Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][O:38][C:39]1[CH:45]=[C:44]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:43]=[CH:42][C:40]=1[NH2:41]>>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]4)=[CH:45][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: COc1cc(CCN2CCN(C)CC2)ccc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(CCN4CCN(C)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Yield: 67 %

Procedure:
The title compound (0.12 g, 0.17 mmol, 67%) was prepared from 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) and 2-(methyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (Example 131, step D) in an analogous manner to that described for Example 26, step E. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (t, J=6.8 Hz, 3H), 2.10 (s, 3H), 2.28 (br. s., 4H), 2.40 (br. s., 3H), 2.49 (d, J=8.4 Hz, 3H), 2.63-2.72 (m, 2H), 3.79 (s, 3H), 4.23 (q, J=6.9 Hz, 2H), 6.57 (d, J=4.9 Hz, 1H), 6.71-6.79 (m, 1H), 6.91-6.99 (m, 2H), 7.16 (t, J=8.1 Hz, 2H), 7.23 (d, J=9.0 Hz, 1H), 7.30-7.37 (m, 1H), 7.37-7.46 (m, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.64-7.74 (m, 2H), 8.02 (s, 1H), 8.23 (d, J=5.3 Hz, 1H), 8.47 (s, 1H), 9.35 (d, J=6.8 Hz, 1H), 9.71 (s, 1H). MS (M+H, ES+) 720.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([OH:14])=[O:13])=[CH:3]1.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([O:14][CH3:20])=[O:13])=[CH:3]1
Reactant: CO
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 20 g of 1-methyl-3-indole acetic acid in 120 mL of methanol was added 0.5 mL of concentrated sulfuric acid and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated by evaporation and the residue was dissolved in dichloromethane, and then poured into a solution of aqueous saturated sodium bicarbonate. The mixture was then extracted with dichloromethane and excess magnesium sulfate was added to the extract. The product was purified by distillation to give 25 g of yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.C(=O)([O-])[O-].[Ca+2].[NH:24]1[CH:28]=[C:27](/[CH:29]=[CH:30]/[C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[CH:26]=[N:25]1>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:24]1[CH:28]=[C:27](/[CH:29]=[CH:30]/[C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[CH:26]=[N:25]1)[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: N#Cc1ccc(/C=C/c2cn[nH]c2)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: C[C@@H](n1cc(/C=C/c2ccc(C#N)cc2)cn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methyl oxiran-2-yl)methyl)-1H-1,2,4-triazol obtained in step 3 (55.9 mg) was suspended in N,N-dimethylformamide (1.6 mL), and calcium carbonate (41.9 mg) and 4-((E)-2-(1H-pyrazol-4-yl)vinyl)benzonitrile (39.5 mg) were added thereto. The mixture was stirred at room temperature for 20 minutes under an argon atmosphere, and reacted by microwave irradiation at 180° C. for 15 minutes. After completion of the reaction, the resulting mixture was extracted with ethyl acetate (10 mL) and the extract was washed successively with saturated amoniumchloride (10 mL) and brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound (0.039 g, yield 43.5%).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[CH:18][C:19]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)C(=O)OC(C)(C)C)[CH3:2].Cl>CO>[CH2:1]([NH:3][CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[CH:18][C:19]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)[CH3:2]
Reactant: CCN(CCN1CCCc2cc(NC(=N)c3cccs3)ccc21)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCNCCN1CCCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A solution of tert-butyl ethyl(2-(6-(thiophene-2-carboximidamido)-3,4-dihydroquinolin-1(2H)-yl)ethyl)carbamate (compound 8, 115 mg, 0.268 mmol) in HPLC grade methanol (10 mL) was treated with 2N aq. HCl (1.35 mL, 2.7 mmol) and the mixture heated to reflux for 90 minutes. After cooling to room temperature, the solution was concentrated and dried briefly on high-vac pump. The residue was purified directly on silica gel eluting with 10% 2M NH3 in methanol/90% dichloromethane to yield a yellow solid, 9 (78 mg, 88%). 1H-NMR (DMSO-d6) δ 7.66 (d, 1H, J=3.0 Hz), 7.54 (dd, 1H, J=5.0, 0.9 Hz), 7.06 (dd, 1H, J=5.0, 3.7 Hz), 6.59-6.52 (m, 2H), 6.47 (br s, 1H), 6.21 (br s, 2H), 3.32-3.20 (m, 4H), 2.70-2.64 (m, 4H), 2.56 (q, 2H, J=7.1 Hz), 1.88-1.80 (m, 2H), 1.04 (t, 3H, J=7.0 Hz). MS (ESI+): 329 (MH+, 100), 258 (100); ESI-HRMS calculated for C18H25N4S (MH+): 329.1794; observed: 329.1798.
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([S:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1)C=C.[Cl:39]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:39][CH:5]1[N:8]([C:9](=[C:23]([S:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Sc1ccc(C)cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(SC(C(=O)C(C)(C)C)=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)CC2Cl)cc1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
To a solution of 2.28 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-methylthiophenoxy)-3-trimethylacetylthiopropenate in dichloromethane at -20° , was added solution of 7.6 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures afforded 1.48 g of the title compound as a yellow foam (69% of the theoretical yield).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([O:31]C)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[OH-].[Na+].Cl.O>O1CCOCC1>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([OH:31])=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)Nc3cccc(C(C)C)c3)c1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Temperature: 25 °C
Reaction time: 1.8 h
Yield: 80.5 %

Procedure:
A mixture of methyl 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylate (298 mg, 0.694 mmol) and 1.0 M NaOH (3.5 mL, 3.5 mmol) in 8.0 mL dioxane was rapidly stirred at rt for 1.8 hours. The pH of the mixture was adjusted to pH 4 using 10% aqueous HCl, and then water added to form a yellow precipitant. The precipitant was filtered, washed with H2O then 30% EtOAc/hexane to give the title compound as a yellow solid (232 mg, 81%). 1H NMR (DMSO-d6 plus D2O) δ: 10.10 (s, 1H), 8.82 (s, 1H), 8.63 (s, 1H), 7.56-7.65 (m, 2H), 7.54 (s, 1H), 7.33-7.41 (m, 2H), 7.22-7.29 (m, 2H), 6.98 (d, J=7.3 Hz, 1H), 4.55 (s, 2H), 3.60-3.65 (m, 2H), 3.27 (t, J=5.4 Hz, 2H), 2.79-2.94 (m, 1H), 1.21 (d, J=6.7 Hz, 6H)
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH3:19])[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:32]>C1COCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([N:14]([CH3:32])[C:15](=[O:17])[CH3:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH3:19])[CH2:3][CH2:2]1
Reactant: CCOc1ccc(C(C)c2nc3cc(NC(C)=O)ccc3n2CC2CC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(C)c2nc3cc(N(C)C(C)=O)ccc3n2CC2CC2)cc1
Reaction time: 2 h
Yield: 110 %

Procedure:
To a solution of N-[1-(cyclopropylmethyl)-2-[1-(4-ethoxyphenyl)ethyl]-1H-benzimidazol-5-yl]-acetamide (2.13 g, 5.64 mmol) in THF (100 mL) was added NaH (0.45 g, 11.28 mmol) at 0° C. After stirring for 2 h, iodomethane (1.60 g, 11.28 mmol) was added at room temperature. The mixture was stirred overnight, quenched with MeOH (2 mL) and diluted with ether (200 mL) which was washed with saturated solution of ammonium chloride (100 mL) and dried with Na2SO4. After filtration and evaporation, the title compound (2.43 g, 100%) as a crude product was obtained. MS (ES) (M+H)+=392.40.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:3]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:22][O:23][C:24](=[O:47])[C@H:25]([CH2:43][CH2:44][S:45][CH3:46])[NH:26][C:27](=[O:42])[C:28]1[CH:33]=[CH:32][C:31]([C:34]#[CH:35])=[CH:30][C:29]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C>C(Cl)Cl.CCOCC.[Cu]I>[CH3:22][O:23][C:24](=[O:47])[C@H:25]([CH2:43][CH2:44][S:45][CH3:46])[NH:26][C:27](=[O:42])[C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:8](=[O:10])[CH2:7][C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)=[CH:30][C:29]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cn1cnc(CC(=O)O)c1
Reactant: C#Cc1ccc(C(=O)N[C@@H](CCSC)C(=O)OC)c(-c2ccccc2)c1
Agent: [Cu]I
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C#CC(=O)Cc2cn(C)cn2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-methyl-4imidazoleacetic acid (5 mmol) in methylene chloride at 0° C. is added oxalyl chloride (6 mmol) and DMF (0.05 mmol). After 30 minute, the solvent is evaporated in vacuo. The residue is redissolved in dichioromethane, followed by the addition of the resultant acetylene from Example 47A (5 mmol), triethylamine (10 mmol), and copper(I) iodide (1 mmol). The reaction is stirred at 25° C. until TLC analysis indicates no starting material is left in the reaction mixture. The reaction is diluted with ether, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[IH:11]>C(Cl)Cl>[I:11][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(C)nc(Cl)n1
Reactant: I
Solvent: ClCCl
Product: CSc1nc(C)nc(I)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
A mixture of 2-chloro-4-methyl-6-(methylthio)-1,3,5-triazine (2110 mg, 12.01 mmol) and 67% hydriodic acid solution (2.260 mL, 30.0 mmol) in CH2Cl2 (4 mL) was stirred at room temperature for 3 h. The solid was filtered off and washed with CH2Cl2. The solid was treated with sat. aqueous NaHCO3 (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give crude product as a yellow solid. This was purified by silica gel chromatography eluting with 50% CH2Cl2/hexanes to give 2-iodo-4-methyl-6-(methylthio)-1,3,5-triazine (2.1 g, 7.86 mmol, 65.4% yield). 1H NMR (300 MHz, CDCl3) δ 2.53 (s, 3H); 2.51 (s, 3H). m/z (ESI, +ve ion) 267.8 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:25]O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]#[N:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C#N)cc1OCc1ccccc1
Yield: 87.4 %

Procedure:
3-Benzyloxy-4-methoxybenzaldehyde (50 g, 0.21 mol) was added to a solution of sodium acetate (33.9 g, 0.41 mol) and hydroxylamine hydrochloride (28.73 g, 0.41 mol) in acetic acid (200 ml) and the resulting suspension was heated to reflux for 18 hours. After cooling, the reaction mixture was partitioned between dichloromethane and water and the aqueous phase was further extracted with dichloromethane. The combined organic layers were dried over MgSO4 and evaporated to afford the subtitle compound as a buff-coloured solid (43.9 g, 89%). Rf 0.70 (toluene:EtOAc 4:1, v/v).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>CO>[CH3:13][O:12][C:8](=[O:11])[CH2:9][CH2:10][NH:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C=CC(=O)OC
Reactant: NN1CCCCC1
Solvent: CO
Product: COC(=O)CCNN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of 1-aminopiperidine (100 g, 1.00 mol) in dry methanol at 0° C., methyl acrylate (99.0 ml, 1.10-mol) was added dropwise. The resulting mixture was stirred at room temperature overnight. After evaporation of the solvent, heptane was added to the residue, and the white solid (impurity) removed by filtration. The filtrate was concentrated to dryness to afford 80.0 g (43%) of the title compound as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[O:9][CH2:10][CH2:11][C:5]=2[CH:4]=1)=C.I([O-])(=O)(=O)=[O:13].[Na+].O1CCOCC1>O.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[O:9][CH2:10][CH2:11][C:5]=2[CH:4]=[C:3]([CH:1]=[O:13])[N:8]=1
Reactant: C=Cc1cc2c(nn1)OCC2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cc2c(nn1)OCC2
Reaction time: 3 h
Yield: 20.7 %

Procedure:
A mixture of 3-ethenyl-5,6-dihydrofuro[2,3-c]pyridazine (110 mg, 0.74 mmol), 4% osmium tetroxide in water (0.66 ml), sodium periodate (367 mg), 1,4-dioxane (6.6 ml) and water (1.3 ml) was stirred for 3 hours. The mixture was evaporated and the residue treated with chloroform and added to the top of a column. Elution with ethyl acetate afforded the product (23 mg).
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C@@H:13]4[C:17]([CH3:19])([CH3:18])[C@@:10]([CH3:20])([CH2:11][CH2:12]4)[C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:20][C@@:10]12[C:17]([CH3:19])([CH3:18])[C@@H:13]([C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:9]=31)[CH2:12][CH2:11]2
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Reactant: BrCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2)n1CCc1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 14.4 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 150 mg, 0.56 mmol), tetrabutylammonium iodide (200 mg, 0.54 mmol) and (2-bromoethyl)benzene (500 μL, 3.7 mmol) in dimethylformamide (1.5 mL) was heated in a pressure tube in an oil-bath at 100° C. for 2 days. Dichloromethane (100 mL) was added and the solution was washed with water (4×25 mL) and aqueous sodium thiosulfate (25 mL), dried (magnesium sulfate), filtered, evaporated and purified using an ISCO 40 g column, eluting with 60-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated and co-evaporated successively with dichloromethane/petroleum ether and then methanol, and dried under high vacuum over the weekend at room temperature and then at 80° C. for 4 h. The residue was treated with petroleum ether to give a solid. The solvent was evaporated and the solid was dried overnight at 70° C. to give (4S,7R)-7,8,8-trimethyl-1-phenethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (30 mg, 14%) as a pale yellow solid. ES(+)-MS (M+H) 373.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[CH:4]=O.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:28])[CH:22]=1>CC(N(C)C)=O>[CH3:18][O:19][C:20]([C:21]1[CH:26]=[CH:25][C:24]2[N:27]=[C:4]([C:3]3[CH:6]=[C:7]([C:10]4[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=4)[CH:8]=[CH:9][C:2]=3[OH:1])[NH:28][C:23]=2[CH:22]=1)=[O:29]
Reactant: COc1ncccc1-c1ccc(O)c(C=O)c1
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc2nc(-c3cc(-c4cccnc4OC)ccc3O)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
To an ice-cold flask with a rubber stopper were added 2-hydroxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (2.29 g, 10 mol) and 3,4-diamino-benzoic acid methyl ester (1.83 g, 11 mmol) and the solid mixture was stirred at 0° C. for 15 min. Then DMA (10 mL) was added into the mixture via a syringe and the resulting solution was stirred at 0° C. for 1.5 h, and at the room temperature for 1.5 h. The rubber stopper was removed and the reaction mixture was stirred at 110° C. for 14 h open to the air. The DMA was removed under reduced pressure and the residue was mixed with 50 mL MeOH, and sonicated for 15 min. The mixture was filtered to get the solid precipitate, which was re-crystallized in 300 mL MeOH to afford the title compound (1.6 g, 42%). 1H NMR (DMSO-d6) δ 3.90 (s, 3H), 3.93 (s, 3H), 7.12-7.17 (2H), 7.65 (d, J=9 Hz, 1H), 7.76 (d, J=9 Hz, 1H), 7.83 (d, J=9 Hz, 1H), 7.91 (d, J=9 Hz, 1H), 8.20 (d, J=6 Hz, 1H), 8.26 (s, 1H), 8.29 (s, 1H). ESI-MS m/z 376.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/B(O)O)=[CH:4][CH:3]=1.Br[C:14]1[C:18]([CH:19]=[O:20])=[CH:17][S:16][CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(#N)C>O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:14]2[C:18]([CH:19]=[O:20])=[CH:17][S:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cscc1Br
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=Cc1cscc1C=Cc1ccc(Cl)cc1
Temperature: 94 °C
Reaction time: 32 h
Yield: 54.8 %

Procedure:
To a 40-mL scintillation vial containing trans-2-(4-chlorophenyl)vinylboronic acid (0.42 g, 2.30 mmol), 3-bromo-4-formylthiophene (0.40 g, 2.09 mmol), K3PO4 (0.490 g, 2.30 mmol), TPP (22 mg, 0.08 mmol, 4 mol %), Pd(OAc)2 (4.7 mg, 0.02 mmol, 1 mol %) and a stir-bar, was added acetonitrile (2.5 mL). The vial was purged with N2, capped tightly and heated at 94° C. (aluminum multi-reaction block) while vigorously stirred for 32 h. The reaction was diluted with water and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (Isco CombiFlash) 0-10% EtOAc in heptane afforded the desired 4-[2-(4-chlorophenyl)-vinyl]-thiophene-3-carbaldehyde (285 mg, 54%). 1H NMR (400 MHz, CDCl3) δ ppm 6.99 (d, J=16.38 Hz, 1H), 7.31-7.36 (m, 2H), 7.45-7.49 (m, 2H), 7.50 (d, J=3.20 Hz, 1H), 7.76 (dd, J=16.34, 0.78 Hz, 1H), 8.13 (d, J=3.20 Hz, 1H), 10.07 (d, J=0.82 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1.[Br:30][C:31]1[N:36]=[C:35]([C:37](O)=[O:38])[CH:34]=[CH:33][C:32]=1[F:40]>>[Br:30][C:31]1[N:36]=[C:35]([C:37]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]2)=[O:38])[CH:34]=[CH:33][C:32]=1[F:40]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(c2ccncc2N)C1
Reactant: O=C(O)c1ccc(F)c(Br)n1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C1

Procedure:
Following Method 11 of Example 305, tert-butyl (3S,5R)-1-(3-aminopyridin-4-yl)-5-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and 6-bromo-5-fluoropicolinic acid were coupled to yield tert-butyl (3S,5R)-1-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-5-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate. LCMS (m/z): 624.1/626.1 (MH+).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[Cl:14][C:15]1[N:20]=[C:19]([O:21][C:22]2[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28][NH2:29])=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([O:21][C:22]2[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28][NH:29][C:11]([CH:8]3[CH2:10][CH2:9]3)=[O:12])=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)C1CC1
Reactant: NCCOc1ccc(Oc2cccc(Cl)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCOc1ccc(Oc2cccc(Cl)n2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
At room temperature, 1.1 g of triethylamine and then 1.0 g of cyclopropanecarboxylic acid chloride are dripped into 2.6 g of 2-[4-(6-chloropyridin-2-yloxy)-phenoxy]-ethylamine in 50 cm3 of dichloromethane. The reaction is slightly exothermic. The mixture is stirred at room temperature for 14 hours.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][N:25]=[C:26]([C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:18]=2)C(=O)OC(C)(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][NH:9][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][N:25]=[C:26]([C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nnnc1C(=NOCc1cccc(N(CCC2CCCCC2)C(=O)OC(C)(C)C)n1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnnc1C(=NOCc1cccc(NCCC2CCCCC2)n1)c1ccccc1
Yield: 79.6 %

Procedure:
To a stirred solution of tert-butyl (2-cyclohexylethyl){6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (0.252 g, 0.413 mmol, 1 eq.) in 5 ml of dry DCM, was added TFA (1.41 g, 12.39 mmol, 30 eq.) in one portion. The reaction was refluxed for 5 hrs. Then the solvent and excess TFA were evaporated. The residue was neutralised with TEA and purified by chromatography on silica gel to give N-(2-cyclohexylethyl)-6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (0.138 g, 76% yield) as a viscous oil.