Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:46]=[CH:45][C:12]([O:13][CH2:14][C@@H:15]([OH:44])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:43]=[CH:42][C:23]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:32])[CH2:27][CH2:26]3)=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:44][C@H:15]([CH2:14][O:13][C:12]1[CH:45]=[CH:46][C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:16][NH:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH:25]2[CH2:26][CH2:27][N:28]([C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:32])[CH2:29][CH2:30]2)=[CH:42][CH:43]=1
Reactant: CCCCCCCCNC(=O)N1CCC(Oc2ccc(CCNC[C@H](O)COc3ccc(OCc4ccccc4)cc3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCNC(=O)N1CCC(Oc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Reaction time: 11 h
Yield: 53.1 %

Procedure:
A suspension of 4-{4-[2-({(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl}amino)ethyl]phenoxy}-N-octyl-1-piperidinecarboxamide (0.2 g, 0.32 mmol), and 10% palladium on carbon (0.3 g) in ethanol (5 mL) was stirred under atmospheric hydrogen for 11 hours. The catalyst was filtered and the filtrate evaporated in vacuo to a residue (0.1 g). The residue was treated with a solution of anhydrous hydrogen chloride in methanol followed by ethyl acetate and diethyl ether. The precipitate was filtered and after drying in vacuo overnight yielded the title compound (0.1 g, 0.17 mmol).
Reaction SMILES: Br[C:2]1[C:3]([Cl:12])=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.N1C=CC=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1(C)C=CC=CC=1.C(O)C.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>[Cl:12][C:3]1[C:2]([CH:14]=[CH2:15])=[CH:7][N:6]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[CH:4]=1
Reactant: CC(=O)Nc1cc(Cl)c(Br)cn1
Reactant: c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1cnc(NC(C)=O)cc1Cl
Temperature: 85 °C
Yield: 98.6 %

Procedure:
To a stirred solution of N-(5-bromo-4-chloropyridin-2-yl)acetamide (7 g, 28.1 mmol), 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane complex with pyridine (1:1) (8.78 g, 36.5 mmol), and sodium carbonate (5.95 g, 56.1 mmol) solution in 7 mL of water in a mixture of toluene (50 mL) and ethanol (8 mL), was added Pd(PPh3)4 (0.973 g, 0.842 mmol). The solution was purged with nitrogen gas was bubbled for 5 min then heated at 85° C. for 14 h. The reaction was cooled to room temperature and was diluted with ethyl acetate (50 mL) ten filtered through a bed of celite. The filtrate was diluted with water and the organic layer was separated, washed with brine, dried over sodium sulphate. The organics were concentrated under reduced pressure and residue was purified by silica gel column chromatography using a gradient of ethyl acetate in hexanes. Product eluted at 30% ethyl acetate in hexane and required fractions were concentrated to yield N-(4-chloro-5-vinylpyridin-2-yl)acetamide (5.92 g, 27.7 mmol, 99% yield) as yellow solid. LCMS (ESI) m/e 197.2 [(M+H)+, calcd for C9H10ClN2O 197.04] LC/MS retention time (method A): tR=1.50 min; 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.64 (s, 1H), 8.18 (d, J=6.40 Hz, 1H), 6.88 (dd, J=11.2, 17.6 Hz, 1H), 5.99 (dd, J=17.60, 0.80 Hz, 1H), 5.47 (dd, J=11.40, 0.80 Hz, 1H), 2.12 (s, 3H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].CCN(CC)CC.Br[CH2:17][C:18](OCC)=[O:19]>CN(C=O)C>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:8][CH2:17][C:18]1=[O:19]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CNc2ccccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.8 %

Procedure:
To a solution of o-phenylenediamine (1.08 g, 10 mmol) in DMF (50 mL) was added Et3N (2.9 mL, 21 mmol), and ethyl 2-bromoacetate (1.2 mL, 11 mmol). The reaction mixture was stirred at room temperature for 16 h, then at 80° C. for 3 h. The DMF was evaporated under reduced pressure and the reaction mixture partitioned between H2O and EtOAc. The EtOAc layer was washed with sat. NaHCO3, brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue purified by flash chromatography eluting with petroleum ether/EtOAc (4/1) to give 3,4-dihydroquinoxalin-2(1H)-one (560 mg, 38%) as yellow solid. LC-MS (ES-API); rt 7.40 min; m/z calculated for C8H8N2O [M+H]+ 149.0, found 149.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][N:32]1[CH2:33][CH2:34][CH:29]([C:25]2[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=2)[CH2:30][CH2:31]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1cccc(Oc2ccc(Cl)c(Cl)c2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(Oc4ccc(Cl)c(Cl)c4)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-(3,4-dichlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 497.15 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:23]=[CH:22][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:24][S:25]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])=[O:26].[CH2:34]=O>C(O)=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[O:12])=[CH:22][CH:23]=2)=[N:4][C:3]=1[CH2:24][S:25]([CH:28]1[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]1)(=[O:27])=[O:26]
Reactant: Cc1oc(-c2ccc(C(=O)NCCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Reactant: C=O
Solvent: O=CO
Product: Cc1oc(-c2ccc(C(=O)NCCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C)CC1
Reaction time: 0.2 h
Yield: 11 %

Procedure:
A solution of 4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-[2-(pyridin-3-yl)ethyl]benzamide (322 mg, 0.69 mmol, 1.00 equiv) and paraformaldehyde (0.21 g, 10.00 equiv) in formic acid (15 mL) was stirred overnight at 110° C. The resulting mixture was concentrated under vacuum and the crude product (320 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm Sum; mobile phase, CH3CN/H2O (5% up to 60% in 12 min, up to 100% in 1 min, down to 5% in 1 min); Detector, UV 254 nm, to give 36.5 mg (11%) of 4-[5-methyl-4-[(1-methylpiperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-[2-(pyridin-3-yl)ethyl]benzamide as a white solid. LC-MS: (ES, m/z): 483 [M-PH]+, 242. 1HNMR (400 MHz, CD3OD, ppm): δ 8.47 (s, 1H), 8.42-8.40 (s, 1H), 8.08-8.06 (d, 2H), 7.90-7.88 (d, 2H), 7.81-7.79 (d, 1H), 7.42-7.39 (m, 1H), 4.41 (s, 2H), 3.69-3.66 (t, 2H), 3.21-3.06 (m, 1H), 3.06-2.99 (m, 4H), 2.50 (s, 3H), 2.30 (s, 3H), 2.26-2.23 (m, 2H), 2.12-2.06 (m, 2H), 1.95-1.87 (m, 2H).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:30]2[CH:37]=[CH:36][C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:5]1)=[N+]=[N-]>C(O)C>[NH2:1][C@@H:4]1[C@@H:8]([CH2:9][O:10][C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:30]2[CH:37]=[CH:36][C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 5 h
Yield: 69.2 %

Procedure:
Lidlar's catalyst (20 mg) was added to compound 30 (0.10 g, 0.20 mmol), and was then suspended in ethanol (5 ml). Air was removed from the flask by flushing with nitrogen several times. The nitrogen was then removed and replaced with hydrogen. The mixture was stirred for 5 hours, and then filtered through Celite. Fresh Lidlar's catalyst (20 mg) was added to the filtrate. The flask was flushed with nitrogen and then hydrogen as previously, and the reaction was left stirring for another 3 hours. The reaction mixture was filtered through Celite. The solvent was evaporated and the concentrated solution was purified by column chromatography (MeOH/DCM 2%→10%) which gave the title product as a white solid (0.065 g, 70%). Rf: 0.3 in DCM/MeOH 90:10.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[N:19]=[CH:18][N:17]=[C:16]([CH:20]3[NH:24][CH:23]([C:25]([O:27]C)=[O:26])[CH2:22][CH2:21]3)[CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:13][CH2:12]1>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[N:19]=[CH:18][N:17]=[C:16]([CH:20]3[NH:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22][CH2:21]3)[CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:13][CH2:12]1
Reactant: COC(=O)C1CCC(c2cc(-c3ccc(OC4CC4)c(Cl)c3)ncn2)N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1CCC(c2cc(-c3ccc(OC4CC4)c(Cl)c3)ncn2)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.9 %

Procedure:
NaOH (2M solution, 0.04 ml, 0.073 mmol) was added in one portion to a stirred solution of methyl 5-[6-(3-chloro-4-cyclopropoxyphenyl)pyrimidin-4-yl]pyrrolidine-2-carboxylate (0.008 g, 0.02 mmol) in THF (2 ml) and the mixture was stirred at room temperature for 16 hours. After this time, the mixture was concentrated and the resulting residue purified by prep HPLC to give the title compound (0.001 g, 5% yield) as a white solid.
Reaction SMILES: [N:1]1([C:13](=[O:14])[C:12]2[N:10]([CH3:11])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].S(=O)(=O)(O)O.[F:20][C:21](I)([F:23])[F:22].OO>[Fe].CS(C)=O>[F:20][C:21]([F:23])([F:22])[C:9]1[N:10]([CH3:11])[C:12]2[C:13](=[O:14])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=1
Reactant: FC(F)(F)I
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: [Fe]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Product: Cn1c(=O)c2c(nc(C(F)(F)F)n2C)n(C)c1=O
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
0.19 g (1.0 mmol) of caffeine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 0.016 g (0.3 mmol) of iron powder, 2.0 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 8-trifluoromethylcaffeine (19F-NMR yield: 37%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:21]([O:23]CC)=[O:22])[S:6][C:7]=1[N:8]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[S:9]([CH3:12])(=[O:11])=[O:10].[ClH:26]>O1CCOCC1>[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:21]([OH:23])=[O:22])[S:6][C:7]=1[N:8]([CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)[S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: CCOC(=O)c1cc(OC)c(N(CCN2CCOCC2)S(C)(=O)=O)s1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)sc1N(CCN1CCOCC1)S(C)(=O)=O
Temperature: 100 °C

Procedure:
To a solution of ethyl 4-methoxy-5-(N-(2-morpholinoethyl)-methylsulfonamido)-thiophene-2-carboxylate (Int. 70, 375 mg, 0.955 mmol) (prepared as described in Step 6 hereabove reported) in dioxane (8 ml), aqueous 37% HCl (3 ml) was added drop wise, and the resulting mixture was heated under MW irradiation at 100° C. for 3.5 hours. The volatiles were removed under vacuum to afford 4-methoxy-5-(N-(2-morpholinoethyl)-methylsulfonamido)thiophene-2-carboxylic acid hydrochloride (Int. 71) (383 mg, 0.955 mmol, MS/ESI+364.9 [MH]+).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:9][CH:8]1[CH2:10][C:11]1[N:19]2[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]2)=[C:13]([C:21]2[CH:22]=[CH:23][C:24]3[C:28]([CH:29]=2)=[N:27][N:26]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=3)[CH:12]=1)(=O)=O.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:30]([N:26]1[CH:25]=[C:24]2[C:28]([CH:29]=[C:21]([C:13]3[CH:12]=[C:11]([CH2:10][CH:8]4[CH2:9][CH:7]4[CH2:6][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[N:19]4[C:14]=3[C:15]([NH2:20])=[N:16][CH:17]=[N:18]4)[CH:22]=[CH:23]2)=[N:27]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)OCC1CC1Cc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnn2c(CC3CC3CN3CCCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 80 °C
Yield: 5.8 %

Procedure:
To a solution of (2-{[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}cyclopropyl)methyl methanesulfonate (0.2 g, 0.4 mmol) in DMF (2 mL) was added pyrrolidine (84 mg, 1.2 mmol) and DIEA (102 mg, 0.8 mmol), and the mixture was heated to 80° C. for 3 hours. The mixture was concentrated in vacuo and the residue was dissolved in methanol and purified by preparative HPLC to provide 11 mg (6%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 720 (s, 1 H), 5.70 (s, 2 H), 2.9-2.8 (m, 2 H), 2.4-2.2 (m, 6 H), 1.7 (m, 4 H), 1.1-0.9 (m, 2 H), 0.5-0.4 (m, 2 H); ES-MS m/z 478.2 [M+H]P, HPLC RT (min) 2.29.
Reaction SMILES: [CH3:1][N:2]([CH:4]1[C:23](=[O:24])[C:22]([C:25]([NH2:27])=[O:26])=[C:21]([OH:28])[C:20]2([OH:29])[CH:5]1[CH2:6][CH:7]1[C:17]([C:18]2=[O:19])=[C:16]([OH:30])[C:10]2[C:11]([OH:15])=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8]1)[CH3:3].[Br:31]N1C(=O)CCC1=O.C(OCC)C.[S:44](=[O:48])(=[O:47])([OH:46])[OH:45]>>[S:44]([OH:48])([OH:47])(=[O:46])=[O:45].[Br:31][C:14]1[CH:13]=[CH:12][C:11]([OH:15])=[C:10]2[C:9]=1[CH2:8][CH:7]1[C:17]([C:16]2=[O:30])=[C:18]([OH:19])[C:20]2([OH:29])[CH:5]([CH:4]([N:2]([CH3:1])[CH3:3])[C:23]([OH:24])=[C:22]([C:25]([NH2:27])=[O:26])[C:21]2=[O:28])[CH2:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)C1C(=O)C(C(N)=O)=C(O)C2(O)C(=O)C3=C(O)c4c(O)cccc4CC3CC12
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CN(C)C1C(O)=C(C(N)=O)C(=O)C2(O)C(O)=C3C(=O)c4c(O)ccc(Br)c4CC3CC12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 4.14. g of 6-demethyl-6-deoxytetracycline, prepared by the described literature procedure, and 1.99 g of N-bromosuccinimide dissolved in 50 ml of concentrated sulfuric acid is stirred at 0° C. for 45 minutes or until solution occurs. The reaction mixture is added dropwise to 2 L of cold diethyl ether. The resulting precipitate is collected and dried. The solid is dissolved in 2-methoxyethanol, triturated with methanol, collected, washed with methanol and diethyl ether and dried to give 6.22 g of crude product. The solid is recrystallized from 2-methoxyethanol and methanol to give 3.1 g of pure product. MS(FAB): m/z 493 (M+H). 1H NMR(CD3SOCD3): δ 4.3(s, lH, 4-H), 6.8(d, lH, 9-H) and 7.75(d, IH, 8-H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>CS(C)=O.[Cu]I>[C:18]1([O:24][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Br)cc2C1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Oc3ccccc3)cc2C1
Temperature: 190 °C
Yield: 47.7 %

Procedure:
A reaction mixture of N-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (100 mg, 0.31 mmol, Description 1), phenol (30 mg, 0.32 mmol), caesium carbonate (308 mg, 0.94 mmol), copper(I) iodide (66 mg, 0.35 mmol) and N,N-dimethylglycine (39 mg, 0.38 mmol) in DMSO (1.5 ml) was heated in a microwave at 190° C. for 30 minutes. The mixture was quenched with hydrochloric acid (2M) and then partitioned between dichloromethane and water. The organic solution was dried (MgSO4) and evaporated under reduced pressure to yield the crude product. The crude product was purified using MDAP to obtain the title product as a yellow gum (49 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:13]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[CH2:4]1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>C(Cl)Cl>[OH:19][C:13]1([C:3]2([CH2:2][NH:1][C:28](=[O:29])[O:30][CH2:31][CH3:32])[C:6]3[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=3[CH2:4]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COc1ccc2c(c1)C(CN)(C1(O)CCCCC1)C2
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NCC1(C2(O)CCCCC2)Cc2ccc(OC)cc21
Reaction time: 24 h

Procedure:
A solution of 2 g (7.65 mM) of the compound obtained in Step D and 2.6 ml (19.8 mM) of triethylamine in 100 ml of methylene chloride is poured into a solution, cooled to 0° C., of 0.61 ml (7.65 mM) of ethyl chloroformate in 50 ml of methylene chloride. Stirring is carried out for 24 hours at room temperature, and the mixture is siluted with water and extracted with methylene chloride. The organic phases are washed first with 1N HCl and then with water until neutral and finally dried over MgSO4 to yield, after evaporation, 2.2 g of the expected product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1O.[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][C:24]=2[F:26])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: Oc1ccc(F)cc1F
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(-c2ccc(F)cc2F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 94.7 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.17 g of 2,4-difluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.27 g of 4-(2-butynyloxy)-6-(2,4-difluorophenyl)pyrimidine (the present compound (44)), m.p.: 63.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([C:7]1[C:8]([NH:18][CH2:19][CH3:20])=[N:9][C:10]([CH:13]([O:16]C)OC)=[CH:11][CH:12]=1)=O.[H-].[Na+].Cl[CH:27]([CH2:33][CH2:34][C:35]([O-])=[O:36])[C:28]([O:30]CC)=[O:29].C[O-].[Na+].S(=O)(=O)(O)O.Cl>C(O)C.O1CCOCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[N:9][C:10]([CH:13]=[O:16])=[CH:11][CH:12]=3)[N:18]([CH2:19][CH3:20])[C:35](=[O:36])[C:34]=2[CH2:33][CH2:27][C:28]([OH:30])=[O:29])[CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(Cl)CCC(=O)[O-]
Reactant: CCNc1nc(C(OC)OC)ccc1C(=O)c1cccc(Cl)c1
Agent: C[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCn1c(=O)c(CCC(=O)O)c(-c2cccc(Cl)c2)c2ccc(C=O)nc21
Temperature: 80 °C

Procedure:
A DMF solution of 3-(3-chlorobenzoyl)-6-dimethoxymethyl-2-ethylaminopyridine was treated with sodium hydride at 0° C. and then monoethyl chloroglutarate was added thereto, followed by heating at 80° C. under stirring. Thereafter, the reaction mixture was worked up in a usual manner. The resulting compound was dissolved in ethanol and sodium methoxide was added thereto at 0° C., followed by heating under reflux for 1 hour. The reaction mixture was cooled to 0° C. and then concentrated sulfuric acid was added thereto, followed by heating under reflux for 1 hour. Thereafter, the reaction mixture was worked up in a usual manner. The resulting compound was dissolved in dioxane and 6M hydrochloric acid was added thereto at 0° C. and, after being warmed to room temperature, the whole was stirred for 3 hours. Thereafter, the reaction mixture was worked up in a usual manner to obtain 3-[4-(3-chlorophenyl)-1-ethyl-7-formyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid. NMR1: 10.12 (1H, s), 7.70 (1H, d, J=8.1 Hz), 1.44 (3H, t, J=6.9 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:25])=[O:4].O.[OH-].[Li+]>C1COCC1.O.CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][CH2:10][C:8]3[S:9][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:25])[N:7]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1sc(CCc2c(-c3ccc(F)cn3)noc2C)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a suspension of 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid methyl ester (1.02 g, 2.82 mmol) in THF (7 mL), water (7 mL) and MeOH (1.4 mL) was added lithium hydroxide monohydrate (237 mg, 5.65 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was then evaporated to half volume and then acidified to pH 1 with HCl (1 N) and cooled to 0° C. for 15 min. A solid precipitated and was filtered off and dried to afford the title compound (867 mg, 88%) which was obtained as an off white solid. MS: m/e=346.2 [M−H]−.
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][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[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]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[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:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f45) and commercially available propionyl chloride the title compound is obtained as colorless solid.