Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][C:12]1[C:13]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:14][CH:15]=[C:16]([CH:19]=1)[C:17]#[N:18]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:13]3[C:12]([CH3:11])=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=3)[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1cc(C#N)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(Br)nc1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Yield: 74.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 6-bromonicotinic acid (500 mg) and 5-methyl-6-piperazin-1-ylnicotinonitrile (501 mg), the title compound (709 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:17](Cl)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl>N1C=CC=CC=1>[S:13]1[CH:14]=[N:15][N:16]=[C:12]1[NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)Nc2nncs2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Compound 100 (50 mg, 0.20 mmol) was suspended in pyridine (0.3 mL). Decanoyl chloride (39.1 mg, 0.21 mmol) was added gradually over 15 min. The reaction mixture was heated to 95° C. and stirred at this temperature for 1 h, then poured into 10% aqueous HCl solution and extracted with EtOAc (3×0.5 mL). The combined organic extracts were washed with water (3×5 mL), brine (3×5 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent yielded the product (80 mg, 0.20 mmol, 95%). It was recrystallized from hexanes/ethyl acetate to yield an analytical sample, mp 151-152° C.; 1H NMR (250 MHz, CD3OD) δ 0.88 (3, t, J=7.5 Hz), 1.24-1.45 (12, m), 1.68 (2, t, J=7.5 Hz), 2.37 (2, t, J=7.5 Hz), 7.72 (2, d, J=8.5 Hz), 7.79 (2, d, J=8.5 Hz), 8.49 (1, S); 13C NMR (125 MHz, CD3OD) δ 14.4, 23.7, 26.7, 30.3, 30.4, 30.5, 30.6, 33.0, 38.1, 102.4, 128.3, 137.5, 144.0, 145.0, 170.0, 174.9; MS (ESI+) 411.1 (M+H)+; HRMS (IonSpec. HiRES ESI+) calcd. for C18H27N4O3S2 (M+H)+411.1525, obsd. 411.1524.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])[NH2:3].[C:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])O)#[N:15].[Na]>FC(F)(F)C(O)=O>[CH2:22]([O:21][C:19]([C:17]1[CH:16]=[C:14]([NH2:15])[N:2]([C:4]2[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=2[CH3:13])[N:3]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C(O)=CC#N
Reactant: Cc1ccc(C(=O)O)cc1NN
Agent: Cl
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(N)n(-c2cc(C(=O)O)ccc2C)n1
Yield: 84 %

Procedure:
To a solution of the above phenyl hydrazine intermediate, (50 mg, 0.247 mmol) in trifluoroacetic acid (TFA) (500 μL) was added sodium 2-cyano-1-ethoxycarbonyl-ethenol (49 mg, 0.298 mmol). The red mixture was heated to reflux for 2 h then cooled and concentrated. Purification by silica-gel chromatography (2% NH4OH/25% MeOH in EtOAc) provided 5-amino-1-(5-carboxy-2-methyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (60 mg, 83%) as a white solid: ESI MS m/z 290 [C14H15N3O4+H]+.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[CH:16]=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.S1[C@@H]2CC(=O)N2C([C:37]([OH:39])=[O:38])=CC1.[ClH:40]>CO.O1CCCC1.C(OC(C)C)(C)C>[ClH:40].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:37]([OH:39])=[O:38])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: COCC1=CN2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Reactant: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 4 h
Yield: 111.3 %

Procedure:
To a suspension of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-3-cephem-4-carboxylic acid (syn isomer) (0.52 g) in a mixture of methanol (3 ml) and tetrahydrofuran (2 ml) was added conc. hydrochloric acid (0.18 g), and the mixture was stirred at 30° C. for 4 hours. After the reaction mixture was cooled and diluted with diisopropyl ether, the precipitated crystals were collected by filtration, washed with diisopropyl ether and then dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (0.45 g).
Reaction SMILES: Br[C:2]1[C:3]([NH:22][CH2:23][CH2:24][CH2:25][OH:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:3]1[C:2]([C:32]2[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCCO)c(Br)c1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2NCCCO)cn1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 161.1, 72 mg, 0.15 mmol), (6-methoxypyridin-3-yl)boronic acid (23.1 mg, 0.15 mmol) and Na2CO3 (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL), EtOH (0.43 mL) and water (0.64 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (5.3 mg, 0.0075 mmol) and the mixture subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=2.33 min, m/z=463.1 [M+H]+, m/z=461.1 [M−H]−.
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:7])[CH2:5][OH:6].C(Cl)Cl.Cl[C:12]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>O.C1COCC1>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([O:6][CH2:5][CH:4]([F:7])[F:3])[N:20]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)c1ccc(Cl)nc1OCC(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaH (55% dispersion in oil; 5.0 g, 114.6 mmol) is added portionwise at 10° C. to 2,2-difluoroethanol (6.25 mL, 99.0 mmol), DCM (200 mL) and THF (75 mL). After 10 min 2,6-dichloro-nicotinic acid (5.0 g, 24.7 mmol) is added to the reaction mixture and it is stirred at rt overnight. Then water is added and it is concentrated. The residue is diluted with water and extracted with Et2O. Formic acid is added to the aqueous layers the precipitate is filtered off, washed with water and dried to give the sub-title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH2:15][C:16]#[CH:17])=[C:6]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])[CH:7]=1.[NH2:18][C:19]1[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([O:26][CH3:27])[N:20]=1.CCCCCCCC>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH2:15][C:16]#[CH:17])=[C:6]([S:8]([NH:11][C:12]([NH:18][C:19]2[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([O:26][CH3:27])[N:20]=2)=[O:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1cc(Cl)nc(N)n1
Reactant: C#CCOc1ccc(C)cc1S(=O)(=O)N=C=O
Solvent: CCCCCCCC
Solvent: C1CCOC1
Product: C#CCOc1ccc(C)cc1S(=O)(=O)NC(=O)Nc1nc(Cl)cc(OC)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 9.4 g of crude 5-methyl-2-propargyloxyphenylsulfonylisocyanate in 50 ml of absolute tetrahydrofuran is added dropwise at room temperature, within 10 minutes, to a solution of 3.7 g of 2-amino-4-chloro-6-methoxy-pyrimidine and 0.1 g of 1,4-diazadicyclo[2.2.2]-octane in 60 ml of absolute tetrahydrofuran, in the course of which the temperature rises slightly. The reaction solution is stirred for 18 hours at room temperature; it is then filtered, and concentrated by evaporation. The residue is crystallised from ethyl acetate to thus obtain 5.8 g of N-(5-methyl-2-propargyloxyphenylsulfonyl)-N'-(4-chloro-6-methoxy-pyrimidin-2-yl)-urea, m.p. 202°-204° C.
Reaction SMILES: ClCCCO[C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:10]=2[CH:11]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)/[CH:32]=[CH:33]/[C:34]([O-])=[O:35]>CC(OC)(C)C.C(O)(C)C>[CH3:17][O:16][C:13]1[C:14]([O:35][CH2:34][CH2:33][CH2:32][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[CH:15][C:9]2[O:8][C:7](=[O:18])[CH:6]=[CH:11][C:10]=2[CH:12]=1
Reactant: COc1ccc2oc(=O)c(OCCCCl)cc2c1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: COc1cc2ccc(=O)oc2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 94 %

Procedure:
Method B (9 h at 70° C.); starting materials: 7-[3-(chloropropoxy)-6-methoxy-2H-1-benzopyran-2-one (see example 69) and 1-phenylpiperazine; yield 94%; fusion point 82° to 83° (from isopropanol and TBME). Fumarate: method E; yield 94%; fusion point 168° to 170° C. (from isopropanol and TBME).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:22])[C:8]=1[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]([CH3:21])[CH3:20])[NH2:5].C([O-])(=O)C.[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[C:7]([CH3:22])[C:8]=1[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]([CH3:20])[CH3:21]
Reactant: Cc1cc(N)cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1cc(C)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(Cl)c1
Yield: 37 %

Procedure:
120 mg of 3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylaniline (Example III) are heated to reflux with 62 mg of sodium acetate and 63 mg of ethyl bromoacetate in 5 ml of ethanol for 17 hours. A further 21 mg of ethyl bromoacetate are added and the mixture is refluxed for 3 hours. The solvent is removed in vacuo, the residue is taken up with water and dichloromethane, the organic phase is washed with saturated sodium chloride solution, dried and the solvent is removed in vacuo. Chromatographic purification (cyclohexane/ethyl acetate) affords 56 mg of ethyl N-{3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylphenyl}glycinate.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1>O1CCCC1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[N:1][N:2]2[CH:6]=[N:5][CH:4]=[N:3]2)=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nn1cncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(C=Nn2cncn2)cc1
Yield: 68.3 %

Procedure:
A solution of 42.3 g (0.377 mol) of 75% pure 1-amino-1H-1,2,4-triazole, 40.0 mL (0.372 mol) of 4-fluorobenzaldehyde and 2.0 g of p-toluenesulfonic acid in 600 mL of tetrahydrofuran was stirred at room temperature for 21/2 days. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous Na2CO3, water and brine and dried (MgSO4). Removal of solvent gave a white solid which was recrystallized from n-butylchloride to afford 48.3 g (67%) of desired product as white needles; mp 118°-120° C. Concentration of the filtrate and recrystallization of the residue afforded 12.8 g (18%) more of product; mp 118°-120° C.
Reaction SMILES: [C:1]([C:4]1([C:7]([OH:9])=O)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].[NH2:10][C:11]([CH:38]1[CH2:40][CH2:39]1)([CH:35]1[CH2:37][CH2:36]1)[C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]([NH:24][C:25]3[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[CH:20]=[C:21]([CH3:23])[CH:22]=2)=[CH:15][N:16]=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.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH:38]1([C:11]([CH:35]2[CH2:36][CH2:37]2)([C:12]2[S:13][C:14]([C:17]3[CH:18]=[C:19]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][N:26]=4)[CH:20]=[C:21]([CH3:23])[CH:22]=3)=[CH:15][N:16]=2)[NH:10][C:7]([C:4]2([C:1]([NH2:2])=[O:3])[CH2:6][CH2:5]2)=[O:9])[CH2:39][CH2:40]1
Reactant: NC(=O)C1(C(=O)O)CC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(N)(C3CC3)C3CC3)s2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(NC(=O)C3(C(N)=O)CC3)(C3CC3)C3CC3)s2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
A flask was charged with 1-carbamoylcyclopropanecarboxylic acid (16.23 mg, 0.126 mmol), N-(3-{2-[amino(dicyclopropyl)methyl]-1,3-thiazol-5-yl}-5-methylphenyl)-4-(trifluoromethyl)-pyrimidin-2-amine (56 mg, 0.126 mmol), BOP (83 mg, 0.189 mmol), DIPEA (43.9 μL, 0.251 mmol) and DMF (10 mL). The reaction was stirred at room temperature for 90 minutes. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, followed by brine, dried. (Na2SO4), filtered, and concentrated to afford N-{dicyclopropyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}cyclopropane-1,1-dicarboxamide (67.6 mg, 0.121 mmol, 97% yield) as an off white solid. MS ESI: [M+H]+ m/z 557.1. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.81 (s, 1H), 8.83 (d, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.44 (s, 1H), 7.29 (m, 3H), 7.15 (s, 1H), 2.31 (s, 3H), 1.67-1.46 (m, 2H), 1.28-1.20 (m, 4H), 0.7-0.65 (m, 2H), 0.56-0.54 (m, 2H), 0.44-0.38 (m, 4H). rhSYK activity=+++
Reaction SMILES: C(OC([C:6]1[N:7]=[C:8]([NH2:11])[O:9][CH:10]=1)=O)C.[OH2:12].[OH-].[Li+].C1[CH2:19][O:18]CC1>O>[NH2:11][C:8]1[O:9][C:10]([C:19]([OH:18])=[O:12])=[CH:6][N:7]=1
Reactant: O
Reactant: C1CCOC1
Reactant: CCOC(=O)c1coc(N)n1
Agent: [Li+]
Agent: [OH-]
Product: Nc1ncc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl2-aminooxazole-4-carboxylate (Apollo Scientific; 1.175 g, 7.50 mmol) was dissolved in THF (15 mL) and water (8 mL). Lithium hydroxide monohydrate (1.58 g, 37.52 mmol) was added and the mixture stirred overnight at room temperature. The mixture was neutralised with 2N HCl(aqu) and concentrated. The residue was suspended in water and filtered and the solid collected dissolved in 2N NaOH(aqu), filtered and then acidified with acetic acid to approximately pH4. The mixture was allowed to stand in an ice bath for 10 minutes and then filtered. The solid was dried on the filter and then in a dessicator overnight to give the title compound a s a yellow solid (194 mg, 20%)
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH2:7])[CH2:2]1.[OH-].[Na+].[CH3:10][NH:11][C:12](=[N:15][N+:16]([O-:18])=[O:17])OC.Cl>C(#N)C.O>[CH3:10][NH:11][C:12]([NH:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[N:15][N+:16]([O-:18])=[O:17]
Reactant: CNC(=N[N+](=O)[O-])OC
Reactant: NCC1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CNC(=N[N+](=O)[O-])NCC1CCOC1
Reaction time: 4 h

Procedure:
[(3-tetrahydrofuryl)methyl]amine (38.0 g, 0.38 mole) and 56.99 g of water were mixed, and the resulting mixture was cooled to 5 degree centigrade. Furthermore, 3.05 g (0.07 mole) of 1N NaOH was added to the solution, and then N,O-dimethyl-N′-nitroisourea (49.2 g, 0.37 mole) was introduced to the solution. The suspension was stirred at 5 degree centigrade for 4 hours, and then heated to 10 degree centigrade, and further stirred for 10 hours. 35% hydrochloric acid (6.7 g, 0.07 mole) was added to the suspension so that the pH became not more than 4. Water and acetonitrile were added to the above suspension for complete dissolution. The resulting solution was analyzed by HPLC and as a result, the reaction yield of the titled compound was 86%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([C:11]([OH:13])=O)[CH:3]=1.NC1C(C#N)=C(OCC)N=C(C(O)=O)C=1.[C:29]1([C:35]2[CH:39]=[C:38]([CH2:40][N:41]3[CH2:46][CH2:45][CH:44]([CH2:47][NH2:48])[CH2:43][CH2:42]3)[O:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([C:11]([NH:48][CH2:47][CH:44]2[CH2:43][CH2:42][N:41]([CH2:40][C:38]3[O:37][N:36]=[C:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:39]=3)[CH2:46][CH2:45]2)=[O:13])[CH:3]=1
Reactant: CCOc1cc(N)cc(C(=O)O)n1
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Agent: CCOc1nc(C(=O)O)cc(N)c1C#N
Product: CCOc1cc(N)cc(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)n1

Procedure:
According to the same procedure described in example 225, using 4-amino-6-ethoxypicolinic acid (prepared according to the reported preparation in J. Med. Chem. 2006, 49(15), 4455-4458), instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and the compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, the title compound having the following physical data was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[C:22]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2-c1ccccc1
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: Cc1ccccc1
Product: Brc1ccc2c(c1)c1cc(-c3ccccc3-c3ccccc3)ccc1n2-c1ccccc1
Temperature: 100 °C
Yield: 42 %

Procedure:
A mixture of 40.1 g (100 mmol) of 3,6-dibromo-9-phenyl-9H-carbazole, 21.8 g (110 mmol) of biphenyl-2-ylboronic acid, 2.31 g (2 mmol) of Pd(PPh3)4, 75 ml of 2M Na2CO3, 150 ml of EtOH and 300 ml toluene was degassed and placed under nitrogen, and then heated at 100° C. for 12 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica to give product (19.9 g, 42.0 mmol, 42%) as a white solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[C:12]([C:13]#[N:14])=[CH:11][C:10]([CH3:15])=[C:9]([CH3:16])[NH:8]1>>[Cl:3][C:7]1[C:12]([C:13]#[N:14])=[CH:11][C:10]([CH3:15])=[C:9]([CH3:16])[N:8]=1
Reactant: Cc1cc(C#N)c(=O)[nH]c1C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C#N)c(Cl)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
Phosphorus oxychloride (15 mL) was added to 2-oxo-1,2-dihydro-5,6-dimethyl pyridine-3-carbonitrile (2.00 g, 13.5 mmol) in a two neck 50 mL round bottom flask, and this mixture was stirred at RT for 1 h, and then refluxed for 12 h. Afterwards, the excess phosphorous oxychloride was distilled off, and the residue was poured into ice cooled water. The aqueous solution was basified with saturated sodium bicarbonate solution, and the precipitate that formed was filtered off to afford the title compound (1.50 g), yield: 66.7%.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:10]=1[O:11][C:12]1[C:13]([C:23]2[C:24]3[CH:33]=[N:32][N:31](COCC[Si](C)(C)C)[C:25]=3[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[CH:14][CH:15]=[C:16]2[C:21]=1[NH:20][C:19](=[O:22])[CH2:18][NH:17]2>C(Cl)Cl>[F:8][C:9]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:10]=1[O:11][C:12]1[C:13]([C:23]2[C:24]3[CH:33]=[N:32][NH:31][C:25]=3[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[CH:14][CH:15]=[C:16]2[C:21]=1[NH:20][C:19](=[O:22])[CH:18]=[N:17]2
Reactant: Cn1cc(-c2ccc3c(c2Oc2ccc(F)cc2F)NC(=O)CN3)c2cnn(COCC[Si](C)(C)C)c2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2ccc3ncc(=O)[nH]c3c2Oc2ccc(F)cc2F)c2cn[nH]c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Trifluoroacetic acid (0.40 mL, 5.19 mmol) was added dropwise at RT to a solution of 8-(2,4-difluorophenoxy)-7-(6-methyl-7-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (10.5 mg, 0.0190 mmol, mixture of oxidized (quinoxalin) and reduced (dihydroquinoxalin) forms from previous step) in methylene chloride (0.40 mL), and the reaction mixture was stirred at RT for 1 h. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (4 mg, 50%). 1H NMR (500 MHz, DMSO-d6) δ 14.05 (br s, 1H), 12.50 (br s, 1H), 8.19 (s, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.3 Hz, 1H), 7.35 (s, 1H), 7.16-6.99 (m, 1H), 6.70-6.56 (m, 1H), 6.55-6.34 (m, 1H), 3.48 (s, 3H); LCMS calculated for C21H14F2N5O3 (M+H)+: m/z=422.1. found: 422.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C:10]1([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:18]1[CH2:19][CH2:20][O:21][CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:17]1
Reactant: BrCc1cccc(Br)c1
Reactant: c1ccc(C2CNCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cccc(CN2CCOC(c3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
1.877 g of 3-Bromobenzyl bromide and 1 g of 2-Phenyl-morpholine in 15 mL of acetonitrile were stirred at room temperature and 2.076 g of potassium carbonate was added. The reaction was stirred at room temperature overnight. The solution was filtered through Celite and concentrated in vacuo to afford a brown solid. Purification by flash chromatography afforded 1.073 g of product. 65% yield ES MS m/z 332
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].C(N([CH:39]([CH3:41])[CH3:40])CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH:5]([C:40]3[CH:39]=[CH:41][CH:8]=[CH:7][CH:6]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(C(c3ccccc3)c3ccccc3)C2)c1
Yield: 97.8 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (58 mg, 0.13 mmol) in CH3CN (5 ml) was added α-Bromodiphenyl methane (48.0 mg, 0.19 mmol), and diisopropylethylamine (45 μl, 0.26 mmol). The reaction was microwaved at 130° C. for 10 minutes. The reaction was diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (39 mg, 49%). Calcd for C39H42F3NO2 (M+H) 613.75, Found 614.4