Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Cl[C:11]1[N:16]2[CH:17]=[N:18][N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1>>[N:19]1[N:18]=[CH:17][N:16]2[C:11]([O:8][C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:9])[CH:6]=3)=[CH:12][CH:13]=[CH:14][C:15]=12
Reactant: Nc1ncc(Br)cc1O
Reactant: Clc1cccc2nncn12
Product: Nc1ncc(Br)cc1Oc1cccc2nncn12

Procedure:
Prepared according to Example 1, step A, using 2-amino-5-bromopyridin-3-ol and 5-chloro-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH2:20][NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH2:20][NH:21][C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NCCO
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=O)NCCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and ethyl 2-hydroxy-ethylcarbamate, there is obtained 2-ethoxycarbonylamino-ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resinous product, mass spectrum m/e: M+ 353 (2), 308 (4), 237 (32), 194 (78), 116 (100), 88 (61);
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].[ClH:12].Cl[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:12])=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C=NO)ccc1Br
Reactant: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: Cc1cc(C(Cl)=NO)ccc1Br
Reaction time: 0.75 h
Yield: 98.2 %

Procedure:
In a solution of 82.0 g of 4-bromo-3-methylbenzaldoxime in 450 mL of tetrahydrofuran, 120.0 g of concentrated hydrochloric acid was added dropwise under cooling with ice and with stirring over 45 minutes. Then, 220 mL of 8% sodium hypochlorite aqueous solution was added dropwise over 75 minutes carefully so that the temperature of the reaction mixture would not exceed 5° C. After the completion of the addition dropwise, it was continued to stir at a temperature of 10° C. or less for further 90 minutes. After the completion of the reaction, the reaction mixture was blown with nitrogen gas for 45 minutes, then precipitated insoluble material was filtered off, tetrahydrofuran was distilled off under reduced pressure. The residual aqueous solution was extracted with 240.0 g of ethyl acetate, and the organic phase was washed with water (240 mL×2). The insoluble material was filtered off, the solvent was distilled off under reduced pressure to obtain 93.5 g of the aimed product as pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:14]C1C(=O)C(Br)=CC(Br)(Br)C=1>C(Cl)Cl>[Br:14][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[C:9]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Reactant: COc1c(N)cccc1C(F)(F)F
Solvent: ClCCl
Product: COc1c(N)ccc(Br)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
To a solution of compound 17C (200 mg, 1.05 mmol) in CH2Cl2 (2 mL) cooled to −20° C. was added dropwise a solution of 2,4,4,6-tetrabromo-2,5-cyclohexadienone (429 mg, 1.05 mmol) in CH2Cl2 (2 mL). After the addition, the reaction was stirred at rt overnight, then additional amount of 2,4,4,6-tetrabromo-2,5-cyclohexadienone (429 mg, 1.05 mmol) was added. The reaction was continued for 2 more days, then concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 10%-20% EtOAc/hexane to yield the title compound (47mg, 16% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH:11]=[C:12]([CH3:14])[CH3:13])=[C:8]([CH3:10])[CH:9]=1)=[O:4].[Li+].[OH-]>CO.C(OCC)C>[CH3:10][C:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[S:6][C:7]=1[CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: COC(=O)c1cc(C)c(C=C(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CC(C)=Cc1sc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A solution of 4-methyl-5-(2-methyl-propenyl)-thiophene-2-carboxylic acid methyl ester (4.08 g, 19.4 mmol) in methanol (33 mL) is treated with 2 N aq. LiOH solution (10 mL). The mixture is stirred at rt for 2 h, then at 45° C. for 3 h. The reaction mixture is diluted with diethyl ether. The org. layer is separated and extracted with water. The combined aq. phase is acidified with 1 M aq. HCl, and extracted twice with diethyl ether. The combined second org. extracts are dried over MgSO4, filtered and concentrated to give 4-methyl-5-(2-methyl-propenyl)-thiophene-2-carboxylic acid (3.05 g) as an off-white solid; LC-MS: tR=0.92 min, [M+1]+=196.98.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[CH:11]=O.Cl.[OH:14][NH2:15].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[CH:11]=[N:15][OH:14]
Reactant: O=C[C@H]1COC2(CCCCC2)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: ON=C[C@H]1COC2(CCCCC2)O1
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
To a solution of (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (9.0 g, 52.9 mmol) in THF (120 mL and 60 mL of water) was added hydroxyl amine hydrochloride (3.73 g, 52.9 mmol) and the reaction stirred until clear (10 minutes). Sodium carbonate (2.75 g, 25.9 mmol) was added and the reaction stirred overnight at ambient temperature. The reaction was poured into ethyl acetate (500 mL) and the layers were separated. The organics were washed with water (200 mL), brine (200 mL), dried over magnesium sulfate and concentrated in vacuo to yield (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (9.08 g, 49 mmol, 92.7%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH:14]=O.C(O)C>C1COCC1>[CH3:7][N:8]([CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH3:14]
Reactant: CN(C)CCCCNC=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CNCCCCN(C)C
Temperature: 0 °C
Yield: 61.5 %

Procedure:
A solution of lithium aluminium hydride in THF (1M, 28 mL) was added dropwise to a stirred, cooled solution of N-(4-dimethylaminobutyl)formamide (Intermediate 79, 2.7 g) in THF (60 mL) while maintaining the temperature at 0° C. under an atmosphere of nitrogen. On completion of the addition, the mixture was stirred and heated at 75° C. for 2 hours. The reaction mixture was cooled to 0° C. and ethanol was added then the mixture was evaporated to dryness. The residue was diluted with a mixture of diethyl ether and DCM (30%) and the solid was filtered off. The filtrate was evaporated to dryness to give N-(4-dimethylaminobutyl)-N-methylamine (1.5 g) as a yellow oil.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19](OC)=[O:20])[CH:13]=[CH:14][CH:15]=1)#[N:10].O>CN(C)C=O>[C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([N:7]=[C:6]([NH2:8])[NH2:5])=[O:20])[CH:13]=[CH:14][CH:15]=1)#[N:10]
Reactant: COC(=O)c1cccc(-n2cccc2C#N)c1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccn1-c1cccc(C(=O)N=C(N)N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
28% Methanolic sodium methoxide (122.2 ml) was added to a solution of guanidine hydrochloride (63.7 g) in dry N,N-dimethylformamide (300 ml) and the mixture was stirred for 20 minutes at ambient temperature. To the mixture was added methyl 3-(2-cyanopyrrol-1-yl)benzoate (30.5 g), and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water under stirring. The isolated precipitate was collected by filtration to give 2-[3-(2-cyanopyrrol-1-yl)benzoyl]guanidine (21.66 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[OH:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([CH2:25][C:26](O)=[O:27])=[CH:19][C:18]=1[O:29][CH3:30].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.Cl>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:26](=[O:27])[CH2:25][C:20]3[CH:21]=[C:22]([O:23][CH3:24])[C:17]([OH:16])=[C:18]([O:29][CH3:30])[CH:19]=3)[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: COc1cc(CC(=O)O)cc(OC)c1O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)Nc2cnn(Cc3c(C)noc3C)c2)cc(OC)c1O
Yield: 28.8 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a) (376 mg, 1.7 mmol), 2-(4-hydroxy-3,5-dimethoxyphenyl)acetic acid (350 mg, 1.7 mmol), PyBop (1 g, 2 mmol) and triethylamine (605 mg, 6 mmol) were stirred together in DMF (10 mL) at room temperature for 2 hours. The reaction mixture was diluted with aqueous 1N HCl (100 mL) and extracted with DCM (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3,5-dimethoxyphenyl)acetamide (189 mg, 29%) as a white solid. 1H NMR (CDCl3, 400 MHz) 2.10 (s, 3H), 2.36 (s, 3H), 3.40 (s, 2H), 3.70 (s, 6H), 5.07 (s, 2H), 6.53 (s, 2H), 7.39 (s, 1H), 7.92 (s, 1H), 8.18 (s, 1H), 10.03 (s, 1H). LC/MS; [M+H] calculated for C, 19; H, 22; N, 4; O, 5; expected 387.16; found 387.6. Melting point: 187-188° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[Cl:17][C:18]1[CH:19]=[N:20][N:21]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH:22]=1>CN1C(=O)CCC1>[Cl:17][C:18]1[CH:19]=[N:20][N:21]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH:28][C:2]3[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=4)[N:3]=3)=[CH:26][CH:25]=2)[CH:22]=1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: Nc1ccc(Cn2cc(Cl)cn2)cc1
Solvent: CN1CCCC1=O
Product: CCc1cc(Nc2ccc(Cn3cc(Cl)cn3)cc2)nc(-c2cccc(Cl)c2)n1
Yield: 47.1 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.100 g, 0.39 mmol) in NMP (3 mL) was reacted with 4-((4-chloro-1H-pyrazol-1-yl)methyl)aniline (0.098 g, 0.47 mmol) to afford the title compound (0.078 g, 78%) as a light brown solid. MW=424.33. 1H NMR (DMSO-d6, 500 MHz) δ 9.67 (s, 1H), 8.34-8.26 (m, 2H), 8.09 (s, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.60-7.52 (m, 3H), 7.32-7.27 (m, 2H), 6.61 (s, 1H), 5.26 (s, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.29-1.24 (m, 3H); APCI MS m/z 424 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]([CH3:22])[NH:11][C:12](=O)[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:24]>ClCCCl>[C:1]1([S:7]([N:10]([CH3:22])[N:11]=[C:12]([Cl:24])[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(NC(=O)c1c(Cl)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CN(N=C(Cl)c1c(Cl)cccc1Cl)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
Into a 1 L three necked round bottom flask equipped with a magnetic stirrer and condenser under an atmosphere of nitrogen was added N-benzenesulfonyl-N-methyl-2,6-dichlorobenzoyl hydrazine (35.9 g, 0.10 mol), 1,2-dichloroethane (500 mL), and phosphorus pentachloride (31.2 g, 0.15 mol). The temperature of the mixture was raised to the point of reflux and was allowed to stir for 30 min. The solvent was removed in vacuo and the residue dissolved in methylene chloride and carefully diluted with water. The organic phase was washed with water, brine, dried (Na2SO4) and the solvent removed in vacuo to give an oil which solidified when triturated with ethyl acetate/hexanes mixture to give 36.1 g (95.7% yield) N-benzenesulfonyl-N-methyl-2,6-dichlorobenzhydrazonoyl chloride as a white crystalline solid: mp 103-104° C.; 1H NMR (CDCl3) δ7.9 (m, 2H), 7.4-7.7 (m, 3H), 7.2-7.4 (m, 3H), 3.1 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18]>>[OH:15][C:16]([CH3:20])([CH3:19])[CH2:17][NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(O)CN
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 2-hydroxy-2-methylpropylamine to provide 4-(2-hydroxy-2-methylpropylamino)-3-nitroquinoline, m.p. 234°-244° C.(dec.). Analysis: Calculated for C13H15N3O3 : %C, 59.8; %H, 5.8; %N, 16.0; Found: %C, 59.8; %H, 5.9; %N, 16.1.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([OH:10])=O)=[O:4].C[N:38]1[CH2:43][CH2:42][O:41]C[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:34])([F:36])[F:35])[O:19][N:18]=2)=[CH:15][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([N:38]1[CH2:43][CH:42]([OH:41])[CH2:39]1)=[O:10])=[O:4]
Reactant: CN1CCOCC1
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCCC(=O)N1CC(O)C1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 26 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Int-V, 25 mg, 0.050 mmol), azetidin-3-ol, HCl (5.45 mg, 0.050 mmol), 4-methylmorpholine (20.13 mg, 0.199 mmol), and HATU (24.60 mg, 0.065 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (Sun Fire C18 5u19×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, product retention=11.15 min (20 mL/min, 220 nM) to provide (R/S)-2-hydroxy-N-(3-(3-hydroxyazetidin-1-yl)-3-oxopropyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (8 mg, 0.013 mmol, 26.2% yield): LCMS=558.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.19 (2 H, d, J=8.36 Hz), 7.52-7.78 (7 H, m), 5.11 (1 H, s), 4.40-4.57(1 H, m), 4.10-4.38(2 H, m), 3.89(1 H, ddd, J=9.52, 4.24, 1.21 Hz), 3.68-3.80 (1 H, m), 3.49 (2 H, t, J=6.27 Hz), 2.27-2.46 (2 H, m); HPLC peak RT=8.1 min (Method A).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH3:19].[Cl:20][C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[CH3:30])=[C:23](Cl)[N:22]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[Cl:20][C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[CH3:30])=[C:23]([O:1][C:2]2[C:3]([CH3:19])=[CH:4][C:5]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=3)=[CH:6][C:7]=2[CH3:8])[N:22]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: COC(=O)c1ccc(-c2cc(C)c(O)c(C)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(C)c(Oc3nc(Cl)nc4c3ncn4C)c(C)c2)cc1

Procedure:
A solution of methyl 4′-hydroxy-3′,5′-dimethylbiphenyl-4-carboxylate (134 mg, 0.52 mmol), 2,6-dichloro-9-methyl-9H-purine (103 mg, 0.51 mmol), and K2CO3 (215 mg, 1.56 mmol) in DME (5 mL) was heated at 80° C. overnight. The desired product was precipitated with H2O and collected by filtration (186 mg). NMR (CDCl3): δ 8.12 (d, 2H), 8.01 (s, 1H), 7.70 (d, 2H), 7.40 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 2.24 (s, 6H).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH2:13][CH2:14][OH:15])[C:11]=1[NH2:12].C(N(CC)CC)C.[C:23]([O:27][C:28]([NH:30][C:31]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=NS(C(F)(F)F)(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:12][C:11]1[N:10]([CH2:13][CH2:14][OH:15])[N:9]=[CH:8][C:7]=1[NH:6][C:31]([NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[N:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: Nc1cnn(CCO)c1N
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cnn(CCO)c1N
Yield: 62.5 %

Procedure:
To a suspension of 4,5-diamino-1-(2-hydroxyethyl)pyrazole sulfuric acid salt (50.0 g) in chloroform (500 ml) were added 4-(dimethylamino)pyridine (2.54 g), triethylamine (116 ml) and 1,3-bis(tert-butoxycarbonyl)-2-(trifluoromethanesulfonyl)guanidine (106 g). The mixture was stirred under reflux for 2 hours. After cooling on an ice bath, the reaction mixture was washed successively with water, 4% aqueous citric acid solution, water and aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixed solvent of ethyl acetate (50 ml) and diethyl ether (200 ml) to give 5-amino-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-1-(2-hydroxyethyl)pyrazole (50 g) as a solid.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[C:16]([OH:18])=O)[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:35])[CH2:3][CH2:2]1.[CH:36]([N:39](C(C)C)[CH2:40]C)(C)C.[Cl-].ClC1N(C)CC[N+]=1C.CNC>CN(C)C=O.C1COCC1>[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:10][CH2:11][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[C:16]([N:39]([CH3:40])[CH3:36])=[O:18])[CH2:13][CH2:14]3)[O:7][CH2:6][C:5]2=[O:35])[CH2:2][CH2:3]1
Reactant: O=C(O)C(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: CCN(C(C)C)C(C)C
Agent: CN1CC[N+](C)=C1Cl
Agent: CNC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)C(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A solution of 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(4-(quinolin-7-yl)phenyl)acetic acid (0.191 mmol) in N,N-dimethylformamide (1 mL) was treated with diisopropylethylamine (0.573 mmol) and 2-chloro-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium chloride (25% in dichloromethane, 0.108 mL) at room temperature. The reaction was stirred for 10 min at which point dimethylamine (2M in THF, 0.286 mmol) was added in one portion. The reaction was allowed to stir overnight, at which point additional dimethylamine (50 μL of a 2M solution in THF) and 2-chloro-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium chloride (25% in dichloromethane, 0.030 mL) was added. The reaction mixture was stirred for an additional 30 minutes and then concentrated in vacuo. The crude material was purified by reverse phase HPLC (5-35% acetonitrile with 0.1% TFA/water with 0.1% TFA). The product fractions were combined, the pH was adjusted to ˜10 with 30% w/v ammonium hydroxide solution, and the mixture was extracted with dichloromethane three times. The combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a white solid (26%). MS(ES)+ m/e 499.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]2[NH:21][N:22]=[N:23][C:19]=2[CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[N:21]1[C:20]2[CH:24]=[CH:25][C:17]([NH:16][C:2]3[C:11]4[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])=[CH:18][C:19]=2[NH:23][N:22]=1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cccc2c(Nc3ccc4nn[nH]c4c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 141, 218.6 mg (1 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 161.0 mg (1.2 mmol) of 5-aminobenzotriazole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was heated at 100° C. for 1 hr. The work up gave 213.5 mg (67.6%) of the product as a yellow solid, m.p.>250 C., mass (electrospray, m/e): M+H 316.9. HRCIMS: calcd 316.107 for C17H12N6O (M+), obsd 316.1079.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]1(=O)[O:18][C:16](=[O:17])[CH:15]=[CH:14]1>ClCCl>[C:13]1(=[O:18])[N:1]([CH2:2][CH2:3][CH2:4][N:5]([CH3:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:16](=[O:17])[CH:15]=[CH:14]1
Reactant: O=C1C=CC(=O)O1
Reactant: CN(CCCN)c1ccccc1
Solvent: ClCCl
Product: CN(CCCN1C(=O)C=CC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-Aminopropyl)-N-methylaniline [S. L. Shapiro et al., J. Am. Chem. Soc., 81, 3081 (1958)](8.3 g) was dissolved in dichloromethane (50 ml). Maleic anhydride (6 g) was added portionwise under ice-cooling and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off and then acetic anhydride (20 ml) was added. The resulting mixture was allowed to stand at room temperature for 2 days. The reaction mixture was stirred at 60° C. for 2 hours and further at 100° C. for 2 hours. The mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was neutralized with an aqueous sodium bicarbonate, washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (4:1). The desired compound thus obtained was recrystallized from the same solvent to obtain the compound as yellow needles (4.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([NH2:14])=[C:12]([C:15]2[C:16]([C:27]([F:30])([F:29])[F:28])=[N:17][N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:19]=2)[O:11][N:10]=1.[C:31](O)(=[O:33])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([NH:14][CH:31]=[O:33])=[C:12]([C:15]2[C:16]([C:27]([F:29])([F:30])[F:28])=[N:17][N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:19]=2)[O:11][N:10]=1
Reactant: Nc1c(-c2c(F)cccc2Cl)noc1-c1cn(-c2cccc(F)c2)nc1C(F)(F)F
Reactant: CC(=O)O
Product: O=CNc1c(-c2c(F)cccc2Cl)noc1-c1cn(-c2cccc(F)c2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A solution of 130 mg (0.295 mmol) 3-(2-chloro-6-fluorophenyl)-5-[1-(3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]isoxazol-4-amine (example 117) in a mixture of 1847 mg (17.4 mmol) trimethylorthoether and 1660 mg (27.7 mmol) acetic acid was stirred at r.t. for 1 h. The suspension was filtered, and the obtained white solid salts were washed on the filter with hexane. Filtrates were combined and evaporated to dryness. The residue was treated by hexane, and the extract was purified by CC on silica gel, (eluent EtOAc/hexane 1/1). The obtained fraction of the pure product (example 141) was evaporated to give 50 mg of a light greenish oil (yield 36%). Result of LC/MS MH+: 469.04; 1H NMR (400 MHz, methanol-d4): 7.29-7.35 (m, 1H) 7.44 (s, 3H) 7.46-7.50 (m, 1H) 7.57-7.67 (m, 2H) 7.72 (s, 1H) 8.26 (s, 1H)