Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:27])=[CH:23][C:24]=3[F:26])[NH:19][C:18]2=[O:28])[CH:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:27][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:28])[C:10]3([CH:9]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[F:36])[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])[C:25]2=[C:24]([F:26])[CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (1.8 g, 3.4 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 20 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a off white solid (1.9 g, 95%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15]CC)=[CH2:14])[CH:7]=[CH:6]2>CC(C)=O>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13](=[O:15])[CH3:14])[CH:7]=[CH:6]2
Reactant: C=C(OCC)c1ccc2cc(Br)ccc2n1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.4 %

Procedure:
3M HCl (aq.) (10 mL, 30.0 mmol) was added to a suspension of 6-bromo-2-(1-ethoxyvinyl)quinoline (780 mg, 2.80 mmol) in acetone (20 mL) and the reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated, dissolved into THF (20 mL) and treated with 3N HCl (aq.) (5 mL) was clear reaction solution was stirred at 60° C. for 5 h. The reaction was, cooled, neutralized with aq. NaOH and NaHCO3 and extracted with EtOAc. The organic layer was dried, and concentrated to yield crude 1-(6-bromoquinolin-2-yl)ethanone (710 mg) as white solid. LC-MS retention time 3.703 min; m/z 250, 251.99 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:22])[NH:10][CH:11]([CH2:20][OH:21])[C:12](=[O:19])[NH:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>ClCCl.CN(C)C=O>[C:1]1([CH2:7][O:8][C:9](=[O:22])[NH:10][CH:11]([CH2:20][O:21][C:23](=[O:25])[CH3:24])[C:12](=[O:19])[NH:13][N:14]2[CH:15]=[CH:16][CH:17]=[CH:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(CO)C(=O)Nn1cccc1)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)OCC(NC(=O)OCc1ccccc1)C(=O)Nn1cccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a stirred solution of (±)-phenylmethyl-[1-(hydroxymethyl)-2-oxo-2-(1H-pyrrol-1-ylamino)ethyl]carbamate (4.26 g) in 100 ml of dichloromethane and 20 ml of dimethylformamide were added acetic anhydride (3.0 ml) and pyridine (2.5 ml). The reaction mixture was stirred overnight at room temperature and then combined with the product from a 5.41 mmol scale reaction which was performed under the same conditions. The reaction mixture was washed with 5% citric acid and water, and dried over magnesium sulfate. After evaporation, the crude product was purified by flash column chromatography (silica gel, DCM/methanol, 30:1). Recrystallization from ethyl acetate/n-hexane afforded the product as a powder (2.96 g, 44%), m.p. 154°-155° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.O.[NH2:30][NH2:31]>C(O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:30][N:31]=[C:19]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCc1ccncc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1c2c(CCc3ccncc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(pyridin-4-yl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (50 mg, 0.13 mmol, prepared in Synthetic Example 1) in ethanol (1 ml) was added hydrazine monohydrate (80%, 20 μl, 0.50 mmol, 3.7 eq.) and the resultant mixture was heated under reflux overnight. The liquid reaction mixture was cooled to room temperature, and then filtered to give precipitates which were dried to obtain 5-phenyl-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (40 mg, 81%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([C:50]([F:53])([F:52])[F:51])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([C:50]([F:52])([F:51])[F:53])[CH:39]=2)[C:35]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of triphenylphosphine (213 mg, 0.84 mmol) in methylene chloride (12 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (144 mg, 0.84 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with the 3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionic acid (150 mg, 0.4 mmol). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-aminothiazole (122 mg, 1.22 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (30 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-propionamide (128 mg, 70%) as an amorphous solid: EI-HRMS m/e calcd for C20H21F3N6OS (M+) 450.1449, found 450.1454.
Reaction SMILES: C(NCCCCO[C:11]1([O:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH2:22][CH2:21][CH:20]=[CH:19][CH2:18][CH2:17][CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1)(=O)C=C.[C:33]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42]C1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2(C)O)C1)(=[O:36])[CH:34]=[CH2:35]>>[C:29]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[O:42][CH2:41][CH2:40][CH2:39][CH2:38][NH:37][C:33](=[O:36])[CH:34]=[CH2:35])(=[O:32])[CH:30]=[CH2:31]
Reactant: C=CC(=O)NCCCCOC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2(C)O)C1
Reactant: C=CC(=O)NCCCCOC1(OCCCCNC(=O)C=C)CCC=CCCC=CCCC1
Product: C=CC(=O)NCCCCOC1CCCCCCCCCCC1OCCCCNC(=O)C=C

Procedure:
1,2-(Bis(4-acrylamidobutoxy)-5,9-cyclododecadiene; 3-(4-Acrylamidobutoxy)-17-methyl-5-androsten-17-ol;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C@H:16]([O:18]C1CCCCO1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:25])([C@H:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](OC1CCCCO1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@H](O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 55 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
In ethanol (50 ml) were dissolved (3R)-2-(2,4-difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy-1-(1H-1,2,4-triazol-1-yl)-2-butanol (4.4 g) and pyridinium p-toluenesulfonate (0.93 g). The solution was stirred for two hours at 55° C. to which was further added pyridinium p-toluenesulfonate (0.20 g), followed by stirring for further two hours at 55° C. The reaction mixture was cooled, then the solvent was distilled off. To the residue was added ethyl acetate (250 ml), which was washed with water (50 ml) and a saturated aqueous solution of sodium chloride (50 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. To the residue was added ethyl ether, then precipitating crystals were collected by filtration to give (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (1.37 g). m.p. 115°-117° C. [α]D =-80.3° C. (c=1.0 in methanol)
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][C@@H:24]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=1)[C@H:25]([OH:41])[CH2:26][NH:27][C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[CH2:30][CH2:29]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.OC1C2N=NNC=2C=CC=1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]([NH:23][C@@H:24]([CH2:42][C:43]3[CH:44]=[C:45]([F:50])[CH:46]=[C:47]([F:49])[CH:48]=3)[C@H:25]([OH:41])[CH2:26][NH:27][C:28]3([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=4)[CH2:30][CH2:29]3)=[O:20])=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc2c1CCN(Cc1ccccc1)C2=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1)c1cccc2c1CCN(Cc1ccccc1)C2=O
Yield: 169.5 %

Procedure:
A solution of 100 mg of 2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 168 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 7.2 mg of hydroxybenzotriazole, 85 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.243 cm3 of N,N-diisopropylethylamine in 10 cm3 of dichloromethane is stirred at a temperature close to 20° C. for 20 h. Dichloromethane is added to the reaction medium. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 400 mg of product obtained are purified by flash chromatography over silica (column: 50 g; particle size: 15-40 μm; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 103 mg of 2-benzyl-N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained.
Reaction SMILES: C[Si]([PH:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([O-:9])[O:6][CH2:7][CH3:8])(C)C.[CH:17]([C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:20])=[CH2:18].C(Cl)(Cl)Cl>O>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]([CH2:17][CH2:18][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8])=[O:20])=[CH:26][CH:25]=1
Reactant: CCOC(OCC)[PH]([O-])(OCC)[Si](C)(C)C
Reactant: C=CC(=O)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(OCC)P(=O)(CCC(=O)c1ccc(Cl)cc1)OCC
Reaction time: 1 h

Procedure:
17.7 g of ethyl trimethylsilyl(diethoxymethyl)phosphonite is added dropwise to a stirred solution of 11.7 g of 4-chlorophenyl vinyl ketone under an atmosphere of nitrogen, at room temperature. The reaction mixture is stirred for a period of 1 hour, 25 ml of chloroform is added followed by 10 ml of water and this mixture is vigorously stirred for a period of 0.5 h. The organic layer is then separated, dried over magnesium sulphate and concentrated under reduced pressure to give ethyl 2-4-chlorobenzoyl-ethyl(diethoxymethyl)phosphinate as an oil, 31P=+45.5 ppm (CDCl3).
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Br)[CH:29]([CH3:31])[CH3:30]>>[CH2:28]([N:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)CCc1ccc(OCc2cccc(Nc3ccccc3)c2)cc1
Reactant: CC(C)CBr
Product: CC(C)CN(c1ccccc1)c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Example 302 from methyl 3-[4-[(3-anilinobenzyl)oxy]phenyl]propanoate and isobutyl bromide. beige powder (yield 12%). MS (APCI−): 402 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH2:18][CH:19]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:20][O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=O.B.[CH2:32]1COCC1.CO.[ClH:39]>C1COCC1.CCOCC>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH2:10][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH2:18][CH:19]([CH2:20][O:21][CH2:22][C:23]([CH3:32])([CH3:25])[CH3:24])[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)COCC(CN(C(=O)c1ccncc1)c1c(Cl)cccc1Cl)N1CCCC1
Reactant: C1CCOC1
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)COCC(CN(Cc1ccncc1)c1c(Cl)cccc1Cl)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 6 g (0.017 m) of N-(2,6-dichlorophenyl)-beta[(2,2-dimethylpropoxy)methyl]-1-pyrrolidineethanamine (the compound of Example 4b.), 4.2 g (0.042 m) of triethylamine, 3.28 g (0.018 m) of 4-picolinoylchloride in 100 ml of dry toluene was stirred at gentle reflux for 2.5 hrs then for 18 hrs at 25° C. Ether (50 ml), then ice and water were added followed by 3N NaOH. The aqueous layer was separated and extracted twice with EtOAc. The combined organic solution was washed with water then brine, dried (Na2SO4 and charcoal) and evaporated to yield a dark oil 7.4 g. This sample was combined with 5.3 g from another run and dissolved in 25 ml of CH2Cl2 and this solution was applied to a silica flash column (2"×71/4") containing 360 ml of silica gel and eluted with acetone:hexane 1:4. A 200 ml second fraction yielded 6 g of pure oily N-(2,6-dichlorophenyl)-N-[3-(2-methylpropoxy)-2-(pyrrolidinyl)propyl]-4-pyridinecarboxamide. A 4 g (0.0086 m) sample of the above 4-pyridinecarboxamide in 20 ml of THF was cooled in an ice bath and 26 ml of 1M (0.026 m) BH3.THF in THF was added over 15 mins. The reaction was stirred for 3 hrs at 25° C. and one hr at reflux. Reaction was cooled to 10° C. and an additional 10 ml of 1M BH3.THF was added. Reaction stirred at reflux for an additional 6 hrs and cooled. After addition of ice, 2 ml of methanol and 3 ml of 3N HCl was added and the solution stirred for 30 min. After making basic with 50% then 3N NaOH, the solution was extracted three times with CH2Cl2 ; extracted aqueous three times with EtOAc and combined all organic extracts (dried Na2SO4) and evaporated solvents off the give 3.35 of oil. Added ether to warm isopropanolic-ethereal HCl solution of the 3.35 g of oil. After cooling 3.1 g of crystalline HCl salt was collected. Recrystallizations from acetonitrile-ether then acetonitrile gave white plates (1.3 g) of title compound m.p. 227° C. (softens), melt 230°-23° C. (dec.)
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Na].[Cl:14][C:15]1[CH:16]=[N+:17]([O-:23])[CH:18]=[C:19]([Cl:22])[C:20]=1[SH:21].C(=O)([O-])[O-].[K+].[K+]>>[Cl:14][C:15]1[CH:16]=[N+:17]([O-:23])[CH:18]=[C:19]([Cl:22])[C:20]=1[S:21][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: [O-][n+]1cc(Cl)c(S)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)c[n+]([O-])cc2Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
To a solution of 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.209 g, 1 mmol) in N,N-dimethylformide (4 mL), was added 3,5-dichloro-1-oxido-pyridin-1-ium-4-thiol sodium salt (0.2 g, 1 mmol) and potassium carbonate (0.348 g, 2.56 mmol). The resulting reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was poured onto ice (5 mL). After stirring for 10 minutes the solid which formed was collected by filtration and washed with water (10 mL) and air dried. The crude solid product was purified by silica gel flash chromatography using a mixture of 90:10 dichloromethane and methanol as eluent to afford the title product as a yellow solid (0.23 g, 63% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.93 (1H, s) 8.54 (1H, s), 2.54 (3H, s). MS m/z: 363.0 [M+H]+.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:35]=[CH:34][C:8]([CH2:9][NH:10][C:11]([C:13]3[C:18](=[O:19])[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)=[C:16]([CH3:30])[N:15]([CH:31]([CH3:33])[CH3:32])[CH:14]=3)=[O:12])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[N:36]#[C:37][NH2:38].BrN1C(=O)CCC1=O.CC(C)([O-])C.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CO>[CH:1]1([S:4]([C:5]2[CH:35]=[CH:34][C:8]([CH2:9][NH:10][C:11]([C:13]3[C:18](=[O:19])[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)=[C:16]([CH3:30])[N:15]([CH:31]([CH3:32])[CH3:33])[CH:14]=3)=[O:12])=[CH:7][CH:6]=2)=[N:38][C:37]#[N:36])[CH2:2][CH2:3]1
Reactant: N#CN
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)NCc2ccc(SC3CC3)cc2)cn1C(C)C
Agent: CC(C)(C)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Solvent: CO
Product: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(=NC#N)C3CC3)cc2)cn1C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid 4-cyclopropylsulfanyl-benzylamide (preparation 63c, 75 mg, 0.15 mmol), cyanamide (8 mg, 0.19 mmol), N-bromosuccinimide (40 mg, 0.22 mmol) and potassium tert-butoxide (20 mg, 0.18 mmol) in methanol (1 mL) is stirred at room temperature for 1 h. Saturated aqueous sodium thiosulfate solution is added, and the mixture is extracted twice with dichloromethane. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by preparative reversed phase HPLC (Xbridge, gradient of acetonitrile in water, 0.1% NH3). Yield: 7 mg (8% of theory); ESI mass spectrum: [M+H]+=541; r.t. HPLC: 0.64 min (X012_S02).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2.Br[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.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]>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)=[N:6]2
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(Nc3ccc(O)cc3)ncc12
Yield: 57.7 %

Procedure:
In a similar manner as described for Example 41, 5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (Intermediate 45) (0.025 g, 0.09 mmol), 4-bromophenol (0.015 g, 0.09 mmol), Pd2(dba)3 (0.008 g, 0.01 mmol), 2-(Di-t-butylphosphino)biphenyl (0.008 g, 0.03 mmol), and NaOtBu (0.011 g, 0.11 mmol) in 1,4-dioxane (1 mL) gave 4-({5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-yl}amino)phenol (0.020 g) as a yellow solid. 1H NMR (Acetone-d6): δ9.06 (s, 1H), 8.91 (s, 1H), 8.68 (d, J=4.8 Hz, 1H), 7.77-7.70 (m, 3H), 7.59 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 2.55 (s, 3H). MS m/z 386 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](N)=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[Cl:8].N([O-])=O.[Na+].N1C=CC=CC=1.[FH:21]>>[Br:1][C:2]1[C:3]([F:21])=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[Cl:8]
Reactant: F
Reactant: Nc1ncc(Br)c(Cl)c1Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Fc1ncc(Br)c(Cl)c1Br
Yield: 83 %

Procedure:
The reaction and post-treatment were carried out according to Example (8a) using 3,5-dibromo-4-chloropyridin-2-amine produced in Example (14a) (10.1 g, 35.4 mmol), sodium nitrite (3.66 g, 53.1 mmol) and hydrogen fluoride-pyridine (50 mL) to obtain the title compound (8.50 g, 83%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29]([C:25]5[S:24][CH:28]=[CH:27][CH:26]=5)=[O:30])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)c1cccs1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cccs4)nc3cc21

Procedure:
Thiophene-2-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and thiophene-2-carbonyl chloride (94 μl, 0.89 mmol). The title compound was obtained as yellow powder (54 mg, 15%).