Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[O:18][CH3:19])[C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:20]OC1C=CC(Br)=CC=1CCC(OCC)=O.[NH2:36][C:37]1[CH:42]=N[CH:40]=[CH:39][N:38]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:17][C:15]1[CH:14]=[CH:13][C:12]([O:18][CH3:19])=[C:11]([CH2:10][C:2]2[N:38]3[CH:39]=[CH:40][CH:20]=[CH:42][C:37]3=[N:36][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:16]=1
Reactant: CCOC(=O)C(=O)C(Br)Cc1cc(Br)ccc1OC
Reactant: Nc1cnccn1
Reactant: CCOC(=O)CCc1cc(Br)ccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1nc2ccccn2c1Cc1cc(Br)ccc1OC
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of 11.94 g of the 3:2 mixture of ethyl 3-bromo-4-(2-methoxy-5-bromophenyl)-2-oxobutanoate and ethyl 3-(2-methoxy-5-bromophenyl)propanoate in 150 mL of ethanol is treated with 2.85 g (30.0 mmol) of 2-aminopyrazine and heated to reflux temperature for 16 hr. The reaction mixture is cooled to room temperature and treated with 10 g of potassium carbonate. The mixture is filtered through Celite and the solvent removed in vacuo to yield the crude material. The resulting residue is flash chromatographed with initially 1% methanol in dichloromethane and then 3% methanol in dichloromethane to afford 3.7 g (48% based on starting material) ethyl 3-[(5-bromo-2-methoxyphenyl)methyl]-imidazolo[1,2-a]pyridine-2-carboxylate.
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@@H:2]([NH:1][C:30](=[O:31])[CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)[C:3]1=[O:20]
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Product: COc1cccc(CC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3-(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylacetyl chloride. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.: m.p 198°-199° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].Br[CH2:17][CH2:18][OH:19]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][CH2:17][CH2:18][OH:19])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: OCCBr
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: OCCNc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 56.5 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)aniline (4.6 g) in 2-bromoethanol (25.0 g) was stirred at 70° C. for 14 hr, and concentrated under reduced pressure. The residue was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate/hexane) to give 2-{[3,5-bis(trifluoromethyl)phenyl]amino}ethanol (3.1 g, 58%) as a brown powder.
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3]([OH:5])=[O:4].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[NH:24][N:23](Cl)[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O.C(OCC)(=O)C>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[NH:24][N:23]([NH:1][CH:2]([CH:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]([OH:5])=[O:4])[N:22]=1
Reactant: COC1=CC(OC)=NN(Cl)N1
Reactant: NC(C(=O)O)C1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC1=CC(OC)=NN(NC(C(=O)O)C2c3ccccc3-c3ccccc32)N1
Temperature: 80 °C
Reaction time: 13 h
Yield: 28.9 %

Procedure:
2.29 g (9.6 mmol) of 2-amino-2-(9-fluorenyl)acetic acid, 0.70 g (4.0 mmol) of 4,6-dimethoxy-2-chlorotriazine and 0.51 g (4.8 mmol) of sodium carbonate were introduced into a mixture of 16 ml of DMF and 16 ml of water and stirred at 80° C. for 13 hours. Then ethyl acetate and water were added and the phases were separated. The aqueous phase was acidified with 6 normal HCl and extracted three times with ethyl acetate. The organic phases were dried with MgSO4 and concentrated. The crude product was chromatographed on silica gel with ethyl acetate/n-heptane (1:1). 0.44 g (29.1%) of a white powder was obtained; RF=0.135, melting point 182-186° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:14]=[CH2:15])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O>CCOC(C)=O.CCO.[Pd]>[NH2:1][C:4]1[C:5]([CH2:14][CH3:15])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=Cc1c(C(=O)OC)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1c(N)cccc1C(=O)OC
Yield: 97.7 %

Procedure:
A mixture of methyl 3-nitro-2-vinylbenzoate (1.1 g, 5.31 mmol), and 5% Pd/C (100 mg) in EtOAc/EtOH 1:1 (50 ml) was hydrogenated at 3 atm over night. The mixture was filtered through Celite, and the filtrate was concentrated to give the title compound 0.93 g (97%) as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:23]([NH:22][C:16]3[C:15]([Cl:14])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:21])=[N:12][C:7]=2[CH:6]=1)=[O:13])[CH3:2]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1

Procedure:
Prepared analogously to example 1c from 3,4-diamino-benzoic acid ethyl ester and 1,3-dichloro-2-thioisocyanato-benzene with DIC in DMF.
Reaction SMILES: [Cl:1][C:2]([O:4]C(Cl)(Cl)Cl)=O.[F:9][C:10]([F:46])([F:45])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:14][N:15]([C@@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[N:30]=2)[NH:25][C@H:24]([CH2:36][CH3:37])[CH2:23]1)[C:16]1[N:17]=[N:18][N:19]([CH3:21])[N:20]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:46][C:10]([F:9])([F:45])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1)[CH2:14][N:15]([C:16]1[N:17]=[N:18][N:19]([CH3:21])[N:20]=1)[C@@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:33])([F:34])[F:35])[N:30]=2)[N:25]([C:2]([Cl:1])=[O:4])[C@H:24]([CH2:36][CH3:37])[CH2:23]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Add trichloromethyl chloroformate (0.36 mL, 3.02 mmol) to a solution of (2R,4S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (1.67 g, 3.02 mmol) and triethylamine (0.84 mL, 6.04 mmol) in toluene (19 mL). Stir the mixture at room temperature under nitrogen for 3 h, then add more triethylamine (0.50 mL, 3.6 mmol) and trichloromethyl chloroformate (0.21 mL, 1.8 mmol). Stir the mixture overnight. Evaporate the solvent and purify the residue by silica gel chromatography (elution with hexane/ethyl acetate) to afford the title compound (1.83 g, 98%). MS (ES+): 616 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2O.P(Cl)(Cl)([Cl:16])=O.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:16][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[C:7]([CH3:12])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)c2cc(Cl)ccc2n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c2cc(Cl)ccc2n1
Yield: 48.1 %

Procedure:
6-Chloro-2-methyl-quinazolin-4-ol (0.75 g, 3.90 mmol, 1 eq.), phosphorous oxychloride (3.47 mL, 37.4 mmol, 9.64 eq.) and triethylamine (1.62 mL, 12.5 mmol, 3.21 eq.) were refluxed for 4 hours. The mixture was stripped twice from toluene and the residue dissolved in ethyl acetate. The organic layer was washed with saturated NH4Cl (2×), dried and stripped. The residue was flash chromatographed in 3:2 ethyl acetate/hexanes to yield 400 mg of a light yellow solid product. MS (ES+)=213/215/217 (M+H)++.
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[C:10]1=[O:33])C1C=CC=CC=1>C1COCC1.[Pd]>[F:25][C:17]1[C:18]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)=[N:19][C:12]2[N:11]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:10](=[O:33])[N:9]([OH:8])[C:14](=[O:15])[C:13]=2[CH:16]=1
Reactant: Cc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCCC4)nc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1ccc(-n2c(=O)n(O)c(=O)c3cc(F)c(N4CCCC4)nc32)cc1
Yield: 93.5 %

Procedure:
Using the method of Example 56, 20% Pd/C (20 mg), 3-benzyloxy-6-fluoro-1-(4-methylphenyl)-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example R-4, 0.16 g, 0.33 mmol) were combined in 25 mL of THF, to give 0.11 g of the title compound as a solid, mp 228-230° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26]Cl.C([O-])([O-])=O.[K+].[K+]>C(OCCCC)(=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:25][CH2:26][N:1]2[CH2:2][CH2:3][CH:4]([CH:7]3[C:13]4=[CH:14][CH:15]=[CH:16][N:12]4[CH2:11][C:10]4[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=4[O:8]3)[CH2:5][CH2:6]2)[CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Reactant: ClCCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Product: Clc1cccc(CCN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)c1

Procedure:
A mixture of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (6.05 g, 0.023 mole), 3-chlorophenethyl chloride (4.74 g, 0.027 mole), K2CO3 (10.9 g) and KI (0.1 g) in 130 ml n-butyl acetate was refluxed for 50 hours. The reaction mixture was cooled, filtered and concentrated to an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[OH:17][C:18]1[C:25]([CH3:26])=[CH:24][C:21]([CH:22]=[O:23])=[C:20]([CH3:27])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:22]([C:21]1[C:20]([CH3:27])=[CH:19][C:18]([O:17][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[C:25]([CH3:26])[CH:24]=1)=[O:23]
Reactant: Cc1cc(C=O)c(C)cc1O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C=O)cc1C
Yield: 70.9 %

Procedure:
(E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (1.0 g, 3.5 mmol) was reacted with 4-hydroxy-2,5-dimethylbenzaldehyde (0.6 g, 4.2 mmol) at room temperature for 3 hours in 20 mL of acetonitrile (CH3CN) in the presence of cesium carbonate (1.7 g, 5.2 mmol) with stirring. After concentration in a vacuum to remove the reaction solvent, the residue was stirred in water (20 mL) and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum. The residue was purified by silica gel chromatography to afford (E)-methyl 2-(2-((4-formyl-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white solid (0.88 g, yield 71%).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH2:22][CH2:23][C:24]([NH:26][CH2:27][C:28]([OH:30])=O)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[CH:7]([N:8]([CH3:9])[C:28]([CH2:27][NH:26][C:24](=[O:25])[CH2:23][CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:30])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Reactant: CNC(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)CNC(=O)CCc1ccccc1)C(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of 2.0 mmol N-(diphenylmethyl)methylamine, 2.0 mmol (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]) and 6.0 mmol DIPEA in 10 ml of acetonitrile was treated with 2.2 mmol of TBTU. After 2 hours at room temperature, the reaction mixture was concentrated, diluted with water and extracted 3 times with ethyl acetate. The organic phase was dried and the residue purified by chromatography (SiO2; dichloromethane/methanol) to give the title compound as a slightly yellowish solid.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1SC=[CH:16][CH:17]=1.[O:18]=[C:19]1[C:27]2C(=CC=CC=2)[CH:21]([S:28][CH2:29][C:30]([NH:32]C2N=CC=CN=2)=O)[N:20]1CC1SC=CC=1>>[CH2:12]([N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]1[O:1][CH2:27][C:19]([NH:20][C:21]1[S:28][CH:29]=[CH:30][N:32]=1)=[O:18])[CH2:13][CH2:17][CH3:16]
Reactant: O=C(CSC1c2ccccc2C(=O)N1Cc1cccs1)Nc1ncccn1
Reactant: O=C1c2ccccc2C(O)N1Cc1cccs1
Product: CCCCN1C(=O)c2ccccc2C1OCC(=O)Nc1nccs1

Procedure:
Compound 53 was prepared using the synthetic sequence in a manner analogous to the method described for the conversion of compound 12 to compound 16 and illustrated in Scheme 1b. 1H NMR (400 MHz, CDCl3): 611.56 (s, 1H), 7.76 (d, J=7 Hz, 1H), 7.60 (d, J=7 Hz, 1H), 7.44 (t, J=7 Hz, 1H), 7.36 (t, J=7 Hz, 1H), 7.07 (d, J=3 Hz, 1H), 6.93 (d, J=3 Hz, 1H), 5.63 (s, 1H), 3.93 (m, 1H), 3.37 (m, 1H), 2.97 (s, 2H), 1.60 (m, 2H), 1.36 (m, 2H), 0.93 (t, J=7 Hz, 3H). MS: m/z (MH+) 362.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[CH3:10][CH2:11]/[CH:12]=[CH:13]/[CH2:14]/[CH:15]=[CH:16]/[CH2:17]/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].[C:30](=[O:33])([O-])[O-:31].[Na+].[Na+].O>C1C=CC=CC=1>[C:27]([OH:28])(=[O:2])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]/[CH:19]=[CH:18]\[CH2:17]/[CH:16]=[CH:15]\[CH2:14][CH2:13][CH2:12][CH2:11][CH3:10].[C:30]([OH:31])(=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2]
Reactant: O=C([O-])[O-]
Reactant: CC/C=C/C/C=C/C/C=C/CCCCCCCC(=O)Cl
Agent: CCC(CO)(CO)CO
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Temperature: 82.22222222222223 °C

Procedure:
308.02 grams (2.30 moles) of trimethylol propane (MW-134 g/mole) were dissolved in benzene and dried by refluxing and draining the azeotrope. The dry solution was added to 3 liters of diglyme dried with sodium ribbon. The solution was warmed with stirring in a 12 liter flask to 180° F. 682 grams (2.30 moles) of linolenoyl chloride (MW-296.45 g) was added dropwise over a period of three hours. The mixture was stirred overnight at 180° F. An additional 682 grams (2.30 moles) of linolenoyl chloride was added over a period of three hours and again heated at 180° F. overnight. After cooling, an excess of sodium carbonate in a water slurry was added to the reaction mixture to remove the hydrogen chloride. The mixture was then filtered. Approximately 250 ml of hexane were added to approximately 500 ml batches of the product, placed in a separatory funnel of appropriate size and washed three times with 200 ml of deionized water to remove any unreacted TMP and acid along with the diglyme and sodium carbonate. The hexane was removed by rotary evaporation, and the product was stored over molecular sieves.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[CH2:6]([CH2:8][NH2:9])[OH:7]>>[OH:7][CH2:6][CH2:8][NH:9][CH2:1][CH:2]([OH:3])[CH2:4][OH:5]
Reactant: OCC1CO1
Reactant: NCCO
Product: OCCNCC(O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
The commercially available glycidol (0.17 mol, 11 ml) was added dropwise to stirred ethanolamine (1 eq, 1.4 mol, 84.3 ml) at 0° C. Once addition was complete the reaction was allowed to warm up to room temperature, while stirring overnight. The product was then distilled (Ethanolamine first distilled at 60° C. at 1 Torr, and the desired product at 170° C. at 1 Torr). The product was obtained a clear oil that cooled to a clear viscous syrup (0.122 mol, yield=72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[C:11]([N:14]([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([N:14]([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CN(C)C(C)(C)C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(C)(C)c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of Intermediate 76a (195 mg, 0.81 mmol), Ph3P (426 mg, 1.62 mmol) and Et3N (452 □L, 3.25 mmol) in THF (9.00 mL) at 0° C. was added hexachloroethane (385 mg, 1.62 mmol). The reaction was stirred at RT overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH. The reaction showed 50% conversion so was re-submitted to the reaction conditions overnight at 50° C. The workup and purification procedures were repeated to give the title compound (153 mg, 85%). 1H NMR (300 MHz, CDCl3): 1.60 (6H, s), 2.20 (6H, s), 7.16 (1H, ddd, J 9.9, 7.4, 2.4), 7.71 (1H, ddd, J 9.9, 5.0, 0.8), 8.89 (1H, ddd, J 4.4, 2.4, 0.8).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:40][C:39]3[CH:42]=[CH:43][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(OC(F)(F)F)cc3)C2)c1
Yield: 83 %

Procedure:
To a solution of compound 33b 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (60.8 mg, 0.136 mmol) in CH3CN (5 ml) was added 4-Trifluoromethoxybenzylbromide) (33 μl, 0.20 mmol) and diisopropylethylamine (47 μl, 0.27 mmol). The reaction was microwaved at 130° C. for 10 minutes, then diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product as a clear oil, (69.7 mg, 83%). Calcd for C34H37F6NO3 (M+H) 621.65, Found 622.3
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([OH:15])=[O:14].Cl.[NH2:25][C:26]1[N:30]2[CH2:31][CH2:32][CH2:33][N:29]2[C:28](=[O:34])[CH:27]=1.CC[O-].[Na+]>CCO.O>[CH2:8]([O:7][C:5]([C:4]1[CH:20]([C:19]2[CH:22]=[CH:23][C:16]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[C:27]2[C:28](=[O:34])[N:29]3[CH2:33][CH2:32][CH2:31][N:30]3[C:26]=2[NH:25][C:3]=1[C:2]([F:12])([F:11])[F:1])=[O:6])[CH3:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1cc(=O)n2n1CCC2
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(C(F)(F)F)Nc2c(c(=O)n3n2CCC3)C1c1ccc(C(=O)O)cc1
Yield: 51 %

Procedure:
A mixture of ethyl 4,4,4-trifluoroacetoacetate (0.3 mL, 2.05 mmol), 4-carboxybenzaldehyde (300 mg, 2.00 mmol), 3-amino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one hydrochloride (refs. R. B. Greenwald, U.S. Pat. No. 4,128,425, and E. E. Boros, F. Bouvier, S. Randhawa and M. H. Rabinowitz, J. Heterocyclic Chem., 2001, 38, 613–616.) (˜350 mg, 2.00 mmol) and NaOEt (170 mg, 2.5 mmol) in EtOH (5 mL) was heated at reflux for 24 h. The reaction mixture was diluted with water and the resulting precipitate was collected by filtration. The filter cake was triturated with EtOAc to afford the title compound as a white solid (460 mg, 1.05 mmol, 51% crude): 1H NMR (400 MHz, DMSO-d6) δ 12.79 (br s, 1H), 10.19 (s, 1H), 7.83 (d, 2H, J=8), 7.25 (d, 2H, J=8), 4.78 (s, 1H), 3.92 (q, 2H, J=7), 3.40 (m, 4H), 2.30 (m, 2H), 0.98 (t, 3H, J=7) ppm; ESI-MS m/z 436 (M−H)−;
Reaction SMILES: O1CCCCC1[NH:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14](C3CCCCO3)[N:15]=[C:16]([C:17]([F:20])([F:19])[F:18])[C:9]=12.FC(F)(F)C(O)=O>CCO.O>[F:19][C:17]([F:18])([F:20])[C:16]1[C:9]2[C:10](=[N:11][CH:12]=[N:13][C:8]=2[NH2:7])[NH:14][N:15]=1
Reactant: FC(F)(F)c1nn(C2CCCCO2)c2ncnc(NC3CCCCO3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: O
Product: Nc1ncnc2[nH]nc(C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of N,1-bis(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (intermediate G15, 88 mg, 0.237 mmol) in EtOH (5 mL), water (0.5 mL) was added. Then 2,2,2-trifluoroacetic acid (0.3 ml, 0.237 mmol) was added and the mixture was stirred at 80° C. overnight. Solvent was removed to give the title compound (45 mg, 93%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:35][CH2:36][C:37](=N)OCC.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>ClCCCl>[Si:27]([O:26][CH2:25][C@@H:13]([N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:37]1[CH2:36][Cl:35])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29]
Reactant: CCOC(=N)CCl
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 65 °C
Yield: 73.3 %

Procedure:
tert-Butyl (4S)-4-[(3-aminoquinolin-4-yl)amino]-5-{[tert-butyl(dimethyl)silyl]oxy}pentylcarbamate (1.65 g, 3.48 mmol) was dissolved in 35 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (1.18 g, 7.47 mmol) was then added and the reaction mixture was heated to 65° C. After stirring overnight, the reaction mixture was cooled and treated with 100 mL of saturated NaHCO3 solution and 100 mL of CHCl3. The layers were separated and the organic portion was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 25-100% ethyl acetate/hexanes) gave tert-butyl (4S)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentylcarbamate (1.36 g) as a golden foam.