Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:12](/Cl)=[N:13]/[OH:14])=[C:6]2[C:10]=1[O:9][C:8]([CH3:11])=[N:7]2.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([C:25]([F:28])([F:27])[F:26])=[CH2:24])[CH:20]=[C:19]([Cl:29])[CH:18]=1.C(=O)([O-])O.[Na+]>CC(O)C>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[N:7][C:6]=2[C:5]([C:12]2[CH2:24][C:23]([C:21]3[CH:20]=[C:19]([Cl:29])[CH:18]=[C:17]([Cl:16])[CH:22]=3)([C:25]([F:26])([F:28])[F:27])[O:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc2c(/C(Cl)=N/O)ccc(Br)c2o1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nc2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc(Br)c2o1
Temperature: 65 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
To a solution of 7-bromo-N-hydroxy-2-methyl-benzo[d]oxazole-4-carbimidoyl chloride (Example 6.8) (3.63 g) in 2-propanol (100 ml) was added 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation described in, for example, EP 1,731,512) (3.43 g) and sodium hydrogen carbonate (1.44 g). The reaction mixture was stirred at 65° C. for 16 hours. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: 2-25% v/v ethyl acetate in heptane) to give 7-bromo-4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-2-methyl-benzo[d]oxazole (3.7 g). 1H-NMR (400 MHz, CDCl3): 7.71-7.42 (m, 5H), 4.50 (d, 1H), 4.06 (d, 1H), 2.73 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>O1CCCC1.O>[C:1]([O:5][C:6]([CH:8]1[CH:14]([C:15]([OH:17])=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)O)C2C(=O)OC(C)(C)C)cc1
Reaction time: 0.75 h

Procedure:
1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester (6 g, 12 mmol) is dissolved in a mixture of 120 ml Tetrahydrofuran and 78 ml Water. LiOH•H2O (1 g, 24 mmol) is added. After 45 min., more Water (15 ml) is added and the reaction solution is stirred at room temp. for 24 h. The solvent is evaporated and the remaining solid is resolved in Water/Diethylether. The water layer is acidified to pH 1. The organic phase is separated and the water phase is extracted twice with Ethylacetate. The combined organic fractions are dried with MgSO4 and filtered. The solvent is evaporated to afford the product: Cal. 412.5, found (M)+412.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]1[N:11]([CH3:19])[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]3[N:11]([CH3:19])[N:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:14]=3)[CH:5]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: COc1ccc(N)cc1-c1cc(C(F)(F)F)nn1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1cc(C(F)(F)F)nn1C
Yield: 87.5 %

Procedure:
4-Methoxy-3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-phenylamine (0.02 g, 0.08 mmol) was treated with 4-chlorophenyl isocyanate (0.01 g, 10.45 μL, 0.093 mmol, 1.2 equiv.) in CH2Cl2 (3.0 mL), in a similar manner as described in Example 1.102. The product was further purified via reverse phase C-18 HPLC to afford Compound 42 (0.03 g, 0.07 mmol, 88% yield) as a white solid: LCMS m/z (%)=425 (M+H37Cl, 100), 427 (M+H35Cl, 34). 1H NMR (400 MHz, MeOH-d4) δ: 7.50 (dd, J=10.0, 2.0 Hz, 1H), 7.42 (dd, J=8.0 Hz, 3H), 7.27 (dd, J=6.0, 2.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 3.84 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].O>CS(C)=O>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([N:24]2[CH2:25][CH2:26][N:21]([C:18](=[O:20])[CH3:19])[CH2:22][CH2:23]2)=[CH:14][C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccccc1
Reactant: CC(=O)N1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The compound (300 mg) prepared in Step 1 and N-acetylpiperazine (300 mg) were dissolved in dimethyl sulfoxide (3 mL), and stirred at 90° C. for 3 hours. The mixture was added with water, and extracted with ethyl acetate. The thus obtained organic layer was washed with saturated brine, the water was removed with sodium sulfate, and the solvent was removed by distillation under reduced pressure. Then, the compound was added with ethyl ether to form a solid, and the solid was filtered to obtain a target compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([N:15]=[C:16]=[O:17])[CH:13]=[CH2:14]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:16]([NH:15][CH2:12][CH:13]=[CH2:14])=[O:17])=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: C=CCN=C=O
Solvent: C1CCOC1
Product: C=CCNC(=O)NNC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 19.00 g (111.4 mmol) of 4-chlorobenzoic acid hydrazide are placed in 150 ml THF. 9.44 g (111.6 mmol) of allyl isocyanate, dissolved in 110 ml THF, are added dropwise at 50° C. and the mixture further stirred overnight at 50° C. The solvent is then evaporated in vacuo, diethyl ether is added to the residue and the solid formed is isolated and purified by filtration and further washing with diethyl ether. 26.80 g (95% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1]([CH:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[OH:20][C:21]1[CH:30]=[C:29](I)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>>[OH:20][C:21]1[CH:30]=[C:29]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[C:14]([CH3:15])=[CH:13][C:12]3[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=3[CH:6]=2)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CC(O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Product: COC(=O)c1ccc(C#CC(O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1O
Yield: 36.4 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.28 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenemethanol [prepared in Example 37(d)] with 1.5 g (5.5 mmol) of methyl 2-hydroxy-4-iodobenzoate, 739 mg (36%) of the expected compound, with a melting point of 112°-113° C., were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>C1COCC1.ClCCl>[CH2:27]([O:14][CH:13]1[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1OCc1ccccc1
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To a solution of benzyl rac-(3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate (600 mg, 1.8 mmol; prepared according to WO2004/050024A2) in THF (8 mL) cooled to 0° C. was added NaH (216 mg, 5.4 mmol [60%]) and the reaction mixture stirred for 1 hour. Benzyl bromide (430 μL, 3.57 mmol) was added and the reaction mixture was allowed to stir at room temperature overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an additional portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography to afford benzyl rac-(3R,4R)-3-(benzyloxy)-4-[(tert-butoxycarbonyl)amino]pyrrolidine-1-carboxylate (200 mg, 26%). To the product was added 4N HCl (in dioxane, 5 mL) and the mixture was stirred 2 hours. All volatiles were removed, and the salt was dissolved in DMF (5 mL), to which was added {[3-(trifluoromethyl)benzoyl]amino}acetic acid (174 mg, 0.705 mmol), HATU (268 mg, 0.705 mmol), diisopropylethylamine (246 μL, 1.41 mmol) and HOBt (95 mg, 0.705 mmol) and the mixture was allowed to stir overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography to afford benzyl rac-(3R,4R)-3-(benzyloxy)-4-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidine-1-carboxylate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[NH2:7][C@H:8]([CH3:11])[CH2:9][OH:10]>>[N:7]1([C@H:8]([CH3:11])[CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H](N)CO
Reactant: BrCCCCBr
Product: C[C@H](CO)N1CCCC1

Procedure:
The title compound was synthesized as described in Intermediate 9 using 1,4-dibromobutane and (R)-2-aminopropan-1-ol as starting materials. 1H NMR (CDCl3): δ 3.61 (m, 1H), 3.38 (m, 1H), 2.97 (br s, 1H), 2.72 (m, 1H), 2.60 (br s, 4H), 1.78 (br s, 4H), 1.06 (d, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1.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.COCCOC>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 80 °C
Yield: 80.9 %

Procedure:
Alternative preparation: [4-(Methylsulfonyl)phenyl]boronic acid (0.17 g, 0.84 mmol) and 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 81, Step 1, 0.25 g, 0.70 mmol) were mixed with DME (4 mL) and 2M Na2CO3 (4 mL). The mixture was degassed with N2, then PdCl2(PPh3)2 (50 mg, 0.07 mmol) was added. The reaction mixture was degassed again with N2 and heated at 80° C. for 6 h, then cooled to ambient temperature, and diluted with EtOAc. The mixture was washed with water and brine and the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown solid. The crude product was purified by chromatography on a silica gel column eluted with 25% EtOAc/CH2Cl2 followed by trituration with hexane containing 1% of MeOH to give 0.245 g (81%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[N:22]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][CH2:29][CH2:28][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: NCCN1CCNCC1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and 2-(piperazin-1-yl)ethanamine (32.3 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a light brown solid, 66.6 mg, (70% yield) MS (ES+): 379.2, (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[NH:53]1[CH:57]=[C:56]([C:58](O)=[O:59])[CH:55]=[N:54]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:58]([C:56]2[CH:57]=[N:53][NH:54][CH:55]=2)=[O:59])[CH2:25]1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)c1cn[nH]c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CN(C(=O)c2cn[nH]c2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 49 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 1H-pyrazole-4-carboxylic acid as the starting materials in 49% yield. LCMS for C26H25ClN9O2 (M+H)+: m/z=530.0.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)(=O)=O.[CH3:39][NH:40][CH3:41].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][CH2:6][N:40]([CH3:41])[CH3:39])[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:36])[C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=3)[C:11]=12
Reactant: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2nn(CCN(C)C)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 70 °C
Yield: 13.3 %

Procedure:
A mixture of 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate (Intermediate 4) (0.080 g, 0.15 mmol), dimethylamine (2.0 M in THF, 0.07 mL, 0.15 mmol), triethylamine (0.021 mL, 0.15 mmol), and sodium iodide (0.021 g, 0.15 mmol) in DMF (2.5 mL) was heated in a resealable tube at 70° C. for 15 h. Additional dimethylamine solution (0.10 mL) was added and the reaction mixture was heated at 70° C. for 20 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Water (5 mL) was added and the resulting precipitate was collected by filtration and purified by silica gel column chromatography (elution with 20% MeOH:CH2Cl2 to 10:30:60 Et3N:MeOH:CH2Cl2); the appropriate fractions were combined and concentrated to afford N2-(4-{4-amino-1-[2-(dimethylamino)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide as a white solid (0.009 g, 0.02 mmol). RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.52.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[C:15]([C:23]3[N:24]=[C:25]4[C:31]([C:32](O)=[O:33])=[CH:30][N:29]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:26]4=[N:27][CH:28]=3)=[N:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:43][C:44]([NH2:47])([CH3:46])[CH3:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C)C=O>[C:44]([NH:47][C:32]([C:31]1[C:25]2[C:26](=[N:27][CH:28]=[C:23]([C:15]3[C:16]4[C:21](=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[N:13]([CH2:12][CH:10]4[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]4)[N:14]=3)[N:24]=2)[N:29]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[CH:30]=1)=[O:33])([CH3:46])([CH3:45])[CH3:43]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CC(Cn2nc(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(C(=O)OC(C)(C)C)C4)c4cc(F)ccc34)nc12
Yield: 91.7 %

Procedure:
2-(1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-6-fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (150 mg, 251 μmol), 2-methylpropan-2-amine (18.4 mg, 251 μmol), HATU (105 mg, 277 μmol) and diisopropylamine (97.5 mg, 754 μmol) in dimethylformamide (12 mL) were stirred at room temperature for 15 h. The mixture was partitioned between ethyl acetate and water then the organic phase was washed with water then dried, filtered and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-6-fluoro-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (150 mg, 91.5%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1.S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:11][C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:13][C:6]=2[CH:7]=1)=[O:12]
Reactant: CO
Reactant: O=C(O)c1cc2cc(O)ccc2o1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2cc(O)ccc2o1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 5-hydroxy-benzofuran-2-carboxylic acid (4.6 g, 26.0 mmol) in MeOH (100 mL) was added concentrated sulfuric acid (1.2 g, 13.0 mmol) and the resultant solution was heated (reflux, 18 h). The reaction was cooled (rt) and concentrated in vacuo. The resultant residue was purified by silica gel flash column chromatography using MeOH:DCM (10%) to provide the title compound (4.14 g, 83%). MS (ESI): mass calcd for C10H8O4, 192.0; m/z found, 193.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.47 (s, 1H), 7.39 (d, J=9.0, 1H), 7.04 (d, J=2.5, 1H), 6.97 (dd, J=9.0, 2.5, 1H), 3.92 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([NH2:28])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C)C=O.O=[Mn]=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([NH2:28])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2N=C(N)CC2c2ccc(OCc3ccccc3)cc2)cc1
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(N)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
MnO2 (3.5 g) was added to a solution of 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-amine obtained by Example 14-1 (12.54 g). in N,N-dimethylformamide (65 ml) and the mixture was stirred at 60° C. for 2 hrs. MnO2 (5.3 g) was added and the mixture was stirred at 60° C. for 1 hr.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2>>[F:23][C:24]1[C:32]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCCC1
Yield: 50.3 %

Procedure:
Using a procedure identical to that described in Example 237, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (2 g, 6.22 mmol), (prepared as described for the starting material in Example 9), was reacted with 4-fluoro-5-hydroxy-2-methylindole (1.23 g, 7.46 mmol), (prepared as described for the starting material in Example 237), to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.41 g, 50%).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH:15]=[C:14]1[C:21](O)=[O:22].N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:21]([C:14]3[S:13][C:17]4[S:18][CH:19]=[CH:20][C:16]=4[CH:15]=3)=[O:22])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cc2ccsc2s1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccsc2s1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and thieno[2,3-b]thiophene-2-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.32 (d, J=5.4 Hz, 1H), 7.53-7.58 (m, 1H), 8.06 (s, 1H). MS (DCI/NH3) m/z 319. Anal. Calculated for C16H18N2OS2.HCl: C, 54.15; H, 5.40; N, 7.89. Found: C, 54.19; H, 5.25; N, 7.72.
Reaction SMILES: Cl.[C:2]([O:5][CH:6]([O:8][C:9](=[O:30])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20](=[O:29])[N:21]([CH3:28])[C:22](=[O:27])[N:23]([CH3:26])[C:24]=2[CH3:25])=[CH:15][CH:14]=1)[NH2:11])[CH3:7])(=[O:4])[CH3:3].[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34](Cl)=[O:35].C(N(C(C)C)CC)(C)C>ClCCl>[C:2]([O:5][CH:6]([O:8][C:9](=[O:30])[C@H:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:20](=[O:29])[N:21]([CH3:28])[C:22](=[O:27])[N:23]([CH3:26])[C:24]=2[CH3:25])=[CH:17][CH:18]=1)[NH:11][C:34]([C:33]1[C:32]([Cl:31])=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:41])=[O:35])[CH3:7])(=[O:4])[CH3:3]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CC(=O)OC(C)OC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
To a suspension of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester hydrochloride salt (0.723 mmol, 399 mg) and 2,6-dichlorobenzoyl chloride (0.8 mmol, 0.17 g) in dichloromethane (5 mL) was added diisopropylethylamine (3.2 mmol, 0.45 mL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 48 h at room temperature. The resulting light brown solution was diluted with dichloromethane (50 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×50 mL), saturated sodium bicarbonate solution (50 mL), and brine solution (50 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product, which was purified by silica gel chromatography using a Biotage (40s) column to afford 0.312 g (67% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester as a white solid: mp 168-170° C. ES-HRMS m/e calcd for C27H27Cl2N3O7 (M+Na) 598.1118, found 598.1122.