Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH2:29][N:30]3[CH2:33][CH:32]([C:34](O)=[O:35])[CH2:31]3)=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1([O:65][C:66](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:37][S:38]([NH:41][C:34]([CH:32]1[CH2:31][N:30]([CH2:29][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[C:18]2=[N:19][O:20][C:16]([C:10]4[O:9][N:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[C:11]=4[C:12]([F:13])([F:14])[F:15])=[C:17]2[CH2:28][CH2:27]3)[CH2:33]1)=[O:35])(=[O:40])=[O:39].[C:66]([OH:65])([C:12]([F:15])([F:14])[F:13])=[O:39]
Reactant: CS(N)(=O)=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CN(Cc2ccc3c(c2)CCc2c-3noc2-c2onc(-c3ccccc3)c2C(F)(F)F)C1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(=O)C1CN(Cc2ccc3c(c2)CCc2c-3noc2-c2onc(-c3ccccc3)c2C(F)(F)F)C1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.8 %

Procedure:
To a stirred mixture of 1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid (Example 7, 80 mg, 0.161 mmol), methanesulfonamide (77 mg, 0.807 mmol), DMAP (3.95 mg, 0.032 mmol), triethylamine (0.113 mL, 0.807 mmol), and anhydrous dichloromethane (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (92 mg, 0.242 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 5 h before being concentrated. The residue was dissolved in MeOH and a little dichloromethane. Purification using reverse phase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration and lyophilization gave N-(methylsulfonyl)-1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxamide, TFA (15 mg, 0.020 mmol, 12.58% yield) as a white solid. The compound had an HPLC retention time=3.21 min (condition C); LC/MS M+1=573.1. 1H NMR (400 MHz, MeOD) δ ppm 8.08 (1H, d, J=7.9 Hz), 7.64-7.69 (2H, m), 7.54-7.64 (4H, m), 7.51 (1H, dd, J=7.9, 1.8 Hz), 4.48 (2H, s), 4.36 (4H, d, J=7.9 Hz), 3.68 (1H, quin, J=8.0 Hz), 3.27 (3H, s), 3.11-3.22 (4H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:4]2[CH2:5][C:6]3[C:10]([CH:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([NH:14][NH2:15])=[O:13].[CH2:17]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH2:28][CH3:29])[N:27]=1)[C:22](O)=O)[CH3:18]>>[CH2:28]([C:26]1[CH:25]=[C:21]([C:22]2[O:13][C:12]([C:7]3[S:8][C:9]([CH3:11])=[C:10]4[C:6]=3[CH2:5][C@H:4]3[C:2]([CH3:16])([CH3:1])[C@H:3]34)=[N:14][N:15]=2)[CH:20]=[C:19]([CH2:17][CH3:18])[N:27]=1)[CH3:29]
Reactant: CCc1cc(C(=O)O)cc(CC)n1
Reactant: Cc1sc(C(=O)NN)c2c1C1C(C2)C1(C)C
Product: CCc1cc(-c2nnc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)o2)cc(CC)n1

Procedure:
2,6-Diethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine is synthesized from 1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid hydrazide and 2,6-diethyl-isonicotinic acid in analogy to Example 5; LC-MS: tR=0.96 min, [M+1]=380.34.
Reaction SMILES: [CH3:1][N:2]([O:32][CH3:33])[C:3](=[O:31])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[NH:20]C(OCC1C=CC=CC=1)=O>C(OCC)(=O)C.CO.[C].[Pd]>[CH3:1][N:2]([O:32][CH3:33])[C:3](=[O:31])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[NH2:20]
Reactant: CON(C)C(=O)c1cc(OCCCc2ccccc2)ccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cc(OCCCc2ccccc2)ccc1N
Temperature: 25 °C

Procedure:
N-Methyl-N-methyloxy-2-benzyloxycarbonylamino-5-(3-phenylpropyloxy)benzamide (1.4 g) was dissolved in a mixture of ethyl acetate (10 ml) and methanol (10 ml). To the solution was added 10% palladium-carbon (0.3 g). The mixture was stirred for 24 houks at room temperature under hydrogen atmosphere. The reaction mixture was subjected to filtration. From the filtrate was distilled off the solvent to leave N-methyl-N-methyloxy-2-amino-5-(3-phenylpropyloxy)benzamide as an orange oily product (1.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:7])[CH3:2].C(O)(=O)C.[N:20]([O-])=[O:21].[Na+]>O>[CH2:1]([O:3][C:4](=[O:15])[C:5](=[N:20][OH:21])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:7])[CH3:2]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)c1cccc(F)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-(3-fluoro-phenyl)-3-oxo-propionic acid ethyl ester (4.85 mmol) in acetic acid (1.90 mmol) is cooled to 10° C. and a solution of sodium nitrite (5.63 mmol) in water (0.68 mL) is added dropwise. The mixture is allowed to reach RT, stirred for 2 h, poured into water (10 mL) and cooled to 0° C. The precipitate is filtered off and dried by azeotropic removal of water with toluene to give crude 3-(3-fluoro-phenyl)-2-hydroxyimino-3-oxo-propionic acid ethyl ester which is dissolved in a mixture of acetic anhydride (1.38 mL) and acetic acid (1.80 mL). Sodium acetate (0.30 mmol), HgCl2 (0.01 mmol) and zinc powder (14.6 mmol) are added successively. The mixture is stirred under reflux for 1 h, cooled to RT and filtered and the residue is washed with ether. The filtrate is washed three times with water and once with aq. K2CO3 solution (1.0 M). The organic layer is dried over MgSO4 and concentrated in vacuo to give the desired crude product which is purified by FC (heptane to heptane/EtOAc 3/7). LC-MS: tR=0.82 min; [M+H]+=268.1.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=[O:21])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Br[CH2:23][CH:24]=[CH2:25].[In].Cl>C1COCC1.O.CCOC(C)=O>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]([OH:21])[CH2:25][CH:24]=[CH2:23])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Reactant: C=CCBr
Agent: Cl
Agent: [In]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC(O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.5 %

Procedure:
To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (5.1 g, 17 mmol) in THF (100 mL) and water (33.3 mL) was added 3-bromoprop-1-ene (2.86 mL, 33.9 mmol) followed by indium (3.89 g, 33.9 mmol). The reaction mixture was stirred for about 15 h at ambient temperature and then aqueous HCl (1 N, 150 mL) and EtOAc (150 mL) were added. The organic layer was separated, dried over anhydrous Na2SO4, filtered, coned in vacuo and purified by chromatography on silica gel eluting with 20-60% EtOAc in heptane to provide 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-ol (4 g, 69%) as a thick oil: LC/MS (Table 1, Method a) Rt=2.30 min; MS m/z: 344 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.Cl[C:17]1[C:18]2[CH:25]=[CH:24][N:23]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:19]=2[N:20]=[CH:21][N:22]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[S:26]([N:23]1[C:19]2[N:20]=[CH:21][N:22]=[C:17]([NH:1][CH:2]3[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]3)[C:18]=2[CH:25]=[CH:24]1)([C:29]1[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=1)(=[O:27])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCCCC(N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Temperature: 90 °C
Yield: 61.3 %

Procedure:
To a solution of tert-butyl 3-aminoazepane-1-carboxylate (1 g, 4.7 mmol), 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.1 g, 5.1 mmol) in DMF (10 mL) was added DIEA (1.2 mL, 7.0 mmol) and the reaction mixture was heated to 90° C. for 3 h. The reaction was cooled to rt and diluted with ice cooled water (50 mL). The mixture was extracted with EtOAc (3×100 mL), the EtOAc layers were combined, dried over Na2SO4 and evaporated in vacuo to give the crude product that was purified by column chromatography (silica gel, gradient 0-20% EtOAc hexane) to afford the titled intermediate (1.4 g, 89%). LC-MS: m/z [M+1]=486.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][NH:8][CH2:9][C:2]=12.[H-].[Na+].I[CH2:13][CH3:14]>C1COCC1>[CH2:13]([N:8]1[CH2:7][C:3]2[C:2](=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9]1)[CH3:14]
Reactant: c1cnc2c(c1)CNC2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1Cc2cccnc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (5.00 g) in THF was added 80% NaH (3.00 g) at rt. The reaction mixture was stirred for 30 min at room temperature, and 5.3 mL of iodoethane was added dropwise. The reaction mixture was stirred for another 5 h, then quenched with ice water, and extracted with CH2Cl2 (70 mL×5). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (2.80 g, 45.00%), HPLC: 90.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 149.3 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.02 (t, J=4.8 Hz, 3H), 2.64 (m, 2H), 3.62 (s, 2H), 3.95 (s, 2H), 7.11-7.83 (m, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1.[CH3:31][N:32]([CH:34]([CH3:37])[CH2:35]Cl)[CH3:33]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:35][CH:34]([N:32]([CH3:33])[CH3:31])[CH3:37])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)cc(OC)c1OC
Reactant: CC(CCl)N(C)C
Product: COc1cc(-c2nc3ccc(OCC(C)N(C)C)cc3n2Cc2ccccc2Br)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 114 with 2-(N,N-dimethylamino)propyl chloride essentially as previously described. mp 152° C., NMR, IR, MS 553, 555.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:7]=[C:6]([CH2:8][OH:9])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:4]=1.I([O-])(=O)(=O)=[O:21].[Na+]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:7]=[C:6]([C:8]([OH:21])=[O:9])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:4]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2CO)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-n2nc(C(F)(F)F)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To the solution of 3-trifluoromethyl-5-hydroxymethyl-1-(4-methoxyphenyl)-1H-pyrazole (4.4007 mmol, 1.198 g) in acetonitrile (20 mL) and water (20 mL) was added sodium periodate (1.977, 2.1 eq.) and several crystals of ruthenium(III) chloride at 0° C. This reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was filtered through Celite to remove white solid impurity and the filter cake washed with 1:1 acetonitrile:water. The filtrate was evaporated in vacuo and the residue was taken up in water. The aqueous was made acidic (pH 3) by the dropwise addition of conc. HCl at 0° C. then extracted with ethyl acetate (3×); the ethyl acetate extracts were washed with brine, dried (MgSO4), and evaporated to gave 1.13 g of pure product (90%).
Reaction SMILES: CO[C:3](=O)[NH:4]/[C:5](/SC)=[N:6]/[C:7](=[O:10])[O:8][CH3:9].[Cl:14][C:15]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:16]=1[CH2:17][O:18][C:19]1[CH:20]=[C:21]([NH2:26])C(N)=[CH:23][CH:24]=1>CO.C(O)(=O)C>[Cl:14][C:15]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:3]2[N:4]=[C:5]([NH:6][C:7](=[O:10])[O:8][CH3:9])[NH:26][C:21]=2[CH:20]=1
Reactant: Nc1ccc(OCc2c(Cl)cccc2Cl)cc1N
Reactant: COC(=O)/N=C(/NC(=O)OC)SC
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2[nH]1
Yield: 64.5 %

Procedure:
add 728 mg of dimethyl[(Z)-(methylsulphanyl)methylylidene]biscarbamate to a solution of 1 g of 4-[(2,6-dichlorobenzyl)oxy]benzene-1,2-diamine in a mixture of 60 cm3 of methanol and 212 mg of glacial acetic acid. The mixture is refluxed for 5.5 hours then concentrated under reduced pressure (0.2 kPa). The residue is taken up in 80 cm3 of a saturated aqueous solution in sodium hydrogen carbonate and the mixture obtained is extracted five times with 150 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is taken up in 25 cm3 of acetonitrile, washed twice with 5 cm3 of acetonitrile, then dried under reduced pressure over sodium hydroxide. We obtain 834 mg of methyl {6-[(2,6-dichlorobenzyl)oxy]-1H-benzimidazol-2-yl}carbamate in the form of a white powder, which has the following characteristics:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[C:8]([F:20])=[CH:9][C:10]2[CH:16]3[CH2:17][CH:14]([CH2:15]3)[C:13](=O)[CH2:12][C:11]=2[CH:19]=1.CN(C)[CH:23]=[O:24]>>[Br:6][C:7]1[C:8]([F:20])=[CH:9][C:10]2[CH:16]3[CH2:17][CH:14]([CH2:15]3)[C:13]([Cl:3])=[C:12]([CH:23]=[O:24])[C:11]=2[CH:19]=1
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Cc2cc(Br)c(F)cc2C2CC1C2
Product: O=CC1=C(Cl)C2CC(C2)c2cc(F)c(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To anhydrous N,N-dimethylformamide (0.1 mL) at 0-5° C. under an atmosphere of nitrogen was introduced phosphorous oxychloride (0.09 mL, 0.94 mmol) dropwise over 10 minutes and the reaction mixture warmed to room temperature for 1 hr. The reaction mixture was cooled to +5-10° C. and a solution of 2-bromo-3-fluoro-6,7-dihydro-5H-5,7-methanobenzo[7]annulen-8(9H)-one (100 mg, 0.37 mmol) in anhydrous N,N-dimethylformamide (0.2 mL) introduced. After 1 hr at this temperature, the reaction mixture was warmed to 72° C. for 3.5 hr. After cooling to room temperature, ice-water (−5 mL) was introduced and the aqueous solution extracted with ethyl acetate (2×5 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and evaporated in vacuo to furnish the crude title compound (125 mg at 79% purity LC-MS (UV215) as an orange wax. This compound was carried through to the next synthetic step without further purification: 1H NMR (500 MHz, CDCl3) δ1.66-1.74 (m, 2H), 2.76-2.84 (m, 2H), 3.36 (td, J=7.88, 4.10 Hz, 1H), 3.48 (td, J=7.88, 4.10 Hz, 1H), 6.91 (d, J=8.83 Hz, 1H), 7.96 (d, J=7.25 Hz, 1H), 10.33 (s, 1H)
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[CH3:17][N:18]([CH3:26])[C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[CH3:17][N:18]([CH3:26])[C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:10]2[N:11]=[CH:12][C:7]3[CH:6]=[CH:5][C:4](=[O:16])[N:3]([CH2:1][CH3:2])[C:8]=3[N:9]=2)=[CH:21][CH:20]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: CCn1c(=O)ccc2cnc(S(C)=O)nc21
Product: CCn1c(=O)ccc2cnc(Nc3ccc(N(C)C)cc3)nc21
Temperature: 175 °C
Yield: 50 %

Procedure:
A mixture of 8-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (155 mg, 0.65 mmol) and 500 μL of 4-dimethylaminoaniline was heated at 175° C. for 10 minutes, then cooled to room temperature and partitioned between saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resultant solid was washed with hexane and ethyl acetate then purified by flash chromatography eluting with ethyl acetate. The fractions containing product were concentrated and a 2:1 mixture of hexane and ethyl acetate was added to the residue. The resultant precipitate was collected by filtration to give 110 mg (50%) of 2-(4-dimethylamino-phenylamino)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 189-191° C.
Reaction SMILES: [C:1]([NH:4][C:5](=[S:22])[NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])(=[O:3])[CH3:2].[C:23]([N:27]=[C:28]=[S:29])([O:25][CH3:26])=[O:24]>CC(C)=O>[C:1]([NH:4][C:5](=[S:22])[NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[NH:21][C:28]([NH:27][C:23]([O:25][CH3:26])=[O:24])=[S:29])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(C(=O)c2ccccc2)cc1NC(=S)NC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a suspension of 3-(3-acetylthioureido)-4-aminobenzophenone (1.1 g.) in acetone (15 ml.) is added carbomethoxy isothiocyanate (0.41 g.). The mixture is heated to reflux and then is stirred at room temperature for 18 hours. The crude product is collected by filtration, washed with acetone and ether and then dried to afford 0.6 g. (40% yield) of 3-(3-acetylthioureido)-4-(3-carbomethoxythioureido)benzophenone, m.p. 203°-204° C., dec.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]=[C:22]=[O:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[CH:4][N:3]=[C:2]3[CH3:1])=[O:23])=[CH:18][CH:19]=1
Reactant: Cc1nccc2c(N)cccc12
Reactant: O=C=NCc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: Cc1nccc2c(NC(=O)NCc3ccc(Br)cc3)cccc12
Temperature: 90 °C

Procedure:
The product from Example 65A (480 mg, 3.04 mmol) in toluene (9 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.43, 3.07 mmol) with stirring. After heating the mixture at 90° C. for 1 hour, the mixture was allowed to cool to room temperature, filtered, and the filter cake washed with toluene to provide the title compound. The corresponding di-hydrochloride salt was prepared using methanolic HCl (680 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.38 (d, J=6.1 Hz, 1H), 8.25 (d, J=7.8 Hz, 1H), 7.78-7.85 (m, 2H), 7.53-7.61 (m, 3H), 7.32 (d, J=8.5 Hz, 2H), 7.11 (t, J=6.1 Hz, 1H), 4.34 (d, J=6.1 Hz, 2H), 2.88 (s, 3H); MS (ESI+) m/z 370/372 (M+H+, 79Br/81Br).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17]Br)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]=1.C(=O)([O-])O.[Na+]>C(O)C>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]3[CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(OC(=O)c2ccccc2)cc1
Reactant: COc1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(OC(=O)c4ccccc4)cc3)cn2c1
Yield: 70.7 %

Procedure:
13.33 g (corresponding to 43.68 mmol) of 4′-benzoyloxy-2-bromoacetophenone and 5.67 g (corresponding to 45.67 mmol) of 2-amino-5-methoxypyridine were dissolved in 481 mL of ethanol. The resulting solution was refluxed for 2 hours. After the reaction solution was cooled, 6.64 g (corresponding to 79.09 mmol) of sodium hydrogencarbonate was added thereto. The resulting reaction mixture was further refluxed for 4 hours. After the completion of the reaction, the solvent was concentrated under reduced pressure. The resulting residue was dissolved in chloroform and then washed with water. After the chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography (elution solvent: chloroform/ethyl acetate=20/1) to obtain 10.20 g (corresponding to 30.87 mmol) of 2-(4′-benzoyloxyphenyl)-6-methoxyimidazo[1,2-a]pyridine (FIG. 3, Step 5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15](O)=[O:16])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH:28]1[C:32]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)=[N:31][N:30]=[N:29]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([C:32]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:34][CH:35]=3)=[O:16])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[CH2:10]([NH:11][CH2:12][CH3:13])[CH3:9]
Reactant: N#Cc1ccc(Cl)cc1-c1ccn(C(Cc2ccccc2)C(=O)O)c(=O)c1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Product: CCNCC
Product: N#Cc1ccc(Cl)cc1-c1ccn(C(Cc2ccccc2)C(=O)Nc2ccc(-c3nnn[nH]3)cc2)c(=O)c1

Procedure:
77 mg (purity 85%, 0.17 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-phenylpropanoic acid (racemate) (Example 7.1C) and 31 mg (0.19 mmol) of 4-(1H-tetrazol-5-yl)aniline were reacted according to General Method 1. Yield: 17 mg (purity 94%, 16% of theory)
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f3) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.C[CH2:11][N:12]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN>CN(C=O)C>[CH3:11][NH:12][C:7]([C:5]1[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=1)=[O:9]
Reactant: Cc1nc(C(=O)O)c[nH]1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c[nH]c(C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
2-Methyl-1H-imidazole-4-carboxylic acid (378 mg, 3 mmol), EDCI (745 mg, 3.9 mmol), HOBt (253 mg, 1.5 mmol), DIEA (1.6 mL, 9 mmol) and methyl amine (2M in THF) (3.6 mL, 7.2 mmol) were dissolved in DMF (10 mL) and stirred at room temperature for 16 hours. After removal of DMF, the residue was dry loaded and purified by flash chromatography (SiO2, 0-10% methanol in DCM and 1% NH4OH) to give 280 mg (67%) of the title compound. m/z (ES+) 140 (M+H)+.