Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:36]1([N:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)N)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:37]4[C:36](=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:42]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:22]=3[C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(C(F)(F)F)cc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 624.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[F:11].Br[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:4][C:3]=1[F:11]
Reactant: Brc1ncccn1
Reactant: OB(O)c1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1cc(-c2ncccn2)ccc1Br
Reaction time: 8 h

Procedure:
4-Bromo-3-fluorophenyl boronic acid (28AB) (1.0 g, 4.57 mmol, 1 equiv), 2-bromopyrimidine (1AB) (2.18 g, 13.7 mmol, 3 equiv), and 2M sodium carbonate (12 mL) were added in a pressure vessel (150 mL) and a (1v:1v) mixture of toluene and ethanol (25 mL: 25 mL) was added. The mixture was then bubbled with nitrogen gas for about 10 minutes. Tetrakistriphenylphosphine palladium (0) (266 mg, 0.23 mmol, 0.05 equiv) was added to the mixture. The reaction vessel was tightly capped, placed in an oil bath at 90° C., and stirred overnight.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][CH:15]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:15][CH2:14][CH2:13][CH2:12][CH:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:11]3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CCCCC1CC(c2ccccc2)=NO1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(C2=NOC(CCCCN3CCN(c4ccccc4)CC3)C2)cc1
Yield: 79.8 %

Procedure:
4-(3-Phenyl-4,5-dihydroisoxazol-5-yl)butanal (29.4 mg, 0.135 mmol), 1-phenylpiperazine (20.0 mg, 0.123 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (78.4 mg, 0.369 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 35.7 mg (68.4%) of the target compound was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([CH:14]([F:16])[F:15])=[CH:12][CH:13]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:15][CH:14]([F:16])[C:11]1[N:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)F)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(C(F)F)nc1
Reaction time: 5 h
Yield: 82.6 %

Procedure:
To a solution of tert-butyl[6-(difluoromethyl)pyridin-3-yl]carbamate (1.11 g, 4.54 mmol) in dichloromethane (8 ml), trifluoroacetic acid (8 ml) was added at room temperature. The reaction mixture was stirred for 5 hours at the same temperature, and then was concentrated under reduced pressure. Dichloromethane and saturated aqueous sodium hydrogencarbonate were added to the resulting residue. The organic layer was taken, and the organic layer was dried over anhydrous sodium sulfate and filtered. Subsequently, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=2:1 was concentrated under reduced pressure to obtain the title compound (540 mg, 3.75 mmol, 82%) as a pale green oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH:13]([C:17]3[N:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[S:20][CH:21]=3)[CH2:12]2)=[CH:5][CH:4]=1.Br.C(=O)([O-])[O-].[K+].[K+].BrC[C:35]([O:37][CH3:38])=[O:36]>CC(C)=O>[C:35]([CH2:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH:13]([C:17]3[N:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[S:20][CH:21]=3)[CH2:12]2)=[CH:5][CH:4]=1)([O:37][CH3:38])=[O:36]
Reactant: COc1ccc(CCN2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Reactant: COC(=O)CBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CCN2CCOC(c3csc(C(F)(F)F)n3)C2)cc1

Procedure:
0.6 g (1.6 mmol) of N-[2-(4-Methoxyphenyl)ethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine are heated on a steam bath with 6 ml of 48% strength aqueous hydrobromic acid for 3 hours. The mixture is then concentrated, toluene is added, and the mixture is again evaporated to dryness. The foamy residue is boiled under reflux in 15 ml of acetone with 1.2 g (8.7 mmol) of potassium carbonate and 0.3 ml (1.65 mmol) of methyl bromoacetate for 1 hour. The mixture is then filtered, the filtrate is concentrated, and the residue is purified on a silica gel column using toluene/acetone=4:1.
Reaction SMILES: [CH2:1]([N:5]=[C:6]1[S:10][CH:9]=[N:8][C:7]1([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[N:28](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:27]=[N:26][N:25]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.O1CCCC1.O>[CH2:1]([N:5]=[C:6]1[S:10][CH:9]=[N:8][C:7]1([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:25][N:26]=[N:27][N:28]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C1SC=NC1(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)OCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCN=C1SC=NC1(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)OCC
Yield: 30 %

Procedure:
5-Butylimino-4,5-dihydro-4-ethoxycarbonyl-4-[[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl]thiazole, the compound resulting from Example 2A (B), (170 mg, 0.241 mmol) in 15:15:1 (v/v/v) acetic acid/tetrahydrofuran/water (4 mL) was heated at reflux for 90 minutes. The solvent was evaporated under reduced pressure, and toluene was added and evaporated. Chromatography of the residue on silica gel eluting with 2-6% methanol in chloroform afforded 33.6 mg (30%) of the desired product as a yellow foam solid. TLC (10% methanol/90% chloroform) Rf =0.33. 1H NMR (CDCl3, 300 MHz) d 0.88 (t, 3H), 1.23 (t, 3H), 1.10-1.65 (envelope, 4H), 3.61 (d, 1H), 3.75 (dt, 2H), 3.81 (d, 1H), 4.08-4.32 (m, 2H), 7.08 (d, 2H), 7.27 (d, 2H), 7.38 (dd, 1 H), 7.50-7.63 (m, 2H), 7.75 (s, 1H), 8.20 (dd, 1H). MS (DCl/NH3) m/e 463 (M+H)+. Anal calcd for C24H26N6O2S.0.25 H2O: C, 61.72; H, 5.72; N, 17.99. Found: C, 61.89; H, 5.32; N, 17.76.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Chloro-5-nitroaniline (3.36 g) was dissolved in CH2Cl2 (45 mL) at 0° C. and pivaloyl chloride (1.99 mL) was added dropwise followed by TEA (4.06 mL). The mixture was stirred at RT for 2 days and a solid precipitated. Solid was filtered, rinsed with MeOH. Mother liquid was evaporated, solid was filtered on silica pad and solvent evaporated. Combined white solids were dried.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1([CH3:7])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:4](=[O:5])[CH2:3]1
Reactant: c1ccccc1
Reactant: CC(C)=CC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(C)CC(=O)c2ccccc21
Yield: 73 %

Procedure:
A solution of 25.0 g (0.25 moles) of 3,3-dimethyl acrylic acid in 250 ml of benzene was cooled to 0° C. in an ice bath. To this solution, 99 g (0.75 moles) of anhydrous aluminum chloride was slowly added using a spatula over a period of 20 minutes with stirring, after which the ice bath was removed and the reaction mixture was gradually heated to reflux. The reaction mixture was refluxed for ˜7-8 h, then excess benzene was distilled off and the mixture was quenched with ice-cold dilute hydrochloric acid (HCl). The mixture was then diluted with ethylacetate (100 ml), the organic layer was separated and the aqueous layer was again washed with ethyl acetate (50 ml). The combined organic layer was washed with water (3×100 ml) until the pH was neutral, and then dried over anhydrous sodium sulfate and concentrated under vacuum. 43.0 g of reddish brown liquid was obtained, which was distilled under vacuum to give 29 g of the desired product, 3,3-dimethyl-indan-1-one (distilled at 82-84° C. at ˜10 mm). Yield=73%, purity=99%. 1H NMR (DMSO-d6, 300 MHz): δ 7.3-7.8 (m, 4H, Ar-H), δ 2.5 (s, 2H, O═C—CH2), δ 1.3 (s, 6H, —CH3). LC/MS: 161 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:12]([O-])([O-:14])=[O:13].[K+].OS(O)(=O)=O>C(Cl)Cl.CCCCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])[O-]
Reactant: Clc1cccc2ncccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCCCC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Yield: 49.3 %

Procedure:
In a similar fashion using route 7 general procedure 15, 5-chloroquinoline (1.0 g, 6.13 mmol), potassium nitrate (0.8 g, 7.98 mmol) and H2SO4 (3 ml) gave the title compound (630 mg, 51%) after trituration from DCM/n-pentane.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10](Cl)=[O:11].[NH:14]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:15]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C.Cl>O1CCCC1>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]([N:14]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:15]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:11]
Reactant: CCOC(=O)C1CCCCN1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCCN1C(=O)Cc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
223 g (1.125 mol) of mesityleneacetyl chloride are added dropwise at 0° to 10° C. to 182 ml (1.157 mol) of ethyl pipecolinate and 162 ml (1.157 mol) of triethylamine in 1,200 ml of absolute tetrahydrofuran (THF), followed by stirring for 1 hour at room temperature. After the mixture has been stirred into 5 liters of ice water and 500 ml of 1 N HCl, the product is filtered off with suction, washed with water and dried in vacuo at 50° C. over P2O5. 342.3 g (95.2% of theory) of ethyl N-(2,4,6-trimethylphenylacetyl)-piperidine-2-carboxylate are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([N:11]([CH2:24][C:25]([F:26])([F:27])[F:28])[CH2:10][CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:3][CH:4]=2)=[CH:13][C:14]=1[C:20]([F:21])([F:22])[F:23])#[N:17]
Reactant: N#Cc1ccc(N(CCOc2ccc(N)cc2)CC(F)(F)F)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Reaction time: 22 h
Yield: 73.6 %

Procedure:
To a solution of 4-[{2-[(4-aminophenyl)oxy]ethyl}(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.0423 g, 0.105 mmol) in dry pyridine (1 mL) at rt, under nitrogen, was added MsCl (0.010 mL, 0.12 mmol) in one portion. The mixture was stirred 22 h and concentrated in vacuo. The residue was partitioned between EtOAc and 10% v/v HCl and the layers were separated. The organic layer was washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.0372 g of the title compound as a colorless film: 1H NMR (300 MHz, CD3OD) δ 7.74 (d, J=8.8 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.26 (dd, J=8.8, 2.5 Hz, 1H), 7.19-7.12 (m, 2H), 6.90-6.83 (m, 2H), 4.43 (q, J=8.9 Hz, 2H), 4.22 (t, J=5.1 Hz, 2H), 4.04 (t, J=5.1 Hz, 2H), 2.85 (s, 3H); MS (APCI) m/z 480 (M−1).
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[CH2:7]([OH:13])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12]>C1COCC1.[Co](Br)Br.[I-].[Zn+2].[I-].[Zn].C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:3][C:2]1[CH2:1][CH:12]=[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][OH:13])[CH2:5][C:4]=1[CH3:6]
Reactant: C=C(C)C(=C)C
Reactant: C#CCCCCO
Agent: Br[Co]Br
Agent: [I-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=C(C)CC(CCCCO)=CC1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
In 40 mL of THF, 1,2-bis(diphenylphosphino)ethane (800 mg, 2.00 mmol), cobalt bromide (437 mg, 2.00 mmol), zinc iodide (1.28 g, 4.00 mmol), and zinc (260 mg, 4.00 mmol) were dissolved, followed by stirring at 70° C. for 15 minutes. After cooling to room temperature, 2,3-dimethyl-1,3-butadiene (9.86 g, 120 mmol) was added. Then, 5-hexyn-1-ol (9.8 g, 100 mmol) was slowly added dropwise with cooling in a water bath. After stirring at 35° C. for 1 hour, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1). Thus, 11.5 g of the title compound, an alcohol, was obtained as a colorless oily substance. Yield: 63.4%.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[C@@H:7]1[CH2:9][C@@H:8]1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)C.[H-].C([Al+]CC(C)C)C(C)C.Cl>CCCCCC>[F:17][C:16]([F:18])([F:19])[C:12]1[CH:11]=[C:10]([C@H:8]2[CH2:9][C@H:7]2[CH2:6][CH:5]=[CH:4][OH:3])[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)/C=C/[C@@H]1C[C@@H]1c1cccc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Product: OC=CC[C@@H]1C[C@@H]1c1cccc(C(F)(F)F)c1
Reaction time: 18 h
Yield: 97.8 %

Procedure:
(±)-(E)-Ethyl-3-[cis-2-(3-trifluromethylphenyl)cyclopropyl]prop-2-enoate (0.18 g) (example 7) was dissolved in dicyhloromethane (3 ml) and cooled to -20° under nitrogen. Diisobutylaluminiumhydride (1.3 ml of a 1M solution in hexane) was added and the solution stirred at 25° for 18 hours. Careful addition of dilute hydrochloric acid was followed by work up in the usual manner to give cis-2-(3-trifluoromethylphenyl)-1-(3-hydroxyprop-2-en-1-yl)cyclopropane (0.15 g). NMR 1H: 7.43(4H,m), 5.79(1H,dt), 4.98(1H,dd), 3.95(2H,d), 2.40(1H,m), 1.94(1H,m), 1.33(1H,m), 1.10(2H,m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](/[CH:12]=[C:13](\[CH2:17][CH2:18][CH3:19])/[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.F[B-](F)(F)F.[H][H]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCC/C(=C\S(=O)(=O)c1ccc(OC)cc1)C(=O)O
Reactant: [H][H]
Agent: F[B-](F)(F)F
Solvent: CO
Product: CCCC(CS(=O)(=O)c1ccc(OC)cc1)C(=O)O
Reaction time: 2 h
Yield: 99.2 %

Procedure:
(E)-3-(4-Methoxybenzenesulfonyl)-2-propylacrylic acid (1.0 g, 3.52 mmol) was dissolved in degassed methanol (15 ml) and [(S,S)-MeDuPHOS Rh (COD)]BF4 (22 mg, 3.52×10−2 mmol) was added under a stream of nitrogen. This solution was injected into the pressure vessel under nitrogen, and then the bomb was charged with hydrogen. The mixture was hydrogenated at 1035 kPa (150 psi) for 2 hour at room temperature. The methanol was removed under reduced pressure to give the title compound (1.0 g, 99% yield). E.e. was determined by chiral HPLC to be 96% [Chirocel OD; 20% IPA-80% heptane; 1 ml/min; 254 nm; major enantiomer Rf 10.91 min., minor enantiomer Rf 9.71 min.]
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][NH:5][C:4](=[S:7])[CH:3]1[C:8]([O:10][CH2:11]C)=[O:9]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(OC)(=O)CC>[CH3:1][CH:2]1[CH2:6][NH:5][C:4](=[S:7])[CH:3]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)C1C(=S)NCC1C
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCC(=O)OC
Product: COC(=O)C1C(=S)NCC1C
Yield: 52.8 %

Procedure:
To 4.5 g of ethyl 4-methyl-2-thioxopyrrolidine-3-carboxylate, were added 200 ml of methyl propionate and 7.0 ml of titanium tetraisopropoxide. The resulting mixture was heated under reflux for 3 days. After distilling off the excessive methyl propionate under reduced pressure, water and chloroform were added to the residue and insoluble matters were filtered off. The chloroform layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the chloroform, ethyl ether was added to the residue to thereby crystallize the same. Thus 2.2 g of the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1.O1CCCC1.[Li]CCCC.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]([C:2]2[CH:3]=[C:4]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[S:5][C:6]=2[C:7]2[NH:11][CH:10]=[N:9][N:8]=2)[OH:35])=[CH:32][CH:31]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Brc1cc(-c2ccncc2)sc1-c1nnc[nH]1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cc(-c3ccncc3)sc2-c2nnc[nH]2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
To a mixture of 4-[4-bromo-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridine (222.0 mg, 0.730 mmol) in tetrahydrofuran (5.9 mL, 72.3 mmol) cooled to −78° C. was added dropwise n-BuLi in hexanes (2.50 M, 1.2 mL, 2.90 mmol) under an atmosphere of argon and the mixture was stirred at −78° C. for 30 min. To the solution was added dropwise a solution of 4-methoxybenzaldehyde (0.53 mL, 4.34 mmol) in tetrahydrofuran (5.0 mL, 60 mmol) and the resulting solution was stirred for 30 min at −78° C. The reaction mixture was quenched by the addition of water (2 mL) and the resulting mixture was warmed to room temperature and stirred for 30 min. The mixture was extracted with EtOAc (5 mL) then the organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated under the reduced pressure. The obtained residue was purified by prep HPLC to yield 62.0 mg as a yellow solid (23.5%). LCMS: (FA) ES+, 365. 1H NMR (400 MHz, d6-DMSO) δ: 8.68 (s, 1H), 8.55-8.57 (dd, J=1.5 Hz, 2H), 7.81 (s, br, 1H), 7.63-7.65 (dd, J=1.5 Hz, 2H), 7.40-7.44 (d, J=8.78 Hz, 2H), 6.82-6.84 (d, J=8.78 Hz, 2H), 6.72 (s, br, 1H), 3.68-3.69 (s, br, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[CH2:16][CH2:17][NH:18][C:19](=[O:20])[C:8]1=2.[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Br)[C:25]=1[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+].CNCCN>[Cu](I)I.O1CCOCC1>[Br:23][C:24]1[C:25]([CH3:31])=[C:26]([N:18]2[CH2:17][CH2:16][C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:22])([CH3:21])[CH3:1])[C:8]=3[C:19]2=[O:20])[CH:27]=[CH:28][CH:29]=1
Reactant: C[Si](C)(C)CCOCn1c2c(c3ccccc31)CCNC2=O
Reactant: Cc1c(Br)cccc1Br
Agent: I[Cu]I
Agent: CNCCN
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c(Br)cccc1N1CCc2c(n(COCC[Si](C)(C)C)c3ccccc23)C1=O
Temperature: 100 °C
Yield: 41 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 117a (400 mg, 1.27 mmol), 2,6-dibromotoluene (633 mg, 2.53 mmol), cesium carbonate (828 mg, 2.54 mmol), N-methylethylenediamine (112 mg, 1.27 mmol) and 1,4-dioxane (20 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper iodide (121 mg, 2.54 mmol) was added. A reflux condenser was attached to the flask, and the reaction mixture was heated at 100° C. for 16 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column to afford 117b in 41% yield (251 mg) as a yellow oil: 1H NMR (500 MHz, CDCl3) d 7.71 (d, 1H, J=8.0 Hz), 7.68 (d, 1H, J=8.0 Hz), 7.63 (d, 1H, J=8.0 Hz), 7.47 (t, 1H, J=8.0 Hz), 7.32-7.28 (m, 2H), 7.21 (t, 1H, J=8.0 Hz), 6.13 (s, 2H), 4.15 (m, 1H), 3.93 (m, 1H), 3.69 (m, 2H), 3.29 (m, 2H), 2.45 (s, 3H), 0.95 (t, 2H, J=8.0 Hz), −0.07 (s, 9H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[K+].CN(C)[CH:20]=[O:21]>O>[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:20]=[O:21])=[CH:12][NH:13]2)=[CH:9][CH:8]=1
Reactant: Cc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc2c(C=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A 12-l. three-necked flask, equipped with a mechanical stirrer, a thermometer and a dropping funnel provided with a Drierite drying tube was charged with 610 ml (7.9 moles) of N,N-dimethylformamide. The flask was immersed in an ice bath and 217 g (1.42 moles) of phosphorus oxychloride was added at 5-10° with stirring over 1 hour. The dropping funnel was rinsed with 20 ml of diemthylformamide and the light pink orange oil was stirred for further 10 minutes in the ice bath. Then a solution of 156 g (1.19 moles) of 6-methylindole in 156ml of dimethylformamide was added at 5-10° C. over a period of 1 hour. The ice bath was removed and the red orange solution was stirred for an additional hour, while the flask content warmed up to room temperature. At the end of the reaction period, 1.17 kg of crushed ice was added. The temperature fell to -10° and after a short time a light yellow slurry was formed. The reaction mixture was stirred for 1 hour, as the temperature came to 15°. Then a solution of 840 g (13.0 moles) of potassium hydroxide pellets (87% assay) in 2 l of water was added over 30 minutes, during which time the pot temperature rose to 50°. After the addition was complete, the dropping funnel was replaced by a reflux condenser and the orange solution was heated rapidly with stirring on a steam bath to 93° and kept at this temperature for 30 minutes. The mixture was allowed to stand at room temperature overnight. The precipitate was collected by suction filtration, washed with water and dried at 60° (constant weight) to give 186.5 g (98%) of product as orange crystals, m.p. 183-186°.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH2:24]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]#[CH:26]>>[O:27]([CH2:24][C:25]1[N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:2]=[N:3][CH:26]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C#CCOc1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1COc1ccccc1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and (prop-2-yn-1-yloxy)benzene. MS (+ESI) m/z: 403.1.