Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH2:29])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:30](=O)[CH3:31].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH3:31])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC=O
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNc1nn(C(=O)OC(C)(C)C)c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a stirred mixture of 13.40 g (25.74 mmol) 3-amino-5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-1-carboxylic acid tert-butyl ester, from Synthetic Example 18, in 335 mL dry methanol, was added 2.19 mL acetaldehyde and 2.06 mL glacial acetic acid and the resulting mixture was stirred overnight at room temperature. The reaction was cooled (ice bath) before 3.24 g sodium cyanoborohydride was added in three portions. The mixture was stirred overnight at room temperature before the reaction was concentrated to roughly half volume under vacuum. The residue was partitioned between EtOAc and saturated aqueous sodium hydrogen carbonate solution and the organic extract washed with saturated aqueous sodium chloride solution and concentrated under vacuum. The residue was taken up in hot EtOAc and allowed to cool to room temperature before being triturated with diisopropyl ether. The stirred suspension was cooled (ice bath), filtered and the crude product washed with diisopropyl ether. The product was dried under vacuum to afford 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-3-(ethylamino)-1H-indazole-1-carboxylic acid tert-butyl ester (8.25 g, 76.6%) (Cpd. No. 117, Table 2). 1H-NMR (DMSO-D6, 300 MHz): δ=9.54 (br s, 1H), 7.86 (d, 1H), 7.73 (m, 1H), 7.41 (dd, 1H), 6.82 (t, 1H), 4.47 (s, 1H), 3.26-3.34 (partially obscured by solvent, m, 2H), 2.02 (s, 6H), 1.57 (s, 9H), 1.21 (t, 3H) ppm.
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1)=[O:4].CCOC(C)=O.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[C:3]([CH2:5][O:6][C:7]1[C:8]([N+:21]([O-:23])=[O:22])=[CH:9][C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1)([OH:2])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)COc1ccc(C)[n+]([O-])c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])c(OCC(=O)O)c[n+]1[O-]
Temperature: 40 °C

Procedure:
The pyridine N-oxide (b) (18.5 g) was dissolved in a cold mixture of fuming nitric acid (90 ml) and concentrated sulfuric acid (90 ml) and heated to 40° C. for 1 hour, then 65° C. overnight. The mixture was cooled, poured onto ice and EtOAc (250 ml) added. When the ice had melted, the mixture was shaken and solid filtered off The EtOAc was dried and evaporated, the residue triturated with ether and filtered affording a solid (8.4 g).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][C@@H:17]([OH:19])[C@H:16]([OH:20])[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I>O1CCCC1>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:15][C@@H:16]([O:20][CH3:23])[C@H:17]([OH:19])[CH2:18]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1O
Reaction time: 1 h

Procedure:
To a mixture of 5.35 g of 2-benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]pyridine and 40 ml of tetrahydrofuran was added dropwise 800 mg of oily (60%) sodium hydride gradually under stirring, and the mixture was stirred as it was for 1 hour. Then, 1.24 ml of methyl iodide was added thereto and the resultant mixture was stirred overnight as it was. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane), to give 2.18 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18]([OH:20])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:44][C:45]1[N:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][N:46]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=[C:10]([C:18]([NH:52][CH2:51][C:48]3[CH:47]=[N:46][C:45]([CH3:44])=[N:50][CH:49]=3)=[O:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Reactant: Cc1ncc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (45 mg, 0.15 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol), 1-hydroxybenzotriazole hydrate (24 mg, 0.15 mmol), and CH2Cl2 (3 mL) were added (2-methylpyrimidin-5-yl)methanamine (29 mg, 0.23 mmol) and N,N-diisopropylethylamine (54 μL, 0.31 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% MeCN-water[10 mM Et2NH]) to afford a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[CH:3]=1.[Br:10][CH2:11][C:12](Br)=[O:13].C(N(CC)CC)C>C(Cl)Cl>[Br:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[CH:3]=1)=[O:13]
Reactant: Nc1cc(Cl)nc(Cl)c1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)Nc1cc(Cl)nc(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 4-amino-2,6-dichloro-pyridine (4.7 g, 28.8 mmol) in DCM, bromoacetyl bromide (2.56 ml, 29.4 mmol) is added. The solution is cooled to 0° C. and stirred for 5 minutes before treating dropwise with triethylamine (7.87 ml, 57.7 mmol). The reaction mixture is gradually allowed to warm to RT and stirred for 48 hours. The reaction mixture is diluted with DCM and washed with water several times. The organic extracts are dried, filtered and concentrated in vacuo. The crude product is purified using flash column chromatography on silica (DCM/Isohexane) to afford the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([OH:14])=O)[CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH2:40][CH:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(Cl)Cl.O>[CH2:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:51][CH2:52][N:43]1[CH2:42][CH:41]([OH:53])[CH2:40][NH:39][C:12](=[O:14])[CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: O=C(O)Cc1cccc2cccnc12
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1cccc2cccnc12)NCC(O)CN1CCc2ccccc2C1
Reaction time: 3 h
Yield: 13.3 %

Procedure:
A solution of 2-(quinolin-8-yl)acetic acid (187 mg, 1 mmol), HATU (387.6 mg, 1.02 mmol) and TEA (196.1 mg, 1.94 mmol) in DCM (10 mL) was stirred at room temperature for 10 min. 1-Amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (210 mg, 1.0 mmol) was then added, and the solution stirred at for another 3 h, at which point LCMS indicated completion of the reaction. The reaction mixture was diluted with water and extracted with DCM (10 mL×3). The organic layers combined and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give the desired compound (50 mg, Yield 13%). 1H NMR (400 MHz, MeOD): 8.92 (d, J=2.8 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.73 (d, J=6.8 Hz, 1H), 7.55-7.50 (m, 2H), 7.10-6.97 (m, 4H), 4.25 (dd, J1=10.8 Hz, J2=14.0 Hz, 2H), 3.90 (m, 1H), 3.54-3.51 (m 2H), 3.32-3.25 (m, 2H), 2.82-2.80 (m, 2H), 2.67-2.66 (m, 2H), 2.40-2.39 (m, 2H). LCMS (m/z): 376.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[C:18]([CH3:19])=[CH:17][S:16][CH:15]=2)[N:11]([CH3:20])[N:10]=1.[Br:21]Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[C:18]([CH3:19])=[C:17]([Br:21])[S:16][CH:15]=2)[N:11]([CH3:20])[N:10]=1
Reactant: Cc1cscc1-c1nc(-c2c(F)cccc2Cl)nn1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)csc1Br
Temperature: 45 °C
Reaction time: 14 h

Procedure:
A suspension of 3-(2-chloro-6-fluorophenyl)-1-methyl-5-(4-methylthien-3-yl)-1H-1,2,4-triazole (2.35 g, 7.6 mmol) in glacial acetic acid (15 mL) was heated to 45° C. in order to effect solubilization. After cooling to 10° C., a solution of bromine (1.34 g, 0.43 mL, 8.4 mmol) in glacial acetic acid (4 mL) was added and the thick gel formed was stirred for 14 hours at room temperature. The reaction mixture was poured into cold water (100 mL) and extracted with ether (3×70 mL). The combined ethereal extracts were washed with water (100 mL), saturated aqueous sodium bicarbonate (2×100 mL), aqueous sodium bisulphite (10% solution, 300 mL) and brine (100 mL), dried over magnesium sulphate and concentrated under reduced pressure. Recrystallisation from ethyl acetate/hexane afforded yellow cubes. The mother liquor was chromatographed over silica gel to afford the product as colorless cubes (2.6 g, 89%): mp 133–134° C.; 1H NMR (CDCl3) δ 7.51 (s, 1H), 7.29–7.39 (m, 2H), 7.11 (t, 1H), 3.98 (s, 3H), 2.27 (s, 3H); EI/MS 386 m/e (M+).
Reaction SMILES: [OH-].[Na+].O.[CH:4]1([NH:7][C:8]2[N:18]=[C:17]([OH:19])[C:16]([F:20])=[CH:15][C:9]=2[C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1>C(O)C>[CH:4]1([NH:7][C:8]2[N:18]=[C:17]([OH:19])[C:16]([F:20])=[CH:15][C:9]=2[C:10]([OH:12])=[O:11])[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cc(F)c(O)nc1NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(F)c(O)nc1NC1CC1
Yield: 70.5 %

Procedure:
To a solution of 95% ethanol (20 ml) and 2N NaOH/H2O (40 ml) was added 2.65 g of ethyl 2-cyclopropylamino-5-fluoro-6-hydroxynicotinate. The inital suspension was refluxed for a total of six hours, then cooled, and evaporated to a solid. The solid was dissolved in 30 ml of H2O and acidified to pH=1 with 2N HCl solution. The solid formed upon acidification was collected by filtration and washed with H2O to give the crude acid product. This product was triturated with hot 95% ethanol, filtered, and dried to give 1.65 g of a beige colored solid, 2-cyclopropyl-5-amino-6-hydroxynicotinic acid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1I)[CH:2]=[CH:3][CH3:4].[C:13]([O-])([O-])=O.[Na+].[Na+].CC([O-])=O.[Na+]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:3]([C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:1]=1)[CH2:4][CH3:13]
Reactant: CC=CCOc1ccccc1I
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1coc2ccccc12
Yield: 81 %

Procedure:
To a solution of 1-but-2-enyloxy-iodobenzene (4.00 g, 13.8 mmol) in DMF (46 mL) was added n-Bu4NCl (5.36 g. 19.3 mmol), Pd(OAc)2 (0.168 g, 0.690 mmol), Na2CO3 (2.99 g, 28.2 mmol) and NaOAc (1.13 g, 13.8 mmol). The mixture was heated to reflux under nitrogen atmosphere overnight. The mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine and dried over Na2SO4. Purification by column chromatography (silica gel, hexanes) gave the title compound (1.79 g, 81%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.63-7.60 (m, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.33-7.22 (m, 2H), 2.64-2.59 (m, 2H), 1.72-1.64 (m, 2H), 0.96 (t, J=7.2 Hz, 3H); ESI MS m/z 161 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:29])[C@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][S:22][C:21]2=[O:25])[C@H:17]1[C:26](Cl)=[O:27].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:15][C:16]1([CH3:29])[C@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][S:22][C:21]2=[O:25])[C@H:17]1[C:26]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:27]
Reactant: OCc1cnc(Oc2ccccc2)s1
Reactant: CC1(C)[C@H](C=C2CCSC2=O)[C@H]1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C=C2CCSC2=O)[C@H]1C(=O)OCc1cnc(Oc2ccccc2)s1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
2 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of (1R,3R)2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylic acid chloride [described in French Pat. No. 70-21682 published under No. 2.097.244] prepared from 2.2 g of the corresponding acid in 30 ml of benzene and 0.81 ml of pyridine were added thereto at -10° C.The reaction mixture was stirred at 20° C. for 17 hours and was poured into aqueous dilute hydrochloric acid. The decanted aqueous phase was extracted with ether and the combined organic phases were washed with water, dried and evaporated to dryness under reduced pressure. The residuewas chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 2.9 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3R) 2,2-dimethyl-3[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].BrC1SC(C)=CC=1C(O)=O.S(Cl)(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[OH:34]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[OH:34][C:27]1[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:26]=1[NH:25][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[S:3][C:2]=1[Br:1])=[O:8]
Reactant: COc1ccc(N)c(O)c1
Reactant: Cc1cc(C(=O)Cl)c(Br)s1
Agent: Cc1cc(C(=O)O)c(Br)s1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cc(C)sc2Br)c(O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.5 %

Procedure:
2-Bromo-5-methyl-3-thiophenecarbonyl chloride (2.6 g), prepared in the same manner as above from 2-bromo-5-methyl-3-thiophenecarboxylic acid and thionyl chloride, was suspended in toluene (20 ml). This toluene solution was added dropwise to a solution of 2-amino-5-methoxyphenol (2.0 g) in pyridine (50 ml) at 0° C. The mixture was stirred at room temperature for 2.5 hours and the solvent was evaporated under reduced pressure. The precipitated crystals were collected by filtration, and washed with diluted hydrochloric acid and diisopropyl ether to give N-(2-hydroxy-4-methoxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide (2.1 g).
Reaction SMILES: [CH2:1]([Si:3]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:4]1[O:8][CH:7]=[C:6]([CH:9]=O)[CH:5]=1)[CH3:2].[O:15]=[C:16]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:17]P(=O)(OCC)OCC.C([Li])CCC>>[CH2:1]([Si:3]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:4]1[O:8][CH:7]=[C:6]([CH:9]=[CH:17][C:16](=[O:15])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:5]=1)[CH3:2]
Reactant: CCCCCCCCCCCC(=O)CP(=O)(OCC)OCC
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Agent: [Li]CCCC
Product: CCCCCCCCCCCC(=O)C=Cc1coc([Si](CC)(CC)CC)c1

Procedure:
5-Triethylsilyl-3-furaldehyde is reacted with diethyl 2-oxotridecylphosphonate and n-butyl lithium to give 5-triethylsilyl-3-(3-oxo-1-tetradecenyl)furan. Oxidizing using Rose Bengal and oxygen gives 4-(3-oxo-1-tetradecenyl)-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2/[C:8](=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])/[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)/C=C1\COc2ccc(Br)cc2-c2nc(C(=O)OC)sc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC1COc2ccc(Br)cc2-c2nc(C(=O)OC)sc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a stirred solution of 9-Bromo-4-[1-methoxycarbonyl-meth-(E)-ylidene]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (70 mg, 0.17 mmol) in EtOAc (15 mL), 10% Pd/C (1% H2O) (30 mg) was added. The reaction mixture was degassed with H2. The mixture was stirred at 50° C. under 50 Psi of H2 overnight. Then the mixture was filtered thought Celite, and the filtrate was concentrated in vacuo, and purified by flash column chromatography to afford 9-Bromo-4-methoxycarbonylmethyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (60 mg, 85%) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.75 (d, J=2.5 Hz, 1H), 7.38 (dd, J1=8.6 Hz, J2=2.5 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 4.62 (dd, J1=12.2 Hz, J2=3.7 Hz, 1H), 4.07 (m, 1H), 4.04 (s, 3H), 3.98 (m, 1H), 2.79 (s, 3H), 2.88 (m, 1H); LC-MS (ESI & APCI): 414.4 (M+2).
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.O=[C:9]1[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]1>>[F:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: F[C@@H]1CCNC1
Agent: Cl
Product: NC1CCC(N2CC[C@@H](F)C2)CC1
Yield: 45.9 %

Procedure:
Following General procedure I, (R)-3-fluoropyrrolidine hydrochloride (407 mg, 3.26 mmol) was reacted with tert-butyl 4-oxocyclohexylcarbamate (500 mg, 2.34 mmol) to afford the desired product (200 mg, 51%) as a colorless oil: ESI MS m/z 187 [C10H19FN2+H]+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][N:8]([CH3:42])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][N:20]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=1)[C:21](=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H][H]>C(O)C.[Pd]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[NH2:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][CH2:31][N:20]([CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9][N:8]([CH3:42])[CH3:7])[C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:34][CH:35]=1
Reactant: CN(C)CCCOc1ccccc1CN(CCc1ccc([N+](=O)[O-])cc1)C(=O)C=Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CN(C)CCCOc1ccccc1CN(CCc1ccc(N)cc1)C(=O)C=Cc1ccccc1

Procedure:
A suspension of 10 parts of N-[[2-[3(-dimethylamino)-propoxy]phenyl]methyl]-N-[2-(4-nitrophenyl)ethyl]-3-phenyl-2-propenamide, oxalate salt (1:1) in 100 ml of ethanol is treated with 1 part of 5% palladium on carbon and placed under 3 atmospheres of gaseous hydrogen. The mixture is shaken until one equivalent of hydrogen is consumed, filtered and the solvent evaporated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[S:21][CH:22]=1>CN(C)C=O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[S:21][CH:22]=[C:18]([CH2:17][N:3]3[C:4](=[O:15])[C:5]4[C@@H:6]5[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]5)[C:10]=4[N:2]3[CH3:1])[N:19]=2)=[CH:28][CH:27]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1csc(-c3ccc(Cl)cc3)n1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 43.9 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 4-chloromethyl-2-(4-chlorophenyl)-thiazole (Maybridge plc, Tintagel, Cornwall, UK; 153 mg, 0.63 mmol) in dimethylformamide (5 mL) was heated at 100° C. for 2 days. The solvent was evaporated and ethyl acetate (50 mL) was added. The solution was washed with water (twice) and brine, dried (magnesium sulfate), filtered, evaporated and purified by chromatography, eluting with 2-3% methanol/dichloromethane to give (4S,7R)-2-[2-(4-Chloro-phenyl)-thiazol-4-ylmethyl]-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (89 mg, 44%) as an off-white foam. APCI(+)-MS (M+H) 414.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13]Br)=[N:5]1)(=[O:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][N:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:27][CH2:26]2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1nc(CBr)c2ccccc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)n1nc(CN2CCN(c3ccc(F)cc3)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
1-Acetyl-3-bromomethyl-1H-indazole (160 mg, 0.63 mmol) in CH2Cl2 (5 mL) was treated with 1-(4-fluorophenyl)piperazine (228 mg, 1.26 mmol) and Hunig's base (102 mg, 0.79 mmol) and the mixture stirred at 20° C. for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (10%→25% EtOAc in hexane) to give the title compound as a white solid. This was recrystallised from ether/hexane to give colourless crystals (184 mg, 83%); mp 119°-120° C. (from ether/hexane); 1H NMR (360 MHz, d6 -DMSO) δ8.31 (d, J=8.3 Hz, 1 H, indazole), 8.08 (d, J=8.3 Hz, 1H, indazole), 7.63 (t, J=8.3 Hz, 1H, indazole), 7.43 (t, J=8.3 Hz, 1H, indazole), 7.03 (m, 2H, Ph), 6.93 (m, 2H, Ph), 3.95 (s, 2H, Ar--CH2N), 3.08 (m, 4H, piperazine), 2.70 (s, 3H, Ac), 2.64 (m, 4H, piperazine); MS (CI+) m/e 353 M+H+); Anal. calcd for C20H21N4OF: C, 68.16; H, 6.01; N, 15.90. Found: C, 68.15;H, 5.85; N, 15.64.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][NH:10][NH2:11]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:10]([CH3:9])[NH2:11])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CNN
Product: CN(N)c1ccc(Cl)nn1
Reaction time: 16 h
Yield: 39.9 %

Procedure:
3,6-Dichloro-pyridazine (1 g, 6.75 mmol) was placed in a flask fitted with a water condenser and methylhydrazine (1.31 mL, 25 mmol) was added dropwise. An immediate exotherm was observed and methylhydrazine begins to reflux. When the reaction had subsided, the mixture was left for 16 hours, and the excess methylhydrazine was removed under reduced pressure. The cooled residue was stirred with aqueous sodium hydroxide solution (20 ml of 20%), and the resulting solution was extracted with ether (6×100 ml). The combined extracts were dried (K2CO3) and concentrated to give 427 mg of N-(6-Chloro-pyridazin-3-yl)-N-methyl-hydrazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[C:5](I)[CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14](B(O)O)[C:15]([F:18])=[N:16][CH:17]=1>[F-].[K+].C(#N)C.O>[Br:11][C:12]1[CH:13]=[C:14]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[N:8]=[CH:7][C:6]=2[NH2:9])[C:15]([F:18])=[N:16][CH:17]=1
Reactant: OB(O)c1cc(Br)cnc1F
Reactant: COc1cc(I)c(N)cn1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(-c2cc(Br)cnc2F)c(N)cn1
Temperature: 95 °C
Yield: 70.6 %

Procedure:
A mixture of 6-methoxy-4-iodopyridin-3-amine (9.5 g, 38 mmol), 5-bromo-2-fluoropyridin-3-ylboronic acid (16.7 g, 76 mmol), and 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (1.5 g, 2 mmol) in 1N aqueous potassium fluoride (95 mL) and acetonitrile (200 mL) was heated at 95° C. for 16 h. The cooled reaction mixture was diluted with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layer was dried over sodium sulfate, filtered, and evaporated to afford a residue which was purified by flash chromotagraphy (silica, 120 g column, ISCO, 0-40% ethyl acetate in hexanes) to afford the title compound as a yellow/orange solid (8.0 g, 71%).