Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5](F)=[C:6]([F:23])[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=O)[CH3:2].C(O)(=O)C.[CH:29]([NH2:31])=O.CC([N:35](C)C)=O>CCOC(C)=O>[F:22][C:16]1[CH:17]=[C:18]([I:21])[CH:19]=[CH:20][C:15]=1[NH:14][C:7]1[C:6]([F:23])=[C:5]2[C:4]([C:1]([CH3:2])=[N:35][CH:29]=[N:31]2)=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(=O)N(C)C
Reactant: NC=O
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccc(I)cc1F
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(C)ncnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 95 °C
Yield: 88 %

Procedure:
A mixture of methyl 5-acetyl-2-(2-fluoro-4-iodophenylamino)-3,4-difluorobenzoate (230 mg, 0.55 mmol) and formamide acetate (68 mg, 0.66 mmol) in DMA (5 ml) was heated at 95° C. for 6 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford 205 mg (88%) of the title compound.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11]C.[CH2:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:21]1[CH2:25]OC[CH2:22]1>>[CH3:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]\[CH2:22][CH2:21][CH2:25][CH:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCC/C=C\CCCCCCCO
Reactant: C=CCCCCC
Reactant: C1CCOC1
Product: CCCCC/C=C\CCCC(O)CCCCCCCCCC
Yield: 70 %

Procedure:
According to the procedure for compound 12, compound 18 (1.0 g, 4.2 mmol) and 1-heptene (4 mL) in THF (4 mL) were reacted with 1 (0.015 g, 0.5 mol %) to provide 19 (0.91 g, 70% yield, 88% Z as determined by quantitative 13C-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.36 (2H, m), 3.59 (1H, m), 2.03 (4H, m), 1.21-1.54 (29H, m), 0.88 (6H, m); 13C NMR (CDCl3): δ 130.4, 129.4, 71.9, 37.6, 37.1, 31.9, 31.6, 29.7 (2C), 29.6 (2C), 29.4 (2C), 27.2 (2C), 25.8, 25.7, 22.7, 22.6, 14.1 (2C); HRMS (FAB): 309.3162, [C21H42O−H]+ requires 309.3157.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](=O)[C:8]([OH:10])=O.[CH2:12]([C:19]1[C:20]([NH2:31])=[N:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C:19]1[NH:24][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:22][N:21]2[C:8](=[O:10])[C:7]([CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[N:31][C:20]=12)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Reactant: O=C(O)C(=O)Cc1ccco1
Product: O=c1c(Cc2ccco2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2

Procedure:
Synthesized from method C using 3-(furan-2-yl)-2-oxopropanoic acid and 3-benzyl-5-phenylpyrazin-2-amine as starting materials. 1H NMR (300 MHz, dmso) δ 8.88 (s, 1H), 8.02 (d, J=7.9, 2H), 7.61-7.38 (m, 6H), 7.37-7.14 (m, 3H), 6.38 (s, 1H), 6.26 (d, J=3.2, 1H), 4.64 (s, 3H), 4.40 (s, 3H); exact mass calculated for C24H20N3O2+ m/z+382.16, found m/z+382.
Reaction SMILES: [F:1][C:2]1[C:3]([F:14])=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][NH:5]2.[N:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=O)=[CH:17][CH:16]=1.[BH4-].[Na+].Cl>CO.C(Cl)Cl.O>[F:1][C:2]1[C:3]([F:14])=[C:4]2[C:11]([C:7]([CH2:8][CH2:9][NH:10][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([O:21][C:18]4[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=4)[CH:23]=3)=[CH:6][NH:5]2)=[CH:12][CH:13]=1
Reactant: NCCc1c[nH]c2c(F)c(F)ccc12
Reactant: O=Cc1cccc(Oc2ccncc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Fc1ccc2c(CCNCc3cccc(Oc4ccncc4)c3)c[nH]c2c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 6,7-difluoro tryptamine (0.285 g, 1.450 mmol), 3-pyridin-4-yloxybenzaldehyde (0.303 g, 1.52 mmol, 1.05 eq.) and molecular sieves 4 A (0.30 g) and stir in methanol (12 mL). After 4 h. filter the molecular sieves and wash several times with MeOH. To this MeOH solution, add portionwise NaBH4 (55.0 mg, 1.45 mmol), and stir at room temperature for 1 h. Remove MeOH in vacuo, dilute the residue with CH2Cl2/water, extract with CH2Cl2, combine organic layers, dry over Na2SO4 and concentrate in vacuo. Purification by flash chromatography on silica gel (CH2Cl2/MeOH) to give the free base which is converted to the hydrochloride salt: 1H NMR (300 MHz, DMSO-d6) 3.13 (s, 4H), 4.20 (s, 2H), 6.85–7.55 (m, 10H), 8.47–8.50 (m, 1H), 9.58 (br, 1H), 11.57 (br, 1H): MS (electrospray) m/e: 380.2 (M+1-HCl), 378.3 (M−1-HCl).
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.[NH2:20][C:21]1[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)[CH:22]=1.N1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([CH2:34][CH2:33][C:23]2[CH:22]=[C:21]([NH:20][C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:19][CH:18]=3)[NH:25][N:24]=2)[CH:36]=[C:37]([O:43][CH3:44])[CH:38]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COc1ccc(C(=O)O)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)Nc2cc(CCc3cc(OC)cc(OC)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
1-Chloro-N,N,2-trimethylprop-1-en-1-amine (89 μl, 0.63 mmol, 1.05 eq) was added dropwise to 4-methoxybenzoic acid (97 mg, 0.63 mmol, 1 eq) in DCM (1.5 ml) at ambient temperature. After stirring at ambient temperature for 1.5 h, a solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (199 mg, 0.57 mmol, 0.9 eq) and pyridine (142 μL, 1.74 mmol, 2.75 eq) in DCM (2 ml) was added to the reaction mixture and stirring was continued at ambient temperature for a further 3 h. A solution of TFA (386 μL, 5.2 mmol, 8.25 eq) in DCM (3.5 ml) was then added and stirring was continued at ambient temperature for 18 h. The reaction mixture was concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a 33-53% gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a colourless foamy solid (113 mg, 52% yield).
Reaction SMILES: [OH2:1].[C:2](Cl)(=[O:4])[CH3:3].C[NH:7][C:8](=O)[CH:9](CO)[NH:10][C:11](=[O:25])[C:12]1[C:17]([I:18])=[C:16]([NH2:19])[C:15]([I:20])=[C:14]([C:21]([OH:23])=[O:22])[C:13]=1[I:24]>CC(N(C)C)=O>[C:21]([C:14]1[C:13]([I:24])=[C:12]([C:17]([I:18])=[C:16]([NH:19][C:2](=[O:4])[CH3:3])[C:15]=1[I:20])[C:11]([NH:10][C:9](=[O:1])[CH2:8][NH2:7])=[O:25])([OH:23])=[O:22]
Reactant: O
Reactant: CNC(=O)C(CO)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(=O)CN)c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under agitation and cooling with water, 13.5 ml. of acetyl chloride is added dropwise to 40.0 g. (65 millimoles) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine amide (IV c), m.p. 248°-249° C. (decomposition), in 80 ml. of dimethylacetamide. Then, the reaction mixture is stirred at room temperature for 11/2 hours, another 2 ml. of acetyl chloride is added thereto, and the mixture stirred for another hour. After the addition of 10 ml. of water, the reaction mixture is concentrated under vacuum, 70 ml. of water is added to the residue, and the mixture is stirred for 16 hours. The precipitate is vacuum-filtered and washed free of salt with water.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:15][C@H:16]([C:21]([O:23]C)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11].[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:15][C@H:16]([C:21]([OH:23])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:10]([N:12]([CH3:13])[CH3:14])=[O:11]
Reactant: COC(=O)[C@H](CC(C)C)NC(C(=O)N(C)C)c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(C(=O)N(C)C)c1ccc(F)cc1F)C(=O)O
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a solution of methyl N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (100 mg) in methanol (3 ml) was added a solution of lithium hydroxide (15.4 mg) in water (1 ml). After stirring vigorously for 4 hours the solvent was removed in vacuo. The residue was diluted with water (10 ml) then neutralised with 2N hydrochloric acid. This solution was applied to an Oasis™ cartridge (6 g) and eluted with water (×2) and methanol (×2). The required fractions were combined and evaporated to afford N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (95 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.F[C:8]1[CH:13]=[C:12]([F:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:14][C:12]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]([O:18][CH3:19])=[C:8]([N:4]2[CH:5]=[N:6][C:2]([CH3:1])=[N:3]2)[CH:13]=1
Reactant: Cc1nc[nH]n1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])c(F)cc1-n1cnc(C)n1
Temperature: 80 °C
Yield: 18.6 %

Procedure:
A mixture of 3-methyl-1H-1,2,4-triazole (2.20 g, 26.4 mmol), 1,5-difluoro-2-methoxy-4-nitrobenzene (5.00 g, 26.4 mmol), and potassium carbonate (3.65 g, 26.4 mmol) in anhydrous DMSO (50 mL) was heated at 80° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into 500 mL of water/10 mL brine solution. The aqueous mixture was extracted with EtOAc (2×250 mL). The combined organic extracts were washed with water (500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel column chromatography (50% EtOAc/hexane) to afford 1-(5-fluoro-2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (1.24 g, 18% yield). LC-MS (M+H)+=253.2. 1H NMR (500 MHz, CDCl3) δ ppm 8.95 (s, 1H) 8.00 (d, J=11.60 Hz, 1H) 7.80 (d, J=6.10 Hz, 1H) 4.09 (s, 3H) 2.50 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:27])([CH3:26])[CH3:25])[CH2:20][CH2:19]3)[N:8]2C2CCCCO2)=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:3]=1.Cl.[H-].[Na+].[C:37]([O:40][CH2:41][CH2:42]Br)(=[O:39])[CH3:38]>CO.CN(C=O)C.O>[C:37]([O:40][CH2:41][CH2:42][N:8]1[C:7]([CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:27])([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OCCBr
Reactant: CC(C)(O)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C2CCCCO2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)OCCn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 33.4 %

Procedure:
To a solution of 2-(1-((2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (328 mg, 0.685 mmol) in methanol (10 mL) was added concentrated HCl (0.15 mL). The resulting mixture was stirred at 50° C. for 18 hours. The reaction mixture was then concentrated to give a yellow paste which was then taken up in DMF (10 mL) and cooled to 0° C. To this cooled solution was then added sodium hydride (60% dispersion, 88 mg, 2.2 mmol). The mixture was stirred at 0° C. for 5 minutes before the addition of 2-bromoethanol acetate (0.2 mL, 1.8 mmol). After 18 hours of stirring at room temperature, the reaction was diluted with water. The aqueous mixture was the extracted three times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (10% MeOH in DCM) to give the title compound (110 mg, 26%). LCMS: M+H+=481.2.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]([C:41](Cl)=[O:42])=[CH:37][CH:38]=[CH:39][CH:40]=1>C(Cl)Cl.O>[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]([C:41]([N:1]2[C:2]3[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=3[CH2:4][N:5]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:11]2)=[O:42])=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)c2ccccc2-c2ccccc2)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.5 g (3.8 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 2.65 ml of triethylamine in 12 ml of CH2Cl2 chilled at 0° C. was added a solution of [1,1′-biphenyl]-2-carbonyl chloride in 6 ml of CH2Cl2. The mixture was stirred at room temperature overnight and diluted with CH2Cl2 and H2O. The organic layer was separated and washed with 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 2.2 g of a white foam. Anal. for C31H28N2O6S: Calc'd: C, 66.9; H, 5.1; N, 5.0; Found: C, 67.3; H, 5.2;N, 4.7.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:27])[CH:17]=3)[CH2:13][CH:12]([C:28]([OH:30])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]1[CH:33]=[C:34]([C:38](=[N:40]O)[NH2:39])[CH:35]=[CH:36][CH:37]=1>>[F:31][C:32]1[CH:33]=[C:34]([C:38]2[N:40]=[C:28]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:27])[CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:30][N:39]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: Cc1cc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)ccc1OC(F)(F)F
Reactant: NC(=NO)c1cccc(F)c1
Product: Cc1cc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCC(O)CC3)C2)ccc1OC(F)(F)F

Procedure:
100 mg (0.22 mmol) of the compound from Example 170A and 51 mg (0.33 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 60 mg (50% of theory)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC1C=CC=CC=1C.[Cu]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: Oc1ccc(Cl)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=C(O)Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 27.5 °C

Procedure:
To a solution of o-chlorophenylacetic acid (330 g) in o-xylene (4000 mL) is added 4-chlorophenol (306 g), K2CO3 (354 g), and copper powder (18 g) at 25-30° C. The mixture is heated at reflux for 2-3 hours and water is removed by azeotropic distillation. The reaction mixture is maintained for 1-2 hours at 25-30° C. and water (4000 mL) is added. Organic and aqueous layers are separated and the organic layer is washed with water (4000 mL). The pH of combined aqueous layers is adjusted to 1-1.5 by addition of aqueous HCl (100 mL) at 0-5° C. The formed solid is collected by filtration, washed with water (3000 mL) and hexane (500 mL), and then is dried to afford the title compound. Yield: 465 g. Purity by HPLC: 97.81%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].[N+:15]([C:18]1[CH:23]=[CH:22][C:21](Cl)=[CH:20][CH:19]=1)([O-:17])=[O:16].[OH-:25].[K+]>CS(C)=O.O>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:21]2[CH:22]=[CH:23][C:18]([N+:15]([O-:16])=[O:25])=[CH:19][CH:20]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: [OH-]
Reactant: Oc1ccccc1-c1ccccc1O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 80 °C
Yield: 15 %

Procedure:
37.2 g (0.2 mol) of 2,2'-dihydroxy-biphenyl and 63 g (0.4 mol) of p-nitrochlorobenzene are dissolved in 160 ml of dimethylsulphoxide (DMSO) in a sulphonation flask and the solution is warmed to 80° C. A solution of 26.4 g (0.4 mol) of 85% strength potassium hydroxide in 20 ml of water is then added dropwise, whilst stirring, and the reaction solution is subsequently further stirred for 3 hours at 100°-110° C. After cooling, the reaction solution is poured into ice water and the resulting precipitate is washed several times with water. The resulting crude product is then dried for 20 hours under a high vacuum at 70° C. and unconverted nitrochlorobenzene sublimes away during drying. The residue is recrystallised twice from ethanol. 12.4 g (15% of theory) of 2,2'-di-(p-nitrophenoxy)-biphenyl are obtained in the form of slightly yellowish crystals; melting point 158° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:15][C:14]([CH3:16])([CH3:17])[CH2:13][CH:12]([F:20])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: CC1(C)CCc2nc3cc(Br)ccc3c(=O)n2C1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(F)c2nc3cc(Br)ccc3c(=O)n2C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To a solution of 3-bromo-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one (0.1 g, 0.327 mmol, 1 equiv) in DMF (5 mL), Selectfluor (0.12 g, 0.327 mmol, 1 eq) was added. The reaction mixture was heated to 90° C. and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL), dried over Na2SO4. After filtration and concentration, 80 mg of the desired product was obtained, which was directly used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:18]1[CH2:20][CH2:19]1)([OH:17])[CH3:16].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:21](=[O:22])[O:17][C:15]([CH:18]4[CH2:20][CH2:19]4)([CH3:16])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(O)(c1cc(-c2cccc(Cl)c2)ccc1N)C1CC1
Product: CC1(C2CC2)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
The title compound was prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-cyclopropyl-ethanol and 1,1′carbonyldiimidazole according to Procedure C. Off-white solid: mp 158-159° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.74 (t, 1H, J=1.71 Hz), 7.67-7.57 (m, 3H), 7.47 (t, 1H, J=7.88 Hz), 7.39 (d, 1H, J=8.1 Hz), 6.95 (d, 1H, J=8.12 Hz), 1.7 (s, 3H), 1.45 (m, 1H), 0.48 (m, 2H), 0.28 (m, 2H); MS (APCI) m/z 314 ([M+H]+, 100%); Anal. Calc. For C18H16ClNO2: C, 68.9; H, 5.14; N, 4.46. Found: C, 68.13; H, 5.01; N, 4.36.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[N:3]=1.[H-].[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(O)nc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)nc(N)n1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
2-Amino-4-methyl-6-hydroxypyrimidine (62.5 g., 0.50 mole) is dissolved in 500 ml of dimethylformamide and sodium hydride (0.5 mole) is added over a 1 hour period under a nitrogen atmosphere. The mixture is heated at 75° C. for 11/2 hours. Benzyl chloride (69.3 g., 0.55 moles) is then added over 15 minutes and the mixture is heated at 90° C. and stirred for 11/2 hours. After cooling, the reaction mixture is filtered and concentrated under vacuum to an oil from which 2-amino-4-methyl-6-benzyloxypyrimidine melting at 108°-109.5° C. is obtained by crystallization from n-butyl chloride.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:12]=3[CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:30][C:31]([NH:23][S:20]([C:18]2[CH:17]=[CH:16][C:13]3[CH2:14][CH2:15][N:9]([C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[O:8])[CH2:10][CH2:11][C:12]=3[CH:19]=2)(=[O:22])=[O:21])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCCC1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCOCC1)CC2
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCOCC1)CC2

Procedure:
By the reaction of 2,3,4,5-tetrahydro-3-morpholinocarbonyl-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-[(2,3,4,5-tetrahydro-3-morpholinocarbonyl-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 190°-191° C. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with 4-morpholinecarbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13](OC)=[C:12](F)[CH:11]=2)[CH:5]=[C:4]([Cl:19])[C:3]=1[N:20]=[CH:21][N:22]([CH3:24])[CH3:23].[F:25][C:26]([F:36])([F:35])C1C=C(C=CC=1)C=O.C(O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:26]([F:36])([F:35])[F:25])[CH:11]=2)[CH:5]=[C:4]([Cl:19])[C:3]=1[N:20]=[CH:21][N:22]([CH3:24])[CH3:23]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(C=Nc2cc(Cl)c(N=CN(C)C)c(Cl)c2)cc1F
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN(C)C=Nc1c(Cl)cc(N=Cc2cccc(C(F)(F)F)c2)cc1Cl

Procedure:
A mixture of 9.3 g. of N'-(4-amino-2,6-dichlorophenyl)-N,N-dimethylformamidine (Example 9) and 6.9 g. of m-trifluoromethylbenzaldehyde in 25 ml. of absolute ethanol is refluxed for 18 hours. The solution is evaporated in vacuo to give a syrup. The syrup is extracted into hot heptane. The solvent is evaporated to provide an oil. The oil is dissolved in chloroform and the solution is filtered through a magnesium silicate column packed with chloroform. The column is washed with chloroform until the wash is colorless. The filtrate is evaporated to give a yellow syrup which crystallizes on cooling. The product is recrystallized from n-hexane to give 8.3 g. of the product of the Example as granular yellow crystals, m.p. 62°-64° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1>CN(C)C=O>[ClH:1].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[C:25]([CH3:30])[CH:24]=1
Reactant: Cc1cc(F)ccc1N
Reactant: Clc1nc(N2CCc3ccccc3C2)c2ccccc2n1
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(N2CCc3ccccc3C2)c2ccccc2n1
Product: Cl
Yield: 46 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 2.2 g of the compound(7 mM) prepared in Example 1 and 15 ml of dimethylformamide, 1.7 ml of 4-fluoro-2-methylaniline(15 mM) was added, 1.35 g of the title compound was prepared.