Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH2:14]O)=[C:11]([CH3:16])[CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.S(Cl)([Cl:28])=O>C(Cl)Cl>[Cl:28][CH2:14][C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:10][C:11]=1[CH3:16]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reaction time: 8 h

Procedure:
To a solution of 62.6 (63 mg, 0.23 mmol) in DCM (2.3 mL) were added triethylamine (32 μL, 0.23 mmol) and thionyl chloride (25 μL, 0.35 mmol) at room temperature. The mixture was stirred overnight and concentrated to afford 62.7. The crude product was used without further purification.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.[CH2:17](OCC)C.CO.Cl>S(Cl)(Cl)=O.[Li].[Cu]>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8](=[O:10])[CH3:17])=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: CCOCC
Agent: [Cu]
Agent: Cl
Agent: [Li]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CC(=O)Cc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Yield: 96 %

Procedure:
10.5 g of 4-biphenylylacetic acid was dissolved in 50 ml of thionyl chloride, and the solution was heated at 80° C. for 3 hours. Then, excess thionyl chloride was distilled off under reduced pressure. Benzene was added to the residue, and the solvent was again distilled off. This operation was repeated again. Then, the formed acid chloride was dissolved in 100 ml of ethyl ether. Separately, 23.7 g of cuprous iodide was suspended in 50 ml of ethyl ether, and 166 ml of a 1.5M methyllithiumethyl ether solution was added thereto with stirring under cooling with ice to obtain a uniform solution. This solution was dropwise added to the ethyl ether solution of the acid chloride obtained by the above reaction under a nitrogen atmosphere while stirring and cooling to -70° C. After completion of the dropwise addition, the mixture was stirred at the same temperature for further one hour. Then, methanol was added thereto to decompose the excess copper lithium reagent. Ethyl ether and 2N hydrochloric acid were added to the reaction solution. After removing the formed insoluble matters by filtration, the filtrate was subjected to liquid separation. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure to obtain 9.93 g (yield: 96%) of the above-identified compound as colorless oily substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH2:29])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:4][CH:3]1[CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34].ClC(Cl)(Cl)C[O:45][C:46](=O)[NH:47][C:48]1[N:49]([C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)[N:50]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:52]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:53]([C:51]1[CH:52]=[C:48]([NH:47][C:46]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH:3]([CH2:30][O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:4]5)=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:45])[N:49]([C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)[N:50]=1)([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)[Si](OCC1CN(Cc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CCN1C)(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CN5CCN(C)C(CO[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Yield: 51.1 %

Procedure:
A mixture of Intermediate 56e (87.0 mg, 0.15 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 66.8 mg, 0.17 mmol), DIPEA (39.2 μL, 0.23 mmol) and 1,4-dioxane (2.5 mL) were heated to 60° C. for 18 h. After cooling the solvent was evaporated in vacuo and the residue purified by FCC, using 0-10% MeOH in DCM, to provide the title compound as a pale yellow foam (64 mg, 51%). LCMS (Method 3): Rt 3.63 min, m/z 834 [M+].
Reaction SMILES: [N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([OH:45])=O)=[O:39])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[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][CH3:19].C(Cl)Cl.[NH2:49][CH2:50][C:51]([NH:53][CH2:54][C:55]([NH:57][CH2:58][C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])=[O:56])=[O:52].CC1C=CC(S(O)(=O)=O)=CC=1>CCN(CC)CC>[N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([NH:49][CH2:50][C:51]([NH:53][CH2:54][C:55]([NH:57][CH2:58][C:59]([O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:60])=[O:56])=[O:52])=[O:45])=[O:39])([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][CH3:19])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)O
Reactant: NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of (C18H37)2NCOCH2OCH2COOH (1.0 g, 1.5 mmol) in CH2Cl2 (30 mL) 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.31 g, 1.6 mmol) was added and the reaction was stirred at room temperature. After 0.5 h Gly-Gly-Gly-OCH2Ph.TsOH (0.66 g, 1.5 mmol) and Et3N (0.6 mL) were added and the mixture was stirred overnight. The reaction mixture was then washed with water (20 mL), 0.5 N HCl (20 mL), water (20 mL), 10% aqueous Na2CO3 (20 mL), brine (20 mL), and then dried over MgSO4. The solvent was evaporated and the residue was crystallized form MeOH to yield (C18H37)2NCOCH2OCH2CO-Gly-Gly-Gly-OCH2Ph as a deliquescent white solid (1.26 g, 89%), mp 41–42° C. 1H-NMR (300 MHz, δ, CDCl3) 0.86 (6H, t, J=6.9 Hz), 1.24 (64H, m), 1.49 (4H, bs), 3.04 (2H, t, J=7.5 Hz), 3.24 (2H, t, J=7.5 Hz), 3.95–4.05 (6H, m), 4.09 (2H, s), 4.29 (2H, s), 5.12 (2H, s), 7.23 (1H, t, J=6.0 Hz), 7.30–7.35 (5H, m), 7.93 (1H, t, J=5.7 Hz), 8.27 (1H, t, J=5.7 Hz). 13C-NMR (75 MHz, δ, CDCl3): 13.9, 22.5, 26.7, 26.9, 27.4, 28.6, 29.2, 29.3, 29.6, 31.8, 41.0, 42.9, 46.3, 46.7, 66.9, 69.6, 71.7, 128.2, 128.4, 128.6, 135.3, 168.6, 169.7, 169.8, 170.0, 171.5. IR (KBr, cm−1): 1749 (CO), 1651 (CO).
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:31][O:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:23])=[O:24])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(O)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1cc(S(=O)(=O)c2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Yield: 85.1 %

Procedure:
To a solution of the product of step A (470 mg, 1.06 mmol) in acetone (45 mL) under a nitrogen atmosphere was added potassium carbonate (1.34 g, 9.7 mmol) and dimethylsulfate (0.22 mL, 2.11 mmol). The reaction mixture was refluxed for 2 h, cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography (SiO2, 8:2, hexanes/ethyl acetate) to provide tert-butyl 6-methoxy-8-phenylsulfonyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (400 mg, 82%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.96-7.94 (m, 2H), 7.71 (br s, 1H), 7.58-7.48 (m, 3H), 7.33 (s, 1H), 4.55 (s, 2H), 4.04 (s, 3H), 3.82 (br s, 2H), 2.87 (br s, 2H), 1.50 (s, 9H).
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.CCOC([C@H:14]1[CH2:18][CH2:17][C@@H:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[N:15]1C(OC(C)(C)C)=O)=O.[Cl-].[NH4+].C([O:39][CH2:40][CH3:41])(=O)C>>[F:26][C:21]1[CH:20]=[C:19]([C@H:16]2[NH:15][C@@H:14]([C:40]([OH:39])([CH3:41])[CH3:5])[CH2:18][CH2:17]2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(O)[C@H]1CC[C@@H](c2ccc(F)c(F)c2)N1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere and under ice-cooling, methyl magnesium bromide (20.7 mL, 0.97 M tetrahydrofuran solution) was added dropwise into a tetrahydrofuran (60 mL) solution of (2R,5S)-5-(3,4-difluorophenyl)pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-ethyl ester (2.5 g). After stirring for 2 hours at the same temperature, ammonium chloride aqueous solution and ethyl acetate were added, and the organic layer was partitioned. The organic layer was washed with brine and dried with magnesium sulfate, and the solvent was removed under a vacuum. Ethyl acetate (7 mL) and 4 N hydrochloric acid/ethyl acetate (20 mL) were added to the residue, and stirring was continued for 1 hour at room temperature. The solvent was removed under a vacuum, and ethyl acetate and sodium bicarbonate aqueous solution were added, and the organic layer was partitioned. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum, and the title compound (1.66 g) was obtained. The physical property values are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.[C:13]([C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][C:24]2[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([NH:30][C:25]1[C:24]([NH:23][C:21](=[O:22])[C:20]2[CH:31]=[CH:32][C:17]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:18][CH:19]=2)=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:8]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: COc1cc(C(=O)O)ccc1C
Product: COc1cc(C(=O)Nc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)ccc1C
Yield: 28 %

Procedure:
Using the procedure described in Example 102, Part A, 3-methoxy-4-methylbenzoic acid (3.6 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (1.8 mmol) yielded 210 mg (28%) of the title compound. MS-FD m/e 416.3 (M+). Anal. for C26H28N2O3: Calc: C, 74.98; H, 6.78; N, 6.73; Found: C, 69.00; H, 6.30; N, 5.91.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[O:11]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:4]([NH:22][C:21]2[CH:20]=[CH:19][C:18]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:24][CH:23]=2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccnc1Cl
Reaction time: 48 h

Procedure:
2-Chloronicotinoyl chloride (9.15 g, 0.052 mol) was added to a stirred solution of 4-phenoxyaniline (10 g, 0.054 mol) and DIEA (10 ml, 0.057 mol) in CH2Cl2 (100 ml) at RT. The mixture was stirred for 48 h before removal of solvent under reduced pressure. The resulting residue was dissolved in EtOAc and washed several times with saturated NaHCO3 aqueous solution and brine, respectively. The organic layer was dried over Na2SO4 and evaporated to leave a solid. This material was re-crystallized from EtOAc/Hexane mixture, followed by filtration and rinsing with Et2O to give the desired compound as a white solid. MS m/z: 325 (M+1); 323 (M−1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:3]1>CCO.[Pd]>[CH3:1][NH:2][CH2:6][CH2:5][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3]
Reactant: CN1CCC(c2ccccc2)O1
Agent: [Pd]
Solvent: CCO
Product: CNCCC(O)c1ccccc1
Temperature: 45 °C

Procedure:
2-Methyl-5-phenylisoxazolidine (12.6 g, 77.3 mmol) in EtOH (134 g) is mixed with 5% Pd/C (1.2 g) in a glass pressure reactor. The reactor is warmed to 40-50° C. and the pressure is maintained at 40 psig with H2 until the pressure becomes constant (ca. 24 hours). The mixture is filtered through Celite and the solvent is removed to give N-methyl-3-phenyl-3-hydroxypropylamine.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1.[OH2:17].[C]=O.CN([CH:23]=[O:24])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:11][C:9]1[C:10]2[C:2]([C:23]([OH:24])=[O:17])=[CH:3][N:4]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O
Reactant: CN(C)C=O
Reactant: Clc1ncnc2c1c(I)cn2C1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Product: O=C(O)c1cn(C2CCCC2)c2ncnc(Cl)c12

Procedure:
Starting material (1B, 10 g, 29 mmole) was taken in 500 mL DMF and 100 mL H2O together with palladium acetate (0.32 g, 1.4 mmole). The reaction mixture was stirred in a pressure reactor at 50° C. under 100 psi carbon monoxide for 6.5 h and room temperature for 16 h. The reaction mixture was then concentrated and residue triturated with 100 mL of 1:1 EtOAc/Ch2Cl2 followed by 50 mL CH2Cl2, The solid was collected after filtration and dried over P2O5 to furnish 21 g of an off-white solid. This solid was then triturated with a mixture of formic acid/H2O (21 mL/5 mL). The solid collected after filtration and drying over P2O5 furnished 6.5 g of 1 C (m/z 265.1, retention time 2.5 min. with HPLC method 1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:16])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1cc(-c2ccc(F)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (43 mg, 78%), MS (ISP) m/z=295.4 [(M+H)+], mp 257° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 10) (52 mg, 0.186 mmol) and commercially available 4-fluoro-phenylboronic acid (33.9 mg, 0.24 mmol).
Reaction SMILES: [CH:1]1([C:7]2[N:16]=[C:15](O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:20])=O.CN(C)C1C=CC=CC=1>>[CH:1]1([C:7]2[N:16]=[C:15]([Cl:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1nc(C2CCCCC2)nc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1nc(C2CCCCC2)nc2ccccc12

Procedure:
2-Cyclohexyl-4-hydroxyquinazoline was treated with phosphorus oxychloride and N,N-dimethylaniline according to the procedure described in S. Lee et al., J. Med. Chem. 1995, 38(18), 3457, to give a nearly quantitative yield of 2-cyclohexyl-4-chloroquinazoline as a yellow solid, which was used immediately in the next step.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]([OH:15])=O)=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][C:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:13]([C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:5][C:6]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=4)=[N:7][C:8]=23)=[O:15])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])([CH3:41])[CH3:40]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Pale-yellow solid. MS (ISP) 574.5 [(M+H)+]; mp 228-230° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:30]3[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH:35]=O)=[N:28][CH:27]=[N:26][C:25]=3[O:24][C:23]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:18][CH:17]=1>C1COCC1.ClCCl.O>[CH3:1][O:2][C:3](=[O:4])/[CH:5]=[CH:35]/[CH2:34][CH2:33][CH2:32][NH:31][C:29]1[C:30]2[C:22]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[C:23]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[O:24][C:25]=2[N:26]=[CH:27][N:28]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCC=O)c23)cc1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/C=C/CCCNc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Reaction time: 1 h

Procedure:
Add 0.095 ml (0.588 mmol) trimethyl phosphonoacetate dropwise at RT to a suspension of 21.6 mg sodium hydride (60% dispersion in oil, approx. 0.539 mmol) in 2 ml THF. Stir the mixture for a further 1 h and then add 190 mg (0.49 mmol) 4-{[5-(4-methoxyphenyl)-6-phenylfuro-[2,3-d]pyrimidin-4-yl]amino}butanal. Stir overnight at RT and then dilute the mixture with dichloromethane and water. Wash the organic phase with saturated sodium chloride solution, dry, and concentrate under vacuum. The target compound is isolated from the raw product by preparative RP-HPLC (twice) (gradient: water/acetonitrile). 23.4 mg (10.8% of theor.) of the desired product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].[C:31](#[N:35])[CH2:32][CH2:33][CH3:34]>Cl[Cu].C(O)C>[NH:35]=[C:31]([N:21]1[CH2:20][CH2:19][C:18]([CH2:17][N:15]([CH3:16])[C:8]2[N:7]=[C:6]([NH2:30])[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)[CH2:32][CH2:33][CH3:34]
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Reactant: CCCC#N
Agent: Cl[Cu]
Solvent: CCO
Product: CCCC(=N)N1CCC(CN(C)c2nc(N)c3cc(OC)c(OC)cc3n2)(c2ccccc2)CC1
Temperature: 90 °C

Procedure:
To 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (129.8 mg) was added CuCl (31.8 mg), butyronitrile (84 μl), and ethanol (1.0 ml). The reaction mixture was heated in a 90° C. block for one day. Additional CuCl (31.8 mg) and butyronitrile (84 μl) were added and the reaction heated for an additional day. This was chromatographed on silica gel to provide N2-[1-(1-imino-butyl)-4-phenyl-piperidin-4-ylmethyl]-6,7-dimethoxy-N2-methyl-quinazoline-2,4-diamine 17 as indicated by 1HNMR and MS: 477 ([M+H]+). This material was further purified by preparative HPLC to afford the corresponding trifluoroacetic acid salt.
Reaction SMILES: [Al+3].[Cl-:2].[Cl-:3].[Cl-].Cl[C:6]1[CH:7]=[C:8]([CH3:13])[C:9]([CH3:12])=[CH:10][CH:11]=1.[C:14](Cl)(=[O:18])[C:15](Cl)=O>C(=S)=S>[Cl:2][C:11]1[CH:10]=[C:9]([CH3:12])[C:8]([CH3:13])=[CH:7][C:6]=1[C:14]([C:15]1[CH:10]=[C:9]([CH3:12])[C:8]([CH3:13])=[CH:7][C:6]=1[Cl:3])=[O:18]
Reactant: Cc1ccc(Cl)cc1C
Reactant: [Cl-]
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: S=C=S
Product: Cc1cc(Cl)c(C(=O)c2cc(C)c(C)cc2Cl)cc1C
Reaction time: 20 h
Yield: 67.9 %

Procedure:
146 g of AlCl3 are added to a solution of 140 g of 4-chloro-o-xylene and 68 g of oxalyl chloride in 500 ml of CS2 at 0°-5° C. in the course of 2 hours, with stirring. After 20 hours, the mixture is poured onto ice and extracted with 600 ml of CHCl3. The extract is washed with water, dried and evaporated completely. Recrystallisation of the residue from diisopropyl ether gives 103.8 g of 2,2'-dichloro-4,4',5,5'-tetramethylbenzophenone (D).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[CH:11](O)([CH3:13])[CH3:12].[CH3:15][C:16]1C=CC(S(O)(=O)=O)=C[CH:21]=1>C1C=CC=CC=1>[C:6]([C@@H:4]([C@H:2]([C:1]([O:10][CH:16]([CH3:21])[CH3:15])=[O:9])[OH:3])[OH:5])([O:8][CH:11]([CH3:13])[CH3:12])=[O:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)O
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: c1ccccc1
Product: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C

Procedure:
Diisopropyl (R,R)-tartrate was prepared according to the procedure described in J. Am. Chem. Soc., 1981, 6237. 400 g of (R,R)-tartaric acid, 400 mL of isopropanol and 5 g of p-TsOH were heated in refluxing benzene to afford, following distillation, 201 g (55%) of the above-titled compound: bp.=103-105° C. (2 torr) (lit. 152° C. (12 torr)).
Reaction SMILES: [CH:1](NN=NC1C=CC(C)=CC=1)([CH3:3])[CH3:2].[OH:14][C@@H:15]1[CH2:19][C:18](=[O:20])[C@H:17]([S:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][C:27]([OH:29])=[O:28])[C@H:16]1/[CH:30]=[CH:31]/[C@@H:32]([OH:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CC(C)=O>[CH:1]([O:28][C:27](=[O:29])[CH2:26][S:25][CH2:24][CH2:23][CH2:22][S:21][C@H:17]1[C:18](=[O:20])[CH2:19][C@@H:15]([OH:14])[C@@H:16]1/[CH:30]=[CH:31]/[C@@H:32]([OH:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N=NNC(C)C)cc1
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1SCCCSCC(=O)O
Solvent: CC(C)=O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1SCCCSCC(=O)OC(C)C
Reaction time: 1 h
Yield: 38 %

Procedure:
Isopropyl-p-tolyltriazene (200 μL) was added dropwise to a solution of carboxylic acid 9 (10.5 mg, 0.026 mmol) in acetone (5.0 mL) at 23° C. After stirring for 1 h the reaction was quenched with 1N HCl and the solvent was removed in vacuo. The residue was extracted with CH2Cl2 (2×). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 4:1 hex/EtOAc) gave 4.3 mg (38%) of the above titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C1(N[C:23](=O)[O-:24])C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[NH:33][CH2:32][CH2:31]2>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[C:37]([F:40])([F:38])[F:39])[N:33]([C:23](=[O:24])[NH:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][S:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:15][CH:14]=1)[CH2:32][CH2:31]2
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: O=C([O-])Nc1ccccc1
Reactant: Nc1ccc(CSc2ccncc2)cc1
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(CSc3ccncc3)cc1)CC2
Yield: 64 %

Procedure:
4-(Pyridin-4-ylthiomethyl)aniline (0.37 g, 1.71 mmol) was converted to the phenylcarbamate and treated with 5-methoxy-6-trifluoromethylindoline (D111) (0.37 g, 1.71 mmol) as in the method of Example 26 to give the title compound (0.5 g, 64%) as a white crystalline solid m.p. 174-5° C.