Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 736.1 %

Procedure:
A suspension of tert-butyl 4-(2-(4-chlorophenoxy)acetyl)piperazine-1-carboxylate (example 58, 0.58 g, 0.16 mmol) in dichloromethane (8 ml) was treated dropwise at room temperature with TFA until the solid completely dissolved. The reaction mixture was stirred under nitrogen at room temperature overnight. The volatiles were evaporated to dryness, diluted with water and the solid was collected by filtration. The solid was washed with water and dried to yield the title compound as a white solid (0.30 g, 72%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][C:36]2[C:41]([Cl:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=2[Cl:44])=[CH:28][CH:27]=1)[C:10]([N:12]([CH:22]1[CH2:24][CH2:23]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[CH3:21])=[O:11])(C)(C)C.Cl>C(Cl)Cl>[NH2:7][CH2:8][CH:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][C:36]2[C:37]([Cl:44])=[CH:38][C:39]([CH3:43])=[CH:40][C:41]=2[Cl:42])=[CH:28][CH:27]=1)[C:10]([N:12]([CH:22]1[CH2:23][CH2:24]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[CH3:21])=[O:11]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)C(=O)N(Cc3cccc(C)c3C)C3CC3)cc2)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CN)C(=O)N(Cc3cccc(C)c3C)C3CC3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a CH2Cl2 solution (0.05 M) of tert-butyl(3-[cyclopropyl(2,3-dimethylbenzyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (I eq.) was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 97:3 (v/v) CH2Cl2: 2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound as a white froth. MS (ESI+): 555.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][O:13][CH2:12][C@H:11]1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:4].[Li+].[CH3:30][CH:31]([N-]C(C)C)[CH3:32].C(I)C=C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:9]=1[N:10]1[C@H:11]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][O:13][C@H:14]([CH2:32][CH:31]=[CH2:30])[C:15]1=[O:16])=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)COC[C@H]1C1CCCCC1
Agent: C=CCI
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1OC[C@@H](C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 9.1 %

Procedure:
To a solution of 3-((R)-3-Cyclohexyl-5-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (600 mg, 1.49 mmol, 1.0 equiv) in THF (5.0 mL) at −78° C. was added LDA (0.82 mL, 2.0 M in THF, 1.64 mmol, 1.1 equiv) and the resulting solution was stirred at −78° C. for 20 minutes. To the solution was then added allyliodide (300 mg, 1.78 mmol, 1.2 equiv). The solution was warmed to room temperature and stirred at this temperature for 30 minutes. The reaction was quenched by addition of sat. aq. NH4Cl solution. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, EtOAc/heptane 25% to give 3-((2S,5R)-2-Allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl 140 mg, 3-((2R,5R)-2-Allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester 60 mg and mixed fraction 200 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]([NH:6][CH2:7][C:8]([C:10]1[C:18]2[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:11]=1)=O)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[S:30][C:8]([C:10]2[C:18]3[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:11]=2)=[CH:7][N:6]=1)=[O:28]
Reactant: COC(=O)C(=O)NCC(=O)c1cn(CC2CCCCC2)c2c(OC)cccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ncc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)s1
Yield: 98.2 %

Procedure:
To a solution of N-[(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-2-oxo-ethyl]-oxalamic acid methyl ester (429 mg, 1.11 mmol) in chloroform (20 ml) was added phosphorus pentasulfide (538 mg, 1.21 mmol) and the reaction mixture heated at reflux for 3.5 h. The reaction mixture was cooled, poured into a separating funnel and washed with water and then brine. The organic layers were then dried over magnesium sulfate, filtered and the solvent removed in vacuo. The resulting solid was purified by flash column chromatography eluting with dichloromethane to give 5-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)thiazole-2-carboxylic acid methyl ester (418 mg, 1.09 mmol) as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: Clc1ncccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ncccn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 2-chloropyrimidine in Step 4. LC-MS Method 2 tR=1.401, m/z=436.1; 1H NMR (CDCl3) 1.53 (d, 3H), 1.62 (m, 1H), 1.81-1.98 (m, 3H), 2.15 (m, 2H), 2.31 (m, 1H), 2.76 (m, 1H), 3.51 (t, 2H), 5.67 (m, 1H), 6.92 (m, 4H), 7.11 (m, 1H), 7.19 (m, 1H), 8.15 (d, 2H), 8.71 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[C:5]([F:11])=[CH:4][N:3]=1>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]([F:11])=[CH:4][N:3]=1
Reactant: CC(O)c1cc(Br)ncc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(Br)ncc1F
Temperature: 95 °C
Yield: 88.9 %

Procedure:
To a 350 mL sealed flask was dissolved 1-(2-bromo-5-fluoro-4-pyridinyl)ethanol (9.4 g, 42.3 mmol) in 60 mL dry CHCl3. Added next to the stirring solution was manganese(IV)oxide (14.7 g, 169 mmol). The vigorously stirred contents were sealed and heated at 95° C. for 2.5 h. After cooling to room temperature, the black heterogeneous mixture was vacuum filtered through a pad of Celite, and the filter pad washed with CH2Cl2 (10 mL). The yellow colored filtrate was concentrated in vacuo to a yellow oil, which was purified by silica gel column chromatography (eluent: 9:1 PE/EtOAc) to afford 1-(2-bromo-5-fluoropyridin-4-yl)ethanone as a pale yellow oil (8.2 g, 88%). ESI MS m/z=218 (M+1)
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:14])=O>ClCCl>[C:1]([Cl:14])(=[O:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C=Cc1ccccc1

Procedure:
The polymeric main chain having the above repeating structure was synthesized according to the same procedures as described in Example 1. The side chain was synthesized as follows. First, 1 g (0.006 mol) of cinnamic acid was reacted with 0.71 g (0.006 mol) of thionyl chloride in dichloromethane at a temperature of 35° C. for 1 hour to form cinnamoyl chloride. Then, the cinnamoyl chloride was reacted with 0.98 g (0.006 mol) of 4-hydroxybenzoic acid and an aqueous solution of NaOH/DMSO with stirring for 1 hour at a room temperature. The product was again reacted with thionyl chloride in dichloromethane to form a side chain as follows.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[C:10]([C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([CH2:24][CH2:25][CH3:26])[C:22]=1[OH:23])[N:19]=[C:18]([C:27]([O:29][CH3:30])=[O:28])[CH:17]=[C:16]2Cl)(=[O:12])[CH3:11]>>[C:10]([C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([CH2:24][CH2:25][CH3:26])[C:22]=1[OH:23])[N:19]=[C:18]([C:27]([O:29][CH3:30])=[O:28])[CH:17]=[C:16]2[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CCCc1c(O)c(C(C)=O)cc2c(Oc3ccccc3)cc(C(=O)OC)nc12
Reaction time: 1.5 h

Procedure:
Phenol (10.0 g) which had been crushed in a mortar and pestle, was added to crushed potassium hydroxide (0.36 g) in a flask which was immersed in an oil bath. This was stirred at 60°-65° C. for 5 minutes before methyl 6-acetyl-4-chloro-7-hydroxy-8-propyl-quinoline-2-carboxylate (1.0 g) was added. The whole was stirred at 60°-65° C. for 1.5 hours and the phenol was then removed by steam distillation.
Reaction SMILES: [N:1]1([CH:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[CH:15]=[CH:16]C3C=CC=CC=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[N:1]1([CH:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[CH:12]=[C:11]3[C:10](=[CH:9][CH:8]=2)[NH:13][C:14](=[O:23])[CH:15]=[CH:16]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(C=Cc1ccccc1)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=c1ccc2cc(C(c3ccccc3)n3ccnc3)ccc2[nH]1
Temperature: 120 °C
Reaction time: 3 h
Yield: 15.4 %

Procedure:
To a stirred solution of 10.5 parts of N-[4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]-3-phenyl-2-propenamide in 110 parts of chlorobenzene were added 18.5 parts of aluminium chloride. The reaction mixture was stirred for 3 hours at 120° C. After cooling to room temperature, the product was extracted with ethyl acetate. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and methanol. The product was filtered off and dried, yielding 1.3 parts (15.4%) of 6-[(1H-imidazol-1-yl)phenylmethyl]-2(1H) -quinolinone; mp. 226.9° C. (compound 2).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.CC(C)([O-])C.[K+].[C:14]([O:18][C:19](=[O:22])[CH2:20]Br)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[CH:6]([C:4]1[CH:5]=[N:1][N:2]([CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:22])[CH:3]=1)=[O:7]
Reactant: O=Cc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(C=O)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
A mixture of 1H-pyrazole-4-carbaldehyde (0.5 g, 5.2 mmol), potassium tert-butoxide (0.7 g, 6.25 mmol) in N,N-dimethylformamide (6 mL) was stirred at room temperature for 5 minutes. Tert-butylbromoacetate (1.11 g, 5.72 mmol) was added and the resulting mixture was stirred for 2 hours at room temperature. The reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was collected, washed with water then brine, passed through a hydrophobic fit and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 15-100% ethyl acetate in iso-hexane, to afford the title compound (0.678 g, 62%) as colorless oil.
Reaction SMILES: [Sn](C)(C)(C)[CH3:2].Br[C:7]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)=[N:9][S:10][C:11]=1[NH:12][C:13]([C@@H:15]1[CH2:17][C@H:16]1[CH3:18])=[O:14]>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:8]2[C:7]([CH3:2])=[C:11]([NH:12][C:13]([C@@H:15]3[CH2:17][C@H:16]3[CH3:18])=[O:14])[S:10][N:9]=2)=[CH:20][CH:21]=1)[CH3:27]
Reactant: C[Sn](C)(C)C
Reactant: CCOc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2C)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Add PdCl2(PPh3)2 (0.07 g, 0.09 mmol) and Sn(CH3)4 (0.34 mL, 0.44 g, 2.48 mmol) to (R,R)—N-[4-bromo-3-(4-ethoxyphenyl)isothiazol-5-yl]-2-methylcyclopropane-carboxamide (0.24 g, 0.62 mmol) in DMF (1 mL) and stir the reaction mixture at 130° C. in a sealed tube overnight. Dilute with EtOAc (100 mL) and brine (100 mL). Collect the organic phase, dry (MgSO4), and evaporate. Filter over silica gel and wash with EtOAc. Evaporate and crystallize from EtOAc/hexane to afford (R,R)—N-[3-(4-ethoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide. Yield: 81.7%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].CCN=C=NCCCN(C)C.[NH2:23][NH:24]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C1COCC1.CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:23][NH2:24])=[O:5]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)c1cc(F)ccc1F
Reaction time: 16 h

Procedure:
To a solution of 2,5-difluorobenzoic acid (3.5 g, 22 mmol) in THF/DMF (20 mL/20 mL) was added EDCI (4.7 g, 24 mmol), DMAP (50 mg) and NH2NHBoc (3.07 g, 23.2 mmol). After stirring for 16 hours, the reaction was quenched with water (30 mL) and diluted with EtOAc (30 mL). The organic layer was then washed with HCl (0.5 M, 20 mL), saturated NaHCO3 (20 mL), and brine (20 mL). The organic layer was then dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude Boc-protected product, which was then dissolved in DCM (60 mL) at 0° C. TFA (50 mL) was added to the above DCM solution. After stirring for 2 hours, the reaction mixture was concentrated and the residue was dissolved in DCM (60 mL). The solution was washed with saturated NaHCO3 (40 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired crude product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:9]=2)[CH:4]=[CH:3]1.[C:18](Cl)(=[O:22])[C:19]([Cl:21])=[O:20].C(Cl)Cl>CCOCC>[F:16][C:13]([F:14])([F:15])[C:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4]([C:18](=[O:22])[C:19]([Cl:21])=[O:20])=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1)=[O:17]
Reactant: Cn1ccc2ccc(NC(=O)C(F)(F)F)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1cc(C(=O)C(=O)Cl)c2ccc(NC(=O)C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
200 mg of 1-methyl-6-trifluoroacetylaminoindole was taken into 5 mL ether and cooled to 0° C. It was treated with 0.485 mL 2.0 M oxalyl chloride/methylene dichloride and stirred at 0° C. for 2 h. The yellow crystals were collected and washed with ether and dried in vacuo to yield 240 mg of (6-trifluoroacetylamino-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([C:31]1[O:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[CH:35]=1)=[O:30]>>[O:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[CH:35]=[C:31]1[C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:11]([CH3:12])[C:4]2[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])(=[O:15])=[O:14])=[CH:21][CH:20]=1)=[O:30]
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Reactant: O=C(NCCCO)c1cc2ccccc2o1
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCNC(=O)c2cc3ccccc3o2)cc1
Yield: 53 %

Procedure:
The product of Example 2 (0.442 g, 1.37 mmol) was coupled to N-(3-hydroxypropyl)-1-benzofuran-2-carboxamide (0.3 g, 1.37 mmol) using the procedure of Example 3 to provide 0.37 g (53% yield) of an off white powder. MP 184-186° C.; 1H NMR (DMSO-d6): δ1.9 (s, CH3), 2.04 (t, CH2), 3.16 (s, CH3), 3.46 (q, CH2), 4.0 (t, CH2), 7.01 (d, 2 Ar H) 7.30-7.78 (m, 10 Ar H), 8.56 (t, NH), 12.4 (br s, OH). Electrospray Mass Spec: m/z 523.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:6][CH2:5][NH:4][CH2:3]1.C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[F:1][C:2]1([F:7])[CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:16]([NH:17][C:18]([C:20]3[C:25]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)=[CH:24][CH:23]=[C:22]([CH:33]4[CH2:35][CH2:34]4)[N:21]=3)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=2)=[O:9])[CH2:3]1
Reactant: FC1(F)CCNC1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CCC(F)(F)C2)n1
Yield: 14 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3,3-difluoropyrrolidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (14%) as sticky yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH3:6][CH:7]([CH3:17])[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH:11]=[CH:10]1.C(N(CC)CC)C.O>ClCCl.C(OCC)C.CCCCCC>[CH3:6][CH:7]([CH3:17])[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:10]1
Reactant: CC(C)CN1C=CC(C)(C)CC1
Reactant: CCC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)C1=CN(CC(C)C)CCC1(C)C
Yield: 80.6 %

Procedure:
Propionyl chloride (9.25 g, 0.1 mol) was added dropwise to a solution of 1-(2-methylpropyl)-4,4-dimethyl-1,4,5,6-tetrahydropyridine (16.7 g, 0.1 mol) and triethylamine (12.1 g, 0.12 mol) in dichloromethane (100 ml) stirring under an atmosphere of nitrogen at ice bath temperature. After one hour at this temperature, water (50 ml) was added, the organic layer was separated, washed with 5% aqueous sodium carbonate and dried over anhydrous MgSO4. Removal of the organic solvent afforded a yellow oil (22.3 g, quantitative) which was essentially pure by 90 MHz NMR spectroscopy. After column chromatography on silica-gel (Merck Kieselgel 60, 70-230 mesh) using 5% diethyl ether in dichloromethane (or 3:7 ether: n-hexane) as eluent, the pure 1-(2-methylpropyl)-3-propionyl-4,4-dimethyl-1,4,5,6-tetrahydropyridine (18.0 g, 81%) was obtained as a very pale yellow oil. UV λ max MeOH 307 nm, 29,300. 1H NMR (CDCl3) δ7.13 (1H, s), 3.10 (2H, m, AAIXXI system), 2.94 (2H, d, J7.4Hz), 2.44 (2H, q, J7.5Hz), 1.95 (1H, m, J6.6Hz, J7.4Hz), 1.60 (2H, m, AAIXXI system), 1.27 (6H, s), 1.08 (3H, t, J7.5 Jz), and 0.90 (6H, d, J6.6Hz). 13C NMR (CDCl3) δ195.9 (s), 147.9 (d), 114,4 (s), 64.1 (t), 43.3 (t), 39.3 (t), 30.0 (s), 29.7 (t), 28.1 (q), 27.4 (d), 19.8 (q), and 10.3 (q). MS 223.1913 (M+), 25.2%, 194 (100%).
Reaction SMILES: [ClH:1].CO[C:4](=[O:20])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[NH2:21][NH-]>O1CCOCC1>[ClH:1].[N+:17]([C:14]1[CH:15]=[C:16]2[C:11]([NH:10][CH:9]=[C:8]2[CH2:7][C@@H:5]([C:4]([NH2:21])=[O:20])[NH2:6])=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: [NH-]N
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)[C@@H](N)Cc1c[nH]c2ccc([N+](=O)[O-])cc12

Procedure:
(S)-5-Nitrotryptophan methyl ester hydrochloride (see example 47) was converted to the corresponding amide derivative following the procedure described in example 44 for the 5-hydroxy derivative. The amino amide was then converted to its hydrochloride salt using 4N HCl in dioxane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:26]([O:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(OCC)C>[C:26]([O:30][C:31](=[O:32])[NH:33][CH2:34][C:35](=[O:36])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:25])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[O:11])[CH:3]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1

Procedure:
The title compound is prepared from N-(3-aminophenyl)-2-(4-benzyl-piperidin-1-yl)-2-oxo-acetamide (Example 11) and N-(tert-butoxycarbonyl)glycine (Aldrich) according to the method described in Example 1c. Melting Point: 81-85° C. (diethylether)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[NH:8][C:7](=O)[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)[nH]1
Product: FC(F)(F)c1ccc(-c2cc(Cl)nc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared from 6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (23.7 g, 77 mmol) and phosphoryl chloride (35.2 mL, 386 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (16.5 g, 66%). MS (ISP) 326.1 [(M+H)+] and 328 [(M+2+H)+].
Reaction SMILES: FC(OC1C=CC(C=CC#N)=CC=1)CC(F)(F)F.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.[F:28][C:29]([F:35])([CH:32]([F:34])[F:33])[CH2:30][OH:31]>>[F:28][C:29]([F:35])([CH:32]([F:34])[F:33])[CH2:30][O:31][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1
Reactant: OCC(F)(F)C(F)F
Reactant: N#Cc1ccc(F)cc1
Agent: N#CC=Cc1ccc(OC(F)CC(F)(F)F)cc1
Product: N#Cc1ccc(OCC(F)(F)C(F)F)cc1

Procedure:
According to Ann. N.Y. Acad. Sci (1988), 544, pages 86 to 100 (Chem. Abstr. 111, 208650), 4-tetrafluoropropoxycinnamonitrile can be prepared in the following manner. 4-Fluorobenzonitrile is reacted with 2,2,3,3-tetrafluoropropanol to give 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile which is then reduced by complex hydrides to give 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde. The 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde leads to the 4-tetrafluoropropoxycinnamonitrile by reaction with the anion of diethyl cyanomethylphosphonate in the context of a Wittig-Horner reaction.