Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[Cl-].[NH4+].C(OCC)(=O)C.O1CCCC1>C(O)C.O.[Fe]>[NH2:23][C:21]1[CH:20]=[CH:19][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:22]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
Pyrrolidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (610 mg) was dissolved in ethanol (15 ml)-water (3 ml), and then electrolytic iron powder (610 mg) and ammonium chloride (1.20 g) were added thereto, followed by heating under reflux for 30 min. The reaction mixture was cooled down to room temperature, and ethyl acetate-tetrahydrofuran (1:1) was then added thereto, followed by stirring. The mixture was filtered through celite to remove an insoluble portion, which was washed with ethyl acetate and water. The organic layer of the filtrate was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:1 to 1:5). Fractions containing the target compound was concentrated under a reduced pressure, and dried in vacuum to provide the titled compound (495 mg, 88.6%) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7](=[O:17])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pt]=O>[NH2:9][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:17]
Reactant: [H][H]
Reactant: O=C(C(=NO)c1ccccn1)c1ccccc1
Agent: O=[Pt]
Solvent: CCO
Product: NC(c1ccccn1)C(O)c1ccccc1

Procedure:
25.3 g of 1-phenyl-2-pyridin-2-ylethane-1,2-dione 2-oxime were dissolved in 300 ml of ethanol and, after addition of 1.0 g of platinum oxide, hydrogenated under atmospheric pressure until no further hydrogen was taken up. Filtration and concentration of the solution resulted in 21.6 g of 2-amino-1-phenyl-2-pyridin-2-ylethanol as mixture of 2 diastereomers.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([O:28][CH2:29][CH2:30][OH:31])[CH:25]=[CH:24][CH:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([O:28][CH2:29][CH2:30][OH:31])[N:27]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OCCOc1cccc(Br)n1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(OCCO)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 205, Step 2 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (60 mg, 0.20 mmol) and 2-[(6-bromopyridin-2-yl)oxy]ethanol (48.8 mg, 0.22 mmol) as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[S:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[NH:10][C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[S:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[N:10]([S:33]([CH:30]3[CH2:32][CH2:31]3)(=[O:35])=[O:34])[C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2cc3scnc3c(F)c2n1-c1ccc(Br)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1n(-c2ccc(Br)cc2Cl)c2c(F)c3ncsc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of 5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (100 mg, 0.25 mmol) in CH2Cl2 (10 mL) was added triethylamine (76 mg, 0.75 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (53 mg, 0.38 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (15 mL×2). The combined organic phase was washed with water (15 mL) and brine (20 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (120 mg, 95.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 7.99 (s, 1H), 7.91 (d, 1H), 7.73 (d, 1H), 7.50 (m, 1H), 3.37 (m, 1H), 1.70 (m, 2H), 0.93 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH:14]2[CH2:16][CH:17]([OH:19])[CH2:18][CH:13]2[CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH:14]2[CH2:16][C:17](=[O:19])[CH2:18][CH:13]2[CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CC3CC(O)CC3C2)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC2CN(c3ccc([N+](=O)[O-])cc3F)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
And, then, the 2-(2-fluoro-4-nitrophenyl)-octahydro-5-hydroxycyclopenta[c]pyrrol (44.4 mmol) prepared in the step 2 was dissolved in 100 ml of methylene chloride and slowly added over 30 minutes, the mixture was stirred for 1 hour while maintaining the temperature, and then, 30.93 ml (221.9 mmol) of triethylamine was slowly added over 20 minutes, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. After the reaction was completed, 100 mL of methylene chloride was added to dilute the mixture, and then, the mixture was washed with water and a saturated aqueous solution of sodium chloride, and the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was recrystallized under ethanol solvent to obtain 11.1 g (95%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-])=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1>O.CO>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)cn1
Solvent: O
Solvent: CO
Product: Nc1ccc(OCc2ccc(Cl)cc2)cn1
Reaction time: 15 h

Procedure:
A mixture of 5-(4-chlorobenzyloxy)-2-nitropyridine (0.5 g), Na2S (0.25 g) and methanol (12 ml) is heated to reflux for about 3 hours. Then, a few drops of water is added and refluxing continued about 15 hours. After cooling, the reaction is diluted with methanol, filtered through celite and stripped. The concentrate is taken up in CHCl3, washed with water, dried and stripped giving 2-amino-5-(4-chlorobenzyloxy)pyridine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:35].[OH-]>>[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccco1
Agent: [OH-]
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccco3)c2F)n1
Temperature: 120 °C

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide (150 mg, 0.287 mmol) and NH4OH (5 mL, 128 mmol) was heated in a microwave reactor at 120° C. for 40 min. LC-MS looks good for desired product. The reaction mixture was neutralized with 5N HCl and extracted with DCM×2. The crude mixture was evaporated onto silica gel and chromatographed (10-50% 1:9 MeOH:EtOAc in DCM). The title compound was obtained as a yellow solid after trituration in MeOH (102 mg, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 7.78-7.94 (m, 2H), 7.34 (td, J=7.4, 2.0 Hz, 1H), 7.14-7.30 (m, 2H), 7.03 (d, J=3.5 Hz, 1H), 6.44-6.61 (m, 3H), 5.64 (d, J=5.3 Hz, 1H), 3.67 (t, J=4.7 Hz, 4H), 3.41 (t, J=4.6 Hz, 4H). MS (ESI): 502.2 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Na+].[CH:13]([Br:16])(Br)Br>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[Br:16][C:13]1[CH:6]=[N:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: BrC(Br)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc2ncc(Br)cc2c1
Temperature: 40 °C
Reaction time: 48 h
Yield: 15 %

Procedure:
To a solution of 5-Fluoroindole (2.00 g, 14.8 mmol) and benzyltriethylammonium chloride (168.5 mg, 0.740 mmol) in toluene (3.00 mL) and bromoform (3.00 mL) at 40° C. was added a solution of sodium hydroxide (4.44 g, 111 mmol) in water (12.0 mL) in a dropwise manner. The reaction then stirred at 40° C. for 48 h. After cooling, the solvent was evaporated and the residue was diluted with methyl tert-butyl ether (100 mL) and water (100 mL). The aqueous layer was extracted with methyl tert-butyl ether. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 2.00 g of crude material. Purification by silica gel flash chromatography (0-2% ethyl acetate in petroleum ether) provided 3-bromo-6-fluoroquinoline (503 mg, 15% yield) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.87 (d, J=2.0 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 8.08 (dd, J=9.2, 5.6 Hz, 1H), 7.52-7.41 (m, 1H), 7.35 (dd, J=8.8, 2.8 Hz, 1H). (M+1): 225.6.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])S[CH2:4][CH2:3]1.OO.[S:19]([O-:22])(O)=[O:20].[Na+]>C(O)(=O)C>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])[S:19](=[O:22])(=[O:20])[CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCCC2C
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2C
Yield: 98 %

Procedure:
A 30-ml eggplant type flask was charged with 0.75 g (3.2 mmol) of the 4,5,8-trimethylthiochroman-6-carboxylic acid, 1.1 g (9.5 mmol) of 30% hydrogen peroxide and 1 ml of acetic acid, and the mixture was allowed to react at 100° C. for 2 hours. The reaction mixture was poured into a sodium hydrogensulfite aqueous solution and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate, and the solvent was distilled off to give 0.76 g (yield 98%) of 4,5,8-trimethylthiochroman-6-carboxylic acid-1,1,dioxide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20]([C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:21]([CH3:24])[C:22]=3[CH3:23])[CH2:13][C@H:12]2[CH3:33])=[N:9][CH:10]=1)=[O:4].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20]([CH:25]([OH:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[C:21]([CH3:24])[C:22]=3[CH3:23])[CH2:13][C@H:12]2[CH3:33])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCN(c3nnc(C(=O)c4ccccc4)c(C)c3C)C[C@H]2C)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCN(c3nnc(C(O)c4ccccc4)c(C)c3C)C[C@H]2C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (R)-4-(6-benzoyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (8 mg, 0.017 mmol) in MeOH (2 mL) is added sodium borohydride (170 μg, 0.004 mmol) in 15 minutes and the reaction mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with DCM and washed with NaHCO3 and water. The organic solvent is separated and the solvent is removed under reduced pressure. Purification by HPLC of the crude product with acetonitril in water (from 10% to 100% with 3% 1-propanol) at 220 nm wavelength detection provides the desired product as off white powder. (6 mg, 79%).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:16]=1[N:23]=[C:24]=[S:25]>>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:16]=1[N:23]=[C:24]1[N:8]([CH2:7][C:6]2[CH:12]=[CH:13][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:9][CH2:10][S:25]1
Reactant: ClCC[NH2+]Cc1ccc(Cl)cc1
Reactant: N#Cc1ccc(N=C=S)c(Cl)c1
Agent: [Cl-]
Product: N#Cc1ccc(N=C2SCCN2Cc2ccc(Cl)cc2)c(Cl)c1

Procedure:
2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-chloro-4-cyanophenyl isothiocyanate to give 2-(2-chloro-4-cyanophenylimino)-3-(4-chlorobenzyl)-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([CH2:17]Cl)[NH:8][SH:9](=[O:16])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>CO>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([CH2:17][N:24]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:22][CH3:23])[NH:8][SH:9](=[O:16])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1
Reactant: CCCNCCC
Reactant: O=[SH]1(c2ccccc2)NC(CCl)=Nc2ccc(Cl)cc21
Solvent: CO
Product: CCCN(CCC)CC1=Nc2ccc(Cl)cc2[SH](=O)(c2ccccc2)N1
Reaction time: 12 h

Procedure:
5g 7-chloro-3-chloromethyl-1-phenyl-benzo-1,2,4-thiadiazine-1-oxide and 20 g di-n-propylamine are dissolved in 80 ml methanol and left standing for 12 hours at room temperature. Thereafter the solution is evaporated and the residue distributed between chloroform and water. The chloroform phase is extracted with water several times, dried, evaporated, and the base (oil) dissolved in ethanol. After addition of ethanolic hydrochloric acid, the dihydrochloride precipitates. M.p. 192°-195° (decompn.).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:11]1[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]=3[S:8][CH2:7][C:6]2=1.Cl.N1C=CC=CC=1>>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:12]1[C:11]2[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]=3[S:8][CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([OH:2])[CH:4]=2
Reactant: COc1ccc2c(c1)c1c(n2CCN(C)C)-c2ccccc2SC1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)CCn1c2c(c3cc(O)ccc31)CSc1ccccc1-2
Temperature: 210 °C

Procedure:
A mixture of [2-(8-methoxy-6H-5-thia-11-aza-benzo[a]fluoren-11-yl)-ethyl]-dimethyl-amine (800 mg, 2.39 mmol) and Pyridine HCl (3.01 g, 23.7 mmol, 10 eq.) was heated to 210° C. for 30 minutes. The reaction mixture was then partitioned between EtOAc and saturated NaHCO3 aqueous solution. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a crude material. The crude material was purified by silica gel (EtOAc to CH2Cl2:MeOH 5:1) to yield the title compound as a brown solid.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:26])=[CH:22][C:23]=4[F:25])[N:18]([CH3:27])[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:26])=[CH:22][C:23]=4[F:25])[N:18]([CH3:27])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)cc(F)c34)nc12
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)cc(F)c34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
2-(6-Chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (46 mg, 0.09 mmol) was dissolved in dichloromethane (1.2 ml) and cooled in ice bath. Trifluoroacetic acid (0.6 ml) was slowly added and the reaction was stirred at room temperature for 2 h. The reaction was evaporated and the residue was dissolved in dichloromethane (1 ml). Ethylenediamine (0.36 ml, 5.3 mmol) was added and the mixture was stirred for 18 h. Water and then ethyl acetate were added to the mixture. The resulting precipitate was filtered off, rinsed with water diethyl ether and ethyl acetate and set aside. The organic filtrate was separated, washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was combined with the precipitate collected above. The solids were dried under high vacuum to afford 34 mg (98%) of 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide. MS: (M+H)+=387; mp=347-349° C. 1H NMR (300 MHz, DMSO-d6) δ: 9.01 (s, 1H), 8.42 (s, 1H), 8.22-8.33 (m, 1H), 7.88 (s, 1H), 7.20-7.32 (m, 1H), 4.13-4.30 (m, 1H), 4.18 (s, 3H), 1.24 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[C:7]([NH2:14])[C:6]=1[NH2:15])[CH3:2].COC(C1C2N=C(N)[NH:26][C:25]=2C=CC=1)=O.BrC#N>CO>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:15]=[C:25]([NH2:26])[NH:14][C:7]=2[CH:8]=[C:9]([O:11][CH2:12][CH3:13])[CH:10]=1)=[O:16])[CH3:2]
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: CCOC(=O)c1cc(OCC)cc(N)c1N
Agent: N#CBr
Solvent: CO
Product: CCOC(=O)c1cc(OCC)cc2[nH]c(N)nc12

Procedure:
4.0 g (17.9 mmol) of 2,3-diamino-5-ethoxy-benzoic acid ethyl ester was subjected to a similar cyclization condition as illustrated in intermediate A by using 5.7 g (53.7 mmol) of BrCN in methanol to produce 2-amino-6-ethoxy-1H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 250 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14]3[O:15][C:16]4[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=O)[O:28]C(C)(C)C)[CH3:25])[N:19]=[CH:18][C:17]=4[N:34]=3)=[CH:8][C:7]=2[F:35])[CH2:3][CH2:2]1.Cl.[C:37](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14]3[O:15][C:16]4[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:28])[CH3:37])[CH3:25])[N:19]=[CH:18][C:17]=4[N:34]=3)=[CH:8][C:7]=2[F:35])[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: COc1cc(-c2nc3cnc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3o2)cc(F)c1OCC1CC1
Agent: Cl
Product: COc1cc(-c2nc3cnc(OC[C@H](C)NC(C)=O)cc3o2)cc(F)c1OCC1CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3-fluoro-5-methoxyphenyl) [1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (1.35 g) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the reaction mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF and methanol, and the solution was subjected to NH silica gel column chromatography (ethyl acetate). The solvent was evaporated, and the obtained solid was washed with ethyl acetate to give the title compound (995 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[NH:12][NH2:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:13][NH:12][C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NN
Product: CC(C)(C)OC(=O)NNC(=O)c1cccc(Cl)c1

Procedure:
The title compound (4.41 g, colorless powder) was synthesized from 3-chlorobenzoyl chloride (2 mL) and tert-butyl carbazate (2.49 g), as in Reference Example P-Q1b.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][CH:10]=[N:9]1.[CH2:14]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23](Cl)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:13][C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH:12]=[N:11][CH:10]=[N:9]3)=[C:2]([F:1])[CH:3]=2)[N:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: Nc1ccc(-n2cncn2)c(F)c1
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(-n3cncn3)c(F)c2)n1

Procedure:
The title compound was prepared from 3-fluoro-4-[1,2,4]triazol-1-yl-phenylamine (81.4 mg, 0.46 mmol) and 4-benzyl-2-chloro-6-methyl-pyrimidine (100 mg, 0.46 mmol) in analogous manner to the procedure described in example 1e). Obtained as a light yellow wax (98 mg, 60%).
Reaction SMILES: FC1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C@@H:11](C)[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:22])=CC=1.C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)CC=C.[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][NH2:51])[CH:45]=1>>[CH2:6]([N:7]1[CH2:11][CH2:10][N:9]([C:13]2[S:14][C:15]([C:19]([NH:51][CH2:50][C:46]3[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=3)=[O:21])=[C:16]([CH3:18])[N:17]=2)[C:8]1=[O:22])[CH2:5][CH:23]=[CH2:24]
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: C=CCCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Product: C=CCCN1CCN(c2nc(C)c(C(=O)NCc3cccnc3)s2)C1=O
Yield: 62 %

Procedure:
Following the procedure as described in Example 2, making variations as required to replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(but-3-enyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as an off-white solid in 62% yield: mp 144-145° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.57-8.52 (m, 2H), 8.45 (d, J=3.8 Hz, 1H), 7.70 (ddd, J=7.8, 7.8, 1.8 Hz, 1H), 7.35 (dd, J=7.8, 4.8 Hz, 1H), 5.85-5.72 (m, 1H), 5.15-5.01 (m, 2H), 4.39 (d, J=5.8 Hz, 2H), 3.98 (d, J=9.0, 7.1 Hz, 2H), 3.59-3.54 (m, 2H), 3.31 (t, J=7.0 Hz, 2H), 2.47 (s, 3H), 2.32-2.25 (m, 2H); 13C NMR (75 MHz, DMSO-d6) 8161.9, 157.4, 154.9, 151.2, 148.8, 148.0, 135.5, 135.1, 135.1, 123.4, 117.3, 116.8, 42.4, 41.9, 41.6, 40.4, 31.1, 17.1; MS (ES+) m/z 372.1 (M+1).
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:10][CH:11]([CH3:15])[C:12](O)=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([O:9][C:12](=[O:13])[CH:11]([SH:10])[CH3:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(S)C(=O)O
Reactant: OC1CCCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(S)C(=O)OC1CCCCCCC1

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, thermometer, hot plate, spin bar and heating mantle are placed 12.8 grams of cyclooctanol; 22 grams of 2-mercaptopropionic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and maintained at reflux for a period of 10 hours. At the end of the reaction mass, the reaction product is washed with one 25 ml volume of water and dried over anhydrous sodium sulfate. The reaction mass is then distilled on a micro distillation column yielding the compound having the structure: ##STR99##