Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH:11]1([CH2:16][C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH:6][C:17](=[O:18])[CH2:16][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([Cl:10])[CH:3]=1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC1CCCC1)Nc1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Yield: 79.4 %

Procedure:
4-Bromo-2,6-dichloroaniline (12.1 g) and cyclopentylacetyl chloride (8.1 g) were dissolved in tetrahydrofuran (100 mL) and sodiumcarbonate (6.4 g) is added, followed by heating to reflux for 6 hours. The reaction mixture was cooled to ambient temperature and filtered and diluted with water (250 ml). After extraction, the combined organic phase was concentrated in vacuo to furnish 14.0 g (80% yield) of the title compound as a white solid. LC-MS (m/z) 352 (MH+); tR=3.47, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.12 (m, 2H), 1.50 (m, 4H), 1.80 (m, 2H), 2.15 (m, 1H), 2.50 (d, 2H), 5.70 (broad s, 1H), 7.45 (s, 2H).
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:10]=[C:11]2[C:16]=1[C:15](=[O:17])[N:14]([CH3:18])[C:13](=O)[NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:35]>>[CH2:1]([C:8]1[N:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:10]=[C:11]2[C:16]=1[C:15](=[O:17])[N:14]([CH3:18])[C:13]([Cl:35])=[N:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)c(Cc3ccccc3)c2c1=O
Product: Cn1c(Cl)nc2nn(Cc3ccc(-c4ccccc4)cc3)c(Cc3ccccc3)c2c1=O
Yield: 100 %

Procedure:
3-benzyl-2-(biphenyl-4-ylmethyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (10 mg, 0.024 mmol) is refluxed in POCl3 (10 mL) for 4 days, and then the mixture is evaporated to dryness. The residue is purified by silica gel flash chromatography to give 10.4 mg product as white solids (Yield: 100%). MS (FAB) m/z 441.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH3:28]>C(#N)C.ClCCl>[CH3:26][CH:27]([N:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14]1)[CH3:28]
Reactant: CCCI
Reactant: COc1cc(N2CCCNCC2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(N2CCCN(C(C)C)CC2)ccc1[N+](=O)[O-]
Reaction time: 60 h
Yield: 83.5 %

Procedure:
1-[3-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine (580 mg, 2.3 mmol) was dissolved in acetonitrile (10 mL). Potassium carbonate (952 mg, 6.9 mmol) and 1-iodopropane (0.344 mL, 3.45 mmol) were added. Reaction was stirred at it for 60 h. At this time the reaction mixture was diluted with dichloromethane and washed with a saturated sodium bicarbonate solution, water and a saturated sodium chloride solution, dried over Na2SO4 and filtered. Solvents were removed under reduced pressure and purified by SiO2 chromatography to afford 1-(1-methylethyl)-4-[3-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine (0.565 g, 1.92 mmol). ESIMS (M+H)+=295.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[O:28]=[C:29]1[NH:33][C:32](=[O:34])[CH:31]([CH2:35][C:36]2[CH:46]=[CH:45][C:39]([O:40][CH2:41][C:42](O)=[O:43])=[CH:38][CH:37]=2)[S:30]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:28]=[C:29]1[NH:33][C:32](=[O:34])[CH:31]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:40][CH2:41][C:42]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:43])=[CH:45][CH:46]=2)[S:30]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 84.5 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-trifluoromethylphenoxy)phenyl]-N-methylcarbamate (0.68 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.73 g), diethyl cyanophosphonate (0.49 g), triethylamine (0.30 g) and anhydrous tetrahydrofuran (50 ml) and the reaction mixture was purified to give the desired product (0.97 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH:31](=O)[CH3:32]>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:31][CH3:32])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC=O
Product: CCN1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2Cl)CC1

Procedure:
Using alkylation method A, 3-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (600 mg, 1.3 mmol) and acetaldehyde (0.4 mL, 6.7 mmol) afforded, after purification (SiO2: 10:10:1 hexane:EtOAc:isopropylamine) and recrystallization (acetonitrile), 275 mg (43%) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][P:9](=O)([O:18]CC2C=CC=CC=2)[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:27][C@@H:28]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:29]([NH:31][C@H:32]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30]>>[C:12]1([CH2:11][O:10][P:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([O:27][C@@H:28]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:29]([NH:31][C@H:32]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](O)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=P(CCc1ccccc1)(OCc1ccccc1)OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)OP(=O)(CCc1ccccc1)OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
This (2-phenylethyl)phosphonic acid, dibenzyl ester is reacted with N-[(S)-2-hydroxy-3-phenyl-1-oxopropyl]-L-leucine, phenylmethyl ester according to the procedure described in Example 76 to give N-[(S)-2[[(phenylmethoxy)(2-phenylethyl)phosphinyl]oxy]-1-oxo-3-phenylpropyl]-L-leucine, phenylmethyl ester as a colorless oil.
Reaction SMILES: [C:1]1([C:7]#[C:8][Sn:9]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([N:29]=[N+:30]=[N-:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:8]([Sn:9]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:18][CH2:19][CH2:20][CH3:21])[N:31]=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Reactant: [N-]=[N+]=NCc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2ccccc2)c1-c1ccccc1
Temperature: 150 °C

Procedure:
Phenylethynyltri-n-butyltin (8.25 g, 21.1 mmol) and benzyl azide (2.3 mL, 18.4 mmol) were combined and heated to 150° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 526.3 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][S:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O.O>CN(C)C(=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH2:36][C:37]([F:40])([F:39])[F:38])[S:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(CNS(=O)(=O)Cc3ccccc3)cc2)CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)N1CCN(c2ccc(CN(CC(F)(F)F)S(=O)(=O)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of N-[[4-(4-acetylpiperazin-1-yl)phenyl]methyl]-1-phenyl-methanesulfonamide (100 mg, 0.25 mmol) in N,N-dimethylacetamide (3 mL) was added sodium hydride (60% in mineral oil) (11.3 mg, 0.28 mmol) and stirred at ambient temperature for 30 minutes. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (72 mg, 0.31 mmol) was then added and stirred at ambient temperature for 16 hours. Water was added and the reaction was partitioned between water and dichloromethane. The dichloromethane layer was isolated with a phase separator cartridge and concentrated and purified by preparative reverse phase HPLC to yield 47 mg of N-(4-(4-acetylpiperazin-1-yl)benzyl)-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.47-7.32 (m, 5H), 7.21 (d, J=8.5 Hz, 2H), 6.95 (d, J=8.5 Hz, 2H), 4.52 (s, 2H), 4.27 (s, 2H), 3.83 (q, J=9.3 Hz, 2H), 3.62-3.51 (m, 4H), 3.22-3.13 (m, 2H), 3.13-3.03 (m, 2H), 2.03 (s, 3H); LCMS (m/z) ES+ 470.1 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1.Cl.Cl[CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[N:51]1([CH2:50][CH2:49][O:46][C:43]2[CH:42]=[CH:41][C:40]([C:17]3[C:16]([C:13]4[CH:14]=[CH:15][C:10]5[N:11]([C:7]([C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=6)=[CH:8][N:9]=5)[CH:12]=4)=[CH:20][N:19]([C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:18]=3)=[CH:45][CH:44]=2)[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: Oc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cc(-c3ccc4ncc(-c5ccccn5)n4c3)c(-c3ccc(OCCN4CCOCC4)cc3)n2)cc1
Yield: 58.8 %

Procedure:
90 mg 4-{4-[3-(pyridin-2-yl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl}phenol (compound in Example 353) and 42 mg N-(2-chloroethyl)morpholine hydrochloride were reacted under the same conditions as in Example 190, to give 63 mg of the title compound as a colorless amorphous matter.
Reaction SMILES: O[Li].O.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:30]([F:33])([F:32])[F:31])[O:16][N:15]=[C:14]([C:17]3[S:29][C:20]4=[N:21][CH:22]=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=[C:19]4[CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1.Cl>O.C1COCC1>[Cl:11][C:9]1[CH:8]=[C:7]([C:12]2([C:30]([F:32])([F:31])[F:33])[O:16][N:15]=[C:14]([C:17]3[S:29][C:20]4=[N:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=[C:19]4[CH:18]=3)[CH2:13]2)[CH:6]=[C:5]([Cl:4])[CH:10]=1
Reactant: COC(=O)c1cnc2sc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2sc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2c1
Reaction time: 12 h
Yield: 73.7 %

Procedure:
Add a solution of LiOH—H2O (76 mg, 2 mmol) in water (0.5 mL) to a solution of methyl 2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyridine-5-carboxylate (237 mg, 0.5 mmol) in THF (3 mL). Stir the mixture at temperature for 12 hours. After addition of 10 mL of water, acidify the mixture with concentrated HCl to PH=6˜7. Extract the resultant mixture with ethyl acetate (3×10 mL). The combined organic layers are washed brine, dried over anhydrous Na2SO4 and concentrated under vacuum to afford 2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]thieno[2,3-b]pyridine-5-carboxylic acid as pale yellow solid (170 mg, 73.9%), which is used in next step without further purification. MS (m/z): 461 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)[N:13]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:12]=2)[CH:2]=1.Br[C:37]1[S:38][C:39]([S:42][CH3:43])=[N:40][N:41]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:43][S:42][C:39]1[S:38][C:37]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH:12]=[C:11]3[C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[N:41][N:40]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cnc3ccccc3c2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CSc1nnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1nnc(-c2ccc3c(c2)c(-c2cnc4ccccc4c2)cn3C(=O)OC(C)(C)C)s1
Temperature: 120 °C
Yield: 50.8 %

Procedure:
A mixture of tert-butyl 3-(quinolin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (80 mg, 170 μmol), 2-bromo-5-(methylthio)-1,3,4-thiadiazole (54 mg, 255 μmol), Pd(PPh3)4 (9.8 mg, 8.5 μmol) and potassium carbonate (71 mg, 510 μmol) in dioxane (1.0 mL) was added H2O (0.2 mL). The reaction was heated in a microwave at 120° C. for 70 min. The solvent was then removed and the residue was purified with silica gel chromatography to give tert-butyl 5-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-3-(quinolin-3-yl)-1H-indole-1-carboxylate (41 mg, 51%). MS (ESI, pos. ion) m/z: 475 (M+1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[Cl:16][CH2:17][C:18]([N:20]=[C:21]=[O:22])=[O:19]>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:21]([NH:20][C:18](=[O:19])[CH2:17][Cl:16])=[O:22])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=C=NC(=O)CCl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=C(CCl)NC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
22.9 g (0.1 mol) of 3,5-bis-trifluoromethyl-aniline were dissolved in 150 ml of dry toluene. 11.9 g (0.1 mol) of chloroacetyl isocyanate in 50 ml of dry toluene were added. The mixture was stirred at 50° C. for 1 hour and then cooled to room temperature. The product which had precipitated was filtered off and rinsed with toluene/ligroin 1:2 and then dried. 26 g (74.5% of theory) of N-(3,5-bis-trifluoromethylphenyl)-N'-(chloroacetyl)-urea with a melting point of 170° C. were thus obtained.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH3:8])[C:6]([C:9]([O:11]CC)=[O:10])=[CH:5][C:4]=1[CH3:14]>[C].[Pd].C(O)C>[CH3:8][N:7]1[C:3]([CH3:2])=[C:4]([CH3:14])[CH:5]=[C:6]1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1cc(C)c(CO)n1C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C(=O)O)n(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
A mixture of ethyl 5-hydroxymethyl-1,4-dimethyl-1H-pyrrole-2-carboxylate (2.2 g), ethanol (15 ml), and palladium-carbon (2.2 g) was stirred at room temperature for 2 hours under a hydrogen atmosphere of 3 atmospheres. The insolubles of the reaction mixture were separated by filtration through Celite and the filtrate was concentrated to about 10 ml under reduced pressure. THF (10 ml) was added to the residue, and a 1 M aqueous sodium hydroxide solution (20 ml) was further added at room temperature, followed by stirring at room temperature for 13 days. The reaction mixture was washed with diethyl ether, and 1 M hydrochloric acid (20 ml) was added to the aqueous layer under ice-cooling. The solid precipitated was collected by filtration and washed with water to obtain 1,4,5-trimethyl-1H-pyrrole-2-carboxylic acid (0.79 g).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52](=[O:55])[O:53][CH3:54])[CH:48]([CH3:50])[CH3:49])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:57]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].[CH3:64][O:65][C:66](N[C@@H](C(C)C)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52](=[O:55])[O:53][CH3:54])[CH:48]7[CH2:50][CH2:66][O:65][CH2:64][CH2:49]7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:57]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(-c3cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]3)cc2CO4)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(-c3cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]3)cc2CO4)[nH]1)C1CCOCC1

Procedure:
This compound was made in an analogous manner to methyl (S)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amide coupling. LCMS-ESI+: calculated for C50H52N8O8: 893.00; observed [M+1]+: 894.07.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([Cl:26])=[CH:7][C:8]([F:25])=[C:9]([CH:24]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)(=[O:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30]O.C(P(CCCC)CCCC)CCC>C(Cl)Cl>[C:1]([O:4][C:5]1[C:6]([Cl:26])=[CH:7][C:8]([F:25])=[C:9]([CH:24]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:30][CH2:29][O:28][CH3:27])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Nc3cc(OC(C)=O)c(Cl)cc3F)ncnc2cc1O
Reactant: COCCO
Agent: CCCCP(CCCC)CCCC
Solvent: ClCCl
Product: COCCOc1cc2ncnc(Nc3cc(OC(C)=O)c(Cl)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
1-1′-(Azodicarbonyl)dipiperidine (413 mg, 1.6 mmol) was added portionwise to a stirred mixture of 4-(5-acetoxy-4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.66 mmol), 2-methoxyethanol (63 ml, 0.8 mmol) and tributylphosphine (405 ml, 1.6 mmol) in methylene chloride at 0° C. The resulting solution was allowed to warm to ambient temperature and stirred for 2 hours. The precipitated solid was removed by filtration, the solvent removed from the filtrate by evaporation and the residue purified by flash chromatography eluting with acetonitrile/methylene chloride (1/9 increasing in polarity to 4/6) to give 4-(5-acetoxy4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline (180 mg, 62%) as a solid.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH:14]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28](N(CC)CC)C.CI>CO>[CH3:28][N:11]([CH2:12][CH2:13][CH:14]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][CH2:9][CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: Oc1ccc(C(CCNCCCSc2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CI
Product: CN(CCCSc1ccccc1)CCC(c1ccccc1)c1ccc(O)cc1

Procedure:
To a solution of 0.8 g (0.0021 moles) of N-(3-phenylthiopropyl)-3-p-hydroxyphenyl-3-phenylpropylamine in 20 ml methanol and containing 0.3 ml triethylamine are added gradually 0.13 ml (0.0021 moles) methyl iodide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]([N+:24]([O-])=[O:25])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C)C=O.O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[C:3]([C:9](=[N:24][OH:25])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:20])[F:22])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCC(c1ncc(Cl)cc1Cl)[N+](=O)[O-])c1ccccc1C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 18 h
Yield: 43.9 %

Procedure:
To 14.00 g of N-[2-(3,5-dichloropyridin-2-yl)-2-nitroethyl]-2-(trifluoromethyl)benzamide in 70 ml of a mixture of N,N-dimethylformamide-water (7:1), 16.62 g of sodium nitrite was added, and the mixture was stirred at 60° C. for 18 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, poured into 100 ml of water and extracted with ethyl acetate (100 ml×2). The resulting organic layers were combined, washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 3:7 to 1:1) as the eluent to obtain 5.90 g of the desired product as pale yellow crystals.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH:6]=CC2C=CC(OC)=C(OC)C=2)[NH:2]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:19]1([C:18]([N:1]2[CH2:5][CH2:4][CH:3]([NH2:2])[CH2:6]2)=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C=CC2CCNN2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: NC1CCN(C(=O)c2ccccc2)C1

Procedure:
4-(2-aza-2-pyrrolidin-3-ylvinyl)-1,2-dimethoxybenzene (3 mmol) and benzoyl chloride (3.5 mmol), a compound of formula (10), were added to a mixture of dry methylene chloride (15 mL) and sodium carbonate (600 mg). The mixture was stirred for hours and then filtered through a Celite™ bed. Solvent was removed from the filtrate by evaporation, and the residue was dissolved in a mixture of methanesulfonic acid (3.84 g) in 20 mL tetrahydrofuran:water (3:1), and stirred for 60 hours. The solution was neutralized with sodium carbonate, filtered, and solvent removed from the filtrate under reduced pressure. The residue was purified on a silica gel flash chromatography column, to obtain 3-aminopyrrolidinyl phenyl ketone as an oil.