Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][CH2:9][O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH:6]=[N:5][NH:4]1)[CH3:2].[C:18]1([C:24]2[O:28][N:27]=[CH:26][C:25]=2[CH2:29][CH2:30][C:31](O)=[O:32])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:1]([N:3]1[CH:7]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH:15][C:31](=[O:32])[CH2:30][CH2:29][C:25]3[CH:26]=[N:27][O:28][C:24]=3[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH:6]=[N:5][NH:4]1)[CH3:2]
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: CCN1NN=CC1CCOc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCN1NN=CC1CCOc1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
A mixture of 4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]aniline (1.12 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (1.04 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.89 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.11 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide (1.58 g, yield 76%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from acetone-hexane. melting point: 167–168° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([N:9]2[C:13]3=[C:14]4[CH:20]=[CH:19][NH:18][C:15]4=[N:16][CH:17]=[C:12]3[NH:11][C:10]2=[O:21])[CH2:4]1.C(N(CC)CC)C.[N:29]([Si](C)(C)C)=[C:30]=[O:31]>CN1CCN(C)C1=O>[O:21]=[C:10]1[N:9]([C@@H:5]2[CH2:6][CH2:7][CH2:8][N:3]([C:30]([NH2:29])=[O:31])[CH2:4]2)[C:13]2=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=[C:12]2[NH:11]1
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1[C@@H]1CCCNC1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCN(C)C1=O
Product: NC(=O)N1CCC[C@@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-[(3R)-3-piperidinyl]-3,6-dihydroimidazo-[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one dihydrochloride (20 mg) in 1,3-dimethyl-2-imidazolidinone (1 ml) was added triethylamine (51 μl) and isocyanato(trimethyl)silane (24 μl) which was stirred at 110° C. for 1 hour. The solvent was evaporated and purified by column chromatography on Hi-Flash™ (NH2)*(YAMAZEN CORPORATION) eluting with chloroform:methanol=100:0-85:15 to give (3R)-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)-1-piperidinecarboxamide (12 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 130 °C
Reaction time: 17 h
Yield: 95.8 %

Procedure:
4-Chloro-3-(trifluoromethyl)phenol (1.19 g, 6.06 mmol), methyl 4-fluorobenzoate (0.934 g, 6.06 mmol) and potassium carbonate (2.51 g, 18.2 mmol) were stirred in dimethylsulfoxide (10 mL) at 120° C. overnight under an atmosphere of nitrogen. The temperature was then increased to 130° C. and the reaction mixture stirred for a further 17 hours. The reaction mixture was cooled to room temperature. Water (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The combined organic phase was washed sequentially with water (50 mL) and brine (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (1.92 g, 96%, contains residual dimethylsulfoxide). This material was taken on crude in subsequent steps.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:8]#[N:9])([O-])=O.[OH-].[Na+]>>[NH2:2][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([NH2:13])[CH:12]=1)[C:8]#[N:9]
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc(N)cc(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 210 grams of stannous chloride dihydrate in 590 ml. of concentrated hydrochloric acid is added portionwise 25 grams of 3,5-dinitrobenzonitrile. The mixture is stirred for 3 hours at room temperature, then cooled to 0° in an ice-salt bath and a cold 50% sodium hydroxide solution added to the mixture until the mixture is strongly basic. During the addition the temperature is kept below 5°.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1.FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.Cl>CN(C)C=O>[CH3:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:5]=1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)nn1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 22.8 %

Procedure:
To a suspension of sodium hydride (1.62 g, 40.4 mmol) in N,N-dimethylformamide (250 mL) was added dropwise a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate (5660 mg, 36.8 mmol) in N,N-dimethylformamide (50 mL) over 10 min under ice-cooling. After the completion of the dropwise addition, the reaction mixture was stirred at 0° C. for 10 min and at room temperature for 40 min. To the mixture was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (9.87 g, 40.4 mmol), and the mixture was stirred at room temperature for 3 hr. Under ice-cooling, 1N hydrochloric acid (36 mL) was added to the mixture, and the solvent was evaporated under reduced pressure. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution were added to the residue, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→60/40), and recrystallized from ethyl acetate/hexane to give ethyl 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylate (1.98 g, 23%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]3[O:15]C=CC=3)=[CH:12][C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CC(C)=[O:25].[Mn]([O-])(=O)(=O)=O.[K+]>O>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([OH:15])=[O:25])=[CH:12][C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)=O
Reactant: FC(F)(F)c1cc(-c2ccco2)n(-c2ncc(Cl)cc2Cl)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1Cl
Temperature: 65 °C
Yield: 58 %

Procedure:
To a 100 mL flask, 3,5-dichloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine (1.47 g, 4.22 mmol), acetone (10 mL) and a solution (10 mL) of potassium permanganate (3.33 g, 21.1 mmol) in water were added. The reaction mixture was heated to 65° C. for 4 hours and cooled to room temperature, then isolated via filtration, a cake is obtained. The cake was washed with hot solution of potassium hydroxide. To the filtrate was added ethyl acetate (80 mL), water (100 mL) and partitioned. The aqueous layer was acidified with concentrated hydrochloric acid to pH of 2-3, and extracted with ethyl acetate (200 mL). The organic extracts were washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated by rotary evaporator to give the product (0.80 g) as yellow oil in 58% yield.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=1.ClC1C=CC(C(NC2C=CC=C(C3OCCO3)C=2)=O)=CC=1.N1CCC(C(OC)=O)C1.C([O:46][C:47]([CH:49]1[CH2:54][CH2:53][N:52]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([NH:62]C(=O)C3C=CC(Cl)=CC=3)[CH:57]=2)[CH2:51]C1)=[O:48])C>>[F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([C:9]([NH:62][C:58]2[CH:57]=[C:56]([CH:61]=[CH:60][CH:59]=2)[CH2:55][N:52]2[CH2:53][CH2:54][CH:49]([C:47]([OH:46])=[O:48])[CH2:51]2)=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)n1
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Agent: COC(=O)C1CCNC1
Agent: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(Cl)cc1
Product: O=C(Nc1cccc(CN2CCC(C(=O)O)C2)c1)c1cccc(C(F)(F)F)n1

Procedure:
The title compound is prepared according to the reaction sequence 2.001a-2.001d described above using 6-(trifluoromethyl)picolinoyl chloride instead of 4-chlorobenzoyl chloride as in 2.001a and methyl pyrrolidine-3-carboxylate instead of ethyl isonipecotate as in 2.001c: LC-MS A: tR=0.64 min; [M+H]+=394.00.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([F:15])=[CH:13][CH:14]=2)[N:5]=[C:4]([NH2:16])[N:3]=1.[H-].[Na+].IC.[CH3:21]COC(C)=O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:9]2[CH:10]=[N:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH3:21])[N:5]=[C:4]([NH2:16])[N:3]=1
Reactant: Nc1nc(Cl)nc(Nc2ccc(F)nc2)n1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc(F)nc1)c1nc(N)nc(Cl)n1
Reaction time: 0.08 h
Yield: 16 %

Procedure:
To a solution of 6-chloro-2-N-(6-fluoropyridin-3-yl)-1,3,5-triazine-2,4-diamine (Intermediate 159, 0.52 g, 2.17 mmol) in DMF (1 mL) at 0 C under nitrogen was added portionwise sodium hydride (60% dispersion in mineral oil, 0.0869 g, 2.17 mmol). The mixture was stirred for 5 min, then iodomethane (0.3 g, 2.17 mmol) was added and the mixture was heated to 50 C for 16 h. EtOAc was added and the organic layer was washed with saturated aq. sodium bicarbonate, dried over sodium sulfate and concentrated. The residue was purified by FCC, eluting with 10-50% EtOAc in heptane to afford the title compound (0.089 g, 16% yield). Method B HPLC-MS: MH+ requires m/z=255 Found: m/z=255, Rt=1.52 min (74%).
Reaction SMILES: [ClH:1].C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:43][O:44][CH2:45][CH2:46][NH:47]C(OC(C)(C)C)=O)[C:11]([NH:13][CH:14]2[C:41](=[O:42])[N:16]3[C:17]([C:38]([OH:40])=[O:39])=[C:18]([CH2:21][S:22][C:23]4[N:27]([CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[N:26]=[N:25][N:24]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>CO>[ClH:1].[ClH:1].[ClH:1].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:43][O:44][CH2:45][CH2:46][NH2:47])[C:11]([NH:13][CH:14]2[C:41](=[O:42])[N:16]3[C:17]([C:38]([OH:40])=[O:39])=[C:18]([CH2:21][S:22][C:23]4[N:27]([CH2:28][CH2:29][NH2:30])[N:26]=[N:25][N:24]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCN)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Conc. hydrochloric acid (3.2 g.) was added to a solution of 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.5 g.) in methanol (50 ml.) and stirred at room temperature for 2 hours. After removing the solvent in vacuo, methanol was added to the residue. The mixture was concentrated in vacuo again. The precipitates were collected by filtration and washed with diethyl ether to give 7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid trihydrochloride (syn isomer, 2.8 g.)
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[C:33]1=[O:41].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:38]([C:34]5[C:33](=[O:41])[N:32]([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[CH3:25])[CH:37]=[CH:36][CH:35]=5)=[O:39])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccccc1-n1cccc(C(=O)O)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1cccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c1=O
Yield: 53.7 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.613 mmol), 1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (169 mg, 0.735 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (211 μL, 1.23 mmol) and HATU (280 mg, 0.735 mmol) and in the same manner as in Example 24, the title compound (177 mg, 54%) was obtained as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[CH:4][C:5]([NH:8][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][OH:11])=[N:6][CH:7]=1.[C:28](O)(=O)C.C(N)=N.C([O-])(O)=O.[Na+].CCOC(C)=O>CCO>[CH:25]1([C:23]2[NH:22][N:21]=[C:20]([N:19]3[C:3]4[CH:4]=[C:5]([NH:8][C@H:9]([C:12]5[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=5)[CH2:10][OH:11])[N:6]=[CH:7][C:2]=4[N:1]=[CH:28]3)[CH:24]=2)[CH2:27][CH2:26]1
Reactant: CC(=O)O
Reactant: Nc1cnc(N[C@@H](CO)c2ccc(F)cc2)cc1Nc1cc(C2CC2)[nH]n1
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC[C@H](Nc1cc2c(cn1)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 153 %

Procedure:
A mixture of (R)-2-(5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Method 93, 0.14 g, 0.38 mmol) and formamidine acetate (0.079 g, 0.76 mmol) in EtOH (5 ml) was heated at reflux for 2 hours. After cooling to 25° C., the reaction mixture was treated with saturated NaHCO3 solution (10 ml) and EtOAc (30 ml). The organic layer was separated, washed with brine (10 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc-MeOH=20:1) to give the title compound as an off-white solid (0.22 g, 32%). 1H NMR (400 MHz) 12.76 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 7.43 (m, 2H), 7.10 (m, 2H), 6.92 (s, 1H), 6.72 (d, J=7.2 Hz, 1H), 6.25 (s, 1H), 4.92 (m, 2H), 3.62 (m, 2H), 1.97 (m, 1H), 1.02 (m, 2H), 0.77 (m, 2H). MS: Calcd.: 378; Found: [M+H]+ 379.
Reaction SMILES: Cl.[F:2][C:3]([F:8])([F:7])[CH2:4][NH:5][CH3:6].Cl[C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=2)[C:13]([C:28]#[N:29])=[C:12]([S:30][CH2:31][C:32]2[N:33]=[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[S:35][CH:36]=2)[N:11]=1>CN(C=O)C.O.C1COCC1>[Cl:43][C:40]1[CH:39]=[CH:38][C:37]([C:34]2[S:35][CH:36]=[C:32]([CH2:31][S:30][C:12]3[C:13]([C:28]#[N:29])=[C:14]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][OH:27])=[CH:22][CH:23]=4)[C:15]([C:16]#[N:17])=[C:10]([N:5]([CH3:6])[CH2:4][C:3]([F:8])([F:7])[F:2])[N:11]=3)[N:33]=2)=[CH:42][CH:41]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CNCC(F)(F)F
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(CC(F)(F)F)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
41 mg (0.27 mmol) of 2,2,2-trifluoro-N-methylethanamine hydrochloride were dissolved in 2 ml of DMF, 40 mg of Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to 100 mg (0.14 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), and the solution was stirred at RT overnight. In a separate flask, another 82 mg (0.54 mmol) of 2,2,2-trifluoro-N-methylethanamine hydrochloride were then dissolved in 0.5 ml of DMF, 80 mg of Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to the first solution. The reaction mixture obtained was stirred at RT overnight. The mixture was then warmed to 60° C., and the reaction mixture was stirred at this temperature overnight, after which it was heated to 100° C. After stirring at 100° C. overnight, the mixture was diluted with a little water/THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 64 mg (74% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=2)[C:17]([OH:19])=[O:18])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[H-].[Na+].[CH2:25]([Li])CCC.CI>C1COCC1>[Cl:21][C:15]1[CH:14]=[C:13]([F:22])[C:12]([C:3]2[C:2]([CH3:25])=[C:6]([C:7]([F:10])([F:9])[F:8])[N:5]([CH3:11])[N:4]=2)=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: [Li]CCCC
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Br)c1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(-c2cc(C(=O)O)c(Cl)cc2F)nn(C)c1C(F)(F)F
Temperature: 60 °C

Procedure:
A solution of 30 g of 5-[4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2-chloro-4-fluorobenzoic acid in 800 mL of anhydrous THF was stirred with a mechanical stirrer and treated with 3.36 g of 80% NaH. The stirred mixture was kept under a nitrogen atmosphere and heated to 60° C. for one hour. After formation of the sodium carboxylate salt, the mixture was cooled to -110° C. and 32.3 mL of 2.5M n-butyllithium in hexanes was added never allowing the temperature to exceed -100° C. The reaction was stirred at -110° C. for ten minutes, subsequently treated with 9.3 mL of methyl iodide and allowed to warm to room temperature. The mixture was quenched with 3N HCl and the volatiles removed. A precipitate formed which was collected and recrystallized from ethanol/water to give 24.5 g of a white solid: mp 155.0° C.; 1HNMR (CDCl3) δ 2.06 (m, 3H), 4.01 (s, 3H), 7.27 (d, 1H, J=9.6 Hz), 8.17 (d, 1H, J=7.6 Hz). Anal. Calcd for C13H9O2Cl1N2F4 : C, 46.38; H, 2.69; N, 8.32. Found: C, 46.46; H, 2.65; N, 8.33.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl.[CH3:12][O:13][C:14](=[O:19])[C@H:15]([CH2:17][SH:18])[NH2:16].CCN=C=NCCCN(C)C.CN1CCOCC1>CC#N.CCOC(C)=O>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:16][C@@H:15]([CH2:17][SH:18])[C:14]([O:13][CH3:12])=[O:19])=[O:10]
Reactant: O=C(O)c1ccccc1O
Reactant: COC(=O)[C@@H](N)CS
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CS)NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Separately, salicylic acid (152 mg, 1.10 mmol) was taken up in CH3CN (10 mL) along with L-cysteine methyl ester hydrochloride (189 mg, 1.10 mmol), EDCI (350 mg) and N-methylmorpholine (120 μL). The reaction mixture was stirred at room temperature for 3 h. It was then diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude (R)-methyl 2-(2-hydroxybenzamido)-3-mercaptopropanoate. This material was then taken up in CH3CN (3 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-(2,5-dioxo-2H-pyrrol-1(5H)-yl)ethyl)docosa-4,7,10,13,16,19-hexaenamide (315 mg, 0.7 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. Purification by silica gel chromatography (CH2Cl2) afforded (R)-methyl 3-(1-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2,5-dioxopyrrolidin-3-ylthio)-2-(2-hydroxybenzamido)propanoate (140 mg). Mass calculated for C39H51N3O7S: 705.34; found: [M+H]+=706.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH:4](O)[C:5]#[C:6][CH3:7].[C:15]([OH:19])(=[O:18])[CH2:16]C.[CH2:20](O)[CH3:21]>>[CH3:7][C:6](=[C:5]=[CH:4][CH2:3][CH:2]([CH3:1])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:16][C:15]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CC#CC(O)CC(C)CCCC(C)C
Reactant: CCO
Reactant: CCC(=O)O
Product: CCOC(=O)CC(C)=C=CCC(C)CCCC(C)C

Procedure:
A mixture of 18.5 g. of 6,10-dimethylundec-2-yn-4-ol, 80 g. of triethylorthacetate and 0.75 g. of propionic acid is refluxed under a spinning band column to remove ethanol as it is formed. After the elimination of ethanol is about complete, the crude reaction product is distilled under vacuum to yield ethyl 3,7,11-trimethyldodeca-3,4-dienoate. Alternatively, the crude reaction product is purified by chromatography on silica.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][NH:13][C:14]2=[O:17])=[CH:9][CH:8]=1.O.CCOC(C)=O>C(Cl)Cl>[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][NH:13][C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)C(=O)NCC2
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1NCCc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
BBr3 (4.75 mL, 47.5 mmol, in CH2Cl2) was added to a cold solution (ice-bath) of intermediate 18 (3.36 g, 18.98 mmol) in CH2Cl2 (100 mL). The mixture was then warmed to rt and stirred overnight. Water was carefully added dropwise to quench the reaction. EtOAc was added and the mixture was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated to afford 7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (intermediate 19) (2.46 g, 80%) as a white solid. mp: 201-203° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.CN1CCOCC1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([NH:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: Nc1cccc(-c2cnn(-c3cccnc3)c2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1cccc(-c2cnn(-c3cccnc3)c2)n1
Reaction time: 8 h

Procedure:
146 mg (585 μmol) of 6-[1-(pyridin-3-yl)-1H-pyrazol-4-yl]pyridine-2-amine and 54.0 μl (701 μmol) of N-methylmorpholine were initially charged in 10 ml of dichloromethane, and methanesulphonyl chloride was added at room temperature. The mixture was stirred overnight and the reaction mixture was filtered through silica gel (eluent: ethyl acetate). After concentration, the crude product was purified by chromatography (dichloromethane/methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH2:20][C:19]=3[CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:26]O>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH2:20][C:19]=3[CH:25]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)COC(=O)N3)cc1C
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)COC(=O)N3)cc1C

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dimethyl-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.