Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[CH3:3][N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][NH:7]2.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:3][N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CN1C[C@@H]2C[C@H]1CN2
Agent: Br
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([N+](=O)[O-])ccc1N1C[C@@H]2C[C@H]1CN2C

Procedure:
Alternatively, a heterogeneous mixture of (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane 2HBr salt (0.544 g, 2 mmol), 2-fluoro-5-nitrotoluene (0.310 g, 2 mmol) and DIPEA (0.387 g, 6 mmol) in NMP was refluxed for 2 days. The resulting residue was purified by column chromatography (silica gel, hexanes then 5-10% EtOAc in hexanes to afford 2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-nitrotoluene, which was reduced by hydrogenation (H2, 10% Pd/C, MeOH, 40 PSI) to afford 3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]aniline; LCMS: purity: 91%; MS (m/e): 218 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[N:17]1([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:25][CH:26]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: Nc1ccc(CCN2CCCC2)cc1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CCN2CCCC2)cc1

Procedure:
A solution of 0.300 g (1.06 mmol) of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione and 0.222 g (1.17 mmol) of 4-(2-pyrrolidin-1-yl-ethyl)-phenylamine in 1.8 mL of N,N-dimethylformamide (DMF) is heated at 120° C. for 1 h. The reaction is placed in a freezer and the precipitated material is collected, washed with cold N,N-dimethylformamide (DMF) (2×), cold MeOH (2×) and Et2O and dried in vacuo to give 0.307 g (66%) of brick red crystals: mp 212-214° C. (dec);
Reaction SMILES: [CH:1]([C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=O.Cl.[NH2:24][OH:25].C[O-].[Na+]>CO>[OH:25][N:24]=[CH:1][C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: NO
Reactant: COC(=O)c1cccc(C2=C(C=O)CCc3ccccc32)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(C2=C(C=NO)CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 77.8 %

Procedure:
Methyl 3-(2-formyl-3,4-dihydro-1-naphthyl)benzoate (0.44 g) was added to a mixture of hydroxylamine hydrochloride (0.11 g) and 28 methanolic sodium methoxide (0.31 ml) in methanol (10 ml) and the whole was stirred for 19 hours at ambient temperature. The solvent was removed by concentration. To the residue was added a mixture of ethyl acetate, tetrahydrofuran and water and adjusted to pH 2 with 6N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting a mixture of chloroform and methanol (50:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-(2-hydroxyiminomethyl-3,4-dihydro-1-naphthyl)benzoate (0.36 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][C:9]([NH2:11])=[O:10].[F:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[C:32]([CH:33]3[CH2:37][CH2:36][CH2:35][NH:34]3)=[CH:31][C:21]3[NH:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[N:24][C:20]=3[CH:19]=2)=[CH:15][CH:14]=1>C(#N)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[C:32]([CH:33]3[CH2:37][CH2:36][CH2:35][N:34]3[CH2:8][C:9]([NH2:11])=[O:10])=[CH:31][C:21]3[NH:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[N:24][C:20]=3[CH:19]=2)=[CH:38][CH:39]=1
Reactant: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)CN1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.4 mg of potassium carbonate and 11.1 mg of iodoacetamide were added in order to an acetonitrile (1 ml) solution of 20 mg of 5-(4-fluoro-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 168, and the reaction liquid was stirred overnight at room temperature. The reaction liquid was concentrated, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid], and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10]C)[C:4]1[S:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[S:5][C:6]([CH2:9][Br:12])=[CH:7][CH:8]=1)=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(OC)c1ccc(C)s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)s1

Procedure:
To a mixture of 2-dimethoxymethyl-5-methylthiophene (3.44 g, 20 mmol) and N-bromosuccinimide (4.63 g, 26 mmol) in carbon tetrachloride (50 ml) was added a catalytic amount of benzoylperoxide. The mixture was refluxed for 1 hour. Undissolved materials were filtered off. The filtrate and the washings were combined and evaporated in vacuo to give 2-methoxycarbonyl-5-bromomethyl-thiophene as a yellow oil (4.65 g}, which was used in a following reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:41].[NH2:42][CH:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]1.C(N(CC)CC)C.O1CCOCC1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH:43]3[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=4)=[O:36])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:41]
Reactant: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(S(C)(=O)=O)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(NC4CCN(C(=O)OC(C)(C)C)CC4)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Temperature: 60 °C
Reaction time: 24 h

Procedure:
The compound N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide, (0.1 g, 0.172 mmol), 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.11 g, 0.549 mmol) and triethylamine (0.5 mL) were suspended in stirred THF (4 mL) and heated to 60° C. under argon for 4 days. Dioxane (4 mL) was added and the reaction warmed to 85° C. for 2 days and then 95° C. for 1 day. The reaction mixture was diluted with EtOAc and the organics were washed with water, brine (twice), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/CH2Cl2 —50% EtOAc/CH2Cl2 to afford the title compound as a white solid. LC-MS m/z 702 (M+H)+, 2.41 min (ret. time)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:23][CH2:22][O:21][CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: COCCN
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCCOC
Yield: 89 %

Procedure:
The compound prepared in Example 3 was reacted with 2-methoxy-ethylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 89%).
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][C:7](=O)[CH2:6]1)([O-:3])=[O:2].[CH2:24]([OH:27])[CH2:25][OH:26].Cl[Si](C)(C)C>C(Cl)Cl>[N+:1]([CH2:4][CH:5]1[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][C:6]21[O:27][CH2:24][CH2:25][O:26]2)([O-:3])=[O:2]
Reactant: OCCO
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C(C[N+](=O)[O-])C1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: O=[N+]([O-])CC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2
Yield: 80.3 %

Procedure:
A solution of 3-nitromethyl-4,4-diphenylcyclohexanone (69 g), ethylene glycol (30.48 g) and chlorotrimethylsilane (106.8 g) in anhydrous methylene chloride (1 liter) is brought to reflux for 2 hours, then cooled to +25° C., washed with saturated aqueous sodium hydrogen carbonate solution (600 cc) and then with saturated aqueous sodium chloride solution (300 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel with a slight excess pressure of nitrogen (0.04-0.063 mm, diameter 6.5 cm, height 45 cm), eluting with a mixture of cyclohexane and ethyl acetate (90:10 by volume) and collecting 500-cc fractions. Fractions 1 to 3 are combined and concentrated to dryness under reduced pressure (2.7 kPa). (RS)-6-Nitromethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (63.3 g) is obtained in the form of white crystals, m.p. 148° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](/[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C(\c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Solvent: CCO
Product: COC(=O)CC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 7 h
Yield: 64 %

Procedure:
(E)-methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylacrylate was dissolved in 30 mL EtOH in a Parr bottle and flushed with N2. 10% Pd on carbon was added and the reaction was put on a Parr shaker under 50 psi of H2 for 7 hours. LC-MS after this time indicated that the reaction was complete so the catalyst was filtered off and the solution concentrated in vacuo. The residue was purified using a 40 g MPLC column using a 10 to 25% EtOAc in hexanes gradient to give methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoate (1.1 g, 64%). MS found: (M+H)+=375.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C:28]3[CH:41]=[CH:40][C:31]([O:32][C:33]([CH3:39])([CH3:38])[C:34](OC)=[O:35])=[CH:30][CH:29]=3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[BH4-].[Li+].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[OH:35][CH2:34][C:33]([CH3:38])([CH3:39])[O:32][C:31]1[CH:40]=[CH:41][C:28]([N:18]2[C:17](=[O:42])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)=[CH:29][CH:30]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)(C)C(=O)OC)cc2)c2ncnn12
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)(C)CO)cc2)c2ncnn12
Reaction time: 18 h
Yield: 51 %

Procedure:
To a solution of methyl 2-(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}phenoxy)-2-methylpropanoate (2.0 g) in tetrahydrofuran (16 mL) was added lithium borohydride (0.49 g) and the mixture was stirred for 18 hr. Ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.97 g, 51%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28]>>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([S:6]([CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28])[C:4]([O:3][CH2:1][CH3:2])=[O:20])(=[O:7])=[O:8])=[CH:14][CH:13]=1)[C:17]#[C:18][CH3:19]
Reactant: N#CCCCCCBr
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C(CCCCCC#N)C(=O)OCC)cc1
Yield: 60 %

Procedure:
Ethyl 2-{[4-(2-butynyloxy)phenyl]sulfonyl}-7-cyanoheptanoate was prepared according to the general method as outlined in example 1 (step 4), starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (10 g, 33.8 mmol) and 6-bromohexanenitrile (4.48 ml, 33.8 mmol); 7.9 g white solid. mp 63° C.; Yield 60%; MS (EI): 391.4 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:16][C:17](=O)[CH3:18])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.C[CH2:24][N:25](CC)CC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]([CH2:16][CH:17]([NH:25][CH3:24])[CH3:18])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CN
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(C)CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-N-(2-oxopropyl)glycine (2.29 g, 8.63 mmol) in CH2Cl2 (44 mL) were added a solution of methylamine hydrochloride (1.52 g, 22.45 mmol) and Et3N (3.13 mL, 22.45 mmol) in CH2Cl2, acetic acid (0.99 mL, 17.27 mmol), and sodium triacetoxyborohydride (5.12 g, 24.17 mmol). The suspension was stirred at room temperature overnight and concentrated in vacuo to afford the product.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24]([CH:29]=[CH2:30])[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.C>[OH-].[OH-].[Pd+2].O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24]([CH2:29][CH3:30])[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1nc(CC)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reaction time: 2 h
Yield: 99.2 %

Procedure:
Intermediate (16c) (7.8 g, 16.6 mmol) was dissolved in ethanol (420 mL, 7.2 mol). Pearlman's Catalyst, wet (0.1:0.4:0.5, palladium hydroxide:carbon black:water, 6 g, 4 mmol) was added. The mixture was degassed and stirred under hydrogen for 2 hours. The palladium was filtered off and the solvent was concentrated to yield intermediate (16d) (7.7 g). MS m/z: [M+H+] calcd for C26H30FN3O4, 468.2. found 468.4.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1.[CH2:15]1[CH2:20][O:19][CH:18]=[CH:17][CH2:16]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(#N)C>[O:19]1[CH2:20][CH2:15][CH2:16][CH2:17][CH:18]1[N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1
Reactant: COC(=O)Cc1n[nH]c2ncccc12
Reactant: C1=COCCC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Product: COC(=O)Cc1nn(C2CCCCO2)c2ncccc12
Temperature: 75 °C

Procedure:
To a solution of methyl 1H-pyrazolo[3,4-b]pyridin-3-ylacetate (84 mg, 0.439 mmol) in acetonitrile (3 mL) was added DHP (37 mg, 0.439 mmol) and DDQ (10 mg, 0.044 mmol). This mixture was heated to 75° C. for 20 minutes. After this time, additional DHP (37 μL, 0.44 mmol) was added and the reaction mixture heated to 85° C. for 1.5 hours. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (2×20 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated in vacuo. This residue was purified by chromatography using RediSep column (12 g) and eluting with gradient of 0-20% EtOAc/CH2Cl2. The desired fractions were combined and the solvent evaporated in vacuo to give the title compound. LRMS (M+1): 276.1.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]1[C:19]([OH:21])=[O:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:22](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[CH3:22][O:20][C:19]([C@@H:9]1[CH2:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[O:21]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)C[C@H]1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4.48 g of commercially available (2S,4S)-Boc-4-phenyl-pyrrolidine-2-carboxylic acid (15.37 mmol) were dissolved in 50 ml dimethylformamide. 2.59 g of potassium carbonate (18.76 mmol) and 2.66 g of methyl iodide (18.76 mmol) were added and the reaction was stirred for 48 h at room temperature. Standard work-up with ethyl acetate yielded 5.3 of the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[CH:4][CH:3]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(CSc2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(CSc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 30.1 %

Procedure:
A mixture of 1-methylethyl 4-{[(4-bromophenyl)thio]methyl}-1-piperidinecarboxylate (292 mg, 0.78 mmol), [4-(methylsulfonyl)phenyl]boronic acid (157 mg, 0.78 mmol), 2M Na2CO3 (2 mL), and Pd(PPh3)2Cl2 (200 mg, 0.28 mmol) in DME (8 mL) stirred at 80° C. for 3 h, then at ambient temperature overnight. The mixture was poured onto a Varian Chem Elut column, flushed with EtOAc, and the organics concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 30% EtOAc/hexanes to give 105 mg (30%) of the title compound as a tan solid. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 2H, J=8.4 Hz), 7.73 (d, 2H, J=8.4 Hz), 7.51 (d, 2H, J=8.4 Hz), 7.38 (d, 2H, J=8.4 Hz), 4.89 (septet, 1H, J=6.2 Hz), 4.20-4.10 (m, 2H), 3.07 (s, 3H), 2.89 (d, 2H, J=6.8 Hz), 2.75-2.64 (m, 2H), 1.90-1.80 (m, 2H), 1.79-1.65 (m, 1H), 1.28-1.12 (m, 8H); LRMS (ESI), m/z 448 (M+H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)=[N+:2]=[N-:3].[CH3:18][NH2:19]>O1CCCC1.C(N(CC)CC)C.ClC(OCC)=O.C(OCC)(=O)C>[CH3:18][NH:19][C:9](=[O:10])[C:8]1[CH:12]=[C:13]([Br:14])[C:5]([CH2:4][N:1]=[N+:2]=[N-:3])=[CH:6][C:7]=1[O:15][CH2:16][CH3:17]
Reactant: CN
Reactant: CCOc1cc(CN=[N+]=[N-])c(Br)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOc1cc(CN=[N+]=[N-])c(Br)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving the 4-(azidomethyl)-5-bromo-2-ethoxybenzoic acid (7.67 g) in tetrahydrofuran (100 ml), triethylamine (3.2 ml) and ethyl chloroformate (2.11 ml) were added in that order and the mixture was stirred at room temperature for 30 minutes. Aqueous methylamine (3.2 ml) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and washed with water and 1 N hydrochloric acid, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to yield the title compound (5.328 g) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[F:8][CH:9]([F:18])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(OCC)(OCC)OCC>>[CH2:1]([O:4][CH:5]=[C:11]([C:10](=[O:17])[CH:9]([F:18])[F:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)C(F)F
Temperature: 65 °C
Reaction time: 6 h

Procedure:
Acetic anhydride (3.6 moles) is heated to 100 to 105° C., to which a mixture of crude ethyl difluoroacetoacetate (˜0.96 moles) and triethyl orthoformate (1.8 moles) is added drop-wise. The reaction mixture is kept at 100 to 105° C. for 6 hours. The reaction mixture is cooled to 60 to 70° C. and then concentrated under vacuum to remove excessive acetic anhydride, triethyl orthoformate, and generated ethyl acetate. A pale brown liquid is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[F:14][CH:15]([F:25])[O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][NH2:21].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:21][CH2:20][C:19]3[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH:15]([F:14])[F:25])[CH:18]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1cccc(OC(F)F)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(OC(F)F)c3)ccc12
Yield: 8.4 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.578 mmol), 3-(difluoromethoxy)benzylamine (0.074 mL, 0.645 mmol), Pd2(dba)3 (48 mg, 0.052 mmol), rac-BINAP (108 mg, 0.173 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (6 mL) was heated at 80° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3-difluoromethoxy-benzylamino)-2H-phthalazin-1-one (17 mg) as an off white solid, 1H (400 MHz, CDCl3) δ: 4.32 (s, 2H), 6.36 (t, 1H), 6.77 (d, 1H), 6.90 (t, 2H), 6.99 (s, 1H), 7.08 (d, 1H), 7.21 (t, 1H), 8.00 (d, 1H), 10.15 (s, 1H) ppm; m/z (M+1) 351.92.