Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([O:19][CH3:20])[C:17]=1[F:18])[N:14]=[CH:13][C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:11]2[OH:26].[N+:27](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:27][N:14]1[C:15]2[C:10](=[CH:9][C:8]([F:7])=[C:17]([F:18])[C:16]=2[O:19][CH3:20])[C:11](=[O:26])[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13]1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOC(=O)c1cnc2c(OC)c(F)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
1.10 g (0.008 mole) of potassium carbonate was added to a solution of 1.13 g (0.004 mole) of ethyl 6,7-difluoro-4-hydroxy-8-methoxyquinoline-3-carboxylate (IX) [prepared as described in Preparation 14 (B3)] in 20 ml of dimethylformamide and the mixture was stirred at room temperature for 3 hours. 0.81 g (0.0041 mole) of O-(2,4-dinitrophenyl)hydroxylamine was then added, and the mixture was stirred at room temperature for 6 hours. At the end of this time, the solvent was distilled from the reaction mixture under reduced pressure. The residue was washed, in turn, with water and with ethanol. The solid produced was extracted with chloroform, and the solvent was stripped from the extract, to give 0.62 g of ethyl 1-amino-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XV) as an ocherous powder.
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:5])[CH:3]=[O:4].[CH3:16][O:17][C:18]([CH:20]1[O:24][CH:23]([C:25]([CH2:27][S:28][C@H:29]2[NH:32][C:31](=[O:33])[C@H:30]2[NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:26])[CH2:22][CH2:21]1)=[O:19].C(N(CC)CC)C>ClC(Cl)C>[OH:4][CH:3]([N:32]1[CH:29]([S:28][CH2:27][C:25]([CH:23]2[CH2:22][CH2:21][CH:20]([C:18]([O:17][CH3:16])=[O:19])[O:24]2)=[O:26])[CH:30]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]1=[O:33])[C:2]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[O:5]
Reactant: COc1ccc(COC(=O)C=O)cc1
Reactant: COC(=O)C1CCC(C(=O)CS[C@H]2NC(=O)[C@H]2NC(=O)Cc2ccccc2)O1
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(C(=O)CSC2C(NC(=O)Cc3ccccc3)C(=O)N2C(O)C(=O)OCc2ccc(OC)cc2)O1
Temperature: 25 °C

Procedure:
4-Methoxybenzyl glyoxylate hydrate (1.50g) in dichloroethane (30ml) was heated at reflux for 1h using a Dean and Stark apparatus for heavy entrainers. The mixture was cooled to room temperature and then a solution of (3R,4R)-4-[(2RS,5SR)-5-methoxycarbonyltetrahydrofuran-2-ylcarbonylmethylthio]-3-phenylacetamidoazetidin-2-one (2.208g) in dichloroethane (20ml) was added followed by triethylamine (0.1ml). The mixture was stirred at room temperature for 1h and then the solvents were evaporated. The title compound was obtained as a mixture of isomers (2.66g) by column chromatography of the residue using gradient elution (silica gel, 1:1 hexane:ethyl acetate going to neat ethyl acetate); vmax (CHCl3) 3412, 1776, 1741 and 1681cm-1.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17]3)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[O:24]=[C:25]1[C:30]2=[CH:31][NH:32][C:33]([CH:34]=O)=[C:29]2[CH2:28][CH2:27][O:26]1>>[N:1]1([S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[C:17]3=[CH:34][C:33]2[NH:32][CH:31]=[C:30]3[C:25](=[O:24])[O:26][CH2:27][CH2:28][C:29]=23)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCCc4ccccc43)ccc2N1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-(3,4-Dihydro-2H-quinoline-1-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:5]2[O:6][C:7]([CH2:10][CH2:11][OH:12])([CH3:9])[CH2:8][C:4]=2[C:3]=1[CH3:17].[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[C:26](C(C)C(O)=O)=[CH:25][CH:24]=[CH:23]2.CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC.[O:56]1C[CH2:59][CH2:58][CH2:57]1>C(OCC)(=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([CH:58]([CH3:59])[C:57]([O:12][CH2:11][CH2:10][C:7]1([CH3:9])[O:6][C:5]3=[C:13]([CH3:16])[C:14]([CH3:15])=[C:2]([OH:1])[CH:3]([CH3:17])[CH:4]3[CH2:8]1)=[O:56])[CH:24]=[CH:23]2
Reactant: Cc1c(C)c2c(c(C)c1O)CC(C)(CCO)O2
Reactant: C1CCOC1
Reactant: COc1ccc2c(C(C)C(=O)O)cccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C(C)C(=O)OCCC3(C)CC4C(=C(C)C(C)=C(O)C4C)O3)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.5 %

Procedure:
A solution of 2-(5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo[1,2-b]furan-2-yl)ethanol (1.30 g, 5.51 mmol) and 6-methoxy-a-methyl naphthaleneacetic acid (Aldrich, 1.39 g, 6.06 mmol) was stirred in the presence of dimethylaminopyridine (0.67 g, 5.51 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.06 g, 5.51 mmol), in tetrahydrofuran (25 mL). The reaction mixture was stirred at ambient temperature under nitrogen for 24 hours, diluted with ethyl acetate (150 mL), washed with water (2×40 mL) and then brine (30 mL). The organic extract was dried (sodium sulfate) and concentrated in vacuo. The residue was subjected to flash chromatography (silica gel, 100-50:0-50, v:v, hexanes:ethyl acetate), and the appropriate fractions were combined to give 1.84 g (74.5% yield) of a foam residue. Fractional crystallization and recrystallization from methylene chloride-hexanes gave 0.40 g (13.0% yield) of white solid.
Reaction SMILES: [CH2:1](I)[CH3:2].[C:4]1([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[K+].O>CN1CCCC1=O.[Cu]>[C:4]1([N:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH2:1][CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Reactant: CCI
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCN(c1ccccc1)c1cccc2ccccc12
Yield: 98 %

Procedure:
A mixture of ethyl iodide (0.1M), 1-phenylaminonaphthalene (0.05M), KOH (0.1M) and copper bronze (1 g) was stirred for 31/2 hours in N-methylpyrrolidone (20 cm3) at 120° C. under an atmosphere of nitrogen. The mixture was cooled, poured into water (2 liters) and extracted with CH2Cl2 (3×300 cm3). The combined extracts were washed with water, dried over MgSO4 and the CH2Cl2 solvent removed in vacuo to give 229 g (98% yield) of 1-(N-phenyl-N-ethylamino)naphthalene as a yellow liquid.
Reaction SMILES: [Li][CH3:2].[CH2:3]([O:10][CH2:11][N:12]1[C:16]([CH:17]=O)=[CH:15][CH:14]=[N:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:3]([O:10][CH2:11][N:12]1[C:16]([CH:17]=[CH2:2])=[CH:15][CH:14]=[N:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [Li]C
Reactant: O=Cc1ccnn1COCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccnn1COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyltriphenylphosphoniumbromide (7.85 g, 22.0 mmol) in THF (40 mL) is cooled to 0° C. then MeLi (12.2 mL, 1.6 M in ether) is added dropwise. The mixture is stirred for 1 h then a solution of 2-benzyloxymethyl-2H-pyrazole-3-carbaldehyde (3.4 g, 15.7 mmol) in THF (15 mL) is added dropwise. The reaction is stirred for an hour at 0° C., then warmed to RT over 1 h. The mixture is partitioned between aqueous NH4Cl and EtOAc and the organic layer is concentrated. Chromatography (10-15% EtOAc/hexane) affords the title compound as a yellow oil: (M+1)+=215.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42](C=O)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][N:51]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.[C:58](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:50][N:51]6[CH2:57][CH2:56][CH2:55][N:54]([CH3:58])[CH2:53][CH2:52]6)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)c1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(CN4CCCN(C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,3-benzene-dicarboxamide (0.033 g, 0.05 mmol), 1-methylhexahydro-1H-1,4-diazepine (0.007 g, 0.06 mmol), and acetic acid (0.0036 g, 0.06 mmol) were combined in CH2Cl2 (2 mL). Sodium triacetoxyborohydride (0.0148 g, 0.07 mmol) was added and the mixture stirred overnight at room temperature. Solvents were concentrated and the residue taken up in EtOAc. It was washed with 1N NaOH and dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The product was purified using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed 3× with 2.5 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a white solid. LC-MS m/z 757.2 (M+H)+, 1.38 min (ret time); mp 107-109° C. Analytical HPLC shows 95.3% purity, (ret time 10.035 min).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]1=[O:14].[CH3:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:17]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[ClH:1].[CH3:13][O:12][C:8]1[C:7](=[O:14])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][N:26]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:23]=3[CH:24]=[CH:25][C:16]([CH3:15])=[N:17]4)[CH2:27][CH2:28]2)[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc2c(N3CCNCC3)cccc2n1
Reactant: COc1cccn(CCCCCl)c1=O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccn(CCCCN2CCN(c3cccc4nc(C)ccc34)CC2)c1=O
Product: Cl
Yield: 48 %

Procedure:
A mixture of 1-(4-chlorobutyl)-3-(methyloxy)-2(1H)-pyridinone (67.8 mg, 0.31 mmol), 2-methyl-5-(1-piperazinyl)quinoline (see WO2004/046124 D3) (77.5 mg, 0.34 mmol), triethylamine (0.09 mL, 0.64 mmol) and a catalytic amount of sodium iodide in anhydrous N,N-dimethylformamide (2.50 mL) was stirred at 110° C. overnight. The reaction mixture was concentrated in vacuo, taken-up in dichloromethane (5 mL) and washed with water (2×5 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo. The crude product was passed through a SCX cartridge, washing with methanol and eluting with ammonia 2M in methanol and then purified by flash chromatography on silica gel, eluting with 2% methanol in dichloromethane, to afford the corresponding free base of the title compound as a yellow solid (65.9 mg, 52%).
Reaction SMILES: [CH2:1]([N:8]1[N:17]=[C:16](Cl)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[OH:37].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[N:17]=[C:16]([C:26]2[CH:25]=[CH:24][C:23]([OH:37])=[C:22]([O:21][CH3:20])[CH:27]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccccc2c(Cl)nn1Cc1ccccc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2nn(Cc3ccccc3)c(=O)c3ccccc23)ccc1O
Temperature: 25 °C
Reaction time: 19 h
Yield: 7.5 %

Procedure:
A mixture of 2-benzyl-4-chloro-2H-phthalazin-1-one (1.35 g, 5 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenol (1.50 g, 6 mmol), Pd(PPh3)4 (0.87 g, 0.75 mmol) and Na2CO3 (2.12 g, 20 mmol) in toluene (25 mL), ethanol (12.5 mL) and water (12.5 mL) was degassed and then heated to reflux with stirring for 19 h. After that time, the reaction was cooled to rt and diluted with ethyl acetate (150 mL) and water (100 mL). The organic phase was separated, washed with water (2×30 mL) then brine (50 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was triturated with hexanes (100 mL) to give a yellow solid. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate) followed by recrystallization from CHCl3/hexanes to give 2-benzyl-4-(4-hydroxy-3-methoxyphenyl)phthalazin-1(2H)-one (0.135 g, 7.5%) as a white solid: mp 197-200° C.; 1H NMR (400 MHz, CDCl3) δ 8.54-8.52 (m, 1H), 7.79-7.71 (m, 3H), 7.52 (d, J=7.2 Hz, 2H), 7.34-7.25 (m, 4H), 7.11-7.04 (m, 2H), 5.82 (s, 1H), 5.47 (s, 2H), 3.93 (s, 3H); ESI MS m/z 359 [M+1]+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC(O)=CC=1[Cl:24].[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30](B(O)O)[CH:31]=1>>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:28]3[CH:27]=[C:26]([F:25])[CH:31]=[CH:30][C:29]=3[O:35][CH3:36])=[C:12]([Cl:24])[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: O=S(=O)(c1ccccc1)c1ccccc1
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)cc1Cl

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-fluoro-2-methoxybenzene boronic acid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([OH:13])=[O:12])=[C:5]([CH3:7])[N:6]=1.IC1NC(C2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=NC=1C.IC1NC(C)=NC=1C>>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:1]([C:2]2[NH:3][C:4]([C:8]3[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=3[CH3:17])[C:11]([OH:13])=[O:12])=[C:5]([CH3:7])[N:6]=2)[CH2:25][CH2:26]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Reactant: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1I
Agent: Cc1nc(C)c(I)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except tert-butyl 4-(5-iodo-4-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[O:19])[CH2:17][O:18][C:13]=3[CH:12]=2)[CH2:6]1)=O.[NH3:23]>CO.CCOCC>[CH3:20][N:15]1[C:14]2[CH:21]=[CH:22][C:11]([N:7]3[CH2:6][C@H:5]([C:3]([NH2:23])=[O:2])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[O:18][CH2:17][C:16]1=[O:19]
Reactant: N
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)OCC(=O)N3C)C(=O)O1
Solvent: CCOCC
Solvent: CO
Product: CN1C(=O)COc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Reaction time: 16 h
Yield: 81 %

Procedure:
To a stirred solution of (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester (Step 2, 2.41 g, 7.87 mmol) in MeOH (25 mL) is added 2M NH3 in MeOH (25 mL, 50 mmol). The resulting clear solution becomes turbid after ˜10 min. This mixture is stirred for 16 h at which time the reaction is diluted with ether (20 mL) and the resulting white solid filtered off. This white solid is washed with several portion of ether (50 mL) and dried under high vacuum to give the title compound (1.87 g, 81%), 1H NMR (300 MHz, DMSO) δ 7.85 (br s, 1H), 7.60 (br s, 1H), 7.31-7.14 (m, 3H), 5.00 (dd, 1H), 4.65 (s, 2H), 4.21 (t, 1H), 3.97 (dd, 1H), 3.32 (s, 3H); MS for C14H13N3O5 m/z 292.5 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[CH3:14].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][C:2]([F:16])([CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:12])=[CH:7][C:6]=1[CH3:14]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(C)(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)ccc1OCC(C)(F)F
Yield: 88 %

Procedure:
The title compound is prepared in 88% yield (693 mg, pale yellow oil) from 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanone (539 mg, 2.36 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (716 mg, 5.90 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[S:14]1[C:18]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)O)=[CH:17][C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]1=2>>[S:14]1[C:18]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:4]2[C:3](=[O:7])[C:2]([CH3:1])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[OH:6])=[CH:17][C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]1=2
Reactant: OC(c1ccccc1)c1cc2ccccc2s1
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Product: CC1(c2ccccc2)C(=O)C(C(c2ccccc2)c2cc3ccccc3s2)=C1O

Procedure:
Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with benzo[b]thiophen-2-yl-phenyl-methanol to give the title compound as a colorless solid. MS: 395.3 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:17])[C:4]([C:6]1([C:13]([F:16])([F:15])[F:14])[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])(=O)=O>C(Cl)Cl>[CH3:1][O:2][N:3]([CH3:17])[C:4]([C:6]1([C:13]([F:14])([F:15])[F:16])[CH2:11][CH2:10][CH:9]([O:12][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CON(C)C(=O)C1(C(F)(F)F)CCC(O)CC1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CON(C)C(=O)C1(C(F)(F)F)CCC(O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 16 h

Procedure:
6.00 g (23.5 mmol) of 4-Hydroxy-1-trifluoromethyl-cyclohexanecarboxylic acid methoxy-methyl-amide (69) were dissolved in 20 ml of CH2Cl2 and 6.8 ml of 2,6-lutidine were added. Afterwards, 6.48 ml (28.2 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate were added at 0° C. and the mixture allowed to stand at ambient temperature for 16 h. The mixture was then diluted using 30 ml of CH2Cl2 and washed successively twice using 30 ml of water, twice using 30 ml of a 0.1; N aqueous HCl-solution and once using 30 ml of a saturated aqueous NaHCO3-solution respectively. The organic layer was then dried over MgSO4 and evaporated to yield 8.40 g. Rt=0.99 min (Method Q).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:34][O:33][CH2:32]5)[CH2:27][CH2:26]4)=[CH:21][N:20]=3)[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=2)=[CH:10][C:9]([F:37])=[CH:8][C:7]=1[N:38]1[CH2:49][CH2:48][N:47]2[C:40](=[CH:41][C:42]3[CH2:43][C:44]([CH3:51])([CH3:50])[CH2:45][C:46]=32)[C:39]1=[O:52])(=O)C.O.[Li+].[OH-]>C1COCC1>[F:37][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:32][O:33][CH2:34]5)[CH2:27][CH2:26]4)=[CH:21][N:20]=3)[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=2)[C:6]([CH2:5][OH:4])=[C:7]([N:38]2[CH2:49][CH2:48][N:47]3[C:40](=[CH:41][C:42]4[CH2:43][C:44]([CH3:50])([CH3:51])[CH2:45][C:46]=43)[C:39]2=[O:52])[CH:8]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cc(F)cc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Yield: 53.5 %

Procedure:
To a solution of (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-fluoro-6-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl)methyl acetate (200 mg, 0.28 mmol) in THF/iPA/H2O (6 mL/6 mL/2 mL) at room temperature was added LiOH (70 mg, 2.9 mmol) while stirring. This mixture was stirred for 0.5 h. Then, 20 mL H2O was added and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were dried with Na2SO4 and concentrated to give a yellow solid which was further purified by prep-HPLC to afford 304 as a white solid (100 mg, 53%). LCMS: [M+H]+ 668. 1H NMR (500 MHz, DMSO): δ 1.23 (s, 6H), 2.37-2.39 (m, 5H), 2.53-2.57 (m, 2H), 3.07 (s, 4H), 3.43-3.45 (m, 2H), 3.60 (s, 3H), 3.85-3.87 (m, 1H), 4.16-1.19 (m, 3H), 4.32 (d, J=6.0 Hz, 2H), 4.45-4.50 (m, 2H), 4.54-4.58 (m, 2H), 4.86 (s, 1H), 6.47-6.51 (m, 1H), 7.18-7.25 (m, 2H), 7.34-7.39 (m, 3H), 7.83-7.86 (m, 1H), 8.35-8.37 (m, 1H), 8.53-8.56 (m, 1H).
Reaction SMILES: Cl.Cl.[Cl:3]C1C2C(=CC(S(N(CCN(C)C)C3(C(O)=O)CCCC3)(=O)=O)=CC=2)C(NC(N)=N)=NC=1.Cl.[NH2:36][C:37]([NH2:39])=[NH:38].Cl.[CH2:41]([O:43][C:44](=[O:71])[C:45]1([CH2:70][CH2:69][CH2:68][CH2:67]1)[N:46]([S:52]([C:55]1[CH:64]=[C:63]2[C:58]([C:59]([Cl:66])=[CH:60][N:61]=[C:62]2[Cl:65])=[CH:57][CH:56]=1)(=[O:54])=[O:53])[CH2:47][CH2:48][N:49]([CH3:51])[CH3:50])[CH3:42].O>CS(C)=O>[ClH:3].[ClH:65].[CH2:41]([O:43][C:44](=[O:71])[C:45]1([CH2:70][CH2:69][CH2:68][CH2:67]1)[N:46]([S:52]([C:55]1[CH:64]=[C:63]2[C:58]([C:59]([Cl:66])=[CH:60][N:61]=[C:62]2[NH:38][C:37]([NH2:39])=[NH:36])=[CH:57][CH:56]=1)(=[O:54])=[O:53])[CH2:47][CH2:48][N:49]([CH3:51])[CH3:50])[CH3:42]
Reactant: N=C(N)N
Reactant: CN(C)CCN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Reactant: CCOC(=O)C1(N(CCN(C)C)S(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1(N(CCN(C)C)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Temperature: 50 °C
Yield: 65.6 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-[2-(dimethylamino)ethyl]cycloleucine dihydrochloride ##STR52## NaH (32 mg, 80% dispersion by wt in mineral oil, 1.05 mmol) was added in one portion to a stirred solution of guanidine hydrochloride (145 mg, 1.52 mmol) in DMSO (4 mL) and the mixture was heated at 50° C. under N2 for 20 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-[2-(dimethylamino)ethyl]cycloleucine ethyl ester hydrochloride (160 mg, 0.305 mmol) was added in one portion and the mixture heated at 90° C. for 1 h. The cooled mixture was poured into water, extracted with EtOAc (2×20 mL) and the combined organic extracts were then washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in Et2O, filtered, and a solution of HCl in Et2O (1 M) was added which gave a precipitate. The solvents were evaporated in vacuo and the residue recrystallised from hot EtOH to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-[2-(dimethylamino)ethyl]cycloleucine ethyl ester dihydrochloride (123 mg, 0.20 mmol) as a pale yellow solid.