Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].[CH2:17](I)[CH3:18]>CC(=O)CC.O>[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH:11]=[O:12]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOc1ccc(C=O)cc1O
Yield: 43.5 %

Procedure:
Anhydrous potassium carbonate (2.25 g, 16.3 mmol) was added to 3,4-dihydroxybenzaldehyde (1.5 g, 10.8 mmol), in butanone (30 ml), at room temperature. The reaction was stirred for 10 min after which ethyl iodide (0.872 ml, 10.8 mmol) was added dropwise and the reaction was refluxed for 3 h. The reaction mixture was diluted with water and the product was extracted with dichloromethane (3×25 ml), the combined organic layers were dried over magnesium sulphate and reduced in vacuo. Purification by column chromatography (SiO2, petroleum:ether (40:60) with an increasing gradient of ethyl acetate) afforded 0.78 g (43%) of 3-hydroxy4-ethoxybenzaldehyde as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.S(O)(O)(=O)=O.Cl[C:25]1[NH:26][CH2:27][CH2:28][N:29]=1>CC(O)C.C(OCC)(=O)C>[NH:29]1[CH2:28][CH2:27][N:26]=[C:25]1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(CCC(=O)c2ccc(F)cc2)cc1
Reactant: ClC1=NCCN1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccc(NC2=NCCN2)cc1)c1ccc(F)cc1
Yield: 67.4 %

Procedure:
A mixture of 3-(4-aminophenyl)-1-(4-fluorophenyl)propan-1-one (1.17 g, 4.81 mmol) and 2-chloro-4,5-dihydro-1H-imidazole sulfate (1.95 g, 9.62 mmol) (prepared according to the procedure described in Trani, A and Bellasio, E., J. Het. Chem. 1974, 11, 257) in 2-propanol (20 mL) was heated under reflux for 15 minutes. The reaction mixture was cooled and diluted with ethyl acetate (150 mL) and washed with 5% sodium hydroxide solution, water, and brine. The organic layer was separated and dried with potassium carbonate, and evaporated in vacuo. Purification by silica gel chromatography, eluting with 10% methanol/dichloromethane containing 1% ammonium hydroxide, gave 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-fluorophenyl)propan-1-one as an oil (1.01 g, 76.5%). The oil was converted to the hydrochloride salt, m.p. 190.2-190.8° C. Analysis for C18H19CIFN3O.0.2H20: Calcd.: C, 61.52; H, 5.56, N, 11.96. Found: C, 61.40; H, 5.47; N, 11.97.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.[C:36](Cl)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:21][CH:20]=2)[C:36](=[O:38])[CH3:37])[CH:25]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(NCc2cccnc2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(N(Cc2cccnc2)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
To a room temperature solution of 2.49 g of product from Example 83, 1.27 ml of pyridine and 30 ml of methylene chloride is added, dropwise, 0.985 g of acetyl chloride. The reaction is stirred at room temperature for 1.5 hours, poured into saturated sodium bicarbonate and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 95% ethyl acetate/hexane) to give 2.65 g of the desired product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([NH2:42])[CH:33]=1>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:17](=[O:23])[N:42]([C:34]3[CH:33]=[N:32][C:41]4[C:36]([CH:35]=3)=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cnc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(-c3cnc4ccccc4c3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 228.1 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.35 g) and triethylamine (0.6 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added quinolin-3-amine (1 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (25 mL), sodium methoxide (28% methanol solution, 1.3 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.87 g, 100%).
Reaction SMILES: Cl[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]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[O:19]C)[N:3]=1.C(OC(N1CCCCC(N)C1)=O)(C)(C)C.C(OC([N:43]1[CH2:49][CH2:48][CH2:47][CH:46]([NH2:50])[CH2:45][CH2:44]1)=O)(C)(C)C>>[NH:43]1[CH2:49][CH2:48][CH2:47][CH:46]([NH:50][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[OH:19])[N:3]=2)[CH2:45][CH2:44]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Reactant: COc1ccc(F)cc1-c1nc(Cl)c2ccccc2n1
Agent: CC(C)(C)OC(=O)N1CCCCC(N)C1
Product: Oc1ccc(F)cc1-c1nc(NC2CCCNCC2)c2ccccc2n1

Procedure:
The title compound was prepared using a method analogous to that described in Synthesis 52, replacing 4-chloro-2-(2-methoxyphenyl)quinazoline with 4-chloro-2-(5-fluoro-2-methoxyphenyl)quinazoline in Synthesis 52-A and tert-butyl-3-aminoazepane-1-carboxylate with tert-butyl-4-aminoazepane-1-carboxylate in Synthesis 52-B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:18][OH:19])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28](=[O:38])[C:29]1[CH:34]=[C:33]([CH3:35])[C:32](O)=[C:31]([CH3:37])[CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:26][O:27][C:28](=[O:38])[C:29]1[CH:30]=[C:31]([CH3:37])[C:32]([O:19][CH2:18][CH:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:33]([CH3:35])[CH:34]=1
Reactant: OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(OCC(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(C)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 27 %

Procedure:
To a solution of 2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethanol (20 mg, 56 umol) in THF (1 ml) was added 4-hydroxy-3,5-dimethyl-benzoic acid methyl ester (11 mg, 62 umol; CAS Reg. No. 34137-14-9) and tri-phenylphosphine (18 mg, 68 umol) at ambient temperature under an argon atmosphere. The mixture was cooled to 0° C., di-tert-butyl azodicarboxylate (16 mg, 68 umol) was added and the suspension was stirred for 14 h at ambient temperature. The solvent was removed under reduced pressure to give a solid which was purified by column chromatography (silica gel, iPrOAc/heptane) to obtain the title compound (8 mg, 15 umol; 27%) as colorless oil. MS: m/e=517.3 [M+H+].
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C1C(=CC=CC=1)O>C(OCC)C>[C:12]1([C:11]2[O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:9])[N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)c1ccccc1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C(O)c1ccccc1O
Solvent: CCOCC
Product: O=c1nc(-c2ccccc2)oc2ccccc12
Reaction time: 0.5 h

Procedure:
6.85 g (50 mmol) of salicylic acid amide are added, dropwise, to 11.5 ml of benzoyl chloride and the mixture is heated to 170° C. The mixture is then stirred for 30 minutes at this temperature. During this time, the salicylic acid dissolves to produce, on cooling, a honey-like mass which is then stirred with diethyl ether to yield a white solid which is filtered off, washed with diethyl ether and dried. There are obtained 8.78g of 2-phenyl-4H-1,3-benzoxazin-4-one as a white powder melting at 104-105° C. and having the following elemental analysis:
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].[CH3:8][N:9]([CH3:24])[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([N:21]([CH3:23])[CH3:22])[C:19]=1[CH3:20])[C:13](OC)=[O:14]>CS(C)=O>[CH3:23][N:21]([CH3:22])[C:18]1[CH:17]=[C:12]([C:13](=[O:14])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:11]=[C:10]([N:9]([CH3:24])[CH3:8])[C:19]=1[CH3:20]
Reactant: COC(=O)c1cc(N(C)C)c(C)c(N(C)C)c1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(N(C)C)cc(C(=O)CS(C)(=O)=O)cc1N(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 18.8 g. of dimethylsulfone and 3.6 g. of sodium hydride (50% dispersion in oil) in 80 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 2 hours at 50° C. Thereupon, 23.6 g. of methyl 3,5-bis(dimethylamino)-4-methylbenzoate were added and the mixture was stirred at room temperature for 1.5 hours. The solution was diluted with 400 ml. of water and extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. After recrystallization of the residue from methanol, there was obtained 3',5'-bis(dimethylamino)-4'-methyl-2-methylsulfonylacetophenone, having a melting point of 161°-163° C.
Reaction SMILES: CO[C:3]1[CH:10]([CH2:11][CH:12]=[CH2:13])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]=1.[Cl-:14].[NH4+:15]>CO>[ClH:14].[CH2:11]([CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[NH:15])[CH:12]=[CH2:13]
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: C=CCC1CCCCCN=C1OC
Solvent: CO
Product: C=CCC1CCCCCNC1=N
Product: Cl

Procedure:
The product of EXAMPLE 204 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH:3]=1.[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][NH2:26]>>[ClH:1].[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][NH:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH:3]=1
Reactant: Clc1cc(N2CCc3ccccc3C2)nc2ccccc12
Reactant: NCC(O)CN
Product: Cl
Product: NCC(O)CNc1cc(N2CCc3ccccc3C2)nc2ccccc12

Procedure:
The title compound, m.p. 265-275° C., MS: m/e=348 (M+), was prepared from 4-chloro-2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline and 1,3-diamino-2-propanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][S:9][C:8]=2[CH:21]=1)([O-])=O.O.NN>CO.[Ni]>[N:15]1([CH2:14][CH2:13][N:12]2[CH2:11][CH2:10][S:9][C:8]3[CH:21]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]2=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2CCN1CCCCC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc2c(c1)SCCN2CCN1CCCCC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
A mixture of 7-nitro-4-(2-(piperidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.9 g, 2.93 mmol) in methanol (10 mL) under an argon atmosphere was treated first with hydrazine hydrate (1.424 mL, 29.3 mmol) and then with Raney-Nickel (˜0.172 g, 2.93 mmol). The reaction was transferred to oil bath pre-heated to 65° C. After one hour, the reaction mixture was poured over a pad of Celite. The pad of Celite was then rinsed with methanol (25 mL). The purple filtrate was concentrated and subjected to a short column on silica gel (1:9 (2M NH3 in MeOH):CH2Cl2). The fractions were concentrated, and the residue was carried on to the next step. 1H-NMR (DMSO-d6) δ 6.49 (d, J=8.7 Hz, 1H), 6.26-6.23 (m, 2H), 4.41 (s, 2H), 3.38-3.35 (m, 2H), 3.20 (t, J=7.2 Hz, 2H), 2.98-2.94 (m, 2H), 2.40-2.34 (m, 6H), 1.50-1.46 (m, 4H), 1.38-1.36 (m, 2H); ESI-MS (m/z, %): 278 (MH+, 100).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.Cl.[CH:9]12[CH2:14][CH:13]1[CH2:12][NH:11][CH2:10]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:9]12[CH2:14][CH:13]1[CH2:12][N:11]([C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1)[CH2:10]2
Reactant: Brc1csc(Br)n1
Reactant: C1NCC2CC12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Brc1csc(N2CC3CC3C2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
To a stirred solution of 2,4-dibromothiazole (0.5 g. 2.06 mmol) in DMF (15 ml) were added 3-azabicyclo[3.1.0]hexane hydrochloride (prepared according to the procedure given in Bioorganic and Medicinal Chemistry Letters, 2005, 15, 2093-2096, 0.27 g, 2.26 mmol) and DIPEA (0.80 g, 1.0 ml, 6.17 mmol) under a stream of nitrogen. The reaction was then stirred at 80° C. for 18 hrs; the progress of reaction was monitored by TLC. The reaction was quenched with cold water (20 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layer was washed with water (2×10 ml), dried over sodium sulphate and concentrated to give crude compound; which was purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.29 g, 58.5%). MS: m/z 246 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13](CC#N)[C:12]=3[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:21]([OH:24])(=[O:23])[CH3:22].S(=O)(=O)(O)O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:22][C:21]([OH:24])=[O:23])[C:12]=3[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: N#CCc1cccc2c(-c3ccc(Br)cc3)nccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1cccc2c(-c3ccc(Br)cc3)nccc12
Reaction time: 3 h

Procedure:
A mixture of 7.5 g of 1-(4-bromophenyl)isoquinoline-5-acetonitrile, 70 ml of acetic acid and 35 ml of 50% sulfuric acid was heated with stirring for 3 hours. After the reaction, water was added, and the pH of the reaction mixture was adjusted to 2 with an aqueous solution of sodium hydroxide. The crystals that precipitated were collected by filtration, and recrystallized from tetrahydrofuran-acetone to afford 7.0 g of 1-(4-bromophenyl)isoquinoline-5-acetic acid having a melting point of 230.5° to 232.5° C.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[C:8]2[C:7](=[CH:20][CH:19]=1)[NH:6][C:4](=[O:5])[N:3]([CH2:1][CH3:2])[C:9]2([OH:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCN1C(=O)Nc2ccc(Cl)cc2C1(O)c1ccccc1
Yield: 83.8 %

Procedure:
A solution of 28.4 g (31.7 ml, 0.4 mole) of ethyl isocyanate and 46.3 g (0.2 mole) of 2-amino-5-chlorobenzophenone in 100 ml of methylene chloride was refluxed for 20 hr. The reaction mixture was cooled, and the solid portion was collected on a filter and washed with methylene chloride to give 50.72 g (84%) of 6-chloro-3-ethyl-3,4-dihydro-4-hydroxy-4-phenyl-2(1H)-quinazolinone as colorless crystals: mp 182°-184°; 13C nmr (DMSO-d6) δ 86.9 ppm (for COH) and δ 151.0 ppm (for NHCO).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[NH2:1])[CH3:18]
Reactant: CCO
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(F)cc1N
Temperature: 25 °C

Procedure:
A total of 10 g of 2-amino-4-fluoro-benzoic acid was dissolved in 129 ml of ethanol, 6.45 ml of sulfuric acid was added and the mixture was heated under reflux for 11 hours. After cooling to room temperature, the solvent was evaporated to about half. Water was added and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:5), to give 7.57 g of the title compound as a pale yellow oil.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:16][C:17]1[CH:47]=[CH:46][C:20]2[NH:21][C:22]([C:27]3[C:28](=[O:45])[C:29]([CH2:42][CH2:43][CH3:44])([CH2:39][CH2:40][CH3:41])[C:30]4[C:35]([C:36]=3[OH:37])=[CH:34][C:33]([F:38])=[CH:32][CH:31]=4)=[N:23][S:24](=[O:26])(=[O:25])[C:19]=2[CH:18]=1.C(N(CC)CC)C>ClCCl>[F:38][C:33]1[CH:34]=[C:35]2[C:30]([C:29]([CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH3:44])[C:28](=[O:45])[C:27]([C:22]3[NH:21][C:20]4[CH:46]=[CH:47][C:17]([NH:16][S:2]([NH:5][C:6](=[O:7])[O:15][CH2:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)(=[O:4])=[O:3])=[CH:18][C:19]=4[S:24](=[O:25])(=[O:26])[N:23]=3)=[C:36]2[OH:37])=[CH:31][CH:32]=1
Reactant: OCc1ccccc1
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2cc(F)ccc21
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)=C(O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
A solution of chlorosulfonyl isocyanate (14.2 μL, 0.163 mmol) in dichloromethane (2 mL) was treated with benzyl alcohol (17 μL, 0.163 mmol) followed by stirring at ambient temperature for 30 min. The solution was added to the product of Example 17C (62 mg, 0.136 mmol) in dichloromethane (2 mL) followed by addition of triethylamine (76 μL, 0.54 mmol). The solution was stirred at ambient temperature for 2 h, and diluted with dichloromethane and extracted with water (2×). Drying (Na2SO4) and concentration in vacuo afforded the title compound (28 mg, 31%) as a brown solid. 1H NMR (300 MHz, DMSO-d6): δ 0.69 (m, 8 H) 0.92 (m, 2 H) 2.00 (dd, J=12.13, 8.82 Hz, 2 H) 2.16 (m, 2 H) 5.12 (s, 2 H) 7.35 (m, 5 H) 7.47 (dd, J=8.82, 2.57 Hz, 1 H) 7.63 (m, 3 H) 7.82 (m, 2 H) 11.09 (s, 1 H) 12.13 (s, 1 H) 13.54 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[NH4+:26]>O1CCOCC1>[ClH:1].[I:11][C:10]1[C:3]2[C:2]([NH2:26])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:9]=1
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(N)ncnc43)CC2)CC1
Product: Cl
Temperature: 120 °C

Procedure:
A mixture of trans-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (750 mg, 1.63 mmol) and 1,4-dioxane (10 mL) and 30% aqueous ammonium hydroxide (10 mL) was heated at 120° C. in a sealed tube for 18 hours. The mixture is cooled and lyophilized to give trans-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride (750 mg, quantitative): 1H NMR (DMSO-d6, 400 MHz) δ 10.2 (bs, 1H), 8.08(s, 1H), 7.53(s, 1H), 6.59(bs, 2H), 4.50(m, 1H), 2.5-3.2 (m, 9H), 2.51(s, 3H), 1.8-2.0(m, 6H), 1.46 (m, 2H); MS MH+441.2; RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 3.85 min.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[CH2:9]([CH2:13][C:14](=O)[CH3:15])[C:10]([CH3:12])=O.O>C1(C)C=CC=CC=1>[CH3:15][C:14]1[N:7]([C:6]2[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=2)[C:10]([CH3:12])=[CH:9][CH:13]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(=O)CCC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(O)cc1

Procedure:
A mixture of 4.0 g of p-aminophenol and 4.0 g of acetonylacetone is heated under reflux in toluene for 3 hours using a Dean Stark water separator to yield 4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenol. Condensation with ethyl alpha-bromoisobutyrate in ethyl alcohol in the presence of potassium carbonate gives ethyl 2-[4-(2,5-di-methyl-1H-pyrrol-1-yl)-phenoxy]-2-methylpropanoate. Hydrolysis with 1.5 N sodium hydroxide solution yields 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenoxy]-2-methyl-propanoic acid, m.p. 178°-180°.
Reaction SMILES: [F:1][CH:2]([F:44])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16][CH2:15]3)[N:11]=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[C:31]([NH:36]C(=O)OC(C)(C)C)[CH:32]=[C:33]([O:34][CH3:35])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl.O>[F:44][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][N:17]([S:20]([CH3:23])(=[O:21])=[O:22])[CH2:18][CH2:19]3)[N:11]=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[C:31]([NH2:36])[CH:32]=[C:33]([O:34][CH3:35])[C:5]=2[N:4]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cc(N)cc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
A mixture of tert-butyl 2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamate (0.20 g, 0.31 mmol) and TFA (5 mL) in CH2Cl2 (20 mL) was stirred at room temperature for 2 hrs. The mixture was diluted with CH2Cl2 (100 mL) and water (100 mL), and the aqueous layer was made basic with aqueous NH3. The organic layer was dried and concentrated under vacuum. Recrystallization of the residue from CH2Cl2/MeOH gave 0.145 g (86% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylamine: mp 280-283° C.; 1H NMR (CDCl3) δ 7.59 (t, JHF=53.4 Hz, 1H), 7.05 (d, J=1.7 Hz, 1H), 6.26 (d, J=1.7 Hz, 1H), 5.45 (s, exchangeable with D2O, 2H), 3.93 (m, 4H), 3.87 (s, 3H), 3.80 (m, 4H), 3.69 (m, 4H), 3.24 (m, 4H), 2.91 (s, 3H); Anal. Calcd. for C21H27F2N9O4S: C, 46.75; H, 5.0; N, 23.4. Found: C, 47.0; H, 5.2; N, 23.4%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20](S(C)(=O)=O)C=1.C(=O)([O-])[O-].[K+].[K+].C[N:37](C)C=O>>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:1][C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[C:12]([O:14][CH3:15])=[O:13])[N:37]=1
Reactant: COC(=O)c1c(O)ccc2ncccc12
Reactant: COc1cc(OC)nc(S(C)(=O)=O)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2ncccc12
Temperature: 0 °C
Yield: 89 %

Procedure:
0.8 g of methyl 6-hydroxyquinolin-5-carboxylate, 0.96 g of 4,6-dimethoxy-2-methylsulfonylpyridine and 0.82 g of potassium carbonate were stirred in 30 ml of N,N-dimethylformamide at 80° C. for 3 hours. The mixture was returned to room temperature, then poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure, was crystallized from a solvent mixture of dichloromethane/isopropyl ether to obtain 1.21 g (yield: 89.0%) of the desired compound. mp: 160°-162° C.