Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=[NH:16].[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)(C)(C)C.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=[N:16][C:24]([NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[N:23][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N=c1ccccn1CCc1ccccc1Br
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCCCC
Solvent: CC(C)(C)O
Product: Brc1ccccc1CCn1ccccc1=NC(=NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Yield: 12 %

Procedure:
A solution of 1-[2-(2-bromophenyl)ethyl]-2-iminopyridine (2.77 g, 0.01 mole) and dicyclohexylcarbodiimide (2.06 g, 0.01 mole) in 30 ml of t-butanol is heated at reflux for 21.5 hours under a nitrogen blanket. The solution is cooled to room temperature and diluted with 60 ml of hexane. The diluted solution is cooled and scratched in a dry ice bath to induce crystallization. The mixture is allowed to warm to room temperature and is filtered to give 0.58 g of material which sinters at 121°C and melts at 125°-129°C. The filtrate is concentrated in vacuo and the residual oil is cooled in an ice bath and scratched under 40 ml of hexane to give 1.32 g of material which sinters at 100°C and melts at 108°-110°C. The two batches of material are combined and dissolved in a boiling solution of 60 ml of cyclohexane and 60 ml hexane and filtered. The solution is cooled for several hours at -30°C, filtered and washed with cooled hexane to yield 1.33 g of the title compound, melting point 127°-129.5°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[NH:23]1[C:27]([S:28](Cl)(=[O:30])=[O:29])=[N:26][CH:25]=[N:24]1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[N:11]([S:28]([C:27]3[NH:23][N:24]=[CH:25][N:26]=3)(=[O:30])=[O:29])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ncn[nH]1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1n(S(=O)(=O)c2ncn[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg (1.27 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 36A] were dissolved in 10 ml of THF, and 143 mg (1.27 mmol) of potassium tert-butoxide were added at −78° C. Over a period of 30 min, the reaction mixture was warmed to RT, and the mixture was stirred at this temperature for a further 20 min. The mixture was then once more cooled to −78° C., and 213 mg (1.27 mmol) of 1H-1,2,4-triazole-5-sulfonyl chloride, dissolved in 5 ml of THF, were added. Over a period of 30 min, the reaction mixture was warmed to RT, and the mixture was stirred at this temperature for a further 20 h. For work-up, 10 ml of water were added. The mixture was extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 136 mg (29% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])[CH2:5]O.C(N(S(F)(F)[F:23])CC)C>ClCCl>[CH3:1][O:2][N:3]=[C:4]([CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])[CH2:5][F:23]
Reactant: CON=C(CO)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CON=C(CF)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
To a stirred brown suspension of 1-hydroxy-3-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime (33 g; 117 mmol) in dichloromethane (235 ml) at −20° C. under nitrogen was added dropwise a solution of diethylaminosulfur trifluoride (16 ml; 123 mmol) in dichloromethane (62 ml). During addition, temperature rose to −10° C. The mixture turned to a brown orange solution which was allowed to warm at 20° C. and was stirred for 2 hours. The organic solution was washed with saturated hydrogen carbonate solution (200 ml), 1N hydrochloric acid (200 ml), brine (200 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 37 g (110% of theory) of crude 1-fluoro-3-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime (isomers E/Z) as a brown oil.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][N:6]2[CH:13]=1.S(Cl)([Cl:16])=O>ClC(Cl)Cl>[ClH:16].[Cl:1][CH2:11][C:9]1[CH:8]=[CH:7][N:6]2[CH:13]=[C:3]([CH3:2])[N:4]=[C:5]2[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cn2ccc(CO)cc2n1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1cn2ccc(CCl)cc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a stirred mixture of 10.7 parts of 2-methylimidazo[1,2-a]pyridine-7-methanol monohydrochloride and 150 parts of trichloromethane were added dropwise 9.6 parts of thionyl chloride. The resulting solution was stirred for 15 minutes at room temperature. The reaction mixture was evaporated in vacuo and the residue was stirred in 80 parts of 2-propanone. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 11.8 parts (100%) of 7-(chloromethyl)-2-methylimidazo[1,2-a]pyridine monohydrochloride; mp. 178.5 (intermediate 16).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[N:20][C:21]([Cl:27])=[CH:22][CH:23]=2)[N:18]=1.C(O)C>O>[Cl:27][C:21]1[N:20]=[C:19]2[C:24]([CH:25]=[CH:26][C:17]([NH:16][C:6](=[O:8])[C:5]3[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:18]2)=[CH:23][CH:22]=1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)Nc2ccc3ccc(Cl)nc3n2)cc(OC)c1OC
Temperature: 4 °C
Yield: 44.3 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 3,4,5-trimethoxybenzoic acid (17 g), N,N'-carbonyldiimidazole (13 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product obtained by precipitation in water (10.3 g; m.p. 90° C.) is dissolved in boiling ethanol (500 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with ethanol (20 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3,4,5-trimethoxybenzamide (8.2 g), m.p. 210° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH2:28][CH:29]([OH:31])[CH3:30]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH:29]([OH:31])[CH3:30])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: CC(O)CN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Product: CC(O)CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 45 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg) and 1-amino-2-propanol (150 mg) were added to pyridine (500 mg), and the mixture was stirred at 45° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (150 mg) was added to the residue, and the mixture was concentrated under reduced pressure. Ethanol (1 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (157 mg) as a pale brown powder.
Reaction SMILES: C(N(CC)C(C1C=CC=CC=1S([C:14]1[C@H:15]([CH3:38])[C@@H:16]2[C@@H:33]([C@H:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=O)C.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@H:52]([NH:55][C:56]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][C:63]([N+:66]([O-:68])=[O:67])=[CH:62][CH:61]=3)=[O:57])[CH2:51]2)=[O:49])[CH2:43]1>>[N+:66]([C:63]1[CH:62]=[CH:61][C:60]([CH2:59][O:58][C:56]([NH:55][C@H:52]2[CH2:53][CH2:54][N:50]([C:48]([C@H:44]3[N:45]([CH3:47])[CH2:46][C@@H:42]([S:41][C:14]4[C@H:15]([CH3:38])[C@@H:16]5[C@@H:33]([C@H:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]5[C:18]=4[C:19]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=4)=[O:20])[CH2:43]3)=[O:49])[CH2:51]2)=[O:57])=[CH:65][CH:64]=1)([O-:68])=[O:67]
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 60 %

Procedure:
Following a procedure similar to that described in Example 27(b), but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate [prepared as described in Example 27(a)] and (2S,4S)-4-mercapto-2-[3 (S)-(4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-ylcarbonyl]-1-methylpyrrolidine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a powder in a yield of 60%.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[NH2:19][C:20]1[C:25]([S:26](Cl)(=[O:28])=[O:27])=[CH:24][C:23]([Br:30])=[CH:22][N:21]=1>O1CCOCC1.O>[NH2:19][C:20]1[C:25]([S:26]([N:1]2[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]2)(=[O:28])=[O:27])=[CH:24][C:23]([Br:30])=[CH:22][N:21]=1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2cc(Br)cnc2N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of tert-butyl azetidin-3-ylcarbamate (64 mg, 0.37 mmol) and potassium carbonate (102 mg, 0.74 mmol) in dioxane (2 mL) and water (400 uL) was added 2-amino-5-bromopyridine-3-sulfonyl chloride (100 mg, 0.37 mmol, prepared according to the methods in WO2008144463). The reaction mixture was stirred for 1 h at room temperature then quenched by addition of saturated aqueous sodium bicarbonate, and the aqueous solution was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to provide tert-butyl 1-(2-amino-5-bromopyridin-3-ylsulfonyl)azetidin-3-ylcarbamate (120 mg, 0.30 mmol, 80% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, 1H), 8.00 (d, 1H), 5.76 (br s, 2H), 4.80 (br s, 1H), 4.50-4.36 (m, 1H), 4.11 (t, 2H), 3.75 (t, 2H), 1.42 (s, 9H); MS (EI) for C13H19BrN4O4S: 407, 409 (Br isotopes, MH+).
Reaction SMILES: [O:1]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C@@H:2]1[C:3]([O:5]C)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23].C1(C)C(C)=CC=CC=1>CS(O)(=O)=O.CO>[OH:1][C@H:2]1[C:3](=[O:5])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][C@H:7]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Reactant: Nc1ccccc1S
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: Cc1ccccc1C
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A mixture of 40 g of methyl (2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate, 26.5 g of 2-aminothiophenol and 300 ml of xylene is heated at 110° to 120° C. for 1 hour, whereby the reaction mixture containing methyl (2S,3S)-3-[(2-aminophenyl)thiol]-2-hydroxy-3-(4-methoxylphenyl)propionate is obtained. 380 mg of methanesulfonic acid are added to the mixture and the mixture is refluxed for 7 hours. During the reaction, methanol formed is removed by the azeotropic distillation with xylene. The mixture is cooled to under 10° C. and then stirred for 1 hour. Precipitated crystals are collected by filtration, washed with cooled methanol and then dried, whereby 49.1 g of (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained. Yield: 84.8% m.p.: 204°-205° C. [α]D20 +115° (c=0.5, dimethylformamide)
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:21][CH2:20][CH2:19]1)=[O:17])[CH3:14].[CH3:22][S:23]([O:26][C@H:27]([CH2:29][CH2:30]I)[CH3:28])(=[O:25])=[O:24]>C1COCC1>[CH3:22][S:23]([O:26][C@@H:27]([CH3:28])[CH2:29][CH2:30][C:18]1([C:16]([O:15][CH2:13][CH3:14])=[O:17])[CH2:21][CH2:20][CH2:19]1)(=[O:25])=[O:24]
Reactant: C[C@@H](CCI)OS(C)(=O)=O
Reactant: CCOC(=O)C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(CC[C@H](C)OS(C)(=O)=O)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
To a solution of diisopropylamine (9.1 mL, 65 mmol) in 43 mL of THF was added n-BuLi (26 mL, 65 mmol) at 0° C. slowly (5 min). The mixture was stirred at 0˜5° C. for 30 min. After the mixture was cooled to −78° C. (10 min), Ethylcyclobutanecarboxylate (8 mL, 59.6 mmol, 1.1 eq.) was added dropwise and stirred at −78° C. for 30 min. The enolate was added into the solution of (S)-4-iodobutan-2-yl methanesulfonate 96 (15 g, 54 mmol) in 100 mL of THF at −78° C. Cooling bath was removed to allow the reaction to warm up to RT. After 30 min at RT, reaction was quenched by addition of water and extracted with EtOAc. The organic layer was washed with brine then dried over MgSO4, filtered and concentrated down. The residue was purified by silica gel chromatography first with (5% to 30% EtOAc in hexanes) then 100% DCM to (98% DCM/2% EtOAc) to provide 5.3 g (36% isolated yield) of (S)-ethyl 1-(3-(methylsulfonyloxy)butyl)cyclobutanecarboxylate 97.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:15]([F:16])=[C:14]([CH2:17]Br)[CH:13]=[CH:12][C:11]=2[Cl:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH3:20]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:15]([F:16])=[C:14]([CH2:17][NH2:20])[CH:13]=[CH:12][C:11]=2[Cl:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N
Reactant: Fc1c(CBr)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Solvent: CO
Solvent: ClCCl
Product: NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of 2-[(3-bromo-5-chlorophenyl)oxy]-4-(bromomethyl)-1-chloro-3-fluorobenzene (2.0 g, 4.7 mmol) in CH2Cl2 (10 mL) was added ammonia in methanol (7N, 100 mL). The reaction mixture was stirred for 4 h and concentrated. The resulting crude material was triturated from water to afford the title compound (1.55 g, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d5): δ ppm 7.57-7.49 (m, 3H), 7.12-7.11 (m, 1H), 7.05-7.04 (m, 1H), 5.99 (br s, 2H), 3.95 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][O:18][CH2:19][CH2:20][NH2:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:21][CH2:20][CH2:19][O:18][CH3:17]
Reactant: COCCN
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
In 43 ml of dichloromethane were dissolved 2.45 g of 3,5-bistrifluoromethylbenzaldehyde, 835 mg of 2-methoxyethylamine and 687 μl of acetic acid, added thereto was 3.12 g of sodium triacetoxy borohydride, and the mixture was stirred at room temperature for an hour under nitrogen atmosphere. The reaction mixture was washed with a 0.5M aqueous sodium hydroxide solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=19:1→9:1), to give 2.76 g of 3,5-bistrifluoromethylbenzyl-2-methoxyethylamine.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:33][CH2:32][N:24]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=3[CH:31]=[C:23]2[C:22]1=[O:34])(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:60][O:59][CH2:58]4)[CH2:53][CH2:52]3)=[CH:47][N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[CH:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:58][O:59][CH2:60]4)[CH2:53][CH2:52]3)=[CH:47][N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 53.2 %

Procedure:
Following Example 148b, 464 mg of 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a and 420 mg of 188e were reacted to give 188f as a yellow solid (360 mg, 54%). LCMS: [M+H]+ 678
Reaction SMILES: [OH:1][CH:2]([CH2:23][OH:24])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[K+].[C:27](OC)(=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[OH:1][CH:2]([CH2:23][OH:24])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCCCCCCCCNCC(O)CO
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCN(CC(O)CO)C(=O)CCCCCCCCCCCCCCC

Procedure:
N-(2,3-dihydroxypropyl)-octadecylamine (1.0 g, 0.0029 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum. Methyl palmitate (0.7885 g, 0.0029 mole) was heated and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=1.59 g). The waxy solid was recrystalized from hot hexane (yield=0.99 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:10](CC2C=CC(OC)=CC=2OC)[CH2:9][C:8]2[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:23][S:24][C:7]=2[C:6]1=[O:32])=[O:4].S(Cl)(Cl)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]2[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:23][S:24][C:7]=2[C:6]=1[OH:32])=[O:4]
Reactant: COC(=O)C1C(=O)c2scc(-c3ccc(F)cc3)c2CN1Cc1ccc(OC)cc1OC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ncc2c(-c3ccc(F)cc3)csc2c1O
Reaction time: 5 h
Yield: 61.3 %

Procedure:
5-(2,4-dimethoxy-benzyl)-3-(4-fluoro-phenyl)-7-oxo-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-6-carboxylic acid methyl ester (0.39 g, 0.86 mmol), example 31-e, was dissolved in 6 mL of anhydrous dichloromethane. To the solution was added 93.7 μL of thionyl chloride, and the reaction mixture was stirred for 5 hours. The solution was filtered on a fine glass frit filter to collect a white solid precipitate. The solid was washed twice with cold dichloromethane and then partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated to produce 0.16 g of a white solid. MS: (+) m/z 304.0 (M+1)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16]Br>>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: O=Cc1c[nH]c2ccccc12
Product: O=Cc1cn(Cc2ccc(F)c(F)c2)c2ccccc12

Procedure:
The same procedures used in Example 1 were repeated except for using 870 mg of indole-3-carbaldehyde and 3,4-difluorobenzyl bromide in place of the benzyl bromide used in Example 1 to give 1.59 g of 1-(3,4-difluorobenzyl)indole-3-carbaldehyde as pale brown crystals. The yield thereof was found to be 98%.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([OH:21])[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:22][N:23]([CH3:27])[C:24](Cl)=[S:25].O>CN(C=O)C>[CH3:22][N:23]([CH3:27])[C:24](=[S:25])[O:21][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([C:3]23[CH2:4][CH:5]4[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]4)[CH2:12]2)[CH2:10]3)[CH:14]=1
Reactant: COc1ccc(O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC(=S)N(C)C)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C

Procedure:
600 mg (20 mmol) of sodium hydride (80% in oil) and 50 ml of DMF were introduced into a round-bottomed flask under a stream of nitrogen. The mixture was cooled to 0° C. and a solution of 5.5 g (20 mmol) of 3-(1-adamantyl)-4-methoxyphenol in 100 ml of DMF was added dropwise, tand he mixture was stirred until the evolution of gas had ceased. A solution of 3.3 g (26 mmol) of dimethylthiocarbamoyl chloride in 50 ml of DMF was then added thereto and the mixture was stirred for eight hours at room temperature. The reaction medium was poured into water and extracted with ethyl acetate. The organic phase was separated out after settling had taken place, washed with water, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and hexane (70/30). After evaporation of the solvents, 3.1 g (46%) of the expected compound having a melting point of 162°-4° C., were recovered.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][CH2:32][CH2:33][OH:34])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[F:35][C:36]([F:44])(S(F)(=O)=O)C(O)=O>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][CH2:32][CH2:33][O:34][CH:36]([F:44])[F:35])=[N:10][N:11]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: Cc1nc(Cl)cc2c1c(OCCO)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1nc(Cl)cc2c1c(OCCOC(F)F)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 59 %

Procedure:
In a manner similar to that previously described (e.g. synthesis of Intermediate 59B/Step 2), 2-((6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)oxy)ethanol was reacted with 2,2-difluoro-2-(fluorosulfonyl)acetic acid (copper(I) iodide, acetonitrile, 80° C. 30 min) to provide 6-chloro-3-(2-(difluoromethoxy)ethoxy)-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine 59% yield) as a white crystalline solid. MS: [M+H]+ m/z 520.