Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>O1CCCC1>[CH3:1][N:2]1[CH:3]=[C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]1=[O:8]
Reactant: C1COCCN1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N2CCOCC2)cc1
Yield: 105.6 %

Procedure:
A mixture 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (60 mg), morpholine (17 mg), benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (108 mg, BOP reagent) and N-ethyldiisopropylamine (62 mg) in tetrahydrofuran (0.6 ml) was stirred overnight at room temperature. The mixture was concentrated to dryness. The product was purified by chromatography (SiO2, dichloromethane/methanol 1:0 to 9:1) to give the title compound (75 mg) as a colorless foam, MS (ESI+): m/z=445.4 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10](=[O:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13](O)[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CN1CCOCC1.O>[CH2:13]([O:12][C:10]1[NH:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1)[CH3:14]
Reactant: CCO
Reactant: O=C1CC(c2ccccc2)=NN1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCOCC1
Solvent: O
Product: CCOc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 3-phenyl-1H-pyrazol-5(4H)-one (1.0 g, 6.24 mmol), ethanol (0.288 g, 6.24 mmol) and triphenylphosphine (1.638 g, 6.24 mmol) in N-methylmorpholine (7 mL) was added diethylazo dicarboxylate (0.988 mL, 6.24 mmol) dropwise at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was poured into H2O and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.89 g). LCMS m/z=189.19 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (t, J=4.2 Hz, 3H), 4.32 (q, J=4.2 Hz, 2H), 6.45 (s, 1H), 7.41-7.94 (m, 5H), 11.3 (s, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)(S)=[S:8])C=CC=CC=1.[NH2:16][C:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[CH3:28])=[CH:23][CH:22]=1)=[CH:18][C:19]#[N:20]>CC(O)C.CCOC(C)=O>[NH2:16][C:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[CH3:28])=[CH:23][CH:22]=1)=[CH:18][C:19]([NH2:20])=[S:8]
Reactant: CC(F)(F)c1ccc(C(N)=CC#N)cc1
Reactant: S=P(S)(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(F)(F)c1ccc(C(N)=CC(N)=S)cc1
Temperature: 45 °C
Yield: 67.2 %

Procedure:
Add diphenylphosphinodithioic acid (13.2 g, 52.9 mmol) to a solution of 3-amino-3-[4-(1,1-difluoroethyl)phenyl]acrylonitrile (5.50 g, 26.4 mmol) in propan-2-ol (264 mL). Heat to 45° C. for 4 h. Dilute with EtOAc (400 mL), wash with brine 3× (100 mL), and evaporate. Crystallize from EtOAc/hexane to afford 3-amino-3-[4-(1,1-difluoroethyl)-phenyl]thioacrylamide. Yield: 67.2%. ES-MS: m/e 243.0 (m+1).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1B(O)O)([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[C:17]([F:28])[CH:16]=1>>[F:28][C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])[CH:20]=[CH:19][C:18]=1[C:21]1[N:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=1
Reactant: CC(C)Oc1ccccc1B(O)O
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: CC(C)Oc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 3 using (2-isopropoxyphenyl)boronic acid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C19H18FN3O, 323.14; m/z found, 324.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.63-8.57 (m, 1H), 8.12 (d, J=1.4, 1H), 7.97-7.87 (m, 1H), 7.48-7.42 (m, 1.5H), 7.42-7.34 (m, 1.5H), 7.34-7.28 (m, 1H), 7.07-6.97 (m, 2H), 4.65 (s, 2H), 4.59-4.44 (m, 1H), 1.29 (d, J=6.1, 6H).
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17](=[N:21]O)C(O)=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(OC(=O)C)(=O)C>[C:1]1([C:7]2[C:15]([CH2:16][C:17]#[N:21])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(Cc1c(-c2ccccc2)nn2ccccc12)=NO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N#CCc1c(-c2ccccc2)nn2ccccc12
Yield: 63.3 %

Procedure:
A solution of 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-hydroxyiminopropionic acid (0.20 g) in acetic anhydride (1 ml) was stirred for an hour at 80° C. After cooling, to the mixture was added water (10 ml). The resulting precipitates were collected by filtration to give 2-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acetonitrile (0.10 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:13][N:12]=[C:11]2[C:7]=1[CH2:8][CH:9]1[C:14]([CH3:16])([CH3:15])[CH:10]12)=O)C.[NH3:17]>>[CH3:15][C:14]1([CH3:16])[CH:9]2[CH2:8][C:7]3[C:11]([CH:10]12)=[N:12][NH:13][C:6]=3[C:4]([NH2:17])=[O:3]
Reactant: CCOC(=O)c1[nH]nc2c1CC1C2C1(C)C
Reactant: N
Product: CC1(C)C2Cc3c(n[nH]c3C(N)=O)C21
Temperature: 100 °C

Procedure:
(±)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (1.280 g, 5.81 mmol) was taken up in 7M methanolic ammonia (60 mL) in a sealed flask and heated to 100° C. for 18 hours. The resulting suspension was collected by vacuum filtration to give 1,1-dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide as a cream solid. Solvent was removed from the mother liquor and the residue purified by preparative HPLC to give further (±)-1,1-dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide as a cream solid. m/z (ES+): 192 [M+H]+, 175 [M−NH2]+; 1H NMR (CD3OD): δ 2.9-2.65 (m, 1H), 2.55 (t, 1H, J=19.9), 2.0-1.8 (m, 2H), 1.03 (s, 3H), 0.63 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CO.C[O-].[Na+].[C:11]([NH:14][C:15]1[S:16][C:17]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[C:18]([CH2:20][CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26](OC)=[O:27])=[CH:24][CH:23]=2)[N:19]=1)(=[O:13])[CH3:12]>CN(C=O)C>[C:11]([NH:14][C:15]1[S:16][C:17]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)=[C:18]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([NH:4][C:3]([NH2:5])=[NH:2])=[O:27])=[CH:30][CH:31]=2)[N:19]=1)(=[O:13])[CH3:12]
Reactant: N=C(N)N
Reactant: COC(=O)c1ccc(CCc2nc(NC(C)=O)sc2Cc2ccc(S(C)(=O)=O)cc2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CCc2ccc(C(=O)NC(=N)N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.1 %

Procedure:
Guanidine hydrochloride (152 mg) was dissolved in DMF (3 ml), and then 28% sodium methoxide methanol solution (0.3 ml) was added to the solution at r.t. The suspension was stirred at r.t. for 15 minutes, and methyl 4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)benzoate (150 mg) was added to the mixture at r.t. The reaction mixture was stirred at r.t. for 14 hours, and concentrated in vacuo. The residue was dissolved in water, and neutralized with 1N—HCl. The precipitate was collected through filtration, and purified by preparative silica gel chromatography with CHCl3/MeOH (10:1) as an eluent. The solid was washed with ethyl ether to give 4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)-N-[amino(imino)methyl]benzamide (36.6 mg) as an off-white solid.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(F)cc2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2ccc(F)cc2)nc1-c1ccnn1-c1ccccc1
Yield: 27 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-fluorophenyl)pyridazin-4(1H)-one (crude 840 mg, 2.93 mmol) in 20 mL of methanol was added phenylhydrazine (474 mg, 4.39 mmol) The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(4-fluorophenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (260 mg, 27% for two steps) as a brown solid.
Reaction SMILES: [OH-].[K+].CS(C)=O.[F:7][C:8]1[C:9]([O:18][CH3:19])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[NH2:17].Cl[CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>O>[NH2:17][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([F:7])[C:9]=2[O:18][CH3:19])[N:13]([CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[N:12]=1
Reactant: N#Cc1cccc(CCl)c1
Reactant: COc1c(F)ccc2[nH]nc(N)c12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1c(F)ccc2c1c(N)nn2Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 48 %

Procedure:
Finely ground potassium hydroxide (6.59 g, 118 mmol, 2.5 equiv.) was treated with DMSO (100 mL). To this was added 5-fluoro-4-(methyloxy)-1H-indazol-3-amine (for a preparations see Intermediate 56) (8.5 g, 47 mmol) and the mixture stirred at room temperature for 50 minutes. To the red coloured mixture was added 3-chloromethyl benzonitrile (8.9 g, 59 mmol, 1.25 equiv.) in one portion. A small exotherm of ˜5° C. was observed. The mixture was allowed to stir at room temperature for 25 minutes before pouring into water (600 mL) and extracting with chloroform (400 mL). The aqueous was re-extracted with chloroform (2×400 mL). The organic extracts were combined, washed with water (3×500 mL), dried over MgSO4, filtered and evaporated to give the crude product. This was dry loaded onto silica and chromatographed eluting with 20% petrol up to 70% EtOAc-petrol. The material came off impure so was re-chromatographed on a suction column. The impure material was loaded in DCM and eluted with DCM up to 30% EtOAc-DCM to give the title compound (8.25 g, 48%) as an off-white solid. LCMS (System A) RT=0.96 min, ES+ve m/z 297 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[C:14]([Si:18]([O:31][CH2:32][CH:33]([F:36])[CH2:34]I)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Si:18]([O:31][CH2:32][CH:33]([F:36])[CH2:34][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[N:7]=[CH:8][C:9]1=[O:13])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)[Si](OCC(F)CI)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2ncc(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ncc(=O)n(CC(F)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
7-Methoxyquinoxalin-2(1H)-one (synthesized with Reference to WO2009/1126; 1.50 g, 8.50 mmol) and tert-butyl(2-fluoro-3-iodopropoxy)diphenylsilane (Reference Example 29; 5.64 mmol, 12.75 mmol) were dissolved in N,N-dimethylformamide (60 ml). Cesium carbonate (3.88 g, 11.90 mmol) was added to the solution, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 690 mg (17%) of the title compound in the form of a light brown solid.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([C:12]12[CH2:19][CH2:18][N:15]([CH2:16][CH2:17]1)[C:14](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]2=[O:27])[CH:10]=[CH2:11].C[Si](Cl)(C)C.CN(P(N(C)C)(N(C)C)=O)C>[Cu].C1(C)C=CC=CC=1>[CH2:9]([C:12]12[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]1)[CH:14]([CH:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]2=[O:27])[CH:10]=[CH2:11]
Reactant: C=CCC12CCN(CC1)C(=Cc1ccccc1)C2=O
Reactant: Br[Mg]c1ccccc1
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: C=CCC12CCN(CC1)C(C(c1ccccc1)c1ccccc1)C2=O
Temperature: 0 °C
Yield: 67.5 %

Procedure:
Copper(I) bromide dimethyl sulfide complex (1.06 g, 5.16 mmol) and 100 ml of toluene were placed in a reaction vessel, which was immersed into an dry-ice acetone bath. Phenylmagnesium bromide (3.0M in ether, 42 ml, 126 mmol) was slowly added to the copper catalyst keeping the inner temperature below -60° C. To this yellow-white suspension was added a solution prepared from 4-allyl-2-benzylidene-1-azabicyclo[2.2.2]octane-3-one (25.9 g, 103 mmol), trimethylsilyl chloride (31.4 ml, 247 mmol), HMPA (43 ml, 247 mmol) and toluene (120 ml) keeping below -60° C. After addition was completed, the reaction mixture was warmed up to 0° C. The reaction was quenched with 14.5 ml of acetic acid at -60° C. Water was added to the reaction mixture, which was neutralized with Na2CO3 (pH=6.5). The resulting solution was worked-up by an ordinal procedure (extraction with ether at pH=6.5, and then at pH=8.0, washing with brine, drying over Na2SO4, concentration by evaporation) to provide a crude product, which was triturated with ether to afford 4-allyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-one, 58 (23.04 g, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10])=[O:5]>C(Cl)Cl.FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:35]=2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][C:8]=1[C:9]([OH:11])=[O:10])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ncccn2)ccc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2ncccn2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution mixture of the obtained tert-butyl 2-(2-hydroxy-5-(pyrimidin-2-yl)benzamido)-4-phenylbenzoate (5 mg) in methylene chloride (2 mL) and trifluoroacetic acid (0.50 mL) was stirred at room temperature for 3 hours and 30 minutes. The solvent was evaporated under reduced pressure, and water and chloroform were added to the residue. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 4 mg of 2-(2-hydroxy-5-(pyrimidin-2-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([NH:12][OH:13])[CH2:9]2)=[CH:4][CH:3]=1.[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:11][C@H:10]([N:12]([OH:13])[C:24]([NH:23][S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:26])=[CH:15][CH:16]=3)(=[O:22])=[O:21])=[O:25])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: ON[C@H]1C[C@@H](c2ccc(F)cc2)C1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)N(O)[C@H]2C[C@@H](c3ccc(F)cc3)C2)cc1
Yield: 148 %

Procedure:
To a stirred solution of cis-3-(4-fluorophenyl)cyclobutylhydroxylamine (0.9 g, 3 mmol) in THF (20 ml) was added p-toluenesulfonyl isocyanate (1.085 g, 5.5 mmol) at room temperature. The resultant precipitates were collected by filtration and recrystallized from ethyl acetate/EtOH to provide 1.68 g (89% yield) of the title compound as a colorless solid, m.p. 177-178° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:10]=1.N1(C2C=CC(N[C:40]([C:42]3[CH:43]=[C:44]([CH:52]=[CH:53][CH:54]=3)[CH2:45][S:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])=[O:41])=C(C3C=C(NCC4C=CC=C(C)C=4)N=CN=3)C=2)CCCCC1.NC1C=CC(N2CCCCC2)=CC=1C1N=CN=C(NCC2C=CC=C(C)C=2)C=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:40]([C:42]2[CH:43]=[C:44]([CH:52]=[CH:53][CH:54]=2)[CH2:45][S:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])=[O:41])=[C:3]([C:9]2[CH:10]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=3)[N:12]=[CH:13][N:14]=2)[CH:4]=1
Reactant: Nc1ccc(Cl)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Reactant: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)ncn2)c1
Agent: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3N)ncn2)c1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1

Procedure:
This compound was prepared from 6-(2-amino-5-chlorophenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine 65b using the procedure described for the preparation of 3-((3-((4-(piperidin-1-yl)-2-(6-((3-methylbenzyl)amino)pyrimidin-4-yl)phenyl)carbamoyl)benzyl)thio)propanoic acid 3.2 from 6-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3-methylbenzyl)pyrimidin-4-amine 3.2b. 1H-NMR (400 MHz, DMSO-d6, ppm): δ 8.79 (s, 1H), 8.48 (s, 1H), 7.91 (s, 1H), 7.81 (d, J=5.7 Hz, 2H), 7.63 (s, 1H), 7.56 (m, 6H), 7.09 (s, 1H), 4.74 (s, 2H), 3.88 (s, 2H), 2.57 (d, J=4.8 Hz, 2H). MS (ES, m/z): 601 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]([O:45][CH3:46])(=[O:44])[CH:42]=[CH2:43]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:46][O:45][C:41](=[O:44])/[CH:42]=[CH:43]/[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(C(=O)O)c2ccccc12
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 4-bromo-1-naphthalenecarboxylic acid (which may be prepared by the methods described in Can. J. Chem. 1981, 59, 2629-41) (100 mg, 0.4 mmol), triethylamine (0.42 ml, 3 mmol), palladium acetate (12 mg, 0.04 mmol), triphenylphosphine (13 mg, 0.04 mmol) and methyl acrylate (1.19 ml, 0.11 mmol) in anhydrous DMF (8 ml) was heated to 100° C. for 4 h under nitrogen. The mixture was allowed to cool to room temperature, evaporated to dryness under reduced pressure and purified by aminopropyl cartridge, eluting with MeOH, followed by 4M HCl in dioxane and then 2M ammonia in MeOH. The ammonia in methanol fractions were combined to afford a residue that was partitioned between DCM and water, the DCM layers combined, dried over magnesium sulfate filtered and evaporated to afford the title compound (99 mg, 97%). LCMS RT=3.25 min, ES−ve m/z 255 (M−H)−.
Reaction SMILES: [N:1]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=O)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>O1CCCC1>[N:1]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2ncccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: c1cnc2c(c1)NCCCC2
Yield: 70.9 %

Procedure:
A mixture of 1.56 g of 5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepine-6-one, 3.31 g of lithium aluminum hydride in 40 ml of tetrahydrofuran is refluxed for 4 hours. The mixture is cooled (0° C.) and 25 ml of methanol is added dropwise. The mixture is filtered through diatomaceous earth, the filter cake washed with tetrahydrofuran and the filtrate concentrated to dryness under vacuum. Water (50 ml) is added to the residue and the mixture extracted with diethyl ether. The extract is dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate (pad washed with) diethyl ether. The filtrate is concentrated under vacuum to give 1.01 g of crystals, m.p. 70°-71° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:14])[CH2:12][NH2:13])=[C:6]([O:15][CH3:16])[CH:5]=1)[CH:2]=[CH2:3].[CH:17]1[CH:22]=[N:21][CH:20]=[C:19]([C:23](O)=[O:24])[CH:18]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:14])[CH2:12][NH:13][C:23]([C:19]2[CH:20]=[N:21][CH:22]=[CH:17][CH:18]=2)=[O:24])=[C:6]([O:15][CH3:16])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(OC(=O)CN)c(OC)c1
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CCc1ccc(OC(=O)CNC(=O)c2cccnc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
To a solution of Amino-acetic acid 4-allyl-2-methoxy-phenyl ester (510 mg, 1.7 mmol), in DCM (20 mL) were added niacin (0.23 g, 1.9 mmol), N-methyl morpholine (0.96 mL, 8.8 mmol), EDC.HCl (0.67 g, 3.5 mmol) at ice temperature (0° C.). The mixture was allowed to stir at room temperature (25° C.) over a period of 2 hrs. The resulting mixture was diluted with DCM (200 mL) washed with water (2×100 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was purified by silica gel column chromatography to obtain product as off-white solid (210 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:15](=[O:17])[CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[OH:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)O
Reactant: NCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-hydroxy-acetic acid and benzyl amine.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[H-].[Na+].[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].O>CN(C)C=O>[CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])[CH:5]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(CN(C)C)c2cccnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Dimethyl-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine 109 (5.0 g, 28 mmol), was dissolved in N,N-dimethylformamide (80.0 mL) and sodium hydride (60% dispersion in mineral oil, 1.25 g, 31.4 mmol) was added, followed by triisopropylsilyl chloride (6.3 mL, 30.0 mmol). The reaction was stirred at room temperature for 12 hours, then poured into water and extracted with ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel chromatography to give the compound (110, 6.5 g, 70%).