Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][N:4]=1.[H][H]>[C].[Pd].C(O)C>[CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:12]([F:15])([F:13])[F:14])=[CH:5][N:4]=1
Reactant: CNc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNc1ncc(C(F)(F)F)cc1N
Yield: 83.8 %

Procedure:
A mixture of N-methyl-(3-nitro-5-trifluoromethyl-pyridin-2-yl)-amine (6.93 g), 5% of palladium-carbon (0.69 g), and ethanol was stirred under about 1 atm of hydrogen at room temperature for 10 hours. The reaction mixture was filtered through Celite®, and then the filtrate was concentrated under reduced pressure to give 5.02 g of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (Compound (1F)-1).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:29]=O)=[N:18][CH:19]=[C:20]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[CH3:28])[N:21]=1.[CH2:31]([NH:38][CH2:39][CH2:40][OH:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:31]([N:38]([CH2:29][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[CH3:28])=[CH:19][N:18]=1)[CH2:39][CH2:40][OH:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC1CCCCN1c1cnc(C=O)c(Cl)n1
Reactant: OCCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC1CCCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 21 h
Yield: 88.3 %

Procedure:
Sodium triacetoxyborohydride (1.56 g) was added to a solution of 3-chloro-5-(2-methylpiperidin-1-yl)pyrazine-2-carbaldehyde (1.18 g), N-benzylethanolamine (0.83 g) and acetic acid (0.84 mL) in acetonitrile (8 mL), and the mixture was stirred at room temperature for 21 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (1.63 g, 89%) as a pale-yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:13]=[C:12]([CH2:14][F:15])[CH:11]=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:15][CH2:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:7])[N:13]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc(CF)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc(CF)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of (4-fluoromethylpyrimidin-2-yl)carbamic acid tert-butyl ester (140 mg, 0.62 mmol) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 1 hour then concentrated under reduced pressure. The residue was purified by SCX-2 chromatography (washing with methanol and eluting with 2M ammonia in methanol) to afford the title compound as a yellow solid (78 mg, quant. yield). 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J=5.1 Hz, 1H), 6.79-6.78 (m, 1H), 5.33-5.30 (m, 1H), 5.21-5.19 (m, 1H), 5.13 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=1)=[CH:10][C:9]([NH:27][C:28](=[O:35])/[CH:29]=[CH:30]/CN(C)C)=[CH:8][CH:7]=2)#[N:2].C(N(CC)CC)C.C(Cl)(=O)C=C.NC1C=C2C(=CC=1)N=CC(C#N)=C2NC1C=CC(OC2C=CC=CC=2)=CC=1>C1COCC1.O>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=1)=[CH:10][C:9]([NH:27][C:28](=[O:35])[CH:29]=[CH2:30])=[CH:8][CH:7]=2)#[N:2]
Reactant: CN(C)C/C=C/C(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1
Agent: C=CC(=O)Cl
Agent: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Oc2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Example 3 was prepared as an off-white solid using a procedure similar to that described for the synthesis of compound 21 (Example 2). Triethylamine (1.03 g, 10.2 mmol, 1.2 eq) and acryloyl chloride (926 mg, 10.2 mmol, 1.2 eq) were added to an ice cold solution of 6-amino-4-((4-phenoxyphenyl)amino)quinoline-3-carbonitrile (3.0 g, 8.5 mmol, 1.0 eq) in THF (50 mL) under nitrogen. The reaction was stirred at rt for 2 hours. The water was added. The water layer was extracted with EA, dried over anhydrous sodium sulfate. The crude product was purified by column chromatography on silica gel to give N-(3-cyano-4-((4-phenoxyphenyl)amino)quinolin-6-yl)acrylamide as an off-white solid 1.2 g.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:18]=[N:17][CH:16]=[CH:15][C:9]=3/[C:10](=[N:13]/[OH:14])/[C:11](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:23].[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:26]=1[CH:27]=O>C(O)(=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:26]=1[C:27]1[N:13]([OH:14])[C:10]2[C:9]3[CH:15]=[CH:16][N:17]=[CH:18][C:8]=3[NH:7][C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:11]=2[N:23]=1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: O=c1/c(=N\O)c2ccncc2[nH]c2ncccc12
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: On1c(-c2c(Cl)cccc2Cl)nc2c1-c1ccncc1Nc1ncccc1-2
Reaction time: 1 h
Yield: 93.4 %

Procedure:
(6Z)-5H-dipyrido[2,3-b:4′,3′-f]azepine-5,6(11H)-dione 6-oxime (11.0 g, 0.0435 mol), ammonium acetate (50 g, 0.65 mol), 2,6-dichlorobenzaldehyde (15.2 g, 0.0870 mol) and acetic acid (200 mL) were heated at 90° C. for 30 minutes. The reaction was concentrated in vacuo to rigorously remove the acetic acid and then the residue was diluted with water (250 mL) and sodium bicarbonate saturated solution (250 mL) added to achieve a basic pH. Ethyl acetate (100 mL) and diethyl ether (300 mL) were then added. The desired product precipitated from the vigorously stirred mixture and was allowed to stand one hour prior to filtration that afforded the product as an off-yellow solid (16.1 g, 93%). This material was used without further purification in the next step. LCMS calculated for C19H12Cl2N5O (M+H)+: m/z=396. Elemental Analysis calculated for C19H13Cl4N5; C, 50.36; H, 2.89; Cl, 31.29; N, 15.45. Found: C, 48.93; H, 2.81; Cl, 30.57; N. 14.94.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][C:9]([N:18]([CH3:20])[CH3:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:4].[Cl-].[CH3:22][O:23]C1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([CH:48]([CH3:52])C(O)=O)=[CH:40]1>CO>[CH3:19][N:18]([CH3:20])[C:9]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:11][CH:6]([NH:5][C:3]([CH2:2][NH:1][C:22](=[O:23])[CH2:52][CH2:48][C:41]2[C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[NH:39][CH:40]=2)=[O:4])[CH2:7][CH2:8]1
Reactant: CC(C(=O)O)c1c[nH]c2ccccc12
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)CN)CC1
Agent: [Cl-]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)CNC(=O)CCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The more nonpolar diastereomer of 2-amino-N-(4-dimethylamino-4-phenylcyclohexyl)-acetamide (276 mg, 1.0 mmole) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (415 mg, 1.5 mmole) were added to a solution of indol-3-yl-propionic acid (189 mg, 1.0 mmole) in MeOH and stirred for 24 h at room temperature. Working up was performed by removing MeOH by distillation. The batch was re-dissolved with water, adjusted to pH 11 with 5M NaOH and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and evaporated. The more nonpolar amide was obtained as a colorless oil in a yield of 446 mg (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:18][CH2:19][N:20]([S:36]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)(=[O:38])=[O:37])[CH2:21][CH2:22]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Nc1nc(N2CCN(S(=O)(=O)c3ccccc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.15 mmol) and pyridine (18 μl, 0.23 mmol) in DMF (1 ml) was added benzenesulfonyl chloride (21 μl, 0.17 mmol). The reaction mixture was stirred for 3 hours at room temperature. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 80:1) to yield the title compound as a white solid (32 mg, 45%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[CH:17](=O)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17]=[C:2]1[C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4]
Reactant: O=Cc1ccccc1O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) in DMF (0.5 mL) was added salicylaldehyde (61 mg, 53 μL, 0.5 mmol) followed by potassium carbonate (138 mg, 1.0 mmol) and the resulting mixture stirred vigorously at room temperature for 2 h. The mixture was then poured onto ice-water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over Na2SO4 and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate:=100:0 to 1:1) afforded the title compound (131 mg, 86%) as a white solid. MS m/e: 304.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:16][CH2:15][CH2:14][C:5]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6]2)[CH2:4][CH2:3]1.[H-].[Na+].I[CH3:20]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][N:16]1[C:2](=[O:1])[CH2:3][CH2:4][C:5]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6]2)[CH2:14][CH2:15]1
Reactant: O=C1CCC2(CCN1)COc1ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCC2(CCC1=O)COc1ccccc12
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
1,2,3,5,6,7-Hexahydro-7-oxospiro[4H-azepine-4,3'(2H)-benzofuran] (D25, 0.42 g, 1.9 mmol) was dissolved in dry DMF (10 ml) and added under Ar to sodium hydride (80% in mineral oil, 0.09 g, 3 mmol) in dry DMF (1 ml). After stirring for 5 min, iodomethane (0.24 ml, 3.8 mmol) was added. The mixture was stirred for 1 h, diluted with ethyl acetate (150 ml), washed with water and brine, dried (Na2SO4) and evaporated to give the title compound (0.36 g, 79%) as yellow semi-solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+]>O.C1(C)C=CC=CC=1>[CH2:11]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 9.4 %

Procedure:
A mixture of 13.11 g (0.1 mole) of 2-methylindole, 13.92 g (0.11 mole) of benzyl chloride, 33 g (0.5 mole) of 85% KOH, 14 mL of H2O, 2.5 g (2.5 mmoles) of PEG-1000, and 100 mL of toluene was stirred and heated at 60° for 23 hours. After cooling to room temperature, 100 mL of H2O was added. The layers were separated. The aqueous layer was extracted with 100 mL of toluene. The combined toluene phases were washed 2N HCl (2×50 mL), H2O (2×50 mL), and 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 26.98 g of dark brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 20-22 were combined giving 2.08 g (9%) of 1-benzyl-2-methylindole as a yellow oil which solidified.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[C:14]([NH:16][CH2:17][C:18]([O:20]C)=[O:19])=[O:15].CO.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:24][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: COC(=O)CNC(=O)c1c(O)c2ccccc2n(C)c1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(=O)NCC(=O)O)c(=O)n(C)c2ccccc12

Procedure:
Methyl 2-(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.394 g, 1.4 mmol), methanol (0.33 ml, 8.1 mmol) and triphenyl phosphine (0.94 ml, 4.1 mmol) were placed in a 50 mL round bottomed flask with 25 mL of THF. The flask was placed in an ice bath. Diethyl azodicarboxylate (0.64 ml, 4.1 mmol) was added dropwise. A white solid was filtered and this solid was purified by silica flash chromatography (0-3% MeOH/DCM) to give the desired product.
Reaction SMILES: [Br:1]/[C:2](=[C:6](/[CH3:18])\[CH:7]=[CH:8]\[C:9]1[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]=1[CH3:17])/[C:3]([OH:5])=[O:4].[H-].[Na+].[H][H].[CH3:23]I>CN(C)C=O.O1CCCC1>[Br:1]/[C:2](=[C:6](/[CH3:18])\[CH:7]=[CH:8]\[C:9]1[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]=1[CH3:17])/[C:3]([O:5][CH3:23])=[O:4].[Br:1]/[C:2](=[C:6](\[CH3:18])/[CH:7]=[CH:8]/[C:9]1[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]=1[CH3:17])/[C:3]([O:5][CH3:23])=[O:4]
Reactant: CC1=C(/C=C/C(C)=C(\Br)C(=O)O)C(C)(C)CCC1
Reactant: CI
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)/C(Br)=C(C)/C=C/C1=C(C)CCCC1(C)C
Product: COC(=O)/C(Br)=C(C)\C=C\C1=C(C)CCCC1(C)C
Temperature: 55 °C

Procedure:
A mixture of (2E,4E) and (2Z,4E)-2-bromo-3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienoic acid (75 g) was dissolved in dimethylformamide (500 ml) and slowly added to a suspension of sodium hydride (10.5 g; 65% in oil) in tetrahydrofuran (1100 ml) at 10° C. and then stirred until all hydrogen evolution ceased. Methyl iodide (50 g) was then added and the resulting mixture was heated for 2 hours at 50-60° C., poured onto an ice-water mixture and extracted with hexane. The hexane extracts were washed with water, dried (magnesium sulphate) and concentrated. The mixture of methyl esters was then separated by HPLC (2.5% ether/hexane) to give pure methyl (2Z,4E)-2-bromo-3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienoate (20 g) and methyl (2E,4E)-2-bromo-3-methyl-5-(2,6,6-trimethyl-cyclohexen-1-yl)-2,4-pentadienoate (37 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.[CH2:23](O)C>S(=O)(=O)(O)O.C(OCC)(=O)C>[CH2:1]([O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1)[CH3:23]
Reactant: COC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 20 %

Procedure:
A solution of [5-(4-fluoro-phenylcarbamoyl)-pyridin-2-yloxy]-acetic acid methyl ester (0.030 g, 0.99 mmole), ethanol (2 mL), and sulfuric acid (1 drop) was heated in a sealed tube at 80° C. After 6 h the reaction mixture was poured into ethyl acetate and washed with saturated sodium bicarbonate and dried over sodium sulfate. Removal of the solvents provided 6 mg (20%) of the titled product as a white solid:
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:21]2[CH2:23][C:22]2([F:25])[F:24])O)=[CH:15][CH:14]=1.[CH3:26][S:27]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2)(=[O:29])=[O:28]>ClCCCl.ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:21]2[CH2:23][C:22]2([F:25])[F:24])[C:36]2[C:35]3[C:39](=[C:31]([CH2:30][S:27]([CH3:26])(=[O:29])=[O:28])[CH:32]=[CH:33][CH:34]=3)[NH:38][CH:37]=2)=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Reactant: OC(c1ccc(Cl)cc1)C1CC1(F)F
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CS(=O)(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3(F)F)c[nH]c12

Procedure:
In three parallel batches in each case 3.08 g (13.9 mmol) of indium(III) chloride and 1.6 ml (20.9 mmol) of trifluoroacetic acid were added to in each case 2.54 g (11.6 mmol) of the compound from Example 159A and 2.92 g (13.9 mmol) of the compound from Example 86A in 125 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was diluted in each case with dichloromethane, and the three batches were combined and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered through kieselguhr and concentrated. The residue was purified by preparative SFC (ethylpyridine column; mobile phase: carbon dioxide/methanol gradient; 150 bar; 35° C.) to result in 995 mg (7% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[CH2:9][CH2:10][C:11]([CH2:13][C:14]([O-:16])=[O:15])=O.[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:17][O:16][C:14](=[O:15])/[CH:13]=[C:11](\[NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)/[CH2:10][CH3:9]
Reactant: Nc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCC(=O)CC(=O)[O-]
Solvent: CCOCC
Product: CC/C(=C/C(=O)OC)Nc1cccnc1
Reaction time: 96 h
Yield: 467.6 %

Procedure:
A mixture of 3-aminopyridine (5.0 g), methylpropionylacetate (7.6 g) and p-toluenesulphonic acid (0.5 g) was stirred for 96 hours and then ether (100 ml) was added. The solution was washed with water (100 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue purified by flash chromatography, eluting with ethyl acetate to give methyl-(Z)-3-(3-pyridylamino)-2-pentenoate (B3) (2.8 g) as an oil; NMR (CDCl3): 1.1(t,3H), 2.5(q,2H), 3.7(s,3H), 4.95(s,1H), 7.3(m,1H), 7.4(m,1H), 8.4(m,2H), 10.3(br,1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:5][N:6]=1.[CH3:15][CH:16]([C:29](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:30])[C:17](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:18].ClC1C=CC=CC=1>CCCCCC>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:29]([OH:30])=[C:16]([CH3:15])[C:17](=[O:18])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCSc1nnc(N)s1
Reactant: CC(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: CCCCCC
Solvent: Clc1ccccc1
Product: CCCCCCCSc1nn2c(=O)c(C)c(O)nc2s1
Reaction time: 0.75 h
Yield: 78 %

Procedure:
A mixture of 19.7 g of the thus obtained 2-amino-5-heptylthio-1,3,4-thiadiazole, 40.9 g of bis (2,4,6-trichlorophenyl) 2-methyl-malonate and 55 ml of chlorobenzene was stirred at 140°~144° C. for 45 minutes. After cooling, n-hexane was added thereto, the precipitate was collected by filtration. Further n-hexane was added to the filtrate, and the precipitate was collected. The collected precipitates were combined. The combinedprecipitate was washed with n-hexane and thus 21.2 g of 2-heptylthio-7-hydroxy-6-methyl-5H-1,3,4-thiadiazolo-[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[CH3:30][NH:31][CH3:32]>CN1C(=O)CCC1.CO>[CH3:30][N:31]([CH3:32])[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1
Reactant: CNC
Reactant: Cc1ccc(NC(=O)c2ccccc2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)c2ccccc2)cc1-c1cc2cnc(N(C)C)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
N-(3-(7-chloro-1,2-dihydro-1-methyl-2-oxo-1,6-naphthyridin-3-yl)-4-methylphenyl)benzamide A6 (45 mg, 0.11 mmol) is dissolved in NMP (1 mL) and treated with dimethyl amine (0.56 mL of a 2.0 M solution in methanol). The reaction mixture is heated to 100° C. for 12 h. Upon cooling to rt, the reaction is purified by preparative LCMS. 1H NMR 400 MHz (DMSO-d6) δ 10.23 (s, 1H), 8.51 (s, 1H), 7.97-7.94 (m, 2H), 7.78 (s, 1H), 7.68-7.66 (m, 2H), 7.61-7.51 (m, 3H), 7.23 (d, J=9 Hz, 1H), 6.37 (s, 1H), 3.61 (s, 3H), 3.20 (s, 6H), 2.12 (s, 3H); MS m/z 413.2 (M+1).
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][N:11]([C:13]([O:15]C(C)(C)C)=O)[C@H:10]([C:20]([OH:22])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:31])[CH2:25][CH2:26][CH2:27]C(Cl)=O.[CH2:32]([N:34]1[C:46]2[CH:45]=[CH:44][C:43]([NH2:47])=[CH:42][C:41]=2[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:33]>>[CH:1](=[C:8]1[CH2:12][N:11]([C:13](=[O:15])[CH2:27][CH2:26][CH2:25][N:24]([CH3:31])[CH3:23])[C@H:10]([C:20]([NH:47][C:43]2[CH:44]=[CH:45][C:46]3[N:34]([CH2:32][CH3:33])[C:35]4[C:40]([C:41]=3[CH:42]=2)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2ccccc2)C[C@H]1C(=O)O
Reactant: CN(C)CCCC(=O)Cl
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=Cc4ccccc4)CN3C(=O)CCCN(C)C)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 4-(dimethylamino)butanoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=509.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10]([N:17]=[CH:18][N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]CN)=[CH:34][CH:33]=1)[CH3:30])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][CH2:38][C:35]4[CH:36]=[CH:37][C:32]([CH2:31][N:29]([CH3:30])[C:27](=[O:28])[O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:33][CH:34]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: CN(Cc1ccc(CCN)cc1)C(=O)OC(C)(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
A mixture of methyl 5-(4-chlorophenyl)-3-(dimethylaminomethyleneamino)thiophene-2-carboxylate (0.2 g), 2-[4-(N-tert-butyloxycarbonyl-N-methylaminomethyl)phenyl]ethanamine (0.19 g) and ethanol (4 ml) were stirred at 70° C. for 3 hr. The reaction mixture was allowed to cool, ethyl acetate was added, and the precipitate was collected by filtration to give the title compound (160 mg) as a colorless powder.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH3:14][C:15]1[C:16](B(O)O)=[N:17][CH:18]=[CH:19][CH:20]=1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:24][C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)[N:3]=[CH:4][C:5]=2[C:16]2[C:15]([CH3:14])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:10]=1
Reactant: Cc1csc(N)n1
Reactant: Cc1cccnc1B(O)O
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Product: Cc1csc(Nc2ncc(-c3ncccc3C)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=348.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3-methylpyridine-2-boronic acid and 2-amino-4-methylthiazole.