Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[C:14]([OH:17])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2].I[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2]
Reactant: CCCn1c(COCC)nc2cnc3ccc(O)cc3c21
Reactant: CC(C)(C)OC(=O)NCCCCCCI
Product: CCCn1c(COCC)nc2cnc3ccc(OCCCCCCNC(=O)OC(C)(C)C)cc3c21

Procedure:
The synthesis of 2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol is described in Parts A-I of Example 2. The general method described in Part L of Example 2 was followed. 2-(Ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (4.43 g, 15.5 mmol) was treated with tert-butyl 6-iodohexylcarbamate (prepared as described in Part F of Example 45, 6.1 g, 18.6 mmol). After the work up, the crude product was not purified to yield 9.9 g of tert-butyl 6-{[2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexylcarbamate as a tan waxy solid that contained DMF and dichloromethane.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:28][CH3:29])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=O)[O:20]C3C=CC=CC=3)=[CH:12][CH:11]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[C:1]([C:5]1[N:6]=[C:7]([CH2:28][CH3:29])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19]([NH:40][S:37]([C:34]3[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][CH:35]=3)(=[O:39])=[O:38])=[O:20])=[CH:12][CH:11]=2)[CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCc1nc(C(C)(C)C)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: CCc1nc(C(C)(C)C)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(4-tert-butyl-2-ethyl-1H-imidazol-1-yl)phenyl]ethylcarbamate and 4-chlorobenzenesulfonamide. MS (ESI) m/z 489 [M+H]+, 487 [M−H]−, 1H-NMR (CDCl3)δ1.12 (3H, t, J=7.5 Hz), 1.31 (9H, s), 2.62 (2H, q, J=7.5 Hz), 2.84 (2H, t, J=7.0 Hz), 3.45-3.54 (2H, m), 6.48 (1H, br),6.65 (1H, s), 7.17 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz), 7.43 (2H, d, J=8.4 Hz), 7.82 (2H, d, J=8.8 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].CS(O[CH2:11][C@@H:12]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH3:13])(=O)=O>C(#N)C>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:13][C@@H:12]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH3:11]
Reactant: C[C@@H](COS(C)(=O)=O)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: NCCCO
Solvent: CC#N
Product: C[C@@H](CNCCCO)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 92.9 %

Procedure:
To a solution of 3-Aminopropanol (5.00 kg, 66.6 mol) in acetonitrile (35 L) was added (S)—N-(1-methanesulfonyloxypropan-2-yl)-2-nitrobenzenesulfonamide (7.00 kg, 20.7 mol) was added at an internal temperature of 10° C. to 20° C. The reaction mixture was further stirred for 16 hours. After confirming the disappearance of the starting materials by TLC, the mixture was concentrated under reduced pressure. To the residue was added water. The resulting solution was acidified with 6 N hydrochloric acid until pH 4, and the insoluble materials were filtered off. The filtrate was made alkaline by adding potassium carbonate until pH 9 and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the target product as a pale yellow oil (6.10 kg, 92.8%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1.[OH:28][CH2:29][CH:30]1[O:35][CH2:34][CH2:33][N:32]([C:36]2[S:37][CH2:38][C:39](=[O:41])[N:40]=2)[CH2:31]1>>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:38]3[S:37][C:36]([N:32]4[CH2:33][CH2:34][O:35][C@H:30]([CH2:29][OH:28])[CH2:31]4)=[N:40][C:39]3=[O:41])=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1
Reactant: O=C1CSC(N2CCOC(CO)C2)=N1
Reactant: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Product: O=C1N=C(N2CCO[C@H](CO)C2)SC1=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-2(S)-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde and 2-(2-Hydroxymethyl-morpholin-4-yl)-thiazol-4-one following General Procedure E.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.S(OC)(O[CH3:20])(=O)=O>C1COCC1>[CH3:20][O:3][CH2:4][C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: CCOC(=O)C1(CO)CCCCO1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(COC)CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60% NaH (40.3 mg, 1.007 mmol) was added to a cold (−20° C.) solution of ethyl 2-(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylate (158 mg, 0.839 mmol) in THF (3 mL) and the mixture was allowed to warm to rt over ˜30 min. Neat dimethyl sulfate (127 mg, 1.007 mmol) was added at 0° C. and allowed to warm to rt and stirred overnight. Excess dimethyl sulfate was quenched with TEA, and then acidified with 1N HCl, product was extracted with ether, washed with water, brine and dried (MgSO4). Crude isolate was purified by silica gel FCC (0-2% MeOH in DCM) to afford ethyl 2-(methoxymethyl)tetrahydro-2H-pyran-2-carboxylate. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.34-4.22 (m, J=7.2, 7.2, 7.2, 4.1 Hz, 2H), 3.96-3.87 (m, 1H), 3.86-3.77 (m, 1H), 3.55-3.43 (m, 2H), 3.36 (s, 3H), 2.17-2.07 (m, 1H), 1.80-1.70 (m, 1H), 1.69-1.56 (m, 2H), 1.55-1.42 (m, 3H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.Cl.Cl.N1([S:41]([CH2:44][CH2:45][CH2:46][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)(=[O:43])=[O:42])CCNCC1.CCN(C(C)C)C(C)C>C1COCC1>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:41]([CH2:44][CH2:45][CH2:46][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)(=[O:43])=[O:42])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Reactant: O=S(=O)(CCCN1CCOCC1)N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCCN3CCOCC3)CC2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) (150 mg, 0.378 mmol), 4-[3-(1-piperazinylsulfonyl)propyl]morpholine dihydrochloride (WO 2006/046040) (172 mg, 0.491 mmol) and DIPEA (0.40 mL, 2.27 mmol) in THF was stirred at room temperature for 17 hrs. The solvent was removed under vacuum, and the residue was diluted with water and extracted with CH2Cl2. The CH2Cl2 was dried (Na2SO4) and removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (98:2) followed by recrystallization from CH2Cl2/hexanes gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[3-(4-morpholinyl)propyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (188 mg, 78%). Treatment with methanesulfonic acid in CH2Cl2/MeOH and recrystallization from MeOH/EtOAc gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[3-(4-morpholinyl)propyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole methanesulfonate: mp 216-218° C.; 1H NMR (DMSO-d6) δ9.50 (br s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 4.01-3.93 (m, 6H), 3.98 (s, 3H), 3.82 (m, 4H), 3.70 (br s, 4H), 3.63 (t, J=12.1 Hz, 2H), 3.45 (d, J=12.6 Hz, 2H), 3.32 (m, 4H), 3.21 (t, J=7.1 Hz, 4H), 3.09 (dd, J=21.2, 11.8 Hz, 2H), 2.30 (s, 3H), 2.09 (m, 2H); Anal. Calcd for C28H41F2N9O8S2: C, 45.8; H, 5.6; N, 17.2. Found: C, 45.7; H, 5.6; N, 17.2%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([N:16]=[C:17]=[S:18])[CH:15]=1.[C:21]([O:25][C:26]([NH:28][CH2:29][CH2:30][NH2:31])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(OCC)(=O)C>[C:21]([O:25][C:26](=[O:27])[NH:28][CH2:29][CH2:30][NH:31][C:17]([NH:16][C:14]1[CH:15]=[C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:11]=[CH:12][C:13]=1[O:19][CH3:20])=[S:18])([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N=C=S
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NC(=S)NCCNC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
The product from Example 26, Step A, [5-(1H-indol-2-yl)-2-methoxy-phenyl]-isothiocyanate, (0.272 g, 1.0 mmol) and mono-tert-butyloxycarbonyl ethylenediamine (0.156 g, 1.0 mmol) were heated briefly to 50° C. in ethyl acetate (20 mL). The reaction mixture was allowed to stand 1 hour at room temperature and was then concentrated. The residue was filtered through silica gel using hexanes/ethyl acetate as eluant The purest product-containing factions were combined, concentrated, and triturated with 3/1, hexanes/ethyl acetate, v/v, to give the product as an off-white solid (0.09 g), mp 159-160° C.
Reaction SMILES: CS(O[CH2:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.CCOC(C)=O>[N:18]([CH2:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)=[N+:19]=[N-:20]
Reactant: CS(=O)(=O)OCC/C=C/c1ccc(Cl)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCC/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.5 %

Procedure:
To a solution of Intermediate 2C (1.3 g, 4.4 mmol) in DMF (7 mL) was added NaN3 (0.86 g, 13 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (100 mL). The organic layer was washed with 10% aqueous LiCl solution (3×200 mL), dried over Na2SO4 and dried in vacuo. The product was isolated by silica gel chromatography to obtain 570 mg (87% yield) of Intermediate 2D. HPLC/MS (Method C) RT=4.02 min, [M+Na]+ 263.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:38]=[CH:37][C:9]2[N:10]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:30])[NH:24][CH:25]([C:27](=O)N)[CH3:26])[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[Cl:39][C:40]1[CH:46]=CC(N)=C[CH:41]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:38]=[CH:37][C:9]2[N:10]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:30])[NH:24][C:25]3[CH:27]=[CH:46][C:40]([Cl:39])=[CH:41][CH:26]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NC(C)C(N)=O)ccc3c1)n2C1CCCCC1
Reactant: Nc1ccc(Cl)cc1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)Nc4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1

Procedure:
The title compound was prepared as described for Compound 497a using 4-chloroaniline in place of L-alaninamide yielding 91 mg yellow solid. MS: 553.23 (M+H+).
Reaction SMILES: N1C=CN=C1.[I:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15]>ClCCl>[C:14]([Si:18]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([I:6])[CH:8]=1)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1cccc(I)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.2 %

Procedure:
Imidazole (7.8 g, 115 mmol) was added to a solution of 3-iodophenol (12.7 g, 58 mmol) and tert-butyl(chloro)dimethylsilane (9.9 g, 65 mmol) in dichloromethane (80 mL) at 0° C. The reaction mixture was stirred at rt overnight. The suspension was washed three times with water and once with brine, dried and concentrated to give crude tert-butyl(3-iodophenoxy)dimethylsilane (20 g, 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][S:21]([OH:24])(=[O:23])=[O:22])[C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][S:21]([OH:24])(=[O:23])=[O:22])[C:13]=3[N:14]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(OS(=O)(=O)O)c2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(OS(=O)(=O)O)c2nc(-c3ccc(N)cc3)sc2c1
Yield: 62.4 %

Procedure:
To a solution of 2-(4′-nitrophenyl)-6-methylsulfoxy benzothiazole (35 mg, 0.10 mmol) dissolved in ethanol (10 mL) was added SnCl2.2H2O (50 mg). The reaction mixture was heated to reflux for 1.5 hr. The solvent was then removed under reduced pressure. The residue was dissolved in ethyl acetate (10 mL), washed with 1N NaOH, water, dried over MgSO4. Evaporation of the solvent afforded 2-(4′-aminophenyl)-6-methylsulfoxy benzothiazole (21 mg, 65%) as pale brown solid. 1HNMR (300 MHz, CDCl3) δ (ppm): 8.02 (d, J=6.2 Hz, 1H), 7.92 (d, J=8.7 Hz, 2H), 7.84 (d, J=2.4 Hz, 1H), 7.38 (dd, J1=2.4 Hz, J2=6.2 Hz, 1H), 6.78 (d, J=8.7 Hz, 2H), 2.21 (s, 3H, CH3).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[CH:26]=[C:25]([O:27][C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[NH:32][C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)[C:22]([C:23]#[N:24])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:38][C:36]1[C:31]2[NH:32][C:33](=[O:35])[O:34][C:30]=2[CH:29]=[C:28]([O:27][C:25]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:26]=2)[CH:37]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1cc(Oc2cc(Cl)ncc2C#N)cc2oc(=O)[nH]c12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncc2C#N)cc2oc(=O)[nH]c12

Procedure:
40 mg (0.16 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 40 mg (0.12 mmol) 6-chloro-4-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yloxy)-nicotinonitrile and 0.08 mL (0.47 mmol) DIPEA in 0.80 mL NMP were stirred for 1 h at 140° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with aqueous NaHCO3 solution. The precipitate formed was suction filtered and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24](O)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH:10]([CH3:29])[CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[CH3:62][C:63]1([CH3:68])[CH2:67][CH2:66][NH2+:65][CH2:64]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:21][CH:22]([C:24]([N:65]4[CH2:66][CH2:67][C:63]([CH3:68])([CH3:62])[CH2:64]4)=[O:25])[CH2:23]3)[N:14]3[C:18]([N:19]=[C:11]2[CH:10]([CH3:29])[CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCc2c1nc1ccnn1c2N1CC(C(=O)O)C1
Reactant: CC1(C)CC[NH2+]C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OC(C)(C)C)CCc2c1nc1ccnn1c2N1CC(C(=O)N2CCC(C)(C)C2)C1
Reaction time: 0.5 h

Procedure:
To 300 mg (0.57 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5-methyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) in 6.0 mL DMF was added 484 mg (1.51 mmol) TBTU and 243 μL (1.41 mmol) DIPEA and stirring was continued at room temperature for 30 min. Then 84.3 mg (0.62 mmol) of 3,3-Dimethyl-pyrrolidinium chloride was added and the reaction mixture was stirred additional 4 h. The reaction mixture was filtered and the purified by HPLC.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][NH:34][CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>CN(C=O)C>[C:44]([N:34]1[CH2:35][CH2:36][N:29]2[CH:30]([CH2:31][O:32][CH:27]([C:19]3[N:20]4[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[C:17]([C:12]4[CH:13]=[CH:14][C:15]5[C:10]([CH:11]=4)=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:16]=5)[CH:18]=3)[CH2:28]2)[CH2:33]1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCN2CC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
To a stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.10 mmol), triethylamine (29 μL, 0.21 mmol), in DMF (1 mL) at 0° C., acetic anhydride (11 μL, 0.11 mmol) was added. The reaction was allowed to stir for 20 minutes while warming to rt. The mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous K2CO3 solution (10 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 19 mg (35%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.35-7.28 (m, 5H), 7.10 (dd, 1H), 6.71 (s, 1H), 5.64 (s, 2H), 5.14 (dd, 1 H), 4.33-4.21 (m, 1H), 3.91-3.84 (m, 1H), 3.79-3.68 (m, 1H), 3.39-3.27 (m, 2H), 3.06-3.00 (m, 1H), 2.76-2.64 (m, 2H), 2.41-2.37 (m, 1H), 223-2.11 (m, 1H), 2.07-1.95 (m, 1H), 1.99 (s, 3H); LC-MS [M+H]+=523, RT=2.24 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[I:11].[OH-].[K+].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].Cl>CS(C)=O.O>[I:11][C:3]1[C:2]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[N:7][CH:6]=[C:5]([CH:4]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(I)c1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
6-Chloro-5-iodo-3-pyridinecarboxylic acid (CAN 59782-87-5, 4.7 g, 16.6 mmol) was dissolved in DMSO (49.5 ml). Potassium hydroxide pellets (2.79 g, 49.7 mmol) and 2,2,2-trifluoroethanol (2.16 g, 1.55 ml, 21.6 mmol) were added slowly at room temperature under argon. The reaction mixture was stirred for 2 h at rt; water (35 mL) was added and the mixture was cooled to 0-5° C. Concentrated HCl solution (8 mL) was added drop by drop and the precipitated solid was collected, washed with cold water and dried. The crude material was purified by flash chromatography (silica gel, 150 g, 0% to 20% i-propyl acetate in n-heptane +10% of acetic acid) to give the title compound (1.6 g, 28%) as colorless solid; MS (ESI) 345.7 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][C:14]([C:20](O)=[O:21])=[CH:13]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:45])[C@@H:28]([NH2:44])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:32][CH:31]=1>>[CH3:25][O:26][C:27](=[O:45])[CH:28]([NH:44][C:20]([C:14]1[N:15]=[CH:16][C:17]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:9][C:8]1[CH:23]=[CH:24][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)=[CH:19][CH:18]=2)=[O:21])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cnc(C(=O)O)cc3c2)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)c1cc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2cn1
Yield: 75.5 %

Procedure:
870 mg (2.71 mmol) of 6-(4-tert-butylphenoxy)-isoquinoline-3-carboxylic acid (example 295) was reacted with 871 mg (2.71 mmol) of (2S)-amino-3-(4-benzyloxy-phenyl)-propionic acid methyl ester as described in general procedure A. The crude product was purified by flash column chromatography on silica using 3:2 hexane/ethyl acetate as eluent to afford 1.205 g of 3-(4-benzyloxy-phenyl)-2-{[6-(4-tert-butyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-propionic acid methyl-ester as a white solid. LCMS 590 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[CH:17]=[C:16]([C:35]([F:38])([F:37])[F:36])[CH:15]=1>>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[CH:17]=[C:16]([C:35]([F:37])([F:38])[F:36])[CH:15]=[C:14]([NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)[N:19]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: COc1cc(Nc2cc(C(F)(F)F)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Nc1cccc(OC(F)(F)F)c1
Product: COc1cc(Nc2cc(C(F)(F)F)cc(Nc3cccc(OC(F)(F)F)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-(trifluoromethoxy)aniline and (6-chloro-4-trifluoromethyl-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a yellowish solid (Yield=63%). MS ISP (m/e): 524.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.65 (d, 1H), 7.42 (s broad, 1H), 7.35-7.25 (m, 2H), 7.19 (d, 1H), 7.12 (d, 1H), 7.00 (dxd, 1H), 6.95-6.85 (m, 2H), 6.77 (d, 1H), 6.50 (s, 1H), 6.46 (s, 1H), 3.73 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.C([Li])CCC.[CH3:15][C:16]([CH3:18])=[O:17]>C1(C)C=CC=CC=1>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:16]([OH:17])([CH3:18])[CH3:15])=[N:3][CH:4]=1
Reactant: CC(C)=O
Reactant: Cc1cc(Br)ncc1Br
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)(C)O)ncc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
2,5-Dibromo-4-methylpyridine (4.0 g, 15.94 mmol) was dissolved in toluene (60.0 mL) and the reaction was cooled to −78° C. Butyllithium (7.01 mL, 17.54 mmol) was added dropwise and the reaction was allowed to stir for 30 min. Acetone (4.69 mL, 63.8 mmol) was then added and the reaction was allowed to warm to rt and stir for 16 h. The reaction was quenched with saturated ammonium chloride, extracted into ethyl acetate (3×200 mL) and washed with water followed by brine. The organics were dried over magnesium sulfate and volatiles removed under reduced pressure. The compound was purified on silica gel chromatography (0-50% ethyl acetate in hexanes) to afford 2-(5-bromo-4-methylpyridin-2-yl)propan-2-ol (2.33 g, 10.13 mmol, 63.5% yield). MS (ESI) m/z 230.3 [M]+, 232.3 [M+2]+.