Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[C:10]2[CH:27]=[CH:28][CH:29]=[CH:30][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl.C(Cl)Cl>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:31])[CH2:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:10]2[CH:27]=[CH:28][CH:29]=[CH:30][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCN1C(=O)c2ccccc2C(CC(=O)OC(C)(C)C)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CC1c2ccccc2C(=O)N(CCC(=O)O)c2ccccc21
Temperature: 25 °C

Procedure:
Ethyl 3-[11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5-H-dibenzo[b,e]azepin-5-yl]propanoate 5 (2.55 g, 6.02 mmol) was dissolved in 15 ml of 2:1 dioxane/H2O and, after addition of 0.17 g of LiOH, stirred at RT. After the reaction was complete, the mixture was acidified with 2N HCl and, after addition of CH2Cl2, washed with saturated NaCl solution, dried and concentrated.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=[C:7]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:6]=1.[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][NH2:29]>ClCCl>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][NH:29][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[CH:5]=[CH:6][C:7]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])=[CH:8][CH:9]=1
Reactant: CN(C)CCCN
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C)CCCNC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 4 °C
Reaction time: 16 h

Procedure:
1.25 ml of thionyl chloride is added at 0° C., under an inert atmosphere, to a solution of 1.61 mmol of chlorambucil in 5 ml of dichloromethane The reaction mixture is stirred at 4° C. for 16 hours and then excess SOCl2 is evaporated off under reduced pressure. The residue obtained is taken up in 10 ml of dichloromethane. 1.61 mmol of 3-(dimethylamino)propylamine dissolved in 10 ml of dichloromethane are added to the resulting solution at 0° C. under an inert atmosphere. The mixture is then stirred at ambient temperature for 1 hour. At the end of that time, a second addition of 1.61 mmol of diamine is carried out. After 4 hours+ stirring, the reaction mixture is evaporated under reduced pressure. Following neutralisation with a 1N NaHCO3 solution, the aqueous phase is extracted several times with dichloromethane. The different organic phases are combined, washed with water until neutral, dried, filtered and evaporated under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluant: gradient of ethanol in dichloromethane starting from 0 and going up to 50% and then, to finish, the eluant: dichloromethane/ethanol/ammonia, 50/49/1, is used). The expected product is obtained in the form of an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]([C:15]2[N:19]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:18]=[CH:17][CH:16]=2)=[C:11]([CH3:28])[N:10]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:9]1=[O:39].C(N(CC)CC)C.[C:47](Cl)(=[O:49])[CH3:48].C(=O)([O-])O.[Na+]>ClCCl>[C:24]([C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:15]([C:12]3[C:13](=[O:14])[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2][C:47](=[O:49])[CH3:48])[C:9](=[O:39])[N:10]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:38])[F:37])[CH:30]=4)[C:11]=3[CH3:28])=[CH:16][CH:17]=[N:18]2)=[CH:27][CH:26]=1)#[N:25]
Reactant: CC(=O)Cl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(CCCCCN)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCCCn1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 0.08 h
Yield: 59.6 %

Procedure:
To a solution of 4-[5-[3-(5-aminopentyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile hydrochloride (prepared in Example 85) (6.4 mg) and triethylamine (10 μl) in dichloromethane (1.0 ml) was added acetyl chloride (0.7 mg) in ice-cooling and the resulting mixture was stirred for five minutes and stirred at room temperature for thirty minutes. To the reaction mixture was added aqueous saturated sodium hydrogen carbonate solution (10 ml) and the resulting mixture was extracted with chloroform (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford N-[5-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]pentyl]acetamide (3.0 mg).
Reaction SMILES: C[Si](N[Si](C)(C)C)(C)C.[Li][CH2:11][CH2:12][CH2:13]C.[O:15]=[C:16]1[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:18][CH2:17]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].BrCC=C>C1COCC1.CCCCCC>[CH2:13]([C@H:17]1[C:16](=[O:15])[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:18]1)[CH:12]=[CH2:11]
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: [Li]CCCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC[C@@H]1C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
To a solution of HMDS in anhydrous THF (200 mL) was added dropwise 2.5 M n-BuLi in hexane (130 mL) and the mixture was stirred at −78° C. for 1 hr. To a solution of (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (8.0 g, 0.311 mol) in anhydrous THF (1600 mL) stirred at −78° C. was added lithium hexamethyldisilazide in THF. After the reaction mixture was stirred at −78° C. for 1 hr, 3-bromopropene (38.47 g, 0.318 mol) in THF (200 mL) was added and stirring was continued for 2 hr. The reaction mixture was quenched with saturated ammonium chloride solution (600 mL) at −78° C. and extracted with EtOAc (3×500 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The crude product was separated by column chromatography to afford (2S,4R)-1-tert-butyl 2-ethyl 4-allyl-5-oxopyrrolidine-1,2-dicarboxylate (15 g, 16%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)/[CH:10]=[CH:11]/[C@H:12]1[C@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:15][C:14](=[O:25])[C@@H:13]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].OO.[Na+].[Cl-]>C1COCC1>[Si:1]([O:8][C@@H:9]([CH2:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)/[CH:10]=[CH:11]/[C@H:12]1[C@H:16]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20])[CH2:15][C@H:14]([OH:25])[C@@H:13]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@H](CCc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](CCc2ccccc2)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Yield: 30 %

Procedure:
To a cold solution of crude compound 10b (about 400 g) prepared in EXAMPLE 19 in THF (1.2 L) was added a solution of L-selectride in THF (1 M, 400 mL) with stirring. 30% H2O2 (150 mL) was added at −30° C., the mixture was warmed and then stirred for 0.5 h. Saturated aqueous NaCl (1400 mL) was added and the mixture was extracted twice with MTBE (1 L each), concentrated under reduced pressure. The crude product was purified by column chromatography to give about 120.5 g of compound (11b).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.O.CCOC(C)=O.[CH3:33][N:34](C=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10]([C:33]#[N:34])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NC4CC4)nc(Cl)nc32)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of 2-chloro-N-cyclopropyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (200 mg, 0.409 mmol), Pd2 dba3 (23 mg, 0.025 mmol) and dppf (45 mg, 0.081 mmol) in DMF (2 mL) was degassed with Ar before being charged with Zn(CN)2 (28 mg, 0.24 mmol). The mixture was stirred at 70° C. for 2 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a flash silica gel column, eluted with EtOAc/hexane (0-15%) to give 2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (110 mg).
Reaction SMILES: [CH2:1]([C:8]1[N:13]([CH3:14])[C:12](=[O:15])[C:11](Br)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:28]>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.O.C(Cl)Cl.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>[CH2:1]([C:8]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([F:28])[CH:21]=2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(Cc2ccccc2)ncc(Br)c1=O
Reactant: COc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc(Cc3ccccc3)n(C)c2=O)cc1F
Temperature: 25 °C

Procedure:
2-Benzyl-5-bromo-3-methyl-3H-pyrimidin-4-one (Step 3, 11.1 g, 39.9 mmol), 4-methoxy-3-fluorophenylboronic acid (10.12 g, 59 mmol) and Pd(PPh3)4 (2.3 g, 1.9 mmol) in 2 M Na2CO3 (100 mL) and dioxane (150 mL) were heated to 90° C. for 1 h. The reaction was cooled to RT, and diluted with H2O and CH2Cl2. The organics were separated and washed with brine, dried (Na2SO4) and filtered through a plug of silica. The filtrate was concentrated under reduced pressure. Et2O/hexane (1:1) were added and the reaction was concentrated under vacuum to a brown solid. The solid was triturated with 20% Et2O/hexane to afford the title compound as a yellow solid. MS (ESI pos. ion) m/z: 325.2. Calc'd for C19H17FN2O2: 324.13.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.Cl.[OH-].[Na+]>O.[Zn]>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[CH:7]([C:16]([OH:18])=[O:17])[C:6](=[CH2:5])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)O
Yield: 55.7 %

Procedure:
Zinc powder (40 g) was added to a solution of 7-aminocephalosporanic acid (27.3 g) and conc. hydrochloric acid (70 ml.) in water (200 ml.) for 5° C. and stirred for an hour. The resultant solution was adjusted to pH 4.0 with 4 N sodium hydroxide and concentrated to 100 ml. of the volume. After adjusting the solution to pH 4.0, the solution was allowed to stand under cooling overnight. The precipitates were collected by filtration to give 7-amino-3-methylenecepham-4-carboxylic acid (11.96 g.).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([CH3:20])[C:11]=1[CH:21]([C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[C:27]([Cl:33])[N:26]=[C:25](Cl)[C:24]=1[Cl:35])[OH:22]>CO.[C].[Pd]>[CH3:8][O:9][C:10]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([CH3:20])[C:11]=1[CH:21]([C:23]1[C:24]([Cl:35])=[CH:25][N:26]=[C:27]([Cl:33])[C:28]=1[C:29]([F:30])([F:32])[F:31])[OH:22]
Reactant: COc1cc(C)c(C(O)c2c(Cl)c(Cl)nc(Cl)c2C(F)(F)F)c(OC)c1OC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(C)c(C(O)c2c(Cl)cnc(Cl)c2C(F)(F)F)c(OC)c1OC
Reaction time: 14 h
Yield: 24 %

Procedure:
2.7 ml (19 mmol) of triethylamine and 0.9 g of 5% palladium carbon were added to a solution having 2,3,4-trimethoxy-6-methylphenyl)(2,3,6-trichloro-5-trifluoromethyl-4-pyridyl)methanol obtained in Step (a) dissolved in 200 ml of methanol, followed by stirring under a hydrogen atmosphere for 14 hours. The mixture was subjected to filtration, 30 ml of water was added, and methanol was distilled off under reduced pressure. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 2.38 g (yield: 24%) of (2,3,4-trimethoxy-6-methylphenyl)(2,5-dichloro-3-trifluoromethyl-4-pyridyl)methanol (melting point 162 to 165° C.).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([NH2:10])[C:8]#[N:9].C(N(CC)CC)C.[CH3:18][N:19]1[CH:23]=[C:22]([C:24](Cl)=[O:25])[C:21]([CH2:27][O:28][CH3:29])=[N:20]1.Cl.C(N(CC)CC)C>C(OCC)(=O)C.O>[CH3:18][N:19]1[CH:23]=[C:22]([C:24]([NH:10][CH:7]([C:3]2[O:2][CH:6]=[CH:5][CH:4]=2)[C:8]#[N:9])=[O:25])[C:21]([CH2:27][O:28][CH3:29])=[N:20]1
Reactant: N#CC(N)c1ccco1
Reactant: COCc1nn(C)cc1C(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COCc1nn(C)cc1C(=O)NC(C#N)c1ccco1
Yield: 77.8 %

Procedure:
In 100 ml of ethyl acetate was suspended 3.2 g of alpha-(2-furyl)-aminoacetonitrile hydrochloride, and with ice cooling, 4.5 g of triethylamine was added. Then, 3.8 g of 1-methyl-3-methoxymethylpyrazole-4-carboxylic acid chloride was gradually added at 0° to 5° C. with stirring. After the addition, the mixture was further stirred at room temperature for 2 hours. Water (50 ml) was added to dissolve the precipitated triethylamine hydrochloride. The ethyl acetate layer was separated, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was chromatographed on a silica gel column, and the column was eluted with hexane/ethyl acetate to give 4.3 g (yield 78.6%) of the desired alpha-(1-methyl-3-methoxymethylpyrazol-4-ylcarbonylamino)-(2-furyl)acetonitrile.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH3:10][C:11]([CH3:22])([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])[CH3:12]>>[F:9][C:2]([F:1])([F:8])[C:3]([N:19]1[CH2:18][CH2:17][N:16]([C:14]([O:13][C:11]([CH3:22])([CH3:12])[CH3:10])=[O:15])[CH2:21][CH2:20]1)=[O:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(F)(F)F)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Ethyl trifluoroacetate (3.9 g, 0.027 mole) was added over 10 minutes to a warm (40° C.) stirred melt of 5.2 g (0.028 mole) 1-[1,1-dimethylethoxycarbonyl]piperazine. The mixture was heated at 120° C. for 2 hours, cooled to room temperature, treated with 1.0 g (0.007 mole) ethyl trifluoroacetate, and reheated for an additional 2 hours. The mixture was allowed to stand 18 hours at room temperature and then was evaporated in vacuo. The residue was dissolved in ether, passed through an alumina-packed column (2.2×16 cm), the eluent collected, washed with dilute aqueous HCl, dried (MgSO4), filtered, and evaporated in vacuo to yield 6.6 g yellow oil which solidified on standin g Recrystallization from hexane gave 6.0 g of white, crystalline solid, m.p. 66°-68° C. Calc. for C11H17F3N2O3 (282.26): C, 46.81; H, 6.07; N, 9.92. Found: C, 46.76; H, 6.40; N, 10.12.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH2:20]O)([CH2:18]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.FC(S(OS(C(F)(F)F)(=O)=O)(=O)=O)(F)F.[C:46]1([CH:52]([NH2:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(Cl)Cl.C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]2([CH2:20][N:59]([CH:52]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:18]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CO)(CO)c2ccc(Cl)cc21
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2(CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a stirred mixture of 6-chloro-3,3-bis-hydroxymethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.31 g, 1 mmol), DIPEA (0.645 g, 5 mmol) and acetonitrile (5 mL) at −25° C. under nitrogen was added a solution of trifluoromethylsulfonic anhydride in DCM (1 M, 2.1 mL) dropwise over 0.3 h (T<−20° C.) and resulting mixture was stirred at −20° C. for 1 h), then a solution of C,C-diphenylmethylamine (0.179 g, 0.98 mmol) in acetonitrile (2 mL) was added (T<−20° C.) and stirring continued for 0.5 h. Mixture was warmed slowly to 20° C. and left thus for 16 h, heated at 75° C. for 8 h and then evaporated in vacuo. Chromatography (SiO2; gradient elution with 0-40% Et2O in petrol) gave the title compound (0.273 g). 1H NMR (CDCl3): 7.47 (4H, d), 7.35-7.27 (6H, m), 7.22 (2H, t), 7.05 (1H, dd), 4.41 (1H, s), 4.15-4.10 (2H, m), 3.37 (2H, d), 3.30 (2H, d), 1.64-1.55 (9H, m).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:23])([F:22])[C:9]1[CH:10]=[C:11]([C:16]#[C:17][Si](C)(C)C)[C:12]([NH2:15])=[N:13][CH:14]=1>CN1C(=O)CCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[F:7][C:8]([F:23])([F:22])[C:9]1[CH:10]=[C:11]2[CH:16]=[CH:17][NH:15][C:12]2=[N:13][CH:14]=1
Reactant: C[Si](C)(C)C#Cc1cc(C(F)(F)F)cnc1N
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 59.3 %

Procedure:
To a stirred solution of potassium tert-butoxide (53.6 g, 479 mmol) in anhydrous NMP (200 mL) under a nitrogen atmosphere at 80° C. was added a solution of 5-trifluoromethyl-3-((trimethylsilyl)ethynyl)pyridin-2-amine (62 g, 239 mmol) in NMP (100 mL) at a rate to maintain the internal temperature below 100° C. After complete addition the reaction was deemed complete by LCMS. The reaction mixture was allowed to cool to room temperature and poured carefully into saturated brine (700 mL) cooled in an ice bath to 10° C. The precipitate that formed was aged for 45 min at this temperature and isolated by filtration through buchner funnel. The collected precipitate was stirred in ethyl acetate (1 litre) and water then filtered through celite to remove insoluble polymeric material and organic layer was separated. The aqueous layer was further extracted with ethyl acetate and the combined organic layers dried over magnesium sulfate and concentrated to give a brown solid which was triturated by stirring for an hour in hot heptane and then cooling before filtration, to afford 5-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine as a crystalline solid (26.38 g, 59% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CC(C)([O-])C.[K+].F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([O:31][CH3:32])[CH:23]=1>O1CCCC1>[CH3:32][O:31][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[N+:28]([O-:30])=[O:29])[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.49 g) and tetrahydrofuran (30 mL), potassium tert-butoxide (830 mg) was added under ice cooling and stirred for 30 minutes, followed by addition of a mixture of 4-fluoro-2-methoxy-1-nitrobenzene (1.00 g) and tetrahydrofuran (20 mL). After stirring at room temperature for 3 hours, the reaction mixture was extracted by addition of water and ethyl acetate, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; n-hexane:diethyl ether=4:1) to give tert-butyl 4-(3-methoxy-4-nitrophenoxy)piperidine-1-carboxylate (898 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([NH2:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].Br[C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O>C(#N)C>[NH2:12][C:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:11]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: NC(=O)CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCC(N)=O
Temperature: 80 °C

Procedure:
3-(2-Hydroxyphenyl)propionamide (5.6 g, 33.9 mmol) was dissolved in acetonitrile (15 mL), and potassium carbonate (18.7 g, 135 mmol) was added thereto. Subsequently, tert-butyl 2-bromoisobutyrate (30.3 g, 135 mmol) was added, and the mixture was stirred at 80° C. After completion of reaction, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=40/1), whereby the target compound was obtained (2.67 g, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([Cl:22])[C:3]=1[O:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6]1.[Cl-].[NH4+]>C(O)C.C1COCC1.O.[Fe]>[Cl:1][C:2]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:15]([Cl:22])[C:3]=1[O:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6]1
Reactant: O=[N+]([O-])c1cc(Cl)c(OC2C=Nc3ccccc3C2)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(OC2C=Nc3ccccc3C2)c(Cl)c1
Yield: 89.1 %

Procedure:
To a solution of compound II (6.9 g) in ethanol/THF/water (ratio 40:20:10) was added ammonium chloride (3.3 g) and powdered iron (3.4 g). This mixture was heated to reflux for 5 h. The hot mixture was then filtered through Celite and concentrated. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 solution followed by water and then brine. The solution was dried over magnesium sulfate and concentrated to afford compound III as an off-white solid (5.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[C:5]#[N:6].Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])/[C:5](=[N:12]/[OH:13])/[NH2:6]
Reactant: N#Cc1ccc(Cl)c(Cl)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N/C(=N\O)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 3,4-dichlorobenzonitrile (2.00 g, 11.6 mmol), hydroxylamine hydrochloride (1.65 mL, 12.8 mmol) and sodium hydroxide (4.15 mL, 12.4 mmol) in ethanol (40 mL) was stirred at rt for 1 h. The reaction mixture was concentrated and refluxed in hexanes for 30 min and concentrated in vacuo. The product, intermediate 33A was used directly without purification. HPLC/MS (Method C) retention time=1.24 min [M+H]+204.9.