Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:18])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[Cl:17][C:13]1[CH:12]=[C:11]([C:5]2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=[C:3]([CH2:2][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[N:21][CH:22]=3)[C:4]=2[F:18])[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: COc1ccc(CBr)c(F)c1-c1cccc(Cl)c1
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: Cc1ccccc1
Product: COc1ccc(Cc2ccc(F)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 80 °C
Yield: 93.4 %

Procedure:
A flask was charged with 3-Bromomethyl-3′-chloro-2-fluoro-6-methoxy-biphenyl (I-32, 3.3 g, 10 mmol), 2-fluoro-pyridine-5-boronic acid (1.4 g, 10 mmol), toluene (40 mL), 2M aq. Na2CO3 (10 mL, 20 mmol), ethanol (10 mL) and Pd(PPh3)4 (577 mg, 0.5 mmol). The reaction mixture was bubbled with nitrogen gas for 5 minutes. Then the yellow reaction mixture was stirred at 80° C. After overnight stirring the reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was diluted in EtOAc (20 mL) and washed with water (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in-vacuo. The crude was purified by silica gel column chromatography, eluted with hexane/EtOAc (9:1) to produce 3.23 g (93% yield) of 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) 3.73 (s, 3H), 3.98 (s, 2H), 6.95 (d, J=8.6 Hz, 1H), 7.11 (dd, J=8.4, 2.8 Hz, 1H), 7.25-7.51 (m, 5H), 7.82 (td, J=8.2, 2.4 Hz, 1H), 8.14 (s, 1H), 8.32 (s, 1H) ppm.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21](O)[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@@H:10]([OH:30])[CH2:9]1)=[O:6])[CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>CN(C)C=O>[CH3:4][CH:3]([CH2:2][CH3:1])[C:5]([O:7][CH:8]1[CH:13]2[C:12]([CH:17]=[CH:16][CH:15]([CH3:18])[CH:14]2[CH2:19][CH2:20][CH:21]2[CH2:22][CH:23]([OH:28])[CH2:24][C:25](=[O:26])[O:27]2)=[CH:11][CH:10]([OH:30])[CH2:9]1)=[O:6]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CCC(C)C(=O)OC1CC(O)C=C2C=CC(C)C(CCC3CC(O)CC(=O)O3)C21
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a dry 100 ml round-bottomed flask equipped with a stir bar and CaSO4 drying tube was added 3.32 g (7.44 mmol) of pravastatin, 3.47 g (16.8 mmol) of dicyclohexylcarbodiimide (DCC), 1.93 g (16.8 mmol) of N-hydroxysuccinimide and 50 ml of dry dimethylforamide (DMF) (distilled from CaO) and the mixture stirred at room temperature for 16 hours. The resulting suspension was filtered and the filtrate evaporated at 30° C. under reduced pressure. The residue was taken up in 50 ml of 20:1 CHCl3 :MeOH, filtered and evaporated. The resulting yellow oil was applied to 300 g of silica gel and eluted in a stepwise manner (1 liter of 40:1 CHCl3 :MeOH; 1 liter of 30:1 CHCl3 :MeOH, 1 liter of 20:1 CHCl3 :MeOH). The product was eluted with the 20:1 eluant. The good fractions (TLC, 8:1 CHCl3 :isopropyl alcohol (IPA) were combined and evaporated and the resulting oil triturated with ether to yield 2.15 g (71%) of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[NH:14][CH:13]=[C:12]([S:15](Cl)(=[O:17])=[O:16])[CH:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(Cl)Cl>[N:22]1([CH2:21][CH2:20][NH:19][S:15]([C:12]2[CH:11]=[C:10]([C:8]([C:7]3[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[NH:14][CH:13]=2)(=[O:17])=[O:16])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: O=C(c1cc(S(=O)(=O)Cl)c[nH]1)c1cccnc1Cl
Reactant: NCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(S(=O)(=O)NCCN2CCOCC2)c[nH]1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a solution of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonyl chloride (500 mg, 1.64 mmol) in DCM (5 mL) was added 4-(2-aminoethyl)morpholine (427 mg, 3.28 mmol) and triethylamine (0.5 mL). The mixture was stirred at room temperature for 4 hours. The reaction was extracted with DCM, the combined DCM was washed with water and brine, dried and concentrated. The residue was purified on a silica gel column to give 450 mg (69%) of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonic acid (2-morpholin-4-yl-ethyl)-amide as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[CH:14]=3)[N:9](C3CCCCO3)[N:8]=2)[CH:4]=[N:3]1.Cl>CO.O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[CH:14]=3)[NH:9][N:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3c(-c4cnn(C)c4)nn(C4CCCCO4)c3cn2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1cc(-c2cc3c(-c4cnn(C)c4)n[nH]c3cn2)cn1
Yield: 34.2 %

Procedure:
3,5-bis(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine in methanol was treated with 4M HCl in 1,4-dioxane at 50° C. for 3 h. Volatile solvent was evaporated in vacuo. The resultant residue was purified by reverse phase HPLC to give 163 as a white solid (34.2%). 1H NMR (500 MHz, DMSO) δ 13.35 (s, 1H), 8.96 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 8.15 (s, 1H), 8.10 (d, J=5.6 Hz, 2H), 3.96 (s, 3H), 3.90 (s, 3H). LC/MS: m/z 280.0 [M+1]
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:22].C(Cl)Cl.C([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=O)C>C(N(CC)CC)C>[C:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:22])=[C:2]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[N:11]=3)[C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)c1cn(-c2ccccc2)c2nc(Cl)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1cn(-c2ccccc2)c2nc(N3CCNCC3)c(F)cc2c1=O

Procedure:
Alternately, the title compound is prepared as follows: To a solution of 1.6 g. of compound (III) (R1 =C2H5, R=phenyl, X=Cl) (product of 1(c) in 50 ml. of methylene chloride is added 1 ml. of triethylamine and 710 mg. of N-acetylpiperazine. After heating for 2 hours, the solvent is washed with 50 ml. of 1N HCl solution and then with water. The methylene chloride solution is dried and evaporated to dryness, yielding 2.1 g. of compound (I) ##STR14##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:29][Mg]Br>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:18]([CH3:22])([CH3:21])[CH:19]([OH:20])[CH3:29])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)C(C)(C)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanal (from Ex 116(b), 25 mg, 0.067 mmol) in THF (1 ml) at 0° C. was added a solution of 1.4 M methylmagnesium bromide in 1 ml of THF (1.4 M) dropwise. After 1 hr, the reaction was quenched with sat. NH4Cl and was extracted with ethyl acetate. The organic phase was washed, dried over MgSO4, filtered, and concentrated to give 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-4-phenylbutan-2-ol as a white solid (24 mg, 92% yield). It is a mixture of diastereomers in a 1:1 ratio. 1H NMR (400 MHz, MeOD) δ ppm 8.20 (1 H, d, J=5.09 Hz) 7.96 (1 H, d, J=9.16 Hz) 7.68-7.75 (2 H, m) 7.59-7.67 (2 H, m) 7.53 (2 H, dd, J=7.63, 2.54 Hz) 7.23-7.35 (4 H, m) 7.14-7.20 (1 H, m) 4.40 (1 H, s) 3.50-3.60 (1 H, m) 1.10 (3 H, 2 singlets,) 1.05 (3 H, s) 0.99 (3 H, 2 singlets). LC/MS (m/z) 389.3 [(M+1)+]; HPLC Rt: 3.96 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21].C([BH3-])#N.[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:22][CH2:19][CH2:20][CH3:21])[CH:12]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Reactant: CCCN
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 76.9 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.20 g, 0.78 mmol), n-propylamine (140 μL, 101 mg, 1.7 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 5 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[3-(propylaminomethyl)phenoxy]benzonitrile fumarate (250 mg, 78%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[C:35]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C:43]1=O)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>ClC(Cl)C>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][NH:10][CH:45]2[CH2:46][CH2:47][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:43][CH2:44]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCCC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
3,3-diphenylpropylamine (5.8 g, 27.5 mmol), sodium triacetoxyborohydride (6.36 g, 30 mmol) and 0.5 ml of acetic acid are added to 5 g (25 mmol) of N-Boc-piperidone in 100 ml of dry dichloroethane. The turbid yellow solution is agitated at ambient temperature for 1 hour. 50 ml of a soda solution (0.1 M) is then added and the mixture is agitated for 30 minutes. The organic phase is washed with a saturated solution of sodium bicarbonate, with sodium chloride, dried over magnesium sulphate, filtered and concentrated in order to produce 10 g of a yellow solid. This solid is purified by flash chromatography on silica gel eluting with a heptane/ethyl acetate mixture (4/1, 3/1, 2/1 then 1/1) then with pure ethyl acetate. The fractions are concentrated under vacuum in order to produce 5.6 g (yield=57%) of a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:19][NH:20][CH3:21].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([N:20]([CH3:21])[CH3:19])=[O:6]
Reactant: COc1cc(NC(=O)C(C)(C)C)ccc1C(=O)Cl
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C(C)(C)C)ccc1C(=O)N(C)C
Reaction time: 1 h

Procedure:
2-Methoxy-4-(2',2'-dimethylpropionamido)-benzoyl chloride (1.12 g) in dry THF (10 ml) was added dropwise over 30 minutes to a stirred solution of dimethylamine (1.17 g of a 40% aqueous solution) in THF (15 ml) at 0°-5° C. After completion of the addition the solution was stirred for 1 hour at 5°-10° C., stood at room temperature overnight, poured into water, and extracted with ethyl acetate. The extract was dried and evaporated to give the product as a yellow solid (0.889 g), m.p. 143°-144° C.
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[N+:11]([C:9]1[CH:8]=[CH:7][C:4]2[S:5][CH:6]=[C:2]([C:17]3[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=3)[C:3]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc2scc(Br)c2c1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc2scc(-c3ccncc3)c2c1
Yield: 56.1 %

Procedure:
A stirred mixture of 3-bromo-5-nitrobenzo[b]thiophene (J.Amer. Chem. Soc, 1948, 1955) (4.2 g, 0.016 mole,) pyridin-4-ylboronic acid (2.0 g, 0.016 mole) and sodium carbonate (4.3 g, 0.048 mole) in DME (150 ml) and water (150 ml) was de-gassed by bubbling argon through for 15 minutes, then tetrakis(triphenylphosphine)palladium (0) (400 mg) was added and the mixture heated at reflux under argon for 18 hours. The reaction mixture was cooled and concentrated in vacuo to approx 150 ml volume, then acidified with 2M HCl acid (200 ml) and shaken well with ethyl acetate (400 ml). The solid present was filtered off, shaken with 10% Na2CO3 solution and dichloromethane, and the organic layer separated, dried (Na2SO4) and concentrated in vacuo to afford the title compound as an orange/yellow solid (2.3 g, 56%).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])[CH2:34]3)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][C:35](=[O:40])[CH2:34]4)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc5c(c4)CC(=O)N5)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (from Combi-Blocks) LCMS calculated for C24H23N4O3 (M+H)+: m/z=415.2. Found 415.3.
Reaction SMILES: [Si](O[C@H](C1C=CC(O)=C2C=1C=CC(=O)N2)CNCCCCCCCCNC(C1C=C(S(C2C=C3C(=C(C)C=2)N=CC(C(N)=O)=C3NC2C=CC=C(OC)C=2)(=O)=O)C=CC=1)=O)(C(C)(C)C)(C)C.[NH2:67][CH2:68][C@@H:69]([C:71]1[CH:80]=[CH:79][C:78]([OH:81])=[C:77]2[C:72]=1[CH:73]=[CH:74][C:75](=[O:82])[NH:76]2)[OH:70].[CH3:83][O:84][C:85]1[CH:86]=[C:87]([NH:91][C:92]2[C:101]3[C:96](=[C:97]([CH3:126])[CH:98]=[C:99]([S:102]([C:105]4[CH:110]=[CH:109][CH:108]=[C:107]([CH2:111][N:112]([C:114]([C:116]5[CH:121]=[CH:120][CH:119]=[C:118]([CH2:122][C:123](=O)[CH3:124])[CH:117]=5)=[O:115])[CH3:113])[CH:106]=4)(=[O:104])=[O:103])[CH:100]=3)[N:95]=[CH:94][C:93]=2[C:127]([NH2:129])=[O:128])[CH:88]=[CH:89][CH:90]=1>>[OH:70][C@H:69]([C:71]1[CH:80]=[CH:79][C:78]([OH:81])=[C:77]2[C:72]=1[CH:73]=[CH:74][C:75](=[O:82])[NH:76]2)[CH2:68][NH:67][CH:123]([CH3:124])[CH2:122][C:118]1[CH:117]=[C:116]([CH:121]=[CH:120][CH:119]=1)[C:114]([N:112]([CH2:111][C:107]1[CH:106]=[C:105]([S:102]([C:99]2[CH:100]=[C:101]3[C:96](=[C:97]([CH3:126])[CH:98]=2)[N:95]=[CH:94][C:93]([C:127]([NH2:129])=[O:128])=[C:92]3[NH:91][C:87]2[CH:88]=[CH:89][CH:90]=[C:85]([O:84][CH3:83])[CH:86]=2)(=[O:104])=[O:103])[CH:110]=[CH:109][CH:108]=1)[CH3:113])=[O:115]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(CN(C)C(=O)c5cccc(CC(C)=O)c5)c4)cc23)c1
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(CN(C)C(=O)c5cccc(CC(C)NC[C@H](O)c6ccc(O)c7[nH]c(=O)ccc67)c5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 148, using Intermediate 6 in place of Intermediate 2 and Intermediate 137 in place of Intermediate 112.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[S:10][C:5]=2[N:4]=[CH:3]1.[OH-].[Na+]>CO>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[S:10][C:5]=2[N:4]=[CH:3]1
Reactant: COC(=O)c1cc2[nH]c(=O)cnc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2[nH]c(=O)cnc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To a solution of methyl 2-oxo-1,2-dihydrothieno[3,2-b]pyrazine-6-carboxylate 21 (50 mg, 0.238 mmol) in methanol (3 mL) was added a solution of 2N sodium hydroxide (0.238 mL, 0.476 mmol). The reaction was stirred at rt for 2 h. Quenched with 2N HCl solution and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated to give crude 2-oxo-1,2-dihydrothieno[3,2-b]pyrazine-6-carboxylic acid 84 (27 mg, 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][C:3]=1Cl>CO.[C].[Pd]>[NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:24])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)c(Cl)c3)ccn2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reaction time: 72 h
Yield: 70.8 %

Procedure:
4-(4-Amino-3-chlorophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (122 mg) was dissolved in methanol (15 ml). After then adding 10% palladium-carbon (123 mg), the mixture was stirred for 3 days under a hydrogen atmosphere. The catalyst was filtered and washed with methanol. The filtrate and the washings were combined and concentrated under reduced pressure, and the resultant residue was dried under reduced pressure to provide the title compound (79 mg, 71%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[S:12][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C1COCC1>[C:23]([O:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[S:12][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])(=[O:25])[CH3:24]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)CCCO)s1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCCCS(=O)(=O)c1ccc(S(N)(=O)=O)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(3-hydroxypropanesulfonyl)thiophene-2-sulfonamide (1.2 g, 4.2 mmol) in 75 ml of THF was added 0.5 ml of pyridine and 0.5 ml of acetyl chloride. The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The oily residue was dissolved in ethyl acetate and the ethyl acetate was washed with aqueous sodium bicarbonate solution and then brine. After drying over sodium sulfate the ethyl acetate was concentrated under vacuum, giving a solid residue. This solid was recrystallized from dichloroethane to give 1.0 g of product; m.p. 103°-104.5°. 1H-NMR,δ (DMSO, d6) 7.97 (2H, S); 7.75 (1H, d, J=3); 7.57 (lH, d, J=3); 4.00 (2H, t, J=6); 3.50 (2H, m); 1.90 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[C:20](=[O:42])[N:21]([CH2:40][CH3:41])[C:22]4[C:27]([CH:28]=3)=[CH:26][N:25]=[C:24]([N:29](CC3C=CC(OC)=CC=3)[CH3:30])[CH:23]=4)[C:16]([CH3:43])=[CH:15][C:14]=2[F:44])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[C:20](=[O:42])[N:21]([CH2:40][CH3:41])[C:22]4[C:27]([CH:28]=3)=[CH:26][N:25]=[C:24]([NH:29][CH3:30])[CH:23]=4)[C:16]([CH3:43])=[CH:15][C:14]=2[F:44])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(Cl)c3)c(F)cc2C)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(Cl)c3)c(F)cc2C)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.2 %

Procedure:
A solution of 1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (0.105 g, 0.170 mmol) in TFA (3 mL) was treated with anisole (0.093 ml, 0.849 mmol) and stirred at RT for 4 h. The mixture was concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The combined fractions were neutralized with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford 1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (62 mg, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.69 (s, 1H), 8.40 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.35 (s, 1H), 7.27 (dt, J=11.3, 2.1 Hz, 1H), 7.14 (d, J=12.1 Hz, 1H), 7.00-6.95 (m, 2H), 6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 2.07 (s, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 498.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][C:13]([C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])=[C:12]3[NH:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27][CH2:26]2)[CH:5]=[CH:6][C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[NH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:24][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=4)[CH:10]=3)[N:15]=[CH:14][C:13]=2[C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)c1cnc2ccc(-c3ccc(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)c1cnc2ccc(-c3ccc(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[6-(3-chloro-4-hydroxyphenyl)-3-isobutyrylquinolin-4-ylamino]cyclohexylcarbamate (39 mg, 0.072 mmol) was reacted with TFA (2 mL) to afford the desired product (15.4 mg, 41%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.05 (s, 1H), 8.40 (s, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.72 (d, J=2.3 Hz, 1H), 7.54 (dd, J=8.4, 2.3 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 4.31 (s, 1H), 3.80-3.72 (m, 1H), 3.29-3.26 (m, 1H), 2.44 (d, J=12.7 Hz, 2H), 2.22 (d, J=10.6 Hz, 2H), 1.84-1.74 (m, 2H), 1.67-1.56 (m, 2H), 1.25 (d, J=6.8 Hz, 6H); ESI MS m/z 438 [C25H28ClN3O2+H]+; HPLC 96.5% (AUC), tR=9.19 min.