Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)(C)C([N:5]([CH2:23][CH:24]1[CH2:28][O:27]C(=O)[O:25]1)[C:6]1[C:11]([CH2:12][CH2:13][C:14](OCCCC)=[O:15])=[CH:10][CH:9]=[C:8]([O:21][CH3:22])[N:7]=1)=O.Cl>CO>[OH:25][CH:24]([CH2:28][OH:27])[CH2:23][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:21][CH3:22])[N:7]=2)[CH2:12][CH2:13][C:14]1=[O:15]
Reactant: CCCCOC(=O)CCc1ccc(OC)nc1N(CC1COC(=O)O1)C(=O)C(C)(C)C
Agent: Cl
Solvent: CO
Product: COc1ccc2c(n1)N(CC(O)CO)C(=O)CC2
Yield: 66.3 %

Procedure:
A solution of butyl 3-[2-{(2,2-dimethylpropanoyl)[(2-oxo-1,3-dioxolan-4-yl)methyl]amino}-6-(methyloxy)-3-pyridinyl]propanoate (6.065 g, 13.911 mmol) in methanol (100 ml) was treated with concentrated aqueous HCl (12M, 50 ml) and then heated at reflux for 48 h. The reaction mixture was then concentrated to approximately 50 ml, neutralised with potassium carbonate and extracted with 20% methanol/DCM (3×100 ml). The organic extracts were dried (MgSO4), and evaporated to give the crude product as a yellow oil (2.325 g, 66%).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][Mg][Cl:7].Cl[CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2.O1CCCC1.Cl>CCOCC>[ClH:7].[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH:10]1[C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: CN(C)CCC[Mg]Cl
Reactant: ClC1c2ccccc2C=Cc2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CCCC1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C

Procedure:
The Grignard solution prepared in Step A. is cooled to room temperature and stirred while a solution of 5.05 g. (0.0221 mole) of 5-chloro-5H-dibenzo[a,d]cycloheptene in 25 ml. of dry tetrahydrofuran is added dropwise, external cooling being applied as required to maintain the temperature close to room temperature. When the addition is complete, the mixture is heated to refluxing for 15 minutes. The bulk of the tetrahydrofuran then is distilled under reduced pressure, keeping the water-bath temperature at 50°-60°C. The syrupy mixture is dissolved in 75 ml. of benzene and water, 15 ml., is added dropwise with stirring. The benzene layer is decanted from the gelatinous precipitate which then is re-extracted with three 20 ml. portions of boiling benzene. The combined benzene extracts are washed with water and extracted with three 15 ml. portions of 3N hydrochloric acid. The acid extract is made basic with sodium hydroxide and the yellow oily base that separates is extracted into hexane. After washing the combined extracts with water, the hexane is evaporated and the product obtained as a yellow oil in a yield of 4.61 g. The base is converted to the hydrochloride by dissolving it in a mixture of 15 ml. of absolute alcohol and 15 ml. of absolute ether and adding 1.8 ml. of a 10.28 N solution of dry hydrogen chloride in absolute alcohol. The solution then is diluted to incipient crystallization by the addition of 25 ml. of absolute ether. The yield of 5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene hydrochloride, m.p. 186°-190°C. is 4.17 g. Recrystallization from mixtures of absolute alcohol and absolute ether gives the product, m.p. 191°-193°C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:27])([C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1)[CH3:27]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1cnc(C(C)(C)N)s1
Product: Cc1cnc(C(C)(C)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)s1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α,α,5-trimethyl-2-thiazolemethanamine (CAN 1155530-59-8) as starting materials; LC-MS (UV peak area/ESI) 94%, 372.1743 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:22][CH2:21][CH:20]([NH:23][C:24]3[N:29]=[C:28]([N:30]4[C:38]5[C:33](=[C:34]([O:39][CH2:40][CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31]4)[CH:27]=[CH:26][N:25]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1)(C)(C)C.CCO>Cl>[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24]3[N:29]=[C:28]([N:30]4[C:38]5[C:33](=[C:34]([O:39][CH2:40][CH2:41][CH2:42][S:43]([CH3:46])(=[O:44])=[O:45])[CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31]4)[CH:27]=[CH:26][N:25]=3)[CH2:21][CH2:22]2)=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(=O)C2CCC(Nc3nccc(-n4ccc5c(OCCCS(C)(=O)=O)cccc54)n3)CC2)CC1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)N3CCC(CN)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 58.3 %

Procedure:
A solution of [1-(4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-yl-amino}-cyclohexanecarbonyl)-piperidin-4-ylmethyl]-carbamic acid t-butyl ester (0.827 g, 1.236 mM) in 10 mL of 10% HCl soln./EtOH was briefly heated on a steam bath, stirred for 7 hours at RT, concentrated to half volume and cooled in an ice bath. The light yellow solid was collected by filtration, washed with cold EtOH, and dried at 60° C. in vacuo. The product was extracted into DCM, crystallized from EtOH, and dried in vacuo at 60° C. to yield (4-aminomethyl-piperidin-1-yl)-(4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (Compound 304) as a white solid (0.41 g, mp 124-126° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]=[C:15]3[C:11]([NH:12][C:13](=[O:24])[N:14]3[CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:10]([C:25]([O:27]C)=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Si](OC1C=C(C2N=C3C(NC(=O)N3CC3CCOCC3)=C(C(OC)=O)[N:54]=2)C=CC=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]=[C:15]3[C:11]([NH:12][C:13](=[O:24])[N:14]3[CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:10]([C:25]([NH2:54])=[O:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)nc2c1[nH]c(=O)n2CC1CCOCC1
Reactant: COC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2CC1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Methyl 2-(3-hydroxyphenyl)-8-oxo-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9-dihydro-7H-purine-6-carboxylate. Methyl 2-(3-(tert-butyldiphenylsilyloxy)phenyl)-8-oxo-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9-dihydro-7H-purine-6-carboxylate (0.202 g, 0.367 mmol) was dissolved in tetrahyrdrofuran (10 mL) and tetrabutylammonium fluoride on silica gel (0.294 g, 0.404 mmol) was added to the solution. The solution stirred at ambient temperature for two h. LCMS confirms product and no starting materials. The solution was filtered and condensed to give the crude title compound (0.110 g, 58%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)[CH2:2][CH3:3].[CH3:18][NH:19][O:20][CH3:21].CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1>[CH3:21][O:20][N:19]([CH3:18])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:5]=1[O:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCOc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CNOC
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCOc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Yield: 49.3 %

Procedure:
2-Propoxy-4-(trifluoromethyl)benzoic acid (457 mg, 1.93 mmol) in THF was reacted with N,O-dimethylhydroxy amine (378 mg), NMM (0.65 ml) and DMTMM (947 mg) at room temperature overnight. The reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with 1 M NaHCO3 (30 ml), 1N HCl (30 ml) and brine (30 ml) and dried over MgSO4. The filterate was purified with column chromatography (Hex/EtOAc=4/1) to yield the title compound (277 mg, 49%).
Reaction SMILES: [CH2:1]([N:5]([C:19]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:28][CH2:29][C@@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[OH:31]>>[CH2:1]([N:5]([C:19]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])[C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH2:14][CH:15]([NH:28][CH2:29][C@H:30]([OH:31])[C:32]3[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=3)[CH2:16][CH2:17]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCCCN(C(=O)NCC(=O)OCC)c1ccc(N2CCC(=O)CC2)cc1
Product: CCCCN(C(=O)NCC(=O)OCC)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from ethyl ({[butyl-4-(4-oxo-1-piperidineyl)anilino]carbonyl}amino)acetate (which was obtained in Example 367) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.1 Hz, 3H), 1.17 (t, J=7.1 Hz, 3H), 1.15-1.40 (m, 6H), 1.80-1.95 (m, 2H), 2.50-2.80 (m, 5H), 2.90 (s, 3H), 3.49 (t, J=6.9 Hz, 2H), 3.55-3.60 (m, 2H), 3.65 (d, J=5.9 Hz, 2H), 4.04 (q, J=7.1 Hz, 2H), 4.48 (dd, J=7.9, 4.4 Hz, 1H), 5.60 (t, J=5.9 Hz, 1H), 6.80 (d, J=8.2 Hz, 1H), 6.90-7.10 (m, 5H), 7.17 (d, J=2.0 Hz, 1H); MS (ES) m/z: 606.3 (MH+); HRMS Calcd. for C29H44N5O7S(MH+): 606.2956. Found: 606.2955.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([C:12]([O-:14])=[O:13])C([O-])=O)[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Na+].CS(C)=O.[C:28](OCC)(=O)[CH3:29]>O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:15])[C:12]([O:14][CH2:28][CH3:29])=[O:13])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C(=O)[O-])(C(=O)[O-])c1ccc(-c2ccccc2)c(F)c1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1

Procedure:
A mixture of 100 millimoles diethyl 2-(2-fluoro-4-biphenylyl)-methylmalonate VI, 110 millimoles sodium chloride, 200 millimoles water and 50 milliliters dimethyl sulfoxide is heated under nitrogen at about 130° to 180° C. for about 6 hours. On cooling the mixture is diluted with 100 milliliters water and 100 milliliters ethyl acetate. The layers are separated and the organic layer is washed two times with 25 milliliters of water. After drying over disodium sulfate the organic layer is concentrated in vacuo to give the desired ethyl 2-(2-fluoro-4-biphenylyl)propionate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[C:9]([CH2:20][CH3:21])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH2:20][CH3:21])[C:8]=4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])=[CH:14][CH:15]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:27])[CH3:24]
Reactant: CCc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4NC(=O)OC(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using the following starting materials: [5-(4-bromo-phenyl)-3-ethyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]cnc2cc(Br)c([N+](=O)[O-])cc12
Temperature: 25 °C

Procedure:
A solution of 7-bromo-4-quinazolinone (2.6 g) in 5 mL of concentrated H2SO4 and 5 mL of fuming HNO3 was heated at 100° C. for 1 h. After the reaction was cooled to room temperature, the mixture was poured into ice-water. The solid was collected via filtration, and used without further purification, 7-bromo-6-nitro-4-quinazolinone (mixed with 7-bromo-8-nitro-4-quinazolinone, LCMS ESI(+) m/z: 270/271 (M+1).
Reaction SMILES: [NH:1]([CH2:3][C:4]1([OH:19])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)N.C(OCC)(=O)C.[H][H]>[Pt](=O)=O.C(O)(=O)C>[NH2:1][CH2:3][C:4]1([OH:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: [H][H]
Reactant: NNCC1(O)c2ccccc2CCc2ccccc21
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NCC1(O)c2ccccc2CCc2ccccc21

Procedure:
A mixture of 8 g. of freshly prepared 5-hydrazinomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol, 40 mg. of platinum dioxide, 120 ml. of ethyl acetate and 40 ml. glacial acetic acid is hydrogenated at room temperature and about atmospheric pressure until the uptake of hydrogen is about stoichiometric. The resulting mixture is filtered, evaporated in vacuo and the residue taken up in 400 ml. of chloroform, made neutral by shaking with 10% sodium bicarbonate solution, and the aqueous phase discarded. The organic phase is extracted twice with water and then with saturated sodium chloride solution, followed by drying and evaporation in vacuo to about 50 ml. to effect crystallization which is completed by adding 50 ml. of diethyl ether to obtain 5-aminomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol, m.p. 147°-149° C.
Reaction SMILES: [CH3:1][C@H:2]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>C(O)C.[Pd]>[CH2:23]([N:19]([CH2:20][CH2:21][CH3:22])[C@@H:2]([CH3:1])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([NH2:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4])[CH2:24][CH3:25]
Reactant: CCCN(CCC)[C@@H](C)C(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CCCN(CCC)[C@@H](C)C(=O)N1CCc2cc(OC)c(N)cc21

Procedure:
A solution of N-{(1S)-1-methyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-N-propyl-1-propanamine (0.6 g, 1.72 mmols) in absolute ethanol (50 mL) was maintained under 45 psi H2(g) with catalytic 10% Pd/C for 16 hours. The catalyst was removed by vacuum filtration through a celite pad and rinsed with methanol. The filtrate was collected, concentrated under reduced pressure, and dried under high vacuum to give 1-[(2S)-2-(dipropylamino)propanoyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine. ESIMS (M+H)+=320.
Reaction SMILES: C([NH:4][C:5]1([CH2:22][CH2:23][CH2:24][CH3:25])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=O)C.[ClH:26].C>CO>[ClH:26].[NH2:4][C:5]1([CH2:22][CH2:23][CH2:24][CH3:25])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: CCCCC1(NC(C)=O)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Solvent: CO
Product: CCCCC1(N)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 0.5 h

Procedure:
1.3 g of 10-acetamido-10-butyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are dissolved in 25 ml of boiling 2N hydrochloric acid and the solution is stirred for 1 hours 30 minutes at boiling, cooled and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 60° C. The product obtained is dissolved in 30 ml of methanol and, after addition of decolorizing charcoal, the solution is filtered. The filter is washed with 10 ml of methanol, and the filtrate and washing are combined, 400 ml of acetone are added and the solution is stored for 1 hour at a temperature in the region of 20° C. The insoluble product formed is isolated by filtration, washed twice with 100 ml in total of acetone and dried under reduced pressure (1 mmHg; 0.13 kPa) at 20° C. 0.83 g of 10-amino-10-butyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one hydrochloride (1.8 mol of acid per mole of base) is thus obtained, decomposing without melting above 250° C. (Analysis, % calculated C: 57.01, H: 5.56, Cl: 17.32, N: 15.64, O: 4.47, % found C: 56.9, H: 5.4, Cl: 17.5, N: 15.7).
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1.C1([Mg]Cl)C=CC=CC=1.[CH3:23][C:24]([CH3:28])([CH3:27])[CH:25]=[O:26]>C1COCC1>[CH3:12][O:11][C:5]1[C:4]([O:13][CH3:14])=[CH:3][C:2]([CH:25]([OH:26])[C:24]([CH3:28])([CH3:27])[CH3:23])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: CC(C)(C)C=O
Reactant: COc1cc(I)c([N+](=O)[O-])cc1OC
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(O)C(C)(C)C)c([N+](=O)[O-])cc1OC
Temperature: 40 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a solution of 4-iodo-5-nitro-1,2-dimethoxybenzene (4.6 g, 15 mmol) in anhydrous THF (10 mL) at minus 40° C. under a nitrogen atmosphere, phenylmagnesium chloride (2 M in THF, 7.5 mL, 15 mmol) was added dropwise at a rate such that the temperature would not exceed minus 35° C. Upon completion of the addition, the mixture was stirred at minus 40° C. for two hours, followed by addition of trimethyl acetaldehyde (2.0 mL, 18 mmol). The mixture was stirred at minus 40° C. for two hours and then at room temperature for another one hour. The reaction was quenched with brine (100 mL), and the mixture was extracted with CH2Cl2 (40 mL) three times. The combined organic phase was dried over Na2SO4 and concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield racemic (R/S)-1-(4,5-dimethoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (0.8 g, 20%). 1H NMR (400 MHz, CDCl3): δ 7.41 (1, 1H, Ph-H), 7.21 (s, 1H, Ph-H), 5.60 (s, 1H, PhCH), 3.95 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 0.90 (s, 9H, (CH3)3).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[NH:20][C:21](=[O:48])[N:22]([C:24]1[N:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[CH:33][C:32]=2[NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:25]=1)[CH3:23].[C:49]([O:53][C:54](=[O:59])[NH:55][CH2:56][CH:57]=O)([CH3:52])([CH3:51])[CH3:50].C([BH3-])#N.[Na+]>C1COCC1.CO>[C:44]([NH:43][C:32]1[CH:33]=[C:34]([N:37]2[CH2:38][CH2:39][N:40]([CH2:57][CH2:56][NH:55][C:54](=[O:59])[O:53][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:41][CH2:42]2)[CH:35]=[CH:36][C:31]=1[NH:30][C:26]1[CH:25]=[C:24]([N:22]([CH3:23])[C:21]([NH:20][C:10]2[C:9]([Cl:8])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[Cl:19])=[O:48])[N:29]=[CH:28][N:27]=1)(=[O:47])[CH:45]=[CH2:46]
Reactant: C=CC(=O)Nc1cc(N2CCNCC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(=O)Nc1cc(N2CCN(CCNC(=O)OC(C)(C)C)CC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.4 %

Procedure:
To the solution of N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(piperazin-1-yl)phenyl)acrylamide 2,2,2-trifluoroacetate (Procedure 2L, Example 157) (30 g, 0.042 mmol) in THF (1.0 ml) and MeOH (1.0 ml) was added tert-butyl(2-oxoethyl)carbamate (13 g, 0.08 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Sodium cyanoborohydride (7.0 g, 0.12 mmol) was added and the reaction mixture was stirred at room temperature over night. Solvent was evaporated and saturated NaHCO3 solution was added. The mixture was extracted three times with DCM. Combined organic layer was dried over Na2SO4 and evaporated. The remaining material was purified by flash chromatography on silica eluting with 0% to 15% MeOH in DCM to afford the title compound (17 mg, yield: 54%) ESI-MS: 744 [M+H]+.
Reaction SMILES: ClC1C=CC(C2(O)CCN(CCC=C3C4C(=NC=CC=4)OC4C=CC=C(OCC(OCC)=O)C=4C3)CC2)=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH:55]=[C:56]3[C:66]4[C:61](=[N:62][CH:63]=[CH:64][CH:65]=4)[O:60][C:59]4[CH:67]=[CH:68][CH:69]=[C:70]([O:71][C:72]([C:75]([O:77]CC)=[O:76])([CH3:74])[CH3:73])[C:58]=4[CH2:57]3)[CH2:49][CH2:48]2)=[CH:43][CH:42]=1>>[C:75]([C:72]([O:71][C:70]1[C:58]2[CH2:57][C:56](=[CH:55][CH2:54][CH2:53][N:50]3[CH2:49][CH2:48][CH:47]([C:44]4[CH:43]=[CH:42][C:41]([Cl:40])=[CH:46][CH:45]=4)[CH2:52][CH2:51]3)[C:66]3[C:61]([O:60][C:59]=2[CH:67]=[CH:68][CH:69]=1)=[N:62][CH:63]=[CH:64][CH:65]=3)([CH3:74])[CH3:73])([OH:77])=[O:76]
Reactant: CCOC(=O)C(C)(C)Oc1cccc2c1CC(=CCCN1CCC(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: CCOC(=O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Product: CC(C)(Oc1cccc2c1CC(=CCCN1CCC(c3ccc(Cl)cc3)CC1)c1cccnc1O2)C(=O)O

Procedure:
The titled compound was prepared by following the procedure of example 133, but replacing the product of example 48 with the product of example 158.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]2[O:9][CH:10]=[C:11]([CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[C:15]([NH:14][CH2:13][CH2:12][C:11]1[C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:19]=[CH:18][C:8]=2[O:9][CH:10]=1)(=[O:17])[CH3:16]
Reactant: COC(=O)c1ccc2occ(CCNC(C)=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NCCc1coc2ccc(C(=O)O)cc12
Reaction time: 8 h

Procedure:
To the ester obtained in Example 62 (2 mmol), dissolved in methanol (90 ml), there is added aqueous 30% sodium hydroxide solution (30 ml), and the mixture is stirred overnight. After evaporating off the methanol, the temperature of the reaction mixture is lowered with the aid of an ice bath and the mixture is acidified with hydrochloric acid solution (6N). The aqueous phase is extracted with ethyl acetate, and the organic phase is dried over magnesium sulphate and then evaporated to dryness. The residue obtained is recrystallised.