Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:35][CH2:34]3)=[C:26]([C:28]([O:30]C)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].Cl.CCOCC>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:32][N:33]3[CH2:34][CH2:35][N:36]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH2:37][CH2:38]3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CN1CCN(c2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CN3CCN(c4ccccc4)CC3)s1)CC2
Reaction time: 8 h

Procedure:
Compound 62A (50 mg, 0.066 mmol) in DCM (3.5 ml) was treated with 2 N hydrogen chloride in ether (3.31 ml, 6.62 mmol) for 30 min. The reaction was concentrated and the residue was dissolved in THF (3 ml) and methanol (3 ml). NaOH (10% aq., 1 ml) was added. The resulting mixture was stirred overnight and concentrated. The residue was purified by purified by reverse phase HPLC (mobile phase: 0%-70% acetonitrile in 0.1% TFA aqueous solution during 40 min) to provide the title compound: 1H NMR (400 MHz, DMSO-D6) δ ppm 12.91 (1H, s), 8.02 (1H, d), 7.78 (1H, d), 7.70 (1H, d), 7.44-7.50 (2H, m), 7.41 (1H, t), 7.35 (1H, t), 7.20-7.27 (2H, m), 6.96 (2H, d), 6.84 (1H, t), 4.89 (2H, s), 4.73 (2H, s), 3.82 (2H, t), 3.45 (8H, s), 3.07 (2H, t). LCMS (APCI) m/e 611 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[Br:10]Br.S(=O)(=O)(O)[O-].[Na+]>ClCCCl.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([Br:10])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: BrBr
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Fe]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1cc(F)c(Br)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
Iron powder (16.49 g, 291 mmol) is added to 1-bromo-2,4-difluorobenzene (110 mL, 968 mmol) in 1,2-dichloroethane (968 mL) in a 3-neck flask at ambient temperature under a stream of nitrogen. A solution of bromine (59.7 mL, 1.16 mol) in 1,2-dichloroethane (968 mL) is added dropwise over 1 hour and the reaction mixture is stirred at ambient temperature for 18 h. The reaction mixture is cooled to 0° C. and a saturated aqueous solution of sodium bisulfate (1.11 L, 533 mmol) is added portionwise and the mixture is separated. The aqueous phase is extracted with dichloromethane. The organic layer is washed with a saturated aqueous solution of sodium bicarbonate, water, and brine. The organic layer is dried over sodium sulfate, and the solvent is removed under reduced pressure to give a residue purified with a pad of silica using diethyl ether to give the title compound (229 g, 76%). 1H NMR (400 MHz, CDCl3) δ 7.70 (dd, J=4.6, 6.8 Hz, 1H), 6.95-6.92 (m, 1H).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].CO[CH:7]=[C:8]([C:13](=[O:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10]>>[C:1]([NH:4][CH:7]=[C:8]([C:13](=[O:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC=C(C(C)=O)C(=O)OC
Reactant: CC(N)=O
Product: COC(=O)C(=CNC(C)=O)C(C)=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Acetamide (10.0 g) and methyl 2-methoxymethylene-3-oxobutanoate (30.0 ml) were heated with stirring at 100° C. for 4 hours. On cooling the product was flash chromatographed on Merck silica 9385 using a 50/50 mixture of ether/hexane to give the title compound (18.5 g) m.p. 60°-62° C. (hexane/ether).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:28][F:29])[CH2:7][CH2:6][N:5]([C:8]2[C:17]([O:18][CH3:19])=[C:16]3[C:11]([C:12](=[O:26])[C:13]([C:23]([OH:25])=[O:24])=[CH:14][N:15]3[CH:20]3[CH2:22][CH2:21]3)=[CH:10][C:9]=2[F:27])[CH2:4]1.S(Cl)(Cl)=O.[CH3:34]O>>[NH2:1][CH2:2][C:3]1([CH2:28][F:29])[CH2:7][CH2:6][N:5]([C:8]2[C:17]([O:18][CH3:19])=[C:16]3[C:11]([C:12](=[O:26])[C:13]([C:23]([O:25][CH3:34])=[O:24])=[CH:14][N:15]3[CH:20]3[CH2:22][CH2:21]3)=[CH:10][C:9]=2[F:27])[CH2:4]1
Reactant: COc1c(N2CCC(CN)(CF)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cn(C2CC2)c2c(OC)c(N3CCC(CN)(CF)C3)c(F)cc2c1=O

Procedure:
7-(3-Aminomethyl-3-fluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (8.9 g) obtained in Example 1 was suspended in methanol (100 ml) and thionyl chloride (3.2 ml) was dropwise added with stirring under ice-cooling. After the dropwise addition, the mixture was refluxed overnight. Methanol and excess thionyl chloride were distilled away under reduced pressure. The residue was dissolved in water and the solution was made alkaline with potassium carbonate. The mixture was extracted twice with chloroform, dried and concentrated to dryness to give 9.8 g of the object compound, melting point 143°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][OH:16])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][O:16][CH2:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: Cc1nn(C)c(Oc2ccc(Cl)cc2)c1C=NO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CON=Cc1c(C)nn(C)c1Oc1ccc(Cl)cc1
Reaction time: 5 h
Yield: 64 %

Procedure:
2.0 Grams (0.00755 mole) of 5-(4-chlorophenoxy)-1,3-dimethyl-pyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dimethylformamide, and after adding 0.5 g (0.0125 mole) of powdery sodium hydroxide, the resulting mixture was thoroughly stirred. To this solution was added 1.73 g (0.00755 mole) of methyl 2-bromomethylbenzoate, and reaction was carried out at from 70° to 80° C. for 5 hours. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 2.0 g cf the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Br:12]Br.O>ClCCl.[Fe]>[Br:12][C:7]1[C:2]([OH:1])=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=[C:5]([CH3:8])[CH:6]=1
Reactant: BrBr
Reactant: CC(=O)c1cc(C)ccc1O
Agent: [Fe]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc(C)cc(Br)c1O
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
To a solution of 21.5 g (0.143 mol) of 28 in 40 mL of dry dichloromethane, 0.3 g of iron turnings was added. A solution of 10.7 mL (34.2 g, 0.215 mol) of bromine in 100 mL of dichloromethane was added dropwise with vigorous stirring for 20 min. This mixture was refluxed for 30 min, and then 300 mL of water was added. The organic layer was separated, and the aqueous layer was extracted with 2×100 mL of dichloromethane. The combined organic extracts were washed with saturated aqueous Na2SO3, dried over K2CO3, and then evaporated to dryness. Drying the residue in vacuum gave 15.7 g (48%) of 29 (bp 105-115° C./1 mm).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[C:11]1([S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH:5]([C:21](=[O:22])[NH:20][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:18])=[O:19])[C:4](=[O:9])[CH2:3]1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: CC1(C)CC(=O)C(C(=O)NS(=O)(=O)c2ccccc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5,5-dimethyl-1,3-cyclohexanedione with benzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5,5-DIMETHYL-2-(N-BENZENESULFONYLCARBAMOYL)1,3-CYCLOHEXANEDIONE, m.p. 101°-103° C. (corr.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[P:14]([O-:19])([O:17][CH3:18])[O:15][CH3:16]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([P:14]([O:17][CH3:18])([O:15][CH3:16])=[O:19])([OH:12])[CH3:11])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: COP([O-])OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(C)(O)P(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-acetyl-benzoic acid methyl ester (1.0 g, 5.61 mmol) in THF (5.6 mL) was cooled to 0° C. and dimethyl phosphite (0.7 g, 6.17 mmol) and N,N,N′N′-tetramethyl-guanidine (0.07 g, 0.56 mmol) were added dropwise. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes. The reaction mixture was diluted with EtOAc and washed with 1N aqueous HCl (2×), brine, then dried (MgSO4) and concentrated in vacuo. The residue was purified by MPLC (Isocratic CH2Cl2 for 6 CV then 0-7.5% MeOH in CH2Cl2) to afford the title compound: MS: cal'd 289 (MH+), exp 289 (MH+)
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCN(C(=O)CO)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][OH:12])[NH:8]2)=[CH:4][CH:3]=1>C1COCC1.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:11]=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: OCc1cc2ccc(Cl)cc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To (6-chloro-1H-indol-2-yl)-methanol (37.7 mmol) in THF at 0° C. was added manganese (IV) oxide and the mixture was stirred at rt for 16 h. The mixture was filtered over celite and rinsed with THF and EtOAc and evaporated to near dryness. The solid was filtered and washed with cold EtOAc/hex to give 6-Chloro-1H-indole-2-carbaldehyde (62%, 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[NH:12][CH2:13][CH3:14].Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1>CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[CH:26][CH:25]=1)[C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[NH:12][CH2:13][CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: CCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCNC1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)OC(C)(C)C)cc2)c2ccc(Cl)cc21
Yield: 47.5 %

Procedure:
This compound is prepared according to the procedure described in step A of EXAMPLE 96 from 1.19 g of 5-chloro-3-(2-chlorophenyl)-3-(ethylamino)-1,3-dihydroindol-2-one and 1.1 g of tert-butyl 4-bromomethylbenzoate. Chromatography on silica using a gradient of a hexane/AcOEt mixture (from 95/5; v/v to 90/10; v/v) as the eluent gives 0.9 g of the expected product, which is used as such.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][N:15]([CH2:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:16]2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([S:32](Cl)(=[O:34])=[O:33])([CH3:31])[CH3:30]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][N:11]1[CH2:12][CH:13]2[O:19][CH:17]([CH2:16][N:15]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=3)[CH2:14]2)[CH2:18]1)[S:32]([CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CN2CC3CN(CCNCc4ccccc4)CC(C2)O3)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N(CCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2)Cc1ccccc1
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
4-[7-(2-Benzylamino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-ylmethyl]-benzonitrile (0.5 g, 1.33 mmol, from step (iii) above) was taken in 30 ml of DCM/10% aq. NaHCO3 (1:1) and stirred for 15 min. Isopropane sulfonyl chloride (0.28 g, 1.99 mmol) was added and stirring continued at RT for 1.5 h. The organic layer was separated, washed with brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by purification over silica gel using 10% ethyl acetate in petroleum ether as eluent afforded the desired product (280 mg) as white solid. This was further purified by prep HPLC (0.1% TFA in acetonitrile), evaporated under reduced pressure, and the residue was partitioned between sat NaHCO3 and DCM. The organic layer was washed with brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded the title compound (140 mg) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([F:29])=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](Cl)=[O:27])=[CH:21][CH:20]=[CH:19]2.[CH2:30]([NH2:32])[CH3:31]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([F:29])=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([NH:32][CH2:30][CH3:31])=[O:27])=[CH:21][CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)Cl)cccc4c3F)c2cc1OC
Reactant: CCN
Solvent: C1CCOC1
Product: CCNC(=O)c1cccc2c(F)c(Oc3ccnc4cc(OC)c(OC)cc34)ccc12

Procedure:
6-(6,7-Dimethoxyquinolin-4-yloxy)-5-fluoro-1-naphthoyl chloride (70 mg) was stirred in a solution of 2M EtNH2 in THF (3 mL) at RT for 4 days. Solvent was evaporated and residue purified by prep plate using 5% MeOH in CH2Cl2 as the eluent. The solid obtained was rinsed with ether and dried to afford the title compound. MS (ESI pos. ion) m/z: 421.1 (M+H). Calc'd for C24H21FN2O4−420.43.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=O)=[CH:16][CH:15]=1)([O-])=O>>[Cl:10][C:5]1[C:6]([Cl:9])=[C:7]2[NH:8][C:18]([C:17]3[CH:21]=[CH:22][C:14]([NH2:11])=[CH:15][CH:16]=3)=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ncc(Cl)c(Cl)c1N
Product: Nc1ccc(-c2nc3ncc(Cl)c(Cl)c3[nH]2)cc1

Procedure:
By at procedure similar to Examples 258 and 259 but starting from 2,3-diamino-4,5-dichloropyridine (Example 206a) and 4-nitrobenzoyl chloride, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH:15]([NH2:17])[CH3:16])[N:8]=1.C([O-])(O)=O.[Na+].C1COCC1.Cl[C:33]([O:35][CH3:36])=[O:34]>C1COCC1.O>[Br:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:33](=[O:34])[O:35][CH3:36])[CH3:16])[N:8]=1
Reactant: CC(N)CNc1nccc(-c2[nH]c(C3CCC3)nc2Br)n1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C3CCC3)nc2Br)n1
Reaction time: 0.08 h
Yield: 108 %

Procedure:
A solution of S)—N1-(4-(4-bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine (0.25 g, 0.72 mmol) in THF-water (1:1, 8 mL) was cooled to 0° C. and then solid NaHCO3 (0.10 g, 1.2 mmol) was added with concomitant frothing. After 5 minutes, a THF solution of methyl chloroformate (0.1 M in THF, 4.3 mL, 0.43 mmol) was added dropwise to the mixture and the reaction was maintained overnight allowing the cooling bath to expire. LCMS indicate incomplete reaction and addition methyl chloroformate solution and NaHCO3 was added. After the reaction was deemed complete by LCMS, the reaction mixture was extracted with EtOAc. The organic phase was washed with brine and dried (Na2SO4), and concentrated to give (S)-methyl 1-(4-(4-bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate as a yellow solid (0.19 g): LCMS (m/z) 409.0 (MH+), tR=0.63 minute.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]([NH2:23])=[NH:22])[C:16]3=[O:24])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:27].[C:28]([OH:34])([C:30](F)(F)F)=O>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[NH:23][C:26]5[C:28](=[O:34])[CH:30]=[CH:6][CH:5]=[CH:4][C:3]=5[N:22]=4)[C:16]3=[O:24])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:27]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(C(=O)C2CCN([C@@H]3CCN(CC(=N)N)C3=O)CC2)cc1C
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(=O)C2CCN([C@@H]3CCN(Cc4nc5ccccc(=O)c5[nH]4)C3=O)CC2)cc1C

Procedure:
The title compound (18 mg) was prepared following the general procedures of Example 28 starting with 2-{(R)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-yl}-acetamidine (405 mg, 0.85 mmol). HRMS calculated for C27H30N4O4 474.5646. found (ESI, [M+H]+). found 475.2345. 1H NMR (400 MHz, CDCl3-d) 8 ppm 1.74-2.11 (m, 4H) 2.22-2.44 (m, 5H) 2.57 (d, J=8.03 Hz, 1H) 3.09 (d, J=6.53 Hz, 3H) 3.28-3.40 (m, 1H) 3.50 (t, J=8.28 Hz, 2H) 3.62-3.83 (m, 1H) 3.89-3.97 (m, 3H) 4.82 (br. s, 2H) 6.87 (d, J=8.53 Hz, 1H) 7.00-7.11 (m, 1H) 7.26-7.36 (m, 5H) 7.38-7.47 (m, 1H) 7.72-7.86 (m, 3H) HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.874 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:34])[NH:27][CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:22][CH:21]=1)=[O:18]>ClCCl>[CH3:31][C:30]([CH3:33])([CH3:32])[CH2:29][CH2:28][NH:27][C:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:17]([N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)=[O:18])=[CH:25][CH:24]=1)=[O:34]
Reactant: COc1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(C)CCNC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: ClCCl
Product: COc1ccc(CN2CCN(C(=O)Oc3ccc(C(=O)NCCC(C)(C)C)cc3)CC2)cc1
Reaction time: 16 h

Procedure:
The title product was prepared from 1-(4-methoxy-benzyl)-piperazine (0.35 mmol) was dissolved in dichloromethane (5 ml). 4-(3,3-Dimethyl-butylcarbamoyl)-phenyl chloroformate (0.35 mmol) was added at room temperature. The reaction mixture was stirred for 16 h and evaporated to dryness and subjected to preparative HPLC (method C). (54%, colourless semicrystaline oil). HPLC-MS m/z=454.3 (M+1), Rt: 2.78 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@H:12]1[C:24]([O:26][CH3:27])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]1[C:24]([O:26][CH3:27])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CNCC[C@@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A solution of 260C (1.01 g, 2.58 mmol) in dichloromethane (50 mL) at 0° C. was treated with TFA (5 mL). The reaction mixture was stirred at 0° C. for 1.0 hour then allowed to slowly warm to room temperature and stirred for an additional 2.0 hours. The mixture was concentrated, and then azeotropically evaporated with MeOH and toluene. The residue was dissolved in dichloromethane and washed with saturated NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give 0.61 g (yield: 81%) of Compound 260D as an oil. It was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O.N>C(#N)C>[CH:16]1([C:14]2[C:6]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=3)[CH2:11][CH2:12][N:13]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc(CCNC(=O)C2CCC2)cc1OC
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc2c(cc1OC)C(C1CCC1)=NCC2
Reaction time: 16 h

Procedure:
A mixture of N-[2-(3,4-dimethoxyphenyl)ethyl]cyclobutanecarboxamide (44 g, prepared in a similar manner to that described in Example E46), phosphorus oxychloride (150 ml) and acetonitrile (900 ml) was heated under reflux for 2.5 hours. The cooled solution was poured onto dilute aqueous ammonia solution and the product was extracted into ethyl acetate. The extracts were washed with brine, dried and the solvent removed in vacuo. The resulting oil solidified on standing for 16 hours. The solid was recrystallised from petroleum ether (b.p. 60°-80° C.) to give 1-cyclobutyl-3,4-dihydro-6,7-dimethoxyisoquinoline (20 g).
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:5]=2[O:4][C:3]1=[O:19].[OH-:20].[K+].CO>>[OH:4][C:5]1[C:10]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:2]([CH3:1])[C:3]([OH:19])=[O:20]
Reactant: CC1C(=O)Oc2c(Sc3ccccc3F)cccc21
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: CC(C(=O)O)c1cccc(Sc2ccccc2F)c1O

Procedure:
3-Methyl-7-(2-fluorophenylthio)-2,3-dihydrobenzofuran-2-one was hydrolyzed by treating with potassium hydroxide-methanol to give 2-[2-hydroxy-3-(2-fluorophenylthio)phenyl]propionic acid, mp. 116°-117° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9]CC)=[O:8])=[O:5])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([CH:6]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:7]([OH:9])=[O:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(ethoxycarbonyl)-4-(methyl)pentanoate (6 g., 28 mM) was dissolved in ethanol (9 ml.) and 4 N-aqueous sodium hydroxide (7 ml.) was added. The mixture was stirred at ambient temperature for 1 hour and then evaporated. The residue was diluted with water (30 ml.) and the aqueous solution was washed with diethyl ether (3×10 ml.). The combined ethereal washings were backextracted with water (5 ml.). The combined aqueous phases were acidified to pH 3 at 0° C. with citric acid, and the resulting oil was extracted into ethyl acetate (4×20 ml.). The combined extracts were washed with water (2×20 ml.) and dried (MgSO4). The mixture was filtered and the solvent was evaporated to give 2-ethoxycarbonyl-4-methylpentanoic acid as an oil. The structure was confirmed by NMR.