Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=O)[CH2:9]2)=[CH:4][C:3]=1[O:23][CH3:24].COC1C=C(N2CCC[C@H](CN3CCN(C)CC3)C2)C=CC=1[N+]([O-])=O>>[CH3:24][O:23][C:3]1[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[CH2:9]2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Agent: COc1cc(N2CCC[C@H](CN3CCN(C)CC3)C2)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC[C@H](CN3CCN(C)CC3)C2)ccc1N

Procedure:
2-Methoxy-4-[(R)-3-(4-methyl-piperazin-1-ylmethyl)-piperidin-1-yl]-phenylamine was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with 1-[(R)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-ylmethyl]-4-methyl-piperazine. (160 mg, 100%). LC/MS (E/I+) 319.22 (M+H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:12][C:13]1[CH:14]=[C:15]([C:21]#[N:22])[C:16](=[CH:19][CH:20]=1)[C:17]#[N:18])([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:6].C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:5]([NH:12][C:13]1[CH:14]=[C:15]([C:21]#[N:22])[C:16](=[CH:19][C:20]=1[N+:1]([O-:4])=[O:2])[C:17]#[N:18])([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc(C#N)c(C#N)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)Nc1cc(C#N)c(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
To 50 ml ice-cooled 100% nitric acid was added gradually 2.0 g (8.2 mmol) 4-ethoxalylaminophthalonitrile. Stirring was continued at 25° C. for 48 h. The reaction mixture was poured into 300 ml ice-water to give 1.6 g crude product. Column chromatography (200 g kiselgel; eluents: toluene containing ethyl acetate) gave 0.7 g (30%) 4-ethoxalylamino-5-nitrophthalonitrile. M.p. 140°-141° C. 1H-NMR (DMSO-d6): 11.7 (1H, s), 8.97 (1H, s), 8.70 (1H, s), 4.4 (2H, q), 1.4 (3H, t), and 0.75 g (32%) 4-ethoxalylamino-3-nitrophthalonitrile. M.p. 140-141° C. 1H-NMR (DMSO-d6) 11.7 (1H, s), 8.4 (2H, dd, J=9Hz), 4,4 (2H, q), 1.4 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][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:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.Cl.[CH:46]1([CH2:49][C:50](O)=[O:51])[CH2:48][CH2:47]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:46]1([CH2:49][C:50]([N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:24]=[CH:25][C:20]([C:17]4[CH:18]=[C:19]5[C:11]([C:9]6[CH:8]=[N:7][N:6]([CH2:5][C:4]7[CH:42]=[CH:43][CH:44]=[C:2]([F:1])[CH:3]=7)[CH:10]=6)=[CH:12][N:13]([S:32]([C:35]6[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=6)(=[O:33])=[O:34])[C:14]5=[N:15][CH:16]=4)=[CH:21][CH:22]=3)[CH2:31][CH2:30]2)=[O:51])[CH2:48][CH2:47]1
Reactant: O=C(O)CC1CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)CC6CC6)CC5)cc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (75 mg, 0.123 mmol) and 2-cyclopropylacetic acid hydrochloride (26 mg, 0.185 mmol) in DMF (2 mL) was added HATU (71 mg, 0.185 mmol), HOBt (25 mg, 0.185 mmol) and DIPEA (86 μL, 0.494 mmol) and stirred at RT overnight. Added ice water and extracted with 10% methanol in DCM. Organic layer was washed with brine solution, dried over sodium sulphate and distilled out the solvent to get 60 mg (70.58%) yield of the title compound. MS: m/z=689.2 (M+1).
Reaction SMILES: C[N:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[N:8]=[CH:7][C:6]([NH:14][C:15](=[O:28])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)=[CH:5][C:4]=2[CH2:3]1.[Cl:29]C(OC(Cl)C)=O.ClC([O-])=O.Cl>C(OCC)C>[ClH:29].[CH3:12][C:10]1([CH3:13])[C:9]2[N:8]=[CH:7][C:6]([NH:14][C:15](=[O:28])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)=[CH:5][C:4]=2[CH2:3][NH:2][CH2:11]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: COc1ccc(C(=O)Nc2cnc3c(c2)CN(C)CC3(C)C)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])Cl
Solvent: CCOCC
Product: COc1ccc(C(=O)Nc2cnc3c(c2)CNCC3(C)C)cc1C(F)(F)F

Procedure:
N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide (172 mg; 0.44 mmol) was suspended in 1.2-dichloromethane (30 ml) and the mixture treated with 1-chloroethyl chloroformate (62.5 mg; 47 ml; 0.44 mmol). The mixture was heated at reflux and more chloroformate added until little or no starting material remained. At this point, the volatiles were removed under reduced pressure and the residue dissolved in methanol (30 ml) and heated at reflux for 15 min. The volatiles were removed under reduced pressure and the residue treated with a mixture of 0.88 aqueous ammonia/methanol/dichloromethane (0.5:4.5:95) and the resulting, beige solid was collected by filtration. The free base (123 mg; 0.32 mmol) was dissolved in methanol (min. vol) and treated with IM hydrogen chloride in diethyl ether (0.32 ml; 0.32 mmol) and the mixture diluted with diethyl ether to turbidity and refrigerated. The title compound was obtained as white powder (130 mg; 71%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[F:20])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Oc1ccccc1F
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Product: CCCCOC(=O)c1nc(Oc2ccccc2F)c2ccccc2c1O

Procedure:
Synthesized from 1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 2-fluorophenol in analogy to Example D-20 d); MS-(+)-ion: M+1=356.1.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18](C1C=C(OC)C=C2C=1C=CN2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cc(OC)cc2[nH]ccc12
Reactant: N#Cc1c[nH]c2cc(Br)ccc12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2c(C#N)c[nH]c2c1

Procedure:
3-(3-Cyano-1H-indol-6-yl)-3-phenyl-acrylic acid ethyl ester CLII was prepared from 6-bromo-1H-indole-3-carbonitrile using the procedure described above for preparation of 3-(6-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester CXVI (Example 25).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]=2[CH:17]=1.Cl.[N:19]([O-])=[O:20].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([N:19]=[O:20])[CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]=2[CH:17]=1
Reactant: O=N[O-]
Reactant: Cc1ccc2c(c1)OC(c1ccccc1)CN2
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)OC(c1ccccc1)CN2N=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7-Methyl-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.4 g) was dissolved in ethanol (6.5 mL), and to it was added 1N HCl (6.5 mL). The reaction mixture was cooled to 0° C., and a solution of sodium nitrite (0.858 g) in water (23 mL) was added. After addition, the reaction mixture was stirred for 2 h at RT. The reaction was monitored by TLC. After completion of reaction, the mixture was evaporated and dried under high vacuum (1.5 g). The crude compound was carried forward to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[NH2:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22]>>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([NH:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22])=[O:8]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: NC(CO)CO
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NC(CO)CO)c1I
Yield: 95 %

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride was reacted with serinol according to the conditions in Example 24g. The product was isolated in 95% yield.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]5[NH:23][C:24]([C:26]6[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]=6)=[CH:25][C:18]=45)[CH:15]=[CH:16][C:11]=3[N:10]=[N:9]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]5[NH:23][C:24]([C:26]6[CH2:31][CH2:30][NH:29][CH2:28][CH:27]=6)=[CH:25][C:18]=45)[CH:15]=[CH:16][C:11]=3[N:10]=[N:9]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4ccc5nnn(CC6CCOCC6)c5c4)ccnc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2cc3c(-c4ccc5nnn(CC6CCOCC6)c5c4)ccnc3[nH]2)CCNC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of Example 36F (0.315 g, 0.612 mmol) in dichloromethane (8 mL) was treated with trifluoroacetic acid (0.472 mL, 6.12 mmol). The mixture was stirred for 16 hours at room temperature then heated at 40° C. for 4 hours. The reaction was concentrated and the residue was dissolved in 2 mL of methanol and treated slowly with 1.5 mL of 2M HCl in ether. The suspension was stirred for 15 minutes then diluted with ether. The solids were filtered, washed with ether, and vacuum oven dried to give the title compound as the hydrochloride salt. 1H NMR (400 MHz, methanol-d4) δ ppm 1.41-1.60 (m, 4H), 2.33-2.50 (m, 1H), 2.80-2.95 (m, 2H), 3.40 (dd, J=11.4, 3.0 Hz, 1H), 3.51 (t, J=6.1 Hz, 2H), 3.87-4.01 (m, 4H), 4.74 (d, J=7.1 Hz, 2H), 6.55 (dt, J=3.5, 2.0 Hz, 1H), 6.91 (s, 1H), 7.53 (d, J=5.6 Hz, 1H), 7.88 (dd, J=8.7, 1.5 Hz, 1H), 8.11-8.28 (m, 2H), 8.40 (d, J=5.6 Hz, 1H). MS (ESI+) m/z 415.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][CH2:2][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.3 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aminomethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (15 mg, 0.025 mmol) in DCM (4 mL) was added TFA (0.4 ml, 5.19 mmol) and the mixture was stirred at room temperature. The color of the solution turned pinkish. After 6 h, the solvent was removed in vacuo and the crude was purified by reverse phase prep. HPLC to afford the title compound as a white foam (12 mg, 80%). LCMS: m/e 544.49 (MH+), 2.60 min (method 3). 1H NMR (500 MHz, MeOD) δ ppm 7.94 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz), 5.32 (1H, dd, J=6.3, 1.7 Hz), 4.77 (1H, d, J=1.8 Hz), 4.66 (1H, s), 3.10-3.24 (1H, m), 2.73-2.84 (1H, m), 2.50 (1H, td, J=10.6, 5.6 Hz), 2.17 (1H, dd, J=17.1, 6.4 Hz), 1.98-2.11 (1H, m), 1.67-1.89 (8H, m), 1.54-1.66 (3H, m), 1.44-1.56 (5H, m), 1.33-1.45 (2H, m), 1.27-1.34 (3H, m), 1.23-1.28 (1H, m), 1.15-1.24 (4H, m), 1.11 (3H, s), 1.06 (3H, s), 0.92-1.02 (6H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([CH2:24][CH3:25])([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=3)[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:26]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:14]([C:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=1)([C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([CH2:3][OH:2])=[CH:26][C:9]=2[CH:10]=1)[CH2:24][CH3:25])[CH3:15]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(C(=O)OC)ccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(CO)ccc2o1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
A solution of 2-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzofuran-5-carboxylic acid methyl ester (710 mg, 2.02 mmol) in THF (40 mL) at 0° C. are added with LAH (153 mg, 4.03 mmol) and the mixture are stirred for 30 minutes. The reaction is quenched with water (0.5 mL), then NaOH (5N, 3.0 mL) and stirred for 10 minutes. The organic layer is concentrated and loaded on column and purified with EtOAc/Hexanes (50%) to obtain the title compound (653 mg, 100%).
Reaction SMILES: C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:30]1[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=O)[CH2:32][CH2:31]1.[CH3:39][O:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][C:42]=1[N:48]1[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]1>ClCCl>[CH3:39][O:40][C:41]1[CH:47]=[CH:46][C:44]([NH:45][C:36]([CH:33]2[CH2:32][CH2:31][CH:30]([C:24]3[C:23]4[C:27](=[CH:28][CH:29]=[C:21]([F:20])[CH:22]=4)[NH:26][CH:25]=3)[CH2:35][CH2:34]2)=[O:38])=[CH:43][C:42]=1[N:48]1[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C2CCC(c3c[nH]c4ccc(F)cc34)CC2)cc1N1CCN(C)CC1
Reaction time: 1 h

Procedure:
173 μl (1.2 mmol) of triethylamine and 230 mg (1.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride are added to a mixture of 314 mg (1.2 mmol) of 4-(5-fluoro-1H-indol-3-yl)cyclo-hexanecarboxylic acid and 265 mg (1.2 mmol) of 4-methoxy-3-(4-methylpiperazin-1-yl)aniline in 40 ml of dichloromethane. This mixture is initially stirred at 0° for one hour, then at room temperature for 12 h. The reaction mixture is concentrated, the residue is taken up in ethyl acetate, and the mixture is washed with water, 5% citric acid and sat. sodium bicarbonate solution, dried and evaporated. After column chromatographic separation, 4-(5-fluoro-1H-indol-3-yl)-cyclohexanoic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2].[CH2:24](Br)[C:25]#[CH:26].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH2:26][C:25]#[CH:24])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(I)cc1F
Reactant: C#CCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C#CCn1c(C(=O)OCC)c(Nc2ccc(I)cc2F)c2cnccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A mixture of 3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (70.0 mg, 0.164 mmol), propargyl bromide (80% in xylene, 45.5 μL, 0.41 mmol, 2.5 eq), DBU (3.2 mL), and anhydrous THF (3.2 mL) was stirred at 50° C. under N2 for 1 h, and then at ambient temperature for 17 h. The solvent was evaporated and the resultant residue was diluted with ethyl acetate (75 mL). The organic layer was washed with water (20 mL), followed by brine (20 mL), dried (Na2SO4), filtered and evaporated to give a brown oil. The oil was purified by flash column chromatography (silica, ISCO, 45 mL/min, Hexane:EtOAc, gradient 100:1 to 1:100). Crystallization from EtOAc-hexane gave the desired compound as a yellow solid (34.5 mg, 45.3%). 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1H), 8.44 (d, J=5.87 Hz, 1H), 7.60 (s, 1H), 7.45 (dd, J=10.26 Hz, 2.0 Hz, 1H), 7.37-7.27 (m, 2H), 6.87 (t, J=9.20 Hz, 1H), 5.29 (s, 2H), 4.46 (q, J=7.14 Hz, 2H), 2.29 (t, J=2.47 Hz, 1H), 1.49-1.40 (t, J=7.20 Hz, 3H); LC-MS (method D): [M+H]+=464.0, RT=2.40 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]1[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:5]2=1.C(Cl)(=O)C(Cl)=O.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=1)=[O:14])[C:6]1[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:5]2=1
Reactant: Nc1ccc(F)cc1
Reactant: CN1CCc2c(n(CC(=O)O)c3ccc(Cl)cc23)C1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(=O)Nc3ccc(F)cc3)c3ccc(Cl)cc23)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetic acid (0.1 g, 0.39 mmol) was dissolved in dichloromethane (4 mL) and was cooled to 0° C., using an ice-bath; oxalyl chloride (0.04 mL, 0.43 mmol) was added drop-wise to the reaction mixture. Catalytic amount (1 drop) of dimethyl formamide was added and the reaction mixture was stirred for 1 h at room temperature. Excess oxalyl chloride was distilled away under reduced pressure. A solution of 4-fluoroaniline (0.042 g, 0.43 mmol) in dichloromethane (2 mL) and 4-dimethylaminopyridine (0.017 g, 0.143 mmol) was added to the residue under nitrogen at room temperature and the reaction mass was stirred for 30 min. The reaction mixture was quenched with water and neutralized with 10% NaHCO3, extracted with dichloromethane (2×10 mL). The combined organic layer was dried over sodium sulfate and concentrated by rotary evaporation to obtain 2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-N-(4-fluorophenyl)acetamide (6 mg) 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 volume 5 mL). 1 H NMR (DMSO): 11.4 (s, 1H), 10.6 (s, 1H), 7.6 (m, 3H), 7.4 (d, 1H), 7.3-7.1 (m, 3H), 5.1 and 4.9 (d, 2H), 4.4 (q, 2H), 4.1-3.9 (bs, 2H), 3.5 (s, 3H), 3.2-3.1 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:19])=[C:16]([OH:29])[CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[OH-:32].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18](=[O:19])[N:20]([CH:24]([CH3:25])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[C:16]([CH:15]=2)[O:29][C:17]([CH3:27])([CH3:16])[C:18]([OH:19])=[O:32])=[CH:30][CH:31]=1)#[N:2]
Reactant: [OH-]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)C(C)C
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1OC(C)(C)C(=O)O)C(C)C

Procedure:
A stirred, refluxing mixture of 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide (0.5 g, 1.18 mmol), sodium hydroxide (480 mg, 1.2 mmol), and 50 mL of acetone is treated with chloroform (125 uL, 1.6 mmol) in 20 mL of acetone. The reaction is refluxed for 4 hours and concentrated in vacuo. The resulting material is partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The resulting material is purified by chromatography on silica gel (20 g) with 40-100% ethyl acetate/hexane followed by 10% MeOH/ethyl acetate as the eluent to afford 5-[5-[4-cyanophenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetic acid as colorless foam. A stirred, 0° C. solution of 5-[5-[4-cyanophenoxylpentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetic acid (210 mg, 0.411 mmol) in 2.0 mL of anhydrous dichloromethane and 150 mL of anhydrous ethanol at 0° C. is treated with anhydrous hydrogen chloride gas over 30 minutes. This solution is stirred at room temperature for 20 hours and the resulting solution is concentrated in vacuo. The resulting ethyl 4-[5-[3-ethoxycarbonyldimethylmethoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxylpentyloxylbenzenecarboximidoate monohydrochloride is then dissolved in 50 mL of anhydrous ethanol in a pressure tube, and treated with anhydrous ammonia for 5 minutes at 0° C. The pressure tube is sealed and heated to 100° C. for 1 hour. Upon cooling and concentrating in vacuo, the resulting material is purified by chromatography on silica gel (15 g) with 5-20% methanol/dichloromethane as the eluent to afford ethyl 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxyl-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate monohydrochloride as colorless foam.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:19]=[C:20]([C:24]4[N:29]=[C:28]([N:30]5[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]5)[CH:27]=[CH:26][N:25]=4)[CH:21]=[CH:22][CH:23]=3)[N:11]=2)[CH:6]=[C:7]([F:9])[CH:8]=1>O1CCOCC1>[F:9][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:29]=[C:28]([N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][N:25]=4)[CH:19]=3)[N:11]=2)[CH:4]=[C:3]([F:2])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(-c3cccc(Cn4nc(-c5cc(F)cc(F)c5)ccc4=O)c3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(-c2nccc(N3CCNCC3)n2)c1
Reaction time: 18 h

Procedure:
6.3 1.3 ml of 4 N HCl in dioxane are added to a solution of 81 mg (0.14 mmol) of tert-butyl 4-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-4-yl)piperazine-1-carboxylate in 1 ml of dioxane, and the mixture is left at room temperature for 18 hours. The reaction mixture is partitioned between water and ethyl acetate. The aqueous phase is adjusted to a pH of 14 using 1 N NaOH and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated: 6-(3,5-difluorophenyl)-2-[3-(4-piperazin-1-ylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one (“A13”) hydrochloride as colourless amorphous solid; ESI 461.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10]C(C)C)=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:20]=1.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:20]=1
Reactant: Cc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(CNc2c(F)ccc(OCC(=O)O)c2C)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of isopropyl 2-[4-fluoro-3-[[3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2-methyl-phenoxy]acetate (200 mg, 0.46 mmol, 1.0 eq) in THF (10 mL) was added LiOH (2M aqueous solution, 4 mL, 8.0 mmol). The reaction mixture was stirred at room temperature for 2 h then the THF was removed in vacuo. The pH of the aqueous solution that remained was adjusted to pH 5 by addition of 3M HCl. The solid precipitate that formed was collected by filtration, washed with water and dried in vacuo to give the title compound as a yellow solid (150 mg, 83%).