Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][CH:3]=1.[CH:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([OH:25])[CH:17]=1>ClC1C=CC=CC=1>[CH3:13][O:12][C:10]1[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=[C:6]2[C:11]=1[C:2]([O:25][C:18]1[CH:17]=[CH:16][C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)=[CH:3][CH:4]=[N:5]2
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cc(OC)c2c(Cl)ccnc2c1
Solvent: Clc1ccccc1
Product: COc1cc(OC)c2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chloro-5,7-dimethoxyquinoline (100 mg, 0.40 mmol) and p-nitrophenol (124 mg, 0.89 mmol) in chlorobenzene (2 mL) was heated at reflux for 14 h. Then the reaction mixture was cooled to rt, filtered, and the residue washed with toluene. The solid was suspended in 10% NaOH solution and stirred for 1 h at rt. The yellow solid was collected and washed with EtOAc to give 5,7-dimethoxy-4-(4-nitrophenoxyl)quinoline. LCMS m/z=327 (M+1); 1H NMR (CDCl3) δ: 8.60 (d, 1H, J=6.0 Hz), 8.44 (d, 2, J=8.8 Hz), 7.72 (s, 1H), 7.35 (d, 2H, J=8.4 Hz) 6.71 (s, 1H), 6.69 (d, 2H, J=6.4 Hz), 4.08 (s, 3H), 3.97 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[NH2:9].C(N(CC)CC)C.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30]>C(Cl)Cl>[OH:30][C:29]1[C:28](=[O:32])[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[CH:7][CH:6]=[C:5]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=1)[CH:4]=2
Reactant: CNc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1N
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)c(O)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Yield: 46.2 %

Procedure:
A solution of N3-methyl-4′-(trifluoromethoxy)biphenyl-3,4-diamine (1 g) in methylene chloride (35 ml) was cooled in an ice bath, and triethylamine (1.5 ml) was added, followed by dropwise addition of oxalyl chloride (670 mg). After 1 hour the solvent was removed under reduced pressure, and the residue was crystallized from methanol, to provide 3-hydroxy-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one (550 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[F:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][CH2:24][CH2:25]Br)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][CH2:24][CH2:25][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:20][CH:19]=1
Reactant: Brc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: Fc1ccc(OCCCBr)cc1
Product: Fc1ccc(OCCCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Yield: 89.2 %

Procedure:
1-(Piperidin-4-yl)-6-bromoindoline (1.6 g) and 4-fluorophenoxypropyl bromide (1.6 g) were treated as in Example 2 to give the title compound (2.2 g) as a white powder (yield: 90%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][N:24]([CH:26]=O)[CH3:25]>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[CH:23][N:24]([CH3:26])[CH3:25])[CH:14]=[O:16])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (92 g) was added dropwise to stirred DMF (78 ml) between 10°-15° C. To the resulting slurry was added 4-chlorophenylacetic acid (34.12 g). The resulting mixture was stirred at room temperature for one half hour and then heated to 70°-80° C. during 5.5 hours, during which time the mixture became effervescent. The reaction mixture was cooled and poured slowly onto cracked ice. The resulting suspension was brought to pH 10 with solid potassium carbonate. Ice was added intermittently during this addition to maintain the temperature below 15° C. ToIuene (150 ml) was added and the resulting mixture heated at 100° C. for one hour. The mixture was cooled and allowed to stand overnight. The two resulting layers were separated and the aqueous layer extracted with toluene (2×100 ml). The combined organic layers were washed with water (5×200 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the resulting yellow solid was triturated with hexane to yield 26 g of 2-(4-chlorophenyl)-3-dimethylaminopropenal as a tan solid mp. 120°-125° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]#[N:19])=[CH:17][C:12]=2[CH2:11][CH2:10][O:9]1)(=O)=O.[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([N:31]1[CH2:36][CH2:35][NH:34][C@H:33]([CH3:37])[CH2:32]1)=[CH:26][CH:25]=[CH:24]2>>[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([N:31]1[CH2:36][CH2:35][N:34]([CH2:6][CH2:7][CH:8]3[C:13]4[CH:14]=[CH:15][C:16]([C:18]#[N:19])=[CH:17][C:12]=4[CH2:11][CH2:10][O:9]3)[C@H:33]([CH3:37])[CH2:32]1)=[CH:26][CH:25]=[CH:24]2
Reactant: CS(=O)(=O)OCCC1OCCc2cc(C#N)ccc21
Reactant: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1
Product: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CCC1OCCc2cc(C#N)ccc21

Procedure:
Prepared by condensation of 2-(6-cyano-3,4-dihydro-1H-2-benzopyran-1-yl)ethyl methanesulfonate with (3R)-1-(6-Fluoro-1-naphthyl)-3-methylpiperazine, as described for Example 1b).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Br)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Br)cccc2-3)no1
Yield: 83.1 %

Procedure:
1.26 g (3 mmol) of (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature for 5 hours with 0.44 g (6 mmol) of diethylamine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.14 g (82%) of (S)-8-bromo-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 206°-209°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Br:15])[CH:9]=1)=[O:7].[OH-].[K+].Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CS(C)=O>[Br:15][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][C:11]=1[O:14][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=C(c1ccc(O)c(Br)c1)c1cccs1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)c2cccs2)cc1Br
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 2-thienyl-(3-bromo-4-hydroxy-phenyl)ketone (14.5 g; M.p.=185° C.) in dimethylsulfoxide (50 ml) is added potassium hydroxide (2.8 g) and the mixture is heated to 50° C. for 30 minutes, after which ethyl α-bromoisobutyrate (9.75 g) is added thereto at room temperature. After a period of time of 3 hours, the solution is poured into water (100 ml) and the aqueous phase is extracted with ethyl ether. The organic phase is washed with an aqueous sodium hydroxide solution, and then with water, and the solvent is evaporated off after drying over sodium sulfate. The final product is recrystallized from petroleum ether (7 g; M.p.=80° C.).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]([O:23][CH3:24])=[O:22])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:32](O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(COCC)C=C2)CO)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]([O:23][CH2:24][CH3:32])=[O:22])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1
Reactant: CCOCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Product: CCOC(=O)c1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(ethoxycarbonyl)-7-methylquinolin-6-yl)acetic acid was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxycarbonyl)-7-methylquinolin-6-yl)acetic acid of Example 12, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(ethoxymethyl)-7-methylquinolin-6-yl)ethanol was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxymethyl)-7-methylquinolin-6-yl)ethanol. 1H-NMR 300 MHz, (CD3OD) δ8.10-8.00 (m, 2H), 7.90 (d, 1H), 7.70-7.57 (m, 3H), 7.35 (d, 1H), 5.23 (s, 1H), 4.50 (q, 2H), 2.70 (s, 3H), 1.46 (t, 3H) 0.98 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C25H26ClNO5: 456.9. Found: 456.2, 458.2.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:10]=2)[NH:5][CH:4]=1)#[CH:2].Cl[C:25](=[N:42][OH:43])[C:26]1[CH:27]=[C:28]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])[CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C>C1COCC1>[CH:21]([S:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:10]=[C:11]3[C:3]([C:1]4[O:43][N:42]=[C:25]([C:26]5[CH:27]=[C:28]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])[CH:29]=[CH:30][CH:31]=5)[CH:2]=4)=[CH:4][NH:5][C:6]3=[N:7][CH:8]=2)=[CH:17][CH:16]=1)(=[O:20])=[O:19])([CH3:23])[CH3:22]
Reactant: C#Cc1c[nH]c2ncc(-c3ccc(S(=O)(=O)C(C)C)cc3)nc12
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(C(Cl)=NO)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1cccc(-c2cc(-c3c[nH]c4ncc(-c5ccc(S(=O)(=O)C(C)C)cc5)nc34)on2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.8 %

Procedure:
To a solution of 7-ethynyl-2-(4-isopropylsulfonylphenyl)-5H-pyrrolo[2,3-b]pyrazine (72 mg, 0.2213 mmol) and tert-butyl 1-(3-(chloro(hydroxyimino)methyl)phenyl)ethylcarbamate (66.12 mg, 0.2213 mmol) in THF (2.5 mL) was added triethylamine (26.88 mg, 37.02 μL, 0.2656 mmol) The mixture was stirred at ambient temperature for 45 minutes then heated at 65° C. for 3.5 hours. The reaction was cooled to ambient temperature and the solvent removed in vacuo. The residues was dissolved in warm DCM (50 mL) and washed with saturated aqueous NaHCO3(×1), dried (MgSO4), filtered and concentrated in vacuo. The residue triturated from hot MeCN and the precipitate obtained on cooling was isolated by filtration and washed with MeCN to give the sub-title compound as a pale yellow powder (83 mg, 64% Yield). 1H NMR (400 MHz, DMSO) δ 1.28 (d, 6H), 1.41-1.45 (m, 3H), 1.43 (s, 9H), 3.58 (sept, 1H), 4.79 (br t, 1H), 7.52-7.62 (m, 4H), 7.92 (d, 1H), 8.00 (s, 1H), 8.10 (d, 2H), 8.68 (d, 2H), 8.76 (s, 1H), 9.25 (s, 1H) and 13.08 (br s, 1H) ppm; MS (ES) 588.1.
Reaction SMILES: [Cl-].[CH2:2]([O:4][P:5]([CH2:8][CH:9]=[CH2:10])(=O)[OH:6])[CH3:3].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([O:17][P:5]([CH2:8][CH:9]=[CH2:10])(=[O:6])[O:4][CH2:2][CH3:3])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CCP(=O)(O)OCC
Reactant: Oc1ccccc1
Agent: [Cl-]
Product: C=CCP(=O)(OCC)Oc1ccccc1
Yield: 60 %

Procedure:
Allylphosphonic acid ethyl ester-chloride, prepared analogously to synergistic agent 16, was reacted with phenol analogously to agent 16 to give allylphosphonic acid ethyl phenyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:37])([CH2:34][CH2:35][CH3:36])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:33])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])=[CH:20][C:19](C)=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:37])([CH2:34][CH2:35][CH3:36])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:33])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])=[CH:20][CH:19]=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3Cl)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.8 %

Procedure:
A solution of 40 mg (0.073 mmol) of rac-{1-[({7-[(2-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 138A) in 2 ml of dichloromethane was admixed with 0.113 ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for 18 hours and then heated to 40° C. Further trifluoroacetic acid (0.169 ml) was added in portions over the course of 3 hours. The reaction mixture was concentrated under reduced pressure and the remaining residue was purified by preparative HPLC chromatography (Method 21), which gave 11.0 mg (33% yield) of the target compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[N:13]2[C:8]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=32)=[N:7]1.[I-].[K+].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[C:22]1([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:14](=[O:15])[N:13]4[C:8]([CH2:9][O:10][C:11]5[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=54)=[N:7]3)[CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1n(CCCCCl)nc2n1-c1ccccc1OC2
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Product: O=c1n(CCCCN2CCN(c3ccccc3)CC2)nc2n1-c1ccccc1OC2

Procedure:
A solution of 2-(4-chlorobutyl)-2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-1-one (see example 4, part 1), (1.40 g.; 0.005 mole), potassium iodide (0.83 g.; 0.005 mole) and N-phenylpiperazine (1.79 g.; 0.011 mole) was stirred at 100° C. for 5 hours. The reaction mixture was cooled, poured into water and extracted with methylene chloride. The methylene chloride extracts were combined, washed with dilute brine solution, dried over sodium sulfate and concentrated in vacuo. The resulting residue was chromatographed through 125 g. of silica gel, using a 2% v/v diethylamine in ethyl acetate as eluting liquid. The eluted product thus obtained, titled above, was crystallized in the manner described in example 1, hereinabove, from an ethyl acetate/Skellysolve®B hexane mixture to give 1.56 g., m.p. 89°-90° C. and 0.115 g., m.p. 85°-87° C. of the named, titled compound hereinabove. The analytical sample had melting point 89°-90.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][CH:10]=[CH2:11])[CH:3]=1.[NH2:20][NH2:21].[Al]>C(O)C>[NH:20]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][CH:10]=[CH2:11])[CH:3]=1)[NH2:21]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(Cl)ccn1
Reactant: NN
Agent: [Al]
Solvent: CCO
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(NN)ccn1
Reaction time: 18 h
Yield: 85.7 %

Procedure:
A vial with a Teflon septum cap was charged with a solution of 1C (2 g, 7.0 mmol) and hydrazine (35% in water) (10 mL, 111 mmol, 15.75 equiv) in ethanol (10 mL). The solution was heated by an aluminum block set to 115° C. for 18 hours. The reaction was concentrated to give a pink oil. Purification by normal phase silica gel chromatography yielded 222A (1.67 g, 85%) as a yellow, foaming solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (d, J=5.7 Hz, 1H), 6.60 (s, 1H), 6.57 (dd, J=5.5, 2.4 Hz, 1H), 5.79-5.54 (m, 3H), 5.14-4.99 (m, 2H), 4.74-4.62 (m, 1H), 2.59 (t, J=6.7 Hz, 2H), 1.52-1.40 (m, 9H). MS (ESI) m/z: 279.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH3:15][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:13]=[C:6]([C:7](=[O:8])[CH3:15])[C:5]([Cl:14])=[N:4][CH:3]=1
Reactant: CON(C)C(=O)c1cc(Br)cnc1Cl
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cc(Br)cnc1Cl
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Starting material 5-bromo-2-chloro-N-methoxy-N-methylnicotinamide (5.0 g, 17.89 mmol) was charged into a 250 ml round bottom flask and the flask was chilled to −78° C. Methyl magnesium bromide 96.5 ml, 19.68 mmol) in 5 ml THF was added dropwise via addition funnel. The resulting mixture was allowed to stir for 3 hours at −78° C. After removing the THF solvent via rotatory evaporation under reduced pressure, the reaction mixture was partitioned between ethylacetate and saturated aqueous sodium bicarbonate. After removing the ethylacetate, the resulting crude product was subject to a silica gel column with 20% ethylacetate in hexane. The resulting product (2.28 g, y=54.3%) was used for the following step.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1>>[F:32][C:28]1[CH:27]=[C:26]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[CH:10]=2)=[O:5])[CH:31]=[CH:30][CH:29]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Reactant: Fc1cccc(Br)c1
Product: O=C(c1cccc(F)c1)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12l and 1-bromo-3-fluorobenzene
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8]C)=O)=[N:2]1.[CH:10]([NH2:13])([CH3:12])[CH3:11]>CO>[CH3:11][CH:10]([NH:13][C:6]([C:3]1[N:4]=[CH:5][NH:1][N:2]=1)=[O:8])[CH3:12]
Reactant: COC(=O)c1nc[nH]n1
Reactant: CC(C)N
Solvent: CO
Product: CC(C)NC(=O)c1nc[nH]n1
Temperature: 50 °C
Reaction time: 144 h
Yield: 95 %

Procedure:
Methyl 1H-1,2,4-triazole-3-carboxylate (3.53 g, 27.8 mmol) and isopropylamine (11 ml, 128 mmol) were combined in a 20 ml vial to give a white suspension. The vial was sealed and heated to 50° C. After 6 days the reaction mixture had become a translucent solid. The vial was cooled to room temperature and unsealed. The solid was dissolved in methanol and transferred to a 200 ml flask. The solvent was evaporated under reduced pressure and the resulting residue was stripped several times with ethanol to removed excess isopropylamine. The residue was stripped with toluene and placed under high vacuum overnight to give the title compound (4.07 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH2:6])[CH3:5].[Cl:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12]>C1COCC1>[Cl:7][CH2:8][CH2:9][NH:10][C:11]([NH:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])=[O:12]
Reactant: COC[C@H](C)N
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: COC[C@H](C)NC(=O)NCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of (S)-1-methoxypropan-2-amine (500 mg, 5.61 mmol) in THF (15 mL) was treated with 2-chloroethylisocyanate (592 mg, 5.61 mmol), stirred at RT overnight, then concentrated to dryness. The residue was treated with toluene and concentrated to dryness (twice) to afford (S)-1-(2-chloroethyl)-3-(1-methoxypropan-2-yl)urea (100% yield assumed) as a white solid which was used without further purification. MS (ESI) m/z: 195.1 (M+H+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: Brc1cnn(C2CCNCC2)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(n2cc(Br)cn2)CC1
Temperature: 40 °C
Yield: 81.3 %

Procedure:
To a solution of 4-(4-bromopyrazol-1-yl)piperidine hydrochloride (300 mg, 1.13 mmol) in pyridine (3 ml) was added acetic anhydride (0.107 ml, 1.13 mmol) under an inert atmosphere. The reaction was stirred at 40° C., until reaction complete then evaporated under reduced pressure and re-evaporated with toluene twice, then partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the product (250 mg), which was used without further purification MS: [M+H]+=272
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:17][C:10]=12.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][C:38]([CH3:46])=[N:37]2)=[CH:32][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:43]([C:40]2[C:41](=[O:42])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[N:37]=[C:38]([CH3:46])[CH:39]=2)=[O:44])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[S:17][C:10]=12
Reactant: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reactant: Cc1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)n1
Product: Cc1cc(C(=O)Nc2ccc(Oc3ccnc4cc(C#CCN5CCN(C)CC5)sc34)c(F)c2)c(=O)n(-c2ccc(F)cc2)n1
Yield: 14 %

Procedure:
Prepared from 3-fluoro-4-(2-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)aniline (Example 17, Step B) and 2-(4-fluorophenyl)-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 4.5 mg (14%) of the desired product. LRMS (ESI pos) m/e 627.3 (M+1). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 8.47 (d, 1H), 8.32 (s, 1H), 8.0 (dd, 1H), 7.62 (m, 3H), 7.45 (d, 1H), 7.34 (t, 1H), 7.27 (t, 2H), 6.65 (d, 1H), 3.66 (s, 2H), 2.77 (m, 8H), 2.56 (s, 3H), 2.34 (s, 3H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −113.2, −127.6.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.[Br:17][C:18]1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22](Br)[CH:23]=1>>[Br:17][C:18]1[CH:23]=[C:22]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:21]=[C:20]([CH3:25])[CH:19]=1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: Cc1cc(Br)cc(Br)c1
Product: Cc1cc(Br)cc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1

Procedure:
6-(3-Bromo-5-methyl-phenyl)-4,4-dimethyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-one was prepared, using (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 3,5-dibromotoluene according to the procedure of Example 5, as a white solid: mp 231-233° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 7.66 (s, 1H), 7.58-7.56 (m, 2H), 7.50 (s, 1H), 7.37 (s, 1H), 6.95 (d, 1H, J=8.67 Hz), 2.37 (s, 3H), 1.67 (s, 6H); MS (ESI) m/z 344/346 ([M−H]−, 100%); Anal. Calcd. For C17H16BrNO2: C, 58.98; H, 4.66; N, 4.05. Found: C, 58.82; H, 4.62; N, 3.94.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])[CH:7]=1.Cl[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[N:20]=[CH:19][N:18]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:15][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[N:20]=[CH:19][N:18]=2)=[CH:7][C:6]=1[NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(-c2cc(Cl)ncn2)c1
Reactant: CCCS(=O)(=O)Nc1cc(N)ccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1cc(Nc2cc(-c3cccc([N+](=O)[O-])c3)ncn2)ccc1C
Temperature: 80 °C

Procedure:
A mixture of propane-1-sulfonic acid (5-amino-2-methyl-phenyl)-amide (5.5 g, 24 mmol) and 4-chloro-6-(3-nitro-phenyl)-pyrimidine (5.52 g, 23.4 mmol) in DMFA (50 mL) was stirred at 80° C. till the reaction completion (TLC control), the reaction mixture was diluted with water (200 mL), treated with NaHCO3 (4.2 g, 50 mmol). The formed precipitate was filtered out, washed with water (2×200 mL), dried, washed with chloroform (2×50 ml), dried to yield propane-1-sulfonic acid {2-methyl-5-[6-(3-nitro-phenyl)-pyrimidin-4-ylamino]-phenyl}-amide as yellow powder.