Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Cl[C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>C(O)CC>[CH2:1]([NH:4][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)[CH2:2][CH3:3]
Reactant: Clc1ncnc2c1ncn2CCCN1CCN(c2ccccc2)CC1
Reactant: CCCN
Solvent: CCCO
Product: CCCNc1ncnc2c1ncn2CCCN1CCN(c2ccccc2)CC1
Reaction time: 15 h
Yield: 65 %

Procedure:
50 ml of n-propylamine are added to a solution of 10.7 g (0.03 mole) of 6-chloro-9-[3-(4-phenyl-piperazino)-propyl]-purine (produced as hereinabove described) in 100 ml of n-propanol, whereafter the reaction mixture is heated under reflux for 5 hours. After standing for 15 hours at ambient temperature, the reaction mixture is evaporated in a vacuum and the residue extracted with ether. After evaporation of the solvent, there are obtained 9.0 g (79% of theory) of crude product, which has a melting point of 64°-66° C. After recrystallization from ether, there are obtained 7.4 g (65% of theory) of N6 -n-propyl-9-[3-(4-phenyl-piperazino)-propyl]-adenine, which has a melting point of 67°-68° C.
Reaction SMILES: C([Li])CCC.[C:6]1([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:29][CH2:28]1)=[O:26].[Cl-].[NH4+].[Na]>C1COCC1>[C:6]1([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:13]2[CH2:24][C:25]([N:27]2[CH2:28][CH2:29][N:30]([C:33]3[N:34]=[CH:35][CH:36]=[CH:37][N:38]=3)[CH2:31][CH2:32]2)=[O:26])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(-c2cn(-c3ccccc3)cn2)cc1
Reactant: O=C(CBr)N1CCN(c2ncccn2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cc1nc(-c2ccccc2)cn1-c1ccccc1)N1CCN(c2ncccn2)CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 6.9 %

Procedure:
0.5 mL butyllithium (1.6 mol/L in THF) was added to 0.15 g 1,4-diphenyl-1H-imidazole in 10 mL THF at −78° C. under argon. The reaction was stirred 40 min at −78° C. and 0.22 g 2-bromo-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanon was added to the reaction. After stirring 1 h at −78° C. the reaction was decomposed with saturated sodiumammoniumchloride solution. The mixture was extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified by chromatography on Alox (gradient: dichlormethane/EtOAC/MeOH 9:2:0-50:45:5) to yield 20 mg of the desired compound. Rt: 1.13 (method B), (M+H)+: 425
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]4[C:27]([CH3:28])=[CH:26][O:25][C:13]=4[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=4)[N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.B(Br)(Br)Br>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]4[C:27]([CH3:28])=[CH:26][O:25][C:13]=4[N:14]=[C:15]([C:17]4[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=4)[N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3c(C)coc3n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1coc2nc(-c3cccc(O)c3)nc(Nc3ccc4[nH]ncc4c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(1H-indazol-5-yl)-2-(3-methoxyphenyl)-5-methylfuro[2,3-d]pyrimidin-4-amine (50.0 mg, 0.13 mmol) in CH2Cl2 (20 ml) cooled to −78° C. was added BBr3 (0.7 mL, 2.83 mmol, 1M solution in CH2Cl2) drop-wise. The mixture warmed to rt and was stirred overnight. The reaction was quenched with water and the organic and aqueous phases were separated. The organic layer was dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient from 20% to 80% EtOAc/hexane) to afford are product (8.4 mg, 17.5%). HPLC/MS: (M+H)+ 358.1 m/z. Retention time (LC-MS)=3.01 min. 1H NMR (DMSO-D6): 8.54(s, NH); 8.11 (d, 1H); 8.07(s, 1H); 7.75(m, 3H); 7.60(d, 1H); 7.47(d, 1H); 7.20(t, 1H); 6.83(m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([CH:35]5[CH2:39][CH2:38][CH2:37][N:36]5[C:40](=[O:53])[CH:41]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH2:42][CH2:43][C:44]([F:47])([F:46])[F:45])=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:52][O:51][C:49](=[O:50])[NH:48][CH:41]([C:40]([N:36]1[CH2:37][CH2:38][CH2:39][CH:35]1[C:32]1[NH:31][C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:15]4[NH:14][C:13]([CH:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)=[N:17][CH:16]=4)=[CH:19][CH:20]=3)=[CH:29][CH:28]=2)=[CH:34][N:33]=1)=[O:53])[CH2:42][CH2:43][C:44]([F:46])([F:45])[F:47]
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of 2-[5-(4′-{2-[1-(5,5,5-trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (340 mg, 0.46 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred at room temperature for 3 hours and then thoroughly concentrated. The resulting residue was dissolved in dichloromethane and washed three times with saturated aqueous NaHCO3 solution. The organic layer was dried (MgSO4), and concentrated to give the crude free pyrrolidine (270 mg, 92%), which was clean enough to use without further purification. LCMS-ESI+: calculated for C33H36F3N7O3: 635.28; observed [M+1]+: 636.17.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:13][C:14]1[C:32]([F:33])=[CH:31][C:17]([C:18]([NH:20][CH:21]2[CH2:28][C@H:27]3[N:29]([CH3:30])[C@H:23]([CH2:24][CH2:25][CH2:26]3)[CH2:22]2)=[O:19])=[C:16]([F:34])[CH:15]=1.Cl[C:36]1[N:46]=[C:45]2[C:39]([N:40]([CH3:53])[C:41](=[O:52])[CH2:42][CH2:43][N:44]2[CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[CH:38][N:37]=1>CC(C)CC(O)C>[CH:47]1([N:44]2[CH2:43][CH2:42][C:41](=[O:52])[N:40]([CH3:53])[C:39]3[C:45]2=[N:46][C:36]([NH:13][C:14]2[C:32]([F:33])=[CH:31][C:17]([C:18]([NH:20][CH:21]4[CH2:28][C@H:27]5[N:29]([CH3:30])[C@H:23]([CH2:24][CH2:25][CH2:26]5)[CH2:22]4)=[O:19])=[C:16]([F:34])[CH:15]=2)=[N:37][CH:38]=3)[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1[C@@H]2CCC[C@H]1CC(NC(=O)c1cc(F)c(N)cc1F)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)NC4C[C@H]5CCC[C@@H](C4)N5C)cc3F)ncc21
Temperature: 150 °C
Yield: 23.1 %

Procedure:
p-Toluenesulphonic acid monohydrate (338 mg, 1.78 mmol) was added to 4-amino-2,5-difluoro-N-[(1S,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 274; 220 mg, 0.71 mmol), and 2-chloro-9-cyclopentyl-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (Intermediate 1; 200 mg, 0.71 mmol) in 4-methyl-2-pentanol (4 mL) at 25° C. The resulting mixture was heated by microwave irradiation at 150° C. for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX-3 (5 g) column. The desired product was eluted from the column using 2M NH3/MeOH and product-containing fractions were evaporated to dryness. The residue was further purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (91 mg, 23.%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[CH:14][C:6]2[S:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:5]=2[CH:4]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[CH:14][C:6]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2cc(C(=O)O)sc2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a stirred solution of methyl 5,6-dimethoxybenzo[b]thiophene-2-carboxylate (1.0 g, 4 mmol) in MeOH (20 mL) and THF (10 mL) was added 2N NaOH (10 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours before adjusting the pH value to 3 with 1 N HCl and diluting with water. The resulting suspension was filtered and the solid was dried under vacuum to afford 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid as a white solid (890 mg, 94%). LC-MS (ES-API); rt 8.17 min; m/z calculated for C11H10O4S [M+Na]+ 261.0, found 260.9.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].C(Cl)(=O)C.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:2]([C:1]([OH:7])=[O:6])[C:3]([OH:5])=[O:4])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)Cl
Product: O=C(O)C(=Cc1ccc(Cl)cc1)C(=O)O
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
Under nitrogen, malonic acid (powdered, 20 g., 0.192 mole) was mixed with acetyl chloride (15 g., 0.192 mole) and heated to 65° C. in an oil bath. p-Chlorobenzaldehyde (21.6 g., 0.153 mole) was added and the mixture further heated to 80° C. A yellow, slowly refluxing solution resulted, followed by copious precipitation of solids. The mixture was cooled and product recovered by filtration, resuspended in water, stirred for 5 minutes and refiltered to yield title product [21.1 g.; 61% of theory; m.p. 215° C. (dec.)].
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]4[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([N:33]6[CH2:41][C:40]7[C:35](=[CH:36][C:37]([Cl:42])=[CH:38][CH:39]=7)[C:34]6=[O:43])[C:28]=5[CH3:44])=[CH:25][N:24]=[C:23]([C:45]([NH2:47])=[O:46])[C:19]=4[NH:20]3)=[CH:16][CH:15]=2)[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>O1CCCC1>[Cl:42][C:37]1[CH:36]=[C:35]2[C:40]([CH2:41][N:33]([C:29]3[C:28]([CH3:44])=[C:27]([C:26]4[C:18]5[C:17]6[C:21](=[CH:22][C:14]([N:11]7[CH2:12][CH2:13][CH:9]([OH:8])[CH2:10]7)=[CH:15][CH:16]=6)[NH:20][C:19]=5[C:23]([C:45]([NH2:47])=[O:46])=[N:24][CH:25]=4)[CH:32]=[CH:31][CH:30]=3)[C:34]2=[O:43])=[CH:39][CH:38]=1
Reactant: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(N5CCC(O[Si](C)(C)C(C)(C)C)C5)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(N5CCC(O)C5)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Reaction time: 1.25 h
Yield: 29.4 %

Procedure:
To a homogeneous, orange solution of 7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.0456 g, 0.068 mmol) in tetrahydrofuran (0.684 mL) under nitrogen was added 1 M TBAF/THF (0.103 mL, 0.103 mmol). The reaction was stirred for 75 min and concentrated in vacuo. The residue was dissolved in DMSO (0.2 mL) and MeOH, and subjected to autoprep HPLC. The appropriate fractions were collected, basified with NaHCO3 (solid), and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combined extract was dried over Na2SO4 and concentrated in vacuo to give the desired product (0.0112 g, 0.020 mmol, 29.7% yield) as a light yellow solid. LC/MS (M+H)=552.11; 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for major atropoisomer) δ ppm 11.26 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 7.74 (d, J=1.94 Hz, 2H), 7.63-0.65 (m, 2H), 7.45-7.58 (m, 1H), 7.42 (d, J=1.11 Hz, 1H), 7.03 (d, J=8.60 Hz, 1H), 6.83 (d, J=1.66 Hz, 1H), 6.38 (dd, J1=9.0 Hz, J2=2.1 Hz, 1H), 5.02 (d, J=17.76 Hz, 1H), 4.95-4.98 (m, 1H), 4.94 (d, J=17.76 Hz, 1H), 4.43 (br. S, 1H), 3.47 (ddd, J1=10.2 Hz, J2=4.8 Hz, J3=2.2 Hz, 1H), 3.37-3.44 (m, 1H), 3.31-3.37 (m, 1H), 3.15 (d, J=10.0 Hz, 1H), 2.07 (dd, J=8.25, 4.30 Hz, 1H), 1.90-1.96 (m, 1H), 1.88 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:33][C:34]1[CH:35]=[N:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[F:43][C:40]([F:41])([F:42])[C:37]1[N:36]=[CH:35][C:34]([NH:33][C:18]([C:17]2[CH:21]=[CH:22][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:15][CH:16]=2)=[O:20])=[CH:39][CH:38]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cc3)c(C#N)cc21
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (100 mg, 0.283 mmol) was diluted with dichloromethane (1 mL) followed by the addition of oxalyl chloride in dichloromethane (2M) (0.156 mL, 0.311 mmol) and 1 drop of DMF. After stirring for 10 minutes, 3-amino-6-(trifluoromethyl)pyridine (91.8 mg, 0.566 mmol) and diisopropylethylamine (0.123 mL, 0.708 mmol) were added and the reaction was stirred for 5 hours. The reaction was loaded onto a biotage 25 column and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to provide the desired product (141 mg, 100% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.B([C:20]1[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>O.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>[O:11]=[C:6]1[C:5]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=3)[CH:3]=2)[NH:7]1
Reactant: O=C1Nc2ccc(Br)cc2C12CCCCC2
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C1(CCCCC1)C(=O)N2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one (3.4 g, 12 mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere, was added tetrakis(triphenylphosphine)palladium(0) (70 mg, 5 mol %). After 15 minutes, 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq, 3.31 g, 15.6 mmol) and a solution of K2CO3 (2.3 eq, 3.83 g, 27.6 mmol) in water (5 mL) were added sequentially. The solution was heated to 80° C. for 3 hours and allowed to cool. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (150 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc/hexane) to give 2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (3.4 g, 76%) as a white powder, mp 177° C.; 1H NMR (CDCl3; 300 MHz): δ 1.38 (s, 9H), 1.59-1.93 (m, 10H), 6.18 (m, 1H), 6.23 (‘t’, 1H, J=3 Hz), 6.91 (d, 1H, J=8 Hz), 7.21 (d, 1H, J=8 Hz), 7.34 (m, 1H), 7.44 (s, 1H), 8.33 (br s, 1H, D2O ex). MS ((+)-APCI) m/z 367 [(M+H)+]. Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.7; H, 7.16; N, 7.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2Cl)([O-:3])=[O:2].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[Cl:28]>C(O)(C)C>[Cl:28][C:22]1[CH:23]=[C:24]([NH:25][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:10]=[CH:9][N:8]=2)[CH:26]=[CH:27][C:21]=1[O:20][CH2:19][C:18]1[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Yield: 67 %

Procedure:
In a flask equipped with a reflux condenser, 6-nitro-4-chloro-quinazoline 1.20 g (5.7 mmol) and 4-(3-fluorobenzyloxy)-3-chloroaniline 1.37 g (5.6 mmol) were dissolved into 80 mL of isopropanol, and the solution was refluxed for 3 h. Then a lot of yellow solid was deposited, which was filtered, dried under vacuum, and identified as the title compound. Yield: 67%.
Reaction SMILES: [Ca].N.[C:3]1([CH2:9][CH:10]2[S:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCOCC>[C:3]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][SH:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(CC2OCCCS2)cc1
Agent: N
Agent: [Ca]
Solvent: CCOCC
Product: SCCCOCCc1ccccc1
Reaction time: 0.17 h

Procedure:
Calcium turnings (3.5 g) were added portionwise to liquid ammonia (500 ml) and the whole was stirred vigorously for 10 min. The thioacetal from step b) (10 g) in ether (7 ml) was added dropwise to the dark blue solution over a 7 min period. The mixture was stirred for 2 hours and then quenched with ammonium chloride until effervescing had ceased. Excess ammonia was allowed to evaporate by purging under nitrogen overnight. The remaining solid was acidified using dilute 10% aqueous hydrochloric acid to pH 1-2 and the product extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give the subtitled compound (8.29 g).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH:24]2[CH2:33][NH2:34])[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:25][CH:24]2[CH2:33][NH:34][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:14][CH:13]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CC(C)(C)N1CCN(c2ccc(Cl)c(Cl)c2)C(CN)C1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Product: CC(C)(C)N1CCN(c2ccc(Cl)c(Cl)c2)C(CNC(=O)c2ccc(-n3ccnc3)cc2)C1

Procedure:
In a manner similar to preparation 7, react 4-(1H-imidazol-1-yl)benzoic acid, 1,1-carbonyldiimidazole and 1-(3,4-dichlorophenyl)-4-(1,1-dimethylethyl)-2-piperazinemethanamine to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:24]=[CH2:25])[CH:23]=1.[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][CH2:25][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)[CH:21]=[N:20][CH:19]=1
Reactant: C=Cc1cncc(Cl)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccc2c(c1)c1c(n2CCc2cncc(Cl)c2)CCN(C)CC1
Temperature: 110 °C
Yield: 92.1 %

Procedure:
The title compound was prepared by following general procedure 4. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), tetra n-butyl ammonium chloride (6 mg, 0.023 mmol), 3-chloro-5-vinylpyridine (77 mg, 0.55 mmol) were taken into 50% NaOH (3 mL). The reaction mixture was heated overnight at 110° C. The reaction mixture was extracted with ethyl acetate and organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 150 mg of 6-(2-(5-chloropyridin-3-yl)ethyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:27](Cl)=[O:28].CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:27]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22])=[O:28]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccc(Cl)c(Cl)c4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 89.1 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 3,4-dichlorobenzoyl chloride (0.69 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), sat. NaHCO3 (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The product was dried in vacuo to give 3,4-dichloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (1.23 g, 89% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 9.40 min (98.44%); mp: 253-255° C.; 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H, CHH), 2.43-2.62 (m, 2H, CHH, CHH), 2.81-2.96 (m, 1H, CHH), 4.65 (d, J=5.7 Hz, 2H, CH2), 5.15 (dd, J=5.2, 12.5 Hz, 1H, CH), 7.77-7.92 (m, 5H, Ar), 8.14 (d, J=1.8 Hz, 1H, Ar), 9.40 (t, J=5.7 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 42.77, 49.01, 122.14, 123.57, 127.62, 129.27, 129.90, 130.81, 131.36, 131.62, 133.55, 134.23, 134.29, 147.07; Anal Calcd for C21H15N3O5Cl2: C, 54.80; H, 3.28; N, 9.13. Found: C, 54.76; H, 3.29; N, 8.87.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)c1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(OC)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c6) the title compound is obtained as off-white solid.