Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7](OC1C=CC=CC=1)=[O:8].Br.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH2:28])=[CH:21][CH:20]=1.C(N(CC)CC)C>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])=[O:8])=[CH:21][CH:20]=1
Reactant: COc1ccc(OCCN)cc1
Reactant: O=C1CCCN1C(=O)Oc1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Product: COc1ccc(OCCNC(=O)N2CCCC2=O)cc1
Temperature: 110 °C
Yield: 118.5 %

Procedure:
A mixture of 1.16 g (5.64 mmol) of 2-oxo-1-phenoxycarbonylpyrrolidine (II) were added 2.0 g (8.06 mmol) of 2-(4-methoxyphenyloxy)ethylamine hydrobromide and 1.63 g (16.1 mmol) of triethylamine was heated at 110° C. for 3 hr. After evaporation of the solvent, the residue was refined by silica gel column chromatography, whereby 1.86 g of the objective compound (I a-42) was obtained as crystals from the eluate with toluene/ethyl acetate (5/1-3/1 v/v). Yield: 83.0%
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: ClCCCOc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCOc1ccncc1
Temperature: 90 °C
Yield: 56.5 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol), (prepared as described for the starting material in Example 24), 4-(3-chloropropoxy)pyridine hydrochloride (206 mg, 1.0 mmol) and potassium carbonate (303 mg, 2.2 mmol) in NMP (20 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyloxy)propoxy)quinazoline (257 mg, 56%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[C:2]=[S:3].[OH:10][CH2:11][C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][NH:13]1>C(O)C>[OH:10][CH2:11][C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1[C:2](=[S:3])[NH:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: S=C=Nc1cccnc1
Solvent: CCO
Product: OC[C@@H]1Cc2ccccc2CN1C(=S)Nc1cccnc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
3-Isothiocyanatopyridine (6.8 g.) is added to a solution of (S)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (8.15 g.) in ethanol (150 cc.). After 3 hours at a temperature of about 20° C., the solution is cooled to 0° C. The white crystals which have appeared are filtered off and are then recrystallised from propanol (200 cc.). After filtration, the crystals are washed with propanol (2 × 10 cc.) and then dried at 60° C. under reduced pressure (1 mm. Hg). (S)-3-Hydroxymethyl-N-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (12.1 g.) melting at 192° C is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: Cc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(C)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
m-Toluidine (10 ml; 93 mmol) was added to a stirred solution of acetic anhydride (30 ml). The reaction mixture was stirred for 1,5 h at rt., evaporated to dryness, stirred with H2O and filtered to give 13 g product (94%).
Reaction SMILES: Cl.[C:2]1([C:8]2[O:12][N:11]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC([C@H]2CO2)=CC=1.[CH3:29][N:30]1[C:35](=[O:36])[CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][N:38]=2)[N:32]=[C:31]1N1CCOC(C2ON=C(C3C=CC=CC=3)N=2)C1.C(N(CC)CC)C>O1CCCC1>[CH3:29][N:30]1[C:35](=[O:36])[CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][N:38]=2)[N:32]=[C:31]1[N:15]1[CH2:16][CH2:17][O:18][CH:13]([C:10]2[N:9]=[C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:12][N:11]=2)[CH2:14]1
Reactant: c1ccc(-c2nc(C3CNCCO3)no2)cc1
Reactant: Cn1c(N2CCOC(c3nc(-c4ccccc4)no3)C2)nc(-c2ccncn2)cc1=O
Agent: Brc1ccc([C@H]2CO2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCOC(c3noc(-c4ccccc4)n3)C2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of the resulting 2-(5-phenyl-[1,2,4]oxadiazol-3-yl)-morpholine hydrochloride (intermediate 10 in tetrahydrofuran (6.0 ml) was added with 2-chloro-3-methyl-6-(pyrimidine-4-yl)pyrimidin-4-one (intermediate 1, 260 mg, 2.34 mmol) and triethylamine (1.81 ml, 13.0 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The solution was partitioned between water and chloroform, and the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluent; 5% methanol in chloroform) to afford 1-methyl-2-[2-(5-phenyl-[1,2,4]oxadiazol-3-yl)-morpholin-4-yl]-1H-[4,4′]bipyrimidinyl-6-one (compound 2 in Table 1, 749 mg, 64%, 2 steps) as solid
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[C:8]([F:9])=[C:7]([CH2:10][OH:11])[C:6]([F:12])=[C:5]([F:13])[N:4]=1.[Cl:15][C:16]([C:26]([F:29])([F:28])[F:27])=[CH:17][C@@H:18]1[C@H:20]([C:21](Cl)=[O:22])[C:19]1([CH3:25])[CH3:24]>>[Cl:15][C:16]([C:26]([F:27])([F:28])[F:29])=[CH:17][C@@H:18]1[C@H:20]([C:21]([O:11][CH2:10][C:7]2[C:6]([F:12])=[C:5]([F:13])[N:4]=[C:3]([N:2]([CH3:14])[CH3:1])[C:8]=2[F:9])=[O:22])[C:19]1([CH3:25])[CH3:24]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: CN(C)c1nc(F)c(F)c(CO)c1F
Product: CN(C)c1nc(F)c(F)c(COC(=O)[C@H]2[C@@H](C=C(Cl)C(F)(F)F)C2(C)C)c1F

Procedure:
By the method of Example 2, 0.5 g (0.002 mole) of 2-dimethylamino-4-hydroxymethyl-3,5,6-trifluoropyridine (from Example 13) was reacted with 0.6 g (0.002 mole) of cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarbonyl chloride to produce, after purification through a short silica gel column and the Chromatotron, 0.45 g of (2-methoxy-3,5,6-trifluoropyridin-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate as an oil, Compound No. 20 of the tables below.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[N:14]=[CH:13][N:12]([CH2:16][CH3:17])[C:11]=2[CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[CH:8]=1)[CH3:6].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([CH2:45][OH:46])[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.ClC(Cl)C.C1CCCCC1>>[CH2:16]([N:12]1[C:11]2[CH:10]=[C:9]([C:18]([F:21])([F:19])[F:20])[CH:8]=[C:7]([CH:5]([O:46][CH2:45][C:32]3([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:36][CH2:37]3)[CH3:6])[C:15]=2[N:14]=[CH:13]1)[CH3:17]
Reactant: CCn1cnc2c(C(C)OC(=N)C(Cl)(Cl)Cl)cc(C(F)(F)F)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Solvent: C1CCCCC1
Solvent: CC(Cl)Cl
Product: CCn1cnc2c(C(C)OCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc21
Temperature: 0 °C

Procedure:
(±)-(1-(1-Ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)ethyl 2,2,2-trichloroacetimidate (670 mg, 1.7 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (772 mg, 2.5 mmol) were combined in a dichloroethane/cyclohexane mixture (4:2, 6 mL) and cooled to 0° C. The reaction mixture was treated with tetrafluoroboric acid-diethyl ether complex (91 μL, 0.67 mmol), and subsequent processing including extractive work up and purification were carried out as described in example 8 to give 281 mg (30.7%) as white foam-like solid. 1H-NMR (500 MHz, CHLOROFORM-D) δ ppm 7.97 (s, 1 H), 7.54 (s, 1 H), 7.20-7.33 (m, 3 H), 7.00 (t, J=8.7 Hz, 2 H), 5.10 (q, J=6.6 Hz, 1 H), 4.17-4.30 (m, 2 H), 3.56-3.78 (m, 2 H), 3.24-3.40 (m, 2 H), 2.93-3.12 (m, 2 H), 2.02-2.21 (m, 2 H), 1.80-1.99 (m, 2 H), 1.56 (t, 3 H), 1.37-1.47 (m, 12 H). 550.40 (MH)+.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:65])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]2[CH:27]=[C:26]([NH:28][C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:30])[CH:25]=[C:24]([CH3:38])[C:23]=2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([S:45]([C:48]3[CH:52]=[C:51]([C:53]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[NH:54])[S:50][C:49]=3[S:63][CH3:64])(=[O:47])=[O:46])[CH:40]=2)=[O:20])=[CH:8][CH:7]=1.O>O1CCOCC1>[C:59]([O:58][C:56]([NH:55][C:53](=[NH:54])[C:51]1[S:50][C:49]([S:63][CH3:64])=[C:48]([S:45]([C:41]2[CH:40]=[C:39]([C:23]3[C:24]([CH3:38])=[CH:25][C:26]([NH:28][C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:36])[CH3:37])=[O:30])=[CH:27][C:22]=3[NH:21][C:19](=[O:20])[NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]([OH:65])=[O:4])=[CH:7][CH:8]=3)[CH:44]=[CH:43][CH:42]=2)(=[O:46])=[O:47])[CH:52]=1)=[O:57])([CH3:62])([CH3:60])[CH3:61]
Reactant: COC(=O)c1ccc(OCCCCCNC(=O)Nc2cc(NC(=O)OCC[Si](C)(C)C)cc(C)c2-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)OCC[Si](C)(C)C)cc2NC(=O)NCCCCCOc2ccc(C(=O)O)cc2)c1
Yield: 100 %

Procedure:
Lithium hydroxide (45.8 mg, 2.08 mmol) was added to a solution of 4-(5-{3-[3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid methyl ester (280 mg, 0.298 mmol, Example 283: step c) in 1,4-dioxane:water (10 mL, 2:1) over 2 days at rt. The solvents were removed in vacuo. The residue was diluted in water, acidified to pH˜5 with acetic acid, and extracted with EtOAc. The organic layer was washed with brine and dried over magnesium sulfate. The solvents were removed in vacuo to afford the title compound as a yellow solid (276 mg, quantitative). 1H-NMR (CDCl3/CD3OD): δ 7.93–7.99 (m, 3H), 7.83–7.86 (m, 2H), 7.52–7.59 (m, 2H), 7.15–7.20 (m, 2H), 6.85–6.89 (m, 2H), 4.21–4.26 (m, 2H), 3.99 (t, 2H, J=6.43 Hz), 3.13–3.24 (m, 2H), 2.61 (s, 3H), 2.02 (s, 3H), 1.75–1.83 (m, 2H), 1.43–1.56 (m, 13H), 1.02–1.08 (m, 2H), 0.07 (s, 9H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C@@H:7]1([NH2:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH2:5]([O:4][C:2](=[O:3])[NH:17][C@@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: N[C@H]1CCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)N[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl chloroformate (7.74 g, 71.3 mmol) is added dropwise to a mixture of (S)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) and K2CO3 (18.8 g, 136 mmol) in CH3CN (100 mL). The resulting mixture is stirred at room temperature overnight. Water (100 mL) is added and the mixture is extracted with ether (2×100 mL). The combined extract is washed with 1 N HCl (2×TO mL), water, dried (Na2SO4), and concentrated in vacuo to give (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester as a solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][NH:27][CH2:28][CH:29]([CH3:31])[CH3:30]>C(Cl)Cl>[CH2:28]([N:27]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:26])[CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)c1cc(C)cc(CO)c1
Reactant: CNCC(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)cc(CN(C)CC(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. N-Methylisobutylamine (287 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.36 (s, 1H), 3.90 (s, 3H), 3.44 (s, 2H), 2.38 (s, 3H), 2.14 (s, 3H), 2.10 (d, J=8 Hz, 2H), 1.81 (m, 1H), 0.90 (d, J=7 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[C:6]([Cl:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.B(Cl)(Cl)Cl.CO>C(Cl)Cl>[Cl:10][C:6]1[C:7]([OH:8])=[C:2]([Cl:1])[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1
Reactant: COc1c(Cl)nc(-c2ccccc2)nc1Cl
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Oc1c(Cl)nc(-c2ccccc2)nc1Cl
Temperature: 0 °C

Procedure:
15.3 g of 4,6-dichloro-5-methoxy-2-phenylpyrimidine and 30 ml of 25% boron trichloride solution in methylene chloride are heated at 40° C. in a bomb tube for 15 hours. The reaction mixture is subsequently added dropwise to a mixture of methanol and methylene chloride (1:1), and then diluted with ice-water. The organic phase is separated, and the aqueous phase is extracted with methylene chloride. The combined organic phases are concentrated by evaporation and chromatographed on silica gel to thus obtain 8.7 g of 4,6-dichloro-5-hydroxy-2-phenylpyrimidine, m.p. 138°-140° C. (compound No. 34).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:24][N:25]([CH3:32])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[CH3:24][N:25]([CH3:32])[CH2:26]/[CH:27]=[CH:28]/[C:29]([N:21]1[CH2:20][CH2:19][C:18]2[C:11]3[C:10]([NH:9][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])=[N:15][CH:14]=[N:13][C:12]=3[S:16][C:17]=2[CH2:22]1)=[O:30]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: C[C@@H](Nc1ncnc2sc3c(c12)CCNC3)c1ccccc1
Agent: Cl
Product: C[C@@H](Nc1ncnc2sc3c(c12)CCN(C(=O)/C=C/CN(C)C)C3)c1ccccc1

Procedure:
In analogy to Example 89, the title compound was prepared from N-[(1R)-1-phenylethyl]-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 18A (100 mg, 0.32 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (75 mg, 0.45 mmol) to yield 23 mg (17%).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:19](/[CH:20]=[CH:21]/[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:17][CH2:16][C:15]1=[O:29]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH:19]1/[CH:20]=[CH:21]/[CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC(=O)/C=C/C1CCCC(=O)N1CCCCCCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCCCC(O)/C=C/C1CCCC(=O)N1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
Sodium borohydride (42 mg, 1.10 mmol), followed by MeOH (0.38 mL), was added to a solution of 7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester (40 mg, 0.11 mmol) in CH2Cl2 (1.13 mL) at 0° C. The mixture was allowed to warm to rt. After 3 h at rt, the reaction was quenched with aqueous HCl (1.0 M) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL) then dried (Na2SO4), filtered and concentrated in vacuo to afford 40 mg (99%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[O-]S(C(F)(F)[F:19])(=O)=O.ClC1C=[N+](F)C=C(Cl)C=1>C(Cl)Cl>[F:19][C:11]1[C:2]([OH:1])=[CH:3][C:4]([O:12][CH3:13])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)cc1OC
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(O)cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of the methyl 4-hydroxy-2-methoxybenzoate (1 g, 5 mmol, from Step 3) in CH2Cl2 (20 mL) was added 3,5-dichloro-1-fluoropyridinium triflate (2.25 g, 6 mmol). The solution was refluxed for 48 h and then cooled to ambient temperature and stripped down under reduced pressure. The crude oil was purified by pressurized silica gel column chromatography using 99:1 CH2Cl2 :MeOH. Evaporation of the CH2Cl2 :MeOH mixture gave the desired methyl 5-fluoro-4-hydroxy-2-methoxybenzoate as a white powder.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13])[CH:2]=[CH2:3].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([BH3-])#N.[Na+].C(O)(=O)C.Cl>ClCCCl>[CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([NH:11][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]=1[C:12]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=1)=[O:13])[CH:2]=[CH2:3]
Reactant: O=Cc1ccccc1
Reactant: C=CCc1c(O)ccc(N)c1C(=O)c1ccc(C(C)C)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=CCc1c(O)ccc(NCc2ccccc2)c1C(=O)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 39 mg (0.13 mmol) (2-allyl-6-amino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanone and 13.34 μl (13 mmol) benzaldehyde in 1.3 ml 1,2-dichlorethane and 0.3 g molecular sieves (4 Å pore size) are added after 1 h 13 mg (0.18 mmol) sodium cyanoborohydride and 7.55 μl acetic acid (0.13 mmol). After stirring for 16 h at r.t. 1 M hydrochloric acid is added to destroy the excess of hydride equivalents. By adding 1 M NaOH the mixture is basified. The crude product obtained by extraction with dichloromethane is purified by reversed phase preparative chromatography.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8]>C1COCC1>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])=[O:9]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Reactant: CNCCO
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)N(C)CCO
Reaction time: 18 h
Yield: 82.9 %

Procedure:
N-Methylethanolamine (2.96 g, 39.4 mmol) was added to a solution of methyl 2-chlorosulfonyl-6nitrobenzoate (5.5 g, 19.7 mmol) in THF (150 ml) and the mixture stirred at 20°-25° for 18 hours. After removing THF under reduced pressure, the residue was partitioned between EtOAc and H2O. The organic extract was washed with saturated NaCl solution and dried (Na2SO4). Flash chromatography of the residue over silica gel and elution with 1% MeOH-99% CHCl3 afforded pure sulfonamide. Recrystallization from EtOAc-hexane gave analytically pure product (5.2 g, 82.9%), m.p. 98°-101°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([S:10][C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]=1.[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21](O)=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([S:10][C:11]([F:13])([F:12])[F:14])[CH:7]=[C:8]2[N:9]=1
Reactant: O=C(O)c1sccc1Cl
Reactant: CNc1ncc(SC(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(-c2sccc2Cl)nc2cc(SC(F)(F)F)cnc21
Temperature: 90 °C
Reaction time: 10 h
Yield: 89.3 %

Procedure:
A mixture of 0.50 g of N2-methyl-5-trifluoromethylthiopyridine-2,3-diamine, 0.44 g of 3-chloro-thiophene-2-carboxylic acid, 0.51 g of EDCI hydrochloride, 30 mg of HOBt and 5 ml of pyridine was stirred at 90° C. for 10 hours. Water was poured into the cooled reaction mixture, and the deposited precipitate was filtered. The filtrate was applied to a silica gel column chromatography to obtain 0.7 g of 2-(3-chlorothiophen-2-yl)-3-methyl-6-trifluoromethylthio-3H-imidazo[4,5,b]pyridine.
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[C:10]([C:14]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[O:15])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.Br[CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:36]([C:35]1[CH:39]=[CH:40][C:32]([CH2:31][N:2]2[CH2:3][CH2:4][C:5]3[NH:6][C:7]4[CH:8]=[CH:9][C:10]([C:14]([NH:16][CH:17]5[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]5)=[O:15])=[CH:11][C:12]=4[C:13]=3[CH2:1]2)=[CH:33][CH:34]=1)(=[O:37])[NH2:38]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CNCC4)CC1
Reactant: NC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CN(Cc2ccc(C(N)=O)cc2)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of tert-butyl 4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (0.745 g, 1.9 mmol) in DMF (10 mL), 4-bromomethylbenzamide (0.44 g, 2.1 mmol) and TEA (1.2 mL, 0.857 g, 8.5 mmol) were added. The resulting dark yellow reaction mixture was allowed to stir at room temperature under N2 atmosphere overnight and then poured into saturated sodium bicarbonate solution (100 mL). The resulting precipitate was collected and dried under vacuum overnight to provide tert-butyl 4-(2-(4-carbamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (28 in Scheme 1(m)) as a white solid (0.75 g, 75%). 1H NMR (DMSO-d6, 300 MHZ) 10.80 (s, 1H), 7.86-7.79 (m, 4H), 7.55 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.3 Hz, 3H), 7.26 (d, J=8.5 Hz, 2H), 4.00-3.88 (m, 3H), 3.82 (s, 2H), 3.65 (s, 2H), 2.92-2.80 (m, 6H), 1.80 (d, J=9.9 Hz, 2H), 1.54-1.47 (m, 2H), 1.43 (s, 9H) ppm; MS (ES) 532 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: CN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (490 mg, 1.4 mmol) in Acetone (5 mL), Cesium Carbonate (706 mg, 2.17 mmol)was added; after 15 min, Methyl iodide (95.0 uL, 1.53 mmol) was added and the mixture stirred at room temperature. After 4 h, a second aliquot of Methyl iodide (15 uL, 0.24 mmol) was added to drive the reaction to completion. After 30 min, the mixture was partitioned between 20 mL DCM/20 mL water, extracted 2×20 mL DCM. The combined organics were dried over sodium sulfate, filtered and con. in vacuo to afford N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-methyl-methanesulfonamide as an oil in quantitative yield. 1H-NMR (CDCl3): 8.02 (s, 1H), 5.94 (d, 1H, J=7.6 Hz), 4.11 (m, 1H), 3.74 (m, 1H), 2.84 (s, 3H), 2.80 (s, 3H), 2.35 (m, 1H), 1.84 (m, 3H), 1.71 (m, 1H), 1.42 (m, 2H), 1.27 (m, 1H).