Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26](F)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.[OH-].[Na+].Cl>CN1CCCC1=O>[F:24][C:22]1[CH:21]=[CH:20][C:19]([C:25]2[C:26]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:27][CH:28]=[CH:29][CH:30]=2)=[C:18]2[C:23]=1[C@H:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:32])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=1)[CH2:16][CH2:17]2
Reactant: C1COCCN1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5F)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5N5CCOCC5)ccc(F)c43)ccc21
Temperature: 180 °C
Reaction time: 48 h

Procedure:
A mixture of {(S)-6-[(R)-7-fluoro-4-(2-fluoro-pyridin-3-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.10 g), morpholine (0.10 g) and N-methyl-pyrrolidone (2 mL) is stirred at 180° C. for 48 h. After cooling to room temperature, 2 N aqueous NaOH solution (0.5 mL) is added, and the resulting mixture is stirred at 40° C. for 2 h. The mixture is neutralized with 1 N aqueous HCl solution and concentrated. The residue is chromatographed on reversed phase (HPLC; acetonitrile/water) to give the title compound. LC (method 7): tR=0.89 min; Mass spectrum (ESI+): m/z=491 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:16].C(O)C>CCOCC>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH2:16])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: N
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc(-c2c(N)ncnc2Cl)cc1

Procedure:
To a solution of 4,6-dichloro-5-(4-methylphenyl)pyrimidine (4.14 g) in ether (20 ml) is added 27% ammonia-ethanol solution (30 ml), and the reaction mixture is reacted at room temperature in a sealed tube for three days. The mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate=(10:1)~ethyl acetate) to give 6-chloro-5-(4-methylphenyl)pyrimidin-4-amine (1.89 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:23]([F:26])([F:25])[F:24])[C:18]([O:20][CH2:21][CH3:22])=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH2:14][C:13](=[O:15])[NH:12][C:11]4[CH:16]=[C:17]([C:23]([F:26])([F:25])[F:24])[C:18]([O:20][CH2:21][CH3:22])=[CH:19][C:10]=4[N:9]=3)[CH:3]=2)=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c1)=N2

Procedure:
The title compound was prepared from 4-(3-bromo-phenyl)-7-ethoxy-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example B.3) (200 mg, 0.50 mmol) and commercially available 4-tert-butylsulfamoyl-benzeneboronic acid [CAS-no. 208516-15-8] (144 mg, 0.55 mmol) according to the general procedure II. Obtained as a white solid (164 mg, 63%). MS (ISP) 559.7 [(M+H)+]; mp>260° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]2[CH2:23][CH2:22][CH2:21][C:20]=2[C:24]([O:26]CC)=O)=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C>[Br:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:24](=[O:26])[C:20]3[CH2:21][CH2:22][CH2:23][C:19]=3[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Br)cc2F)CCC1
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(F)cc1Br

Procedure:
using isopropyl 2-bromo-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate with sodium isopropylate in isopropanol there is obtained isopropyl 2-bromo-4-fluoro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 214°-216° C.,
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])=[N+]=[N-].C(#N)C>O>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: [N-]=[N+]=NCCOCCOCCOCCNC(=O)COCC(=O)O
Solvent: O
Solvent: CC#N
Product: NCCOCCOCCOCCNC(=O)COCC(=O)O
Reaction time: 0.33 h

Procedure:
A solution of 17-azido-5-oxo-6-aza-3,9,12,15-tetraoxaheptadecanoic acid (8.36 g, 25.0 mmol) in water (100 ml) was reduced using H2(g)-Pd/C (10%). The reaction was run until LC-MS analysis showed complete conversion of starting material (column Vydac 218TP54; solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 4-16% B over 20 min; flow 1.0 ml/min; UV detection at 214 and 284 nm, ES ionisation giving M+H at 335 for starting material and 309 for the product). The solution was filtered and used directly in the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:23])[C:8]2[N:9]=[CH:10][N:11]([C:21]=2[N:22]=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)(=[O:3])[CH3:2].[C:24]([O:32][C@@H:33]1[C@H:37]([F:38])[C@@H:36]([CH2:39][CH:40]([P:48]([O:53][CH2:54][CH3:55])([O:50][CH2:51][CH3:52])=[O:49])[S:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:35][C@H:34]1OC(=O)C)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl.ClCCCl>[C:24]([O:32][C@@H:33]1[C@H:37]([F:38])[C@@H:36]([CH2:39][CH:40]([P:48]([O:53][CH2:54][CH3:55])([O:50][CH2:51][CH3:52])=[O:49])[S:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:35][C@H:34]1[N:11]1[CH:10]=[N:9][C:8]2[C:7](=[O:23])[NH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:22][C:21]1=2)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOP(=O)(OCC)C(C[C@H]1O[C@@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1F)Sc1ccccc1
Reactant: CC(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOP(=O)(OCC)C(C[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NC(C)=O)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1F)Sc1ccccc1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
N-Acetyl Guanosine (108 mg, 0.56 mmol) was suspended in 10 mL anhydrous CH2Cl2. With stirring under nitrogen, BSA (345 mg, 1.4 mmol) was added to the suspension. The mixture was stirred at 80° C. for 2 h and cooled to r.t. Compound 35.14 (200 mg, 0.37 mmol) in 5 mL anhydrous DCE was added to the mixture, followed by SnCl4 (64 mL, 0.55 mmol). The mixture was heated to 65° C. for 6 h and then cooled to r.t., diluted with 50 mL CH2Cl2 and poured onto a mixture of 50 g ice/50 mL saturated Rochelles Salt. The mixture was stirred for another 1 h. The organic layer was separated and the aqueous layer was extracted with 100 mL additional CH2Cl2. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 5% MeOH in CH2Cl2 to give compound 35.15 (73 mg, 30% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][OH:28])[CH:21]=[CH:20][C:19]=2[CH3:29])=[O:17])=[C:12]([N+:30]([O-])=O)[CH:11]=1>CCO>[NH2:30][C:12]1[CH:11]=[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:15]=[CH:14][C:13]=1[C:16]([C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][OH:28])[CH:21]=[CH:20][C:19]=1[CH3:29])=[O:17]
Reactant: Cc1ccc(OCCCO)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1ccc(OCCCO)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 307 (46 mg, 0.1 mmol) was dissolved in EtOH (5 mL), flushed with argon and added Pd/C (cat. amount). The flask was purged with H2 for 2 min. and stirred under an H2-atmosphere at RT for 1 h. The reaction mixture was filtered through Celite and concentrated in vacuo. Purified by continuously gradient flash chromatography using DCM/MeOH (v:v=100:0 to 95:5) as the eluent, affording the title compound as a yellow oil. 13C NMR (DMSO-d6) δ 196.3, 158.9 (dd), 156.2, 155.6 (dd), 154.2, 150.8, 142.2, 135.6, 131.1, 127.0 (dd), 125.2, 124.8 (dd), 114.5, 112.2, 111.6 (dd), 109.7, 104.8 (dd), 104.0, 96.9, 64.6, 57.2, 32.1, 17.9
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)[C:31]([F:34])([F:33])[F:32].[F-].[Cs+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[F:32][C:31]([F:34])([F:33])[C:19]([OH:20])([OH:21])[CH:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(O)(C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1)C(F)(F)F
Reaction time: 4 h
Yield: 96 %

Procedure:
Methyl 2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetate (147d, 2.5 g, 6.6 mmol) was dissolved in THF (15 mL, dried over 4 Å MS) under Argon atmosphere and cooled in an ice-bath. Trimethyl(trifluoromethyl)silane (1.18 mL, 8 mmol) was added followed by Caesium fluoride (100 mg, 0.66 mmol). The cooling bath was removed and the stirring was continued at r.t. for 4 h. A solution of tetrabutylammonium fluoride in THF (1M, 7 mL, 7 mmol) followed by water (4 mL) was then added and the mixture was stirred for additional 1 h and then partitioned between ethyl acetate and water. The organic phase was washed twice with water, then brine and evaporated to afford 1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropane-2,2-diol (2.74 g, 95%)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13]([C:15]1([CH2:29]I)[CH2:19][CH2:18][N:17]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16]1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1([CH2:29][O:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:19][CH2:18][N:17]([C:20](=[O:28])[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:16]1)=[O:14])[CH3:11]
Reactant: Oc1cccc(F)c1F
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Product: CCOC(=O)C1(COc2cccc(F)c2F)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation using 2,3-difluoro-phenol and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a white solid (167 mg, 68%) ES m/z 408 [MH]+
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[C:27]([F:29])[C:26]([Br:30])=[CH:25][C:24]=2[O:31][CH3:32])=[C:13](/[CH:15]=[CH:16]/[C:17](OCC)=[O:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[C:27]([F:29])[C:26]([Br:30])=[CH:25][C:24]=1[O:31][CH3:32])[C:17](=[O:18])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(F)c(Br)cc1OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 100 °C

Procedure:
(E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)-acrylate (0.400 g, 0.775 mmol was added to a flask followed by MeOH (10.00 mL) and sodium methoxide (1.6 mL, 1.641 mmol). The flask was fitted with reflux condensor and heated to 100° C. for 1 hour. The reaction was cooled to RT and poured into 20 mL HCl (IN). Extracted with EtOAc (3×), dried over magnesium sulfate and filtered. The resulting material was concentrated and used without further purification to yield 0.362 g of 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one. m/z (ESI) 516.0 (M+H)+.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[NH2:29][NH2:30].C(OCC)C>C(Cl)Cl>[NH:29]([C:26]([CH:23]1[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21][CH2:22]1)=[O:28])[NH2:30]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NN
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reaction time: 2 h

Procedure:
Carbonyl diimidazole (3.57 g, 22 mmol) was added to a solution of 1-(tert-butoxycarbonyl)-piperidine-4-carboxylic acid (4.59 g, 20 mmol) in methylene chloride (50 mL) and stirred for two hours until gas evolution ceased. Then hydrazine (0.8 mL, ˜26 mmol) was added to the reaction and the reaction was stirred at room temperature for another two hours. The reaction was diluted with more methylene chloride and washed with sat'd aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered and the solvent evaporated to give a viscous residue. Trituration with diethyl ether afforded tert-butyl 4-(hydrazinocarbonyl)-piperidine-1-carboxylate as an off-white solid. NMR (CDCl3): δ6.77 (1H, br s), 4.15 (2H, br s), 3.90 (2H, v br s), 2.75 (2H, b s), 2.22 (1H, m), 1.78 (2H, br d, J=11.9 Hz), 1.66 (2H, br q, J=12.2 Hz, J=27.5 Hz), 1.47 (9H, s).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22](Cl)=[O:23])=[CH:21][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30].CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[O:30]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:28][NH:27][C:22]([C:20]1[CH:19]=[N:18][C:14]2[O:15][CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:13]=2[CH:21]=1)=[O:23]
Reactant: NCC(=O)c1ccccc1
Reactant: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (100 mg, 0.246 mmol), in THF (5 mL) was added 2-amino-1-phenylethanone (34.9 mg, 0.258 mmol), and DIPEA (0.086 mL, 0.492 mmol). The reaction was stirred for 2 hours at room temperature. The reaction mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (5 mL). The aqueous layer was back extracted with EtOAc (2×5 mL). Combined the organic layers were dried over Na2SO4, filtered and concentrated in vacuo to provide N-(2-oxo-2-phenylethyl)-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide (115 mg, 0.246 mmol, 93%) as a light brown oil. The material was used without further purification. LCMS (+ESI) m/z=506.1 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15]2[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([O:29]C)[CH:24]=3)=[CH:17][N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15]2[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([OH:29])[CH:24]=3)=[CH:17][N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(Cc2cnc(CCCOc3cccc(CN4CCCCC4)c3)[nH]c2=O)ccn1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c(CCCOc2cccc(CN3CCCCC3)c2)ncc1Cc1ccnc(O)c1
Yield: 82.2 %

Procedure:
2-[[3-[3-(1-Piperidinylmethyl)phenoxy]propyl]]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone (0.49 g) was dissolved in ethanolic hydrogen chloride (5 ml) and ethanol (25 ml) and the solution refluxed for 45 hours. Solvent was evaporated off under reduced pressure and the residue dissolved in water (25 ml). The solution was adjusted to pH 11 with potassium carbonate solution, whereupon an oily solid precipitated This was extracted with chloroform (3×20 ml) and the combined extracts dried (MgSO4) and chloroform evaporated in vacuo. The residue was recrystallised from isopropanol-ether to give 2-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone as a white solid (0.39 g), m.p. 167°-9° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25]([NH:27][C@@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:31]([O:38][C:39]3[CH:40]=[CH:41][C:42]4[N:43]([C:45]([C@@H:48]5[CH2:52][CH2:51][CH2:50][N:49]5[CH3:53])=[N:46][N:47]=4)[CH:44]=3)[CH2:30][CH2:29]2)=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si](C(C)(C)C)(C)C)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25]([NH:27][C@@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:31]([O:38][C:39]3[CH:40]=[CH:41][C:42]4[N:43]([C:45]([C@@H:48]5[CH2:52][CH2:51][CH2:50][N:49]5[CH3:53])=[N:46][N:47]=4)[CH:44]=3)[CH2:30][CH2:29]2)=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(O[Si](C)(C)C(C)(C)C)cc4)c4ccccc43)cn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(O)cc4)c4ccccc43)cn12

Procedure:
A solution of Intermediate 73a (160 mg, 0.21 mmol) and TBAF (1M in THF, 0.26 mL, 0.26 mmol) in THF (2 mL) was stirred at RT for 30 min, then diluted with water and extracted with DCM (3×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the title compound as a white powder after freeze-drying (107 mg, 79%). LCMS (Method 5): Rt 3.24 min, m/z 621 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.81-2.25 (11H, m), 2.34-2.36 (1H, m), 3.12-3.14 (1H, m), 3.99 (1H, t, J 8.2), 4.81-4.84 (1H, m), 5.39 (1H, t, J 4.3), 6.29 (1H, s), 6.85-6.88 (2H, m), 7.09 (1H, d, J 8.6), 7.28-7.39 (7H, m), 7.75 (1H, dd, J 9.9, 0.8), 7.92 (1H, s), 8.24 (1H, d, J 2.1), 9.72 (1H, s).
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:26][C:27]1[CH:28]=[C:29](/[CH:34]=[CH:35]/[C:36](O)=[O:37])[CH:30]=[C:31]([Cl:33])[CH:32]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O>[C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([C:36](=[O:37])/[CH:35]=[CH:34]/[C:29]3[CH:28]=[C:27]([Cl:26])[CH:32]=[C:31]([Cl:33])[CH:30]=3)[CH2:23][CH2:24]2)=[O:25])[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(O)/C=C/c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCNCC2)nn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCN(C(=O)/C=C/c3cc(Cl)cc(Cl)c3)CC2)nn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred suspension of (4-(4-oxo-4-(piperidin-4-ylamino)butyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (Example 37, step 5)(200 mg, 0.516 mmol) and (E)-3-(3,5-dichlorophenyl)acrylic acid (Example 30, step 2) (112 mg, 0.516 mmol) in DMF (2 mL) at RT was added Huenig's base (0.450 mL, 2.58 mmol) followed by T3P® 50% in DMF (0.602 mL, 1.031 mmol) after a few minutes. The reaction mixture was stirred at RT for 20 hours. The reaction mixture was diluted with EtOAc and washed with a saturated solution of brine, organics dried over MgSO4, filtered, and concentrated under reduced pressure to afford the title crude product;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11]N=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:26][C:27](=O)[CH2:28][CH2:29][CH2:30][CH3:31].CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C1COCC1.CCOCC>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[NH:11][C:27]([CH3:26])=[C:28]2[CH2:29][CH2:30][CH3:31]
Reactant: COc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1OC
Reactant: CCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCc1c(C)[nH]c2cc(OC)c(OC)cc12
Temperature: 25 °C
Yield: 81.2 %

Procedure:
N-(3,4-Dimethoxyphenyl)-benzophenone hydrazone (1.0 equiv., 0.32 mmol, 105 mg), 2-hexanone (5 equiv., 1.58 mmol, 0.19 mL), and TsOH.H2O (10 equiv., 3.2 mmol, 609 mg) were dissolved in THF (10 mL) and heated to reflux for 67 hours. The reaction mixture was then cooled to room temperature, diluted with Et2O (5 mL), neutralized with a saturated NaHCO3 solution, and extracted with Et2O (3×10 mL). The organic extracts were then dried over K2CO3, filtered and concentrated under vacuum. Purification by flash column chromatography (20% EtOAc/Hex) gave the title product as a yellow oil (60 mg, 0.26 mmol, 80% yield).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[CH3:17]O>>[Br:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([O:12][CH3:17])=[O:11]
Reactant: CO
Reactant: Cc1c(Br)cccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Br)c1C

Procedure:
2 mL of concentrated sulfuric acid were added to a solution of 3-bromo-2-methylbenzoic acid (20 g, 93 mmol) in methanol (150 mL). The resultant mixture was refluxed for 6 hours. Methanol was removed under reduced pressure, and the residue was dissolved in a mixture of chloroform (100 mL) and saturated solution of Na2CO3 (100 mL). The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated to provide methyl 3-bromo-2-methylbenzoate (21.1 g). 1H NMR spectrum (in DMSO-d6): δ 7.79 (d, J=8.0 Hz, 1H); 7.69 (d, J=7.9 Hz, 1H); 7.23 (t, 1H); 3.82 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=[O:6].CN1CCOCC1.[N+:19]([C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>C(Cl)Cl>[N+:19]([C:22]1[CH:23]=[C:24]([S:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([OH:7])=[O:6])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(O)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To 1.51 g (10 mmol) of the methyl 3-aminobenzoate prepared in Example 1 in 40 mL of methylene chloride containing 2 mL of N-methylmorpholine was added 2.21 g (10 mmol) of 3-nitrobenzenesulfonyl chloride. After stirred at room temperature for 3 hours, methylene chloride (200 mL) was added and washed with saturated NaHCO3 (2×50 mL), 1N HCl (2×50 mL) and brine (2×50 mL) and dried over Na2SO4. After evaporation of the solvent, the residue was dissolved in THF (50 mL), 2N NaOH (10 mL) was added and the mixture heated to 60° C. for 2 hours. After neutralization with 1N HCl, the mixture was extracted with ethyl acetate (4×50 mL) and the organic phase was washed with brine (2×50 mL), dried over Na2SO4 and evaporated to give 3.05 g (94%) of the title compound as a white solid: 1H-NMR (300 MHz, DMSO-d6): δ 7.38 (m, 2H), 7.65 (t, 1H), 7.70 (s, 1H), 7.87 (t, 1H), 8.13 (dd, 1H), 8.47 (dd, 1H), 8.50 (t, 1H), 10.81 (s, 1H), 13.11 (s, 1H).