Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:24][C:21]=1[CH:22]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:24][C:21]=1/[CH:22]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 7.9 %

Procedure:
A solution of (4-acetylbenzenesulfonylamino)acetic acid (Ex-26A, 226 mg, 0.878 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 216 mg, 0.922 mmol) in DMF (8.0 mL) and MeOH (3.6 mL) was treated with lithium methoxide (140 mg, 3.69 mmol) and stirred for 21 h at room temperature under nitrogen. The reaction mixture was quenched with water (10 mL) and extracted ethyl acetate (2×20 mL). The aqueous phase was acidified with 6N HCl to pH3 and was extracted with (3:1) ethyl acetate/THF (6×25 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Precipitation from dichloromethane (5 mL) gave the title compound (33 mg, 8%) as a brown solid, mp 155–158° C. 1H-NMR (300 MHz, DMSO-d6) 12.06 (br s, 1), 8.22 (m, 3H), 8.04 (d, 1H, J=15.3 Hz), 7.89 (d, 2H, J=7.8 Hz), 7.64 (d, 1H, J=15.3 Hz), 7.18 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.29 (br s, 2H), 3.16 (br s, 4H), 1.82 (br s, 4H). HRMS (ESI) Calcd. for C23H26N2O7S: 475.1539 [(M+H)+]; Found: 475.1547.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH2:23][C:24]([NH:26][NH2:27])=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:27][NH:26][C:24](=[O:25])[CH2:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=1)(=[O:21])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)CC(=O)NN)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)CC(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 82 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-[(4-methylphenyl)sulfonyl]acetohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 199 mg of the title compound (82%) as a yellow solid in 91.1% purity by HPLC (Rt: 5.38, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:36]([CH:38]1[O:40][CH2:39]1)Br>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:36][CH:38]1[CH2:39][O:40]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 453) (50 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (54 mg) and epibromohydrin (0.03 ml) were added to the suspension, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (58 mg, yield 100%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:23]1([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[CH:26][N:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][CH:28]([N:23]5[CH:27]=[CH:26][N:25]=[N:24]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1cn(C2CCNC2)nn1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(F)c(N2CCC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 48.1 %

Procedure:
1-Cyclopropyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (30 mg, 0.1 mmol) was reacted with 35 mg (0.2 mmol) of 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride in 2 ml of dry pyridine under nitrogen in the presence of 30.4 mg (0.2 mmol) of DBU under reflux conditions. The solvent was removed under reduced pressure and to the orange viscous oil water was added and the solid was collected which was further purified from methanol to yield 20 mg of the desired product, m.p. 228°-230° C. 1H NMR (TFA) δ: 9.28 (s, 1H), 8.68 (s, 1H), 8.57 (d, 1.4Hz, 1H), 5.9-5.75 (m, 4.14 (m, 5H), 3.1-2.72 (m, 5H), 1.7-1.2 (m, 4H).
Reaction SMILES: Cl.Cl[C:3]1[N:4]=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[C:10]3([CH2:16][CH2:15]3)[CH2:9][N:8]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:7]=2[N:24]=1.[NH2:25][C:26]1[CH:37]=[CH:36][C:29]([C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])=[CH:28][C:27]=1[O:38][CH3:39]>C(O)C.O>[CH:33]1([NH:32][C:30](=[O:31])[C:29]2[CH:36]=[CH:37][C:26]([NH:25][C:3]3[N:4]=[CH:5][C:6]4[N:12]([CH3:13])[C:11](=[O:14])[C:10]5([CH2:15][CH2:16]5)[CH2:9][N:8]([C@@H:17]5[CH2:21][CH2:20][C:19]([F:22])([F:23])[CH2:18]5)[C:7]=4[N:24]=3)=[C:27]([O:38][CH3:39])[CH:28]=2)[CH2:34][CH2:35]1
Reactant: COc1cc(C(=O)NC2CC2)ccc1N
Reactant: CN1C(=O)C2(CC2)CN([C@@H]2CCC(F)(F)C2)c2nc(Cl)ncc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)NC2CC2)ccc1Nc1ncc2c(n1)N([C@@H]1CCC(F)(F)C1)CC1(CC1)C(=O)N2C
Temperature: 85 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
Concentrated hydrochloric acid (45 μl) was added to a mixture of (R)-2′-chloro-9′-(3,3-difluorocyclopentyl)-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (100 mg, 0.29 mmol) and 4-amino-N-cyclopropyl-3-methoxybenzamide (90 mg, 0.44 mmol) in ethanol (1.4 mL) and water (5.2 mL). The reaction mixture was heated to 85° C. and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up with ethyl acetate, washed with an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the desired compound as a white solid (49 mg, 33% yield).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][CH2:15][C:16]#[CH:17]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:17]#[C:16][CH2:15][CH2:14][C:13]([O:19][CH3:20])=[O:18])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])=[O:7]
Reactant: O=Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C#CCCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: COC(=O)CCC#Cc1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-nitrobenzaldehyde (460 mg), Pd(PPh3)2Cl2 (70 mg), and CuI (38 mg), methyl pent-4-ynoate (269 mg) in TEA(5.0 mL) was stirred at room temperature until the reaction was completed. The crude residue was purified by a silica gel flash chromatography (15% EtOAc in hexanes), affording methyl 5-(4-formyl-3-nitrophenyl)pent-4-ynoate. ESI-MS m/z 262.23 (MH+).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[S:29][C:30]([S:34]([N:37]2[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]2)(=[O:36])=[O:35])=[C:31]([CH3:33])[N:32]=1>>[OH:42][CH:39]1[CH2:40][CH2:41][N:37]([S:34]([C:30]2[S:29][C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])=[N:32][C:31]=2[CH3:33])(=[O:36])=[O:35])[CH2:38]1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)N1CCC(O)C1
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)N1CCC(O)C1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and (RS)-1-(2-amino-4-methyl-thiazole-5-sulfonyl)-pyrrolidin-3-ol (example B.23) according to general procedure II. Light yellow solid. MS (ISP) 621.0 [(M+H)+]; mp 300° C.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C(C(C)=O)C(C)C>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[C:28](=[O:29])[C:27]4=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]4[C:25]3=[O:34])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 95.4 %

Procedure:
A mixture of 500 mg (1.98 mmole) of 4-(diphenylmethyl)piperazine, 530 mg (1.98 mmole) of N-(3-bromopropyl)phthalimide, 840 mg (7.92 mmole) of sodium carbonate, 10 mg of sodium iodide and 12 ml of methyl isobutyl ketone was heated under reflux overnight. The reaction mixture was then filtered, and the solvent was removed from the filtrate by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to afford 830 mg (yield 96%) of the title compound as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O.N1CCCCC1>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 60 °C

Procedure:
A mixture of 4-pyridin-4-yl-1,3-dihydroindol-2-one (50 mg, 0.24 mmol), 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (59 mg, 0.24 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 60° C. for 5 hours. The reaction was concentrated and the residue was column chromatographed to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:11])[C:3]([NH:5][CH2:6][C:7]([F:10])([F:9])[F:8])=[O:4].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1>C(O)(C)C.C(OCC)(=O)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C@@H:2]([CH3:11])[C:3]([NH:5][CH2:6][C:7]([F:8])([F:9])[F:10])=[O:4])[CH:16]=[CH:15][N:14]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[C@H](N)C(=O)NCC(F)(F)F
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ccnc(Cl)n1)C(=O)NCC(F)(F)F

Procedure:
To a solution of (S)-2-amino-N-(2,2,2-trifluoroethyl)propanamide (FF) (1 g, 3.35 mol, 1 equiv.) in iso-propanol (10 mL), Huning's base (1.5 mL) was added, followed by 2,4-dichloropyrimidine (JJ). The resulting mixture was refluxed for 18 h. The reaction mixture was then diluted in ethyl acetate, washed with aqueous HCl 0.5 M and water, and dried over anhydrous Na2SO4. The crude oil was then purified by flash chromatography on silica gel, eluting with hexanes/ethyl acetate mixtures (100:0 to 0:100). The title compound HH was isolated as a white solid (600 mg, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].O[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1
Reactant: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Reactant: OCCc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCc1ccncc1
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-urea (0.1 g, 0.24 mmol), 4-(2-hydroxyethyl)-pyridine (0.0443 g, 0.36 mmol), and triphenylphosphine (0.0944 g, 0.36 mmol) in 10 mL of dry THF was added diisopropylazo-dicarboxylate (0.0728 g, 0.36 mmol) at ambient temperature. The mixture was stirred for 2 hours. Next, additional triphenylphosphine (0.0944 g, 0.36 mmol), 4-(2-hydroxyethyl)-pyridine (0.0443 g, 0.36 mmol), and diisopropylazodicarboxylate were added and the reaction mixture further stirred at room temperature overnight. The solvent from the reaction mixture was evaporated and the crude residue was dissolved in 5.0 mL of DMSO and purified by RP-HPLC. The proper fractions were collected and concentrated to ¼ volume. The aqueous solution was neutralized with 1N NaOH and extracted with ethyl acetate (2×, 59 mL). The organic layer was dried with sodium sulfate, filtered and evaporated to dryness to afford 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyridin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea as a brown solid in 44% yield. LCMS m/z (%)=526 (M+H79Br, 100), 528 (M+H81Br, 67). 1H NMR (DMSO-d6) δ: 9.33 (bs, 1H), 9.24 (bs, 1H), 8.39 (dd, J=4.44 and 1.48 Hz, 2H), 7.63 (d, J=7.28 Hz, 1H), 7.59 (s, 1H), 7.56 (dd, J=8.94 and 2.71 Hz, 2H), 7.48 (m, 1H), 7.34 (d, J=2.67, 1H), 7.31 (d, J=2.67, 1H), 7.28 (dd, J=6.88 and 4.87 Hz, 2H), 7.14 (d, J=9.05 Hz, 1H), 7.09 (d, J=5.93 Hz, 1H), 4.01-4.2 (m, 2H), 3.48 (s, 3H), 2.96-2.91 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:5]([Cl:16])=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([O:23][CH3:24])[NH:20][N:19]=2)[N:3]=1.Cl.[F:26][C:27]1[CH:28]=[N:29][C:30]([C@@H:33]([NH2:35])[CH3:34])=[N:31][CH:32]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:5]1[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[N:7][C:2]([NH:35][C@H:33]([C:30]2[N:31]=[CH:32][C:27]([F:26])=[CH:28][N:29]=2)[CH3:34])=[N:3][C:4]=1[NH:17][C:18]1[CH:22]=[C:21]([O:23][CH3:24])[NH:20][N:19]=1
Reactant: COc1cc(Nc2nc(Cl)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Temperature: 160 °C
Yield: 86.6 %

Procedure:
A microwave reaction vessel was charged with N-{2,5-dichloro-6-[(5-methoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N′,N′-trimethylsulfamide (Method 29, 44.1 mg, 0.112 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 39.5 mg, 0.223 mmol), and DIPEA (0.062 ml, 0.352 mmol). Anhydrous n-BuOH (1 ml) was added, and the tube was sealed and heated in a microwave reactor at 160° C. for 2 hours. The reaction mixture was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexane) to afford the title compound as a white solid (48.6 mg, 87%). LC-MS, 501 (M+1). 1H NMR (DMSO-d6, 400 MHz) δ 12.01 (s, 1H), 9.76 (s, 1H), 8.83 (s, 2H), 8.21 (s, 1H), 5.60 (s, 1H), 5.04-5.06 (m, 1H), 3.76 (s, 3H), 2.80 (s, 3H), 2.70 (s, 6H), 1.59 (d, 3H).
Reaction SMILES: C([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([F:20])=[CH:18][N:17]=[C:16]([NH:21][C@H:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][C:38]([F:41])([F:40])[F:39])[CH:31]=3)[CH2:26][CH2:25]2)[CH3:23])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:27]2[CH2:28][CH2:29][CH:24]([C@@H:22]([NH:21][C:16]3[N:15]=[C:14]([N:9]4[C@@H:8]([C@@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]4=[O:13])[C:19]([F:20])=[CH:18][N:17]=3)[CH3:23])[CH2:25][CH2:26]2)=[CH:31][C:32]=1[O:37][C:38]([F:39])([F:40])[F:41]
Reactant: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@H](C)OC(C)(C)C)n1)C1CCN(c2ccc(Cl)c(OC(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@H](C)O)n1)C1CCN(c2ccc(Cl)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one (34 mg, 0.058 mmole) was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction solution was stirred for 2 hour at room temperature and was concentrated by rotary evaporation. The resulting residue was dissolved in DCM (2 mL) and water 2 mL) and the pH was adjusted to ˜9 with NH4OH. The DCM layer was separated and concentrated by rotary evaporation to afford 28 mg of the title product as a yellow oil (ratio of two peaks with same MS: 96/4% by LC-MS). (400 MHz, CD2Cl2) δ 8.22 (d, J=2.27 Hz, 1H), 7.31 (d, J=8.85 Hz, 1H), 6.88-6.79 (m, 2H), 5.12 (br s, 1H), 4.61-4.50 (m, 2H), 4.46-4.37 (m, 1H), 4.26-4.15 (m, 1H), 3.93 (br s, 1H), 3.77-3.68 (m, 2H), 3.20 (br s, 1H), 2.79-2.67 (m, 2H), 1.96-1.78 (m, 2H), 1.70-1.58 (m, 1H), 1.55-1.28 (m, 2H), 1.23 (d, J=6.63 Hz, 3H), 1.19 (d, J=7.19 Hz, 3H), HRMS(C) tR=4.47 min; MS m/z 548.1689 (M+H)+
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[C:12]([F:28])[CH:11]=1)(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:28][C:12]1[CH:11]=[C:10]([S:7]([NH2:6])(=[O:8])=[O:9])[CH:15]=[CH:14][C:13]=1[O:16][C@H:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(CNS(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(F)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(N)(=O)=O)cc1F
Yield: 94 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-3-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide (0.92 g, 1.88 mmol) prepared in Example 16b, triethylsilane (1.5 mL), trifluoroacetic acid (15 mL) and dichloromethane (15 mL), to yield the title compound (0.60 g, 94%) as a colorless solid.
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[OH2:16]>>[O:16]=[PH:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Reactant: O
Product: O=[PH]1Oc2ccccc2-c2ccccc21

Procedure:
Another reference (German Offenlegungsschrift 27 30 371, pp. 18 and 19) describes that 6-chloro-(6H)-dibenz-oxaphosphorin at 130° C. is combined with a large amount of water, the hydrolysis is carded out, the water is distilled off under reduced pressure and the 6-oxo-dibenzoxaphosphorin is then obtained. The operation described is technically very problematical and can hardly be carried out on a large scale, since water vaporizes at 130° C. and cools the reaction mixture. It is therefore necessary to work under increased pressure if the temperature of 130° C. is to be maintained and thus uncontrolled crystallization is to be prevented, since the target compound melts significantly above the boiling point of water.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([O:10][CH3:11])=[C:7]([F:9])[CH:8]=1.[C-:20]#[N:21].[K+]>CN(C=O)C>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][C:20]#[N:21])[CH:4]=[C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[O:10][CH3:11]
Reactant: [C-]#N
Reactant: COc1c(F)cc(CCl)cc1OCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(F)cc(CC#N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
5-(Chloromethyl)-1-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]benzene (2.88 g, 10.26 mmol.) was taken into DMF (15 mL) followed by addition of potassium cyanide (1.0 g, 15.4 mmol.) and the resulting mixture was allowed to stir at room temperature over 12 hours. The mixture was then partitioned with ethyl ether and water and the organic phase washed with water (3×) then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Filtration and concentration gave {3-fluoro-4-(methyloxy)-5-[(phenylmethyl)oxy]phenyl}acetonitrile (2.69 g, 97% yield) as a clear oil. GCMS for C16H14O2FN: 271 (M+).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Li+].[OH-]>>[CH2:11]([O:10][C:6]1[C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:26])=[O:2])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cccc(OCc2ccccc2)c1OCc1ccccc1

Procedure:
In one embodiment, the compounds can be prepared as shown in Scheme II. A dihydroxy benzoic acid methyl ester is reacted with benzyl chloride, to produce 5a Bis-benzyloxy benzoic acid methyl ester (1). The Bis-benzyloxy benzoic acid methyl ester can then be heated with LiOH to give a Bis-benzyloxy benzoic acid (2). The Bis-benzyloxy benzoic acid (2) is then reacted with an aminophenyl to produce a phenyl-benzamide (3). The phenyl-benzamide (3) is then reacted with hydrazine to give a triazol (4). The hydroxy groups can then be unprotected in the presence of palladium on charcoal to give the final product.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]1([C:29](Cl)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:29]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)=[O:30])[CH2:3][CH2:2]2)[N:12]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4cccc5ccccc45)CC3)cccc2n1
Yield: 28 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 1-Naphthoyl chloride (78.2 mg; 0.41 mmol) to obtain 22.1 mg. (28% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.0 (d, J=7.6 Hz, 2H), 7.75 (br d, 1H), 7.59 (m, 3H), 7.45 (m, 2H), 7.30 (br s, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.89 (dd, J=17.6, 7.6 Hz, 1H), 6.11 (br s, 2H), 4.78 (br t, 1H), 3.42 (m, 2H), 3.24 (m, 3H), 2.89 (m, 2H). ESIMS+400.0 m/z