Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO>[Pd].O1CCCC1>[C:1]([NH:5][C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)Nc1ccccc1N

Procedure:
To a solution of tert-butyl-(2-nitrophenyl)-amine (1.27 g, 6.5 mmol), 5% palladium on carbon (0.5 g), and sodium borohydride (0.49 g, 13.1 mmol) in tetrahydrofuran (20 mL) was added methanol (10 mL) in a dropwise manner. Upon completion of the reaction, it was filtered through a pad of Celite and the filtrate was poured into a saturated aqueous solution of ammonium chloride (50 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo to give N-tert-butyl-benzene-1,2-diamine which was used in the next step without further purification. A solution of N-t-butyl-benzene-1,2-diamine (1.1 g, 6.7 mmol) and carbonyldiimidazole (1.63 g, 10 mmol) in anhydrous tetrahydrofuran (50 mL) was stirred at room temperature for 12 hours. Upon completion, the reaction was poured into a 1 N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified via flash column chromatography (silica, 50% ethyl acetate in hexane) to give 1-tert-butyl-1,3-dihydro-benzimidazol-2-one as an off-white solid. MS (ES) m/z 191.1.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26]([O:28]C4C=CC([N+]([O-])=O)=CC=4)=O)[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.[NH:38]1[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39]1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=4)[CH2:12][N:11]([C:26]([N:38]4[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39]4)=[O:28])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Reactant: OC1CCNC1
Product: O=C(N1CCC(O)C1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
100 mg (0.19 mmol) of the compound from Example 176A and 50 mg (0.58 mmol) of 3-pyrrolidinol were reacted according to the General Method 6. Yield: 50 mg (53% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C[Al](C)C.C([O:15][C:16]([C:18]1[NH:22][N:21]=[C:20]([CH3:23])[CH:19]=1)=O)C>C(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16]([C:18]2[NH:22][N:21]=[C:20]([CH3:23])[CH:19]=2)=[O:15])=[N:3][CH:4]=1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: Nc1ccc(Br)cn1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2ccc(Br)cn2)[nH]n1
Reaction time: 4 h
Yield: 49.1 %

Procedure:
A solution of 2-amino-5-bromopyridine (0.200 g, 1.16 mmol 1.0 equiv), in 5 mls of methylene chloride, under argon, was treated with trimethylaluminum (0.312 mL, 2.0N in hexanes, 4.0 equiv) at room temperature for 30 min. To the solution was added ethyl-3-methylpyrazole-5-carboxylate (0.356 g, 2.0 equiv). After 4 hrs, the volatile was evaporated, and the residue was redissolved into EtOAc, washed with 0.5N HCl, 0.2 N K2CO3, and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, evaporated and purified via flash chromatography on silica gel to give N-(5-bromo-2-pyridinyl)-(3-methyl)-5-pyrazolecarboxamide (0.160 g, 49%). MS found for C10H9BrN4O (M+H)+: 281, 283.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH2:14])[CH2:4][O:3]1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[S:25]>CCCCC>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:14][C@H:5]1[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][C@H:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[S:25]
Reactant: S=C=Nc1ccccc1Br
Reactant: CC1(C)OC[C@H](N)[C@H](c2ccccc2)O1
Solvent: CCCCC
Product: CC1(C)OC[C@H](NC(=S)Nc2ccccc2Br)[C@H](c2ccccc2)O1
Reaction time: 48 h
Yield: 53.3 %

Procedure:
To a solution of 143 mg (0.69 mmol) of (4S,5S)-amine 1 in pentane (2.0 mL) was added dropwise 93 microliters (0.69 mmol) of 2-bromophenyl isothiocyanate. After ˜48 h, a white precipitate was collected, rinsed with pentane and dried under reduced pressure to yield 155 mg (53%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20]([NH2:22])=[O:21].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=2)[C:20]([NH2:22])=[O:21])=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)c1ccnc(N)c1
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(OCC(=O)Nc2cc(C(N)=O)ccn2)cc1
Yield: 56.5 %

Procedure:
A solution of 4-tert-butylphenoxy acetic acid (60.1 mg, 0.29 mmol), 2-amino isonicotinamide (60.3 mg, 0.44 mmol), DIPEA (0.1 ml, 0.58 mmol) and PyBOP (301.8 mg, 0.58 mmol) in DMF 4.0 mL was stirred, then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by Prep-TLC (n-Hexane:EtoAc:MeOH=6:3:1) to give 2-[2-(4-tert-butyl-phenoxy)-acetylamino]-isonicotinamide as a white solid (53.6 mg, 56.5% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:9]C(C)(CC(C)(C)C)C)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.FC(F)(F)C(O)=O>>[CH3:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(NC(C)(C)CC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N)c(C)c1
Temperature: 50 °C
Yield: 88.4 %

Procedure:
3,5-dimethyl-N-(2,4,4-trimethylpentan-2-yl)pyridin-2-amine (6.5 g, 27.7 mmol) was mixed with 2,2,2-trifluoroacetic acid (46 mL, 621 mmol) and heated to 50° C. for 4.5 hours. The mixture was concentrated in vacuo then diluted with dichloromethane (10 mL) and water (10 mL). The layers were partioned and aqueous phase was neutralised to pH 7-8 using saturated bicarbonate solution. The product was then extracted with dichloromethane (3×10 mL) and the organics were dried using a phase separator cartridge. The solvent was evaporated in vacuo to give the title compound (2.99 g) as a white solid. LCMS (2 min, High pH) Rt 0.69 min, m/z (ES+) 123 (M+H).
Reaction SMILES: [OH-].[K+].[C:3]([OH:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.Cl[CH:18]([C:22](=[O:24])[CH3:23])[C:19](=[O:21])[CH3:20]>O>[C:3]([O:11][CH:18]([C:22](=[O:24])[CH3:23])[C:19](=[O:21])[CH3:20])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: O=C(O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C(OC(=O)c1ccccc1)C(C)=O
Temperature: 50 °C
Yield: 96.1 %

Procedure:
A flask was charged with powdered potassium hydroxide (21.89 g, 390.2 mmol), benzoic acid (47.65 g, 390.2 mmol), and DMF (500 mL) was added. The mixture was heated at 50° C. for 1 hour. 3-Chloropentane-2,4-dione (52.5 g, 390.2 mmol) and the reaction was stirred at 50° C. overnight. The reaction was cooled to ambient temperature, diluted in water (1.5 L) and extracted with ether (3×500 mL). The combined organic layers were washed with water, saturated NH4Cl and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 2,4-dioxopentan-3-yl benzoate (82.59 g, 96.12% yield) as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[NH:17][C:16]([CH3:18])=[C:15]([CH3:19])[CH:14]=1)=[O:12].Br[CH2:21][CH:22]=[CH:23][CH3:24]>>[CH2:21]([N:17]1[C:13]([C:11](=[O:12])[CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][C:15]([CH3:19])=[C:16]1[CH3:18])[CH:22]=[CH:23][CH3:24]
Reactant: Cc1cc(C(=O)CCc2ccc(F)cc2F)[nH]c1C
Reactant: CC=CCBr
Product: CC=CCn1c(C(=O)CCc2ccc(F)cc2F)cc(C)c1C
Yield: 55.4 %

Procedure:
The title compound (cis/trans=23/77) was prepared as a yellow oil in 55.4% yield in a similar procedure to that described in Referential Example 97 by using 5-[3-(2,4-difluorophenyl)propionyl]-2,3-dimethylpyrrole and 1-bromo-2-butene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]([CH3:13])[C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[Cl:17][S:18](O)(=[O:20])=[O:19].O>ClCCCl>[F:1][C:2]1[CH:16]=[CH:15][C:14]([S:18]([Cl:17])(=[O:20])=[O:19])=[C:4]([CH2:5][N:6]([CH3:13])[C:7](=[O:12])[C:8]([F:10])([F:11])[F:9])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: CN(Cc1cccc(F)c1)C(=O)C(F)(F)F
Solvent: O
Solvent: ClCCCl
Product: CN(Cc1cc(F)ccc1S(=O)(=O)Cl)C(=O)C(F)(F)F
Temperature: 70 °C

Procedure:
A solution of 3-fluoro-N-methyl-N-(trifluoroacetyl)benzylamine (Intermediate 159, 0.497 g) in DCE (0.5 mL) was added to stirred, cooled chlorosulfonic acid (3 mL). The mixture was allowed to come up to room temperature and then heated at 70° C. for 3 hours. After cooling, the mixture was added carefully to a mixture of ice and water, then extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 2.5-10% to give 4-fluoro-2-[N-methyl-N-(2,2,2-trifluoroacetyl)aminomethyl]-benzenesulfonyl chloride (0.21 g) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8]([NH2:10])=[NH:9])N=1.C(N(CC)C(C)C)(C)C.NCCCC[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29]>O1CCOCC1.O>[NH:4]([CH2:5][CH2:6][CH2:2][CH2:1][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:8]([NH2:10])=[NH:9]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: NCCCCCCCC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: N=C(N)NCCCCCCCC(=O)O

Procedure:
3,5-dimethyl-pyrazole-1-carboxamidine (100 g; 0.5 Mole) and N,N-diisopropylethyl amine (DIEA) (65 g; 0.5 Mole) were suspended in dioxane (300 ml) and water (115 ml). 8-Amino-octanoic acid (48 g; 0.3 Mole) was added to the mixture with stirring. The colorless solution was then refluxed for 2 days. The product was filtered and washed with water (3×50 ml).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19](O)=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.[Cl:23]CCl>CN(C)C=O>[C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([Cl:23])=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: Cc1ccc(NS(=O)(=O)c2cccc(C=CC(=O)O)c2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(NS(=O)(=O)c2cccc(C=CC(=O)Cl)c2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a suspension of 3-(3-p-tolylsulfamoyl-phenyl)-acrylic acid (5d) (0.75 g, 2.36 mmol) in dichloromethane (10.0 ml) oxalyl chloride (0.62 ml, 7.08 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.79 g).
Reaction SMILES: [CH2:1]([N:4]([C:10]1[C:15](Br)=[CH:14][N:13]=[C:12]([Cl:17])[N:11]=1)[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH:2]=[CH2:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:17][C:12]1[N:13]=[CH:14][C:15]2[C:2]([CH3:3])=[CH:1][N:4]([CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[C:10]=2[N:11]=1
Reactant: C=CCN(c1nc(Cl)ncc1Br)C(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)n1cc(C)c2cnc(Cl)nc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of allyl-(5-bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (2.76 g, 8.7 mmol) in anhydrous DMF (15 mL) is added Pd(OAc)2 (156 mg, 0.69 mmol) and PPh3 (182 mg, 0.69 mmol) and triethylamine (2.4 mL, 17.3 mmol). The reaction mixture is, stirred at 100° C. overnight. The reaction mixture is diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, EtOAC/hexane 1:2) gives 0.95 g of 2-chloro-7-(1-ethyl-propyl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][C:16]=2[C:27]([F:30])([F:28])[F:29])=[N:22]1)=[O:12])[CH3:9]
Reactant: Cc1cc(Oc2ccc(Cl)cc2C(F)(F)F)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ccc(Cl)cc2C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.2 %

Procedure:
Triethylamine (0.17 g, 1.65 mmol) and ethyl isocyanate (0.31 g, 2.2 mmol) were added to a solution of 3-(4-chloro-2-trifluoromethylphenyloxy)-5-methylpyrazole (0.55 g, 2.0 mmol) in ethyl acetate (5 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a colorless viscous substance of N-ethyl-3-(4-chloro-2-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.53 g, yield: 75.9%). 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (t, J=7.3 Hz, 3H), 2.59 (d, J=0.7 Hz, 3H), 3.37 (q, J=7.3 Hz, 2H), 5.73 (q, J=0.7 Hz, 1H), 6.91 (br s, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.49 (dd, J=2.5 and 8.8 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:12])([F:11])[C:6]([O:8]CC)=O.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[O:15].Cl>C1(C)C=CC=CC=1.O>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([C:14](=[O:15])[CH2:13][C:6](=[O:8])[C:5]([F:4])([F:11])[F:12])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc(C(C)=O)cc1OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
216 g (4 mol) of anhydrous sodium methylate and 3.5 l of toluene are introduced into a 10 liter round-bottomed flask and, under vigorous stirring, 705 g (5 mol) of ethyl trifluoroacetate are then run in; the temperature rises slowly to 30° C. After cooling in an ice bath, a solution of 720 g (4 mol) of 3,4-dimethoxyacetophenone in 0.5 l of toluene is added dropwise to the reaction mixture; a white precipitate slowly forms. The mixture is next left stirred overnight and then heated to 50° C. for three hours. After cooling, 2 1 of water and 330 ml of concentrated hydrochloric acid are added, the organic phase is separated off after settling has taken place, dried over magnesium sulphate, filtered and evaporated to obtain 1060 g (96%) of a yellow solid melting at 87°-89° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:12])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Mg]Br)(C)C.[O:18]1CC[CH2:20][CH2:19]1.C(=O)C.[Cl-].[NH4+]>O1CCCC1>[Br:12][C:4]1[S:3][C:2]([CH:19]([OH:18])[CH3:20])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1
Reactant: CCOC(=O)c1cc(Br)sc1Br
Reactant: C1CCOC1
Agent: CC(C)[Mg]Br
Agent: CC=O
Agent: [Cl-]
Product: CCOC(=O)c1cc(Br)sc1C(C)O
Reaction time: 1 h
Yield: 49 %

Procedure:
Ethyl 2,5-dibromothiophene-3-carboxylate (22.3 g) synthesized above was dissolved in tetrahydrofuran (200 mL), and 1.0M isopropylmagnesium bromide-tetrahydrofuran solution (78.0 mL) was added dropwise at −45° C. After stirring under an argon atmosphere for 1 hr, acetaldehyde (19.9 mL) was added dropwise, and the mixture was stirred at −45° C. for 1 hr, and at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give the title compound (9.63 g, 49%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:17])[CH3:16])=[C:8]([N+:19]([O-])=O)[CH:7]=1)=[O:4].[H][H]>[Pt]=O.CO>[NH2:19][C:8]1[CH:7]=[C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:11]=[CH:10][C:9]=1[NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:17])[CH3:16]
Reactant: COC(=O)Nc1ccc(NC(=O)CN(C)C)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: COC(=O)Nc1ccc(NC(=O)CN(C)C)c(N)c1
Yield: 69 %

Procedure:
N-(4-methoxycarbonylamino-2-nitrophenyl)-2-dimethylaminoacetamide (25.3 g), platinum oxide (0.4 g) and methanol (250 ml) were shaken together in an atmosphere of hydrogen at atmospheric pressure and laboratory temperature until the uptake of hydrogen was complete. Six litres of hydrogen were absorbed. The mixture was filtered and the ethanol evaporated. The residual solid was recrystallised from isopropanol to give N-(2-amino-4-methoxycarbonylaminophenyl)-2-dimethylaminoacetamide (15.7 g), m.p. 140°-142° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37]>CO.CCOCC>[ClH:37].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:36])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Reaction time: 18 h
Yield: 85 %

Procedure:
tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (12.0 g, 24.7 mmol) was dissolved in MeOH (100 mL), and 2 N HCl in Et2O (300 mL) was added. The reaction was allowed to proceed for 18 h. The mixture was concentrated, and the residue was partitioned between CH2Cl2 and sat. Na2CO3 solution. The organic phase was removed, and the aqueous phase was back extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness providing the free base of the title compound (8.1 g, 85%) as a yellow solid. A portion of the free base was converted to the HCl salt for biological testing. Free base: 1H NMR (500 MHz, CDCl3) δ 7.47-7.34 (m, 6H), 7.32-7.28 (m, 2H), 6.98 (d, J=7.1 Hz, 1H), 6.07 (d, J=2.6 Hz, 1H), 6.04 (dd, J=7.5, 2.6 Hz, 1H), 5.05 (s, 2H), 4.15 (s, 2H), 3.61 (s, 3H), 3.34 (br s, 2H), 2.78 (br s, 2H). HCl salt: melting point (mp) 296-302° C.; 1H NMR (500 MHz, CD3OD) δ 7.61-7.57 (2×d, 2H), 7.47-7.46 (m, 3H), 7.43-7.40 (m, 2H), 7.37-7.34 (m, 1H), 7.05 (dd, J=8.3, 1.7 Hz, 1H), 6.33 (dd, J=7.5, 2.7 Hz, 1H), 6.16 (d, J=2.6 Hz, 1H), 5.19 (s, 2H), 4.57 (s, 2H), 3.73 (s, 3H), 3.67 (t, J=6.2 Hz, 2H), 3.20 (t, J=6.1 Hz, 2H); ESI MS m/z 386 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=13.6 min.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(Cl)Cl.[F:15][C:16]1[C:17]([C:32]2[N:33]=[C:34]([S:42][CH3:43])[N:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]=23)=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:22]=[CH:21]2>>[F:15][C:16]1[C:17]([C:32]2[N:33]=[C:34]([S:42]([CH3:43])=[O:9])[N:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]=23)=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:22]=[CH:21]2
Reactant: CSc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2F)c2c(N)nccn12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc(-c2ccc3ccc(-c4ccccc4)nc3c2F)c2c(N)nccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of m-chloroperbenzoic acid (0.013 g, 0.000075 mol) in DCM (0.4 g, 0.005 mol) was added slowly to a solution of 1-(8-fluoro-2-phenyl-quinolin-7-yl)-3-methylsulfanyl-imidazo[1,5-a]pyrazin-8-ylamine (30 mg, 0.000075 mol) in DCM (2 mL, 0.04 mol) at −78° C. The reaction mixture was allowed to stir at that temp for 30 min. The reaction mixture was transferred to an ice-bath and stirred for 1 h. 50% consumption of SM was observed. The reaction mixture was stirred in ice-bath for 1 h. An additional 0.5 eq of m-chloroperbenzoic acid was added to the reaction mixture and the reaction mixture was warmed to rt and stirred for 2 h. The reaction mixture was concentrated in vacuo. Purification by prep TLC (7% MeOH in DCM) afforded the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ=5.13 (br. s., 2H), 7.32 (d, J=5.05 Hz, 1H), 7.48-7.60 (m, 3H), 7.69 (dd, J=8.46, 6.44 Hz, 1H), 7.76-7.81 (m, 1H), 8.06 (d, J=8.84 Hz, 1H), 8.15 (d, J=5.05 Hz, 1H), 8.25 (dd, J=8.21, 1.39 Hz, 2H), 8.32 (dd, J=8.72, 1.39 Hz, 1H). MS (ES+): m/z 417.95 (100)[MH+]. HPLC: tR=2.63 min (Open Lynx polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[N:6]3[N:13]=[C:14]([CH2:16][OH:17])[CH:15]=[C:5]3[C:4]=2[CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[N:6]3[N:13]=[C:14]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH:15]=[C:5]3[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c2cc(CO)nn12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cc2c3cc(Cl)ccc3[nH]c(=O)n2n1

Procedure:
2.50 g (0.01 mole) of 9-chloro-2-(hydroxymethyl)pyrazolo-[1,5-c]quinazolin-5(6H)-one and 1.02 g of acetic anhydride in 50 ml pyridine are stirred for 12 hours then refluxed for 30 minutes. The reaction is evaporated; the residue is taken up in chloroform, washed with dilute aqueous sodium bicarbonate, with water and dried. The solvent is evaporated to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[Cl:13].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19].O>CS(C)=O>[Cl:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH:19][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=1
Reactant: NCc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(CCBr)c(Cl)c1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(CCNCc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a solution of 1-(2-bromoethyl)-2-chloro-4-nitrobenzene (0.6 g, 1.84 mmol) in DMSO (20 mL), 3-chlorobenzylamine (1.21 g, 4.61 mmol) was added at room temperature. The reaction mixture was stirred for 3 hours at room temperature. After the completion of reaction, water (80 mL) was added and reaction mass was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and the solvents removed under reduced pressure. The product was purified by column chromatography on neutral silica gel using 5-15% EtOAc in hexane to give the title compound (0.43 g, 55%) as a solid.