Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][C:9](=[O:16])[O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[N:4][O:5][C:6]=1[CH3:7].[C:17]([O:25][CH3:26])(=[O:24])[CH:18]([CH2:20][CH:21]([CH3:23])[CH3:22])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.CN(C=O)C>[Br:1][C:2]1[C:3]([N:8]([C:9]([O:10][CH2:11][C:12]([Cl:14])([Cl:13])[Cl:15])=[O:16])[C@H:18]([C:17]([O:25][CH3:26])=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: Cc1onc(NC(=O)OCC(Cl)(Cl)Cl)c1Br
Reactant: COC(=O)C(O)CC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1noc(C)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry degassed DMF solution (50 mL) of 2,2,2-trichloroethyl 4-bromo-5-methylisoxazol-3-ylcarbamate (2.67 g, 7.58 mmol), DL methyl leucate (2.31 g, 15.8 mmol), and triphenyl phosphine (4.11 g, 15.7 mmol) was added diisopropyl azodicarboxylate (3.1 ml, 15.7 mmol) at 0° C. over 2 hours. The reaction was allowed to warm to room temperature while stirring overnight. Water was added and the product was extracted with ether (2×) then ethyl acetate (2×), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (20% ethyl acetate/hexane) to afford methyl N-(4-bromo-5-methylisoxazol-3-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7](Cl)(=[O:9])=[O:8].[N:11]1([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=3)[N:22]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([N:14]1[CH2:13][CH2:12][N:11]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([F:27])([F:28])[F:29])=[N:24][N:25]=3)[N:22]=2)[CH2:16][CH2:15]1)(=[O:9])=[O:8]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=S(=O)(Cl)c1ccccn1
Product: O=S(=O)(c1ccccn1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 32 %

Procedure:
Obtained in 32% yield by an analogous method to Example 394, starting from pyridine-2-sulfonyl chloride and 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:25](OC)(OC)OC.CN(C=O)C>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]2[N:9]=[CH:25][NH:8][C:6]=2[CH:7]=1
Reactant: COC(OC)OC
Reactant: Nc1cc(Cl)c(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1cc2nc[nH]c2cc1Cl
Temperature: 100 °C
Yield: 79.1 %

Procedure:
A mixture of 5-chloro-2-nitro-4-trifluoromethoxy-phenylamine (2.00 g, 7.80 mmol), sodium dithionite (7.06 g, 40.5 mmol), trimethyl orthoformate (23.1 mL, 210 mmol), DMF (23 mL), and acetic acid (4.0 mL) was heated in a sealed tube for 15 h at 100° C. The reaction mixture was cooled to 23° C. and partitioned between EtOAc (100 mL) and saturated aq. NaHCO3 (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×80 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-15% MeOH/DCM) to yield the titled compound (1.46 g, 78%). MS (ESI/CI): mass calcd. for C8H4ClF3N2O, 236.0; m/z found, 237.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.11 (s, 1H), 7.74 (s, 1H), 7.64 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:9]([NH:11][CH:12]2[CH2:17][CH:16]([OH:18])[CH2:15][CH2:14][CH:13]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:9]([NH:11][CH:12]3[CH:13]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH2:14][CH2:15][CH:16]([O:18][C:37](=[O:39])[CH3:38])[CH2:17]3)=[O:10])[CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:35][CH2:36]2)[CH2:2][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2CCC(O)CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Product: COc1ccc(C2CCC(OC(C)=O)CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Temperature: 100 °C

Procedure:
3.65 g of (±)-3,4-bis-cyclopropylmethoxy-N-[(1RS,2RS,5SR)-2-(3,4-dimethoxyphenyl)-5-hydroxycyclohexyl]benzamide (compound B2) are dissolved in 50 ml of acetic anhydride and the solution is heated to 100° C. for 3 h. The solution is concentrated and the residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 6/3/1. 1.8 g of the title compound of m.p. 90-95° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]([S:16](=[O:26])(=[O:25])[NH:17]C(OC(C)(C)C)=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[O:14][CH3:15]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]([S:16](=[O:25])(=[O:26])[NH2:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[O:14][CH3:15]
Reactant: COC(=O)CN(c1ccc(OC)cc1OC)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN(c1ccc(OC)cc1OC)S(N)(=O)=O

Procedure:
A solution of 1.7 g (4.2 mmol) of the title B compound, N-(t-butoxycarbonyl-sulfamoyl)-N-(2,4-dimethoxyphenyl)glycine methyl ester in 9 mL of TFA/CH2Cl2 (1:1) is stirred at RT for 30 min. The solvent is removed under reduced pressure. CH2Cl2 is added to the residue and the solvent is removed under reduced pressure. The resulting oil is purified by chromatography using 10% EtOAc in CH2Cl2 as the eluant to afford N-sulfamoyl-N-(2,4-dimethoxyphenyl)glycine methyl ester as an oil which crystallizes on standing: mp=100-103° C.; 1H-NMR (CDCl3) δ 7.50 (d, J=8.09, 1H), 6.51-6.44 (m, 2H), 4.98 (br s, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([N:14]([CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([N:22]1[CH2:21][CH2:20][CH:19]([CH2:18][N:14]([CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:11]2)[CH2:15][CH2:16][CH3:17])[CH2:24][CH2:23]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.3 %

Procedure:
To an ice-cold solution of (7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-ylmethyl-propyl-amine (420 mg, 1.3 mmol) and pyridine (154 μl, 1.5 mmol, 1.2 eq.) in methylene chloride (30 mL) under an inert atmosphere methanesulfonyl chloride (154 μl, 1.9 mmol, 1.5 eq) was added dropwise. The reaction was allowed to warm to room temperature and stir for 24 h. The reaction was quenched with water and the methylene chloride layer separated, dried (MgSO4), and concentrated to afford (1-methanesulfonyl-piperidin-4-ylmethyl)-(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine as a beige solid (454 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH:11]=O)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:14][OH:15].[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[C:3]2[C:10]([CH:11]=[N:14][OH:15])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=Cc1c[nH]c2ncnc(Cl)c12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (1.17 g, 6.47 mmol, 1.0 eq) and hydroxylamine hydrochloride (0.54 g, 7.77 mmol, 1.2 eq) in EtOH (25 mL), aqueous NaOH solution (0.31 g, 7.77 mmol, 1.2 eq) in H2O (4 mL) was added dropwise. The resulting mixture was stirred at RT for 30 min and then was diluted with a sufficient amount of EtOH to allow stirring for additional 30 min. The solid was collected by filtration, rinsed with H2O and dried in vacuo to afford 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime (0.89 g, 70% yield) as a mixture of isomers. ESI-MS m/z: 194.8 [M−H]−.
Reaction SMILES: [NH3:1].C([Li])CCC.[C:7]1([C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH2:18][CH:19]2[CH2:24][CH:23]3[CH2:25][CH2:26][N:20]2[CH2:21][CH2:22]3)[C:14]([O:16]C)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)=O>CCCCCC.O1CCCC1>[C:27]1([C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([CH2:18][CH:19]2[CH2:24][CH:23]3[CH2:25][CH2:26][N:20]2[CH2:21][CH2:22]3)[C:14]([NH2:1])=[O:16])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)C(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1
Reactant: N
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: NC(=O)C(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 25 parts by volume liquid ammonia in 22 parts dry tetrahydrofuran is added dropwise over a 5 minute period 10 parts by volume of a 2.3 M solution of butyl lithium in hexane under reflux under a dry ice condenser. Then, a solution of 3.9 parts methyl 2,2-diphenyl-3-(1-azabicyclo[2.2.2]oct-2-yl)propionate in 18 parts dry tetrahydrofuran is added dropwise, with stirring. After stirring the resulting mixture under reflux for 3 hours the dry ice condenser is removed, and the mixture stirred at ambient temperature for a further two hours. The solvents are then removed in vacuo. The residual gum is suspended in water and extracted with a 1:1 ether-benzene solution. The ether-benzene extract is separated, washed with water, dried over anhydrous sodium sulfate and stripped in vacuo. The residue is triturated with 50 parts of n-pentane. The undissolved solid is filtered off, washed with n-pentane and air dried to give a white powder. This powder is recrystallized from a mixture of benzene and petroleum ether to afford, as white needles, 2,2-diphenyl-3-(1-azabicyclo[2.2.2]oct-2-yl)propionamide. This compound melts at about 192°-194° C. and is represented by the following structural formula. ##STR12##
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.C(N(CC)CC)C.Br[CH2:36][CH2:37][OH:38]>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][CH2:36][CH2:37][OH:38])[CH2:23][CH2:22]2)[N:3]=1
Reactant: OCCBr
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NCCO)CC2)nc1N

Procedure:
To a stirred solution of trans-[4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (100 mg, 0.27 mmol, Example 120) and triethylamine (200 uL) in tetrahydrofuran (3 mL), 2-bromoethanol (20 uL, 0.28 mmol, Aldrich) was added and the mixture was stirred at reflux for 5 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate (3×10 mL) and the extracts were dried with sodium sulfate. Removal of solvent gave a yellow solid which was purified by reverse phase HPLC to give a pale yellow solid. 86 mg, 75%. MS (ES) MH+=422. CDK4 IC50=0.020 μM; CDK1 IC50=0.018 μM; CDK2 IC50=0.005 μM; HCT 116 IC90=0.179 μM.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>ClCCl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:25])=[O:24])=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
To a stirred solution of morpholine (5.2 mL, 59.7 mmol) and triethylamine (11.2 mL, 79.6 mmol) in dichloromethane (300 mL) was added the solution of 4-nitro-benzenesulfonyl chloride (8.8 g, 39.8 mmol) in dichloromethane (50 mL) at 0° C. The mixture solution was stirred at room temperature for 4 h and then washed with brine (50 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford 4-(4-nitro-benzenesulfonyl)-morpholine (10.0 g, 92.5%) as a white powder: MS (ESI) M+1=273.0.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([C:17]([NH2:24])([C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[CH3:18])[CH:14]=[CH:15][CH:16]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl.[NH4+].[Cl-]>[Br:10][C:11]1[CH:12]=[C:13]([C:17]([NH:24][C:27](=[O:28])[CH2:26][Cl:25])([C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[CH3:18])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)CCl
Reactant: CC(N)(c1cccc(Br)c1)c1cc[nH]n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)CCl)(c1cccc(Br)c1)c1cc[nH]n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
DIPEA (1.18 mL, 6.77 mmol) was added to a solution of rac-1-(3-bromo-phenyl)-1-(1H-pyrazol-3-yl)-ethylamine (1.2 g, 4.51 mmol) in DCM (20 mL) and the mixture was cooled in an ice bath. Then chloroacetyl chloride (0.40 mL, 4.96 mmol) was added and the mixture was stirred at 0° C. for 3 hours. The mixture was diluted with NH4Cl (aq. sat. solution) and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo. The residue was dissolved in EtOH (10 mL) and NaHCO3 (aq. sat. solution) (1 mL) and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water and the product extracted with DCM. The combined organic layers were concentrated in vacuo to yield rac-N-[1-(3-bromo-phenyl)-1-(1H-pyrazol-3-yl)-ethyl]-2-chloro-acetamide (1.22 g, 79% yield) as a colourless oil, which was used in the next step without further purification.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=4[Cl:33])=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[Cl:33])=[CH:22][C:21]2=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (prepared as in Example 79, 145 mg, 0.27 mmol) in tetrahydrofuran (20 mL) was treated with 2N aqueous hydrochloric acid (10 mL). The reaction mixture was stirred for 4 h at 25° C. The reaction mixture was diluted with ethyl acetate, washed with water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated to afford (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide as a fluffy material. This material was dissolved in dichloromethane (20 mL) and treated with 1M hydrogen chloride in diethyl ether (2 mL). Solvents were evaporated and the residue was triturated with diethyl ether. The mixture was filtered to give (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide hydrochloride (85 mg, 59%) as a yellow solid: HR-ES-MS m/z calculated for C22H26Cl2N4O5 [M+H]+ 497.1353, observed 497.1355; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.35-1.66 (m, 2H), 1.67-1.86 (m, 1H), 3.19-3.38 (m, 2H), 3.70-3.93 (m, 2H), 4.09 (dd, J=13.4, 3.5 Hz, 1H), 4.16-4.32 (br. s., 2H), 4.23 (m, J=18.4 Hz, 1H), 4.62 (d, J=18.4 Hz, 1H), 4.82-4.91 (m, 1H), 4.92 (s, 1H), 6.41 (d, J=1.5 Hz, 1H), 7.42-7.59 (m, 3H), 7.64 (d, J=7.5 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: C[N:2]([CH:4]=[O:5])C.[CH:6]([O:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:22]=[C:21](C(O)=O)[C:17]=3[NH:18][C:19]=2[CH:20]=1)=[O:11])([CH3:8])[CH3:7].C(Cl)CCl.O.ON1C2C=CC=CC=2N=N1>O>[C:4]([C:21]1[C:17]2[NH:18][C:19]3[CH:20]=[C:12]([C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[O:11])[CH:13]=[CH:14][C:15]=3[C:16]=2[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=1)(=[O:5])[NH2:2]
Reactant: CC(C)OC(=O)c1ccc2c(c1)[nH]c1c(C(=O)O)cc(-c3ccccc3)nc12
Reactant: CN(C)C=O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Product: CC(C)OC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccccc3)nc12
Yield: 90 %

Procedure:
Dry DMF (10 mL) was added to a mixture of 7-(isopropoxycarbonyl)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylic acid (0.95 g, 2.54 mmol), NH4C1 (0.41 g, 7.6 mmol), EDC (1.46 g, 7.61 mmol), and 1-hydroxybenzotriazole hydrate (1.03 g, 7.61 mmol). After stirring for a few minutes, TEA (1.06 mL, 7.61 mmol) was added and the reaction left stirred overnight. It was diluted with water (200 ml) and the precipitate was collected by filtration, washed with water and dried to leave isopropyl 4-carbamoyl-2-phenyl-5H-pyrido[3,2-b]indole-7-carboxylate (0.925 g, 2.28 mmol, 90% yield) as a yellow solid. MS (ESI) m/z 374.04 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.89 (1H, s), 8.66 (1H, br. s.), 8.54 (1H, s), 8.46 (1H, s), 8.38 (1H, d, J=8.24 Hz), 8.33 (2H, d, J=7.32 Hz), 7.92-7.99 (1H, m), 7.88 (1H, dd, J=8.24, 1.22 Hz), 7.57 (2H, t, J=7.63 Hz), 7.46 (1H, t, J=7.32 Hz), 5.22 (1H, dt, J=12.51, 6.26 Hz), 1.39 (6H, d, J=6.41 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][NH:28][CH2:27]2)[CH2:23][CH2:22]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][C@@H:30]([F:31])[C@@H:26]([CH2:25][NH:24][CH:21]5[CH2:22][CH2:23]5)[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 49.8 %

Procedure:
Using 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (212 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (142 mg), the same procedure was followed as in Example 23 to give 1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a pale yellow crystals (157 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)(=[O:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(OCC)(=O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:25]([CH3:24])(=[O:27])=[O:26])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C(=O)c2cccc(N)c2)[nH]c2cc(Cl)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1c(C(=O)c2cccc(NS(C)(=O)=O)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-acetylamino-2-(3-aminobenzoyl)-6-chloroindole (Example 135) and methanesulfonyl chloride. m.p.: 133-142° C. (ethyl acetate/hexane)
Reaction SMILES: C1([C@@H:7]([NH:9]C2C=C(C3C=CC=C4C=3C=CC=N4)N=CC=2N)C)C=CC=CC=1.[C:27]1([C@@H:33]([N:35]2[C:43]3[CH:42]=[C:41]([C:44]4[CH:53]=[CH:52][CH:51]=[C:50]5[C:45]=4[CH:46]=[CH:47][CH:48]=[N:49]5)N=C[C:38]=3[NH:37][C:36]2=[O:54])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.NC(N)=O.O>CN1CCCC1=O>[C:27]1([C@@H:33]([N:35]2[C:43]3[C:38](=[N:9][CH:7]=[C:41]([C:44]4[CH:53]=[CH:52][CH:51]=[C:50]5[C:45]=4[CH:46]=[CH:47][CH:48]=[N:49]5)[CH:42]=3)[NH:37][C:36]2=[O:54])[CH3:34])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C[C@H](Nc1cc(-c2cccc3ncccc23)ncc1N)c1ccccc1
Reactant: C[C@@H](c1ccccc1)n1c(=O)[nH]c2cnc(-c3cccc4ncccc34)cc21
Agent: NC(N)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H](c1ccccc1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)cc21
Temperature: 185 °C
Yield: 19.2 %

Procedure:
(S)-1-(1-Phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one ((1S)-1-Phenylethyl)(3-amino-6-(5-quinolyl)(4-pyridyl))amine (450mg, 1.32 mmol) and urea (158 mg, 2.64 mmol) were combined in 1-methylpyrrolidin-2-one (4 mL) and heated at 185° C. for 2 h. Water (10 mL) was added and the crude product was collected by filtration. The product was purified by reverse-phase preparative HPLC (20-95% acetonitrle in water, over 30 min) to give the product (92.9 mg, 19%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.91 (dd, J=4.10, 1.76, 1H), 8.39 (d, J=0.78, 1H), 8.33 (ddd, J=8.00, 1.27, 1.07, 1H), 8.05 (d, J=8.40, 1H), 7.80 (dd, J=8.49, 7.13, 1H), 7.59 (dd, J=7.13, 1.27, 1H), 7.41-7.47 (m, 3H), 7.29-7.41 (m, 3H), H), 5.75 (d, J=7.22, 1H), 4.16 (d, J=0.78, 1H), 1.87 (d, J=7.22, 3 H); MS (ESI) m/z 367.0 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:21])=[C:4]([CH3:20])[C:5]2[O:10][C:9]([CH3:17])([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:8][C:7](=[O:18])[C:6]=2[CH:19]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CN=C1.O>CN(C=O)C>[CH3:26][C:25]([Si:22]([CH3:24])([CH3:23])[O:1][C:2]1[C:3]([CH3:21])=[C:4]([CH3:20])[C:5]2[O:10][C:9]([CH3:17])([CH2:11][CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])[CH2:8][C:7](=[O:18])[C:6]=2[CH:19]=1)([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)=CCCC1(C)CC(=O)c2cc(O)c(C)c(C)c2O1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCCC1(C)CC(=O)c2cc(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1
Reaction time: 18 h
Yield: 71.7 %

Procedure:
A mixture of 2,3-dihydro-6-hydroxy-2,7,8-trimethyl-2-(4-methylpent-3-enyl )-4H-1-benzopyran-4-one (9.4 q, 34.3 mmole), tert-butyldimethylsilyl chloride (7.75 g, 51.5 mmole), and imidazole (6.99 g, 0.1 mole) were dissolved in 50 mL of dry DMF. The solution was stirred under nitrogen for about 18 hours, poured into water and extracted with ether. The organic layers were dried (brine, MgSO4) and concentrated in vacuo. The crude material was purified by flash chromatography (gradient 20:1 to 10:1 hexanes:ether) to give the title compound as a colorless oil (9.9 g, 24.6 mmole, 72%): 1H NMR (CDCl3) δ 0.20 (s, 6H), 1.0 (s, 9H), 1.37 (s, 3H), 1.55 (s, 3H), 1.55-1.60 (m, 1H), 1.65 (s, 3H), 1.74-1.84 (m, 1H), 2.0-2.1 (m, 2H), 2.14 (s, 3H), 2.16 (s, 3H), 2.63 (ABq, J=16.5 Hz, 2H), 5.07 (t, J=7.0 Hz, 1H), 7.09 (s, 1H); MS m/e 403 (MH+).