Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[C:37](=[O:38])[N:36]2[CH2:39][C@@H:33]([CH2:34][C@H:35]2[C:40]([O:42][CH3:43])=[O:41])[O:32][C:22]2=[N:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]([OH:31])=[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[CH2:44][C@H:14]2[O:13][C:12](=[O:45])[NH:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:65][N:66]([CH3:71])[CH2:67][CH2:68][CH2:69]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[C:37](=[O:38])[N:36]2[CH2:39][C@@H:33]([CH2:34][C@H:35]2[C:40]([O:42][CH3:43])=[O:41])[O:32][C:22]2=[N:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]([O:31][CH2:69][CH2:68][CH2:67][N:66]([CH3:71])[CH3:65])=[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[CH2:44][C@H:14]2[O:13][C:12](=[O:45])[NH:11]1
Reactant: CN(C)CCCO
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1Cc3ccccc3C1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1Cc3ccccc3C1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OCCCN(C)C)O2
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A reaction tube was charged with the product of step 5 (200 mg, 0.326 mmol) and triphenylphosphine (855 mg, 3.26 mmol). The tube was sealed and THF (3259 μl) was added via syringe at 0° C. 3-dimethylamino-1-propanol (381 μl, 3.26 mmol) was added followed by slow addition of diisopropyl azodicarboxylate (631 μl, 3.26 mmol). After 5 minutes the cooling bath was removed and the mixture was allowed to reach room temperature and stirred for 10 minutes. The reaction tube was heated at 40° C. for 3 hours. The reaction mixture was concentrated to dryness in rotavap and the residue was purified on a gold cap silica gel (80 g) column (gradient: 0 to 60% solvent B in dichloromethane (solvent B: 20% methanol in ethyl acetate)) to give the title compound (210 mg, 0.300 mmol, 92% yield) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:18])=[O:17])=[N:14][CH:15]=1.C=O.[OH-].[Na+].[C:34](=O)([O-])[O-:35].[Na+].[Na+]>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:18][CH2:34][OH:35])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(N)=O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 153.7 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxamide (744 mg, 1.84 mmol) obtained in Example 15 in ethylene glycol dimethyl ether (8 ml), an aqueous solution of formaldehyde (37%, 0.4 ml) and 5% aqueous sodium hydroxide (1.6 ml) were added at 0° C., and the resulting mixture was stirred for 3 hours at room temperature. Sodium carbonate (80 mg) was added to the reaction mixture, and the mixture was stirred for 10 minutes at room temperature. The mixture was concentrated under reduced pressure, and then the residue was dissolved in chloroform, dried over magnesium sulfate, and filtered. Subsequently, the filtrate was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether, and then was collected by filtration, to obtain the title compound (524 mg, 1.16 mmol, 63%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:16][CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc([N+](=O)[O-])cc1Br
Temperature: 60 °C

Procedure:
2-Bromo-4-nitrophenol (9.2 g) was dissolved in dimethylformamide (50 ml) and sodium hydride (2.4 g) was added portionwise. The bright yellow solution was stirred until all effervescence ceased. Allyl bromide (4.7 ml) was added and the resulting solution was heated at 60° C. for 30 minutes. The mixture was cooled, quenched by the dropwise addition of water 30 ml, then diluted with water (500 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with sodium hydroxide (2N), water, brine, dried (MgSO4) and evaporated. The residue was purified on silica using 5-10% ethyl acetate in hexane to afford the title compound as a crystalline solid (10 g). 1H NMR (360 MHz, CDCl3) δ 4.72 (2H, d, J=6 Hz), 5.37 (1H, d, J=9 Hz), 5.51 (1H, d, J=15 Hz), 6.94 (1H, d, J=6.5 Hz), 8.18 (1H, dd, J=6.5, 2.6 Hz), 8.47 (1H, J=2.6 Hz).
Reaction SMILES: C([O:3][C:4](=[O:9])[CH2:5][C:6](Cl)=[O:7])C.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:6](=[O:7])[CH2:5][C:4]([OH:3])=[O:9])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Reactant: CCOC(=O)CC(=O)Cl
Product: COc1ccc(N2CCN(C(=O)CC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 127 using chlorocarbonyl-acetic acid ethyl ester and 3(S)-benzyl-1-(3-isopropoxy-4-methoxy-phenyl)-piperazine (Example 9, Compound 97) as starting materials. Product as an oil. LC/MS (Method B) 2.36 min, [M+1]+439.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]1)([C:8]1C=CC=CC=1)C1C=CC=CC=1.[ClH:24]>CO.CC(OC)(C)C.[OH-].[OH-].[Pd+2]>[ClH:24].[CH2:22]([NH:21][C:16]1([C:18]([NH2:20])=[O:19])[CH2:15][CH2:8][CH2:1][NH:14][CH2:17]1)[CH3:23]
Reactant: CCNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: COC(C)(C)C
Product: CCNC1(C(N)=O)CCCNC1

Procedure:
To a suspension of 1-benzhydryl-3-ethylaminoazetidine-3-carboxylic acid amide (I-1A-3d; 36.1 g, 117 mmol) in methanol (560 ml) at room temperature was added concentrated aqueous HCl (19.5 ml, 234 mmol), resulting in a clear solution. To 20% Pd(OH)2 on carbon (3.75 g) was added methanol (85 ml), followed by the methanolic solution of I-1A-3d. The mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature for 20 hours. The reaction was then filtered through Celite® and then concentrated to low volume under reduced pressure, at which point a precipitate formed. The suspension was diluted with MTBE (500 ml), stirred for an additional hour, and the precipitate collected by vacuum filtration. The solid was washed with MTBE and then dried, in vacuo, to afford I-1A-3e (24.8 g, 98%) as a colorless solid.
Reaction SMILES: [C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(O)=[O:2].C(Cl)(=O)C([Cl:30])=O>C(Cl)Cl.CN(C)C=O>[Cl:30][C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:2]
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Under a nitrogen atmosphere at room temperature 1-[3-(carboxy)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.2 g, 3.2 mmol) was added in one portion to oxalyl chloride (5 ml) in methylene chloride (150 ml). After the material solubilized, one drop of N,N-dimethylformamide was added to initiate the reaction. Bubbling of the solution began and was visible for approximately fifteen minutes. The reaction mixture was stirred at room temperature for two hours. The reaction mixture was then concentrated under reduced pressure, reuslting in the formation of a white solid. The solid was triturated in 100 ml of hexanes, filtered and dried in a vacuum oven at 50° C. for one hours to yield the title product (1.3 g, 91%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH:14](O)[CH:13]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:12]2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][CH:13]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:12]2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(O)C2CCCCC21
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCC2CCCCC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepin-2-one (2.1 g), dicyclohexylcarbodiimide (1.8 g) and cuprous chloride (0.2 g) is heated at 80° under nitrogen for 32 hours. The reaction mixture is cooled to room temperature, the residue is dissolved in methylene chloride (200 ml), washed with dilute ammonium hydroxide (2×50 ml) and water (50 ml). The organic phase is dried over sodium sulfate and evaporated to give a mixture of the desired adduct and excess dicyclohexylcarbodiimide. This mixture is dissolved in ethyl acetate (100 ml) and placed in a pressure bottle. 10% Pd/C (0.4 g) is added and the mixture hydrogenated at 3 atmospheres pressure and 40° for 16 hours. The catalyst is filtered off and the filtrate is evaporated to give 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepin-2-one, used without further purification for the next synthetic step.
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[C:20]([CH2:21]O)=[CH:19][C:18]([Cl:23])=[CH:17][N:16]=2)[C:6]1=[O:24])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:32])=O.[Na+].[Cl-]>ClCCl>[C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[C:20]([CH2:21][Cl:32])=[CH:19][C:18]([Cl:23])=[CH:17][N:16]=2)[C:6]1=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)N1C(=O)C(Cc2ncc(Cl)cc2CO)c2cccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(Cc2ncc(Cl)cc2CCl)c2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of 5 (5.8 g, 16.8 mmol) in dichloromethane (30 mL) was added DMF (60 μL) and thionyl chloride (2.2 g) at 5° C. The mixture was stirred for 30 min at this temperature followed by addition of 5% aqueous NaCl (30 mL). The organic layer was separated and washed with 5% aqueous NaCl (30 mL). The solvent was removed and the residue was dissolved in heptane (20 mL). The solution was stirred for 10 min and the product was precipitated. The suspension was cooled to 0° C. and filtered to give 6 (5.8 g, 93%) as a solid: 1H NMR (CDCl3, 400 MHz): δ 8.36 (d, J=2.3 Hz, 1H), 8.13 (dd, J=5.1, 1.4 Hz, 1H), 7.65 (d, J=2.3 Hz, 1H), 7.19 (om, 1H), 6.78 (dd, J=7.3, 5.2 Hz, 1H), 4.58 (m, 2H), 4.06 (m, 1H), 3.66 (dd, J=16.3, 4.6 Hz, 1H), 3.32 (dd, J=16.3, 7.5 Hz, 1H), 1.75 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 178.06, 159.45, 154.58, 147.39, 145.73, 136.87, 132.47, 130.42, 130.11, 123.77, 117.03, 58.51, 43.37, 42.25, 33.69, 28.82.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@@H:14]([OH:15])[CH2:13][C@H:12]([O:16][C@H:17]3[C@@H:22]([OH:23])[CH2:21][C@H:20]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)[O:19][C@@H:18]3[CH3:52])[O:11][C@@H:10]2[CH3:53])[CH2:5][C@H:4]([OH:54])[C@@H:3]1[OH:55].[CH2:56](O)C>>[CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@@H:14]([OH:15])[CH2:13][C@H:12]([O:16][C@H:17]3[C@@H:22]([OH:23])[CH2:21][C@H:20]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)[O:19][C@@H:18]3[CH3:52])[O:11][C@@H:10]2[CH3:53])[CH2:5][C@H:4]([OH:54])[C@@H:3]1[O:55][CH3:56]
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Reactant: CCO
Product: CO[C@H]1[C@@H](O)C[C@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)O[C@@H]1C

Procedure:
4.75 l. of eluate with 40% ethanol contain 3.91 g. of solid material. The mixture contains all non-reacted digoxin, α-metildigoxin and β-metildigoxin and can again be separated on the column. The following fraction of 5 l. contains 4.73 g. of slightly contaminated β-metildigoxin. If the ethanol content is increased, diethers and higher ethers of digoxin are eluted. The main fraction with metildigoxin is reprecipitated from methanol/water, boiled up with chloroform and stirred up with acetone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[O:44][N:43]=[C:42]([CH3:45])[CH:41]=2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[O:44][N:43]=[C:42]([CH3:45])[CH:41]=2)[CH:35]=1)=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J35) (360 mg, 1.04 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (312 mg, 1.04 mmol) according to the general procedure M. Obtained as a light red foam (270 mg, 45%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH2:38][C:39]1([CH2:44][OH:45])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:38][C:39]3([CH2:44][OH:45])[CH2:43][CH2:42][CH2:41][CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: NC1(CO)CCCC1
Product: O=C(Nc1ccc(Oc2ccnc(NC3(CO)CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and (1-amino-cyclopentyl)-methanol according to conditions described in general procedure C.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([OH:13])[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([N:17]=[C:18]=[O:19])[CH2:15][CH3:16].C(N(CC)CC)C>O1CCOCC1>[CH2:1]([C:8]1[N:12]([C:18](=[O:19])[NH:17][CH2:14][CH2:15][CH3:16])[C:11](=[O:13])[O:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN=C=O
Reactant: Oc1nc(Cc2ccccc2)no1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCNC(=O)n1c(Cc2ccccc2)noc1=O
Temperature: 0 °C

Procedure:
8.8 parts of 3-benzyl-5-hydroxy-1,2,4-oxadiazole is stirred for 1 hour at room temperature with 4.3 parts of n-propyl isocyanate and 2 parts of triethylamine in 50 parts of dioxane. The reaction mixture is then poured into ice water, and the precipitated solid is suction filtered and recrystallized from alcohol. There is obtained 8.5 parts (65% of theory) of the desired product; m.p.: 74° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:33])[C:14]2[O:20][C:19]3[C:21]([Cl:29])=[CH:22][C:23]([NH:25][CH2:26][CH2:27]Cl)=[CH:24][C:18]=3[CH2:17][S:16](=[O:31])(=[O:30])[C:15]=2[CH:32]=1)=[O:10]>CN(C=O)C>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:33])[C:14]2[O:20][C:19]3[C:21]([Cl:29])=[CH:22][C:23]([NH:25][CH2:26][CH2:27][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:30])(=[O:31])[C:15]=2[CH:32]=1)=[O:10]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCCC3)cc(Cl)c1O2

Procedure:
Piperidine (0.184 g, 2.16 mmol) was added with stirring to a solution of Example 56k. (0.6 g, 1.4 mmol) in DMF (1 mL) in an inert atmosphere and heated at 90° C. for 4 h. The reaction mixture was concentrated, treated with water, and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.330 g, (48%); 1H NMR (CDCl3): δ 1.18 (bs, 2H, CH2), 1.32 (t, 4H, 2CH2), 2.21 (s, 3H, CH3), 2.3 (t, 2H, CH2), 2.4 (t, 2H, CH2), 2.8 (m, 4H, 2CH2), 3.41 (s, 3H, OCH3), 4.28 (s, 2H, CH2), 5.39 (bs, 1H, NH), 6.15 (s, 2H, Ar), 7.6 (s, 1H, Ar), 7.82 (s, 1H, Ar); MS: m/e (ES+) 478 (M+1).
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[Cl:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:15].[Cl:15][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:14][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(Oc2ccccc2)c(Cl)c1
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(Oc4ccccc4)c(Cl)c3)c2cc1OC
Yield: 56 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to reflux for 16 hours, 4-amino-2-chlorophenyl phenyl ether was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-(3-chloro-4-phenoxyanilino)-6,7-dimethoxyquinazoline hydrochloride salt in 56% Yield, m.p. 260°-265° C.;
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[F:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]([CH3:34])[C:31](=[O:35])[N:30]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[C:37]=1[CH3:51])[C:29]2=[O:52].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.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>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([N:30]2[C:29](=[O:52])[C:28]4[C:33](=[C:24]([F:23])[CH:25]=[CH:26][CH:27]=4)[N:32]([CH3:34])[C:31]2=[O:35])[C:37]=1[CH3:51])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)c2cccc(F)c2n(C)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(-c2c(Cl)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)c2cccc(F)c2n(C)c1=O
Temperature: 90 °C
Yield: 71.8 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (100 mg, 0.262 mmol), 8-fluoro-1-methyl-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 2] (161 mg, 0.393 mmol), tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) and 2 M aqueous K3PO4 (0.26 mL, 0.524 mmol) in THF (2 mL) in a pressure reaction vial was heated at 90° C. for 2.5 h. The cooled mixture was concentrated, and the residue was purified by column chromatography on silica gel (40 g), eluting with DCM-MeOH—NH4OH (gradient from 90:9:1-97:2.7:0.3). The resulting impure product was again purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 50-100%), to give 3-chloro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl) -7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (110 mg, 68% yield). Mass spectrum m/z 567 (M+H—H2O)+. 1H NMR (400 MHz, chloroform-d) δ 10.46 (s, 1H), 8.17-8.10 (m, 1H), 7.76 (s, 1H), 7.69 (d, J=1.1 Hz, 1H), 7.59-7.53 (m, 1H), 7.48 (ddt, J=13.9, 8.1, 1.8 Hz, 1H), 7.39 (dd, J=12.4, 7.8 Hz, 2H), 7.28-7.19 (m, 2H), 6.97 (t, J=8.5 Hz, 1H), 3.87-3.93 (m, 3H), 1.87 (d, J=1.8 Hz, 3H), 1.65 (s, 3H), 1.65 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:11])[N:7]([C:14](=[O:15])[N:13]([CH3:17])[CH3:12])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)Cl
Reactant: CSc1cc(C(C)(C)C)n[nH]1
Solvent: c1ccncc1
Product: CSc1cc(C(C)(C)C)nn1C(=O)N(C)C
Temperature: 115 °C
Yield: 58.8 %

Procedure:
A mixture of 3-t-butyl-5-methylthiopyrazole (6.0 g) and dimethylcarbamoyl chloride (4.3 g) in pyridine (40 ml) were refluxed (at 115° C.) for 16 hours. The pyridine was evaporated, and the residue poured into water and extracted with chloroform. The chloroform layer was washed with 2 N HCl (2×50 ml), then water (50 ml), dried and evaporated to give an oil which soon crystallised. Recrystallisation from 60°-80° petrol at 0° C. gave 5.0 g of 3-t-butyl-1-(dimethylcarbamoyl)-5-(methylthio)pyrazole (59% yield), melting point 56°-8°. Only a single isomer was shown to be present by nuclear magnetic resonance spectroscopy (NMR) and thin layer chromatography.
Reaction SMILES: CS[C:3]1[S:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17]>C(O)CCC>[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH:17][C:3]1[S:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CSC1=Nc2ccccc2CS1
Solvent: CCCCO
Product: Clc1ccc(NC2=Nc3ccccc3CS2)cc1Cl
Yield: 43.7 %

Procedure:
A mixture of 2-methylthio-4H-3,1-benzothiazine (39 g, 0.20 mole) and 3,4-dichloroaniline (32.4 g, 0.20 mole) in n-butanol (150 ml) was refluxed overnight. After cooling in ice, the solid was collected by filtration and recrystallized from ethanol to give 27 g (43.8%) of product. Recrystallization from ethanol gave analytical sample m.p. 207°-208°.