Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.N.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2cccc(Cl)c2C1=O
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(C(N)=O)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7 g (20.5 mmol) of 1-[[7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole are suspended in 20 ml of N,N-dimethylformamide, whereupon the suspension is treated with 3.5 ml (about 46 mmol) of a 25 percent aqueous ammonia solution, the mixture is stirred at room temperature for 1 hour and then poured into 10 ml of water. The product is filtered off under suction after 1 hour, rinsed with water and dried at 80° in a high vacuum. There is obtained 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide of melting point 266°-268°.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20]CC)=[O:19])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[O:34][CH3:35])=[O:3].[OH-].[Li+]>CO>[NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[O:34][CH3:35])=[O:3]
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CCC)cccc1OCC(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CCC)cccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 42 (90 mg, 0.1845 mmol) and 369 μl of 1 M lithium hydroxide were added to 2.0 ml of methanol, and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum, 10 ml of water was added, and the solution was acidified with dilute hydrochloric acid then stirred for 1 hour. The white precipitate that formed was removed by filtration and dried at 40° C. in a vacuum oven to give the product.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]([C:14]([O:16]CC)=[O:15])([C:9]([O:11]CC)=[O:10])[O:5][CH2:6][C:7]=1[CH3:8].[OH-].[K+]>O1CCCC1>[CH3:1][C:2]1[CH2:3][C:4]([C:14]([OH:16])=[O:15])([C:9]([OH:11])=[O:10])[O:5][CH2:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(C)=C(C)CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=C(C)CC(C(=O)O)(C(=O)O)OC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Part B. A solution of the ester compound prepared in Part A above (9.63 g, 37.6 mmol) in tetrahydrofuran (150 mL) was treated with an aqueous solution of potassium hydroxide (150 mL, 10N, 1.5 mol), and stirred vigorously at ambient temperature for 48 hours. The solid salt was collected by filtration, and neutralized by dissolving into 1N aqueous hydrochloric acid (200 mL). This was extracted with ethyl acetate (2×200 mL), and the extracts were combined, dried over anhydrous sodium sulfate, filtered and evaporated to afford the product, 3,6-dihydro-4,5-dimethyl-2H-pyran-2,2-dicarboxylic acid, as a waxy solid (7.46 g, 37.3 mmol, 99%). 1H NMR (CDCl3): δ 4.16 (2H, br s); 2.57 (2H, br s); 1.68 (3H, br s); 1.51 (3H, br s). Mass spectrum (NH3 -CI/DDIP): no M+H+ observed.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([SiH2][O:42][C:43](C)(C)[C@@H:44]1[CH2:49][O:48][CH2:47][CH2:46][NH:45]1)(C)(C)C.[OH-].[Na+]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][C@H:44]3[CH2:43][OH:42])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1COCCN1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1-c1cc(N2CCOC[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 29.1 %

Procedure:
A mixture of 0.30 g (0.56 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.17 g (0.73 mmol) (S)-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine, 0.01 g (0.03 mmol) cetyltrimethylammonium bromide, 0.029 g (0.056 mmol) bis(tri-t-butylphosphine)palladium(0), 0.07 ml NaOH 50% and 3 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under argon at 90° C. for 3 h. After cooling to room temperature the mixture was diluted with water and extracted with three portions of toluene. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was dissolved in a mixture of 10 ml methanol and 0.5 ml concentrated aqueous hydrochloric acid solution. After stirring at room temperature for 90 min. the reaction mixture was neutralized with 0.5 M aqueous sodium hydroxide solution and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.10 g (30%) of the title compound as an off-white solid.
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:20])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:20][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1
Reactant: O=C1CCCN1[C@H]1CC[C@@H](O)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCN1[C@H]1CC[C@H](F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one in CH2Cl2 at −30° C., add 786 mL of DAST dropwise. Allow the resulting mixture to warm up to room temp and let stand for 1 h. To the solution, add 10 mL of 5% aq NaHCO3 and allow to stand at room temp for 1 h. Extract the aqueous layer by CH2Cl2 twice (2×10 mL) and then dry the organic layer over Na2SO4, filter and concentrate. Purify the crude material by chromatography to yield the title compound: mass spectrum (m/z): 186 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@@H:7]2[CH2:8][C@H:3]1[CH2:4][CH2:5][C:6]2=O.Cl.[CH3:12][O:13][NH2:14].N1C=CC=CC=1>C(O)C>[CH3:12][O:13][N:14]=[C:6]1[CH2:5][CH2:4][C@H:3]2[CH2:8][C@@H:7]1[C:2]2([CH3:10])[CH3:1]
Reactant: CON
Reactant: CC1(C)[C@@H]2CCC(=O)[C@H]1C2
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CC[C@H]2C[C@@H]1C2(C)C
Yield: 89.9 %

Procedure:
To a solution of (1S,5R)-6,6-dimethylnorpinan-2-one (3.09 g, 22.35 mmol) in ethanol (70 mL) was added O-methylhydroxylamine hydrochloride (2.05 g, 24.59 mmol) and pyridine (1.29 mL, 15.92 mmol). Heated reaction mixture to 80° C. for 4 hours. Removed solvent under reduced pressure. Diluted residue with 1N HCl and extracted twice with ether. The combined organic phases were washed with aqueous saturated NaHCO3, dried (MgSO4), filtered, concentrated in vacuo to afford 3.36 g of a colorless oil (mixture of oxime isomers) that was used without further purification.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:22]([P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[CH2:23]>CC#N>[CH2:26]([O:25][P:24]([CH2:22][CH2:23][N:18]1[CH2:19][CH2:20][O:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:17]1)(=[O:31])[O:28][CH2:29][CH3:30])[CH3:27]
Reactant: C=CP(=O)(OCC)OCC
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Solvent: CC#N
Product: CCCCCCCCOc1ccc(C2CN(CCP(=O)(OCC)OCC)CCO2)cc1
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A mixture of 2-(4-octyloxy-phenyl)-morpholine (0.83 g; 2.9 mmol) and diethyl vinylphosphonate (0.53 ml; 3.4 mmol) in CH3CN (10 mL) was heated under reflux for 3 days. After cooling to RT the mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO2, EtOAc: MeOH 90:10) to afford {2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethyl}-phosphonic acid diethyl ester (0.42 g)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8]C(=O)[N:6]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1.BrC1C=CC2NC(=O)N3N=CN=C3C=2C=1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:8])=[C:4]([C:5]2[NH:6][N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH:3]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c2nc(-c3ccccc3)nn12
Agent: O=c1[nH]c2ccc(Br)cc2c2ncnn12
Product: Nc1ccc(Cl)cc1-c1nc(-c2ccccc2)n[nH]1
Yield: 92.3 %

Procedure:
As described for example 21c) 9-chloro-2-phenyl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one (6.34 g, 21.4 mmol), instead of 9-bromo-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one, was converted to the title compound (5.35 g, 92%) which was obtained as a light brown solid. MS: m/e=271.0 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:22](/B(O)O)=[CH:23]\[CH2:24][CH2:25][CH2:26][CH3:27].[ClH:31]>CCOCC>[ClH:31].[CH:22](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:23]\[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCC/C=C/B(O)O
Reactant: CN1CCN(CCCNc2ccc3ncc(Br)n3n2)CC1
Agent: Cl
Solvent: CCOCC
Product: CCCC/C=C/c1cnc2ccc(NCCCN3CCN(C)CC3)nn12
Yield: 35 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2. The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (60 mg, 35%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.59 (d, J=9.7 Hz, 1H), 7.50 (s, 1H), 6.77-6.69 (m, 2H), 6.61 (d, J=16.2 Hz, 1H), 3.45 (t, J=6.7 Hz, 2H), 3.35 (m, 2H), 3.13-2.69 (m, 11H), 2.29 (q, J=6.7 Hz, 2H), 2.02-1.93 (m, 2H), 1.53-1.38 (m, 4H), 0.96 (t, J=7.1 Hz, 13C NMR (125 MHz, CD3OD) δ 155.6, 137.1, 133.8, 128.9, 127.2, 125.0, 116.5, 114.6, 56.3, 54.5, 51.8, 44.1, 40.4, 34.4, 32.9, 26.2, 23.4, 14.4; HPLC tR=8.7 min (Luna), 95.1%; ES-MS: (M+H)=357 m/z.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28]C)[CH2:25][CH:26]=O)[C:5]1=[O:30])[CH:2]=[CH2:3].[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:25][CH3:26])[CH2:28][NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC=O)C1=O
Reactant: NCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNCC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (104 mg, 0.234 mmol; Example 130, Step A) in ClCH2CH2Cl (3.9 mL) was added 2,2,2-trifluoroethylamine (74 μL, 0.94 mmol) and sodium triacetoxyborohydride (248 mg, 1.17 mmol) at rt. After being stirred at rt overnight, the reaction was quenched (sat aq. NaHCO3), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a white solid. The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2](=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]=1[N:28]=[C:29]=[O:30])([CH3:18])[CH3:17].C([N-]C(C)C)(C)C.[Li+]>>[CH3:18][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:26])[CH3:27])[C:20]=1[NH:28][C:29](=[O:30])[CH2:1][C:2](=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:17]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCCCCCC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCCCCCC(=O)CC(=O)Nc1c(C(C)C)cccc1C(C)C
Yield: 43.5 %

Procedure:
The title compound was prepared from 2-tetradecanone (5.0 g, 0.023 mol), 2,6-diisopropylphenylisocyanate (4.78 g, 0.023 mol), and lithium diisopropylamide (0.023 mol) using the procedure described in Example 1. Purification by flash chromatography (silica gel, 15% EtOAc/hexane) yielded 4.25 g (0.010 mol, 44%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:5](=[NH:19])[NH:6][C:7]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:16]([CH3:18])[CH3:17].Cl[CH2:25][CH:26]=O.C(=O)(O)[O-].[Na+].CC(O)C>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]([C:7]3[C:8]([CH:16]([CH3:17])[CH3:18])=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]([CH3:15])[CH3:14])[CH:25]=[CH:26][N:19]=2)[CH:20]=[C:21]([CH3:23])[CH:22]=1
Reactant: Cc1cc(Br)cc(C(=N)Nc2c(C(C)C)cccc2C(C)C)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(-c2nccn2-c2c(C(C)C)cccc2C(C)C)c1
Yield: 78.8 %

Procedure:
To a 250 mL round bottom flask was added 3-bromo-N-(2,6-diisopropylphenyl)-5-methylbenzimidamide (2.92 g, 7.82 mmol), 2-chloroacetaldehyde (50%, 2.456 g, 15.64 mmol), sodium bicarbonate (1.314 g, 15.64 mmol), 60 mL 2-propanol. The reaction mixture was heated to reflux overnight under nitrogen. The reaction mixture was cooled and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with 10% LiCl solution, brine, dried over magnesium sulfate, filtered, and evaporated. The material was purified by column chromatography eluting with 15 and 20% ethyl acetate/hexane to give desired product (2.45 g, 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:5]2[N:22]=[CH:23][CH:24]=[C:4]2[N:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].Cl.O1CCOCC1.[OH-].[Na+]>O.C(O)(C)(C)C>[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=3)[C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[N:5]3[N:22]=[CH:23][CH:24]=[C:4]3[N:3]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)c1cccc(Nc2cc(Cl)nc3ccnn23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1cccc(Nc2cc(Nc3cccc(Cl)c3)nc3ccnn23)c1
Temperature: 100 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
To the reaction flask, tert-butyl 3-(5-chloropyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate (2.9 g, 8.2 mmol) was added along with 3-chloroaniline (2.2 mL, 20.6 mmol), 4N HCl in dioxane (2.6 mL, 10.4 mmol), and t-butyl alcohol (41 mL). The reaction was stirred at 100° C. for 2 days then cooled to room temperature. The mixture was diluted with water, made basic with 3N NaOH, filtered and washed with water. The product, tert-butyl 3-(5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate, was collected as a solid in 55% yield after drying under vacuum overnight. LCMS (M+1=436)
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1B(O)O.C(=O)([O-])O.[Na+].COCCOC>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.O>[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(F)c(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-5-methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (174 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 90° C. for 1 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 475 mg, about 100%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][N:11]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=2)[CH:12]=1)(=O)=O.[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][NH:27][CH3:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][N:27]([CH3:28])[CH2:6][CH2:7][C:8]2[CH:9]=[N:10][N:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=3)[CH:12]=2)=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCCc1cnn(-c2cc(C#N)ccn2)c1
Reactant: CNCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1cnn(-c2cc(C#N)ccn2)c1)Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a mixture of 2-[1-(4-cyanopyridin-2-yl)pyrazol-4-yl]ethyl methanesulfonate (476 mg, 1.6 mmol) and (4-flouro-benzyl)-methyl-amine (444 mg, 3.2 mmol) in ACN (30 mL) at rt was added K2CO3 (4.5 g, 32 mmol) and KI (1.0 g, 6.2 mmol. The reaction mixture was heated to 80° C. and stirred overnight. Filtered, solvent removed and purified by prep-HPLC to give the title compound (270 mg, 50%). [M+H] Calc'd for C19H18FN5, 336. Found, 336.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH:25]([NH:28][CH3:29])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:28]([CH:25]([CH3:27])[CH3:26])[CH3:29])=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: CNC(C)C
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)N(C)C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, N-isopropylmethylamine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.49 minutes; C20H20Cl2N4O2 (419.31); mass spectrum: (M+H)+=419.2.
Reaction SMILES: [Cl:1][C:2]([Cl:24])([Cl:23])[CH2:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)CCl>[Cl:24][C:2]([Cl:1])([Cl:23])[CH2:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:34](=[O:35])[CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:37])([F:25])[F:38])=[CH:32][CH:31]=2)=[CH:16][CH:15]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CSc1ccc(CO)cc1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cc1ccc(C(F)(F)F)cc1)OCc1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.4 %

Procedure:
2-(4-Hydroxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (70 mg, 0.173 mmol) was added to a stirred mixture of (4-trifluoromethyl-phenyl) acetic acid (39 mg, 0.190 mmol), EDC×HCl (50 mg, 0.259 mmol), DMAP (2.1 mg, 0.017 mmol) and DCM (3 mL). The reaction mixture was stirred at rt overnight, according to LC-MS analysis the reaction was uncomplete. Additional EDC×HCl (50 mg, 0.259 mmol), DMAP (2.1 mg, 0.017 mmol) and 2-(4-hydroxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (70 mg, 0.173 mmol) were added and the mixture was stirred for 3 h. More DCM was added and the mixture was washed with 0.25M HCl, the organic portion was dried through a phase separator and concentrated to give the titled compound (112 mg, 100%); Mass spectrum: M−H+590.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:20]([O:22]CC)=[O:21])[N:10](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:20]([OH:22])=[O:21])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Reaction time: 8 h

Procedure:
To a suspension of ethyl 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (2.50 g, 6.85 mmol, prepared as in Example 82, Step 1) in THF (20 mL) was added 1.0 M NaOH (20 mL, 20 mmol) and the reaction was stirred overnight. Concentrated HCl was added to acidify (to pH ˜2). The product was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford a white solid. The yield was close to theoretical and the product was used without further purification.
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:14][O:15][CH2:16]Cl.O>CN(C)C=O>[CH:1]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][CH2:14][O:15][CH3:16])[CH2:2][CH2:3][CH2:4]1
Reactant: COCCl
Reactant: Oc1ccccc1C1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccccc1C1CCC1
Reaction time: 0.5 h

Procedure:
2-cyclobutylphenol (871 mg) was dissolved in N,N-dimethylformamide (5 mL), and 60% sodium hydride (1.30 g) was added to the solution at 0° C. After stirring the mixture for 30 minutes, chloromethyl methyl ether (2.1 mL) was added and the mixture was stirred for 14 hours. Water was added to the reaction solution, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to obtain the title compound (1.13 g) as a colorless oily substance.