrough to eliminate excess diazomethane. The methylene chloride solution was washed with an aqueous solution of 10% sodium carbonate, then with water, dried over magnesium sulfate, treated with charcoal, filtered and then evaporated to dryness. The residue was recrystallized from boiling methanol to obtain 3.2 gm of 2-chloro-9 -methoxycarbonylacridine melting at 130°C. The product occurred as a pale yellow solid soluble in chloroform, slightly soluble in ether and alcohol and insoluble in water.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.C1C[O:13][CH2:12]C1.[Li+].CC([N-]C(C)C)C.CN(C=O)C>O>[Br:1][C:2]1[S:6][C:5]([CH:12]=[O:13])=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1csc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1sc(Br)cc1C(=O)O
Temperature: -30 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Under a nitrogen atmosphere, 5-bromo-3-thiophenecarboxylic acid (12 g, 58 mmol) was added to THF (300 ml), and LDA (174 mmol, 232 ml, 0.75 M) was slowly dropped at −78° C. Then, the mixture was stirred for two hours at −30° C., and DMF was slowly dropped at −78° C. Then, water was added to the reaction solution. The reaction solution was then extracted with ethyl acetate, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solvent was distilled off under reduced pressure. With this, a target substance was obtained as a solid (95% yield, crude product). 1H-NMR (400 MHZ, CDCl3, TMS) δ 10.44 (s, 1 H), 7.63 (s, 1 H)
Reaction SMILES: C1([C@@H](C(C2C=CC=CC=2)O)[OH:8])C=CC=CC=1.C1(C)C=CC=CC=1.[Cl:24][C:25]1[C:26]2[S:46][CH2:45][CH2:44][C:27]=2[N:28]=[C:29]([N:31]2[CH2:36][CH2:35][N:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)[N:30]=1.CC(OO)(C)C>O>[Cl:24][C:25]1[C:26]2[S@:46](=[O:8])[CH2:45][CH2:44][C:27]=2[N:28]=[C:29]([N:31]2[CH2:32][CH2:33][N:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)[CH2:35][CH2:36]2)[N:30]=1
Reactant: Clc1ccc(N2CCN(c3nc(Cl)c4c(n3)CCS4)CC2)cc1
Reactant: OC(c1ccccc1)[C@@H](O)c1ccccc1
Agent: CC(C)(C)OO
Solvent: Cc1ccccc1
Solvent: O
Product: O=[S@@]1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Temperature: 0 °C
Yield: 88 %

Procedure:
Using a jacketed reactor with mechanical stirring at 400 rpm, charge (S)-Hydrobenzoin (292 mg) and toluene (50 mL), followed by Ti(i-PrO)4 (0.20 mL) and water (0.25 mL). Stir the mixture at 20° C. for 30 min. then charge 4-Chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine (3a, 5.00 g) and stir the mixture for 15 min at 20° C. before being cooling to 0° C. (it took 20 min). Charge TBHP (70% aqueous) (0.75 mL) to the reaction mixture and stir for 23 h at 0° C. Reaction reached 96% conversion and 89% ee. Quench with 5% Na2SO3 (20 mL). Separate the layers and extract the aqueous layer with dichloromethane (50 mL). Combine organic layers and wash with water (20 mL), dry (MgSO4), filter, and concentrate affording the desired sulfoxide in (4.6 g, 88% yield, 89% ee). The product may be recrystallized from THF/water (5:1) with good recovery to yield material >96% ee. NMR (400 MHz, CDCl3) δ 7.16-7.26 (m, 2H), 6.80-6.90 (m, 2H), 3.90-4.20 (m, 4H), 3.75-3.90 (m, 1H), 3.00-3.30 (m, 7H); 13C NMR (400 MHz, CDCl3) δ 177.5, 162.5, 160.7, 149.8, 129.4, 125.7, 123.9, 118.2, 49.6, 46.5, 44.7, 44.4, 33.7 (3 signals missing due to overlap); LCMS (ESI) for C16H17Cl2N4OS (M+H)+: calcd. 383.1, obsvd. 383.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.Br[CH2:18][CH:19]([CH3:22])[CH2:20][Cl:21]>>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:18][CH:19]([CH3:22])[CH2:20][Cl:21])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Reactant: CC(CCl)CBr
Product: COc1cc2c(cc1OC)CC(=O)N(CC(C)CCl)C=C2

Procedure:
This compound was prepared analogous to Example 1(a) by reacting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one with 1-bromo-2-methyl-3-chloro-propane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH:17]=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].O.[NH2:20][NH2:21]>C(O)C>[NH2:20][N:21]1[C:7]([OH:8])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:15]=2)[N:16]=[CH:17]1
Reactant: NN
Reactant: O=CNc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Yield: 95 %

Procedure:
To a solution of 2.7 parts of 5-chloro-2-formamidobenzophenone in 40 volume parts of ethanol is added 2.5 volume parts of hydrazine hydrate, followed by refluxing for 20 minutes. After cooling, the resulting crystals are recovered by filtration and washed with ethanol and ether and then dried. This procedure gives 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenylquinazoline as crystals melting at 189° to 192° C. Yield: 95%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][F:25])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CN(C)CCN(C)C1C=CC(NC2C(=O)N(C)C=C(B3OC(C)(C)C(C)(C)O3)C=2)=NC=1.[C:57]([O:60][CH2:61][C:62]1[C:67]([N:68]2[CH2:79][CH2:78][N:77]3[C:70](=[CH:71][C:72]4[CH2:73][C:74]([CH3:81])([CH3:80])[CH2:75][C:76]=43)[C:69]2=[O:82])=[CH:66][C:65]([F:83])=[CH:64][C:63]=1Br)(=[O:59])[CH3:58]>>[F:83][C:65]1[CH:64]=[C:63]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][F:25])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:62]([CH2:61][O:60][C:57](=[O:59])[CH3:58])=[C:67]([N:68]2[CH2:79][CH2:78][N:77]3[C:70](=[CH:71][C:72]4[CH2:73][C:74]([CH3:80])([CH3:81])[CH2:75][C:76]=43)[C:69]2=[O:82])[CH:66]=1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(CCF)CC3)cn2)c1=O
Agent: CN(C)CCN(C)c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(CCF)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Yield: 33 %

Procedure:
Following Example 186f, 273a (which was prepared in situ from 217d using conditions analogous to those used to prepare 270d) (200 mg, 0.49 mmol) and 189a (176 mg, 0.39 mmol) were reacted to give 273b (115 mg, 33% yield).
Reaction SMILES: O1CCOCC1.[Cl:7][C:8]1[N:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[O:22][CH3:23])[N:9]=1.[S-2].[Na+].[Na+]>O>[Cl:7][C:8]1[N:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[O:22][CH3:23])[N:9]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)n1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(N)ccc1-n1cnc(Cl)n1
Temperature: 75 °C
Yield: 72.8 %

Procedure:
Water (8 mL) and dioxane (8 mL) were added to a mixture of 3-chloro-1-(2-methoxy-4-nitrophenyl)-1H-1,2,4-triazole (0.900 g, 3.53 mmol) and sodium sulfide (1.379 g, 17.67 mmol) in a 20 mL vial. The vial was capped and heated at 70-80° C. for 24 hours. The mixture was cooled to rt, poured into water (300 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline (577 mg, 73%) as a brown solid. LC-MS (M+H)+225.1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[OH:14])(=O)[CH3:2].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24]Br)=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)C>CN(C=O)C>[CH3:2][C:1]1[C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=2[O:14][C:24]=1[C:22](=[O:23])[C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(C)c(C(=O)c3ccc(C)cc3)oc2c1
Temperature: 60 °C

Procedure:
0.72 g (3.75 mmol) of N-(4-acetyl-3-hydroxy-phenyl)acetamide and 0.81 g (4.1 mmol) of 2-bromo-4-methylacetophenone were dissolved in 5 ml DMF and 1,55 g (11.25 mmol) of potassium carbonate were added. The suspension was heated to 60° C. for 1 h and ethylacetate was added. The organic phase was washed three times with water, one time with a NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was further purified by crystallisation (ethanol).
Reaction SMILES: [F:1][C:2]1[C:3]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:4]([NH:9]C(=O)C(C)(C)C)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Na+].[Na+]>Cl.COCCOC.O>[NH2:9][C:4]1[C:3]([C:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:24])=[C:2]([F:1])[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(F)c(F)c1C(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(F)c(F)c1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a −78° C. solution of 2.5 g (11.724 mmol) N-(3,4-difluorophenyl)-2,2-dimethylpropanamide in 39 ml anhydrous THF was added drop wise over 15 mins 18 mL (28.136 mmol) n-BuLi (1.6M solution in cyclohexanes). After 1 hr at −78° C., 4 mL (26.966 mmol) ethyl 4-fluorobenzoate was added dropwise and the reaction mixture stirred from −78° C. to rt. After 45 mins, the reaction mixture was cooled to 0 C and quenched with saturated ammonium chloride and poured into a 1:1 mixture of ether:water and warmed to room temperature. The organic phase was isolated, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to yield N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-2,2-dimethylpropanamide (6-3). A solution of 3.5 g (10.706 mmol) N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-2,2-dimethylpropanamide in 43 mL 6N HCl and 8.6 mL DME was heated to 100° C. After 24 h at 100° C., the reaction mixture was cooled to room temperature and sodium carbonate was added until reaction mixture was basic. The reactions was diluted with water, extracted three times with ether, and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 0-20% EtOAc:hexane) afforded (6-amino-2,3-difluorophenyl)(4-fluorophenyl)methanone. 1H NMR (CDCl3, 400 MHz) δ 7.85-7.80 (m, 2H, ArH); 7.17-7.11 (m, 3H, ArH); 6.47 (ddd, J=2.01 Hz, 3.66 Hz, 9.16 Hz, 1H, ArH); 4.84 (br s, 2H, ArNH2). ES MS+1=252.1.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C(O[C@@H:13]1[O:30][C@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]1[O:15][C:16](=[O:18])[CH3:17])(=O)C.[Sn](Cl)(Cl)(Cl)Cl.C(#N)C>ClCCCl>[C:16]([O:15][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:30][C@H:13]1[N:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3])(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1cc[nH]c(=O)n1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Cytosine is silylated by the general method of Wittenberg. It is reacted with 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose in 1,2 dichloroethane followed by tin tetrachloride in 1,2-dichloroethane (or acetonitrile) according to the method of Vorbruggen and Niedballa to provide the 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)cytosine 33.1b (Xi=β-cytidin-1-yl). Following methanolysis with sodium methoxide in methanol the 1-(β-D-glucopyranosyl)cytosine is obtained. Following protection of the heterocyclic amine this is converted into the morpholino subunit 32.2b (Xi=β-N4-benzoylcytidin-1-yl) by the general procedure.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.C(OCC)(=O)C>[Si:18]([O:12][CH2:11][CH2:10][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[NH:9][CH:8]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1c[nH]c2ccccc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
A solution of tryptophol (5.0 g, 31 mmol) in DMF (30 ml) was treated with imidazole (4.64 g, 68 mmol) and cooled to 0° C. tert-Butyldimethylsilyl chloride (5.14 g, 34.1 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was then diluted with ethyl acetate (100 ml) and washed with water (2×100 ml) and the aqueous solutions were extracted with ethyl acetate (200 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatogaphy (30% ether/petroleum ether) yielded the title compound (8.43 g, 99% yield) as a colorless oil: IR (CCl4) 3910 (s), 3060 (w), 2960 (s), 2930 (s), 2850 (s), 1450 (m), 1370 (w), 1260 (s), 1100 (s), 900 (m), 840 (s), 780 (s), 750 (s) cm−1; 1H NMR (500 MHz, CDCl3) δ 8.26 (br s, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.64-7.50 (m, 4H), 4.28 (t, J=7.3 Hz, 2H), 3.38 (t, J=7.3 Hz, 2H), 1.29 (s, 2H), −0.43 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 136.08, 127.62, 122.08, 121.75, 119.12, 118.79, 112.84, 111.04, 63.89, 28.98, 25.98, 18.34, −5.29; high resolution mass spectrum (Cl, NH3) m/z 276.1750 [(M+H)+; calcd for C16H25NOSi: 276.1783].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH:15]1([C:18](=[O:23])[CH2:19][C:20](=O)[CH3:21])[CH2:17][CH2:16]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:15]1([C:18]([C:19]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]3[CH:5]=[CH:4][S:3][C:2]3=[N:1][C:20]=2[CH3:21])=[O:23])[CH2:17][CH2:16]1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: Nc1sccc1C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sccc2c(-c2ccccc2)c1C(=O)C1CC1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 8.2 %

Procedure:
To a stirred solution of 60 mg (0.29 mmol) (2-amino-thiophen-3-yl)-phenyl-methanone (the preparation of which is described in example 20) in 2 ml acetic acid was added 50 mg (0.39 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 7 mg (8%) cyclopropyl-(6-methyl-4-phenyl-thieno[2,3-b]pyridin-5-yl)-methanone as a colorless oil. ES-MS m/e (%): 294 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:8]=32)=[N:3]1.CC(NCCC#N)CC1C=CC=CC=1.Cl>CCCCCC.C(O)C>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:8]=32)=[N:3]1
Reactant: CC(=O)NCCC1CCc2ccc3nn(C)cc3c21
Agent: CC(Cc1ccccc1)NCCC#N
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: CC(=O)NCC[C@H]1CCc2ccc3nn(C)cc3c21
Yield: 51.4 %

Procedure:
N-[2-(2-Methyl-2,6,7,8-tetrahydrocyclopenta[e]indazol-8-yl)ethyl]acetamide (about 70 mg) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mm ID×500 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 80 mL/min, column temperature: room temperature, sample concentration: 1.0 mg/mL (hexane/ethanol=90/10), injection amount: about 35 mg). A fraction solution containing an optically active compound having a longer retention time under the above-mentioned high performance liquid chromatography conditions was concentrated. The concentrate was re-dissolved in ethanol, and concentrated to dryness. Hexane was further added, and the mixture was concentrated to dryness again to give the title compound (36 mg, 99% ee). The enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 1.0 mL/min, column temperature: room temperature, sample concentration: 1 mg/mL (hexane/ethanol=90/10), injection volume: 10 μL).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][NH:13][CH:14]=O)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[O:11][C:10]3=[CH:12][N:13]=[CH:14][N:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CNCc1ncc(-c2ccccc2)o1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(-c2cn3cncc3o2)cc1

Procedure:
To 0.6 g (3 mmol) (2) in 15 ml toluene was added dropwise 1 ml phosphorus oxychloride and the resulting solution was heated at 90° overnight. Then, the solvent was removed in vacuo and the residue carefully diluted with 50 ml water. This solution was made basic with 40% NaOH solution and extracted with 4×50 ml portions of methylenechloride. The combined organic extracts were washed with brine, dried and the solvent removed in vacuo to give a dark gum. This was purified by chromatography on silica gel eluting with methylene chloride (97%)-isopropanol (3%) to give pure (3) as a waxy, tan solid, m.p. 128°-131° (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.C(OCC)(=[O:14])C>>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:14][C@@H:9]2[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: OC/C=C/c1cccc(Br)c1
Reactant: CCOC(C)=O
Product: OC[C@H]1O[C@@H]1c1cccc(Br)c1
Yield: 73 %

Procedure:
The title compound was prepared from trans-3-(3-bromophenyl)-2-propenol by a sequence analogous to that described above for compound (9a) but using D-(-)-diethyl tartrate. Column chromatography (ethyl acetate--light petroleum (b.p. 40°-60° C.), 3:7) provided the title compound (73%) as a pale yellow oil. Distilled at 160°-185° C. at 0.1 mmHg. using a Kugelrohr short path distillation apparatus as a colourless oil; [α]D25 +37.6 (c=0.020 gml-1, CHCl3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C.C(OCC)(=O)C>[C:20]([O:19][C:18]([NH:17][CH:12]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11]1)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:24])([CH3:22])([CH3:21])[CH3:23]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C1(c2ccc(O)cc2)CCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C2(C(CC(C)C)NC(=O)OC(C)(C)C)CCC2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of phenol 67 (0.5 g, 0.0015 mole) in 25 mL of anhydrous DMF was added cesium carbonate (Cs2CO3). The resulting mixture was heated at 70° C. for 12 hours. The reaction mixture was cooled to room temperature and added ethyl bromoacetate. The reaction mixture was further stirred at 70° C. for 8 hours and the progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL×2), dried over anhydrous sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel column chromatography using 0-50% gradient of ethyl acetate and hexane as eluent to give the pure ester 69 as colorless liquid in 61% (0.38 g) yield. MS (ESI): m/z=420.00 (M+H+).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:20])[C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([CH3:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]#[N:30].O>CN(C=O)C>[C:29]([CH2:28][O:19][C:16]1[CH:15]=[CH:14][C:13]([S:12][C:9]([CH3:11])([CH3:10])[C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:20])=[CH:18][CH:17]=1)#[N:30]
Reactant: CC(C)(Sc1ccc(O)cc1)C(=O)NC1CCCCC1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(Sc1ccc(OCC#N)cc1)C(=O)NC1CCCCC1
Temperature: 80 °C

Procedure:
N-Cyclohexyl-2-[(4-hydroxyphenyl)thio]-2-methylpropanamide (prepared as example 67) was dissolved in DMF and to this was added potassium carbonate and bromoacetonitrile and the resulting solution was heated to 80° C. for 2 h. The reaction mixture was poured into water and extracted with EtOAC, dried over MgSO4 and concentrated. The product was purified by flash chromatography, eluting with hexane/EtOAc, to provide 19.4 mg of the desired product. LCMS: (M+H)+=333.2.