Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:6][C:7]([C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[O:12])=[O:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:7]([C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[O:12])([OH:8])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(-c2ccncc2)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(-c2ccncc2)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 0.3 %

Procedure:
In dichloromethane (50 ml), 1-[2-tert-butoxycarbonyl-4-(pyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (250 g) was dissolved, followed by the dropwise addition of trifluoroacetic acid (50 ml) under ice cooling. After stirring at room temperature for 5 hours, the solvent was distilled off. The residue was dissolved in methanol and the resulting solution was allowed to stand in a refrigerator for one day. The colorless solid so precipitated was collected by filtration and dried, whereby the title compound (550 mg, 28%) was obtained as a colorless solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.[F:24][C:25](I)([F:27])[F:26]>[Cu].CN(C)C=O>[F:24][C:25]([F:27])([F:26])[C:2]1[CH:3]=[C:4]([C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:9]([F:12])([F:11])[F:10])[CH:18]=2)([C:13]([F:15])([F:14])[F:16])[C:9]([F:10])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)C(c1cccc(I)c1)(c1cccc(I)c1)C(F)(F)F
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(C(c2cccc(C(F)(F)F)c2)(C(F)(F)F)C(F)(F)F)c1
Temperature: 150 °C

Procedure:
A 500 mL autoclave was charged with 44.5 g (80.0 mmol) of 2,2-bis[3-iodophenyl]-1,1,1,3,3,3-hexafluoropropane, 40.09 (204 mmol) of trifluoromethyl iodide, 150 mL of dry N,N-dimethylformamide and copper powder (catalyst), and the mixture was heated at a temperature of 150° C. for 24 hours with stirring. After being cooled, the reaction mixture was filtered to remove the copper powder, and the filtrate was fractionally distillated under a reduced pressure to obtain the aimed compound 2Aa.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2[N+](=O)[O-])CC1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(NCc3ccccc3)c2[N+](=O)[O-])CC1
Temperature: 120 °C
Yield: 54.2 %

Procedure:
4-(3-Fluoro-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.300 g, 0.923 mmol) and benzylamine (0.110 mL, 1.015 mmol) were combined in 1 mL dimethylsulfoxide with potassium carbonate (0.318 g, 2.308 mmol), and the reaction mixture was heated to 120° C. for 2 hours. The reaction mixture was poured onto 100 g icewater and extracted twice with 100 mL ethyl acetate. The combined organic phases were washed twice with 50 mL water, once with 50 mL brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by flash chromatography (1% to 15% ethyl acetate in hexanes) to afford 0.208 g (0.50 mmol, 54%) of 4-(3-benzylamino-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. MS: 413 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1.Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:12]1[N:13]=[C:14]([NH:17][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[S:15][CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2,6-Dimethyl-4-nitrophenyl)thiazol-2-amine (92 mg, 0.37 mmol) in DCM (2 mL) was added DMAP (90 mg, 0.74 mmol) followed by isonicotinoyl chloride hydrochloride (85 mg, 0.48 mmol). Then the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated, and the saturated aqueous sodium bicarbonate (30 mL) was added. The aqueous solution was extracted with DCM (3×10 mL). The combined organic layers were dried with anhydrous sodium sulfate. After removal of all the solvent, the residue was purified by silica gel chromatography (hexane/EtOAc=4:1) to give INH78 (82 mg, 62%) as a white solid; mp 258-260° C. 1H NMR (400 MHz, DMSO-d6) δ 8.79-8.77 (m, 2H), 8.02 (s, 2H), 8.97-8.95 (m, 2H), 7.32 (s, 1H), 2.20 (s, 6H). 13C NMR (125 MHz, DMSO-d6) δ 164.5, 150.9, 147.2, 142.9, 139.8, 139.7, 113.4, 20.7. MS (ESI) m/z 355.0 (M+H+). HRMS calculated for C17H14N4O3SH (M+H+), 355.0865. found, 355.0867.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:14]([O:16][CH2:17][CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][C:37]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38]2)[CH2:31][CH2:30]1)[CH3:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([N:39]1[CH2:40][CH2:41][C:37]([CH2:36][CH2:35][N:32]2[CH2:33][CH2:34][CH:29]([NH:28][C:20]3[N:19]([CH2:18][CH2:17][O:16][CH2:14][CH3:15])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH2:30][CH2:31]2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38]1)=[O:7]
Reactant: COc1ccc(F)cc1C(=O)O
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(F)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-fluorobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13](N)[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]([C:25]([O:27][CH3:28])=[O:26])=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.N([O-])=O.[Na+].O.[ClH:38]>>[C:1]([C:9]1[CH:14]=[C:13]([Cl:38])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]([C:25]([O:27][CH3:28])=[O:26])=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(=O)OC)n(-c2ccc(N)cc2C(=O)c2ccccc2)n1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(=O)OC)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reaction time: 0.33 h

Procedure:
To a solution of 13.1 g. (34.5 mmol) of the final product of Example 2 in 50 ml. HOAc and 75 ml. of 3 N HCl, stirred at 3°, was added dropwise so as to maintain a temperature of 3°-6°, a solution of 2.50 g. (36.3 mmol) of sodium nitrite in 25 ml. H2O. When the addition was complete, the reaction was stirred at 3° for 20 minutes. A fresh solution of cuprous chloride in concentrated hydrochloric acid (prepared from 27 g. cupric sulfate pentahydrate*) was mixed with an equal volume of water and cooled to 3°. The diazotized solution, which had to be kept cold (<5°) at all times, was slowly poured into the vigorously stirred 5° cuprous chloride solution in several portions, in order to control foaming.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1nc(-c2ccccc2)nc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc(-c2ccccc2)nc2ccccc12
Yield: 54 %

Procedure:
A mixture of 4-methyl-2-phenylquinazoline (15 g), N-bromosuccinimide (13.3 g) and benzoyl peroxide (1.65 g) in carbon tetrachloride (150 cc) is brought for 3 hours to 90° C. The mixture is filtered, the filtrate evaporated and the residue chromatographed on silica gel with a cyclohexane/ethyl acetate (9:1 by volume) mixture as eluant. 4-Bromomethyl-2-phenylquinazoline (11 g), m.p. 110° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:19]=[CH:20][C:21](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:21](/[CH:20]=[CH:19]/[C:18]3[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:16]([F:15])[CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1ccc(C=CC(=O)O)cc1F
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(F)c3)nc2n(CC)c1=O
Yield: 44 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.72 g (13.9 mmol) of 3-fluoro-4-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.97 g (yield 44% of Compound 165 as pale yellow flocculent precipitates.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[CH:64]=[CH:63][CH:62]=[CH:61][C:58]=1[C:59]#[N:60])=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[CH:64]=[CH:63][CH:62]=[CH:61][C:58]=2[C:59]#[N:60])=[O:56])[CH2:51][CH2:52]1
Reactant: N#Cc1ccccc1N=C=O
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1NC(=O)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-isocyanatobenzonitrile as the starting materials in 40% yield. LCMS for C32H32ClN8O2 (M+H)+: m/z=595.0.
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[N:10]=1)C1C=CC=CC=1.[F:30][C:31]1([F:46])[CH2:33][C@@H:32]1[CH2:34][O:35][C:36]1[CH:37]=[C:38]([F:45])[C:39]([C:42](O)=[O:43])=[N:40][CH:41]=1>>[F:46][C:31]1([F:30])[CH2:33][C@@H:32]1[CH2:34][O:35][C:36]1[CH:37]=[C:38]([F:45])[C:39]([C:42]([NH:15][C:14]2[C:9]([OH:8])=[N:10][C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:21])=[N:12][CH:13]=2)=[O:43])=[N:40][CH:41]=1
Reactant: C[C@@H](COc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ncc(OC[C@H]2CC2(F)F)cc1F
Product: C[C@@H](COc1ncc(NC(=O)c2ncc(OC[C@H]3CC3(F)F)cc2F)c(O)n1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((4-(benzyloxy)-5-nitropyrimidin-2-yl)oxy)propan-2-yl)carbamate and 5-(((1R)-2,2-difluorocyclopropyl)methoxy)-3-fluoropyridine-2-carboxylic acid, and in the same manner as in Step A of Example 4 and Step D of Example 83, the title compound was obtained.
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]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([Mg]Br)[CH:17]=[CH2:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:18][CH:17]=[CH2:16])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: C=CC[Mg]Br
Product: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 25, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and allyl magnesium bromide.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C.O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4](=[O:5])[NH2:6])=[C:2]([OH:1])[CH:10]=1)[CH3:26]
Reactant: NC(=O)c1ccc(O)cc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc(C(N)=O)c(O)c1
Temperature: 70 °C

Procedure:
To 2,4-dihydroxybenzamide (16.5 g, 108.3 mmol) in DMF (100 mL) was added Cs2CO3 (39.0 g, 119.1 mmol) followed by ethyl 4-bromobutyrate (17.0 mL, 119.1 mmol). The mixture was heated to 70° C. for 2 h, cooled, diluted with water and extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate, concentrated, and chomatographed over silica gel (60% EtOAc/hexane) to a white solid (4.2 g, 15%). MS [M+H]− 267.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[C@H:20]([OH:23])[CH2:21][OH:22].Cl[C:25]1C=CC(C2C(C=C)=C(C)C=C3C=2C=CC(C)=N3)=CC=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[C:3]([C@H:20]([OH:23])[CH2:21][OH:22])=[C:2]([CH3:25])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([CH3:12])=[N:9]3)=[CH:18][CH:17]=1
Reactant: C=Cc1c(C)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](O)CO)c(Cl)cc2n1
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](O)CO)c(C)cc2n1

Procedure:
Compound 2G was prepared following the procedure used to prepare compound 1H of Example 1, except that 5-(4-chlorophenyl)-2,7-dimethyl-6-vinylquinoline (2F) was used instead of compound 1G. LCMS-ESI+ (m/z): 328.2, 330.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:44][C:45]1C=C[CH:48]=[C:47]([Cl:51])[CH:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:44]=[CH:45][CH:46]=[C:47]([Cl:51])[CH:48]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1cccc(CBr)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cccc(Cl)c3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-3-chlorobenzene and isolated as light-yellow gum (7.0 mg, 42%). MS (m/e): 407.4 (MH+).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[O:22]C(=O)C)[C:8]([NH:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:9])(=O)C>CO.O>[OH:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[OH:22])[C:8]([NH:10][NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])=[O:9]
Reactant: CC(=O)Oc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1OC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(O)c(O)c1
Reaction time: 8 h

Procedure:
1-[3,4-bis(Acetyloxy)benzoyl]-2-[(t-butyloxy)carbonyl]hydrazine (2.6 g) was dissolved in 50 ml of methanol and 5 ml of water. At 0° C., ammonia (gas) was bubbled into the solution for 10 minutes. After standing overnight in a refrigerator, the solution was evaporated, and to the remaining oil, 10 ml of dichloromethane was added. This yielded 1.5 g of the title compound, melting point 148° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[Cl:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([C:29]1[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=1)=[O:28]>>[Cl:20][C:16]1[CH:15]=[C:14]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:27]([C:23]4[S:24][CH:25]=[CH:26][C:22]=4[Cl:21])([C:29]4[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=4)[OH:28])[CH:3]=3)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cn1cncc1C(=O)c1sccc1Cl
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3sccc3Cl)c3cncn3C)ccc2n1
Yield: 51.2 %

Procedure:
Following the same procedure as described in example 1E, 6-bromo-4-(3-chloro-phenyl)-2-methoxy-quinoline (300 mg, 0.859 mmol) and (3-chloro-thiophen-2-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (230 mg 1.032 mmol) generated the title compound of 21A as a yellow solid (218.5 mg, 51% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].O>CO.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-n2cnnn2)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-n2cnnn2)cc1C(=O)O
Reaction time: 4 h

Procedure:
Combine methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate (2.86 g, 12.2 mmol) and a 1 M aqueous solution of sodium hydroxide (13.43 mL, 13.43 mmol) in methanol/water 100 mL, 5:1 vol./vol.). Heat to reflux. After 4 hours. concentrate in vacuo to remove most of the methanol, add water (50 mL), and adjust the pH to about 4 using a 1 M aqueous hydrochloric acid solution. Evaporate in vacuo to give a solid, slurry the solid with water, filter, and dry to give 2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]2)[N:8]=[CH:7][N:6]=1.C=O>>[Br:1][C:2]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[N:8]=[CH:7][N:6]=1
Reactant: COc1ccc(Br)c(Nc2ncnc3cccc(OCC4CCN(C(=O)OC(C)(C)C)CC4)c23)c1
Agent: C=O
Product: COc1ccc(Br)c(Nc2ncnc3cccc(OCC4CCN(C)CC4)c23)c1

Procedure:
Using an analogous procedure to that described in Example 8, 4-(2-bromo-5-methoxyanilino)-5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]quinazoline (0.22 g) was reacted with concentrated aqueous formaldehyde solution (0.4 ml) to give the title compound, as a formic acid salt (0.183 g); NMR Spectrum: (CDCl3) 1.7–1.9 (m, 2H), 2.06 (d, 2H), 2.2 (m, 1H), 2.58 (t, 2H), 2.68 (s, 3H), 3.51 (d, 2H), 3.8 (s, 3H), 4.24 (d, 2H), 6.64 (m, 1H), 6.94 (d, 1H), 7.48 (d, 1H), 7.54 (d, 1H), 7.69 (m, 1H), 8.2 (d, 1H), 8.3 (br s, 1H), 8.69 (s, 1H), 9.94 (s, 1H); Mass Spectrum: M+H+ 457 and 459.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([NH:6][C:7]2[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[N+:20]([O-])=O)=[CH:4][CH:3]=1.N.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:20][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:16](=[O:18])(=[O:19])[NH2:17])[C:7]=1[NH:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=1)[C:11]([OH:13])=[O:12]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccc(Cl)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(p-chloroanilino)-3-nitro-5-sulphamyl-benzoic acid (7.43 g), water (50 ml), and concentrated aqueous ammonia (15 ml) was stirred at 25° C, and a solution of sodium dithionite (13.5 g) in water (50 ml) was added dropwise. After 1 hour, the pH of the reaction mixture was adjusted to 2.5, and the precipitated reaction product was filtered off. After repeated recrystallizations from aqueous ethanol, and after drying for 4 hours in vacuo, 3-amino-4-(p-chloroanilino)-5-sulphamyl-benzoic acid was obtained with a melting point of 273°-274° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[CH:11][C:10]=2[O:26][CH3:27])=[N:6][CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:4][C:5]([NH:8][C:9]2[C:10]([O:26][CH3:27])=[CH:11][C:12]([N:18]3[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[C:13]([NH2:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CC[C@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC[C@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 93.6 %

Procedure:
A mixture of 5-chloro-N-[4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 62, 295 mg, 0.58 mmol), iron (194 mg, 3.48 mmol) and NH4Cl (23 mg, 0.43 mmol) were heated at reflux in ethanol (12 mL) and water (4 mL) for 1.5 h. The mixture was then cooled and concentrated in vacuo. The residue was triturated in 10% CH3OH in CH2Cl2 (25 mL) for 15 minutes and then filtered. The residues were triturated again with 10% CH3OH in CH2Cl2 (25 mL) and filtered. The combined filtrates were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (260 mg, 94%) as a yellow gum; 1H NMR: 1.73-1.86 (1H, m), 2.01-2.12 (1H, m), 2.20 (6H, s), 2.81-2.91 (1H, m), 2.92-3.05 (2H, m), 3.16 (1H, dd), 3.2-3.27 (1H, m), 3.67 (3H, s), 4.25 (2H, d), 6.71 (1H, s), 6.93 (1H, s), 7.12 (1H, td), 7.3-7.37 (1H, m), 8.36 (1H, s), 8.38-8.46 (2H, m), 8.82 (1H, dt), 8.94 (1H, s); m/z: ES+ MH+ 479.5.