Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)CC.COC(C1C=NC(Cl)=C(Br)N=1)=O.[F:31][C:32]([F:36])([F:35])[CH2:33][OH:34].N1CCCC1.[OH-].[K+]>>[N:14]1([C:6]2[N:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[N:10][C:5]=2[O:34][CH2:33][C:32]([F:36])([F:35])[F:31])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OCC(F)(F)F
Reactant: CCCOc1nc(C(=O)O)cnc1N1CCCC1
Agent: COC(=O)c1cnc(Cl)c(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNC1
Product: O=C(O)c1cnc(N2CCCC2)c(OCC(F)(F)F)n1
Yield: 41 %

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (example 10, step c), the title compound was synthesized from 6-bromo-5-chloro-pyrazine-2-carboxylic acid methyl ester, 2,2,2-trifluoro-ethanol (commercially available), pyrrolidine (commercially available) and subsequent saponification with KOH in 41% yield. m/z (ES+): 292.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]3[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].CO>C(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]3[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(cc3-4)CCc3nc([C@@H]4CC[C@H](C)N4C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c3-5)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reaction time: 13 h
Yield: 583.8 %

Procedure:
tert-Butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (8.33 g, 1.049 mmol) was suspended in DCM and activated MnO2 (55.0 g, 630 mmol) was added in a single portion. After 13 h, MeOH (200 mL) was added and the slurry was filtered over celite. The filter cake was washed with MeOH (600 mL) and the filtrate was concentrated under reduced pressure. The crude material was purified by silica column chromatography (0% to 45% MeOH/EtOAc) to afford tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (4.85 g, 58%).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10]Br)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:12][C:13]1[CH:14]=[C:15]([OH:34])[CH:16]=[CH:17][C:18]=1[CH:19]([CH3:33])[C:20]([OH:32])([C:25]1[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=1)[C:21]([F:24])([F:23])[F:22]>>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][O:34][C:15]1[CH:16]=[CH:17][C:18]([CH:19]([CH3:33])[C:20]([OH:32])([C:25]2[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=2)[C:21]([F:22])([F:23])[F:24])=[C:13]([Cl:12])[CH:14]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Product: Cc1cnc(C(O)(C(C)c2ccc(OCCNC(=O)OC(C)(C)C)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 2-(BOC-amino)ethyl bromide and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=489.9 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.FC(F)(F)[C:14](O)=[O:15].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O>O>[OH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][C:7]=1[CH:14]=[O:15]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1cc(C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4.91 g of 4-(trifluoromethyl)phenol and 68 ml of trifluoroacetic acid was gradually added 4.67 g of hexamethylenetetramine at room temperature. This mixture was heated under reflux for 24 hours. The reaction mixture was cooled to room temperature, then 35 ml of water and 19 ml of 50% sulfuric acid were added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted three times with diethyl ether. The organic layers were combined and sequentially washed with 5 M hydrochloric acid and water. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.7 g of 2-hydroxy-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:8][S:9]([O:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:11])=[O:10]
Reactant: OCC1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCC1
Temperature: 4 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
Cyclopentanemethanol (50.0 g; 0.484 mol) and methane-sulfonyl chloride (67.0 g; 0.581 mol) in toluene (500 ml) were stirred and cooled to 4° C. Triethylamine (68.0 g; 0.678 mol) was added dropwise with external cooling so that the reaction temperature remained below 20° C. The reaction mixture is stirred under dry nitrogen at room temperature overnight. The reaction mixture was quenched with water (500 ml) and ether (500 ml), the organic phase separated, washed with water (500 ml) and saturated brine (500 ml) and dried (MgSO4). The solution is filtered and the solvent evaporated, to afford cyclopentylmethyl methanesulfonate (86.0 g; 100% yield) as a colorless liquid. NMR - d(CDCl3 ; 60 MHz) 0.8-2.6 (9H, m), 3.1 (3H, s) and 4.15 (2H, d, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[Cl:18])=[O:22])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(-c2cc3ocnc3cc2Cl)cn1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cc3ocnc3cc2Cl)cn1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of 5-(5-chlorobenzoxazol-6-yl)-2-pyridylamine (31) (23 mg, 0.09 mmol) and 2 mg DMAP in 2 ml DCM was added 2-chlorobenzoyl chloride (23 μl, 0.18 mmol) followed by addition of DIEA (94 μl). The resulting brown solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (135 μl) at r.t. for 30 min before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 17 mg 32 as pale yellow solid. (yield: 49%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:16])=O>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CC(C)(C)c1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 4-tert-butylbenzoic acid (1000 g, 5.6 mol) in sulfurous dichloride (1.5 L) was refluxed for 3 hours. Then the mixture was concentrated in vacuo, and the crude 101a was used in next step without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:10](CC3C=CC(OC)=CC=3)[C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:36]=1.[NH:37]1[CH:41]=[N:40][CH:39]=[N:38]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>CN(C=O)C.C(OCC)(=O)C.[Cu](I)I>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]([NH:26][CH2:25][C:7]2([C:21]([F:22])([F:23])[F:24])[C:6]3[CH:36]=[C:2]([N:37]4[CH:41]=[N:40][CH:39]=[N:38]4)[CH:3]=[CH:4][C:5]=3[NH:10][C:9](=[O:20])[O:8]2)=[O:35])=[CH:29][CH:30]=1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(I)ccc32)cc1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(-n3cncn3)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Temperature: 110 °C

Procedure:
A solution of N-{[6-iodo-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (50 mg, 0.081 mmol), 1,2,4-triazole (16.9 mg, 0.244 mmol), potassium phosphate (25.9 mg, 0.122 mmol), N,N′-dimethylethylenediamine (6.9 μL, 0.065 mmol) and copper iodide (I) (3.1 mg, 0.016 mmol) in DMF (0.4 mL) was stirred for 1 hour under heating at 110° C. The temperature of the solution was brought to room temperature, and the solution was diluted with ethyl acetate, which was washed sequentially with a saturated aqueous ammonium chloride solution and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was subjected to the same condition as in Example 154 to effect deprotection of the 4-methoxybenzyl group, whereby the objective compound (8.0 mg, 23%) was obtained as a pale white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[C:11](=[O:20])[C:10]=1[OH:21])=[O:8].[C:27]1([C:33]2([S:36]([NH2:39])(=[O:38])=[O:37])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:19])[NH:39][S:36]([C:33]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)(=[O:37])=[O:38])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8]
Reactant: NS(=O)(=O)C1(c2ccccc2)CC1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)NS(=O)(=O)C2(c3ccccc3)CC2)C1

Procedure:
Compound 757 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and 1-phenyl-cyclopropanesulfonic acid amide using the method described for compound 751. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 50% acetonitrile/water/0.5% TFA) and isolated as a white powder (0.0026 g, 3% yield). HRMS (M−H) calcd for C26H30N3Cl2O6S: 582.12324. found: 582.1215.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:36]=[CH:35][C:34](=[O:37])[N:33]([CH2:38][CH:39]=O)[C:32]=2[N:41]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:39][CH2:38][N:33]4[C:34](=[O:37])[CH:35]=[N:36][C:31]5[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[N:41][C:32]4=5)[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2n1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a solution of 0.16 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate in 3 mL of dichloromethane, 0.10 g of (6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde, 26 μL of acetic acid and 0.15 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash basic silica gel column chromatography using an eluent of chloroform to obtain 0.15 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[N:12]=[C:11]([CH2:13][OH:14])[NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[NH4+].[OH-]>Cl>[NH2:1][C:4]1[CH:5]=[C:6]2[N:12]=[C:11]([CH2:13][OH:14])[NH:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2[nH]c(CO)nc2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Nc1cnc2[nH]c(CO)nc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Stannous chloride dihydrate (1.6 g, 0.0070 mol) was added in one portion to a stirred solution of (6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)-methanol (450 mg, 0.0023 mol) in 10% aqueous hydrochloric acid (20 mL) at 50° C. The mixture was stirred at 50° C. for approx. 2 hours then allowed to cool to room temperature. The mixture was cooled further to 0° C. and then basified to ca. pH 8 using conc. NH4OH. The aqueous layer was then filtered through Celite® to remove tin salts, and the filtrate was concentrated under vacuum to leave a crude solid (380 mg; yield assumed quantitative) which was used directly in the next step (amide formation).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]1[CH:39]=[CH:38][CH:37]=[CH:36][C:15]=1[NH:16][C:17]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:18]=1[C:19]([NH:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20]>>[F:13][C:14]1[CH:39]=[CH:38][CH:37]=[CH:36][C:15]=1[N:16]1[C:17]2[C:18](=[CH:30][C:31]([F:35])=[C:32]([F:34])[CH:33]=2)[C:19](=[O:20])[N:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:1]1=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccccc1F
Product: O=c1c2cc(F)c(F)cc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Yield: 48.5 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (4.9 g, 30 mmol) and crude 2-(2-fluoro-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example Y, 5.6 g, 15 mmol) provided 2.9 g of the title compound as a solid, mp 204-206° C.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[NH2:17][C:18]1[N:23]=[C:22]([Cl:24])[N:21]=[C:20]([O:25][CH3:26])[N:19]=1>O1CCOCC1>[F:16][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:17][C:18]1[N:23]=[C:22]([Cl:24])[N:21]=[C:20]([O:25][CH3:26])[N:19]=1)=[O:15])(=[O:12])=[O:11]
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(F)F
Reactant: COc1nc(N)nc(Cl)n1
Solvent: C1COCCO1
Product: COc1nc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)n1
Yield: 87.9 %

Procedure:
124.6 g of 2-difluoromethoxyphenyl-sulfonyl isocyanate in 100 ml of dioxane are added dropwise to a suspension of 80.3 g of 2-amino-4-chloro-6-methoxy-1,3,5-triazine in 400 ml of absolute dioxane in the course of 10 minutes. The reaction mixture is warmed to 90°-100° for 3 hours, and the solution is then cooled and concentrated to give 180 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-chloro-6-methoxy-1,3,5-triazin-2-yl)-urea of melting point 167°-168°.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:8][CH2:9][CH2:10][CH:11]([OH:25])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)=[O:13]>C(N(CC)CC)C>[C:1]([NH:5][C:6]([O:25][CH:11]([CH2:10][CH2:9][Cl:8])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)C(O)CCCl
Reactant: CC(C)(C)N=C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)OC(CCCl)C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 40.1 %

Procedure:
t-Butylisocyanate (0.093 g) and triethylamine (0.095 g) were added successively to a stirred solution of 4-chloro-2-hydroxy-N(3-trifluoromethylphenyl)butanamide (0.24 g, prepared as described in Example 10, Step 1a above). After a day further aliquots of t-butylisocyanate and triethylamine were added. After a further twenty hours, the mixture was evaporated under reduced pressure and the residue chromatographed under reduced pressure to give the title compound (0.13 g, m.p. 115°-116° C.). NMR (CDCl3): δ 1.4(9H,s); 2.4(2H,m); 3.65(1H,t); 5.0(1H,bs); 5.35(1H,t); 7.35(2H,m); 7.7(1H,d); 7.8(1H,s); 8.6(1H,bs). MS: MH+ 381, 383.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[NH2:30][CH2:29][CH2:28][N:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:9]2[C:8]([C:6]([OH:7])=[O:5])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:18]=1)[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(=O)N(CCNC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCC(=O)N(CCN)Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
4′-[(2-t-Butoxycarbonylaminoethyl)pentanoylamino]methylbiphenyl-2-carboxylic acid t-butyl ester (3b) and 4′-[(2-aminoethyl)pentanoylamino]methylbiphenyl-2-carboxylic acid (3c): Valeryl chloride (4.6 mL, 38.7 mmol) was added to a solution of crude intermediate (3a) (15 g, 35.2 mmol) in toluene (100 mL) at 0° C. followed by the addition of DIPEA (18.4 mL, 105 mmol). The mixture was stirred at room temperature for 3 hours. 1M aqueous NaOH (10 mL) was added and the mixture was concentrated in vacuo. The concentrate was extracted with EtOAc (3×150 mL) and water (80 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford crude intermediate (3b). A solution of crude intermediate (3b), 1,4-dioxane (50 mL) and 4M HCl in 1,4-dioxane (50 mL) was stirred for 40 minutes at room temperature. The precipitate was filtered and purified by reverse phase HPLC to afford intermediate (3c).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=[O:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:12][CH:11]=2)[CH2:7][C:8]1=[O:13])(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O

Procedure:
48.9 g (0.279 mol) 5-acetyl-2-indolinone are stirred in 400 ml acetic anhydride in an oil bath at 140° C. for 2 h. During this time the starting material dissolves. Then the reaction mixture is left to cool, evaporated down, the precipitate is removed by suction filtering, washed with ether and the product is dried.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)(=O)C.C(=O)(O)[O-].[Na+].O.[Cl-].[Na+]>CO>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:11](=[O:20])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[OH:4])=[CH:18][CH:17]=1
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(NC(=O)c2ccccc2O)cc1
Temperature: 80 °C

Procedure:
To a solution of 2-(4-aminophenylcarbamoyl)phenyl acetate (580 mg) in methanol (10 mL) is added saturated sodium bicarbonate (2 mL) and water (3 mL). The mixture is heated at 80° C. for 30 minutes, then poured into half-saturated aqueous sodium chloride and extracted with ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil which is then triturated with diethyl ether to provide the desired product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([NH:25][C:26]1[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:17]([NH:25][C:26]1[CH:38]=[C:37]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
55 mg of 2-nitroaniline, 0.17 g of cesium carbonate, 2.4 mg of tris(dibenzylideneacetone)dipalladium(0), 1.2 mg of palladium acetate and 6.3 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl were added to 2.0 mL of toluene solution containing 0.10 g of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane; ethyl acetate=1:1] to obtain 94 mg of tert-butyl 2-(benzamido)-4-(2-nitroanilino)benzoate as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[NH:9][C:10]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](NC)[N:18]=3)=[C:11]([I:16])[C:12]=2[C:13]([NH2:15])=[O:14])[CH:7]=1.[C:26](C1C=CC(N2CCN(C)CC2)=CC=1)#C>C(#N)C.[Cu]I.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[NH:9][C:10]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:26])[N:18]=3)=[C:11]([I:16])[C:12]=2[C:13]([NH2:15])=[O:14])[CH:7]=1
Reactant: CNc1nccc(-c2[nH]c(-c3cc(Cl)ccc3C)c(C(N)=O)c2I)n1
Reactant: C#Cc1ccc(N2CCN(C)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: Cc1nccc(-c2[nH]c(-c3cc(Cl)ccc3C)c(C(N)=O)c2I)n1
Yield: 90.6 %

Procedure:
2-(5-Chloro-2-methylphenyl)-4-iodo-5-[2-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide (47 mg, 0.1 mmol) in dry ACN (1 mL) was treated with 1-(4-ethynylphenyl)-4-methylpiperazine (40 mg, 0.2 mmol) and TEA (0.14 mL, 1 mmol). The flask was stirred and purged with nitrogen and then solid CuI (1.0 mg, 0.005 mmol) and Pd(Ph3P)2Cl2 (3.5 mg, 0.005 mmol) were added. The reaction was refluxed for 2 h, then the solvent was evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH/7N NH3 in MeOH 95/4/1) to afford the title compound (41 mg, 76%).