Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CC(=O)OCC>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:22][CH2:21]1
Reactant: ClCc1nc2cccnc2s1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-(2-methoxyphenyl)piperazine (229 mg, 1.2 mmol), and D1 EA (380 μL, 2.2 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.74 (m, 4H) 3.02 (m, 4H) 3.78 (s, 3H) 4.04 (s, 2H) 6.91 (m, 3H) 7.56 (dd, J=8.31, 4.75 Hz, 2H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 341 (M+H)+.
Reaction SMILES: C1(C2C=CC(C[NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=CC=2)CC1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]([O:37][CH3:38])([CH3:36])[CH3:35])[CH:29]=O.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]([O:37][CH3:38])([CH3:36])[CH3:35])[CH2:29][NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:13]=1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Reactant: COC(C)(C)c1ccc(C=O)cc1Cl
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: COC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1Cl

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 77 mg of 3-chloro-4-(1-methoxy-1-methyl-ethyl)-benzaldehyde (0.36 mmol), 68 mg of 2-(3-trifluoromethylphenyl)-ethylamine (0.36 mmol) and 21 mg of sodium borohydride (0.54 mmol). The isolated colorless liquid (113 mg, 81%) was used in the following step without further purification. MS (ISP) 386.2 (M+H)+.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:34])[CH:21]([CH3:33])[C:22]([NH:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[O:23])[C:15]2[CH:35]=[CH:36][CH:37]=[CH:38][C:14]=2[C:13]2[CH:39]=[CH:40][CH:41]=[CH:42][C:12]1=2)C1C=CC=CC=1.Cl>CO.[Pd]>[OH:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:34])[CH:21]([CH3:33])[C:22]([NH:24][CH2:25][C:26]([F:31])([F:32])[C:27]([F:29])([F:30])[F:28])=[O:23])[C:15]2[CH:35]=[CH:36][CH:37]=[CH:38][C:14]=2[C:13]2[CH:39]=[CH:40][CH:41]=[CH:42][C:12]1=2
Reactant: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCO)c2ccccc2-c2ccccc21
Reaction time: 48 h

Procedure:
N—[(S)-5-(2-Benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-methyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide (113 mg, 0.19 mmol) were dissolved in methanol (20 ml) and treated with 37% aqueous HCl (0.1 ml) and palladium on carbon (10%, 6 mg) and stirred for 2 days under an atmosphere of hydrogen. After filtration and evaporation of the solvent, the title compound was obtained as white solid (94%). MS: m/e=450(M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.[Br:28]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:28][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[N:16]=[C:15]([C:4]3[CH:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=4)[N:5]=3)[O:19][N:18]=2)=[CH:21][CH:22]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(CO)cc4)no3)cc2C)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(CBr)cc4)no3)cc2C)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mechanically stirred solution of (4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}phenyl)methanol (Example 110, 1.50 g, 4.16 mmol) in dichloromethane (60 mL) was added tetrabromomethane (1.66 g, 5.00 mmol) and triphenyl-phosphane (1.64 g, 6.24 mmol). The mixture was stirred at rt for 5 h and then partly concentrated under reduced pressure. The solid formed was filtered off and dried under reduced pressure to yield the title compound. The filtrate was concentrated and purified by MPLC (silica, cyclohexane/ethyl acetate 9:1) to afford another batch of the title compound (combined 1.55 g, 88%): 1H-NMR (400 MHz, DMSO-d6) δ 8.07 (d, 2H), 7.66 (d, 2H), 7.17 (d, 2H), 7.12 (d, 2H), 6.90 (s, 1H), 5.42 (s, 2H), 4.70 (s, 2H), 2.32 (s, 3H). 2.28 (s, 3H); ES-MS m/z 423 (MH)+; HPLC RT (Method D) 3.05 min.
Reaction SMILES: C(Cl)(=O)C.CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:10][CH:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([OH:51])[CH:29]1[O:33][CH:32]([CH:34]2[CH2:38][CH2:37][CH:36]([CH:39]([OH:50])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[O:35]2)[CH2:31][CH2:30]1)[CH2:12][C:13]1[C:14](=[O:19])[O:15][CH:16]([CH3:18])[CH:17]=1)(C)C.C(=O)(O)[O-].[Na+]>CO.C(OCC)C>[OH:10][CH:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([OH:51])[CH:29]1[O:33][CH:32]([CH:34]2[CH2:38][CH2:37][CH:36]([CH:39]([OH:50])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[O:35]2)[CH2:31][CH2:30]1)[CH2:12][C:13]1[C:14](=[O:19])[O:15][CH:16]([CH3:18])[CH:17]=1
Reactant: CCCCCCCCCCC(O)C1CCC(C2CCC(C(O)CCCCCCCCC(CC3=CC(C)OC3=O)O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CC(=O)Cl
Product: CCCCCCCCCCC(O)C1CCC(C2CCC(C(O)CCCCCCCCC(O)CC3=CC(C)OC3=O)O2)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
To a solution of acetyl chloride (20 μL) in 400 μL of methanol, a solution of 16a (6.8 mg, 8.2 μmol) in 400 μL of diethyl ether was added at room temperature. The solution was stirred at room temperature until TLC showed that no more starting material was left (about 24 h) . Solid sodium bicarbonate was slowly added until no more gas evolution was observed. The mixture was concentrated under reduced pressure. Diethyl ether (5 mL) was added, and the resulting solution was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by MPLC (1:3 hexane:ethyl actate) give 1a (4.0 mg, 82%) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][C:11](OCC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)(C)NCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CCO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
To a solution of ethyl 3-benzylamino-3-methylbutyrate (7.35 g, 31.2 mmol) in THF (150 mL) was added LiAlH4 (2.40 g, 63.2 mmol) portionwise at 0° C. for 0.5 h, and the mixture was stirred at room temperature for 5 h. The mixture was cooled on iced-water bath, then dropped a little water. The mixture was diluted with ethyl acetate, then dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo. Flash chromatography (EtOAc:MeOH=5:1) of the residue gave 3-benzylamino-3-methyl-1-butanol as a pale yellow oil (3.91 g, 65%).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[F:28])=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:29][CH3:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:14]2[C:13]3[C:18](=[CH:19][C:10]([OH:9])=[C:11]([O:29][CH3:30])[CH:12]=3)[N:17]=[CH:16][CH:15]=2)=[C:22]([F:28])[CH:23]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1O
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A mixture of 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinoline hydrochloride (4.7 g, 11 mmol), (prepared as described in Example 41), in TFA (100 ml) was heated at reflux for 4 hours. The volatiles were removed by evaporation. Saturated aqueous sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The combined extracts were dried (MgSO4), and the solvent was removed by evaporation. The residue was dissolved in methanol, aqueous ammonia was added and the mixture was stirred for 1 hour. The volatiles were removed by evaporation and the residue was diluted with water. The precipitated product was collected by filtration, washed with water and dried to give 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinoline (3 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59]C(C)=O)[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[BH4-]>C(O)(=O)C>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:59])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: [BH4-]
Solvent: CC(=O)O
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C

Procedure:
In order to over come the drawbacks of the prior art processes, the applicants have developed a simple and practical process for production of taxols A, B, C; The process comprises (i) isolating the taxol analogues 7-xylosyl-10-deacetyl taxols A, B, C from the stem bark of Taxus wallichiana by an improved process developed by the applicants which involves extracting air, dried pulverized plant materials with alcohols at room temperature, evaporating the solvent to obtain a residue, stirring the resultant residue with water to a precipitate and isolating the taxol analogues 7-xylosyl-10-deacetyl taxol A, (taxol analogue A) 7-xylosyl-10-deacetyl taxol B (taxol analogue B) and 7-xylosyl-10-deacetyl taxol C (taxol analogue C) by flask chromatography over silica gel with yields 0.5% (for taxol analogue A), 0.2% (for taxol analogue B) and 0.0075% (for taxol analogue C), (ii) reacting the isolated taxol analogues A or B or C with periodates in a polar solvent at ambient temperature into dialdehyde (iii) reducing the resultant dialdehyde with borohydride in a polar solvent acetic acid mixture at 0°-40° C. into an acetal, (iv) degrading the acetal in a mixture of mineral acid and chlorinated solvent at 0°-40° C. to give the intermediate product 10-deacetyl taxol A or B or C, (v) protecting the 2', 7-hydroxyl groups of the intermediate 10-deacetyl taxol A or B or C with a suitable silane at 20°-40° C. for 20-40 hours, (vi) acetylating the free 10-hydroxyl group with an a cetylating agent at 10°-40° C. for 12-18 hours, (vii) deprotecting the silyl groups at 21, 7-positions in presence of mineral acid polar solvent mixture at 0°-10° C. to give the final product taxol A or B or C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:22][C:2]([F:1])([F:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:4]
Reactant: CS(=O)(=O)c1ccc(C(O)C(F)(F)F)c(-c2ccccc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)C(F)(F)F)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanol (720 mg, 2.2 mmol)) in CH2Cl2 (50 mL) was added Dess-Martin periodinane (1.1 g, 2.6 mmol). The reaction was stirred for 2 h at RT, then concentrated in vacuo and purified directly on normal phase silica gel to provide 2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanone as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([NH:13][CH3:14])=[N:4][CH:5]=[C:6]([S:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.C(CC(=O)C)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[NH3:28]>[Cu+2].C(CC(=O)C)(=O)C.O.CN1C(=O)CCC1>[CH3:14][NH:13][C:3]1[C:2]([NH2:28])=[CH:7][C:6]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1
Reactant: CNc1ncc(SC(F)(F)F)cc1Br
Reactant: N
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)CC(C)=O
Solvent: CN1CCCC1=O
Product: CNc1ncc(SC(F)(F)F)cc1N
Temperature: 110 °C
Reaction time: 8.5 h

Procedure:
1.96 g of (3-bromo-5-trifluoromethylsulfanylpyridin-2-yl)-methylamine, 89 mg of acetylacetone copper(II), 0.27 g of acetylacetone, 2.34 g of cesium carbonate, 7 ml of NMP and 5 ml of aqueous ammonia (28%) were charged to a pressure-resistant reactor and stirred at 110° C. for 8.5 hours. Water was added to the reaction mixture cooled to room temperature, and the insoluble matter was filtered with celite (registered trademark), and then the filtered matter was washed with ethyl acetate, and the filtrate was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 1.18 g of N2-methyl-5-trifluoromethylsulfanylpyridine-2,3-diamine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[C:3]=1I.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]#[CH:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(NC(C)C)(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:9][C:4]1[C:3]([C:25]#[C:24][CH:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)=[C:2]([Cl:1])[N:7]=[C:6]([CH3:8])[N:5]=1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1nc(N)c(I)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1nc(N)c(C#CC2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)n1
Temperature: 52.5 °C
Yield: 86.8 %

Procedure:
Dissolve 6-chloro-5-iodo-2-methyl-pyrimidin-4-amine (20 g, 74.22 mmol), 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (18.64 g, 89.06 mmol), and diisopropylamine (10.44 mL, 74.22 mmol) in THF (200 mL) in a 3-neck flask. Alternately evacuate and charge the flask with nitrogen 3 times. Add bis(triphenylphosphine)palladium(II) chloride (2.63 g, 3.71 mmol) and copper(I) iodide (0.713 g, 3.71 mmol) to the solution. Heat the mixture to between 50 to 55° C. for 16 h. Cool the mixture to RT and add more bis(triphenylphosphine)palladium(II) chloride (1.31 g, 1.86 mmol), copper(I) iodide (0.356 g, 1.86 mmol) and 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (1.55 g, 7.42 mmol). Heat the mixture to 60° C. for 3.5 h. Cool the mixture to RT and concentrate under reduced pressure. Dilute the material with DCM (300 mL) and wash with saturated aqueous ammonium chloride solution (100 mL), water (100 mL), and saturated aqueous sodium chloride (100 mL). Dry the solution over MgSO4, filter, and concentrate under reduced pressure. Purify the residue using silica gel chromatography (800 g silica gel column) eluting with 20% to 100% EtOAc in hexanes. Concentrate the purified fractions to give the title compound as a pale orange powder (22.6 g, 86%). LC-ES/MS m/z (35Cl/37Cl) 351.2/353.1 (M+1).
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])([O-:5])=[O:4].O>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[C:6]([N+:3]([O-:5])=[O:4])[CH:11]=1
Reactant: BrBr
Reactant: COc1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 87 %

Procedure:
Bromine, Br2 (16 ml, 311 mmol) was added in small portions to a solution of 2-nitroanisole (17.1 ml, 140 mmol) in glacial acetic acid (80 ml). The reaction mixture was then heated at 60° C. for one hour. The reaction was poured into 400 ml water, and extracted with 600 ml diethyl ether/600 ml saturated NaHSO3 (aqueous). The organic layer was washed with NaHSO3 solution, then with water, dried over sodium sulfate, and concentrated under vacuum. The residue was recrystallized from diethyl ether to give 28.4 g (87%) of 4-bromo-2-nitroanisole. 1H NMR (300 MHz, CDCl3) δ7.970 (1H, d, J=2.5 Hz), 7.64 (1H, dd, J=8.9, 2.4 Hz), 7.00 (1H, d, J=8.9 Hz), 3.96 (3H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([N:9]([CH2:22][CH3:23])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20][CH3:21])[CH2:14][CH2:13]1)=[O:11])[CH3:8].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([N:20]([CH3:21])[CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:10](=[O:11])[N:9]([CH2:22][CH3:23])[CH2:7][CH3:8])[CH2:13][CH2:14]1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: CCN(CC)C(=O)N1CCN(CCNC)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)N1CCN(CCN(C)C(=O)N(C)C)CC1
Temperature: 100 °C

Procedure:
5.4 g (0.05 mole) of dimethyl carbamic acid chloride dissolved in 20 cc. of toluene are added dropwise with stirring at room temperature to a solution of 12.1 g (0.05 mole) of 1-diethylcarbamoyl-4-(2-methylamino ethyl)-piperazine and 5.1 g (0.05 mole) of triethylamine in 40 cc. of toluene. Thereafter, the reaction mixture is stirred for another hour at about 100° C. The reaction mixture is cooled and the precipitated triethylamine hydrochloride is filtered off with suction and the filtrate is evaporated. The residue is dissolved in 150 cc. of ether, the ethereal solution is washed twice with 150 cc. of 5 n NaOH each time and the resulting solution is dried over anhydrous Na2SO4. Upon evaporation of the ether, 15.3 g (97.6% of the theoretical) of the oily crude urea are obtained.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][S:11][CH2:10]1)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C.C(OCC)C>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH:13]([C:14]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:16])[CH2:12][S:11][CH2:10]1)=[O:8]
Reactant: C1COCCN1
Reactant: O=C1CC[C@@H](C(=O)N2CSCC2C(=O)O)N1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1CC[C@@H](C(=O)N2CSCC2C(=O)N2CCOCC2)N1
Reaction time: 1 h
Yield: 69.4 %

Procedure:
4.84 g (0.02 moles) of 3-pyroglutamyl-thiazolidine-4-carboxylic acid are suspended in 20 ml of DMF and treated with 3.25 g (0.02 mole) of carbonyldiimidazole. After no more gas is developed, 1.72 g (0.02 moles) of morpholine dissolved in 10 ml of DMF is added thereto and shaken for 1 hour. After diluting with 2 volumes of ethyl ether, the solid is filtered and water recrystallized yielding 4.35 g (70%) of product. m.p. 187°-188° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[C:22]2[C:18](=[N:19][O:20][N:21]=2)[C:17]([S:23](Cl)(=[O:25])=[O:24])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[C:22]2=[N:21][O:20][N:19]=[C:18]2[C:17]([S:23]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:24])=[O:25])=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c2nonc12
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Cl)c3nonc23)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazole as described in the synthetic METHOD B to give a yellow solid (2.5 mg) with purity >90%. MS (pos) m/z 403.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23](Cl)[C:22]3[C:17](=[CH:18][C:19]([O:31][CH3:32])=[C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:38]=[CH:37]2>C(O)(C)C.NC1C=C2C(=CC=1)N(C(OC(C)(C)C)=O)N=C2>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:38]=[CH:37]4)[C:22]3[C:17](=[CH:18][C:19]([O:31][CH3:32])=[C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Reactant: COCCOc1cc2c(Cl)nc(-c3cccc(OCc4ccccc4)c3)nc2cc1OC
Solvent: CC(C)O
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(OCc4ccccc4)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 2-(3-(benzyloxy)phenyl)-4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline (1.55 g, 3.44 mmol) and tert-butyl 5-amino-1H-indazole-1-carboxylate (0.842 g, 3.61 mmol) in iso-propanol (100 mL) was heated at 95° C. for 2 h, upon which the an additional aliquot of tert-butyl 5-amino-1H-indazole-1-carboxylate (0.100 g, 0.43 mmol) was added. Stirring was continued at 95° C. for a further 3 h upon which a third aliquot of tert-butyl 5-amino-1H-indazole-1-carboxylate (0.050 g, 0.22 mmol) was added. Stirring was continued at 95° C. for a further 1 h upon which the mixture was allowed to cool to RT and the precipitate was collected via filtration. The solid was washed with iso-propanol and dried under vacuum to give tert-butyl 5-(2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (2.35 g, 3.44 mmol, 100%). MS 648 (M+1). HPLC retention time 7.79 mins.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[N:3]=1.[C:14]([N:18]=[C:19]=[S:20])([CH3:17])([CH3:16])[CH3:15].C([Li])CCC>C1COCC1.CCCCCC>[C:14]([NH:18][C:19](=[S:20])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[N:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N=C=S
Reactant: N#CCCCSc1cccc(N)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)NC(=S)Nc1cccc(SCCCC#N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
A solution of 4-(2-aminopyrid-6-ylthio)butyronitrile (0.39 g.) and t-butylisothiocyanate (0.25 g.) in THF (10 ml.) was stirred under an argon atmosphere while adding a solution of n-butyl lithium in hexane (1.55M; 2 ml.). The mixture was stirred at room temperature for three hours and then evaporated to dryness. The residue was partitioned between EtOAc and water and the EtOAc phase was dried and evaporated to dryness. The residue was recrystallised from EtOH to give 4-[2-(3-t-butylthioureido)pyrid-6-ylthio]butyronitrile (0.32 g.), m.p. 156°-157°.