Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][C:25](=[O:26])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: O=C(CBr)c1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: O=C(C[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2)c1ccccc1
Product: [Br-]
Yield: 43.1 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0567 g, 0.193 mmol) and 2-bromo-1-phenylethanone (0.0487 g, 0.245 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (0.0410 g, 43.0%). EI-MS m/z 412(M+) Rt (1.90 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[NH2:10])=[CH:4][CH:3]=1.[Br-].[CH2:34]([O:36][C:37](=[O:41])[CH2:38][CH2:39][Zn+])[CH3:35].C(N(CC)CC)C.[F:49][C:50]1[CH:58]=[CH:57][C:53]([C:54](Cl)=[O:55])=[CH:52][C:51]=1[C:59]([F:62])([F:61])[F:60]>C1COCC1.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:49][C:50]1[CH:58]=[CH:57][C:53]([C:54]([NH:10][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH2:39][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:41])=[CH:3][CH:4]=2)=[O:55])=[CH:52][C:51]=1[C:59]([F:60])([F:61])[F:62]
Reactant: NC(Cc1ccc(Br)cc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)CC[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(CC(NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cccc(OC(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)cc1
Temperature: 130 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
To a solution of 2-(4-bromophenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethanamine (26 mg, 0.050 mmol) in THF (0.5 mL) was added a 0.5 M solution of 3-ethoxy-3-oxopropylzinc bromide in THF (0.18 mL, 0.090 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (3 mg, 5 mol %). The reaction mixture was heated at 130° C. under microwave irradiation for 0.5 h. The reaction mixture was filtered through silica gel and eluted with THF. The solvents were removed under reduced pressure and the residue was dissolved into CH2Cl2 (0.5 mL) then triethylamine (0.020 mL, 0.15 mmol) was added followed by 4-fluoro-3-(trifluoromethyl)benzoylchloride (0.020 mL, 0.13 mmol). The reaction mixture was stirred at rt for 3 h then diluted with Et2O (10 mL) and the organic layer was washed with sat. NH4Cl (2 mL), sat. NaHCO3 (2 mL) and sat. NaCl (2 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep TLC plate, eluting with 20% EtOAc/hexane to give ethyl 3-(4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenyl)propanoate (11 mg, 31% yield) as a clear, colorless oil. LCMS: RT=2.26 min [M+H] 731.93 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: C1(C2SC=[C:10]([C:12]([C:14]3[CH:19]=[C:18](OC)[C:17](OC)=[C:16](OC)[CH:15]=3)=O)[N:11]=2)C=CC=CC=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35]1[S:36][CH2:37][CH:38]([C:40]([OH:42])=O)[N:39]=1.N[C@H](C(O)=O)CS>>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35]1[S:36][CH:37]=[C:38]([C:40]([C:10]2[NH:11][C:19]3[C:14]([CH:12]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:42])[N:39]=1
Reactant: O=C(O)C1CSC(c2cc3ccccc3[nH]2)=N1
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Agent: N[C@@H](CS)C(=O)O
Product: O=C(c1csc(-c2cc3ccccc3[nH]2)n1)c1cc2ccccc2[nH]1

Procedure:
(2-(1H-Indol-2-yl)thiazol-4-yl)(1H-indol-2-yl)methanone (8) was prepared using the similar method as used of compound 1h from 2-(1H-indol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid and cysteine. 1H NMR (500 MHz, CDCl3) δ 9.39 (s, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 8.03 (dd, 1H), 7.66 (d, 1H), 7.51 (d, 1H), 7.41 (d, 1H), 7.33 (t, 1H), 7.29 (d, 1H), 7.15 (t, 1H), 7.09 (d, 1H), 6.72 (s, 1H). MS (ESI) m/z 366.1 (M+Na)+, 341.9 (M−H)−.
Reaction SMILES: [I:1][CH3:2].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CC(C)=O>[I-:1].[CH2:3]([N+:10]1([CH3:2])[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CC(C)=O
Product: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (20.2 ml) was added to a solution of 1-benzyl-4-piperidone (50 ml) in acetone (300 ml) and the mixture was stirred at room temperature overnight. The deposited crystals were collected and washed with acetone to obtain a title compound (77.1 g).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17](O)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[NH2:55][CH2:56][CH:57]1[CH2:66][CH2:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[N:58]1[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68]>CN(C=O)C.O>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([NH:55][CH2:56][CH:57]3[CH2:66][CH2:65][C:64]4[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=4)[N:58]3[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CCC1CN
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCC3CCc4ccccc4N3C(=O)OC(C)(C)C)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
120 mg (0.36 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid Example 21A, 139 mg (0.43 mmol) of TBTU and 0.20 ml (1.81 mmol) of 4-methylmorpholine in DMF (2.3 ml) were stirred at RT for 10 min, 119 mg (0.40 mmol) of rac-tert-butyl 2-(aminomethyl)-3,4-dihydroquinoline-1(2H)-carboxylate hydrochloride were added and the reaction mixture was stirred at RT overnight. Water was added, and the mixture was stirred at RT for 30 min. The solid formed was filtered off, washed with water and dried under high vacuum. This gave 182 mg (85% of theory, purity 98%) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]1[N:14]=[CH:15][N:16]=[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:6]2=1.N1C=CC=CC=1.[Cl-].[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][CH:48]=[S:49])=[CH:43][CH:42]=1)(=[O:40])=[O:39].CO>ClCCl>[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48]([N:21]2[CH2:20][CH2:19][N:18]([C:17]3[C:6]4[C:5]5[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=5)[NH:8][C:7]=4[N:14]=[CH:15][N:16]=3)[CH2:23][CH2:22]2)=[S:49])=[CH:43][CH:42]=1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Nc1ncccn1)c1ccc(NC=S)cc1
Reactant: COc1cc2[nH]c3ncnc(N4CCNCC4)c3c2cc1OC
Agent: [Cl-]
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2[nH]c3ncnc(N4CCN(C(=S)Nc5ccc(S(=O)(=O)Nc6ncccn6)cc5)CC4)c3c2cc1OC
Reaction time: 8 h

Procedure:
To a solution of 6,7-dimethoxy-4-piperazino-9H-pyrimido[4,5-b]indole (200 mg, 0.64 mmol) and pyridine (0.5 mL, 6.4 mmol) in dichloromethane (20 mL) was added a solution of product 1d in dichloromethane (20 mL) and this was stirred overnight. Methanol was added to quench excess thiophosgene, and the residue after removal of solvent was purified by silica gel column chromatography and eluted with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 50 mg (16%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([OH:28])([C:18]([CH3:27])([CH3:26])[CH:19](OS(C)(=O)=O)[CH3:20])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1.CO>O1CCCC1.O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C:18]([CH3:26])([CH3:27])[CH:19]([CH3:20])[O:28]1
Reactant: CC(OS(C)(=O)=O)C(C)(C)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1OC(Cn2cncn2)(c2ccc(F)cc2F)C1(C)C
Reaction time: 0.17 h

Procedure:
10 mg of sodium hydride were added to a solution of 77 mg of this 2-(2,4-difluorophenyl)-3,3-dimethyl-4-(methanesulfonyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-pentanol in 1.5 ml of tetrahydrofuran, whilst ice-cooling and stirring, after which 0.1 ml of methanol was added. After 10 minutes, the reaction mixture was diluted with water and extracted with ethyl acetate. The resulting crude product was purified by column chromatography through silica gel, using a 3:2 by volume mixture of ethyl acetate and hexane as the eluent. The resulting compound was recrystallized from cyclohexane to afford 39 mg of a pure specimen of the title compound, melting at 112°-113° C.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18].O>C(O)C>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:20](/[S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)(=[O:19])=[O:18])\[C:21]#[N:22])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#CCS(=O)(=O)c1ccccn1
Solvent: CCO
Solvent: O
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
2-Nitrothiophen-5-carboxaldehyde (0.157 g) and 2-pyridinesulphonylacetonitrile (0.2 g) were stirred in 2 mL of ethanol containing 0.01 mL piperidine for four hours at 100° C. The mixture was cooled to room temperature and water was added for crystalization. The crude product was filtered and recrystalized from ethanol and water to give 0.15 g of (E)-3-(2-nitrothien-5-yl)-2-[(pyridin-2-yl)sulfonyl] acrylonitrile.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9]Br>[Fe](Cl)Cl.O>[Br:9][C:4]1[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=1
Reactant: CSc1ccccc1
Reactant: BrBr
Agent: Cl[Fe]Cl
Solvent: O
Product: CSc1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A one-liter four-necked flask equipped with a stirrer, thermometer, dropping funnel and Liebig condenser was charged with 124.2 g (1.00 mole) of thioanisole and 0.32 g (0.002 mole) of iron(II) chloride, and 160.0 g (1.00 mole) of bromine was added dropwise with stirring at 50° C. over 4 hours. Thereafter, the reaction was further allowed to proceed for 1 hour. After completion of the reaction, 50 g of water was added, and the organic layer was separated, whereby 203.1 g of crude 4-bromothioanisole was obtained. The purity of the thus-obtained crude 4-bromothioanisole was 90.1% as determined by gas chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:30][C:29]#[CH:28])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
First, 70 mg of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-61) was dissolved in 0.25 ml of N,N-dimethylformamide, to which 36 mg of potassium carbonate and 27 mg of propargyl bromide were added, and the mixture was stirred at 50° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 76 mg (yield, 96%) of 3-[4-chloro-2-fluoro-5-(propargyloxy)phenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-156; m.p., 106.9-107.1° C.).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4]([C:6]1[NH:10][N:9]=[C:8]([N+:11]([O-])=O)[CH:7]=1)=[O:5]>[Pd].CO>[NH2:11][C:8]1[CH:7]=[C:6]([C:4]([N:3]([O:2][CH3:1])[CH3:14])=[O:5])[NH:10][N:9]=1
Reactant: CON(C)C(=O)c1cc([N+](=O)[O-])n[nH]1
Agent: [Pd]
Solvent: CO
Product: CON(C)C(=O)c1cc(N)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A 250-mL single-neck round-bottomed flask was purged with nitrogen and charged with 150a (16.0 g, 1.0 eq., 80.0 mmol), 10% palladium on carbon (50% wet, 800 mg), and methanol (100 mL). The mixture was evacuated, charged with hydrogen gas, and stirred under hydrogen atmosphere at room temperature overnight. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE®. The filtrate was concentrated under reduced pressure to afford 150b (11.0 g, 81%) as a white solid. MS-ESI: [M+H]+ 171.1
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3=[C:20]([C:31]([OH:33])=[O:32])[C:21]([C:28]([OH:30])=O)=[C:22]4[CH:23]=[CH:24][C:25]([CH2:26][OH:27])=[C:17]([N:18]34)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([O:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]2[N:18]3[C:19]([C:15]([C:12]4[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:14][CH:13]=4)=[CH:16][C:17]=13)=[C:20]1[C:31](=[O:32])[O:33][C:28](=[O:30])[C:21]1=2)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1c(C(=O)O)c2c(-c3ccc(OCc4ccccc4)cc3)cc3c(CO)ccc1n32
Product: CC(=O)OCc1ccc2c3c(c4c(-c5ccc(OCc6ccccc6)cc5)cc1n24)C(=O)OC3=O

Procedure:
The general synthetic pathway outlined in example 81, step 5, and example 83 have been applied to proper starting materials in the preparation of 3-(4-benzyloxyphenyl)-5-hydroxymethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid, which was reacted with acetic acid anhydride by the general synthetic principles outlined in example 23, step 8, to afford 5-acetoxymethyl-3-(4-benzyloxyphenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid anhydride as red crystals in 86%. 1H-NMR (DMSO-d6, 300 MHz) δ: 2.17 (s, 3H); 5.22 (s, 2H); 5.67 (s, 2H); 7.19 (d, 2H); 7.32-7.48 (m, 3H); 7.52 (d, 2H); 8.10-8.19 (m, 2H); 8.27 (d, 2H); 8.34 (d, 1H).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]=[C:21]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[N:24]=[C:23]([C:36]([O:38][CH3:39])=[O:37])[CH2:22]1.CO.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C1C=CC=CC=1>[CH3:1][O:20][C:21]1[N:25]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=2)[N:24]=[C:23]([C:36]([O:38][CH3:39])=[O:37])[CH:22]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)C1=NN(c2ccc(C(F)(F)F)cc2)C(=O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1cc(OC)n(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A 500 mL round-bottomed flask was charged with triphenylphosphine (6.9 g, 26 mmol), methyl 5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylate 71 (5.0 g, 17 mmol), MeOH (0.88 mL, 22 mmol), and 200 mL of benzene. After cooling to 0° C., diisopropyl azodicarboxylate (DIAD) (5.2 mL, 26 mmol) was added dropwise. The mixture was stirred at room temperature for 18 h, then diluted with water and extracted with CH2Cl2. The combined extracts were dried and concentrated to give an oil that was purified by column chromatography on silica gel (5% to 40% EtOAc in hexanes) to give methyl 5-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate 72.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[N:22]([C:36]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH3:44])[CH2:40][CH2:39]1)=[O:37])[C@H:23]1[CH2:28][CH2:27][C@H:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:25][CH2:24]1)=[O:16].[C:45]1(=[O:51])[CH2:50][CH2:49][CH2:48][CH:47]=[CH:46]1.[NH4+].[Cl-]>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:45]2([OH:51])[CH2:50][CH2:49][CH2:48][CH:47]=[CH:46]2)=[CH:20][C:21]=1[N:22]([C:36]([C@H:38]1[CH2:39][CH2:40][C@H:41]([CH3:44])[CH2:42][CH2:43]1)=[O:37])[C@H:23]1[CH2:24][CH2:25][C@H:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:27][CH2:28]1)=[O:16]
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1
Reactant: O=C1C=CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1sc(C2(O)C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of THF (0.5 mL) and diisopropylamine (31 μl, 0.22 mmol) cooled to −40° C. n-BuLi (1.3 M, 165 μl, 0.21 mmol) was added dropwise. After stirring at this temperature for 30 min it was cooled to −78° C. and 3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (82 mg, 0.18 mmol) in THF (0.5 mL) was added dropwise. The mixture was stirred at this temperature for 30 min. Cyclohex-2-enone (20 μl, 0.21 mmol) was added quickly and it was stirred for 20 min at −78° C. Saturated NH4Cl solution was added and the mixture was allowed to come to room temperature. It was extracted with EtOAc. The extract was washed with brine, dried (MgSO4) and evaporated. Pure 5-(1-hydroxy-cyclohex-2-enyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester was obtained after chromatography over silica gel (hexane:EtOAc—80:20 as eluent) (48 mg, 48%).
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][N:13]([CH3:27])[S:14]([C:17]1[C:18]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15].[Cl:28][C:29]1[N:34]=[C:33]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[C:32](=[O:45])[N:31]([CH3:46])[CH:30]=1.C(O)(=O)C>C(#N)C>[Cl:28][C:29]1[N:34]=[C:33]([NH:35][C:36]([NH:26][S:23]([C:18]2[C:17]([S:14]([N:13]([CH3:27])[CH3:12])(=[O:16])=[O:15])=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:25])=[O:24])=[O:37])[C:32](=[O:45])[N:31]([CH3:46])[CH:30]=1
Reactant: Cn1cc(Cl)nc(NC(=O)Oc2ccccc2)c1=O
Reactant: CN(C)S(=O)(=O)c1ccccc1S(N)(=O)=O
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CN(C)S(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cn(C)c1=O
Reaction time: 3 h
Yield: 84.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.30 mL, 2.00 mmol) was added dropwise over two minutes to a mixture of N,N-dimethyl-1,2-benzenedisulfonamide (0.53 g, 2.00 mmol) and phenyl (6-chloro-3,4-dihydro-4-methyl-3-oxopyrazin-2-yl)carbamate (0.56 g, 2.00 mmol) in anhydrous acetonitrile (20 mL) under nitrogen. After 3 hours at room temperature, glacial acetic acid (0.12 mL, 2.10 mmol) was added. The solvent was rotary evaporated and the residue was chromatographed on a column of silica gel using a solvent mixture of 1:1 dichloromethane-ether containing 2 mL/L acetic acid as eluant. The appropriate fractions were evaporated to leave 0.76 g of N'-[(6-chloro-3,4-dihydro-4-methyl-3-oxopyrazin-2-yl)aminocarbonyl]-N,N-dimethyl-1,2-benzenedisulfonamide as a crystalline solid melting at 227°-230° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]#[C:19][Si](C)(C)C)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO.C(OCC)(=O)C>[C:18]([C:17]1[CH:16]=[N:15][N:5]2[CH:6]=[C:7]([C:9]3[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=3)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=12)#[CH:19]
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C#C[Si](C)(C)C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0.10 M solution of 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-[(trimethylsilyl)ethynyl]pyrazolo[1,5-a]pyridine (788 mg, 2.43 mmol) in tetrahydrofuran and methanol (1:1, v/v) was added potassium carbonate (336 mg, 2.43 mmol). The reaction mixture was stirred at ambient temperature for two hours, and then diluted with ethyl acetate. The mixture was washed with saturated aqueous ammonium chloride and brine. The organic layer was separated, and the aqueous layer was back extracted with ethyl acetate three times. The combined organic layers was dried over sodium sulfate, filtered and concentrated to give 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine. LRMS (ESI) calculated for C14H13N4O [M+H]+, 252.1; found 253.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([S:10][CH2:11][CH:12]([CH3:16])[C:13](Cl)=[O:14])=[O:9])=[CH:4][CH:3]=1.C(SCC(C)C(Cl)=O)(=O)C.C(SCC(C)C([N:35]1[CH2:39][CH2:38][CH:37]=[C:36]1[C:40]([OH:42])=[O:41])=O)(=O)C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([S:10][CH2:11][CH:12]([CH3:16])[C:13]([N:35]2[CH2:39][CH2:38][CH:37]=[C:36]2[C:40]([OH:42])=[O:41])=[O:14])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)SCC(C)C(=O)Cl)cc1
Reactant: CC(=O)SCC(C)C(=O)N1CCC=C1C(=O)O
Agent: CC(=O)SCC(C)C(=O)Cl
Product: Cc1ccc(C(=O)SCC(C)C(=O)N2CCC=C2C(=O)O)cc1

Procedure:
Following the procedure of Example 1 but substituting an equivalent amount of 3-[[(4-methylphenyl)-carbonyl]thio]-2-methylpropanoyl chloride for the 3-acetylthio-2-methylpropanoyl chloride in part 1(b) and subjecting the product to the procedure of Example 1 (c), one obtains (±)-4,5-dihydro-1-[3-[[(4-methylphenyl)carbonyl]thio]-2-methyl-1-oxopropyl]-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].[CH3:6][Si:7](Cl)([CH3:9])[CH3:8]>C[Si](N[Si](C)(C)C)(C)C>[Si:7]([O:4][CH:2]([CH2:1][O:5][Si:7]([CH3:9])([CH3:8])[CH3:6])[CH3:3])([CH3:9])([CH3:8])[CH3:6]
Reactant: CC(O)CO
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CC(CO[Si](C)(C)C)O[Si](C)(C)C

Procedure:
1,2-Propanediol (58.8 g, 0.77 mol) was placed in a 500 mL 3-necked RB flask and treated with 0.2 mL trimethylsilyl chloride. A small volume of HMDS (ca. 10 mL) was added, and an exothermic reaction took place as the mixture became homogeneous. The remainder of the HMDS (170 mL) was added at a controlled rate (ca. 3-5 mL/min), maintaining the reaction temperature at ca. 50°-70° C. Heating was continued at 100° C. (1.5 h), 120° C. (1.0 h),and 140° C. (2.5 h). GC analysis (method 1) revealed excess HMDS and one product. Distillation provided 147 g of colorless oil, bp 70°-72° C./10 mm. 1H NMR (CDCl3): 3.83 (m, 1H), 3.50 and 3.38 (AB pattern with additional coupling, 2H), 1.15 (d, J=7 Hz, 3H), 0.15 (partially resolved singlets, 18H).