Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[O:21][C:22]([CH2:25][N:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:29])[N:3]=1.B([C:33]1[CH:44]=[CH:43][C:36]([CH2:37][C@@H:38]([C:40]([OH:42])=[O:41])[NH2:39])=[CH:35][CH:34]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:39][C@@H:38]([CH2:37][C:36]1[CH:43]=[CH:44][C:33]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[O:21][C:22]([CH2:25][N:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:29])[N:3]=2)=[CH:34][CH:35]=1)[C:40]([OH:42])=[O:41]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: CN(C)Cc1ccc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN(C)Cc1ccc(-c2ccccc2C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)o1
Temperature: 150 °C
Yield: 33.1 %

Procedure:
In a microwave vial, 4-chloro-6-{1-[2-(5-dimethylaminomethyl-furan-2-yl)-phenyl]2,2,2-trifluoro-ethoxy}-pyrimidin-2-ylamine (37 mg, 0.087 mmol), 4-borono-L-phenylalanine (22 mg, 0.10 mmol), 1 ml of actonitrile and 0.7 ml of water were mixed. Then, 0.3 ml of 1N aqueous sodium carbonate was added, followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 16 mg of (S)-2-amino-3-[4-{2-amino-6-{1-[2-(5-dimethylaminomethyl-furan-2-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl]-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 7.88(d, J=8.4 Hz, 2H), 7.71(d, J=7.6 Hz, 1H), 7.62(d, J=7.6 Hz, 1H), 7.42(m, 2H), 7.40(d, J=1.6 Hz,2H), 7.34(d, J=8.4 Hz, 1H), 6.89(q, J=3.6 Hz,2H), 6.66(s, 1H), 4.54(s, 2H), 4.20(q, J=6 Hz, 1H), 3.3(m, 1H), 3.14(m, 1H), 2.84(s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].N#N>O.O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:31]3[CH2:33][CH2:32]3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: OB(O)C1CC1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1cc2c(cn1)c(C1CC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.8 %

Procedure:
To a flask were added 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (3a, 2 g, 3.83 mmol), cyclopropylboronic acid (0.560 g, 6.52 mmol)), potassium carbonate (1.3 g, 9.6 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (0.157 g, 0.192 mmol), dioxane (10 ml), and water (5 ml). The mixture was Vac/N2 purged 6 times and heated at 60° C. After 5 h, the reaction was treated further with cyclopropylboronic acid (0.560 g, 6.52 mmol)), potassium carbonate (1.3 g, 9.6 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (0.157 g, 0.192 mmol), then degassed, and then heated at 80° C. overnight. The mixture was diluted with DCM and water and then filtered through celite. The organic phase was separated and concentrated to afford a dark residue, which was purified on silica gel (40 g, 0-20% ethyl acetate/hexanes) to afford 6-chloro-3-cyclopropyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.4 g, 84% yield) as a white foam. MS ESI calc'd. for C28H22Cl1N3[M+1]+ 436, found 436.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].S(Cl)([Cl:14])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)c(Br)c1
Product: O=C(Cl)c1ccc(F)c(Br)c1
Reaction time: 2 h

Procedure:
2.17 g (9.41 mmol) 3-bromo-4-fluorobenzoic acid were mixed with 20 mL thionyl chloride and then boiled for 2 h. The reaction mixture was evaporated to dryness and coevaporated twice with toluene. The residue was reacted further as the crude product.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:26][C:27]#[CH:28])[C:14]2[C:19]([CH3:20])=[C:18]([CH3:21])[N:17]3[N:22]=[N:23][N:24]=[C:16]3[C:15]=2[N:25]=1)[CH3:9].[OH:29][N:30]=[C:31](Cl)[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.ClN1C(=O)CCC1=O>C1COCC1>[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:26][C:27]2[O:29][N:30]=[C:31]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[CH:28]=2)[C:14]2[C:19]([CH3:20])=[C:18]([CH3:21])[N:17]3[N:22]=[N:23][N:24]=[C:16]3[C:15]=2[N:25]=1)[CH3:9]
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#CCn1c(COCC)nc2c1c(C)c(C)n1nnnc21
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1Cc1cc(-c2cccnc2)no1

Procedure:
In the presence of triethylamine (0.50 mL, 3.4 mmol), 8-(ethoxymethyl)-5,6-dimethyl-7-prop-2-ynyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridine (0.442 g, 1.55 mmol) was reacted with N-hydroxypyridine-3-carboximidoyl chloride generated from 3-pyridinecarboxyaldehyde oxime (prepared as described in Part A of Example 5, 0.38 g, 3.11 mmol) and N-chlorosuccinimide (0.42 g, 3.11 mmol) in THF (5 mL) using the method described in Part B of Example 5. After purification by flash chromatography (silica gel, elution with 95:5 dichloromethane/methanol) and trituration in diethyl ether, the product 8-(ethoxymethyl)-5,6-dimethyl-7-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridine was obtained (0.171 g) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7](C)[C:6]=1[C:15](O)=[O:16].[CH3:22]COC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C(#N)C>[CH3:22][N:1]1[C:2]2[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=2[O:4][C:5]2[C:13]3[C:8]([NH:7][C:6]=2[C:15]1=[O:16])=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: Cn1c(C(=O)O)c(Oc2ccccc2N)c2ccccc21
Solvent: CC#N
Product: CN1C(=O)c2[nH]c3ccccc3c2Oc2ccccc21

Procedure:
In the same way as described in example 4, 3-[o-aminophenoxy]-1-methyl-indole-2-carboxylic acid was cyclized with EEDQ. Analytical material was obtained by recrystallization from acetonitrile, mp. 247°-8°.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH:31]=1)[CH2:27]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S(Cl)([Cl:57])=O.CN(C=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH:31]=1)[CH2:27][Cl:57])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
3,5-Di(docosyloxy)benzyl alcohol (500 mg, 0.66 mmol) was dissolved in chloroform (5 ml), thionyl chloride (71 μl, 0.99 mmol) and DMF (10 μl, 0.13 mmol) were added dropwise, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was precipitated with acetonitrile to give 3,5-di(docosyloxy)benzylchloride (505 mg, 0.65 mmol, 99%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][O:13][CH3:14])=[C:6]([N:8]([CH3:10])[CH3:9])[CH:7]=1.[Li]CCCC.[CH3:20][C:21]1[CH:28]=[C:27]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH:26]=[C:25]([CH3:40])[C:22]=1[CH:23]=[O:24]>C1COCC1>[CH3:9][N:8]([CH3:10])[C:6]1[CH:7]=[C:2]([CH:23]([C:22]2[C:25]([CH3:40])=[CH:26][C:27]([O:29][Si:30]([CH:31]([CH3:33])[CH3:32])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[CH:28][C:21]=2[CH3:20])[OH:24])[CH:3]=[CH:4][C:5]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: COCOc1ccc(Br)cc1N(C)C
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C(O)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1N(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a stirring solution of N-(5-bromo-2-methoxymethoxy-phenyl)dimethylamine (3.4 g, 13.07 mmol) in THF (80 mL) at −78° C. was added n-BuLi (5.22 mL, 2.5 M in hexanes). The mixture was stirred at −78° C. for 1 hr and a solution of 2,6-dimethyl-4-triisopropylsilanyloxy-benzaldehyde (3.6 g, 11.77 mmol) was added. The reaction mixture was stirred at −78° C. for 1 hr, allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was quenched with saturated NH4Cl and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (30:70) to afford (3-dimethylamino-4-methoxymethoxy-phenyl)-(2,6-dimethyl-4-triisopropylsilanyloxyphenyl)methanol as a yellow oil (4 g, 63%): 1H NMR (300 MHz, DMSO-d6): δ 6.89 (d, J=8.4 Hz, 1 H), 6.79 (s, 1 H), 6.61 (m, 1 H), 6.51 (s, 2 H), 6.01 (d, J=4.0 Hz, 1 H), 5.65 (d, J=4.0 Hz, 1 H), 5.14 (s, 2 H), 3.41 (s, 3 H), 2.64 (s, 6 H), 2.17 (s, 6 H), 1.24 (m, 3 H), 1.08 (d, J=7.2 Hz, 18 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=25% ethyl acetate in hexanes; Rf=0.27.
Reaction SMILES: [CH3:1][CH2:2]OCC.[CH3:6][C:7]1[CH:8]=[N:9][NH:10][CH:11]=1.[Li]CCCC.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C>[NH4+].[Cl-]>[CH2:1]([N:9]1[C:8]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[C:7]([CH3:6])[CH:11]=[N:10]1)[CH3:2]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CCOCC
Reactant: Cc1cn[nH]c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: CCn1ncc(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
At 0° C., to the above ether solution of 4-methylpyrazole was added n-BuLi (36.4 mL, 2.5 M in Hexane, 91 mmol) dropwise. The reaction solution was stirred for 1 hour at RT and then cooled to −78° C. [J. Heterocyclic Chem. 41, 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.49 g, 99 mmol). After 15 min at −78° C., the reaction was allowed to warm to 0° C. over 1 hour. The reaction was diluted with saturated NH4Cl solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford 1-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (16 g, 80% purity) as a syrup which was used without further purification: LC-MS (ES) m/z 155 (M+H)+ for [RB(OH)2].
Reaction SMILES: C([Li])CCC.C1CCCCC1.Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1.[CH2:20]([C@H:23]1[CH2:27][O:26][CH:25]([C:28]([F:31])([F:30])[F:29])[NH:24]1)[CH2:21][CH3:22]>CCOCC.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH:25]([NH:24][C@@H:23]([CH2:20][CH2:21][CH3:22])[CH2:27][OH:26])[C:28]([F:30])([F:29])[F:31])=[CH:14][CH:15]=1
Reactant: CCC[C@H]1COC(C(F)(F)F)N1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCCCC1
Product: CCC[C@@H](CO)NC(c1ccc(Br)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
Butyllithium (41 mL of a 2.0M cyclohexane solution) was added at −30° C. to a solution of 1,4-dibromobenzene (19.3 g, 81.89 mmol) in ether (250 mL) over 10 minutes. After 1 hour, a solution of (4S)-4-propyl-2-trifluoromethyloxazolidine (3.00 g, 16.38 mmol) was added in ether (50 mL) over 30 minutes via an addition funnel. After 90 minutes of stirring, water (100 mL) was added. The organic phase was washed with brine (100 mL), dried over MgSO4, filtered, and evaporated to dryness. The residue was purified on a plug of silica gel (10-30% ethyl acetate/hexane elution). An approximately 2:1 mixture of diastomers of (2S)-2-[1-(4-bromophenyl)-2,2,2-trifluoroethylamino]-pentan-1-ol at the CF3 residue was observed based on the norvaline methyl triplet at 0.98 ppm (1H NMR).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:16]1(O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-:23].[Na+]>O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:23])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Reactant: Oc1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(S(=O)(=O)Oc2ccccc2)cc1C(=O)O
Reaction time: 18 h
Yield: 65.7 %

Procedure:
To a rapidly stirred mixture of 2-methoxy-5-chlorosulfonylbenzoic acid (5.0 g, 20 mmol) and phenol (1.88 g, 20 mmol) in water (100 mL) was added dropwise a solution of sodium hydroxide (16 mL, 10%; 40 mmol) over 10 min. The mixture was stirred for 18 h, and then extracted with ether. The aqueous phase was acidified to pH 1 with cone. HCl and the white precipitate filtered off to give the title compound (4.05 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=O.S(Cl)([Cl:20])=O.[CH:22]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[ClH:20].[CH:22]([N:35]1[CH2:40][CH2:39][N:38]([C:7](=[O:9])[CH:6]=[CH:5][C:4]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([O:14][CH3:15])[C:3]=2[O:2][CH3:1])[CH2:37][CH2:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1OC
Reactant: O=S(Cl)Cl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)c(OC)c1OC
Product: Cl
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
In 10 ml of chloroform was suspended 2.5 g (10.5 millimoles) of 2,3,4-trimethoxycinnamic acid, and under ice cooling, 3.5 ml (about 48 millimoles) of thionyl chloride was added dropwise. The mixture was stirred for 30 minutes under ice cooling, and the excess of thionyl chloride and chloroform were distilled off under reduced pressure. The residue was diluted with 20 ml of methylene chloride, and added dropwise under ice cooling to 30 ml of a methylene chloride solution of 2.5 g (9.9 millimoles) of benzhydrylpiperazine and 2 g (19.8 millimoles) of triethylamine. The mixture was stirred for 30 minutes under ice cooling. A 10% aqueous solution of sodium bicarbonate was added, and the mixture was shaken. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting oily product was diluted with 20 ml of ethanol. One milliliter of concentrated hydrochloric acid was added, and then ether was added. The crystals that precipitated were collected by filtration. Recrystallization from ethanol gave 2.2 g (yield 43.7%)of 1-benzhydryl-4-(2,3,4-trimethoxycinnamoyl)piperazine hydrochloride as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17](Cl)[S:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].C([O-])([O-])=O.[K+].[K+].[C:29]1([SH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O.C(OC(=O)C)C>CC#N>[CH3:1][O:2][C:3](=[O:22])[C@H:4]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17]([S:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc2nc(Cl)sc2c1)C(C)C
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](NS(=O)(=O)c1ccc2nc(Sc3ccccc3)sc2c1)C(C)C

Procedure:
(2R)-3-methyl-2-[(2-chlorobenzthiazol-6-sulfonyl)amino]butanoic acid methylester (0.154 mg, 0.44 mmol) prepared in a similar manner as in Example 20 was dissolved in MeCN (3 mL) and added solid K2CO3 (0.1 mg, 1.6 equi.). Thiophenol (0.055 mL, 1.2 equi.) was also added and the reaction solution was refluxed for 3 hours. When starting material was disappeared, H2O/ethylacetate (5 mL/10 mL) was added for extraction of product. The extracted product in organic phase was washed with NaCl solution, dried over MgSO4 and distilled under reduced pressure. The extracted product was crystallized with n-hexane/ethylacetate (3/1) solution to prepare the titled compound, (2R)-3-methyl-2-[(2-phenylthiobenzthiazol-6-sulfonyl)amino]butanoic acid methylester (190 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.[F:50][C:51]1[CH:59]=[CH:58][CH:57]=[CH:56][C:52]=1[CH:53]([OH:55])[CH3:54]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:39](=[O:41])[O:55][CH:53]([C:52]1[CH:56]=[CH:57][CH:58]=[CH:59][C:51]=1[F:50])[CH3:54]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1ccccc1F
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4ccccc4F)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 48.2 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (83 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (134 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2fluoro-α-methylbenzyl alcohol (55 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (60 mg, yield 45%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[NH:40][CH:41]=[CH:42][C:35]=12)[NH2:29].Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([NH:29][C:28]2[CH:30]=[CH:31][C:32]([O:33][C:34]3[CH:39]=[CH:38][N:37]=[C:36]4[NH:40][CH:41]=[CH:42][C:35]=34)=[C:26]([F:25])[CH:27]=2)[N:3]=1
Reactant: Nc1nc(Cl)cc(C2CCCN(C(=O)OCc3ccccc3)C2)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(C2CCCN(C(=O)OCc3ccccc3)C2)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
1.05 g (2.89 mmol) of benzyl 3-(2-amino-6-chloropyrimidin-4-yl)piperidine-1-carboxylate (from example LXXII) and 0.75 g (2.89 mmol) of [3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amine (from example XIX) are suspended in 35 ml of water and 4 ml of ethanol. 0.29 ml (3.47 mmol) of 37% strength hydrochloric acid is added. The mixture is stirred at 100° C. for 18 hours. After cooling, the mixture is neutralized using a saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate (in each case 30 ml). The organic phase is dried over anhydrous magnesium sulfate and concentrated. The residue is purified on a silica gel column using dichloromethane/methanol 20:1. This gives 1.38 g (86% of theory) of product.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21]4CCN(C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:36])[CH:3]=1.F[C:38]1[CH:44]=C(C)C=C[C:39]=1N.[ClH:46].[CH:47](O)(C)C>>[ClH:46].[CH2:20]([O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([NH:6][C:5]3[CH:34]=[CH:35][C:2]([CH3:47])=[CH:3][C:4]=3[F:36])=[N:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[O:17][CH3:18])[C:21]1[CH:22]=[CH:23][CH:44]=[CH:38][CH:39]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(N)c(F)c1
Reactant: CC(C)O
Agent: Cl
Product: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCc1ccccc1
Yield: 91 %

Procedure:
Using an analogous procedure to that described in Example 6,7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.55 g, 5.15 mmol), (prepared, for example, as described in WO 97/22596, Example 1), was reacted with 2-fluoro-4-methylaniline (700 mg, 5.67 mmol) in isopropanol (90 ml) containing 6.2M hydrogen chloride in isopropanol (80 μl, 0.51 mmol) to give 7-benzyloxy-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline hydrochloride (2 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:23][CH:24]=1)=[O:6]
Reactant: CCOC(=O)c1ccc(N)cn1
Reactant: O=C(O)c1ccc(C(F)(F)C(F)(F)F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2F)cn1
Yield: 87.3 %

Procedure:
A solution of 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoic acid (80.48 mg, 0.31 mmol), ethyl 5-aminopyridine-2-carboxylate (57.0 mg, 0.34 mmol), HATU (130.4 mg, 0.34 mmol) and N-methylmorpholine (68.57 μL, 0.62 mmol) in DMF (1 mL) was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, washed with water, brine, dried over Na2SO4, filtered and evaporated to give ethyl 5-[[2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]pyridine-2-carboxylate (110 mg, 87%) as an orange waxy solid. ESI-MS m/z calc. 406.07, found 407.3 (M+1)+; Retention time: 1.64 minutes (3 minutes run).