Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[CH2:2][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:7]
Reactant: COC(=O)CBr
Reactant: CNCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN(C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Methyl bromoacetate (10 g, 65.4 mmol, 1.0 equiv) was dissolved in 100 mL of CH2Cl2 which was then cooled to 0° C. N-Methylbenzylamine (7.92 g, 65.4 mmol, 1.0 equiv) was added dropwise over a 10 min period at which time Hunig's base (21 g, 163 mmol, 2.49 equiv) was added and the reaction was allowed to warm to room temperature and was stirred for 16 h. The reaction was diluted with 50 mL of saturated bicarbarbonate and the layers were separated. The organic layer was washed once more with 50 mL of sodium bicarbonate, dried over Na2SO4, decanted and concentrated to a yellow oil which was used in the next step without further purification.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:27])[CH2:7][C:8]1[N:21]=[C:20]([N:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[C:11]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]=3[S:19][C:10]=2[N:9]=1)C.O>C1COCC1.Cl>[CH:24]1([N:22]([CH3:23])[C:20]2[C:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]=4[S:19][C:10]=3[N:9]=[C:8]([CH2:7][C:6]([OH:27])=[O:5])[N:21]=2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCCC3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1nc(CC(=O)O)nc2sc3c(c12)CCCCC3)C1CC1
Yield: 90.5 %

Procedure:
The LiOH (0.615 g, 0.0150 mol) was added to a solution of [4-(cyclopropyl-methyl-amino)-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl]-acetic acid ethyl ester (1.8 g, 0.0050 mol) in 20 ml of (5:1) THF:water, and the mixture was stirred for 18 h at ambient temperature. The solvent was reduced under vacuum and the residue was diluted with 50 ml dilute aqueous HCl. The mixture was extracted with dichloromethane (50 ml×3) and the combined organic phase was separated, dried over Na2SO4 and concentrated under vacuum. The crude was purified by chromatography on silica gel using 2% MeOH-DCM to give [4-(cyclopropyl-methyl-amino)-6,7,8,9-tetrahydro-5H-10-thia-1,3-diazabenz[a]azulen-2-yl]-acetic acid (1.5 g, 94%) as pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 15.52 (brs, 1H), 3.96 (s, 2H), 3.09 (s, 3H), 2.85-2.98 (m, 4H), 2.72-2.80 (m, 1H), 1.85-1.95 (m, 2H), 1.68-1.78 (m, 2H), 1.85-1.67 (m, 2H), 0.88-0.98 (m, 2H), 0.52-0.67 (m, 2H); LC-MS: [M+H]=332.2 m/z.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10][C:11]2[CH:12]=[CH:13][N:14]3[C:19]=2[C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([C@@H:27]([NH:29]C(=O)OC(C)(C)C)[CH3:28])=[N:15]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.O1CCOCC1>>[NH2:29][C@H:27]([C:16]1[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](=[O:20])[C:19]2=[C:11]([S:10][C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[CH:12]=[CH:13][N:14]2[N:15]=1)[CH3:28]
Reactant: COc1ccc(Sc2ccn3nc([C@H](C)NC(=O)OC(C)(C)C)n(-c4ccccc4)c(=O)c23)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Sc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)cc1F
Yield: 98 %

Procedure:
(S)-tert-Butyl (1-(5-((3-fluoro-4-methoxyphenyl)thio)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (226 mg, 0.44 mmol) was treated with a solution of hydrochloric acid in dioxane (4M, 2.2 mL, 8.8 mmol) according to the method described in Preparation 1 to obtain 293 mg (95% purity, 98% yield) of the title compound as a hydrochloride salt that was used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32](=[NH:35])[NH:33][OH:34])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:36].[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38].[H-].[Na+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32]3[NH:35][C:37](=[O:38])[O:34][N:33]=3)=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:36]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C(=N)NO)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2noc(=O)[nH]2)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a solution of 3-[2-chloro-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)-phenyl]-5-hydroxycarbamimidoyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.1 g) in N,N-dimethylformamide (2 mL) was added 1,1′-carbonyldiimidazole (62 mg) at room temperature. To the mixture was added sodium hydride (55%, 38 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water under ice-cooling, and the mixture was stirred for 30 minutes. The mixture was acidified by adding 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (62 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:28]=[N:29][N:30]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:31]=3)=[CH:17][CH:16]=2)[C:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:57](OCC)=O.[OH-].[Na+]>O1CCCC1.O>[CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:28]=[N:29][N:30]([C:32]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:31]=3)=[CH:19][CH:20]=2)[C:10]2[CH2:9][N:8]([CH3:57])[CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCNC2
Reactant: CCOC=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCN(C)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of 2-ethyl-5,6,7,8-tetrahydro-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,6-naphthyridine (500 mg) in dry tetrahydrofuran (THF) (2 ml) was added dropwise over a period of 20 minutes to a stirred suspension of lithium aluminium hydride (116 mg) in dry THF (2 ml) under an atmosphere of argon. The mixture was cooled to 0° C. and ethyl formate (173 mg) was added dropwise over a period of 10 minutes. The mixture was stirred for 1 hour and then water (0.12 ml), 4M sodium hydroxide solution (0.12 ml) and water (0.36 ml) were added successively. Stirring was continued for 10 minutes, and then insoluble material was removed by filtration and washed with ether (50 ml). The combined filtrate and washings were evaporated to dryness and the residue purified by flash chromatography, eluting with a mixture of methanol and dichloromethane (1:9 v/v). to give 2-ethyl-6-methyl-5,6,7,8-tetrahydro-4-[ (2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)-methoxy]-1,6-naphthyridine (240 mg), as a pale yellow solid, m.p. 143°-144° C.; NMR (d6 -DMSO, d4 -acetic acid): 1.2(t,3H), 2.65(q,2H), 2.95(s,4H), 3.65(s,2H), 5.15(s,2H), 6.8-6.9(m,7H), 7.1(d,2H), 7.3-7.7 (complex m,14H), 7.85(dd,1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([C:25]5[CH:29]=[N:28][NH:27][CH:26]=5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cccc(-c3cn[nH]c3)c21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2c(cccc2-c2cn[nH]c2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36]>C(#N)C.O>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:36][CH:35]=[CH2:34])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C=CCN1CCC(N(Cc2ccccc2)c2ccc(C(=O)N(CC)CC)cc2)CC1
Reaction time: 144 h
Yield: 39.7 %

Procedure:
To a solution of N,N-diethyl-4-[benzyl(piperidin-4-yl)amino]benzamide (Compound 8) (0.25 g, 0.684 mmole) in 10 mL of acetonitrile was added potassium carbonate (0.10 g, 0.752 mmole) and allyl bromide (0.08 g, 0.684 mmol). The reaction mixture was stirred for six days under Argon and then was diluted with water (50 mL). This solution was extracted three times with dichloromethane (50 mL). The organic extracts were combined, washed with sodium carbonate solution, dried (Na2SO4), and concentrated to provide a yellow foam. This material was purified on a flash silica gel column (5% methanol-chloroform to 10% methanol-chloroform) to provide 0.11 g (40%) of N,N-diethyl-4-[benzyl(1-allylpiperidin-4-yl)amino]benzamide as a colorless oil. MS (ES), m/z 406 (MH+). 300 MHz 1H NMR (CDCl3) δ1.17 (t, J=7.0 Hz, 6H), 1.68-1.90 (m, 4H), 2.06 (br t, J=10.6 Hz, 2H), 2.91-3.08 (m, 4H), 3.31-3.52 (m, 4H), 3.75-3.92 (br m, 1H), 4.52 (s, 2H), 5.09-5.25 (m, 2H), 5.75-5.95 (m, 1H), 6.65 (d, J=8.7 Hz, 2H), 7.15-7.38 (m, 7H).
Reaction SMILES: [C:1]1([S:11]([NH:14][C@@H:15]([CH2:19][NH:20][C:21](=[O:39])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)=[CH:24][CH:23]=2)[C:16]([OH:18])=[O:17])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH:45](O)([CH3:47])[CH3:46]>>[CH:45]([O:17][C:16](=[O:18])[C@@H:15]([NH:14][S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12])[CH2:19][NH:20][C:21](=[O:39])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:37][CH2:36][CH2:35][CH2:34][N:33]=2)=[CH:24][CH:23]=1)([CH3:47])[CH3:46]
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)O)cc1)NC1=NCCCN1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2ccccc12
Reaction time: 72 h

Procedure:
1.5 g of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid was dissolved in 250 ml of isopropanol and 1 ml of concentrated sulfuric acid was added. The reaction solution was boiled for 3 days. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted once with dichloromethane and the combined organic phase was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetonitrile and added to water. This mixture was lyophilized. Yield 950 mg. MS (ES+): m/e=594.4 (M+H)+.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[N:9][S:10][CH:11]=1)(=O)=O.[F:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH:23]=[C:24]([F:27])[C:25]=1O>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:7]([CH2:6][O:5][C:25]3[C:24]([F:27])=[CH:23][C:22]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:21][C:20]=3[F:19])=[CH:11][S:10][N:9]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Br)cc1
Product: O=C(O)CCc1cc(F)c(OCc2csnc2-c2ccc(Br)cc2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(4-bromophenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.71 (d, J=6.8 Hz, 2H), 6.76 (d, J=7.2 Hz, 2H), 5.15 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:32])[N:4](CC2C=CC(OC)=CC=2OC)[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[CH:9][C:8]([O:19][CH3:20])=[CH:7][CH:6]=2.CSC>FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:3](=[O:32])[NH:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[CH:9][C:8]([O:19][CH3:20])=[CH:7][CH:6]=2
Reactant: COc1ccc(Cn2c(=O)c(N)c(-c3cccc(F)c3)c3cc(OC)ccc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: COc1ccc2[nH]c(=O)c(N)c(-c3cccc(F)c3)c2c1
Reaction time: 48 h

Procedure:
To a solution of 3-amino-1-(2,4-dimethoxybenzyl)-4-(3-fluorophenyl)-6-methoxyquinolin-2-(1H)-one (62 mg, 0.143 mmol) in 3 mL of trifluoroacetic acid was added dimethyl sulfide (0.30 mL). After stirring for 2 days, the reaction was heated to reflux for 3 hours, then concentrated in vacuo. The crude residue was purified by flash chromatography through SiO2 (1-3% MeOH/CH2Cl2) to provide the titled product as a yellow solid. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C16H13FN2O2 (M+H+): 285.1034. Found 285.1029.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-])=O)=[C:4]([Cl:14])[CH:3]=1>O1CCOCC1.[Ni]>[Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([NH2:11])=[C:4]([Cl:14])[CH:3]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1cc(N)c(Cl)cc1Cl

Procedure:
87.0 g (0.37 mol) of 1,3-dichloro-4,6-dinitrobenzene are dissolved in 1.5 liters of dioxane and, after adding a total of 100 g of Raney Ni, hydrogenated at 40° to 80° C. The catalyst is filtered off and washed with dioxane and the filtrate is concentrated. The product obtained in this way is recrystallised from hexane/toluene. Yield: 40.6 g; melting point 138°-141° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][CH2:18]1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[OH:45]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[N:17]2[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][CH2:18]2)=[CH:3][C:2]([C:34]2[CH:33]=[CH:32][C:31]([OH:45])=[C:30]([O:29][CH3:28])[CH:35]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(C1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1)N(C)C
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(C(C)N(C)C)CC4)c3c2)ccc1O
Yield: 56.6 %

Procedure:
Following general procedure F, (6-bromo-4-{4-[1-(dimethylamino)ethyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (42 mg, 0.097 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (36 mL, 0.146 mmol) to afford the desired product (26 mg, 56%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 8.82 (s, 1H), 8.29 (d, J=1.6 Hz, 1H), 8.19-7.97 (m, 2H), 7.31 (d, J=2.1 Hz, 1H), 7.23 (dd, J=8.2, 2.1 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 3.98 (s, 3H), 3.61 (t, J=12.8 Hz, 2H), 3.48-3.36 (m, 1H), 3.27-3.17 (m, 2H), 2.98-2.84 (m, 5H), 2.67-2.56 (m, 1H), 2.11-1.73 (m, 5H), 1.40 (d, J=6.8 Hz, 3H), 1.34-1.23 (m, 6H); ESI MS m/z 474 [C29H35N3O3+H]+; HPLC 98.6% (AUC), tR=9.95 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.C(N(CC)CC)C.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1.CCOC(C)=O>[CH3:24][O:25][CH2:26][C:27]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:28]
Reactant: COCC(=O)Cl
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1 g, 4.56 mmol) in THF (20 ml) was added triethylamine (0.95 ml, 6.84 mmol) and methoxyacetyl chloride (0.417 ml, 4.56 mmol) dropwise, the resulting mixture was stirred for 2 hours at RT. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4) filtered and concentrated in vacuo to give the product (1.2 g) as an orange oil.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][C:8]1([CH3:47])[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][NH:15][C:16]([C:18]1[CH:19]=[C:20]([NH:25][C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[C:35]([C:37]4[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[C:39]([F:46])[CH:38]=4)[CH:34]=[CH:33][C:32]=23)=[O:27])[C:21]([CH3:24])=[N:22][CH:23]=1)=[O:17].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH3:7][C:8]1([CH3:47])[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][NH:15][C:16]([C:18]1[CH:19]=[C:20]([NH:25][C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[C:35]([C:37]4[CH:45]=[CH:44][C:40]([C:41](=[O:42])[NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[C:39]([F:46])[CH:38]=4)[CH:34]=[CH:33][C:32]=23)=[O:27])[C:21]([CH3:24])=[N:22][CH:23]=1)=[O:17]
Reactant: Cc1ncc(C(=O)NCCN2CCCC2(C)C)cc1NC(=O)c1cnn2cc(-c3ccc(C(=O)O)c(F)c3)ccc12
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(C(=O)NCCN2CCCC2(C)C)cc1NC(=O)c1cnn2cc(-c3ccc(C(=O)NC(C)(C)CO)c(F)c3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-amino-2-methylpropan-1-ol (12.64 mg, 0.142 mmol), 4-(3-(5-(2-(2,2-dimethylpyrrolidin-1-yl)ethylcarbamoyl)-2-methylpyridin-3-ylcarbamoyl)pyrazolo[1,5-a]pyridin-6-yl)-2-fluorobenzoic acid (72 mg, 0.129 mmol) and triethylamine (0.054 ml, 0.387 mmol) in DCM (5 ml) was treated with HATU (53.9 mg, 0.142 mmol) and DMF (1 ml). After stirring at RT for 3 hrs, the reaction mixture was diluted with DCM and washed with sat NaHCO3 and H2O. The organic portion was separated, dried MgSO4 and concentrated in vacuo. The product was purified by flash column chromatography on silica eluting with 0-25% 2M NH3 in MeOH/DCM. The product fractions were combined and concentrated to afford an orange oil which was triturated with EtOAc/hexane to afford a pale brown solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.N.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][N:23]2[C:27]3[CH:28]([CH2:31][C:32](O)=[O:33])[CH2:29][CH2:30][C:26]=3[N:25]=[C:24]2[CH:35]([CH3:37])[CH3:36])[CH:18]=[CH:19][C:20]=1[Cl:21]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][N:23]2[C:27]3[CH:28]([CH2:31][C:32]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:33])[CH2:29][CH2:30][C:26]=3[N:25]=[C:24]2[CH:35]([CH3:37])[CH3:36])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(CC(=O)O)CC2
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: N
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(CC(=O)OCc1ccccc1)CC2
Temperature: 0 °C

Procedure:
Benzyl alcohol (0.193 mL), DMAP (16.96 mg) and EDC (195 mgl) were successively added to a stirring solution of Example 9 (340 mg) in dichloromethane (5 mL) cooled at 0° C. under nitrogen. The RM was warmed to room temp and left stirring under nitrogen atm. overnight. The reaction mixture was partitioned between dichloromethane (10 mL) and water (10 mL). The aqueous phase was again extracted with DCM (20 ml). The 2 phases were separated; the organic extract was dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (380 mg). LC/MS MH+ 457, 459, Rt 3.55 min (5 minute run).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:21].CN(C)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>ClCCCl.C(OCC)(=O)C.O>[Cl:21][C:14]1[C:15]2[CH2:16][CH2:17][N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=c1[nH]cnc2c1CCN(c1ncccc1Cl)C2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Yield: 32.4 %

Procedure:
7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (900 mg, 3.4 mmol) was dissolved in anhydrous 1,2-dichloroethane (100 mL) and stirred under N2(g) atmosphere. To the mixture was added POCl3 (2.6 mL, 27 mmol), followed by N,N-dimethylaniline (0.44 mL, 3.49 mmol). The mixture was refluxed for 2 h and the solvents were removed under vacuum to give a red residue. The residue was dissolved in 20 ml of ethyl acetate and 20 ml of water was added. The solution was neutralized with ice and solid NaHCO3. After neutralization, ethyl acetate was added and the organic layer was washed with water and brine. The organic layer was dried over Na2SO4 and the solvents were removed under vacuum. The resulting red residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as yellow crystals (0.31 g, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(NC(C)C)(C)C.C1C=CC(N[S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:16][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: COc1cc(O)ccc1CN1CCCCC1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a stirred solution of 3-methoxy-4-piperidin-1-ylmethylphenol (456 mg, 2.06 mmol) and diisopropylamine (0.77 mL, 4.54 mmol) in DCM (10 mL) at 0° C. was added N-phenyltriflamide (958 mg, 2.68 mmol). After the addition was complete the reaction mixture was allowed to warm to ambient temperature and then stirred overnight. The reaction mixture was concentrated under reduced pressure and then purified by flash chromatography (silica, 40 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a colourless oil (408 mg, 56%). NMR (CDCl3, 300 MHz): 7.60 (d, J=8.4 Hz, 1H), 6.93 (dd, J=8.4, 2.4 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 3.93 (s, 2H), 3.89 (s, 3H), 2.87-2.74 (m, 4H), 1.82-1.75 (m, 4H), 1.57-1.50 (m, 2H).