Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH2:7].[CH:17]1([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:39]([CH:40]=O)=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:26][CH2:25]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1)[CH2:6][NH:7][CH2:40][C:39]1[C:30]([N:27]2[CH2:26][CH2:25][N:24]([CH2:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:29][CH2:28]2)=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: O=Cc1cc2ccccc2nc1N1CCN(CC2CCCCC2)CC1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(CNCc2cc3ccccc3nc2N2CCN(CC3CCCCC3)CC2)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 67.4 %

Procedure:
3,5-Bis(trifluoromethyl) benzylamine (0.305 g, 1.25 mmol) was added to a solution of 2-(4-cyclohexylmethyl-piperazin-1-yl)-quinoline-3-carbaldehyde (0.4 g, 1.23 mmol) in methanol followed by acetic acid (0.15 mL) at ambient temperature under nitrogen atmosphere. After stirring 1 h, sodium cyanoborohydride (0.237 g, 3.77 mmol) was added carefully, and the reaction was stirred at RT for overnight. The reaction mixture was evaporated to dryness, and water (30 mL) and ethyl acetate (30 mL) were added to the residue, and this was then extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to afford a pale yellow crude product. Purification by silica gel column chromatography and eluting with 2.5% methanol/dichloromethane afforded the title compound (0.468 g, yield: 67%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][C:17]=1[F:21])=[O:8]
Reactant: Fc1cccc(F)c1
Reactant: O=C(Cl)CCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc(F)cc1F

Procedure:
6-Bromohexanoyl chloride (2 g), 1,3-difluorobenzene (20 ml) and aluminum chloride (1.31 g) were reacted and treated in the same manner as in Preparation Example 105 to give 1.16 g of 6-bromo-1-(2,4-difluorophenyl)-1-hexanone.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].CN1CCCC1=O.[CH2:19]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:19]([N:22]([CH2:23][CH:24]=[CH2:25])[C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:4]([NH2:5])[CH:3]=1)[CH:20]=[CH2:21]
Reactant: C=CCNCC=C
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCN(CC=C)c1cc(N)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 98.6 %

Procedure:
A mixture of 3-fluoro-4-nitroaniline (1.56 g, 10 mmol), 1-methylpyrrolidinone (10 mL), diallylamine (1.94 g, 20 mmol) and potassium carbonate (1.38 g, 10 mmol) was heated to 115-125° C. for 9.5 h. The mixture was diluted with water, and extracted with ethyl ether. The combined extracts were washed with water, washed with saturated brine solution, and dried over magnesium sulfate. The extract was concentrated to give N,N-diallyl-6-nitro-1,3-benzenediamine as an orange oil (2.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccccc1C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccccc1CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
A mixture of 4-(2-methoxycarbonyl-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester (from Intermediate B11 step 1) (350 mg; 1.06 mmol; 1 eq.) and 10% Pd/C (˜50% H2O) (67 mg) in MeOH (2 mL) and THF (2 mL) was stirred at room temperature for 3 hours under a H2 atmosphere (10 bars). The catalyst was filtered off and the solution concentrated in vacuo. Purification by column chromatography (heptane/EA) afforded the title compound (330 mg, 94%) as a colourless oil. HPLC (max plot) 97.4%; Rt 5.20 min.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH:2]=1.CC(C)([O-])C.[K+].[CH3:24][N:25]=[C:26]=[S:27]>O1CCCC1>[CH3:24][NH:25][C:26]([C:11]1([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])=[S:27]
Reactant: CN=C=S
Reactant: O=C1CCCCC1c1cnc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=S)C1(c2cnc3ccccc3c2)CCCCC1=O
Yield: 9.4 %

Procedure:
A solution of (±)-2-(quinolin-3-yl)cyclohexanone (0.78 g, 3.5 mmol) in tetrahydrofuran (10 ml) at -5° C. was treated with potassium t-butoxide (0.43 g, 3.9 mmol) in one portion. After 25 minutes at -5° C. the deep red mixture was treated dropwise during 1 minute with a solution of methyl isothiocyanate (0.28 g, 3.9 mmol) in tetrahydrofuran (2 ml). After 4 hours at 0° C. the reaction mixture was partitioned between saturated aqueous ammonium chloride solution (50 ml) and chloroform (50 ml). The aqueous layer was extracted again with chloroform (50 ml). The combined organic extracts were then dried over sodium sulphate and concentrated in vacuo (20° C.; 14 mmHg) to give a crude oil which was purified by flash chromatography over silica gel eluting with ethyl acetate to give (±)-N-methyl-2-oxo-1-(quinolin-3-yl)cyclohexanecarbothioamide (0.1 g, 0.33 mmol), m.p. 235°-236° C.;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[N:16]=[CH:17][CH:18]=[N:19]2)(=[O:12])=[O:11])([O-])=O>CC(O)=O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[N:16]=[CH:17][CH:18]=[N:19]2)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2nccnc12
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccccc1S(=O)(=O)Nc1cccc2nccnc12
Temperature: 80 °C
Yield: 70.4 %

Procedure:
Iron powder (455 mg, 8.14 mmol) was added to a solution of 2-nitro-N-quinoxalin-5-yl-benzenesulfonamide (Intermediate 243) (673 mg, 2.08 mmol) in AcOH (15 ml) and the mixture was heated at 80° C. for 2 h. After cooling, the mixture was concentrated in vacuo. The residue was diluted with EtOAc and the mixture was filtered through celite. The filtrate was washed with sat. NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo to give the title compound (440 mg, 72%) which was used in the next step without further purification.
Reaction SMILES: [K+].[NH:2]1[CH2:6][CH2:5][C@H:4]([S:7][C:8]2[C@H:9]([CH3:22])[C@@H:10]3[C@@H:17]([C@H:18]([OH:20])[CH3:19])[C:16](=[O:21])[N:11]3[C:12]=2[C:13]([O-:15])=[O:14])[C:3]1=[S:23].[C:24]([O:29][CH2:30]I)(=[O:28])[CH:25]([CH3:27])[CH3:26]>>[C:24]([O:29][CH2:30][O:14][C:13]([C:12]1[N:11]2[C:16](=[O:21])[C@H:17]([C@H:18]([OH:20])[CH3:19])[C@H:10]2[C@@H:9]([CH3:22])[C:8]=1[S:7][C@H:4]1[CH2:5][CH2:6][NH:2][C:3]1=[S:23])=[O:15])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3CCNC3=S)[C@H](C)[C@H]12
Reactant: CC(C)C(=O)OCI
Agent: [K+]
Product: CC(C)C(=O)OCOC(=O)C1=C(S[C@H]2CCNC2=S)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
In the same manner as described in Example 48, (1R, 5S, 6S)-2-[(3S)-pyrrolidine-2-thion-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid potassium salt is treated with isobutyryloxymethyl iodide to give (1R, 5S, 6S)-2-[(3S)-pyrrolidine-2-thion-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid isobutyryloxymethyl ester.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].BrBr.[NH2:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([C:25]2[N:29]=[CH:28][O:27][N:26]=2)[CH:9]=1.O>CO>[NH2:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:21])[F:22])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([C:25]2[N:29]=[CH:28][O:27][N:26]=2)[C:9]=1[S:1][C:2]#[N:3]
Reactant: Nc1cc(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CSc1c(-c2ncon2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: -78 °C
Reaction time: 0.13 h
Yield: 98.2 %

Procedure:
Potassium thiocyanate (1.45 g, 14.9 mmol) was dissolved in 20 ml of dry methanol, and then a methanol (5 ml) solution of bromine (0.28 ml, 5.44 mmol) was added dropwise with stirring at −78° C. over 8 minutes (inner temperature: not higher than −65° C.). After the completion of adding dropwise, the mixture was stirred at −78° C. for 10 minutes and a methanol (15 ml) solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1,2,4-oxadiazol-3-yl)pyrazole (1.80 g, 4.94 mmol) was added dropwise over 15 minutes. The solution was stirred at −78° C. for 2 hours, warmed to room temperature and then stirred at the same temperature for 2 hours. The reaction mixture was poured into 100 ml of iced water. After stirring for 30 minutes, the deposited crystal was filtered. The resulting crystal was washed with water and then dried under reduced pressure to obtain 2.04 g (4.85 mmol) of the title compound as a colorless crystal. Yield 98.0%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:9][C:8]=1[CH3:29].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.O>CN(C=O)C>[CH3:29][C:8]1[CH:9]=[C:10]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)[CH:11]=[C:12]([CH3:13])[C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCCBr)c(C)c3)nc2c1
Reactant: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(4-bromo-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (494 mg, 1.07 mmol) in DMF (10 mL) was added pyrrolidine (609 mg, 8.57 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the product was extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous Na2SO4. Solvent was evaporated to give the title compound as a white solid. Yield: 278 mg (57%). MP 180-181° C. 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 2H), 6.83 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.83 (t, J=6.4 Hz, 2H), 2.56 (m, 6H), 2.36 (s, 6H), 1.88 (m, 2H), 1.79 (m, 6H). MS (ES) m/z: 452.21 (M+1).
Reaction SMILES: [C:1]1([C:7]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([CH:17]=[CH2:18])=[CH:13][N:12]3[CH:19]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[CH2:17]([C:14]1[CH:15]=[CH:16][C:11]2[N:12]([CH:19]=[C:9]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[N:10]=2)[CH:13]=1)[CH3:18]
Reactant: C=Cc1ccc2nc(C(=O)c3ccccc3)cn2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2nc(C(=O)c3ccccc3)cn2c1
Yield: 18.6 %

Procedure:
A solution of 80 mg of phenyl(6-vinylimidazo[1,2-a]pyridin-2-yl)methanone in 20 mL of methanol is hydrogenated for 45 minutes at 45° C. under 1 bar of hydrogen in the presence of 34 mg of 10% palladium-on-charcoal. The product is chromatographed on silica, eluting with a gradient of cyclohexane and ethyl acetate, to give 15 mg of (6-ethylimidazo[1,2-a]pyridin-2-yl)(phenyl)methanone in the form of a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[CH:11][C:12]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=2)=[N:13][CH:14]=1>ClCCl>[Cl:8][C:9]1[C:10]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:11][C:12]([NH:15][C:16]2[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=2)=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc(Nc2cc(NCC3CCNCC3)c(Cl)cn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
Trifluoroacetic acid (0.1 mL) was added to tert-butyl 4-((5-chloro-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (12 mg, 0.027 mmol) in dichloromethane (1 mL) and the mixture was stirred at r.t. for 2 hr. Solvent was removed in vacuo and the residue was redissolved in MeOH and adsorbed onto Isolute SCX-II acidic resin (500 mg). The resin was washed with methanol, then 2M ammonia in methanol. The basic fractions were evaporated to dryness to give 5-(5-chloro-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile (2 mg, 22%) as a yellow powder.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:26][CH3:27])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:25]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:35][C:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:26]([CH3:27])[C:42]([C:36]2([CH3:35])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:43])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[C:25]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2cccc3c2OCCO3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)C1(C)CCCCC1)[C@H](CC1CCCCC1)CN1CCN(c2cccc3c2OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 0.7 g (1.87 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2,3dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.3 g (1.87 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (ethyl acetate/hexanes) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.85 g (91%) of the title compound as a white solid; mp=219-220° C.; MS(+)ESI m/z=498 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18](=[O:20])[CH3:19])[CH:14]=[N:15][CH:16]=1>>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:18]([OH:20])[CH3:19])[CH:14]=[N:15][CH:16]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)Cc1cncc(Br)c1
Product: CC(O)C(Cc1ccc(Cl)cc1)c1cncc(Br)c1

Procedure:
The title compound was prepared following the procedure described in Reference Example 67, Step B-C, substituting 2-bromomethyl-5-chloropyridine with 4-chlorobenzyl chloride and 3-bromophenylaceatone with 5-bromo-3-pyridylacetone (Step A). 1H NMR (500 MHz, CD3OD): δ 8.43 (d, 1H), 8.24 (d, 1H), 7.98 (dd, 1H), 7.17 (d, 2H), 7.07 (d, 2H), 4.04 (m, 1H), 3.16 (dd, 1H), 3.0-2.9 (m, 2H), 1.04 (d, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[C:7]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([NH2:24])[CH:18]=2)=[N:6][C:5]1=[O:25])([CH3:3])[CH3:2].[CH:26](OCC)(OCC)OCC>CCOC(C)=O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[CH:7]([C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH:26]=[N:24][C:19]=3[CH:18]=2)[NH:6][C:5]1=[O:25])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)nc(-c2ccc(O)c(N)c2)c2cc3c(cc21)OCO3
Reactant: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Product: CC(C)N1C(=O)NC(c2ccc3ocnc3c2)c2cc3c(cc21)OCO3
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 1-isopropyl-6,7-methylenedioxy-4-(3-amino-4-hydroxyphenyl)quinazolin-2(1H)-one (93 mg) in triethyl orthoformate (3 mL) was refluxed for 1 h, cooled to rt, diluted with EtOAc (30 mL), washed with water, saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo to yield the title compound as a tan solid (70 mg, 71%), mp: 84-86° C. 1H NMR (CDCl3): 8.12 (s, 1H), 7.72 (s, 1H), 7.59 (d, J=8.3, 2H), 7.39 (d, J=8.3, 1H), 6.71 (s, 1H), 6.28 (s, 1H), 5.92 (s, 1H), 5.90 (s, 1H), 5.49 (s, 1H), 5.14 (s, 1H), 4.45 (m, 1H), 1.58 (d, J=6.6, 3H), 1.55 (d, J=6.6, 3H).
Reaction SMILES: C([O:5][C:6](=[O:34])[C@@H:7]([N:10]1[C:15](=[O:16])[C:14]2[N:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]([CH2:21][C:22]2[C:26]3[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=3[S:24][N:23]=2)[C:11]1=[O:33])[CH2:8][CH3:9])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:32][C:27]1[C:26]2[C:22]([CH2:21][N:12]3[C:13]4[CH:20]=[CH:19][CH:18]=[N:17][C:14]=4[C:15](=[O:16])[N:10]([C@@H:7]([CH2:8][CH3:9])[C:6]([OH:34])=[O:5])[C:11]3=[O:33])=[N:23][S:24][C:25]=2[CH:30]=[C:29]([CH3:31])[CH:28]=1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1c(=O)c2ncccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](C(=O)O)n1c(=O)c2ncccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Yield: 88.5 %

Procedure:
A solution of 32 mg of (S)-2-[1-(4,6-dimethyl-benzo[d]isothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-butyric acid tert-butyl ester in 20% trifluoroacetic acid in dichloromethane (1 mL) is stirred at room temperature for 45 min. The resulting mixture is concentrated to give 25 mg (89%) of (S)-2-[1-(4,6-Dimethyl-benzo[d]isothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-butyric acid; LCMS (ESMS): m/z 426 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].P(Cl)(Cl)(Cl)(Cl)[Cl:16].C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:16])=[O:7]
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)Cl)c1[N+](=O)[O-]

Procedure:
Reaction of 30 g of 3-methoxy-2-nitrobenzoic acid and 31.6 g of phosphorus pentachloride in 400 ml of methylene chloride at reflux for 2 hours followed by treatment of the crude product obtained with toluene 3 times gave 3-methoxy-2-nitrobenzoyl chloride as a solid. A solution of 30 g of this acid chloride in 50 ml of tetrahydrofuran was added to a solution of 28.7 g of 5-aminotetrazole monohydrate in 300 ml of tetrahydrofuran and 15 ml of water. A white precipitate appeared immediately but the mixture was allowed to stand for 3 hours. It was then diluted with water and the white solid was separated by filtration and air dried to give 3-methoxy-2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 271° C. after recrystallization from dimethylformamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=3)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3cccc(F)c3)o2)c1

Procedure:
The furyl bromide (99) (125 mg, 0.34 mmol) was coupled to 3-fluoro-phenylboronic acid (48 mg, x 0.41 mmol) acid using Method E. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.CN(C1C=CC=CN=1)C>ClCCl>[O:8]=[C:6]1[NH:7][C@H:3]([CH2:2][O:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CC[C@@H](CO)N1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)N2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
(S)-5-hydroxymethylpyrrolidin-2-one (1.15 g) was dissolved in dichloromethane (40 mL), triethylamine (1.67 mL), p-toluenesulfonyl chloride (2.00 g) and dimethylaminopyridine (0.12 g) were added under ice-cooling, and the mixture was stirred at room temperature 18 hr. The reaction mixture was concentrated under reduced pressure, 0.5N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and the solvent was evaporated to give the title compound (1.88 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:20])=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([N+:21]([O-])=O)[CH:3]=1>C(O)(=O)C.CCOC(C)=O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]2[C:6]([F:20])=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:12])=[O:13])[C:9]=2[CH:10]=1
Reactant: O=[N+]([O-])c1cc(Br)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 44 %

Procedure:
6-Bromo-3-fluoro-4-nitro-1-(phenylsulfonyl)-1H-indazole (5.9 g, 14.74 mmol) was suspended in acetic acid (60 ml) and to it added iron powder (4.12 g, 73.7 mmol). The suspension was heated to reflux for 2 h, then the reaction mixture was cooled, diluted with 100 ml EtOAc and filtered through celite. The filter cake was washed well with ethyl acetate then the filtrate basified till the colour moved from the aqueous layer to the organic (around pH 8-9). The biphasic system was then stirred for around 5 minutes and the aqueous layer turned cloudy. The layers were then separated, the aqueous washed with ethyl acetate and the combined organics washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was dry loaded onto a 330 g silica cartridge, purified on a 0-100% EtOAc/Cyclohexane gradient and the relevant fractions combined and concentrated to yield the title compound as a yellow solid (2.4 g).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]1([F:21])[CH2:19][CH:18]([OH:20])[CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([O:20][CH:18]2[CH2:19][C:16]([F:21])([F:15])[CH2:17]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: OC1CC(F)(F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CC(F)(F)C2)c([N+](=O)[O-])c1
Yield: 97.1 %

Procedure:
1.0 g of Methyl 4-fluoro-3-nitrobenzoate, 1.6 g of 3,3-Difluoro-cyclobutanol, and 3.3 g of Cs2CO3 were stirred in 10 ml of anhydrous DMF for 7 h at 60° C. The reaction mixture was then poured into 100 ml of water and extracted three times using 30 ml of EA each. The organic layer was dried using MgSO4 and volatiles were evaporated to yield 1.4 g of the title compound that was used without further purification.