Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][C:18](Cl)=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:21])[O:5][N:4]=1)[CH3:2].O1CCCC1.[CH3:27][NH:28][CH3:29]>O>[CH3:27][N:28]([CH3:29])[C:18](=[O:19])[CH2:17][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:7]1[C:3]([CH2:1][CH3:2])=[N:4][O:5][C:6]=1[CH3:21]
Reactant: CNC
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1CC(=O)N(C)C
Temperature: 25 °C

Procedure:
A mixture of 11.2 g. (0.036 mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole acetyl chloride in 100 ml. of tetrahydrofuran is added to a vigorously stirred solution of dimethylamine in water (25 ml. 40% dimethylamine in water) at 0° to 10° C. The resulting mixture is allowed to warm to room temperature and poured into ether-water. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered and evaporated to give N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole acetamide; m.p. 176° to 178° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1([CH2:7][C@@H:8]([C:9]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:11])[CH2:12][C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(C[C@@H](CC1CCCCC1)C(=O)O)NCCNc1ccc(F)cc1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C[C@@H](CC1CCCCC1)C(=O)N1CCOCC1)NCCNc1ccc(F)cc1
Yield: 48.1 %

Procedure:
(R)-2-cyclohexylmethyl-N-[2-(4-fluoro-phenylamino)-ethyl]-succinamic acid (220 mg, 0.52 mmol) was treated with morpholine (110 μL, 1.26 mmol, 2.4 eq.) and HATU (238 mg, 0.72 mmol, 1.4 eq.). The reagents were dissolved in dry dichloromethane (4 mL) and treated with diisopropylethylamine (315 μL, 1.81 mmol, 3.5 eq.). The reaction was judged to completion by LC/MS, volatiles were evaporated and the reaction was purified by prep-LC/MS and provided 131 mg (0.25 mmol, 40%) of a off-white solid: HPLC-MS calcd. for C23H34FN3O3 (M+H+) 420.3, found 420.5.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1>CC1C=CC=CC=1>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:1][CH2:2][CH2:3][OH:4])=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=C(Cl)c1ccc(F)cc1[N+](=O)[O-]
Reactant: NCCO
Solvent: Cc1ccccc1
Product: O=C(NCCO)c1ccc(F)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a stirred and cooled mixture of 25 parts of 2-aminoethanol and 135 parts of methylbenzene is added dropwise a solution of 29 parts of 4-fluoro-2-nitrobenzoyl chloride in methylbenzene. Upon completion, stirring is continued for 30 minutes at room temperature. The precipitated product is filtered off, taken up in water and extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated, yielding 28 parts (64%) of 4-fluoro-N-(2-hydroxyethyl)-2-nitrobenzamide as a residue.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:2].[CH3:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH3:24])[CH2:20][CH2:21]1)[CH3:2]
Reactant: CCCBr
Reactant: CCOCCn1c(CN2CCNCC2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCN1CCN(Cc2nc3ccccc3n2CCOCC)CC1
Reaction time: 6.5 h
Yield: 87.3 %

Procedure:
A mixture of 1-(2-ethoxyethyl)-2-(1-piperazinyl)methylbenzimidazole (3.1 g) obtained in the same manner as described in Example 1, n-propyl bromide (2.0 g) and potassium carbonate (2.25 g) in ethanol (60 ml) is refluxed with stirring for 6.5 hours. The reaction mixture is treated in the same manner as described in Example 5 and the crude product is purified likewise to give 1-(2-ethoxyethyl)-2-(4-n-propyl-1-piperazinyl)methylbenzimidazole (3.1 g) as a pale brown liquid. This liquid is treated with fumaric acid (2.0 g), and the crude crystal thus obtained is recrystallized from ethanol to give 1-(2-ethoxyethyl)-2-4-n-propyl-1-piperazinyl)methylbenzimidazole 3/2 fumarate (3.9 g) as colorless needles, m.p. 178.5°-180° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][CH:10]([CH3:13])[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:9]([O:8][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1)[CH:10]([CH3:13])[CH3:11]
Reactant: Nc1cccc(O)c1
Reactant: CC(C)CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)COc1cccc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.4 %

Procedure:
To a mixture of 3-aminophenol (500 mg, 4.60 mmol), 2-methylpropan-1-ol (1.40 g, 18.9 mmol) and triphenylphosphine (4.80 g, 16.2 mmol) in THF (10 mL) was added dropwise diethylazodicarboxylate (3.20 g, 18.3 mmol) over a 30 min period. The mixture was stirred at room temperature for 3 h. The solvent was evaporated and the residue was diluted with water, acidified with aqueous 2N HCl and extracted with ether. The aqueous phase was basified with aqueous 2N NaOH and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. The resulting crude product was purified by silica gel column chromatograph (petroleum ether/EtOAc 15:1) to afford 3-isobutoxybenzenamine as yellow oil (330 mg, 45%).
Reaction SMILES: C([O:9][CH:10]1[CH2:23][CH2:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([Br:24])=[CH:17][CH:18]=3)[C:13](=[O:25])[C:12]=2[CH2:11]1)(=O)C1C=CC=CC=1.O1CCCC1.[OH-].[K+]>CO>[Br:24][C:16]1[CH:15]=[C:14]2[C:19]([O:20][C:21]3[CH2:22][CH2:23][CH:10]([OH:9])[CH2:11][C:12]=3[C:13]2=[O:25])=[CH:18][CH:17]=1
Reactant: O=C(OC1CCc2oc3ccc(Br)cc3c(=O)c2C1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=c1c2c(oc3ccc(Br)cc13)CCC(O)C2
Reaction time: 2 h
Yield: 80 %

Procedure:
45.0 g of 2-benzoyloxy-7-bromo-1,2,3,4-tetrahydro-9-oxo-xanthene obtained in Example 4 was suspended in a mixed solution of 240 ml of tetrahydrofuran and 90 ml of methanol. To the suspension was added dropwise at room temperature 45 ml of an aqueous solution containing 7.0 g of potassium hydroxide. After stirring the resulting solution for two hours, the solvent was removed by distillation. To the thus obtained crystals was added 300 ml of water, and the mixture was thoroughly agitated and filtered. The filtrate was recrystallized from ethanol to obtain 26.6 g (yield: 79.8%) of 7-bromo-2-hydroxy-1,2,3,4-tetrahydro-9-oxo-xanthene as light yellowish prism-like crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:17]=1)[CH2:7][CH2:8][C:9]1[C:10](/[C:15]/2=[C:19]2/[CH2:20][CH:10]([CH3:9])[NH:11][CH2:12][CH:18]/2[CH3:22])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: C1CCOC1
Reactant: O=C1c2ccc(Cl)cc2CCc2cccnc21
Product: CC1C/C(=C2\c3ccc(Cl)cc3CCc3cccnc32)C(C)CN1
Reaction time: 1 h
Yield: 53 %

Procedure:
To a cooled (ice-bath), stirred solution of 8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (6.3 g, 26 mmol) in THF (50 mL) was added the above Grignard reagent. The reaction was allowed to stir for 1 hr. at this temperature and then quenched with NH4Cl solution. The product was extracted 3× with EtOAc, washed once with brine, dried (Na2SO4), filtered and solvent removed to give a crude brown material which was chromatographed to give the title compound (5.1 g, 53% yield) as a yellowish glass.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9](=[O:16])[NH:8][C:7]=3[C:6]=2[CH:17]=1.CO[C:20]1([CH:27](OC)OC)[CH2:24][CH2:23][CH:22](OC)[O:21]1>C(O)(=O)C>[CH:22]([C:23]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]3[CH:14]=[CH:13][C:12]4[NH:11][C:10](=[O:15])[C:9](=[O:16])[NH:8][C:7]=4[C:6]=3[CH:17]=2)[CH:27]=[CH:20][CH:24]=1)=[O:21]
Reactant: COC1CCC(OC)(C(OC)OC)O1
Reactant: Nc1ccc2ccc3[nH]c(=O)c(=O)[nH]c3c2c1
Solvent: CC(=O)O
Product: O=Cc1cccn1-c1ccc2ccc3[nH]c(=O)c(=O)[nH]c3c2c1
Yield: 26.6 %

Procedure:
7.0 g (30.8 mmol) of 9-aminobenzo[f]quinoxaline-2,3(1H,4H)-dione and 6.4 g (30.8 mmol) of 2,5-dimethoxy-2-(1,1-dimethoxymethyl)tetrahydrofuran were refluxed in 170 ml of glacial acetic acid for 30 minutes. The precipitate was filtered off with suction and purified by chromatography on silica gel (mobile phase: toluene/acetone/glacial acetic acid=10/10/1). 2.5 g (27%) of the product were obtained. Melting point >250° C.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:20]([CH:17]3[CH2:19][CH2:18]3)=[O:21])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CC1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCC(NC(=O)C1CC1)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 80 mg (0.74 mmol) cyclopropylcarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:4])=[O:3].[CH2:19](I)[CH3:20]>>[CH2:19]([N:16]1[CH2:15][CH2:14][N:13]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[CH2:18][CH2:17]1)[CH3:20]
Reactant: COc1ccc(N2CCNCC2)cc1S(C)(=O)=O
Reactant: CCI
Product: CCN1CCN(c2ccc(OC)c(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine and Et-I, the title compound was recovered by the procedure described in Example 2: MS m/z (rel. intensity, 70 eV)) 298 (M+, 81), 283 (45), 84 (36), 57 (bp), 56 (41).
Reaction SMILES: C([O:4][CH2:5][CH:6]1[CH2:13][N:12]2[C:8](=[N:9][C:10]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:11]=32)[N:7]1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[N:7]1[C:8]2=[N:9][C:10]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:11]=3[N:12]2[CH2:13][CH:6]1[CH2:5][OH:4]
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(COC(C)=O)N3c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(CC)c1cccc2nc3n(c12)CC(CO)N3c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of [1-(2,4-dichlorophenyl)-5-(diethylamino)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-2-yl]methyl acetate (30.5 mg, 0.0682 mmol) in methanol (0.7 mL) was added potassium carbonate (9.4 mg, 0.0682 mmol) at room temperature. After 1 hr, the mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (24.1 mg, 0.0593 mmol, 87%). Analytically pure material was obtained by recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:25][O:26][C:27]([C:29]1([NH2:36])[CH2:34][CH:33]2[O:35][CH:30]1[CH2:31][CH2:32]2)=[O:28].[CH3:37][O:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][C:40]=1[O:48][CH2:49][CH2:50][C:51]1[CH:52]=[C:53]([CH3:57])[CH:54]=[CH:55][CH:56]=1>CN(C=O)C.CC(=O)OCC>[CH3:25][O:26][C:27]([C:29]1([NH:36][C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:39]([O:38][CH3:37])=[C:40]([O:48][CH2:49][CH2:50][C:51]3[CH:52]=[C:53]([CH3:57])[CH:54]=[CH:55][CH:56]=3)[CH:41]=2)[CH2:34][CH:33]2[O:35][CH:30]1[CH2:31][CH2:32]2)=[O:28]
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(C)c1
Reactant: COC(=O)C1(N)CC2CCC1O2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CC2CCC1O2
Yield: 100.1 %

Procedure:
550 mg of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 300 mg of 2-amino-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester and 410 mg of 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid (example 2) were stirred in 20 ml of anhydrous DMF for 15 h at room temperature. The mixture was diluted with 150 ml of EA and washed three times with 50 ml each of a saturated aqueous sodium carbonate solution and then three times with 50 ml each of a 10% aqueous sodium hydrogensulfate solution. The organic layer was dried with magnesium sulfate, evaporated to dryness and the residue purified by silica gel chromatography (HEP/EA gradient) to yield 630 mg of the title compound as a racemic mixture.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:15])[CH2:6]2)#[N:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][C@H:7]([NH:13][C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[CH2:8]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: N#Cc1ccc2c(c1)C[C@H](NC(=O)NC1CCCCC1)CN2
Product: N#Cc1ccc2c(c1)C[C@H](NC(=O)NC1CCCCC1)CN2Cc1cccc(Cl)c1

Procedure:
The title compound was prepared from (S)-1-[6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-3-cyclohexyl-urea, prepared as described in Example 42A, and 3-chlorobenzaldehyde by procedures analogous to those described in Example 3A. HPLC (method B): retention time=7.50 min. MS (ES): m/z 423 [M+H]+. Chiral HPLC 100% e.e.; retention time=12.2 min; Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in hexanes for 30 min at 1 mL/min.
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.C(N(CC)CC)C.[I-].[Na+].[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>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:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[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: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2nn(CCN3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 60 °C
Yield: 14.5 %

Procedure:
To 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) (0.200 g, 0.373 mmol), triethylamine (0.052 mL, 0.37 mmol), and sodium iodide (0.056 g, 0.37 mmol) in DMF (5 mL) was added morpholine (0.039 mL, 0.45 mmol). The reaction mixture was heated at 60° C. for 60 h. Morpholine (0.100 mL, 1.15 mmol) was added and the reaction mixture was heated at 80° C. for 30 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, washed with water (5 mL) and ether (10 mL), and dried in vacuo to afford a tan solid which was purified twice by silica gel chromatography (elution with 20% MeOH—CH2Cl2); the appropriate fractions were combined and concentrated to afford a beige solid which was triturated from ether and dried in vacuo to afford N2-{4-[4-amino-1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide as a white solid (0.048 g, 0.054 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.44 (1H, s), 8.26 (1H, s), 8.11 (1H, d, J=8.0 Hz), 7.70 (1H, d, J=7.6 Hz), 7.58 (1H, d, J=7.6 Hz), 7.29-7.35 (4H, m), 7.15 (1H, t, J=7.6 Hz), 4.48 (2H, t, J=6.4 Hz), 4.04 (3H, s), 3.96 (3H, s), 3.50-3.53 (4H, m), 2.82 (2H, t, J=6.2 Hz), and 2.47-2.51 (4H, m);); 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 10.02 min. MS: M+ 527.3.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[N:8]=[C:9](SC)[C:10]3[C:11](=[CH:13][S:14][CH:15]=3)[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].O.[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(=O)C>[N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[N:8]=[C:9]([N:31]3[CH2:32][CH2:33][N:28]([CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:29][CH2:30]3)[C:10]3[C:11](=[CH:13][S:14][CH:15]=3)[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CSC1=Nc2ccc([N+](=O)[O-])cc2Nc2cscc21
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)Nc1cscc1C(N1CCN(Cc3ccccc3)CC1)=N2

Procedure:
A solution of 6-nitro-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess N-benzylpiperazine and glacial acetic acid is heated at 140°-160° C. for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: CN(C)CCN(C)C.[Li]CCCC.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.CN([CH:25]=[O:26])C>C1CCCCC1>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([SH:21])=[C:19]([CH:20]=1)[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: Cc1ccc(S)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: Cc1ccc(S)c(C=O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
Tetramethylethylenediamine (TMEDA) (12.6 mL, 83.5 mmol) was added via syringe to n-BuLi (33 mL of 1.6 M in hexanes, 82.5 mmol) and the solution was chilled to 0° C. A solution of p-thiocresol (4.53 g, 36.5 mmol) in cyclohexane (40 mL) was added with stirring over 5 minutes. The resulting tan slurry was stirred overnight at room temperature, chilled to 0° C., and DMF (4.0 mL, 3.77 g, 51.6 mmol) was added via syringe over 2 minutes. The resulting gummy slurry was stirred at room temperature for 1.3 hours. The reaction mixture was added to 3 N HCR (150 mL). This mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo yielding a brown oil. This oil was purified by flash chromatography over silica gel, eluting with 10% ethyl acetate-hexanes to afford 5-methyl-2-mercaptobenzaldehyde (4.47 g, 69%) as an intensely yellow solid suitable for use without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:36][CH3:37])[C:20]([Cl:38])=[CH:19][N:18]=1>>[Cl:38][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][C:25]=2[O:36][CH3:37])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl

Procedure:
Title compound was prepared from 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 1221d. The product was isolated as a bright yellow solid (160 mg, 84%): MP 232-235, HPLC purity 95%, LCMS 524 (M+H), HMNR (CDCl3): 10.68 (s, 1H), 8.21 (s, 1H), 7.90 d, J=8.1 Hz, 1H), 7.82 (s, 1H), 7.49 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H) 6.99 (s, 1H), 6.61 (s, 1H), 6.52 (d, J=9.0 Hz, 1H), 3.94 (m, 7H), 3.30 (m, 4H), 2.41 (t, J=7.0 Hz, 2H), 2.12 (t, J=7.2 Hz, 2H), 1.42 (s, 6H).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:27][S:28]SC.CCCCCC>C1COCC1>[CH3:27][S:28][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CSSC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1(SC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.8 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (2.0 g, 7.75 mmol) in THF (100.0 mL) was cooled to −78° C. followed by drop wise addition of LDA (1.80 M in THF, 8.80 mL, 15.56 mmol) and the mixture stirred at the same temperature for 45 min followed by addition of dimethyl disulfide (2.21 mL, 23.25 mmol) at −78° C. The temperature of the reaction was slowly raised up to rt and left to stir for 6 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 5% EtOAc:hexane to obtain the product as an orange viscous liquid (1.90 g, 83% yield). MS: 304.19 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[N:6]=[CH:5]2.C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>O1CCCC1.CCCCCC>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([B:18]([OH:23])[OH:19])=[CH:10][CH:9]=2)[CH:5]=[N:6]1)[CH3:12]
Reactant: CCn1ncc2cc(Br)ccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCn1ncc2cc(B(O)O)ccc21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A solution of 5-bromo-1-ethyl-1H-indazole (598 mg, 2.67 mmol) in dry tetrahydrofuran (30 mL) was cooled below −60° C. Then a solution of butyllithium in hexane (2.5 ml, 2.5M) was added dropwise. It was warmed to −10° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of triisopropyl borate (1.5 g, 7.98 mmol). After warming to room temperature the mixture was quenched with hydrochloric acid (3N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3×80 ml). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuum to give 1-ethyl-1H-indazol-5-ylboronic acid (450 mg, 89%) which was used for the next step without further purification.