Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([C:20]2[CH:21]=[C:22]3[C:28]([C:29]4[C:30]([CH3:44])=[N:31][N:32]([CH2:35][C:36]5[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=5)[C:33]=4[CH3:34])=[CH:27][N:26](C(OC(C)(C)C)=O)[C:23]3=[N:24][CH:25]=2)[CH:16]=[CH:17][C:18]=1[F:19])[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C>Cl.O1CCOCC1.CO>[F:42][C:40]1[CH:41]=[C:36]([CH:37]=[C:38]([F:43])[CH:39]=1)[CH2:35][N:32]1[C:33]([CH3:34])=[C:29]([C:28]2[C:22]3[C:23](=[N:24][CH:25]=[C:20]([C:15]4[CH:16]=[CH:17][C:18]([F:19])=[C:13]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:14]=4)[CH:21]=3)[NH:26][CH:27]=2)[C:30]([CH3:44])=[N:31]1
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1-c1cn(C(=O)OC(C)(C)C)c2ncc(-c3ccc(F)c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c3)cc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(F)c(NS(C)(=O)=O)c3)cc12
Yield: 42.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-fluorophenyl)-3-(1-(3,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (88 mg, 0.121 mmol) was deprotected in HCl in dioxane/MeOH (5/2 ml). This afforded 27 mg (35% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 13.6 (s, 1H), 8.42 (s, 1H), 8.26 (s, 1H), 7.80-7.77 (d, 1H), 7.50 (s, 1H), 7.33-7.32 (m, 2H), 6.79-6.69 (m, 4H), 5.33 (s, 2H), 3.09 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H). MS: m/z=526.2 (M+1), HPLC: 94.82% in method B.
Reaction SMILES: CS(O[CH2:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=2)[CH:8]=1)(=O)=O.[N:20]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CS(C)=O>[F:17][C:16]([F:19])([F:18])[C:12]1[CH:13]=[C:14]2[S:15][C:7]([CH2:6][N:23]3[CH2:22][CH2:21][N:20]([C:26]4[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=4)[CH2:25][CH2:24]3)=[CH:8][C:9]2=[N:10][CH:11]=1
Reactant: CS(=O)(=O)OCc1cc2ncc(C(F)(F)F)cc2s1
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: CS(C)=O
Product: Oc1ccc(N2CCN(Cc3cc4ncc(C(F)(F)F)cc4s3)CC2)cc1
Reaction time: 72 h

Procedure:
The solution from Example 25C (2 mL) was treated with 4-(1-piperazinyl)phenol (178 mg) in DMSO (1 mL). After 72 hours, the mixture was concentrated under a stream of nitrogen gas and the residue recrystallized from DMSO:methanol (1:1) to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.81 (4H, t, J=4.8 Hz), 3.18 (4H, J=4.8 Hz), 3.95 (s, 2H), 6.78 (2H, d, J=9 Hz), 6.90 (2H, J=9 Hz), 7.48 (1H, s), 8.38 (1H, m), 8.80 (1H, m). MS (DCI/NH3) m/z 394 (M+H)+. Anal. Calcd for C19H18N3F3OS: C, 56.72;H, 4.76; N, 10.44. Found: C, 56.43;H, 4.50; N, 10.35.
Reaction SMILES: [OH:1][C@@:2]1([CH3:23])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C@H:11]([CH2:12][C:13](=[O:22])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH:24](S)([SH:26])[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH2:25]1[O:22][C:13]2([CH2:14][CH2:15][C@@:16]3([CH2:17][OH:18])[C@@H:11]([CH2:10][CH2:9][C@@H:8]4[C@@H:19]3[CH2:20][CH2:21][C@@:3]3([CH3:4])[C@H:5]4[CH2:6][CH2:7][C@@:2]3([OH:1])[CH3:23])[CH2:12]2)[S:26][CH2:24]1
Reactant: C[C@]1(O)CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(CO)[C@H]3CC[C@@]21C
Reactant: CC(S)S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: C[C@]1(O)CC[C@H]2[C@@H]3CC[C@H]4CC5(CC[C@]4(CO)[C@H]3CC[C@@]21C)OCCS5
Reaction time: 4 h

Procedure:
17β,19-Dihydroxy-17α-methyl-5α-androstan-3-one in acetic acid is treated with ethanedithiol and p-toluenesulfonic acid. After standing for 4 hours at room temperature, the solution is poured onto water and the mixture extracted with methylenechloride. The methylenechloride extract is washed well with water, washed with a sodium hydroxide solution, washed again with water, dried over sodium sulfate and evaporated under reduced pressure to leave a residue of 17β,19-dihydroxy-17α-methyl-5α-androstan-3-one 3-ethylenethioketal which is crystallized once from a solution of acetone-hexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]=[CH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:23](#[N:28])/[CH:24]=[CH:25]/[C:26]#[N:27]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@H:12]3[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17]3)=[C:25]([C:26]#[N:27])[C:24]=2[C:23]#[N:28])=[CH:4][CH:3]=1
Reactant: CCCCC[C@H]1CC[C@H](C=CC=Cc2ccc(F)cc2)CC1
Reactant: N#C/C=C/C#N
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(F)cc3)c(C#N)c2C#N)CC1

Procedure:
Using 1-(p-fluorophenyl)-4-(trans-4'-n-pentylcyclohexyl)-1,3-butadiene and fumaronitrile, 3-(p-fluorophenyl)-6-(trans-4'-n-pentylcyclohexyl)phthalonitrile was obtained by the same method as in Example 1. m.p. was 102.5° C.
Reaction SMILES: O[CH:2]1[CH2:8][CH:7]2[N:9](C(OC(C)(C)C)=O)[CH:3]1[CH2:4][O:5][CH2:6]2.C(N(S(F)(F)[F:23])CC)C.Cl.O1CCOCC1>>[F:23][CH:2]1[CH2:8][CH:7]2[NH:9][CH:3]1[CH2:4][O:5][CH2:6]2
Reactant: CC(C)(C)OC(=O)N1C2COCC1C(O)C2
Reactant: CCN(CC)S(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: FC1CC2COCC1N2

Procedure:
Compound 51a was prepared from tert-butyl 6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate G8 by treatment with DAST (diethylaminosulfur trifluoride) followed by HCl/dioxane to remove the N-Boc protection.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11](NC(OC(C)(C)C)=O)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[C@@H]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)[CH:48]=1)C(O)=O)C1C=CC=CC=1.CNC(=O)[C@H](C(C)(C)C)N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CCOC(C)=O.CO.C(Cl)Cl.CCOC(C)=O.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([C:51]1[CH:47]=[CH:48][N:49]([C:52]2[CH:53]=[CH:54][C:55]([C:58]3[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=3)=[CH:56][CH:57]=2)[CH:50]=1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:17])([CH3:18])[CH3:19])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2ccc(-n3ccc([C@H](CC(=O)OCc4ccccc4)C(=O)O)c3)cc2)cc1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)[C@@H](N)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(C)(C)C
Yield: 66 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3-(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]succinic acid 4-benzyl ester and L-t-leucine N-methylamide (see Malon, P.; Pancoska, P.; Budesinsky, M.; Hlavacek, J.; Pospisek, J.; Blaha, K. Coll. Czech. Chem Commun. 1983, 48, 2844-2861) were coupled with TBTU. Successive flash column chromatography with 0-30% EtOAc/CH2Cl2 and 2-5% MeOH/CH2Cl2 gradient eluants, respectively, and radial chromatography with 0-40% EtOAc/hex gradient eluant furnished in 66% yield 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester as a crisp foam. 1H NMR: δ 7.75 (d, 2H, J=8.5 Hz), 7.69 (d, 2H, J=8.5 Hz), 7.64 (d, 2H, J=8.8 Hz), 7.44 (d, 2H, J=8.5 Hz), 7.31 (s, 5H), 7.09 (t, 1H, J=2.6 Hz), 7.04 (t, 1H, J=1.8 Hz), 6.50 (bd, 1H, J=9.6 Hz), 6.28 (dd, 1H, J=1.7, 2.8 Hz), 5.70-5.67 (m, 1H), 5.12 (s, 2H), 4.13 (d, 1H, J=9.2 Hz), 4.02 (t, 1H, J=7.4 Hz), 3.23 (dd, 1H, J=7.5, 16.7 Hz), 2.85 (dd, 1H, J=6.8, 16.7 Hz), 2.76 (d, 3H, J=4.8 Hz), 0.96 (s, 9H). Anal. Calculated for C35H36N4O4•0.5 H2O: C, 71.77; H, 6.37; N, 9.57. Found: C, 71.73; H, 6.35; N, 9.54.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[N:28]1([CH2:34][C:35](O)=[O:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(=O)([O-])O.[Na+].CN(C)C(=O)C>[CH3:26][C:25]1[C:20]([C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]4[N:5]([CH:27]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[N:3]=4)[CH:6]=3)[CH:12]=2)=[O:19])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)CN4CCOCC4)cn3c2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 47.4 %

Procedure:
A mixture of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (129 mg, 0.359 mmol), morpholin-4-ylacetic acid (56.8 mg, 0.391 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (97.8 mg, 0.510 mmol), 1H-benzotriazol-1-ol (50.7 mg, 0.375 mmol), N,N-diisopropylethylamine (123 μL, 0.719 mmol) and N,N-dimethylacetamide (5 mL) was stirred at room temperature for 21 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→75% ethyl acetate-hexane) to give the title compound (82.8 mg, 47%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27](Cl)[C:22]=4[C:21](=[O:29])[N:20]4[CH2:30][CH2:31][C@H:19]4[C:18]=23)[N:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].ClCC1ON=C(C2N=CN3C4C=CC([F:53])=CC=4C(=O)N4CCC4C=23)N=1.C(NCCC)CC>CN(C)C=O>[CH2:1]([N:4]([CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][C:26]([F:53])=[CH:27][C:22]=4[C:21](=[O:29])[N:20]4[CH2:30][CH2:31][C@H:19]4[C:18]=23)[N:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: O=C1c2cc(F)ccc2-n2cnc(-c3noc(CCl)n3)c2C2CCN12
Reactant: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Solvent: CN(C)C=O
Solvent: CCCNCCC
Product: CCCN(CCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1
Yield: 85 %

Procedure:
1.8 g (5 mmol) of (S) 1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with mmol) of dipropylamine and 20 ml of N,N-dimethylformamide. By evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.8 g (85%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: [OH-].[K+].CO.[CH3:5][O:6][C@:7]1([C:19]2[S:20][C:21]([C:24]3[CH:29]=[C:28]([NH:30][C:31]4[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=4)[CH:27]=[C:26]([CH3:41])[CH:25]=3)=[CH:22][N:23]=2)[CH2:12][CH2:11][C@H:10]([C:13]([O:15]C)=[O:14])[C:9]([CH3:18])([CH3:17])[CH2:8]1>>[CH3:5][O:6][C@:7]1([C:19]2[S:20][C:21]([C:24]3[CH:29]=[C:28]([NH:30][C:31]4[N:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:33][N:32]=4)[CH:27]=[C:26]([CH3:41])[CH:25]=3)=[CH:22][N:23]=2)[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[C:9]([CH3:18])([CH3:17])[CH2:8]1
Reactant: COC(=O)[C@H]1CC[C@](OC)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CO[C@]1(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC[C@H](C(=O)O)C(C)(C)C1
Temperature: 65 °C
Yield: 79.3 %

Procedure:
Potassium hydroxide in methanol (3.0 mL, 3.0 mmol) was added to the product of Step 2 (150 mg, 0.23 mmol) and the reaction mixture heated to 65° C. for 110 h. The reaction mixture was cooled and then quenched with HCl (2N in H2O). The mixture was filtered and washed with ˜20 mL of water to obtain an off-white solid. The solid was dried under reduced pressure at 40° C. in a vacuum oven for 1.5 h to provide the title compound (95 mg, 79%) as a yellow solid. ESI: [M+H]+ m/z 521. 1H NMR (500 MHz, DMSO-d6) δ 12.15-11.94 (m, 1H), 10.26 (s, 1H), 8.83 (d, J=4.9, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.45 (s, 1H), 7.28 (d, J=4.9, 1H), 7.16 (s, 1H), 3.07 (s, 3H), 2.31 (s, 3H), 2.22-2.09 (m, 2H), 1.99-1.80 (m, 3H), 1.72 (d, J=14.5, 1H), 1.62 (s, 1H), 1.07 (s, 3H), 1.01 (s, 3H). rhSYK activity=+++
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[N:4]=[CH:3]1.[C:12]12([CH2:22][C:23](Cl)=[O:24])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.N>>[C:12]12([CH2:22][C:23]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[S:9][CH:10]=[CH:11][C:5]=4[N:4]=[CH:3]3)=[O:24])[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][CH:14]([CH2:20]3)[CH2:13]1)[CH2:21]2
Reactant: Nn1cnc2ccsc2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Agent: N
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1cnc2ccsc2c1=O

Procedure:
3-Amino-3,4-dihydrothieno[3,2-d]pyrimidin-4-one and 1-adamantaneacetyl chloride were reacted as described in Example 1: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.57-1.68 (m, 12H), 1.94 (br s, 3H), 2.10 (s, 2H), 7.46 (d, J=5.4 Hz, 1H, 11.15 (s, 1H) ppm; MS (DCI/NH3) m/z 344 (M+H)+.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:21]3[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=3[C:16]([O:24][CH:25]([F:27])[F:26])=[CH:15][CH:14]=2)=[O:12])=CC=1)([O-])=O.[CH3:28][N:29]1[C:33]([NH2:34])=[CH:32][CH:31]=[N:30]1.C(OCC)C>CCCCCC>[CH3:28][N:29]1[C:33]([NH:34][C:11]([C:13]2[C:21]3[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=3[C:16]([O:24][CH:25]([F:26])[F:27])=[CH:15][CH:14]=2)=[O:12])=[CH:32][CH:31]=[N:30]1
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Reactant: Cn1nccc1N
Solvent: CCOCC
Solvent: CCCCCC
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3ccnn3C)c2o1
Yield: 15.7 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid 4-nitro-phenyl ester (100 mg) and 2-methyl-2H-pyrazole-3-ylamine (51 mg). Purification by column chromatography on silica eluting with ethyl acetate afforded, after trituration with a mixture of diethyl ether and hexane, the title compound as a pale yellow solid (14mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][C:20]#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.[N:36](=[CH:44]CCl)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Cl>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][CH2:44][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: ClCC=NCCCCCCCl
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCCCCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-(hexamethyleneimino)ethylchloride
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][CH:10]=[CH2:11])[CH:3]=1.[C:20]([O:24][C:25]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1B(O)O)=[O:26])([CH3:23])([CH3:22])[CH3:21].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1>[C:15]([O:14][C:13]([NH:12][C@H:8]([C:4]1[CH:3]=[C:2]([C:33]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[NH:27][C:25](=[O:26])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:7]=[CH:6][N:5]=1)[CH2:9][CH:10]=[CH2:11])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(Cl)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cnccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccncc2NC(=O)OC(C)(C)C)ccn1
Temperature: 75 °C
Yield: 39.8 %

Procedure:
To 1C (1.080 g, 3.82 mmol) and (3-((tert-butoxycarbonyl)amino)pyridin-4-yl)boronic acid (1 g, 4.20 mmol) in a sealable flask was added THF (19.09 ml), potassium phosphate tribasic (5.09 ml, 15.28 mmol) and degassed with Ar. (DtBPF)PdCl2 (0.249 g, 0.382 mmol) was added, degassed further. The reaction mixture was heated at 75° C. for overnight. Then, the mixture was washed with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, concentrated and purified by ISCO to yield 72A as brown solid (670 mg, 40%). 1H NMR (500 MHz, METHANOL-d4) δ 8.65 (br. s., 1H), 8.62-8.57 (m, 1H), 8.46 (d, J=5.0 Hz, 1H), 7.46 (s, 1H), 7.41 (d, J=5.2 Hz, 1H), 7.39 (m, 1H), 5.86-5.75 (m, 1H), 5.15-5.03 (m, 2H), 4.81-4.75 (m, 1H), 2.68-2.57 (m, 1H), 2.55-2.46 (m, 1H), 1.46-1.27 (m, 18H).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:43])[CH2:4][O:5][C:6]([CH2:8][N:9]([S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)(=[O:32])=[O:31])[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[NH:23])=[CH:20][CH:19]=3)=[N:16][C:12]=2[CH:11]=1)=[O:7].Cl[C:45]([O:47][CH3:48])=[O:46]>CC(C)=O.O>[CH3:2][CH:3]([CH3:43])[CH2:4][O:5][C:6]([CH2:8][N:9]([S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)(=[O:32])=[O:31])[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH2:24])=[N:23][C:45]([O:47][CH3:48])=[O:46])=[CH:25][CH:26]=3)=[N:16][C:12]=2[CH:11]=1)=[O:7]
Reactant: CC(C)COC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)N=C(N)c1ccc(Cc2nc3cc(N(CC(=O)OCC(C)C)S(=O)(=O)c4cccc5cccnc45)ccc3n2C)cc1

Procedure:
Prepared analogously to Example 97 from 4-[(5-(N-(2-methylpropyloxycarbonylmethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and methyl chloroformate in acetone/water.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([O:16][CH3:17])[C:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH2:12]1)=O)C1C=CC=CC=1>CO.[H][H].[C].[Pd]>[C:23]([O:22][C:20]([NH:19][C:13]1([CH3:18])[CH:14]([O:16][CH3:17])[CH2:15][NH:11][CH2:12]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC1CN(C(=O)OCc2ccccc2)CC1(C)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC1CNCC1(C)NC(=O)OC(C)(C)C

Procedure:
To a solution of 1-benzyloxycarbonyl-3-(tert-butoxycarbonylamino)-4-methoxy-3-methylpyrrolidine (fraction β) (0.28 g, 0.77 mmol) in methanol (10 mL) was added 5% palladium-carbon (containing water, 0.14 g), and the mixture was stirred at room temperature for 18 hours in hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound as a colorless oily product. This product was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[N:5][CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].C1C(=O)N([Br:35])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:35][CH2:1][C:2]1[NH:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[N:5][CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccccc1C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of ethyl 6-methyl-2-(thiazol-2-yl)-4-(2-(trifluoromethyl)phenyl)-1,4-dihydropyrimidine-5-carboxylate (7.9 g, 20 mmol) in carbon tetrachloride (100 mL) was added NBS (3.74 g, 21 mmol) under N2 at 60° C. The reaction mixture was stirred at 60° C. for 10 minutes, and cooled to 25° C. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=3/1) to give the title compound as a yellow solid (6.64 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]=[O:18])[CH:11]=[CH:10]2>ClC1C=CC=CC=1>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]=[O:18])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(C=O)ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=Cc1ccc2cc(O)ccc2c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 37.9 %

Procedure:
Aluminum trichloride (1.07 g, 8.06 mmol) was added to a solution of 6-methoxy-2-naphthaldehyde (1.0 g, 5.37 mmol) in chlorobenzene (15 mL). The reaction mixture was stirred at 130° C. for 4 h. The reaction was quenched with water (5 mL) and conc. HCl (2 mL). The reaction mixture was dissolved in ethyl acetate and washed with water and brine and dried over anhydrous magnesium sulfate. Silica gel chromatography eluting with 10% ethyl acetate/hexane yielded 0.35 g of desired product: ESI-MS173.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[NH2:20][C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[CH3:17][N:16]([CH3:18])[C:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:7]=2)[CH2:10][CH2:11]1)=[O:19]
Reactant: Nc1cc2ccccc2cn1
Reactant: CN(C)C(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)N1CCN(Cc2ccnc(Nc3cc4ccccc4cn3)c2)CC1

Procedure:
1-(2-Chloro-pyridin-4-ylmethyl)-4-(N,N-dimethylcarbamoyl)piperazine (1.0 equiv) (Preparation B-12) was mixed with 3-aminoisoquinoline (1.0 equiv), Pd2(dba)3(0.1 equiv), xantphos (0.15 equiv), and Cs2CO3 (1.4 equiv) in toluene. The mixture was refluxed overnight, and EtOAc was added in to dilute the mixture. After filtration, the filtrate was concentrated and applied onto a silica gel column. The title compound was obtained as a yellow solid (50 mg, 22% yield): 1H NMR (CDCl3, 300 MHz) δ: 2.47 (t, J=5.0 Hz, 4H, PyridylCH2NCH2CH2), 2.83 (d, J=4.8 Hz, 3H, NHCH3), 3.41 (t, J=5.0 Hz, 4H, NCH2CO), 3.51 (s, 2H, pyridylCH2), 6.86-8.99 (m, 9H, isoquinolyl+pyridyl).