Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:31][CH:32]([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])[C:9](=[O:30])[C@@H:10]([NH:12]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCCC1.ClCCl>>[NH2:12][C@@H:10]([CH3:11])[C:9]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:31][CH:32]([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[O:30]
Reactant: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)N)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To (S)-(9H-fluoren-9-yl)methyl 1-(benzyl(2,2-diethoxyethyl)amino)-1-oxopropan-2-ylcarbamate (Compound XV-1) 1.12 g (2.1 mmol), 25%-piperidine/dichloromethane 16 ml was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 70:30, chloroform:methanol=100:0 to 80:20) to obtain the title compound 640 mg (yield 100%).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([F:69])[CH:63]=2)[C@@H:59]([C@H:70](O)[CH3:71])[CH2:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([F:69])[CH:63]=2)[C@@H:59]([C@@H:70]([O:27][C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=2)[CH3:71])[CH2:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Reactant: Oc1ccc(Cl)cn1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (216 mg, 0.65 mmol) in THF (10 mL) at 0° C. were added 5-chloro-pyridin-2-ol (58 mg, 0.45 mmol) and then DBAD (110 mg, 0.48 mmol). After 5 minutes was added (R)-1-[(3R,4S)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (100 mg, 0.30 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 100 mg (75%) of the title compound as a colorless oil. ES-MS m/e: 445.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.Cl[C:14]1[N:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[C@:23]([CH2:27][CH3:28])([CH3:26])[NH:22][C:21]2=[O:29])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:12])[C:6]2[C:7]([O:11][C:14]3[N:19]=[CH:18][C:17]([N:20]4[C:24](=[O:25])[C@:23]([CH2:27][CH3:28])([CH3:26])[NH:22][C:21]4=[O:29])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cccc(O)c21
Reactant: CC[C@@]1(C)NC(=O)N(c2ccc(Cl)nc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3cccc4c3C(C)(C)OC4)nc2)C1=O
Temperature: 130 °C
Yield: 45.9 %

Procedure:
3,3-Dimethyl-1,3-dihydro-2-benzofuran-4-ol (Intermediate 193, 68 mg, 0.4 mmol) and (5R)-3-(6-chloropyridin-3-yl)-5-ethyl-5-methylimidazolidine-2,4-dione (Intermediate 194, 126 mg, 0.48 mmol) were dissolved in DMF (1.0 mL) and K2CO3 (143 mg, 1.03 mmol) was added. The resulting suspension was heated to 130° C. under microwave irradiation for 40 minutes. The reaction mixture was diluted with water (25 mL) and ethyl acetate (25 mL), and then two phases were separated. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (Biotage system) on silica gel using cyclohexane/ethyl acetate 50:50 as eluent affording the title compound (70 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]#[N:13])[CH:9]=2)[CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]#[N:13])[CH:9]=2)[CH2:4]1)=[O:1]
Reactant: N#Cc1ccc2c(c1)CC(CO)C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CC(C=O)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-(Hydroxymethyl)-2,3-dihydro-1H-indene-5-carbonitrile (3.7 g, 21 mmol) in 80 mL of DCM was added Dess-Martin reagent (18 g, 43 mmol) in one portion at 0° C. The mixture was stirred at 0° C. for 1 hour, and then stirred at rt. overnight. The reaction mixture was purified with column chromatography (EtOAc:PE=1:20) to obtain 2-Formyl-2,3-dihydro-1H-indene-5-carbonitrile. 1H-NMR (400 MHz, CDCl3) δ 9.77 (d, J=1.2 Hz, 1H), 7.45-7.51 (m, 2H), 7.32 (d, J=7.6 Hz, 1H), 3.32-3.40 (m, 3H), 3.18-3.25 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.C([O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22])C>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([C:21]([OH:22])=[O:20])=[CH:24][CH:25]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: O=C(O)c1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-ethoxycarbonyl-phenylboronic acid to give 4-[3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzoic acid. LC-MS m/e 331(MH+).
Reaction SMILES: [ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[C:20]3[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=3[N:14](COCC[Si](C)(C)C)[CH:13]=2)[CH:3]=1.C(OCC)(=O)C>C(O)C>[ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[C:20]3[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=3[NH:14][CH:13]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cnc3ccccc3c2)c2c(N)ncnc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ncnc2[nH]cc(-c3cnc4ccccc4c3)c12
Reaction time: 0.42 h

Procedure:
Concentrated hydrochloric acid (20 ml) was added at 90° C. to a solution of 5-(quinolin-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10.0 g) obtained in Step 3 in ethanol (200 ml), and the mixture was stirred at the same temperature for 25 minutes. Subsequently, concentrated hydrochloric acid (30 ml) was added thereto, and the mixture was stirred at the same temperature for 75 minutes. After the reaction mixture was cooled, ethanol (100 ml) was added thereto, and stirred at 95° C. for 90 minutes. Subsequently, ethanol (100 ml) and concentrated hydrochloric acid (25 ml) were added, and the mixture was stirred at the same temperature for 4 days. After the reaction mixture was cooled, ethyl acetate was added thereto. The resulting precipitate was then collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the title compound (4.4 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[ClH:19].[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH3:35])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[ClH:20].[ClH:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:21][C:22]1[C:23]([NH:34][CH3:35])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 6 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (250 mg, 1.01 mmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-methylquinolin-2-amine hydrochloride SLA 28154 (276 mg, 1.01 mmol) followed by a 2 N aq. LiOH solution (1.01 mL, 2.02 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with a CH2Cl2:MeOH=9:1 mixture (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided, after evaporation and drying, 39 mg of 6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.40 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to give 6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 48 as a yellow solid (31 mg, 6% yield).
Reaction SMILES: C(N(CC)CC)C.CN(C=O)C.[C:13]1([S:19]([N:22]2[CH:26]=[C:25](I)[C:24]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[N:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:34]#[C:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:13]1([S:19]([N:22]2[CH:26]=[C:25]([C:34]#[C:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:24]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[N:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c(-c2cccnc2)n1
Reactant: C#CCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCC#Cc1cn(S(=O)(=O)c2ccccc2)nc1-c1cccnc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To triethyl amine (10 ml) and DMF (4 ml) containing 36B (0.97 g, 2.36 mmol), was added 3 eq of hex-1-yne (0.81 ml). The resulting mixture was stirred for another 2 hours under N2. Successively were added 10 mol % of CuI (45 mg), 5 mol % of PdCl2(PPH3)2 (83 mg) and 18 mol % of PPH3 (111 mg). After the addition, the resulting solution was warmed at 70° C. for 18 hours under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE (1/1)) to afford 3-(1-phenylsulfonyl-4-hex-1-ynyl-1H-pyrazol-3-yl)-pyridine (43A) as an oil (0.66 g, 77%). 1H-NMR (400 MHz, CDCl3): δ 9.5-9.2 (bs, 1H), 8.8-8.4 (bs, 1H), 8.34 (bd, J=8 Hz, 1H), 8.21 (s, 1H), 8.08-8.04 (m, 2H), 7.67 (bt, J=7 Hz, 1H), 7.57 (bt, J=7 Hz, 2H), 7.41-7.32 (bs, 1H), 2.42 (t, J=7 Hz, 2H), 1.62-1.53 (m, 2H), 1.49-1.39 (m, 2H), 0.93 (t, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:20])[C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)C1CCCCC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C(=O)C1CCCCC1)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.9 %

Procedure:
To a solution of cyclohexanecarboxylic acid (4-fluoro-3-nitro-phenyl)amide (see Example 1) (0.75 g, 2.82 mmol) in DMSO (15 mL) was added a 1M solution of sodium bistrimethylsilylamide (3.36 mL, 3.36 mmol), with stirring at room temperature. After 15 min, iodomethane (0.53 mL, 8.5 mmol) was added. After 1 h, the mixture was diluted with ethyl acetate, washed twice with water, dried over magnesium sulfate, and evaporated. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate (7:3) to give cyclohexanecarboxylic acid (4-fluoro-3-nitro-phenyl)-methyl-amide (402 mg, 51%) as the first eluted component.
Reaction SMILES: [Si](OC(C)C=O)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:23][CH2:24][CH2:25][CH2:26][C@:27]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[N:31]([C:32](=[O:37])[C@@H:33]([O:35][CH3:36])[CH3:34])[N:30]=[C:29]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])[S:28]1>>[NH2:23][CH2:24][CH2:25][CH2:26][C@@:27]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[N:31]([C:32](=[O:37])[C@@H:33]([O:35][CH3:36])[CH3:34])[N:30]=[C:29]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])[S:28]1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Agent: CC(C=O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Product: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN)c1ccccc1

Procedure:
Prepared as described in Example 5. Steps A-G, using (S)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-1)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(tert-butyldiphenylsilyloxy)propan-1-one from Step C. MS ESI (+) m/z 420 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 1H), 7.44 (m, 2H), 7.36 (m, 2H), 7.29 (m, 1H), 7.12 (m, 2H), 4.71 (q, 1H, J=6 Hz), 3.32 (s, 3H), 3.23 (m, 1H), 2.84 (m, 2H), 2.43 (m, 1H), 1.93 (m, 1H), 1.50 (d, 3H, J=6 Hz), 1.44 (m, 2H), 1.34 (m, 1H). Stereochemistry was assigned by inference from (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]([CH3:25])=[CH:8][CH2:9][C:10]1[C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[CH:15][C:14]=2[C:12](=[O:13])[C:11]=1[OH:24]>>[CH3:6][C:7]1([CH3:25])[O:21][C:20]2[C:19]3[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[CH:15][C:14]=3[C:12]([C:11](=[O:24])[C:10]=2[CH2:9][CH2:8]1)=[O:13]
Reactant: COc1ccc2c(c1)C(=O)C(O)=C(CC=C(C)C)C2=O
Agent: O=S(=O)(O)O
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC(C)(C)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
Concentrated H2SO4 (25 mL) was added to compound 52 (2.454 g) at 20° C. After stirring for 20 min, the mixture was diluted with ice water (500 mL). The resulting red precipitate 54 was collected by filtration, washed with water, and dried in vacuo. It was obtained as a red powder (2.36 g, 96%): 1H NMR (CDCl3) δ7.72 (1H, d, J=8.6 Hz), 7.56 (1H, d, J=2.7 Hz), 7.12 (1H, dd, J=8.6, 2.7 Hz), 3.90 (3H,S), 2.55 (2H, t, J=6.7 Hz), 1.84 (2H, t, J=6.7 Hz), 1.46 (6H, S).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[Br:20]N1C(=O)CCC1=O.O.C(=O)(O)[O-].[Na+]>CO>[Br:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:19])=[CH:9][CH:10]=2)[CH:15]=[N:14][C:13]=1[NH2:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(F)cc1-c1ccc2c(Br)c(N)ncc2c1
Yield: 68.9 %

Procedure:
7-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine (51.3 mg, 203 μmol) and N-bromosuccinimide (36.4 mg, 204 μmol) were dissolved together in methanol (2.0 mL) at ambient temperature. After 10 mins the mixture was poured into water and saturated aqueous sodium bicarbonate (1 mL), extracted twice into dichloromethane. The combined organic phases were washed with brine containing sodium thiosulfate (1 mL, 1M), dried over sodium sulfate, filtered and concentrated in vacuo to afford a residue that was purified by flash chromatography (silica, ISCO, 0-10% methanol in dichloromethane) to yield the title compound as a white solid (46.3 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.92 (t, J=9 Hz, 1H), 7.71 (s, 1H), 7.59 (d, J=9 Hz, 1H), 7.27-7.22 (m, 1H), 7.03-6.95 (m, 2H), 5.04 (s, 2H), 2.24 (s, 3H). LCMS: M+H+=331 & 333.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[C:37]([NH2:44])=[C:36]([Cl:45])[CH:35]=3)[C:19](=[O:32])[N:20]3[CH2:25][CH2:24][N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:46]=[CH:47][CH:48]=[CH:49][C:4]=2[NH:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:57]([CH3:64])([CH3:63])[C:58]([O:60][CH2:61][CH3:62])=[O:59]>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([C:40]([F:41])([F:43])[F:42])[C:37]([NH2:44])=[C:36]([Cl:45])[CH:35]=3)[C:19]([N:20]3[CH2:21][CH2:22][N:23]([CH:26]4[CH2:31][CH2:30][N:29]([C:57]([C:58]([O:60][CH2:61][CH3:62])=[O:59])([CH3:64])[CH3:63])[CH2:28][CH2:27]4)[CH2:24][CH2:25]3)=[O:32])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:46]=[CH:47][CH:48]=[CH:49][C:4]=2[NH:3]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCNCC3)CC2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A mixture of 140 mg (0.20 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 29a), 60.8 mg (0.44 mmol) K2CO3 and 45 μL (0.30 mmol) ethyl 2-bromo-2-methyl-propionate in 1.8 mL DMF was shaken at 50° C. for 12 h and then for 48 h at RT. The precipitate was filtered off and the filtrate was purified by HPLC without working up; the fractions containing the product were combined, evaporated down i. vac., the residue was made alkaline with saturated NaHCO3 solution, the precipitate was suction filtered, washed with 20 mL water and dried at 40° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]#[N:13])[CH:5]=[N:4][CH:3]=[N:2]1>[Pd].C(O)C>[N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][NH2:13])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: N#Cc1ccccc1-n1cncn1
Agent: [Pd]
Solvent: CCO
Product: NCc1ccccc1-n1cncn1

Procedure:
A solution of 2-(1,2,4-triazol-1-yl)cyanobenzene (508 mg, 2.99 mmol) and 25% by weight of palladium on carbon, 10% catalyst (134 mg) in ethanol (75 ml) was placed on a PARR Hydrogenation Apparatus under a hydrogen atmosphere at 55 psi. overnight. The mixture was filtered through celite and concentrated to give 2-(1,2,4-triazol-1-yl)-benzylamine; 1H NMR (CD3OD) δ8.80 (s, 1H), 8.22 (s, 1H), 7.64-7.43 (m, 4H), 3.66 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([OH:23])[CH:22]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:20]=[N:19][CH:18]=1
Reactant: Oc1cncc(Cl)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cncc(Cl)c3)c2cc1OC
Temperature: 140 °C
Reaction time: 6 h
Yield: 81.6 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (245 mg), 3-chloro-5-pyridinol (277 mg), and 4-dimethylaminopyridine (377 mg) were suspended in o-dichlorobenzene (13 ml), and the mixture was stirred at 140° C. for 6 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydroxide solution and water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (283 mg, yield 81%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][O:11][CH2:10][CH2:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)=O.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:20]1([C:7]2[CH2:12][O:11][CH2:10][CH2:9][C:8]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)COCC1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2ccccc2)COCC1
Temperature: 100 °C
Yield: 77.8 %

Procedure:
To a solution of ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H-pyran-4-carboxylate (1.77 g, 5.81 mmol) and phenylboronic acid (1.42 g, 11.62 mmol) in dioxane (15 ml) was added Pd(dppf)Cl2 (430 mg, 0.58 mmol) and Na2CO3 (1.85 g, 17.46 mmol) in water (4.5 mL), the mixture was degassed with N2 for 5 min, and was heated at 100° C. for 15 h, after cooling to room temperature the mixture was diluted with EtOAc and washed with Sat. NaHCO3 and brine, organic layer was combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc=4:1) to give ethyl 5-phenyl-3,6-dihydro-2H-pyran-4-carboxylate (1.05 g, 78%).
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[CH:12]=[C:13]([CH:17]2[C:22]([CH3:24])([CH3:23])[O:21][C:20]([NH:25][C@H:26]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)=[N:19][S:18]2(=[O:44])=[O:43])[CH:14]=[CH:15][CH:16]=1.CO.Cl>C1COCC1.C(OCC)(=O)C.O.[OH-].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:2]([C:11]1[CH:12]=[C:13]([CH:17]2[C:22]([CH3:23])([CH3:24])[O:21][C:20]([NH:25][C@H:26]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:27][CH2:28][OH:29])=[N:19][S:18]2(=[O:43])=[O:44])[CH:14]=[CH:15][CH:16]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1c1cccc(Cc2ccccc2)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Under inert gas, 1.72 ml of a 0.5 N solution of benzylzinc bromide in THF were added to a solution of 100 mg of [5-(3-bromophenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine and 14.1 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium in 2 ml of THF. After stirring at 60° C. for 18 hours, 2 ml of methanol and 0.5 ml of concentrated hydrochloric acid were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with 20 ml of ethyl acetate and 10 ml of water and neutralized with aqueous sodium hydroxide solution, and the organic phase was washed once again with saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, extracted with dichloromethane and concentrated by rotary evaporation. The residue was purified further by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (38.2 mg) with a molecular weight of 478.6 g/mol (C27H30N2O4S); MS (ESI): m/e=479 (M+H+).