Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=3[CH:31]=2)[C:10]=1[CH3:11])[C:5](O)=[O:6].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1([NH2:41])[CH2:40][CH2:39]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[C:17]([C:27]([NH:28][CH3:29])=[O:30])[C:16]=3[CH:31]=2)[CH:8]=[C:4]([C:5](=[O:6])[NH:41][C:38]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:40][CH2:39]2)[CH:3]=1
Reactant: NC1(c2ccccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(F)c3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)cc(F)c3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methyl benzoic acid (0.2 g, 0.47 mmol, 1 eq), 1-(pyridin-2-yl)cyclopropanamine (0.075 g, 5.5 mmol, 1.2 eq) (60% purity), HOBT (0.81 g, 0.015 mmol, 1.7 eq), EDC.HCl (0.16 g, 00.83 mmol, 1.8 eq) in DCM at ambient temperature and under nitrogen was added Diisopropylethylamine (0.30 g, 2.3 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer is further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and further purification was done using preparative HPLC. Yield: 0.1 g (50%). 1H NMR (400 MHz, CDCl3): δ 1.39-1.42 (m, 2H), 1.67-1.70 (m, 2H), 2.21-2.22 (d, 3H, J=2.24 Hz), 2.9-3.0 (d, 3H, J=4.88 Hz), 5.98-5.99 (s, 1H), 7.06-7.09 (dd, 1H, J=5.2, 7.2 Hz), 7.18-7.36 (m, 5H), 7.53-7.62 (m, 4H), 7.76 (d, 1H, J=1.36 Hz), 7.94-7.97 (m, 2H), 8.4 (s, 1H). LCMS: (ES+) m/z=538.2 (M+H). LCMS Method: Column-Atlantis dC18 (50×4.6 mm-5 μm) A: 10 mM NH4OAc; B: acetonitrile
Reaction SMILES: C[N:2]([CH:4]=[C:5]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)[CH:6]=O)C.O.[NH2:24]N.C(O)C>O>[NH:2]1[CH:4]=[C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:6]=[N:24]1
Reactant: NN
Reactant: CN(C)C=C(C=O)c1c(-c2ccccc2)nn2ccccc12
Solvent: CCO
Solvent: O
Product: c1ccc(-c2nn3ccccc3c2-c2cn[nH]c2)cc1
Yield: 81.5 %

Procedure:
A mixture of 3-(N,N-dimethylamino)-2-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylaldehyde (0.70 g), hydrazine mono hydrate (0.18 g) and ethanol (7 ml) was refluxed for 4 hours. To the reaction mixture was added water (12 ml), and stirred under ice-cooling. The precipitates were collected and recrystallized from a mixture of ethanol and water to give 3-(4-pyrazolyl)-2-phenylpyrazolo[1,5-a]pyridine (0.51 g).
Reaction SMILES: [ClH:1].C(OC([NH:12][C:13]1[CH:55]=[CH:54][C:16]([O:17][CH2:18][C:19]([NH:21][C@H:22]([C:27]([NH:29][C@@H:30]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:31]([OH:46])[C:32]([N:34]2[CH2:45][CH2:44][CH2:43][C@H:35]2[C:36]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:33])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:20])=[CH:15][CH:14]=1)=O)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([NH:21][C@H:22]([C:27]([NH:29][C@@H:30]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:31]([OH:46])[C:32]([N:34]2[CH2:45][CH2:44][CH2:43][C@H:35]2[C:36]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:33])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:20])=[CH:54][CH:55]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(N)cc1
Yield: 98.2 %

Procedure:
0.16 ml (0.16 mmol) of 1N aqueous hydrochloric acid was added to a solution of 105 mg (0.14 mmol) of 1-[(2S,3S)-3-{N2 -[4-(benzyloxycarbonylamino)phenoxyacetyl]-L-asparaginyl}amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide (prepared as described in Example 16) in 5 ml of methanol, and the mixture was stirred for 2.5 hours in the presence of 70 mg of palladium on charcoal and under an atmosphere of hydrogen. At the end of this time, the catalyst was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with benzene and the mixture was dehydrated by azeotropic distillation. This operation was repeated a second time, and then the residue was triturated with diethyl ether, to give 89 mg of the title compound as a red-brown powder, melting at 165°-168° C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]>CO.[C].[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:30]=[CH:31][CH:32]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][C:15]=2[C:18]#[N:19])=[N:22][CH:23]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc([N+](=O)[O-])cn3)c2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc(N)cn3)c2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.2 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-{4-cyano-3-[(5-nitropyridin-2-yl)oxy]phenyl}benzamide (0.65 g, 1.59 mmol) in methanol (20 mL) was added 10% palladium-carbon (130 mg), and the mixture was stirred at room temperature for 20 hr under a hydrogen atmosphere (2.8 atm). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (0.57 g, 90%) as a pale-yellow oil. This was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3]/[C:4](/[O-:8])=[CH:5]/[N+]#N.[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:5][C:4]([O:3][CH2:2][CH3:1])=[O:8]
Reactant: C1CCOCC1
Reactant: CCO/C([O-])=C/[N+]#N
Product: CCOC(=O)CC1CCCCO1

Procedure:
Following the procedure of Preparative Example 14, 2.0 g (17.5 mmol) of ethyl diazo acetate was reacted with tetrahydropyran to give 1.75 g of the product as a colorless oil, bp 95°-106° C. at 20 mm Hg.
Reaction SMILES: Cl[C:2]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1.[C:22]([O:26][C:27](=[O:48])[NH:28][C:29]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:22]([O:26][C:27](=[O:48])[NH:28][C:29]1([C:33]2[CH:34]=[CH:35][C:36]([C:2]3[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][N:5]4[N:6]=[C:7]5[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]5)=[C:4]4[N:3]=3)=[CH:37][CH:38]=2)[CH2:30][CH2:31][CH2:32]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Fc1ccc2nn3cc(-c4ccccc4)c(Cl)nc3c2c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(F)ccc5nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C

Procedure:
To 620 mg (2.1 mmol) 2-Chloro-9-fluoro-3-phenylpyrimido[1,2-b]indazole (intermediate example Int-1-0) and 1.1 g (2.9 mmol) {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamic acid tert-butyl ester in 7.2 mL 1,2 dimethoxyethane were added 3.8 mL aqueous sodium carbonate (10%) and 170 mg (0.2 mmol) 1,1 bis(diphenylphosphino)ferrocenedichloropalladium(II). The reaction mixture was stirred for 30′ in the microwave at 100° C. and subsequently evaporated to dryness. The residue (770 mg=72.7%) was used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[CH:5]=[C:4]([CH3:27])[N:3]=1.[NH3:28]>C1COCC1.CO>[CH3:27][C:4]1[CH:5]=[C:6]([S:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[N:7]=[C:2]([NH2:28])[N:3]=1
Reactant: N
Reactant: Cc1cc(SCc2cc3cccc(C)c3nc2-c2ccccc2)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(SCc2cc3cccc(C)c3nc2-c2ccccc2)nc(N)n1
Temperature: 120 °C
Yield: 20 %

Procedure:
To a solution of Example 85 (100 mg, 0.26 mmol) in THF (1 mL) was added 7N ammonia in methanol (5 mL). The reaction mixture was heated in a microwave at 120° C. for 1 h and concentrated in vacuo. Purification by preparative HPLC (Method 1) gave the title compound as an off-white solid (24 mg, 20%). δH (DMSO-d6) 8.60 (s, 1H), 8.27 (s, 1H), 7.84 (d, J 8.1 Hz, 1H), 7.66-7.70 (m, 2H), 7.60-7.65 (m, 1H), 7.45-7.58 (m, 3H), 6.61 (br s, 2H), 6.28 (s, 1H), 4.54 (s, 2H), 2.69 (s, 3H), 2.08 (s, 3H). LCMS (ES+) 373.2 (M+H)+, RT 2.99 minutes (Method 3).
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:24][C:25]([CH3:30])([CH3:29])[C:26](Br)=[O:27]>C(Cl)Cl>[Br:24][C:25]([CH3:30])([CH3:29])[C:26]([C:4]1[CH:3]=[CH:2][C:1]([C:7]23[CH2:8][CH2:9][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:13][CH2:14]2)[CH2:11][CH2:12]3)=[CH:6][CH:5]=1)=[O:27]
Reactant: COC(=O)CC12CCC(c3ccccc3)(CC1)CC2
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CC12CCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To an ice water cooled solution of crude methyl (4-phenylbicyclo[2.2.2]oct-1-yl)acetate (Intermediate 16; 961 mg, 3.53 mmol) in DCM (10 mL) was added aluminium chloride (1.4 g, 10.58 mmol) followed by the dropwise addition of 2-bromoisobutyryl bromide (0.45 mL, 3.53 mmol). The reaction mixture was allowed to stir at ˜0° C. for ˜40 mins, it was then poured onto ice-water (˜100 mL). The organic phase was separated and the aqueous phase washed with DCM (3×50 mL), the organic washings were combined, dried (MgSO4) and concentrated to leave a yellow gum. This was purified on a 120 g silicyle silica cartridge, loading in DCM and eluting with 0-10%-20% isohexane-EtOAc, the product eluting at 10% EtOAc. The mixed fractions were combined and recolumned on a 120 g silica cartridge as described above; to yield the title compound as a white solid, (705 mg 1.67 mmol, 47%). 1H NMR (CDCl3) δ 1.09 (d, 3H), 1.50-1.57 (m, 3H), 1.67-1.74 (m, 3H), 1.82-1.86 (m, 6H), 2.03 (s, 6H), 2.27 (q, 1H), 3.67 (s, 3H), 7.37 (d, 2H), 8.11 (d, 2H); GC-MS CI m/e MH+ 421.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][CH:20]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc4cn[nH]c4c3)c2cc1OC
Temperature: 100 °C
Yield: 106.3 %

Procedure:
A solution of 500 mg (2.00 mM) of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile and 975 mg (2.61 mM) of 6-aminoindazole in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 738 mg of the title compound as a tan solid: mass spectrum (electrospray, m/e): M+H 345.9, mp=180-183° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:13](=[O:25])[N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]([CH3:18])[C:16]=1[CH3:17])=[O:11].CC([O-])(C)C.[K+].[Cl:32][C:33]1[C:34]([C:40]([NH2:42])=[O:41])=[N:35][CH:36]=[CH:37][C:38]=1Cl.CCOC(C)=O>CN(C=O)C.O>[Cl:32][C:33]1[C:34]([C:40]([NH2:42])=[O:41])=[N:35][CH:36]=[CH:37][C:38]=1[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])=[C:2]([F:1])[CH:7]=1
Reactant: NC(=O)c1nccc(Cl)c1Cl
Reactant: Cc1c(C(=O)Nc2ccc(O)cc2F)c(=O)n(-c2ccccc2)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3Cl)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A mixture of N-(2-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.879 mmol) and t-BuOK (118 mg, 1.05 mmol) in DMF (3 mL) was stirred at rt for 30 minutes, then 3,4-dichloropicolinamide (201 mg, 1.05 mmol) was added. The reaction mixture was heated to 120° C. and stirred for 12 hours. EtOAc (1 mL) and H2O (20 mL) were added, and the resulted mixture was stirred at rt overnight. Filtered to give the title compound as a brown solid (379 mg, 87.0%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]1[CH:17]2[CH:12]([CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16]2)[O:11][C:10](=[O:19])[CH2:9]1.Cl>CCOCC>[OH:19][CH2:10][CH2:9][CH:8]([CH3:7])[CH:17]1[CH2:16][CH2:15][CH:14]([CH3:18])[CH2:13][CH:12]1[OH:11]
Reactant: CC1CCC2C(C)CC(=O)OC2C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC1CCC(C(C)CCO)C(O)C1
Yield: 78.1 %

Procedure:
Into a four-mouthflask (volume: 100 ml) in which the inside was replaced by nitrogen were supplied diethyl ether (hereinafter referred to as "ether") and lithium aluminum hydride (0.2 g, 5.5 mmol). To this solution was added dropwise at room temperature an ether solution of 5,9-dimethyl-2-oxabicyclo-[4,4,0]-decan-3-one (0.1 g, 0.55 mmol) which had been separately prepared. The mixture was allowed to react at the same temperature for 1 hour, and the reaction solution was poured into a 10% aqueous hydrochloric acid solution for separation. The ether layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The resultant crude product was purified by column chromatography on silica gel to give the title compound (2) (80 mg) (Theoretical yield: 78.1%). Analytical results on the title compound are given below.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10](Cl)[C:11]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13][C:12]=2[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27](B(O)O)[CH2:28][CH2:29][CH3:30]>>[CH2:1]([C:8]1[N:9]=[C:10]([CH2:27][CH2:28][CH2:29][CH3:30])[C:11]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13][C:12]=2[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(Cc2ccccc2)nc2c1CCN(Cc1ccccc1)CC2
Reactant: CCCCB(O)O
Product: CCCCc1nc(Cc2ccccc2)nc2c1CCN(Cc1ccccc1)CC2

Procedure:
The title compound was prepared using a similar method to that of Preparation 39, starting from 2,7-dibenzyl-4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine of Preparation 38, Step B and n-butaneboronic acid. The title compound was obtained as a colourless oil 126 mg, 79%
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH3:22][O:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][CH:29]2[CH2:33][CH2:32][N:31]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:30]2)=[CH:34][CH:35]=1
Reactant: COc1ccc(CC2CCNC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: O=C(O)C(=O)O
Product: COc1ccc(CC2CCN(C(=O)c3cnoc3-c3ccc(C)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-methoxybenzyl)pyrrolidine oxalate (16.9 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (5.5 mg). Calcd for C23H24N2O3: 376.1787, found 376.1801.
Reaction SMILES: [OH-].[Na+].C[C:4]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)([CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:5]([O-:7])=[O:6].O.Cl>C1COCC1.CO>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH:4]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([OH:7])=[O:6])=[CH:18][CH:17]=1)#[N:20]
Reactant: CC(C(=O)[O-])(c1ccc(C#N)cc1)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(C(C(=O)O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
316.5 mg (7.9 mmol) of sodium hydroxide were added to a solution of 192.5 mg (0.79 mmol) of (+/−)-methyl(4-cyanophenyl)(cyclopentyl)acetate in 1.7 ml of THF/methanol (1:1), and the mixture was stirred at RT for 3 h. The reaction mixture was then poured into water, neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and concentrated. This gave 125.6 mg (69% of theory) of the title compound.
Reaction SMILES: NC1C2C(Cl)=CN(C(OCC3C=CC=CC=3)=O)C=2C=CN=1.C(N(CC)CC)C.C1(C(Cl)=O)CC1.[CH:35]1([C:38]([NH:40][C:41]2[C:46]3[C:47]([Cl:60])=[CH:48][N:49](C(OCC4C=CC=CC=4)=O)[C:45]=3[CH:44]=[CH:43][N:42]=2)=[O:39])[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO>[Cl:60][C:47]1[C:46]2[C:41]([NH:40][C:38]([CH:35]3[CH2:36][CH2:37]3)=[O:39])=[N:42][CH:43]=[CH:44][C:45]=2[NH:49][CH:48]=1
Reactant: O=C(Nc1nccc2c1c(Cl)cn2C(=O)OCc1ccccc1)C1CC1
Agent: Nc1nccc2c1c(Cl)cn2C(=O)OCc1ccccc1
Agent: O=C(Cl)C1CC1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(Nc1nccc2[nH]cc(Cl)c12)C1CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
Benzyl 4-amino-3-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (350 mg, 1.16 mmol) was stirred in tetrahydrofuran and triethylamine (0.32 mL, 2.3 mmol) was added. The mixture was cooled to −10° C. and cyclopropanecarbonyl chloride (0.2 mL, 1.73 mmol) was added drop wise. The reaction mixture was stirred at room temperature for about 1 hour, followed by concentration under vacuum to remove tetrahydrofuran. The residue was dissolved in ethyl acetate and organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to give the crude mixture of benzyl 4-[bis(cyclopropylcarbonyl) amino]-3-chlorol H-pyrrolo[3,2-c]pyridine-1-carboxylate and benzyl 4[(cyclopropylcarbonyl)amino]-3-chloro1H-pyrrolo[3,2-c]pyridine-1-carboxylate. The mixture was treated with saturated potassium carbonate solution in methanol (1 mL) and stirred at room temperature. After completion, methanol was removed under vacuum at room temperature. The residue was treated drop wise with saturated aq. sodium bicarbonate solution and the precipitated solid was filtered, washed with water and dried to obtain N-(3-chloro-1H-pyrrolo[3,2-c]pyridin-4-yl)cyclopropanecarboxamide (176 mg, 69%) as a white solid.
Reaction SMILES: [CH2:1]([N:9]1[C:13](=[O:14])C=C[S:10]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)(Cl)(=O)=O.[CH2:21]([Cl:24])[CH2:22][Cl:23]>>[Cl:23][CH:22]1[CH:21]([Cl:24])[S:10](=[O:15])[N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:13]1=[O:14]
Reactant: ClCCCl
Reactant: CCCCCCCCN1C(=O)C=CS1=O
Solvent: O=S(=O)(Cl)Cl
Product: CCCCCCCCN1C(=O)C(Cl)C(Cl)S1=O
Temperature: 25 °C

Procedure:
To a solution of 2.29g. (0.01 mole) of 2-n-octyl-4-isothiazolin-3-one 1-oxide in 3 ml. of EDC is added 1.2g. (0.01 mole) of sulfuryl chloride in 3 ml. of EDC. The mixture is stirred at room temperature over a weekend. The solution is filtered and concentrated to give an oil. The oil is further purified via column chromatography (100% benzene: silica) to give 1.0g. (33%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7]1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][NH:14][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=2)[CH2:10][CH2:11]1
Reactant: NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from Example 3, Step b (2.00 g) was dissolved in TBF (100 ml) and triethylamine (2.10 g) added. The solution was then cooled with stirring to 0° C. and to it 3-methoxybenzoyl chloride was added dropwise as a solution in THF (10 ml). Reaction was left to warm to room temp and left for 24 hours then water was added and the organics extracted into ethyl acetate. The combined organics were dried with MgSO4 and the solvent removed by evaporation. The crude product was purified by flash chromatography to leave the sub-title product as a pale yellow oil (1.38 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=1)[C:13]#[N:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:19][OH:20].C([O-])([O-])=O.[Na+].[Na+]>CCO>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=1)[C:13](=[NH:14])[NH:19][OH:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C#N)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(=N)NO)ccn1
Temperature: 85 °C
Yield: 100 %

Procedure:
Prepared using General Procedure 1. To 2-((tert-butyldimethylsilyloxy)methyl)isonicotinonitrile INT-71 (0.169 g, 0.68 mmol) in EtOH (8 mL) was added hydroxylamine hydrochloride (0.142 g, 2.0 mmol) and Na2CO3 (0.216 g, 2.0 mmol) and the reaction mixture was heated at 85° C. for 12 h. Once cooled to room temperature, the reaction mixture was filtered using EtOH to rinse the filter cake. The filtrate was concentrated under reduced pressure and washed with EA and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated to produce 0.191 g (100%) of 2-((tert-butyldimethylsilyloxy)methyl)-N-hydroxyisonicotinimidamide INT-72 as a light yellow oil. LCMS-ESI (m/z) calculated for C13H23N3O2Si: 281.4; found 282.1 [M+H]+, tR=2.76 min (Method 1). 1H NMR (400 MHz, (CD3)2SO) δ 8.50 (dd, J=5.2, 0.7, 1H), 7.74 (dd, J=1.6, 0.7, 1H), 7.51 (dd, J=5.2, 1.7, 1H), 5.98 (s, 2H), 0.96-0.89 (m, 9H), 0.14-0.07 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:9]O)([CH2:7]O)[N+:4]([O-:6])=[O:5].C(=O)(O)[O-].[Na+].[CH2:16]([NH:23][CH2:24][CH2:25][NH:26][CH3:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([N:23]1[CH2:9][C:3]([CH2:2][OH:1])([N+:4]([O-:6])=[O:5])[CH2:7][N:26]([CH3:27])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])C(CO)(CO)CO
Reactant: CNCCNCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(Cc2ccccc2)CC(CO)([N+](=O)[O-])C1
Temperature: 50 °C

Procedure:
To a mixture of tris(hydroxymethyl)nitromethane (118.9 g), sodium bicarbonate (40 g) and water (1000 ml), N-benzyl-N'-methylethylenediamine (123 g) is added, and the reaction mixture is heated at about 50° C. for 2 hours. After cooling, the solution is extracted with dichloromethane, and the organic layer is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent is evaporated under reduced-pressure to give 1-benzyl-6-hydroxymethyl-4-methyl-6-nitrohexahydro-1H-1,4-diazepine as an oil.