Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:18]=[C:17](O)[C:16]2[C:15](=[O:20])[N:14]([C:21]3[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=3[CH3:30])[CH2:13][CH2:12][C:11]=2[N:10]=1.C(=O)(O)[O-].[Na+].[OH-].[Na+].C(Cl)[Cl:39]>>[Cl:39][C:17]1[C:16]2[C:15](=[O:20])[N:14]([C:21]3[CH:26]=[C:25]([CH:27]([CH3:28])[CH3:29])[CH:24]=[CH:23][C:22]=3[CH3:30])[CH2:13][CH2:12][C:11]=2[N:10]=[C:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH:18]=1
Reactant: ClCCl
Reactant: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)cccc3C)cc(O)c2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)cccc3C)cc(Cl)c2C1=O
Temperature: 25 °C

Procedure:
To a solution of crude 2-(2,6-dimethylphenyl)-4-hydroxy-6-(5-isopropyl-2-methylphenyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (1.4 g, 3.50 mmol) in DCM (35.0 mL) was added Vilsmeier's reagent (0.895 g, 6.99 mmol) as a solid in one portion and the reaction mixture stirred at room temperature. After 2 h 500 mg of Vilsmeier's reagent was added and stirring continued. After 35 min an additional portion of 200 mg of Vilsmeier's reagent was added and stirring continued. After 15 min the reaction mixture was diluted with DCM and poured into saturated aqueous sodium bicarbonate solution containing 1 N NaOH. The layers were separated and the aqueous layer was extracted with DCM (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by FCC (0-20% EtOAc/heptane) to provide 4-chloro-2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one. MS (ESI+) m/z 419.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CO.O>[CH2:12]([NH:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1nc2cccc(N)c2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Cc1nc2cccc(NCc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 1.6 %

Procedure:
A mixture of 3.8 g (0.026 mol) 4-amino-2-methylbenzimidazole, 2.7 g (0.026 mol) benzaldehyde and 0.05 g paratoluene sulfonic acid in 250 ml toluene was refluxed and the water formed was separated during 20 h. Upon cooling the volatiles were removed under reduced pressure. The residue obtained was suspended in 150 ml methanol and 1.8 g (0.048 mol) NaBH4 was added. The mixture was stirred at room temperature for 2 h and methanol was removed under reduced pressure. The residue was dissolved in methylene chloride, washed with water and dried (Na2SO4). After filtration, methylene chloride was removed under reduced pressure. Chromatography on silica gel and elution with methylene chloride:methanol (10:1) gave 0.1 g (0.00042 mol) of 4-benzylamino-2-methyl benzimidazole
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@@H:7]([C:9]#[N:10])[CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(O)C.[Ni]>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@@H:7]([CH2:9][NH2:10])[CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12]
Reactant: COC(=O)[C@@H]1C[C@@H](C#N)CN1C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CCO
Product: COC(=O)[C@@H]1C[C@@H](CN)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of N-tert-butoxycarbonyl-trans-4-cyano-L-proline methyl ester (A, 197 mg) and Raney-Ni (100 mg) in ethanol (6 mL) was stirred at room temperature for 21 hr under hydrogen. The catalysts were removed by filtration and washed with ethanol. The filtrate was evaporated in vacuo to give the title compound (204 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2>O=[Pt]=O.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2
Reactant: Clc1ccc2ncccc2c1
Agent: O=[Pt]=O
Solvent: CO
Product: Clc1ccc2c(c1)CCCN2
Reaction time: 4 h
Yield: 62.7 %

Procedure:
A flask filled with a mixture of 6-chloroquinoline (12.0 g, 73.3 mmol), PtO2 (2.16 g, 13 mol %), and MeOH (500 mL, 6.15 M) was flushed with N2 and then equipped with a balloon filled with H2. The reaction was kept under H2 atmosphere and stirred for 4 h. The mixture was filtered through Celite and washed with CH2Cl2. Purification via silica gel chromatography using 50% CH2Cl2 in hexanes gave 6-chloro-1,2,3,4-tetrahydroquinoline (7.7 g, 62%). 1H NMR (400 MHz, DMSO-d6) δ 6.85-6.83 (m, 2H), 6.42-6.39 (m, 1H), 5.82 (s, 1H), 3.17-3.13 (m, 2H), 2.64 (t, J=6.3 Hz, 2H), 1.78-1.72 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=168.2; tR=1.57 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=C[N:21]([C:24]([N:26]2C=[N:29][CH:28]=[CH:27]2)=O)[CH:20]=1.N1C=C(N)C=NC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:29][C:28]1[CH:20]=[N:21][CH:24]=[N:26][CH:27]=1)=[O:9]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: Nc1cncnc1
Solvent: C1CCOC1
Product: O=C(Nc1cncnc1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method C; 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) in THF (3 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and pyrimidin-5-amine (61.9 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate:triethylamine (4:1:0.01) to yield the title compound. 150 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:19][CH:20]=[C:21]([C:27]#[N:28])[C:22](OCC)=O)C.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:15]=[C:14]2[C:12](=[CH:11][C:10]=1[F:16])[NH:13][CH:22]=[C:21]([C:27]#[N:28])[C:20]2=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)c(F)c1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: N#Cc1c[nH]c2cc(F)c(OCc3ccccc3)cc2c1=O
Temperature: 25 °C
Yield: 31.7 %

Procedure:
A mixture of 4-benzyloxy-3-fluoroaniline (6.06 g, 27.9 mmol) (U.S. Pat. No. 5,622,967) and ethyl (ethoxymethylene)cyanoacetate (5.08 g, 30.0 mmol) is heated at 120° C. for 45 minutes then cooled to room temperature. This solid is added in portions to a 3:1 mixture of diphenyl ether:biphenyl at 245° C. This mixture is heated at 245° C. for 3 hours then cooled and the solids are collected by filtration, washing with hexane and diethyl ether to provides 2.60 g of 6-benzyloxy-7-fluoro-4-oxo-1, 4-dihydro-3-quinolinecarbonitrile, mp>250° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[F:7][C:8]([F:17])([F:16])[C:9]([C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=[O:10]>>[CH3:1][C:2]1[N:3]=[C:4]([C:9]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)([OH:10])[C:8]([F:17])([F:16])[F:7])[S:5][CH:6]=1
Reactant: O=C(c1nccs1)C(F)(F)F
Reactant: Cc1cscn1
Product: Cc1csc(C(O)(c2nccs2)C(F)(F)F)n1

Procedure:
From 4-methylthiazole and 2-trifluoroacetylthiazole using the general method of Example 6. M.p. 89°-90° C.
Reaction SMILES: [NH:1]([C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=3[O:19][CH3:20])[NH:11][C:7]=2[CH:6]=1)[C:2]([CH3:4])=[O:3].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[NH:1]([C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][C:13]=3[O:19][CH3:20])[NH:11][C:7]=2[CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: COc1cc(O)ccc1-c1nc2ccc(NC(C)=O)cc2[nH]1
Reactant: CS(=O)(=O)Cl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(NC(C)=O)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 5-acetamino-2-(2'-methoxy-4'-hydroxy-phenyl)-benzimidazole and methanesulfonic acid chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1.[C:17]1(OB(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCCC1>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.O.C(OCC)(=O)C.O1CCCC1>[C:11]1([C:9]2[NH:10][C:4]3[C:5]([N:8]=2)=[N:6][CH:7]=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Brc1cnc2nc(-c3ccccc3)[nH]c2c1
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: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(-c2cnc3nc(-c4ccccc4)[nH]c3c2)cc1
Temperature: 85 °C
Reaction time: 24 h
Yield: 22.5 %

Procedure:
Under an argon stream, a mixture of 6-bromo-2-phenyl-1H-imidazo[4,5-b]pyridine (Compound of Reference Example 3) (90 mg), phenylboric acid (104 mg), tetrakis(triphenylphosphine)palladium(0) (38 mg), 2 M sodium carbonate (0.82 ml) and tetrahydrofuran (3.3 ml) was stirred at 85° C. for 24 hours. The mixture was distributed into ethyl acetate-tetrahydrofuran (3:1, v/v) and water. The organic layer was washed with water and dried over MgSO4, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-chloroform-hexane (1:1:4, v/v) was concentrated under reduced pressure. The resulting crystals were collected by filtration to obtain 2,6-diphenyl-1H-imidazo[4,5-b]pyridine (20 mg, 22%). The crystals were recrystallized from chloroform-methanol.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([O:9][CH2:10][N:11]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:12](=[O:16])[CH2:13][S:14][CH3:15])[CH3:8]>O.C(O)C>[CH2:7]([O:9][CH2:10][N:11]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=1)[C:12](=[O:16])[CH2:13][S:14]([CH3:15])=[O:2])[CH3:8]
Reactant: CCOCN(C(=O)CSC)c1cccc(C(F)(F)F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOCN(C(=O)CS(C)=O)c1cccc(C(F)(F)F)c1
Reaction time: 24 h

Procedure:
A solution of sodium periodate (20.5 g) in water (190 ml) was added dropwise to a stirred solution of crude product of Step 2 in ethanol (850 ml) at 5° C. The mixture was allowed to reach 20° C. gradually and stirred for 24 hours, then concentrated under reduced pressure. The concentrate was extracted with dichloromethane (500 ml), the extract dried over sodium sulphate, filtered and concentrated under reduced pressure to give the crude product as a brown oil (27.5 g). 1H NMR (CDCl3l ): δ 1.24(3 H,t); 2.76(3 H,s); 3.56(2 H,s); 3.67(2 H, 5.12(2 H,s); 7.51-7.69(4 H,m).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[F:18][C:19]([F:32])([F:31])[C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[O:23][CH:24]1[CH2:27][NH:26][CH2:25]1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:26]1[CH2:27][CH:24]([O:23][C:22]2[CH:28]=[CH:29][CH:30]=[C:20]([C:19]([F:18])([F:32])[F:31])[CH:21]=2)[CH2:25]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 7 %

Procedure:
Prepared in analogy to Example 1 from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 3-(3-trifluoromethyl-phenoxy)-azetidine. The crude material was purified by chromatography (methanol/dichloromethane) to yield the title compound as an amorphous white solid (yield 7%). MS (m/e): 458.2 (M+H+, 100%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][CH:30]=1)[C:8]1[N:9](COCC[Si](C)(C)C)[N:10]=[C:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=3)[C:7]=1[CH2:6]2.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:66][C:67]1[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=1>C1COCC1>[N:69]1[CH:70]=[CH:71][CH:72]=[C:67]([O:66][CH2:2][C:3]2[CH:4]=[C:5]3[C:28](=[CH:29][CH:30]=2)[C:8]2[NH:9][N:10]=[C:11]([C:12]4[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=4)[C:7]=2[CH2:6]3)[CH:68]=1
Reactant: Oc1cccnc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(C#N)nc2)c2c1-c1ccc(CO)cc1C2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2n[nH]c3c2Cc2cc(COc4cccnc4)ccc2-3)cn1
Temperature: 75 °C
Yield: 23.7 %

Procedure:
A mixture of Example 131A (60.0 mg, 0.143 mmol), di-t-butyl azodicarboxylate (39.6 mg, 0.172 mmol), Ph3P on solid support (3 mmol/g, 57.3 mg, 0.172 mmol), and 3-hydroxypyridine (16.4 mg, 0.172 mmol) in THF (2 mL) was stirred at room temperature overnight. The solid was filtered and the solvent was evaporated. The crude product was treated with HCl (concentrated, 4 drops) and EtOH (4 mL). The mixture was heated in a capped vial at 75° C. for 2 hours. The solvent was evaporated and the residue was purified using reversed-phase HPLC to give the desired product (12.4 mg) as TFA salt. MS (ESI) m/z: 366.0 (M+H)+. 1H NMR (300 MHz, DMSO-D6) δ ppm 4.01 (s, 2H) 5.83 (s, 2H) 7.58 (d, J=7.80 Hz, 1H) 7.74 (m, 1H) 7.80 (s, 1H) 7.93-8.05 (m, 2H) 8.18 (d, J=8.14 Hz, 1H) 8.40 (dd, J=8.14, 2.37 Hz, 1H) 8.62-8.84 (m, 2H) 9.19 (s, 1H) 12.14 (s, 1H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[K+].[Br-].S1C2C=CC=CC=2C(N2CCN(CCCCN3C(=O)C[C:32]4([CH2:36][CH2:35][CH2:34][CH2:33]4)C(O)C3=O)CC2)=N1>>[CH2:36]1[C:35]2([CH2:6][C:5](=[O:7])[O:4][C:1](=[O:3])[CH2:2]2)[CH2:34][CH:33]=[CH:32]1
Reactant: O=C1CC2(CCCC2)C(O)C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Reactant: CC(=O)OC(C)=O
Agent: [Br-]
Agent: [K+]
Product: O=C1CC2(CC=CC2)CC(=O)O1

Procedure:
Diacid IVe (10.5 g, 57.0 mmol) was dissolved in acetic anhydride (40.0 g, 0.392 mol) and heated to reflux for 15 h. The excess acetic anhydride was distilled off and the resulting oil taken up in a minimum of hot benzene. Slow dilution with hot hexane afforded 8.90 g (two crops, 95%) of IVf as off-white needles, mp 64-5° C.; IR (KBr) 1800, 1770, 1080, 1065, 955 cm-1 ; 1H NMR (CDCl3) δ 5.68 (s, 2H), 2.78 (s, 4H), 2.34 (s, 4H); mass spectrum, m/z (relative intensity) 167 (M+1, 100), 149 (15), 139 (8), 121 (8), 80 (10).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[C:21]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][N:25]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH3:31]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CCOC(=O)CNC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with ethyl 2-(tert-butylamino)acetate (CAN 37885-76-0) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=426.5 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[N:7]=1.[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:25]>O.[N+]([O-])(O)=O>[Ag:25].[CH3:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:7]=1
Reactant: [Ag+]
Agent: Cc1ccnc(NS(=O)(=O)c2ccc(N)cc2)n1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: [Ag]

Procedure:
Silver Sulfamerazine was prepared using 26.43 g sulfamerazine, 300 ml of water, 4.00 grams of NaOH warming to 70 degree C. until dissolved. 16.99 grams of silver nitrate in 300 grams of water with 1 drop of 10% nitric acid and warming to 70 degree C. The sulfamerazine solution was added to the silver nitrate solution with stirring. Silver sulfamerazine precipitated as a fine white powder. This was filtered and washed three times with water and dried overnight at 60 deg to give an off-white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.CCN(CC)CC.[NH2:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O>O1CCOCC1.[Cl-].[Na+].O>[O:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:2]2[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH2:21][CH2:22]1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: NC1CCOCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1cnc(NC2CCOCC2)cn1
Temperature: 100 °C
Yield: 33.8 %

Procedure:
Methyl 5-chloro-2-pyrazinecarboxylate (507 mg, 2.94 mmol), Et3N (1.08 mL, 7.64 mmol) and 4-aminotetrahydropyran (0.40 mL, 3.82 mmol) were dissolved in dioxane (5 mL) and heated in a microwave reactor at 100° C. for 20 min. Water (50 mL) and brine (25 mL) were added and the reaction mixture was extracted into EtOAc (2×100 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (236 mg, 33.9%) as a yellow oil. LCMS (ES+): 238.2 [MH]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:36])[C@H:17]([NH:26][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@@H:17]([NH:26][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH:29]([CH3:30])[CH3:31])[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8])=[O:36]
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)Nc1ccccc1OCc1ccccc1)c1ccc(F)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)Nc1ccccc1O)c1ccc(F)cc1F
Reaction time: 3 h
Yield: 92.4 %

Procedure:
A mixture of palladium on carbon (10%, 300 mg), methyl N-[(1R)-2-{[2-(benzyloxy)phenyl]amino}-1-(2,4-difluorophenyl)-2-oxoethyl]-L-leucinate (2.88 g) and ethyl acetate (30 ml) was stirred under a hydrogen atmosphere for 3 hours. The reaction was then filtered through Celite and the filter pad was washed with further portions of ethyl acetate. The combined organic fractions were evaporated to give methyl N-{(1R)-1-(2,4-difluorophenyl)-2-[(2-hydroxyphenyl)amino] -2-oxoethyl}-L-leucinate (2.179 g).
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]1=[O:13].[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:14]1([NH:1][N:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[CH:4][C:3]2=[O:13])[CH2:17][CH2:16][CH2:15]1
Reactant: Nn1c(=O)cc(O)c2ccccc21
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1cc(O)c2ccccc2n1NC1CCC1
Reaction time: 48 h
Yield: 59.9 %

Procedure:
A solution of 1-amino-4-hydroxyquinolin-2(1H)-one (0.516 g, 2.9 mmol) and cyclobutanone (1.05 g, 15.0 mmol) in acetic acid (0.90 g, 15.0 mmol) and methanol (20 mL) was treated portion wise with sodium cyanoborohydride (0.94 g, 15.0 mmol), stirred for 48 hours and concentrated. The residue was treated with 0.5 M aqueous sodium bicarbonate, acidified to pH 2 with 1 M hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over sodium sulfate, filtered and concentrated, The crude material was chromatographed on silica gel eluting with 3:2 hexane/ethyl acetate to give 1-(cyclobutylamino)-4-hydroxyquinolin-2(1H)-one (0.400 g, 60%). MS (ESI+) m/z 231 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 1.52 (m, 1H) 1.63 (m, 1H) 1.96 (m, 4H) 3.64 (m, 1H) 5.91 (s, 1H) 6.26 (d, J=6.62 Hz, 1H) 7.20 (t, J=8.09 Hz, 1H) 7.61 (m, 1H) 7.84 (m, 2H) 11.42 (s, 1H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([F:30])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.C(N(C(C)C)CC)(C)C.[CH3:40][O:41][CH2:42][CH2:43][O:44][CH2:45][C:46](Cl)=[O:47]>C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:30])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:29][CH2:28][N:27]([C:46](=[O:47])[CH2:45][O:44][CH2:43][CH2:42][O:41][CH3:40])[CH2:26][CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COCCOCC(=O)Cl
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCC(=O)N1CCC(Oc2cc3ncnc(Nc4cccc(Cl)c4F)c3cc2OC)CC1
Yield: 33.6 %

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 2-(2-methoxyethoxy)acetyl chloride (0.105 g) were stirred in methylene chloride (9 ml) for 2.5 hours. Methylene chloride (20 ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The resulting product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) gave a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.110 g); 1H NMR Spectrum: (DMSO d6 373K) 1.73 (m, 2H), 2.02 (m, 2H), 3.29 (s, 3H), 3.42 (m, 2H), 3.51 (t, J=7 Hz, 2H), 3.60 (t, J=9 Hz, 2H), 3.78 (m, 2H), 3.96 (s, 3H), 4.17 (s, 2H), 4.87 (m, 1H), 7.27 (m, 1H), 7.33 (s, 1H), 7.42 (m, 1H), 7.58 (m, 1H), 7.85 (s, 1H), 8.39 (s, 1H), 9.29 (br s, 1H); Mass Spectrum: (M+H)+ 519; melting point 110 to 111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([F:10])=[C:8]([F:11])[C:6](N)=[C:5]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[C:4]=1[F:23].N(OCCC(C)C)=O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([F:23])=[C:5]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH:6]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: COc1c(F)c(F)c(N)c(N2C(=O)c3ccccc3C2=O)c1F
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Product: COc1c(F)c(F)cc(N2C(=O)c3ccccc3C2=O)c1F
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A solution of 2.90 g (0.009 mole) of 4-methoxy-2-phthalimido-3,5,6-trifluoroaniline (XXXV) [prepared as described in Step (F2) above] in 18 ml of dimethylformamide was added dropwise, whilst stirring at 60°-65° C., to a solution of 1.66 g (0.0144 mole) of isoamyl nitrite in 9 ml of dimethylformamide. After the addition was complete, the reaction mixture was stirred at the same temperature for 1 hour, and then the solvent was removed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography eluted with toluene, to afford 2.18 g of N-(3-methoxy-2,4,5-trifluorophenyl)phthalimide (XXXVI) as colorless powdery crystals.