Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([F:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:45][C:43]1[CH:42]=[C:4]([CH:3]=[C:2]([F:1])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([F:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(F)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)cc(F)c5)c4)c3c2)ccc1F
Yield: 37.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenyl)methane sulfonamide (53 mg, 0.184 mmol) was hydrolyzed by lithium hydroxide (18 mg, 0.407 mmol) in THF/methanol/water (15/5/5 ml) to yield 34 mg (85% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.44-8.43 (d, 1H), 8.35-8.34 (d, 1H), 8.23 (s, 1H), 7.953-7.951 (d, 1H), 7.80-7.77 (dd, 1H), 7.66 (s, 1H), 7.59-7.55 (m, 1H), 7.34-7.29 (m, 1H), 6.90-6.86 (m, 2H), 5.43 (s, 2H), 305 (s, 3H). MS: m/z=498.1 (M+1), HPLC: 93.19% in method B.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:19][NH2:20]>>[NH:19]([C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:20]
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Reactant: NN
Solvent: O
Product: NNc1cc(-c2ccccc2)c2ccccc2n1

Procedure:
Refluxing a 2-chloro-4-phenylquinoline (1) with hydrazine hydrate to give a 2-hydrazino-4-phenylquinoline (II);
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)C3SC=C(C4C=CC=CC=4)C=3N=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.[F:50]C1C=CC(N)=CC=1>C(O)(=O)C>[F:50][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[C:24]=3[N:23]=[CH:12]2)=[CH:2][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3F)c2ncn1-c1ccc(F)cc1
Yield: 27 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (88 mg, 0.35 mmol), triethyl orthoformate (0.77 ml), 4-fluoroaniline (63 ml, 0.46 mmol), and acetic acid (0.09 ml) were used to give 32 mg (0.095 mmol, 27% yield) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C([C:13]1[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=1[N:21]=[CH:22][N:23]([CH3:25])C)#N.C(O)(=O)C>C(O)C>[F:19][C:18]1[CH:17]=[CH:16][C:15]([F:20])=[C:14]2[C:13]=1[C:25]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[N:23][CH:22]=[N:21]2
Reactant: NCCc1ccc(O)cc1
Reactant: CN(C)C=Nc1c(F)ccc(F)c1C#N
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ccc(CCNc2ncnc3c(F)ccc(F)c23)cc1
Temperature: 75 °C
Yield: 78.1 %

Procedure:
A mixture of tyramine (2.62 g, 19 mmol), N′-(2-cyano-3,6-difluorophenyl)-N,N-dimethylformamidine (2.0 g, 9.56 mmol), acetic acid (3.4 mL, 60 mmol) and ethanol (50 mL) was heated at 75° C. for 16 h. Upon cooling, the solvent was removed under reduced pressure and the remaining solid was stirred in water for a few minutes, collected by suction filtration and washed with water. The filter cake was dried under vacuum to give 2.25 g (78%) of 4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-phenol as an off-white solid, M.P. 221-222° C. 1H NMR (d6-DMSO): δ 9.16 (s, 1H), 8.53 (s, 1H), 7.73 (m, 1H), 7.59 (m, 1H), 7.52 (m, 1H), 7.05 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.4 Hz, 2H), 3.74 (q, J=7.8, 5.7 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H). LC/MS: 302.04 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:15]([CH3:16])=[C:14]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[N:20]=3)[C:13]([CH3:26])=[C:12]([CH2:27][NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[N:30]=3)[C:11]=2[CH3:36])[CH:5]=[CH:4][CH:3]=1.CO[CH:39](OC)[CH2:40][C:41](=O)[CH3:42].OP(O)(O)=O>O>[CH3:39][C:40]1[N:35]=[C:31]2[C:32]([CH:33]=[CH:34][C:29]([NH:28][CH2:27][C:12]3[C:11]([CH3:36])=[C:10]([CH2:9][NH:8][C:6]4[CH:5]=[CH:4][C:3]5[C:2](=[N:1][C:4]([CH3:5])=[CH:3][CH:2]=5)[N:7]=4)[C:15]([CH3:16])=[C:14]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]5[C:21](=[N:25][C:11]([CH3:12])=[CH:10][CH:9]=5)[N:20]=4)[C:13]=3[CH3:26])=[N:30]2)=[CH:42][CH:41]=1
Reactant: COC(CC(C)=O)OC
Reactant: Cc1c(CNc2cccc(N)n2)c(C)c(CNc2cccc(N)n2)c(C)c1CNc1cccc(N)n1
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1ccc2ccc(NCc3c(C)c(CNc4ccc5ccc(C)nc5n4)c(C)c(CNc4ccc5ccc(C)nc5n4)c3C)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
1,3,5-Tris[(6-amino-pyridin-2-yl)aminomethyl]-2,4,6-trimethylbenzene (2a) (2.0 g, 4.1 mmol), 4,4-dimethoxy-2-butanone (12.3 mmol), and H3PO4 (50 mL) were held at 90° for 4 h and then stirred at room temperature for 2 h. The reaction mixture was poured into water (200 mL), neutralized, and extracted several times with chloroform. The collected organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified several times by column chromatography (silica gel, CHCl3/CH3OH, 7:1 to 2:1 v/v). Yield 30%. M.p. 207-208° C. 1H-NMR (400 MHz, CDCl3): δ=2.34 (s, 9H), 2.61 (s, 9H), 4.71 (d, 6H, 3H, J=3.0 Hz), 5.12 (t, 3H, J=3.0 Hz), 6.60 (d, 3H, J=8.8 Hz), 6.98 (d, 3H, J=8.0 Hz), 7.65 (d, 3H, J=8.8 Hz), 7.74 (d, 3H, J=8.0 Hz). 13C NMR (100 MHz, CDCl3): δ=15.9, 25.0, 41.1, 112.4, 114.9, 115.9, 133.3, 136.0, 136.5, 137.2, 156.5, 158.7, 161.3. HR-MS calcd for C39H38N9: 632.3250; found: 632.3256. Rf=0.80 (CHCl3/CH3OH 2:1 v/v).
Reaction SMILES: [OH2:1].[O:2]=[C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][CH:5](CCN2CCC(C(O)=O)CC2)[O:4]1.[OH-].[Na+].[O:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[O:2]=[C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][C@H:5]([CH2:3][N:7]2[CH2:6][CH2:5][CH:36]([C:37]([OH:33])=[O:1])[CH2:35][CH2:34]2)[O:4]1
Reactant: O=C(O)C1CCN(CCC2CN(C3CCN(c4ccncc4)CC3)C(=O)O2)CC1
Reactant: O
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCN(C[C@H]2CN(C3CCN(c4ccncc4)CC3)C(=O)O2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 230 mg of the ethyl ester prepared in e) in 2 ml tetrahydrofuran and 1 ml water is admixed with 0.7 ml 1 n sodium hydroxide solution and stirred for 1 h at room temperature. Subsequently the tetrahydrofuran is removed in a vacuum and the product is purified by means of an ion exchanger (Dowex 50, H form). 120 mg of the title compound is obtained in this way as a white powder. FAB=388; 1H-NMR (d6 -DMSO) δ=8.15 ppm (d, 2H); 6.82 (d, 2H); 4.60 (m, 1H); 4.02 (broad d, 2H); 3.75 (m, 1H); 3.50 (t, 1H); 3.15 (dd, 1H); 2.95 (broad d, 2H); 2.80 (m, 2H); 2.52 (m, 2H); 2.10 (m, 3H); 1.80-1.40 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:34]=[N:35][C:36]([O:39][CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:37][CH:38]=2)=CC=1)([O-])=O>C(Cl)Cl>[CH:40]1([O:39][C:36]2[N:35]=[CH:34][C:33]([NH:32][C:31]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:30])=[CH:38][CH:37]=2)[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C(Nc1ccc(OC2CCCC2)nc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(OC5CCCC5)nc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (12 mg, 0.044 mmol), prepared as described in Example 1d, (6-cyclopentyloxy-pyridin-3-yl)-carbamic acid 4-nitro-phenyl ester (20 mg, 0.058 mmol), prepared as described in the previous step, and DCM (500 uL) was treated with TEA (6 uL, 0.043 mmol) in one portion at rt. The homogeneous amber solution was stirred at rt for 2 h, diluted with DCM (2 mL), and washed with H2O (2 mL). The aqueous layer was extracted with DCM (2×2 mL), the organic layers were combined, dried (Na2SO4) and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound (6.0 mg, 29%). 1H-NMR (300 MHz, CDCl3): δ 9.10 (s, 1H), 8.08 (s, 1H), 7.89 (d, 1H), 7.39 (s, 1H), 7.28 (s, 1H), 6.71 (d, 1H), 6.61 (bs, 1H), 5.30 (m, 1H), 4.32 (d, 2H), 4.08 (s, 6H), 3.62 (m, 1H), 3.20 (m, 2H), 2.16 (m, 2H), 1.98 (m, 4H), 1.79 (m, 4H), 1.62 (m, 2H). LC/MS (ESI) calcd for C26H31N5O4 477.56, found [M+1]+ 478.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]1)[N:8]=[CH:7][C:6]([C:23]#[N:24])=[C:5]2[NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=2)=[C:28]([Cl:39])[CH:27]=1.C(N(CC)C1C=CC=CC=1)C.[C:51](Cl)(=[O:53])[CH3:52].CN1CC[CH2:58][C:57]1=[O:61]>>[C:51]([N:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][CH:15]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:16][CH2:17]1)[N:8]=[CH:7][C:6]([C:23]#[N:24])=[C:5]2[NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=2)=[C:28]([Cl:39])[CH:27]=1)[C:57](=[O:61])[CH3:58])(=[O:53])[CH3:52]
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)c(N)cc23)cc1Cl
Reactant: CN1CCCC1=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)c1ccccc1
Product: CC(=O)N(C(C)=O)c1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cold (0° C.-5° C.) solution of 1.2 g (2.14 mmol) of 6-amino-4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamino]-7-(4-pyrrolidin-1-yl-piperidin-1-yl)quinoline-3-carbonitrile and 3.6 ml (22.6 mmol) of N,N-diethyl aniline in 18 mL of 1-methyl 2-pyrrolidinone is added dropwise 1.6 ml (21.2 mmol) of acetyl chloride. The resulting mixture is stirred at room temperature for 4 hours. The solvent is removed in vacuo to yield a residue, which is triturated with ether. A saturated solution of sodium bicarbonate is added to the resulting solid and the mixture is stirred, collected by filtration and dried in vacuo. Purification by silica gel chromatography (gradient 95:5methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 738 mg of N-acetyl-N-[4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-3-cyano-7-(4-pyrrolidin-1-yl-piperidin-1-yl)quinolin-6-yl]acetamide as a beige solid, mp 245-247° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[CH:19]=[N:18]1>>[NH:17]1[C:25]2[C:20](=[CH:21][C:22](/[CH:26]=[C:11]3/[C:12](=[O:16])[NH:13][C:14]4[C:10]/3=[CH:9][CH:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:15]=4)=[CH:23][CH:24]=2)[CH:19]=[N:18]1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Product: O=C1Nc2cc(-c3cccnc3)ccc2/C1=C\c1ccc2[nH]ncc2c1

Procedure:
According to the method of Example A19, utilizing 6-(pyridin-3-yl)indolin-2-one (25 mg, 0.12 mmol) and 1H-indazole-5-carbaldehyde (17.4 mg, 0.12 mmol), the title compound was obtained as an orange solid (7 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.32 (br. s., 1H), 10.81 (s, 1H), 9.04 (s, 1H), 8.89 (d, J=1.26 Hz, 1H), 8.57 (dd, J=4.55, 1.26 Hz, 1H), 8.52 (d, J=7.83 Hz, 1H), 8.25 (s, 1H), 8.06-8.11 (m, 1H), 8.04 (s, 1H), 7.87 (d, J=7.83 Hz, 1H), 7.62 (d, J=8.84 Hz, 1H), 7.49 (dd, J=7.33, 4.55 Hz, 1H), 7.38 (dd, J=7.83, 1.26 Hz, 1H), 7.11 (d, J=1.01 Hz, 1H); MS ESI 339.1 (100) [M+H]+, calcd for [C21H14N4O+H]+ 339.4.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH:8]([CH3:10])[CH3:9])[C:6](=[O:11])[N:5]([CH3:12])[CH2:4][N:3]1[CH3:13].[Br:14]Br>C(Cl)Cl>[Br-:14].[O:1]=[C:2]1[N:7]([CH:8]([CH3:9])[CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[CH2:4][NH+:3]1[CH3:13]
Reactant: CC(C)N1C(=O)N(C)CN(C)C1=O
Reactant: BrBr
Solvent: ClCCl
Product: CC(C)N1C(=O)N(C)C[NH+](C)C1=O
Product: [Br-]
Reaction time: 1 h
Yield: 75.1 %

Procedure:
18.5 g (0.1 mol) of 2,4-dioxo-hexahydro-1,5-dimethyl-3-isopropyl-s-triazine are dissolved in 20 ml of methylene chloride and 24 g (0.15 mol) of bromine are added dropwise. After one hour, the orange-coloured precipitate which has separated out is filtered off and recrystallised from isopropanol. 20 g (75%) of 2,4-dioxo-1,2,3,4-tetrahydro-1,5-dimethyl-3-isopropyl-s-triazinium bromide of melting point 212°-214° C are obtained.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].O>ClCCl>[Cl:18][CH2:19][C:20]([O:11][CH2:10]/[CH:9]=[C:7](\[CH3:8])/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])=[O:21]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/COC(=O)CCl
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Geraniol [1] (7.711 g, 50 mmol) and pyridine (3.955 g, 50 mmol) were suspended in anhydrous dichloromethane (200 ml) and chilled to 0° C. under an atmosphere of dry nitrogen. Chloroacetylchloride (5.647 g, 50 mmol) was added dropwise (violent reaction) and the resulting solution was stirred for 24 hrs at room temperature. Water (100 ml) was added, the organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organic layers were successively washed with 2N HCl, saturated NaHCO3 solution and brine, dried over MgSO4 and the solvent was evaporated. Remaining volatile material was removed under reduced pressure (0.01 mbar) to yield product [2] as yellow liquid. The product was pure according to 1H NMR and directly subjected to the next step without further purification.
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([N:33]1[CH2:32][CH2:31][CH:30]([C:23]2[CH:22]=[C:21]3[C:26]([CH2:27][CH:28]([CH3:29])[N:19]([C:17]4[CH:18]=[C:13]([N:10]5[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]5)[N:14]=[C:15]([NH2:36])[N:16]=4)[CH2:20]3)=[CH:25][CH:24]=2)[CH2:35][CH2:34]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and acetyl chloride. LCMS (M+H)+: m/z=464.4.
Reaction SMILES: CO/[N:3]=[C:4](\[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)/[CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1.O.[OH-].[Na+].C(OCC)C>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:4]([NH2:3])[CH2:5][N:6]2[CH:10]=[CH:9][CH:8]=[N:7]2)=[CH:12][CH:13]=1
Reactant: CO/N=C(/Cn1cccn1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: NC(Cn1cccn1)c1ccc(Cl)cc1
Yield: 55 %

Procedure:
Borane tetrahydrofuran complex (15.00 mL, 15.00 mmol) was added to a stirred solution of (Z) and (E)-1-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)ethanone O-methyl oxime (Intermediate 91) (0.749 g, 3 mmol) dissolved in THF (30 mL) at room temperature under argon. The resulting solution was stirred under reflux for 3 hours. The mixture was cooled in an ice/water bath and water (25 ml) was carefully added followed by 20% NaOH (25 ml). The resulting biphasic mixture was refluxed overnight with vigorous magnetic stirring and allowed to cool. Diethyl ether was added and the layers were separated. The organic layer was further extracted with diethyl ether dried over MgSO4, filtered and evaporated to give the crude product (741 mg, 55%). This was used directly in the following reaction.
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][C@H:22]([NH2:27])[C:23]([O:25][CH3:26])=[O:24])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].FC(F)(F)C(O)=O>C(#N)C>[I:1][C:16]1[CH:17]=[C:18]([O:19][CH3:20])[C:13]([O:12][CH3:11])=[CH:14][C:15]=1[CH2:21][C@H:22]([NH2:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: NC(=O)CCC(=O)NI
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1cc(OC)c(OC)cc1I
Yield: 84.3 %

Procedure:
To a solution of N-iodosuccinamide (8.3 g, 37 mmol) in 80 mL of dry acetonitrile were added (S)-3-(3,4-dimethoxyphenyl)1-methoxy-1-oxopropan-2-amine hydrochloride (4.63 g, 16.8 mmol) and trifluoroacetic acid (2.7 mL, 37 mmol) with stirring. The reaction mixture was stirred at room temperature in a 250 mL round bottom flask protected from light for 2 and half hours. The acetonitrile was removed and the remaining solid was taken up into water. The water solution was treated with saturated sodium bisulfite aqueous solution until the purple color disappeared. The pH was adjusted to 8 using saturated sodium bicarbonate solution. The neutralized aqueous solution was extracted with dichloromethane (3×50 mL) The organic layers were combined and dried over sodium sulfate. The solvent was evaporated to yield (S)-3-(2-Iodo-4,5-dimethoxyphenyl)-1-methoxy-1-oxopropan-2-amine (5.17 g, 98%) as a pale yellow oil. The crude product was dried over dynamic vacuum overnight and was sufficiently pure for subsequent steps.
Reaction SMILES: C([NH:8][C@H:9]([C:11](O)=O)[CH3:10])(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CO[C:49](=O)[C@H:50]([NH:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=1)[CH2:51][CH3:52]>CN(C=O)C.O>[CH2:51]([C@@H:50]1[CH2:49][NH:8][C@@H:9]([CH3:11])[CH2:10][N:53]1[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=1)[CH3:52]
Reactant: CC[C@@H](NCc1ccc(OC)cc1)C(=O)OC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H]1CN[C@@H](C)CN1Cc1ccc(OC)cc1
Reaction time: 8 h
Yield: 145.2 %

Procedure:
To a solution of 3.99 g of Boc-L-alanine in 50 ml of DMF were added 12.02 g of HATU, 4.3 ml of Hünig's base and 5.00 g (R)-2-(4-Methoxy-benzylamino)-butyric acid methyl ester. The reaction was stirred overnight, and 6.01 g of HATU and 2.1 ml of Hünig's base were added, and the reaction was stirred for 24 h at r.t. and then for 4 h at 50° C. The reaction was poured unto water, the layers were separated and the aqueous phase was extracted with EtOAc twice. The combined organic layers war washed with 10% aqueous citric acid twice, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc) to obtain 7.60 g (88%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:19][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[Cl:9])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2Cl)ccn1
Temperature: 160 °C
Reaction time: 144 h
Yield: 10.8 %

Procedure:
2-Amino-4-chloropyridine (2.57 g) was dissolved in dimethylsulfoxide (30 ml), and then 2-chloro-4-nitrophenol (6.94 g) and N,N-diisopropylethylamine (14 ml) were added thereto, followed by stirring at 160° C. for 6 days. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and a 1 N aqueous solution of sodium hydroxide. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2, then ethyl acetate) to provide the titled compound (574 mg, 11%) as brown powder.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][C:8]=2[CH3:16])=[O:6])[CH2:3][CH2:2]1.[Br:17][C:18]1[CH:19]=[C:20]([NH2:27])[C:21]2[N:25]=[CH:24][NH:23][C:22]=2[CH:26]=1.[N+]1([O-])C=CC=CC=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH2:27][C:20]1[C:21]2[N:25]=[CH:24][N:23]([C:10]3[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[C:8]([CH3:16])[CH:9]=3)[C:22]=2[CH:26]=[C:18]([Br:17])[CH:19]=1
Reactant: Cc1cc(B(O)O)ccc1C(=O)NC1CC1
Reactant: Nc1cc(Br)cc2[nH]cnc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [O-][n+]1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(-n2cnc3c(N)cc(Br)cc32)ccc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a stirred solution of [4-(cyclopropylcarbamoyl)-3-methylphenyl]boronic acid (13.95 g, 63.68 mmol) in DCM (160 mL) at rt was added under a nitrogen atmosphere 6-bromo-1H-benzimidazol-4-amine (6.75 g, 31.84 mmol), copper(II)acetate (11.57 g, 63.68 mmol), pyridine N-oxide (3.33 g, 35.02 mmol) and pyridine (7.55 g, 95.53 mmol). After stirring overnight at rt, the mixture was stirred at 40° C. for 3 days. Filtration through ALLOX, extraction with water and evaporation of the organic phase gave the crude product, which was purified by flash chromatography to yield 6 g 4-(4-amino-6-bromo-1H-benzimidazol-1-yl)-N-cyclopropyl-2-methylbenzamide (50%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].CC1C=CC(S(O[CH2:23][CH2:24][CH2:25][S:26][C:27]2[CH:32]=[CH:31][C:30](/[C:33](/[C:40]3[NH:41][C:42](=[O:47])[C:43]([CH3:46])=[CH:44][CH:45]=3)=[CH:34]\[CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:29][C:28]=2[Cl:48])(=O)=O)=CC=1.O>C(#N)C>[Cl:48][C:28]1[CH:29]=[C:30](/[C:33](/[C:40]2[NH:41][C:42](=[O:47])[C:43]([CH3:46])=[CH:44][CH:45]=2)=[CH:34]\[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:31]=[CH:32][C:27]=1[S:26][CH2:25][CH2:24][CH2:23][N:9]([CH2:10][CH3:11])[CH2:7][CH3:8]
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OCCCSc2ccc(/C(=C\C3CCCC3)c3ccc(C)c(=O)[nH]3)cc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN(CC)CCCSc1ccc(/C(=C\C2CCCC2)c2ccc(C)c(=O)[nH]2)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
Potassium carbonate (290 mg) and diethylamine (219 μL) were sequentially added to a solution of 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-methyl-6-oxo-1,6-dihydropyridin-2-yl)ethenyl]phenyl}sulfanyl)propyl 4-methylbenzenesulfonate (33 mg) in acetonitrile (3 mL), and the mixture was stirred at 90° C. for two hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give the title compound (18 mg, 66%) as a colorless amorphous.