Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:20])[O:18][CH3:19]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:19][O:18][C:17]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)=[O:20]
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: COC(=O)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
From 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and methyl chlorocarbonate in a mixture of dioxan and toluene, 5,11-dihydro-11-methoxycarbonyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one was obtained, m.p. 266°-267° C. (D) (from 1,2-dichloroethane);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11].[N+:12]([C:15]1[CH:16]=[C:17]2[C:22](=O)O[C:19](=O)[C:18]2=[CH:24][CH:25]=1)([O-:14])=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[CH2:22][C:17]2[C:18](=[CH:24][CH:25]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[CH2:19]1
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)CN(CCc1ccc(Cl)cc1Cl)C2
Temperature: 150 °C
Reaction time: 2 h

Procedure:
2-(2,4-dichlorophenyl)ethanamine was suspended in toluene with 4-nitrophthalic anhydride (1 eq) and heated to 150° C. After 2 hours, the reaction was cooled and checked for completion by LC/MS. The solvent was then removed in vacuo and the resulting product was taken on to the next step without further purification. Rt 3.91 minutes, LC/MS m/z 365.1 (MH+).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30]([C:32]1([CH2:37][NH2:38])[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CO>[C:25]([O:29][C:30]([C:32]1([CH2:37][NH:38][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=3)=[O:4])[CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)C1(CN)CCCC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CO
Product: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CCCC1

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (200 mg) and 1-aminomethyl-cyclopentanecarboxylic acid tert-butyl ester (250 mg, commercially available from J & W PharmLab LLC, Levittown Pa.) in MeOH (3 mL) was heated at 100° C. in an oil bath for 24 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (164 mg). LC MS ESI+: 488 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:27]=[CH:26][C:23](C#N)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([F:12])[F:11].[F:35]C1C=CC(B(O)O)=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([F:11])([F:12])[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([F:35])=[CH:26][CH:27]=2)=[CH:17][N:18]=1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cc1
Reactant: OB(O)c1ccc(F)cc1
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Oc2ccc(F)cc2)cn1
Yield: 42.4 %

Procedure:
Compound 6 was prepared in a similar manner to compound 5 from (4-fluorophenyl)boronic acid to afford a solid 6 (0.1 g, 0.22 mmol, 42.4%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.20 (d, J=2.5 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.43-7.38 (m, 2H), 7.27 (d, J=2.5 Hz, 1H), 7.26-7.03 (m, 4H), 6.79-6.70 (m, 2H), 5.49 (d, J=14.5 Hz, 1H), 5.15 (d, J=14.5 Hz, 1H). MS (ESI): m/z 494.1 [M++1]. HPLC: 99.43%.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([NH:11][CH2:12][C:13]2[CH:14]=[C:15]([C:21]3[CH:22]=[CH:23][C:24]4[O:28][N:27]=[C:26]([NH:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]=4[CH:35]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:10][CH2:9]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH:8]1([N:11]([CH2:12][C:13]2[CH:14]=[C:15]([C:21]3[CH:22]=[CH:23][C:24]4[O:28][N:27]=[C:26]([NH:29][CH2:30][C:31]([CH3:32])([CH3:34])[CH3:33])[C:25]=4[CH:35]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[S:37]([CH3:36])(=[O:39])=[O:38])[CH2:9][CH2:10]1
Reactant: COc1ccc(-c2ccc3onc(NCC(C)(C)C)c3c2)cc1CNC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc3onc(NCC(C)(C)C)c3c2)cc1CN(C1CC1)S(C)(=O)=O
Temperature: -70 °C
Reaction time: 15 h
Yield: 69.5 %

Procedure:
Triethylamine (0.14 mL, 0.99 mmol, 1.5 equiv.) was added to a solution of 5-(3-((cyclopropylamino)methyl)-4-methoxyphenyl)-N-neopentylbenzo[d]isoxazol-3-amine (exemplary compound 45) (0.25 g, 0.66 mmol, 1 equiv.) in DCM (10 mL) and the mixture was subsequently cooled to −70° C. Methanesulphonic acid chloride (0.06 mL, 0.79 mmol, 1.2 equiv.) was added in drops and the mixture was heated slowly to RT and stirred for 15 hours. The reaction mixture was diluted with DCM (50 mL) and extracted with sat. aq. sodium hydrogen carbonate sol. (1×10 mL) and sat. aq. NaCl solution (1×10 mL), dried (MgSO4) and the solvent removed in a vacuum. After column-chromatographic purification (EtOAc/DCM; 1:1), the desired product (0.21 g, >99%) is obtained.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([NH2:11])=[S:10])(=[O:4])=[O:3].Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCO>[CH2:18]([O:17][C:15]([C:14]1[N:11]=[C:9]([CH2:8][CH2:7][CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[S:10][CH:13]=1)=[O:16])[CH3:19]
Reactant: CS(=O)(=O)NCCCC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(CCCNS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 89.3 %

Procedure:
A solution of 4-methanesulfonylamino-thiobutyramide (0.35 g, 1.8 mmol) and ethyl bromopyruvate (0.37 g, 1.9 mmol) in EtOH (50 mL) was stirred at room temperature for 17 h. Additional ethyl bromopyruvate (0.05 g, 0.26 mmol) was added and the reaction mixture was stirred at room temperature for 5.5 h. The reaction mixture was concentrated and was purified by flash chromatography (79:1 to 19:1 EtOAc:MeOH) to afford the title compound (0.47 g). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 4.40 (q, 2H), 3.24 (t, 2H), 3.17 (t, 2H), 2.96 (s, 3H), 2.10 (t, 2H), 1.39 (t, 3H); MS 293 (M+30 1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]#[C:7][C:8]([OH:10])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][C:31]([C:37]#[N:38])=[C:30]2[NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Br:46])[CH:41]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:46][C:42]1[CH:41]=[C:40]([NH:39][C:30]2[C:29]3[C:34](=[CH:35][CH:36]=[C:27]([NH:26][C:8](=[O:10])[C:7]#[C:6][CH2:5][O:4][CH2:3][O:2][CH3:1])[CH:28]=3)[N:33]=[CH:32][C:31]=2[C:37]#[N:38])[CH:45]=[CH:44][CH:43]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: COCOCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCOCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
To a solution of 0.51 g (3.54 mmol) of 4-(methoxymethoxy)-but-2-ynoic acid and 0.46 g (3.4 mmol) of isobutyl chloroformate in 12 ml of tetrahydrofuran was added at 0° C. with stirring 0.36 g (3.54 mmol) of N-methylmorpholine. After 15 min, 1.0 g (2.95 mmol) of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile was added. After stirring 3 hr at room temperature, the mixture was poured into a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was dries over magnesium sulfate. The solvent was remove and the residue was purified by chromatography on silica gel eluting with chloroform-ethyl acetate mixtures to give 0.66 g of 4-methoxymethoxy-but-2-ynoic acid[4-(3-bromophenylamino)-3-cyano-quinolin-6-yl]-amide as a yellow powder: ma of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile: mass spectrum (electrospray, m/e,): M+H 465.1, 467.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[OH:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35]([O:42][C:43]1[CH:47]=[C:46]([CH2:48]OS(C)(=O)=O)[O:45][N:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC#N.CC#N.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:48][C:46]1[O:45][N:44]=[C:43]([O:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:47]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(Cl)ccc1O
Reactant: CS(=O)(=O)OCc1cc(OCc2ccccc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(Cl)ccc1OCc1cc(OCc2ccccc2)no1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-1-(5-chloro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (159 mg, 0.4 mmol, 1 eq.) in MeCN (0.8 mL), potassium carbonate (166 mg, 1.2 mmol, 3 eq.) and methanesulfonic acid 3-benzyloxy-isoxazol-5-ylmethyl ester (113 mg, 0.4 mmol, 1 eq.) were added. The reaction mixture was stirred at 80° C. for 18 hours. The mixture was diluted with MeCN/H2O 1:1 (1 mL) and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give (±)-1-[2-(3-benzyloxy-isoxazol-5-ylmethoxy)-5-chloro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23]2[C:28]([C:29]3[O:30][C:31](=[CH2:34])[CH2:32][N:33]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[F:35])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:18]([CH3:19])[C:17](=[O:20])[O:16][CH2:15][CH2:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1.Cl.O1CCOCC1>C(#N)C>[Cl:1][C:2]1[C:3]([NH:22][C:23]2[C:28]([C:29]3[O:30][C:31]([CH3:34])=[CH:32][N:33]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[F:35])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:18]([CH3:19])[C:17](=[O:20])[O:16][CH2:15][CH2:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1
Reactant: C=C1CN=C(c2cccc(F)c2Nc2nc(Nc3ccc4c(c3)CCOC(=O)N4C)ncc2Cl)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1cnc(-c2cccc(F)c2Nc2nc(Nc3ccc4c(c3)CCOC(=O)N4C)ncc2Cl)o1
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a solution of 2-{5-chloro-4-[2-fluoro-6-(5-methylene-4,5-dihydro-oxazol-2-yl)-phenylamino]-pyrimidin-2-ylamino}-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (80 mg) in acetonitrile (10 mL) was added 4N HCl/dioxane (0.3 mL). The mixture was stirred for 16 hours, concentrated, and triturated with ethyl ether to provide 66 mg of 2-{5-chloro-4-[2-fluoro-6-(5-methyl-oxazol-2-yl)-phenylamino]-pyrimidin-2-ylamino}-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one as an HCl salt: 1H NMR (300 MHz, CD3OD) δ 8.22 (s, 1H), 7.94 (d, 1H), 7.58 (dd, 1H), 7.42 (t, 1H), 7.22-7.10 (m, 3H), 7.95 (s, 1H), 4.40 (t, 2H), 3.35 (s, 3H), 2.85 (t, 2H), 2.40 (s, 3H); MS (m/e) 495 (M+1).
Reaction SMILES: [Br-:1].[OH:2][CH:3]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][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][CH3:33])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N+:10]([CH3:13])([CH3:12])[CH3:11].C1(C)C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>>[Br-:1].[C:41]([O:2][CH:3]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][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][CH3:33])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N+:10]([CH3:11])([CH3:13])[CH3:12])(=[O:43])[CH3:42]
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COCCCC[N+](C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCC[N+](C)(C)C)OC(C)=O

Procedure:
A solution of 580 mg of 4-[2-hydroxy-3-(octadecyloxy)-propoxy]-N,N,N-trimethyl-1-butanaminium bromide in 5 ml of acetic anhydride is stirred at reflux under inert gas for 15 minutes. Toluene is added and the solvents evaporated followed by several additional toluene evaporations. The residue is stirred with ether and stored at 0° C. for several days. The resulting solid is collected and dried to give 480 mg of the desired product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[Br:19]Br>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:19][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]=1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: BrBr
Reactant: N#Cc1ccc(Cc2cc3ccccc3o2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(Cc2oc3ccccc3c2Br)cc1
Temperature: 2 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1.2 g (5 mmol) of 4-(benzofuran-2-yl)methyl-benzonitrile in 25 ml methylene chloride, a solution of 0.8 g (5 mmol) of bromine in 5 ml carbon tetrachloride is added dropwise at 2° C. The solution is stirred for 90 minutes at 2° C., the precipitate formed is suction filtered, washed with a little methylene chloride and dried.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17](=O)[NH:18][C:19]1[CH:20]=[C:21]2[C:37](=[O:38])[NH:36][N:35]=[CH:34][C:23]3=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:25][C:26]([CH:27]=1)=[C:22]23)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[NH2:7][C@@H:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:17][N-:18][C:19]1[CH:20]=[C:21]2[C:37](=[O:38])[NH:36][N:35]=[CH:34][C:23]3=[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:25][C:26]([CH:27]=1)=[C:22]23
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCc1ccccc1)C[N-]c1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 84 %

Procedure:
Preparation of example 54 from the title compound of Example 53 (30 mg, 0.056 mmol) and 45% TFA in CH2Cl2 (1 mL) was carried out analogously to Example 20. Isolation, also in an analogous manner, afforded the title compound (26 mg, 0.047 mmol) as a yellow powder in 84% yield.
Reaction SMILES: [NH4+].[Cl-].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[C:23]([N+:25]([O-])=O)[C:22]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:21][C:20]=3[O:35][CH3:36])[N:13]=2)=[CH:4]1>O.C(O)C.[Fe]>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[C:23]([NH2:25])[C:22]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:21][C:20]=3[O:35][CH3:36])[N:13]=2)=[CH:4]1
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 105 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A solution of NH4Cl (0.021 g, 0.38 mmol) in water (3 mL) was added in one portion to a stirred suspension of 4-(1H-indol-3-yl)-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]pyrimidin-2-amine (Intermediate 67, 0.235 g, 0.51 mmol) and iron (0.171 g, 3.07 mmol) in ethanol (9 mL) and the mixture was stirred at 105° C. for 18 h. The mixture was then concentrated in vacuo and the resulting residue was dissolved in DMF (20 mL). Purification by ion exchange chromatography, using an SCX column, eluting with 0.35M methanolic ammonia in CH2Cl2 and concentration of the appropriate fractions gave the title compound (0.206 g, 94%) as a yellow solid; m/z: ES+ MH+ 430.51.
Reaction SMILES: [CH:1]([NH:4][C:5]([NH2:7])=[S:6])([CH3:3])[CH3:2].Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH:1]([NH:4][C:5]1[S:6][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:7]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1csc(NC(C)C)n1

Procedure:
The reaction described in Preparation 42 was repeated, but using 3.7 g of isopropylthiourea, 7.4 g of ethyl bromopyruvate and 50 ml of ethanol, giving the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:20]Br>C(Cl)Cl.C(O)(=O)C>[Br:20][C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: BrBr
Reactant: Fc1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1

Procedure:
A solution of 2,3-bis(4-fluorophenyl)thiophene (272 mg, 1 mmole) in 3 ml methylene chloride was diluted with 3 ml glacial acetic acid and cooled to 10°. A solution of 0.5 M bromine in acetic acid (1.1 ml) was added. After 21/2 hours an additional portion of bromine in acetic acid (1.1 ml) was added. After a total rection time of 51/2 hours, the reaction mixture was concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[CH:18]=[C:17]2[C:5]([C:6](=[O:20])[C:7]3[N:16]2[C:15](=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=3)=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CN1C(=O)CCC1>C(Cl)(Cl)Cl>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:18]=[C:17]3[C:5]([C:6](=[O:20])[C:7]4[N:16]3[C:15](=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=4)=[CH:4][CH:3]=2)[CH2:24][CH2:23]1
Reactant: O=C1c2ccc(Cl)cc2-n2c1nc1ccccc1c2=O
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc3c(c2)-n2c(nc4ccccc4c2=O)C3=O)CC1
Yield: 53 %

Procedure:
9-Chloroindolo[2,1-b]quinazoline-6,12-dione (Example 31, 155 mg, 0.55 mmol), N-methylpiperazine (75 μL, 0.68 mmol) and 3 mL of NMP were stirred at at 70° C. for 1 h. Chloroform (50 mL) was added and the mixture was washed with water (3×100 mL), dried (Na2SO4), filtered and solvent removed in vacuo to give the crude product. Silica gel chromatography purification of the residue using (95:5) chloroform:methanol as eluent gave 101 mg (53%) of the title compound: mp 214° C. (dec); 1H NMR(CDCl3) δ 2.40 (s, 3H), 2.55-2.65 (m, 4H), 3.60-3.70 (m, 4H), 6.68-6.74 (dd, 1H), 760-7.70 (t, 1H), 7.73-7.80 (m, 1H), 7.80-7.86 (m, 1H), 7.99-8.05 (d, 1H), 8.10-8.14(d, 1H), 8.36-8.42 (d, 1H); MS (M+H)+ 347.2.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[O:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.Cl>C(OCC)(=O)C>[CH3:8][NH:9][C:10]([N:27]1[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:14]2[C:15]([Cl:23])=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=2[Cl:12])=[N:26]1)=[O:11]
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.1 %

Procedure:
Triethylamine (0.40 g, 4.0 mmol) and methyl isocyanate (0.25 g, 4.4 mmol) were added to a solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (1.24 g, 4.0 mmol) in ethyl acetate (20 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.87 g, yield: 59.0%). mp: 113-114° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.60 (d, J=0.7 Hz, 3H), 2.88 (d, J=4.9 Hz, 3H), 5.77 (d, J=0.7 Hz, 1H), 6.50-6.75 (m, 1H), 7.66 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][CH2:9][C@H:10]1[CH2:15][N:14]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([C:30]3[C:31]4[N:32]([CH:49]=[CH:50][N:51]=4)[CH:33]=[C:34]([Sn](CCCC)(CCCC)CCCC)[N:35]=3)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][CH:17]=2)[CH2:13][CH2:12][O:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:52]([O:56][C:57]([N:59]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C:60]1[CH:65]=[N:64][CH:63]=[C:62](Br)[N:61]=1)=[O:58])([CH3:55])([CH3:54])[CH3:53]>>[C:52]([O:56][C:57]([N:59]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C:60]1[N:61]=[C:62]([C:34]2[N:35]=[C:30]([N:22]([C:19]3[CH:20]=[CH:21][C:16]([N:14]4[CH2:13][CH2:12][O:11][C@@H:10]([CH2:9][O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15]4)=[CH:17][CH:18]=3)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:31]3[N:32]([CH:49]=[CH:50][N:51]=3)[CH:33]=2)[CH:63]=[N:64][CH:65]=1)=[O:58])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2ccnc2c(N(C(=O)OC(C)(C)C)c2ccc(N3CCO[C@@H](COC(=O)OC(C)(C)C)C3)cc2)n1
Product: CC(C)(C)OC(=O)OC[C@H]1CN(c2ccc(N(C(=O)OC(C)(C)C)c3nc(-c4cncc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n4)cn4ccnc34)cc2)CCO1

Procedure:
(R)-tert-Butyl (4-(2-(((tert-butoxycarbonyl)oxy)methyl)morpholino)phenyl)(6-(tributylstannyl)imidazo[1,2-a]pyrazin-8-yl)carbamate XIX was reacted with 2-Bis(tert-butoxycarbonyl)amino-6-bromopyrazine XIV according to the analogous method of CHEMISTRY A as described in Example 2 to provide the desired compound (R)-tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl)(4-(2-(((tert-butoxycarbonyl)oxy)methyl)morpholino)phenyl)carbamate XX.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:35]=[CH:34][C:25]4[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=4[CH:23]=3)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Temperature: 25 °C

Procedure:
Combined 3-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (100 mg, 0.3015 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (75 mg, 0.367 mmol), 4 N HCl in dioxane (76 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 1.5 hours. Let reaction cool to room temperature and evaporated off solvent. Purified with normal phase and reverse phase chromatography to yield a white solid, 3-Chloro-2-[5-chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide. LCMS: m/z=499.59 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.11 (m, 2H), 7.98 (s, 1H), 7.60 (d, 1H, J=8.1 Hz), 7.52 (d, 1H, J=7.6 Hz), 7.43 (m, 2H), 7.21 (s, 1H), 6.70 (d, 1H, J=8.6 Hz), 6.10 (m, 1H), 4.70 (s, 1H), 2.82 (d, 3H, J=4.8 Hz), 2.35 (m, 2H), 2.06 (m, 2H), 1.32 (s, 6H).