Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[NH:10][C:9](=O)[CH2:8]1.O>C1COCC1>[O:7]1[C@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[NH:10][CH2:9][CH2:8]1
Reactant: O=C1CO[C@H]2CCCC[C@H]2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C1CC[C@H]2NCCO[C@H]2C1
Temperature: 80 °C
Yield: 69.7 %

Procedure:
Lithium aluminium hydride (0.22 g, 5.79 mmol) was suspended in THF (2 mL) and to this was added a solution of cis-hexahydro-benzo[1,4]oxazin-3-one (0.224 g), 1.45 mmol) in THF (5 mL) under nitrogen. The mixture was heated at 80° C. for 2 hours and then allowed to cool before cautious addition of water. The resultant white suspension was filtered through Celite® then concentrated. The residue was applied to a 5 g SCX-2 cartridge, washed with methanol then eluted using 2 N ammonia in methanol to afford the title compound as a colourless oil (0.142 g). LCMS m/z 183.28 [M+H+MeCN]+ R.T.=0.37 min (Analytical Method 6).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:7])[CH3:6].[I:9][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1>ClCCl>[C:5]([C:13]1[CH:14]=[CH:15][C:10]([I:9])=[CH:11][C:12]=1[CH3:16])(=[O:7])[CH3:6]
Reactant: Cc1cccc(I)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(I)cc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
To a suspension of 20 gm of aluminum trichloride in 500 mL of dichloromethane was added 10.2 mL of acetyl chloride under Argon. After the reaction mixture was stirred for 15 min, 3-iodotoluene (20 gm) was added through a syringe. The mixture was stirred overnight under Argon and poured into 500 gm of ice-water. Organic layer was separated and washed once with the saturated ammonium chloride solution, and washed once with 10% sodium thiosulfate solution and dried over sodium sulfate. After removing the solvent, the residue was dissolved in hexane for the column purification. Silica gel (260 gm) was packed with hexane, after loading the sample solution, the column was eluted with 750 mL of hexane, 750 mL of 1% v/v ether/hexane, 750 mL of 2% v/v ether/hexane and 1500 mL of 3% v/v ether/hexane. The fractions containing the right isomer were identified by GC-MS and 1H NMR and pooled and concentrated to dryness to afford 12.2 gm (51.2%) of the title product (P 1).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[F:6][C:7]1[CH:24]=[CH:23][C:10]([C:11]([NH:13][CH:14]([C:19](OC)=[O:20])[C:15](OC)=[O:16])=[O:12])=[CH:9][CH:8]=1.[Na]>C(O)C>[OH:20][C:19]1[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:23]=[CH:24][C:7]([F:6])=[CH:8][CH:9]=2)=[C:15]([OH:16])[N:5]=[C:2]([CH3:3])[N:4]=1
Reactant: COC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)OC
Reactant: CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1nc(O)c(NC(=O)c2ccc(F)cc2)c(O)n1
Yield: 78.8 %

Procedure:
Acetamidine hydrochloride (1.05 g, 11.1 mmol) and dimethyl 2-(4-fluorobenzamido)malonate (1.0 g, 3.71 mmol) were added to a solution of sodium (0.26 g, 11.1 mmol) in ethanol (37 ml). The reaction mixture was refluxed for 3 hours. Then, after cooling, the solid product was collected and washed with ethanol. The product was dissolved in a minimal volume of water and acidified to pH 4-5 with 5M HCl. The precipitate was collected, washed with water and dried to give the title compound as a white solid (0.77 g, 79%).
Reaction SMILES: [NH2:1][CH:2]([OH:29])[C:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:14][C:15]3[N:16]=[C:17](Cl)[N:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:20]=3[N:21]=2)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH3:30][C:31]1[O:32][C:33]2[CH:48]=[CH:47][CH:46]=[CH:45][C:34]=2[C:35]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:4][C:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:14][C:15]3[N:16]=[C:17]([C:35]4[C:34]5[CH:45]=[CH:46][CH:47]=[CH:48][C:33]=5[O:32][C:31]=4[CH3:30])[N:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:20]=3[N:21]=2)[CH2:8][CH2:7]1)([CH3:5])[C:2]([NH2:1])=[O:29]
Reactant: CC(C)(C(N)O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: Cc1oc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1oc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C(N)=O)CC3)sc2n1
Temperature: 140 °C
Yield: 60.9 %

Procedure:
A mixture of 1-amino-2-[4-(5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)piperazin-1-yl]-2-methylpropan-1-ol (100 mg, 0.23 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzofuran (88 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (26 mg, 0.02 mmol) and Cs2CO3 (148 mg, 0.45 mmol) in dioxane (6 mL) and H2O (3 mL) was purged with argon then heated at 140° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM/MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 50-100%) to afford 211 as a cream solid (75 mg, 61%). LCMS (Method G): RT 10.35 min, [M+H]+ 536.4. 1H NMR (CDCl3, 400 MHz): δ 8.40-8.37 (m, 1 H); 7.46-7.42 (m, 1 H); 7.32-7.23 (m, 2 H); 7.10 (d, J=5.3 Hz, 1 H); 5.22 (d, J=5.3 Hz, 1 H); 4.40 (m, 4 H); 3.93-3.87 (m, 6 H); 2.92 (s, 3 H); 2.69 (m, 4 H); 2.62 (m, 4 H) and 1.26 (s, 6 H)
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].Cl.[OH:8][CH:9]([CH2:15][C:16](=[O:18])[O-:17])[CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12].C(OCC)C>FC(F)(F)C(O)=O>[C:1]([C:9]([CH2:15][C:16](=[O:17])[O-:18])([CH2:10][N+:11]([CH3:12])([CH3:13])[CH3:14])[OH:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: C/C=C/C(=O)Cl
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: C/C=C/C(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
8 cc (0.08 moles) of crotonyl chloride were added to a solution of carnitine hydrochloride (8 grams; 0.04 moles) in trifluoroacetic acid. The reaction mixture was kept under stirring at 50° C. overnight. Subsequently, ethyl ether was added to the mixture and a precipitate formed. The precipitate was filtered off and used as such in the subsequent reaction.
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:20])([CH3:19])[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]=[CH:9]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:19][C:6]([CH3:20])([CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]=[CH:9]1)[CH2:5][OH:4]
Reactant: CC(=O)OCC(C)(C)Cn1cnc(-c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(CO)Cn1cnc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propyl acetate (20 mg) in methanol was added saturated solution of K2CO3 in metanol (1.5 mL) and the resulting solution was stirred at room temperature for 1 hour. MeOH was evaporated in vacuo and water was added followed by CH2Cl2. The aqueous layer was extracted with CHCl3, the combined organic layers were washed with brine, dired over Na2SO4 and evaporated in vacuo to afford the title compound as a slightly yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:5]=1[CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)([CH3:3])[CH3:2].O.NN>CO>[CH:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[CH2:6][NH2:7])([CH3:24])[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1CN
Yield: 88.2 %

Procedure:
Then, a mixture of 1.01 g (3.14 mmol) of N-(2, 6-diisopropylbenzyl) phthalimide, 0.3 ml of hydrazine hydrate and 15 ml of methanol was refluxed with heating for 3.5 hours. The reaction mixture was concentrated in vacuo, mixed with 20 ml of water and 40 ml of methylene chloride, and made alkaline with aqueous sodium hydroxide. The organic layer was separated, washed with dilute aqueous sodium hydroxide and water, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo to give 0.53 g of 2, 6-diisopropylbenzylamine as an oil.
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][CH:3]=1.Br[CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[I:1][C:2]1[C:7]([O:8][CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(I)c1O
Reactant: CCOC(=O)/C=C/CBr
Product: CCOC(=O)/C=C/COc1c(I)cccc1OC

Procedure:
Substantially the same procedure as in Step A of Reference Example 1 was repeated using 6-iodo-2-methoxyphenol [Heterocyclic Communications, 289 (1995)] (0.4 g) and ethyl 4-bromocrotonate (0.29 ml) to give Compound IIbc-a (0.52 g, 90%) as a pale-yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:20]([C:22]1[NH:26][C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:24][C:23]=1[CH3:32])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:20][C:22]4[NH:26][C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:24][C:23]=4[CH3:32])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(CCC(=O)O)[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(CCC(=O)O)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 85 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-(5-formyl-4-methyl-1H-pyrrol-2-yl)-propionic acid (54.4 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The reaction was concentrated, the residue was dissolved in water and acidified with 1N HCl to pH=2. The resultant solid was then washed with water, ethanol and dried to give 93.9 mg (85%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.18 (br s, 1H, NH), 12.19 (br s, 1H, COOH), 11.61 (br s, 1H, NH), 9.09 (s, 1H), 8.27 (s, 1H), 7.70 (m, 1H), 7.39 (m, 1H), 7.30-7.35 (m, 2H), 6.07 (s, 1H), 2.90 (t, J=7.2 Hz, 2H, CH2), 2.60 (t, J=7.2 Hz, 2H, CH2), 2.16 (s, 3H, CH3). MS 442 [M++1].
Reaction SMILES: [OH:1][CH:2]1[C:6](=[O:7])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH2:3]1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.N1C=CC=CC=1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:1][CH:2]1[C:6](=[O:7])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH2:3]1
Reactant: COC(=O)CCCCCCC1=CCC(O)C1=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCCCCCC1=CCC(OC2CCCCO2)C1=O
Reaction time: 1 h

Procedure:
A solution of p-toluenesulphonic acid (20 mg) in dry dichloromethane (5 ml) was added, dropwise, to a stirred mixture of methyl (±)-7-[4-hydroxy-5-oxocyclopent-1-enyl]-hepatanoate (1.2 g; prepared as described in Example 3) and 2,3-dihydropyran in dry dichloromethane (20 ml), with cooling to maintain the temperature below 30° C. After one hour, a further quantity of 2,3-dihydropyran (0.3 g) was added dropwise, and the mixture was stirred for one hour further. Pyridine (100 mg) was added, and the mixture was washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, and evaporated in vacuo, finally at 0.1 mm Hg and 50° C. for 4 hours, to give methyl (±)-7-[4-(2-tetrahydropyranyloxy)-5-oxocyclopent-1-enyl]heptanoate (1.9 g), in the form of a brown oil, pure enough for use in the next stage without further purification.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:19]1[N:28]=[C:27]([NH:29][CH2:30][C@H:31]2[O:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]2)[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:15][CH:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:19]3[N:28]=[C:27]([NH:29][CH2:30][C@H:31]4[O:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]4)[C:26]4[C:21](=[N:22][CH:23]=[CH:24][N:25]=4)[CH:20]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(Cl)cc3nccnc23)C1
Reactant: C[Sn](C)(C)c1ccc(N2CCC(O)CC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(-c3ccc(N4CCC(O)CC4)cc3)cc3nccnc23)C1
Yield: 27.6 %

Procedure:
1-(4-(trimethylstannyl)phenyl)piperidin-4-ol (398 mg, 1.17 mmol), (R)-tert-butyl 2-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (297 mg, 0.78 mmol), tetrakis(triphenylphosphine)palladium (180 mg, 0.15 mmol) were mixed in 5 mL toluene. The mixture was reacted at 100° C. overnight. Filtrated and concentrated, purified by flash chromatography (PE:EA=1:2) to give 112 mg reddish solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:14][C@@H:13]2[CH2:15][CH2:16][C@H:10]1[CH2:11][NH:12]2)=[O:8])([CH3:5])([CH3:4])[CH3:3].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:2]([O:6][C:7]([N:9]1[CH2:14][C@@H:13]2[CH2:15][CH2:16][C@H:10]1[CH2:11][N:12]2[C:17](=[O:19])[CH3:18])=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H]1CN2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C[C@@H]2CC[C@H]1CN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of (S,S)-2,5-diaza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester hydrochloride (645 mg, 2.59 mmol) in DCM (26 mL) was added acetic anhydride (490 μL, 5.19 mmol) and triethylamine (1.08 mL, 7.77 mmol) and the mixture was stirred (rt, 16 h). The reaction mixture was washed with water (3×8 mL) and brine (1×8 mL). The organic layer was dried, filtered and concentrated in vacuo to provide (S,S)-5-acetyl-2,5-diaza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (658 mg, 100%). This intermediate was dissolved in DCM (3.5 mL), treated with HCl (4 M in dioxane, 3.5 mL) and stirred (rt, 16 h). The dispersion was concentrated in vacuo to provide the title compound as a beige powder (494 mg, 100%). MS (ESI): mass calcd. for C8H14N2O, 154.11; m/z found, 155.2 [M+H]+. 1H NMR (500 MHz, MeOD): 4.71 (s, 0.5H), 4.25 (s, 0.5H), 3.97 (dt, J=12.1, 2.8, 0.5H), 3.87 (d, J=2.6, 1H), 3.84-3.73 (m, 1H), 3.68 (m, 1H), 3.64 (dd, J=13.8, 1.6, 0.5H), 3.54 (m, 0.5H), 3.45 (m, 1.5H), 2.12 (m, 4.5H), 2.06-1.91 (m, 2.5H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])([C:14]#[N:15])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:22].[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:11]1([C:14]#[N:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(c2ccccc2Cl)CCNCC1
Reaction time: 1 h
Yield: 177.5 %

Procedure:
4-(2-Chloro-phenyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.78 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 1 mL). The mixture was stirred for 1 hour and the solvent removed by evaporation under vacuum. The solid was triturated from ether to afford the title compound as a yellow solid (0.178 g). LCMS m/z 221.2 [M+H]+. R.T.=2.18 min (Analytical Method 4).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11](N2CCCCC2)=[O:12])=[CH:5][C:4]2[O:19][CH2:20][O:21][C:3]=2[CH:2]=1.[OH-:22].[K+].CO.Cl>O>[CH2:20]1[O:19][C:4]2[CH:5]=[C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:12])=[O:22])[CH:1]=[CH:2][C:3]=2[O:21]1
Reactant: O=C(/C=C/C=C/c1ccc2c(c1)OCO2)N1CCCCC1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)/C=C/C=C/c1ccc2c(c1)OCO2

Procedure:
To piperine (1) (2 g, 0.7 mmol, 1 eq), 20% of methanolic KOH (100 ml) was added and refluxed for 2 days. After completion of the hydrolysis, methanol was removed under reduced pressure and a yellow coloured oily solid was obtained. This residue was dissolved in water (50 ml) and acidified with 6N HCl to pH<1 yielding a yellowish precipitate of piperinic acid. Recrystallization from methanol gave yellow needles (0.9 g, 60% yield). m.p. 206° C.-208° C. (Lit m.p. 217° C.-218° C.)1
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[O:16][C:17]([CH:20]=O)=[CH:18][CH:19]=4)[CH:11]=[C:10]([C:22]([NH:24][CH2:25][C:26]4[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=4[CH3:32])=[O:23])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37].CCN(C(C)C)C(C)C.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[O:16][C:17]([CH2:20][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:18][CH:19]=4)[CH:11]=[C:10]([C:22]([NH:24][CH2:25][C:26]4[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=4[CH3:32])=[O:23])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)o3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: CS(=O)(=O)CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CNCCS(C)(=O)=O)o3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reaction time: 3 h

Procedure:
To a stirred solution 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-methyl)-6-(5-formylfuran-2yl)-1H-indazole-4-carboxamide (0.09 g, 0.19 mmol) in methanol (2 mL), 2-(methylsulfonyl)ethanamine (0.072 g, 0.581 mmol) and DIPEA (0.05 g, 0.39 mmol) was added at room temperature and reaction stirred for 3 h. Then NaBH3CN (0.012 g, 0.196 mmol) was added and reaction stirred at room temperature for 18 h. On completion, methanol was removed under reduced pressure and then water was added to the residue. The aqueous phase was extracted with 10% MeOH/DCM and the combined organic layers were dried over sodium sulfate and concentrated to obtain crude material which was purified by column chromatography to afford 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)furan-2-yl)-1H-indazole-4-carboxamide. LCMS: 566.90 (M+1)+; HPLC: 90.05% (@ 254 nm) (Rt;5.253); 1H NMR (MeOD, 400 MHz) δ 8.31 (s, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 6.92 (s, 1H), 6.44 (s, 1H), 6.13 (s, 1H), 5.18-5.42 (m, 1H), 4.59 (s, 2H), 4.57 (s, 2H), 3.91 (s, 2H), 3.16 (t, 2H, J=6.4 Hz), 3.02 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H), 2.19-2.23 (m, 2H), 2.11-2.14 (m, 2H), 1.98 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[CH:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c([N+](=O)[O-])cn1)c1ccc(F)cc1
Temperature: 180 °C
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyridin-4-amine (Method 90, 0.15 g, 0.54 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.093 g, 0.67 mmol), and DIEA (0.12 ml, 0.67 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 180° C. for 32 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.168 g, 82%). 1H NMR (400 MHz) 12.37 (s, 1H), 9.59 (b, 1H), 8.83 (s, 1H), 8.20 (b, 1H), 7.37 (m, 2H), 7.13 (m, 2H), 6.69 (b, 1H), 5.88 (b, 1H), 5.29 (m, 1H), 1.91 (m, 1H), 1.43 (d, J=6.4 Hz, 3H), 0.97 (m, 2H), 0.71 (m 2H). MS: Calcd.: 382; Found: [M+H]+ 383.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=O)[CH2:8]1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=[N:22][NH:21][C:18]([NH2:20])=[NH:19])[CH2:8]1
Reactant: N=C(N)NN
Reactant: Cc1n[nH]c2c1C(=O)CC(c1sccc1Cl)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1sccc1Cl)C2
Yield: 148.5 %

Procedure:
A mixture of 6-(3-chloro-2-thienyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (1.2 g), aminoguanidine hydrochloride (0.6 g), concentrated hydrochloric acid (1.1 ml), water (1.1 ml) and ethanol (50 ml) was refluxed for 3 hours. Under reduced pressure, the solvent was evaporated, and the residue was washed with ethanol to give 6-(3-chloro-2-thienyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 119) (1.2 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[CH2:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[CH2:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36])[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: OCC(CO)CC1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2CC(CO)CO)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 44.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.34 g, 0.68 mmol) was reacted with 2-(morpholin-3-ylmethyl)propane-1,3-diol (0.12 g, 0.68 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.18 g, 44%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[C:12]([O:16][CH:17]1[CH:24]2[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:26][CH:18]1[CH2:19]3)[CH2:23]2)(=[O:15])C=C>>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1]/[CH:2]=[CH:3]/[C:12]([O:16][CH:17]2[CH:18]3[CH2:26][CH:22]4[CH2:21][CH:20]([CH2:25][CH:24]2[CH2:23]4)[CH2:19]3)=[O:15])=[CH:5][CH:6]=1
Reactant: C=CC(=O)OC1C2CC3CC(C2)CC1C3
Reactant: C=CCc1ccc(OC)cc1
Product: COc1ccc(C/C=C/C(=O)OC2C3CC4CC(C3)CC2C4)cc1
Yield: 82.1 %

Procedure:
The representative procedure was followed using 4-allylanisole (74 mg, 0.50 mmol), 2-adamantyl acrylate (206 mg, 1.00 mmol) and Grubbs-2 catalyst (8.5 mg, 0.01 mmol). Column chromatography on silica gel (eluting with 5% EtOAc/hexanes) afforded the product as a colorless oil (134 mg, 82%).