Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([NH2:16])[CH2:15][CH2:14][CH:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30](Cl)=[O:31]>ClCCl>[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30]([NH:16][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:15][CH2:14][CH:13]2[N:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8]1)=[O:31]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Reactant: NC1(c2ccccc2)CCC2CCCN2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CCC2CCCN2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 55 mg (0.254 mmol) 6-phenyl-octahydro-indolizin-6-ylamine (example A.3) and 130 ul (0.762 mmol) N-ethyldiisopropylamine in dichloromethane (0.9 ml) was added drop-wise a solution of 63 mg (0.22 mmol) 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (example B.1) in dichloromethane (0.6 ml) at room temperature. The mixture was stirred at room temperature for 1 hour. The solution was washed once with a 2M sodium carbonate solution. The aqueous layer was extracted once with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified with flash column chromatography on silica eluting from n-heptane and ethyl acetate (0 to 50%) to provide 26 mg (y: 22%) of example 3 (2-methoxy-6-methylsulfanyl-N-(6-phenyl-octahydro-indolizin-6-yl)-4-trifluoromethyl-benzamide, diastereoisomer 1, first running compound) as a light yellow gum, MS (m/e): 465.2 (M+H+) and 49 mg (y: 41.5%) of example 4 (2-methoxy-6-methylsulfanyl-N-(6-phenyl-octahydro-indolizin-6-yl)-4-trifluoromethyl-benzamide, diastereoisomer 2, second running compound) as a white solid, MS (m/e): 465.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1([CH2:15][N:16]2[CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=[N:17]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[C:33]([Cl:38])[C:32]=1[CH:39]([O:41][C:42]1[C:43]([NH2:49])=[N:44][CH:45]=[C:46](I)[CH:47]=1)[CH3:40].C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:49][C:43]1[N:44]=[CH:45][C:46]([C:19]2[CH:18]=[N:17][N:16]([CH2:15][C:2]3([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:4][CH2:3]3)[CH:20]=2)=[CH:47][C:42]=1[O:41][CH:39]([C:32]1[C:33]([Cl:38])=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[Cl:30])[CH3:40]
Reactant: CC(Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1cc(-c2cnn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 85 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A reaction mixture of compound (3-4) (361 mg; 0.89 mmol) and 3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-iodopyridin-2-amine (3-5) (378 mg; 0.89 mmol) in 9.0 mL of ethylene glycol dimethylether, anhydrous (DME) was purged with N2 for 15 minutes, then Pd(II)(PPh3)2Cl2 (32 mg, 0.05 mmol) was added and continued to purge with N2 for another 15 minutes. Another 1.0 N Na2CO3 solution (3.9 mL; 3.9 mmol) was added after purging with N2 for 15 minutes. The resulting mixture was stirred at 85° C. under N2 for overnight. The reaction mixture was filtered through Celite pad and washed well with MeOH. The filtrate was concentrated by vacuum. The residue was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (2×50 mL); brine (50 mL). The organic layer was dried (Na2SO4), then concentrated by vacuum. The residue was purified by Dionex system (25% to 95% MeCN:H2O w 0.1% HOAc buffer) to collect the desired fraction to afford 147 mg of (3-6) as a white solid (28% yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.34-1.39 (m, 9H) 1.70-1.77 (m, 2H) 1.79 (d, J=6.57 Hz, 3H) 3.06 (d, J=12.63 Hz, 2H) 3.62 (s, 2H) 4.03 (s, 2H) 4.79 (s, 1H) 5.66 (s, 2H) 6.08 (d, J=6.82 Hz, 1H) 6.86 (d, J=1.52 Hz, 1H) 7.44 (t, J=8.72 Hz, 1H) 7.51-7.58 (m, 2H) 7.58-7.65 (m, 2H) 7.73 (d, J=1.52 Hz, 1H) 7.78 (s, 1H). LCMS calcd for C27H32Cl2FN5O4 (M+H) 581, found 581. HPLC purity 87%.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH:12]=[CH:11][N:10]=1>>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:9]1[N:14]=[C:13]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Reactant: OCCCF
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2cc(-c3ccnc(OCCCF)n3)sc2c1
Yield: 65.4 %

Procedure:
2-[2-(3-Fluoropropoxy)pyrimidine-4-yl]-6-methoxybenzothiophene (1-32, 75 mg, 65%) was prepared in the same manner as in Example 31 as a pale yellow solid using 3-fluoro-1-propanol (40 mL, 0.54 mmol), sodium hydride (NaH, 22 mg, 0.54 mmol) and 2-(2-chloropyrimidine-4-yl)-6-methoxybenzothiophene (105a, 100 mg, 0.36 mmol) obtained in Preparation Example 19.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.CCN=C=NCCCN(C)C.[C:30]1([C:36]2[O:37][C:38]([C:49]([F:52])([F:51])[F:50])=[C:39]([C:41]([NH:43][CH2:44][CH2:45][C:46](O)=[O:47])=[O:42])[N:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>ClCCl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:46](=[O:47])[CH2:45][CH2:44][NH:43][C:41]([C:39]3[N:40]=[C:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:37][C:38]=3[C:49]([F:51])([F:52])[F:50])=[O:42])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: O=C(O)CCNC(=O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Reaction time: 24 h

Procedure:
Trans-[4-(4-aminophenyl)cyclohexyl]acetic acid methyl ester (150 mg, 0.6 mmol), EDCI (290.7 mg, 1.5 mmol), 3-[(2-phenyl-5-trifluoromethyloxazole-4-carbonyl)amino]propionic acid (228.9 mg, 0.7 mmol), HOBt (123 mg, 0.91 mmol) and ethyldiisopropylamine (275 mg, 0.21 mmol) dissolved in dichloromethane (15 mL) were stirred for 24 hours. The reaction mixture was diluted with aqueous NaHCO3 and extracted with dichloromethane. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the desired compound (330 mg, 98%) as a white solid.
Reaction SMILES: N[C:2]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3].C([OH:20])C>[OH-].[Na+]>[C:2]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([OH:20])=[O:3]
Reactant: CCO
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Reaction time: 24 h

Procedure:
A mixture of 4-aminocarbonylphenoxy phenyl methane (10g) in ethanol (100ml) and sodium hydroxide (100ml., 10N) was heated under reflux with vigorous stirring for 24hrs. The reaction mixture was cooled, the precipitated sodium salt was filtered off washed with a little water then converted to 4-carboxyphenoxy phenyl methane by boiling under reflux with concentrated hydrochloric acid (100ml) for 6hr. Dilution of the cooled mixture and extraction with ether yielded 4-carboxyphenoxy phenyl methane, m.p. 188°.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>C(O)C>[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([N:20]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: CC(C)c1ccc(N)cc1
Solvent: CCO
Product: CC(C)c1ccc(N2CCC(C(=O)O)C2=O)cc1
Yield: 5 %

Procedure:
A mixture of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g; 2.94 mmol) and 4-isopropylaniline (1.21 mL; 8.82 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. The mixture was concentrated under reduced pressure and the residue was dissolved in a solution of sodium hydroxide 6N, washed with dichloromethane, acidified with a solution of hydrochloric acid 6N to pH=2, extracted with ethyl acetate dried and concentrated under reduced pressure to yield 0.036 g (5%) of a pale green solid which was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][C:14]#[CH:15])=[O:12])=[CH:7][C:6]=1[N+:16]([O-])=O)(=[O:3])[CH3:2].CO>[Fe].O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][C:14]#[CH:15])=[O:12])=[CH:7][C:6]=1[NH2:16])(=[O:3])[CH3:2]
Reactant: C#CCS(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CO
Product: C#CCS(=O)c1ccc(NC(C)=O)c(N)c1

Procedure:
2 G. of 1-acetamido-2-nitro-4-propargylsulfinylbenzene is treated in a refluxing mixture of 160 ml. methanol and 40 ml. water with 4 g. iron powder (added in two portions) and 1 g. ferrous sulfate for four hours. The mixture is filtered, and the filtrated concentrated. The residue is dissolved in chloroform and washed with water, then the solvent evaporated affording 1-acetamido-2-amino-4-propargylsulfinylbenzene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([O:8][C:9]1[CH:14]=[C:13]([C:15](=[O:23])[NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:12]=[C:11]([O:24][CH3:25])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:43][CH2:44][CH3:45])[C:37]=1[N:38]1[CH:42]=[CH:41][CH:40]=[CH:39]1)[CH:33]=O)[CH3:28].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]([O:8][C:9]1[CH:10]=[C:11]([O:24][CH3:25])[CH:12]=[C:13]([C:15](=[O:23])[NH:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:33][C:32]3[CH:35]=[C:36]([O:43][CH2:44][CH3:45])[C:37]([N:38]4[CH:42]=[CH:41][CH:40]=[CH:39]4)=[C:30]([O:29][CH2:27][CH3:28])[CH:31]=3)[CH2:21][CH2:22]2)[CH:14]=1)([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)NC2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)NC2CCN(Cc3cc(OCC)c(-n4cccc4)c(OCC)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 2-[3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-2-methyl-propionic acid ethyl ester [example 66b)] was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound yellow oil. MS: 608.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)O1>>[OH:29][C:26]1[CH:27]=[CH:28][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COC(=O)C1(c2ccc(Br)cc2)CC1
Product: COC(=O)C1(c2ccc(-c3ccc(O)cc3)cc2)CC1

Procedure:
According to a method similar to Example (8-1), from methyl 1-(4-bromophenyl)cyclopropanecarboxylate (2.96 g, 11.6 mmol) obtained in Example (15-1) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.55 g, 11.6 mmol), methyl 1-(4′-hydroxy-1,1′-biphenyl-4-yl)cyclopropanecarboxylate was obtained as a white powder (2.49 g, yield: 80%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH:9]=[CH2:10])[CH2:6][C:7]#[CH:8].[CH2:16]([SnH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:11][Si:12]([CH3:14])([CH3:13])[CH3:15])([CH:9]=[CH2:10])[CH2:6]/[CH:7]=[CH:8]/[Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(C=C)(CCCCl)O[Si](C)(C)C
Product: C=CC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(CCCCl)O[Si](C)(C)C
Temperature: 140 °C
Reaction time: 0.05 h
Yield: 80 %

Procedure:
A mixture of 7-chloro-4-trimethylsilyloxy-4-vinyl-1-heptyne (17 g, 0.07 mol) and 20.7 g (0.71 mol) of tri-n-butylstannane and 150 mg of azobisisobutrylnitrile (AIBN) is stirred under argon in a 140° oil bath behind a safety shield. After 3 minutes an exotherm occurs and the mixture is maintained at 140° C. for 1.5 hr. After cooling, air is admitted and the unreacted tri-n-butylstannane is removed by distillation via Kuglerohr (140°, 0.5-0.3 mm) to give a very light yellow oil (30 g). This oil consists of a mixture of the E and Z isomers.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:12])OCCl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[C:35]([Cl:36])=[CH:34][C:17]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:23][CH2:22]2)=[O:19])=[C:16]([O:37][CH3:38])[CH:15]=1>C(O)C>[NH2:13][C:14]1[C:35]([Cl:36])=[CH:34][C:17]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]3[CH2:29][CH2:30][N:31]([C:8](=[O:12])[NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:32][CH2:33]3)[CH2:23][CH2:22]2)=[O:19])=[C:16]([O:37][CH3:38])[CH:15]=1
Reactant: O=C(Nc1ccccc1)OCCl
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCNCC2)CC1
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)Nc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 81 %

Procedure:
To a solution of chloromethyl N-phenylcarbamate (220 mg), which is prepared by the method disclosed in Synth. Commun., 1996, 26, 4253, in ethanol (20 ml) is added dropwise a solution of 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide (910 mg) in ethanol (10 ml) at room temperature, and the mixture is stirred at room temperature for 7 hours. The mixture is concentrated to dryness under reduced pressure, and the residue is dissolved in chloroform, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform:methanol=30:1) to give the desired compound (480 mg) as white amorphous.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Br[CH:23]([CH2:29]Br)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[C:8]1([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])([C:7]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:29][CH:23]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(Br)CBr
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC1(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a THF (200 mL) solution of t-BuOK (11.4 g, 102 mmol) at −30° C. was added slowly di-tert-butyl malonate (20 g, 92.6 mmol). The internal temperature was maintained between −30° C. and −10° C. After 30 min, ethyl 2,3-dibromopropanoate (29 g, 111.1 mmol) was added. The cooling bath was removed. After 1.5 h, the reaction mixture was cooled to −10° C. for addition of t-BuOK (11.4 g, 102 mmol). The cooling mixture was removed and the mixture was stirred overnight. The solution was evaporated and the residue was extracted with ethyl acetate (600 mL), dried and purified by CombiFlash (PE:EA=15:1) to afford 1,1-di-tert-butyl 2-ethyl cyclopropane-1,1,2-tricarboxylate (18 g, 62%). 1H NMR (300 MHz, CDCl3): δ 1.34-1.51 (t, J=7.2 Hz, 3H), 1.54-1.56 (d, J=4.4 Hz, 18H), 1.58-1.60 (m, 1H), 1.90-1.94 (m, 1H), 2.52-2.57 (m, 1H), 4.21-4.31 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=1[SH:33]>C(O)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:33][C:27]4[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:26]=4[Cl:25])[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cccc(Cl)c1S
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Product: Cc1cccc(Cl)c1Sc1ccc2ccnc(N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 110 °C
Yield: 86.7 %

Procedure:
A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 2-chloro-6-methyl-thiophenol (0.206 g, 1.3 mmol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in nBuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-heptane: ethyl acetate 8:2) to give 530 mg of the title compound as colourless oil (yield 86.4%). 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.65 (d, 1H), 7.20-7.45 (m, 5H), 7.15 (d, 1H), 3.26-3.40 (m, 4H), 3.10-3.20 (m, 4H), 2.5 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: CN(C)CC(N1C2C(=CC(OC)=C(NC3N4C(=NC5C(C4=O)=C(F)C=C(F)C=5)C4C=CN(S(C5C=CC(C)=CC=5)(=O)=O)C=4N=3)C=2)CC1)=O.CC(N)C.[CH3:53][N:54]([CH3:104])[CH2:55][C:56]([N:58]1[C:66]2[C:61](=[CH:62][C:63]([O:102][CH3:103])=[C:64]([NH:67][C:68]3[N:69]=[C:70]([NH:87][C:88]4[CH:99]=[C:98]([F:100])[CH:97]=[C:96]([F:101])[C:89]=4[C:90]([NH:92][CH:93]([CH3:95])[CH3:94])=[O:91])[C:71]4[CH:76]=[CH:75][N:74](S(C5C=CC(C)=CC=5)(=O)=O)[C:72]=4[N:73]=3)[CH:65]=2)[CH2:60][CH2:59]1)=[O:57].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.O1CCOCC1>[CH3:104][N:54]([CH3:53])[CH2:55][C:56]([N:58]1[C:66]2[C:61](=[CH:62][C:63]([O:102][CH3:103])=[C:64]([NH:67][C:68]3[NH:73][C:72]4=[N:74][CH:75]=[CH:76][C:71]4=[C:70]([NH:87][C:88]4[CH:99]=[C:98]([F:100])[CH:97]=[C:96]([F:101])[C:89]=4[C:90]([NH:92][CH:93]([CH3:95])[CH3:94])=[O:91])[N:69]=3)[CH:65]=2)[CH2:60][CH2:59]1)=[O:57]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cc(F)cc(F)c3C(=O)NC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Agent: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cc(F)cc(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)N
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1nc(Nc3cc(F)cc(F)c3C(=O)NC(C)C)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,10-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added (1-methylethyl)amine (0.757 mL, 8.89 mmol). The resulting mixture was let stir at rt for 16 h at which time it was diluted with ethyl acetate and washed with a saturated ammonium chloride solution, saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid, containing 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluoro-N-(1-methylethyl)benzamide. This crude material was dissolved in 1,4-dioxane (5 mL) and transferred to a 20 ml microwave vessel. A solution of 2 M NaOH (5 ml) was added and reaction heated in microwave at 120° C. for 8 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid which was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4,6-difluoro-N-(1-methylethyl)benzamide (26 mg, 0.045 mmol) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (d, J=6.60 Hz, 6H), 2.23 (s, 6 H), 3.07-3.19 (m, 4 H), 3.76 (s, 3 H), 4.07-4.22 (m, 3 H), 6.18-6.26 (m, 1 H), 6.80-6.91 (m, 1 H), 6.93-7.02 (m, 2 H), 7.79 (s, 1 H), 8.36-8.45 (m, 1 H), 8.46-8.56 (m, 2 H), 10.26 (s, 1 H), 11.28-11.37 (s, 1 H). (ESIMS (M+H)+=579)
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:35][N:34]=2)[CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C1COCC1>[OH:11][N:12]([CH:13]([CH2:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:35][N:34]=2)[CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[N:18]=[CH:19][CH:20]=[CH:21][N:22]=1)[CH:1]=[O:3]
Reactant: O=CO
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ccc(C#Cc3ccccn3)cn2)CC1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccccn3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.4 %

Procedure:
To formic acid (1.5 mL, 39 mmol) at 0° C. was added acetic anhydride (375 μL, 3.9 mmol) and the mixture was stirred at RT for 10 minutes. The reaction was then recooled to 0° C., and a solution of 2-[4-(hydroxyamino)-5-({4-[5-(pyridin-2-ylethynyl)pyridin-2-yl]piperazin-1-yl}sulfonyl)pentyl]pyrimidine (403 mg, 0.79 mmol) in THF (8 mL) was then added. The reaction was brought to RT and stirred for one hour. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (2×5 mL). The residue was then dissolved in MeOH (10 mL) and heated to 40° C. for one hour. The solution was then cooled to RT and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% MeOH in EtOAc) to give the title compound as a pale yellow foam (231 mg, 0.43 mmol, 54%).
Reaction SMILES: [CH3:1][C:2]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-])=O)=[CH:12][CH:11]=2)([CH3:7])[C:3]([O:5][CH3:6])=[O:4]>[Ni].CO>[NH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:2]([CH3:7])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[CH:16]2
Reactant: COC(=O)C(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C(C)(C)c1cc2cc(N)ccc2[nH]1
Reaction time: 8 h
Yield: 37.4 %

Procedure:
A suspension of methyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate (60 mg, 0.23 mmol) and Raney Nickel (10 mg) in MeOH (5 mL) was hydrogenated under hydrogen (1 atm) at room temperature overnight. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5/1) to give methyl 2-(5-amino-1H-indol-2-yl)-2-methylpropanoate (20 mg, 38%). 1H NMR (400 MHz, CDCl3) δ 8.37 (br s, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.63 (dd, J=2.0, 8.4 Hz, 1H), 6.20 (d, J=1.2 Hz, 1H), 3.72 (d, J=7.6 Hz, 3H), 3.43 (br s, 1H), 1.65 (s, 6H); MS (ESI) m/e (M+H+) 233.2.