Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[NH:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])C.[OH-].[K+].Cl.O>C(O)C>[F:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:18][C:17]2=1
Reactant: CCOC(=O)C1CCc2[nH]c3ccc(F)cc3c2C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
6-Fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid ethyl ester (80 g, 0.3 mol) was dissolved in 1 L of ethanol solution of KOH (28 g, 0.5 mol). The resulting mixture was stirred under nitrogen at 40-45° C. until completion of hydrolysis (TLC, HPLC) in 3 hrs. To the cooled solution were added 0.5 L of 1N aqueous HCl and 0.5 L of water; the resulting mixture was concentrated under reduced pressure. The target compound crystallized out of the aqueous solution when ethanol boiled out; 71.2 g (99%) of the title compound were obtained after drying.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11](O)=[O:12])[CH:8]=[CH:7][C:6]=1[N+:14]([O-])=O)([CH3:3])[CH3:2].C(Cl)(C(Cl)=O)=O.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:34]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([C:47]([NH:49][C:50]3[CH:51]=[CH:52][C:53]([C:60]([O:62][CH3:63])=[O:61])=[N:54][C:55]=3[O:56][CH:57]([CH3:59])[CH3:58])=[O:48])=[N:41][C:42]=2[O:43][CH:44]([CH3:46])[CH3:45])=[O:35])=[N:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[NH2:14][C:6]1[CH:7]=[CH:8][C:9]([C:11]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:34]([NH:36][C:37]3[CH:38]=[CH:39][C:40]([C:47]([NH:49][C:50]4[CH:51]=[CH:52][C:53]([C:60]([O:62][CH3:63])=[O:61])=[N:54][C:55]=4[O:56][CH:57]([CH3:59])[CH3:58])=[O:48])=[N:41][C:42]=3[O:43][CH:44]([CH3:46])[CH3:45])=[O:35])=[N:28][C:29]=2[O:30][CH:31]([CH3:32])[CH3:33])=[O:12])=[N:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(NC(=O)c3ccc(N)c(OC(C)C)n3)c(OC(C)C)n2)c(OC(C)C)n1
Reactant: CC(C)Oc1nc(C(=O)O)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2ccc(NC(=O)c3ccc(NC(=O)c4ccc(N)c(OC(C)C)n4)c(OC(C)C)n3)c(OC(C)C)n2)c(OC(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
6-Isopropoxy-5-nitro-2-pyridinecarboxylic acid (24.0 mg, 0.105 mmol), (COCl)2 (0.268 g, 2.12 mmol, 20 eqv), and DMF (cat.) were dissolved in 3 ml of CH2Cl2. The solution was allowed to stir for 2 h at rt and was then concentrated in vacuo. A solution of Methyl 5-{[(5-{[(5-amino-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinecarboxylate (6-1b) (30.0 mg, 0.052 mmol, 0.5 eqv) and DIEA (27.3 mg, 0.21 mmol, 2.0 eqv) in 3 ml of CH2Cl2 was added to the crude acid chloride. The solution was stirred for 12 h at rt. The precipitate was filtered, and washed several times with cold CH2Cl2. The nitro-derivative and 10% Pd/C (5 mg) were added to 5 ml of 1:1 MeOH/CH2Cl2 and the suspension was stirred for 20 min at rt under 1 atm H2. The solution was filtered through celite and the filtrate was concentrated in vacuo to give 36 mg of a white solid (92%): 1H NMR (500 MHz, CDCl3) d 1.45 (d, J=6.5 Hz, 6H), 1.50 (d, J=6.5 Hz, 6H), 1.54 (d, J=6.0 Hz, 12H), 3.94 (s, 3H), 5.55 (m, 1H), 5.68 (m, 3H), 7.00 (d, J=7.5 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 2H), 8.92 (d, J=8.0 Hz, 1H), 9.03 (dd, J1=8.0 Hz, J2=8.0 Hz 2H), 10.24 (s, 1H), 10.27 (s, 1H), 10.28 (s, 1H); 13C NMR (125 MHz, CDCl3) d 22.17, 22.17, 22.20, 22.20, 52.35, 68.56, 69.23, 69.33, 69.36, 117.32, 117.42, 117.86, 119.03, 120.02, 125.03, 125.83, 126.12, 126.63, 126.81, 127.25, 134.52, 135.33, 137.88, 138.71, 139.22, 149.67, 150.81, 150.87, 151.93, 162.78, 162.80, 163.46, 165.47; HRMS (FAB) Submitted.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[CH:4]=1)[CH3:2].CO[CH2:15][Cl:16].C(O)(=O)C>O>[CH2:11]([C:5]1[CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH2:15][Cl:16])[CH3:12]
Reactant: CCc1cc(CC)cc(CC)c1
Reactant: COCCl
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(CC)c(CCl)c(CC)c1
Temperature: 120 °C
Reaction time: 7 h
Yield: 64.6 %

Procedure:
A mixture of 81.1 g of 1,3,5-triethylbenzene, 60.4 g of chloromethyl methyl ether and 6.0 g of acetic acid was stirred in a sealed tube at 120° C. for 7 hours. The reaction mixture was poured into 500 ml of water and extracted with hexane. The organic layer was washed with an aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was distilled under reduced pressure to obtain 68.07 g of 2,4,6-triethylbenzyl chloride. Boiling point: 88 to 98° C. (0.18 kPa).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[NH:3][CH:2]=1.[H-].[Na+].CI.[C:18](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:18][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1cccc2nc[nH]c12
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1ncn2C
Temperature: 0 °C

Procedure:
1.39 g of methyl 3H-benzimidazole-4-carboxylate are dissolved under argon in 20 ml of N,N-dimethylformamide. The solution is cooled to 0° C. in an ice bath and admixed in portions with 0.299 g of sodium hydride (60% dispersion). 0.744 ml of methyl iodide is added and the reaction mixture is heated to 45° C. over 17 hours. The reaction mixture is subsequently poured onto 50 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with 2:1 tetrahydrofuran/tert-butyl methyl ether (2×150 ml). The combined organic phases are washed with 50 ml each of saturated aqueous sodium hydrogencarbonate solution and water, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rt=1.95.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12]CC)=[O:11])[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.CCO.O.O[Li].O>Cl>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1cccc(F)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C(=O)O)n(-c2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a stirring solution of ethyl 3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazole-5-carboxylate (0.786 g, 2.71 mmol) in 1:1:1 THF/EtOH/H2O (36 ml) at RT was added LiOH.H2O (0.568 g, 13.5 mmol). After stirring at RT overnight, the reaction mixture was diluted with 3M HCl (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×30 mL), dried (MgSO4) and concentrated to afford 3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazole-5-carboxylic acid (0.602 g, 85% yield) as white solid. MS (ESI) m/z: 263 (M+H+).
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]#[N:12].N(OCCC(C)C)=O.[I-:21]>>[I:21][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: N#Cc1cc2c(cc1N)CCC2
Reactant: [I-]
Agent: CC(C)CCON=O
Product: N#Cc1cc2c(cc1I)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
A mixture of 6-aminoindane-5-carbonitrile (48.5 mg, 0.307 mmol), isoamyl nitrite (82 μL, 0.614 mmol) and iodide (85.7 mg, 0.338 mmol) was stirred at room temperature for 0.5 h. The mixture was then heated at 80° C. under N2 for 2 h. The reaction mixture was quenched with saturated Na2S2O3 and partitioned between dichloromethane and water. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, 1% EtOAc in hexanes) to yield 6-iodoindane-5-carbonitrile (39.7 mg, 50%). LCMS calc.=268.97; found=270.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.48 (s, 1H), 2.96 (t, J=7.5 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.16-2.10 (m, 2H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]>CS(C)=O.C(OCC)(=O)C.CN(C)CCN(C)C>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCOCCBr
Reactant: Oc1ccccc1
Agent: CN(C)CCN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCOCCOc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
Phenol (15.0 g, 0.159 mol), potassium carbonate (26.4 g, 0.191 mol, 1.2 eq) and tetramethylethylenediamine (0.92 g, 7.95 mmol, 0.05 eq) were dissolved in DMSO (100 mL) and stirred at r.t. for 30 minutes. Then 1-bromo-2-(2-methoxyethoxy)ethane (30.56 g, 0.166 mol, 1.04 eq) was added, the solution heated to 90° C. for 18 h and cooled to r.t. The reaction mixture was diluted with ethyl acetate (600 mL), washed with 1M potassium hydroxide (3×300 mL), dried (Na2SO4) and concentrated in vacuo to afford the title compound (16.50 g, 52%) as an orange oil. 1H NMR (500 MHz, (CD3)2CO) δ: 7.27 (dt, J=8.5 Hz, 1 Hz, 2H), 6.94 (dd, J=8 Hz, 1 Hz, 2H), 6.92 (dt, J=8 Hz, 1 Hz, 1H), 4.12 (t, J=5 Hz, 2H), 3.80 (t, J=5 Hz, 2H), 3.64 (t, J=5 Hz, 2H), 3.50 (t, J=5 Hz, 2H), 3.29 (s, 3H).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:15]=1[SH:23]>>[N+:10]([C:3]1[CH:4]=[C:5]([C:7](=[O:9])[CH3:8])[S:6][C:2]=1[S:23][C:15]1[C:14]([F:13])=[C:19]([F:20])[CH:18]=[C:17]([F:21])[C:16]=1[F:22])([O-:12])=[O:11]
Reactant: Fc1cc(F)c(F)c(S)c1F
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2c(F)c(F)cc(F)c2F)s1
Yield: 17.4 %

Procedure:
Prepared by a similar procedure to that described for example 18 from the 1-(5-chloro-4-nitro-2-thienyl)ethanone (200 mg, 0.98 mmol) and 2,3,5,6-tetrafluorobenzenethiol (178 mg, 0.98 mmol) to afford the title product as a solid (60 mg, 18% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.54 (1H, s), 8.41 (1H, m). MS m/z: 349.75 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([N:27]([CH3:35])C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54].C([O-])([O-])=O.[Cs+].[Cs+].[ClH:61]>O1CCOCC1.C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[ClH:37].[ClH:61].[ClH:37].[Cl:37][C:38]1[CH:43]=[C:42]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:13]3[NH:14][C:15]2[CH:20]=[N:19][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][CH3:35])[CH2:22]3)=[CH:17][CH:16]=2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CNC1CCCN(c2ccc(Nc3c(C(C)=O)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Temperature: 80 °C
Yield: 91.9 %

Procedure:
To a suspension of tert-butyl (1-(5-((3-acetyl-6-bromoquinolin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)(methyl)carbamate (80 mg, 0.144 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (80 mg, 0.28 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2CO3 (1.0 M in H2O, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80° C. for 2 h. The solution was allowed to cool to room temperature, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded a brown solid. This solid was dissolved in THF (3 mL), water (2 mL) and HCl (6 M in water, 2 mL, 12 mmol). The reaction mixture was heated at 65° C. for 3 h, cooled to room temperature and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The residue was dissolved in methanol (8 mL) and HCl (6 M in water, 1.0 mL, 6 mmol) was added. The resultant solution was concentrated to give the desired product (55.4 mg, 60%) as an orange solid. 1H NMR (500 MHz, MeOD) δ 9.30 (s, 1H), 8.29-8.21 (m, 2H), 8.06-8.00 (m, 2H), 7.83 (dd, J=9.1, 2.7 Hz, 1H), 7.30 (s, 2H), 7.30-7.26 (m, 1H), 4.47 (br s, 1H), 3.98 (d, J=13.4 Hz, 1H), 3.63 (br s, 1H), 3.50-3.40 (m, 1H), 3.37-3.32 (m, 1H), 2.80 (s, 3H), 2.80 (s, 3H), 2.30-2.23 (m, 1H), 2.03-1.95 (m, 1H), 1.88-1.69 (m, 2H). ESI MS m/z 536 [C28H27Cl2N5O2+H]+; HPLC>99% (AUC), tR=10.17 min.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([C:28]2[O:29][CH:30]=[CH:31][CH:32]=2)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[H][H]>C(O)C.[Pd]>[CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([CH:28]2[CH2:32][CH2:31][CH2:30][O:29]2)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ncc(-c2ccco2)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCOc1ncc(C2CCCO2)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1

Procedure:
A solution of the title compound from example 12 (50 mg, 0.11 mmol) in ethanol (10 ml) was charged with 10% Pd on carbon (15 mg) and stirred at room temperature for 6 h under 60 psi of hydrogen. After removal of the catalyst by filtration, the reaction mixture was concentrated in vacuo and purified by column chromatography (eluting with methylene chloride to 98:2 methylene chloride:methanol) to afford the title compound as a white solid after precipitation from diethyl ether (15 mg, 0.03 mmol).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:11]1[O:15][CH2:14][CH2:13][O:12]1.[Li]CCCC.[B:21](OC(C)C)([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24]>C1COCC1>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][CH3:10])[C:2]=1[B:21]([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24]
Reactant: CCOc1cccc(C2OCCO2)c1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cccc(C2OCCO2)c1B(OC(C)C)OC(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To the solution of 2-(2-bromo-3-ethoxyphenyl)-1,3-dioxolane (132 g, 0.48 mol) in anhydrous THF (500 mL) was dropwise added n-BuLi (2.5 M in THF, 386 mL, 0.97 mol) at −78° C. under nitrogen protection. The mixture was stirred at −78° C. for 2 h and then triisopropyl borate (227 mL, 0.97 mol) was dropwise added. The resulting mixture was stirred at this temperature for 4 h. After the reaction was quenched by adding saturated aqueous NH4Cl solution (200 mL), the resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give the target compound (136 g, yield 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:48]([NH2:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C=O)C.CCOCC.CCOC(C)=O>[CH2:48]([NH:55][C:20]([CH:17]1[CH2:18][CH2:19][N:14]([C:12]([C:8]2[N:7]([CH2:6][C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:11]=[CH:10][CH:9]=2)=[O:13])[CH2:15][CH2:16]1)=[O:22])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C1CCN(C(=O)c2cccn2Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(NCc1ccccc1)C1CCN(C(=O)c2cccn2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
The following was dissolved in anhydrous DMF (3 mL): 1-(1-(4-chlorobenzyl)-1H-pyrrole-2-carbonyl)piperidine-4-carboxylic acid (115 mg, 0.332 mmol), Hunig's Base (0.174 ml, 0.995 mmol), EDC (76 mg, 0.398 mmol), HOBt (60.9 mg, 0.398 mmol), and benzylamine (0.040 ml, 0.365 mmol). This was stirred at room temperature for 1 day with 3 Å molecular sieves. At this time, a 1:1 solution of EtOAc:Et2O (20 mL) was added and the organic layer was washed with 10% aq. Na2CO3 (2×10 mL) and brine (1×10 mL). The organic solution was then dried (anhydrous MgSO4) and concentrated in vacuo. Trituration in Et2O provided 101 mg of the title compound as a fine, ruddy brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O>[CH:19]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Reaction time: 24 h
Yield: 83.2 %

Procedure:
A mixture of 3-hydroxy-4-methoxybenzaldehyde (100 grams (g hereinafter), 0.66 moles (mol hereinafter)), potassium carbonate (100 g, 0.73 mol) and bromocyclopentane (80 miliLiters (mL hereinafter), 0.79 mol) in dimethylformamide (0.5 Liters (L hereinafter)) was heated under an argon atmosphere at 100° Centigrade (C hereinafter). After 22 hours (h hereinafter), additional bromocyclopentane (10 mL, 0.1 mol) and potassium carbonate (20 g, 0.14 mol) were added and heating was continued for 24 h. The mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between ether and aqueous sodium carbonate. The organic extract was washed with aqueous sodium carbonate and dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 2:1 hexanes/ether to provide a pale yellow oil (121 g, 84%). Analysis Calc. for C13H16O3 :C 70.89, H 7.32; found: C 70.71, H 7.33.
Reaction SMILES: [C:1]1([C@@:7]2([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9][C@H:8]2[CH2:10][O:11]CC2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[OH:11][CH2:10][C@@H:8]1[CH2:9][C@:7]1([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@]1(c2ccccc2)C[C@H]1CO
Yield: 96.3 %

Procedure:
1,1-dimethylethyl [((1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]carbamate (8.0 g, 21.7 mmol), accessed via the method of Preparation 11B, was combined with 10% palladium on activated carbon (0.8 g) in ethyl alcohol and hydrogenated under 1 atm H2(g) for 2.5 h at ambient temperature. The catalyst was filtered off through celite and the filtrate concentrated to a colorless oil. The crude material was purified by flash chromatography (SiO2, eluted with EtOAc/hexanes (4:6)) to give the title compound (5.8 g, 20.9 mmol, 96%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35-7.25 (m, 5H), 3.52-3.48 (m, 1H), 3.35-3.30 (m, 1H), 3.23-3.19 (m, 1H), 3.10-3.07 (m, 1H), 1.45-1.37 (m, 11H), 1.04-1.04 (m, 1H), 0.87-0.84 (m, 1H). LCMS m/z 300.1 (M+Na).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:38])[N:18]([CH:28]3[CH2:31][CH:30]([C:32]([O:34]CCC)=O)[CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[OH-].[Na+].Cl.[CH3:42][Mg]Br.[Cl-].[NH4+]>O1CCCC1.O.CO>[C:32]([C@H:30]1[CH2:31][C@H:28]([N:18]2[C:17](=[O:38])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:29]1)(=[O:34])[CH3:42]
Reactant: CCCOC(=O)C1CC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)C1
Reactant: C[Mg]Br
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](C(C)=O)C2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of propyl 3-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate (5 g), 1N aqueous sodium hydroxide solution (10 mL), methanol (10 mL) and tetrahydrofuran (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1 N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained extract was dissolved in N,N-dimethylformamide (50 mL), N-methoxymethanamine hydrochloride (1.4 g), 1-hydroxybenzotriazole (2.3 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.8 g) and triethylamine (2.1 mL) were added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by purification by silica gel column chromatography was dissolved in tetrahydrofuran (20 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 8.1 mL) was added at room temperature. The reaction mixture was stirred for 3 hr, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.3 g, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:20][O:21][CH2:22][CH:23]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][CH2:22][O:21][CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCC=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COCCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (400 mg, 1.22 mmol) and 2-methoxyacetaldehyde (1.3 mg, 17.56 mmol) in 7 ml of dichloroethane, acetic acid (0.42 mL, 7.33 mmol) was added and stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (777 mg, 3.66 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was then neutralized with sat. NaHCO3 and extracted with DCM, and the organic layer was dried over Na2SO4, concentrated under reduced pressure to get 260 mg of crude product.