Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6](CCCl)[N:7]=2)[CH:3]=1.Br[C:15]1[CH:16]=[C:17]([C:34]([NH2:36])=[O:35])[C:18]2[NH:19][C:20]3[CH:21]=[C:22]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:23]=[CH:24][C:25]=3[C:26]=2[N:27]=1>>[O:31]1[CH2:32][CH2:33][N:28]([C:22]2[CH:23]=[CH:24][C:25]3[C:26]4[N:27]=[C:15]([C:2]5[CH:3]=[C:4]6[C:8](=[CH:9][CH:10]=5)[N:7]([CH2:21][CH2:22][N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[N:6]=[CH:5]6)[CH:16]=[C:17]([C:34]([NH2:36])=[O:35])[C:18]=4[NH:19][C:20]=3[CH:21]=2)[CH2:29][CH2:30]1
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Reactant: ClCCn1cc2cc(Br)ccc2n1
Product: NC(=O)c1cc(-c2ccc3c(cnn3CCN3CCOCC3)c2)nc2c1[nH]c1cc(N3CCOCC3)ccc12

Procedure:
This was similarly prepared from 5-bromo-2-(2-chloroethyl)-2H-indazole and 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide. MS (ESI) m/z 526.24 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.20 (1H, s), 8.50-8.61 (3H, m), 8.34 (1H, s), 8.26 (1H, d, J=9.15 Hz), 8.09 (1H, d, J=8.85 Hz), 7.80 (1H, br. s.), 7.73 (1H, d, J=9.16 Hz), 7.22 (1H, s), 7.01 (1H, d, J=8.55 Hz), 4.59 (2H, t, J=6.26 Hz), 3.77-3.87 (4H, m), 3.56-3.61 (4H, m), 3.20-3.27 (4H, m), 2.91 (2H, t, J=6.41 Hz), 2.42-2.48 (4H, m).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:47])[CH2:30][CH2:31][N:32]([C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1)[C:33]([C:35]1[O:36][CH:37]=[CH:38][CH:39]=1)=[O:34]>>[CH3:28][N:29]([CH3:47])[CH2:30][CH2:31][N:32]([C:40]1[CH:41]=[CH:42][C:43]([NH:44]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:45][CH:46]=1)[C:33]([C:35]1[O:36][CH:37]=[CH:38][CH:39]=1)=[O:34]
Reactant: CN(C)CCN(C(=O)c1ccco1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(=O)c2ccco2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-(furan-2-carbonyl)-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C32H30N4O5
Reaction SMILES: C(O[C:6]([N:8]([CH3:35])[CH:9]([CH2:25][O:26][CH2:27][CH:28]1[CH2:32][O:31]C(C)(C)[O:29]1)[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.C1C([N+]([O-])=O)=CC=C([Cl-]C([O-])=O)C=1.[Cl:65][C:66]1[C:73]([F:74])=[CH:72][CH:71]=[CH:70][C:67]=1[CH2:68][NH2:69]>C(Cl)Cl.C1COCC1>[Cl:65][C:66]1[C:73]([F:74])=[CH:72][CH:71]=[CH:70][C:67]=1[CH2:68][NH:69][C:6](=[O:7])[N:8]([CH:9]([CH2:25][O:26][CH2:27][CH:28]([OH:29])[CH2:32][OH:31])[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:35]
Reactant: CN(C(=O)OC(C)(C)C)C(COCC1COC(C)(C)O1)COC(=O)Nc1cc2ccccc2cn1
Reactant: NCc1cccc(F)c1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)NCc1cccc(F)c1Cl)C(COCC(O)CO)COC(=O)Nc1cc2ccccc2cn1
Temperature: 24 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
To a solution of Isoquinolin-3-yl-carbamic acid 2-(tert-butoxycarbonyl-methyl-amino)-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-propyl ester (2.9 g, 5.93 mmol) in DCM (200 mL) was added TFA (12 mL) at 0° C. The mixture was stirred for 2 h, concentrated under reduced pressure, and re-dissolved in THF (10 mL) and DIEA (6.6 mL, 37.8 mmol). To this THF solution was added pre-stirred solution of 4-nitrophenylchloroformate (1.33 g, 6.62 mmol), 2-chloro-3-fluorobenzylamine (1.0 g, 6.3 mmol), and DIEA (1.2 mL, 6.9 mmol) in THF (85 mL) at 0° C. The reaction mixture was stirred for 2 h allowing the reaction to gradually warm to 24° C. The mixture was concentrated under reduced pressure, re-dissolved in MeOH, filtered, and purified by RP-HPLC using a mixture of acetonitrile and H2O to give isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-3-(2,3-dihydroxy-propoxy)-propyl ester (1.1 g, 45% over two steps). LRMS (M+H+) m/z 535.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:12])[N:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:5]2=[O:18].[Cl:20][C:21]1[C:26]([CH:27]=O)=[C:25]([O:29][CH3:30])[N:24]=[CH:23][CH:22]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][N:24]=[C:25]([O:29][CH3:30])[C:26]=1[C:27]1[NH:11][C:10]2=[CH:9][C:8]3[C:7](=[O:12])[N:6]([CH2:13][CH2:14][N:15]([CH3:16])[CH3:17])[C:5](=[O:18])[C:4]=3[C:3]([CH3:19])=[C:2]2[N:1]=1
Reactant: Cc1c(N)c(N)cc2c1C(=O)N(CCN(C)C)C2=O
Reactant: COc1nccc(Cl)c1C=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1nccc(Cl)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Temperature: 50 °C

Procedure:
A mixture of 5,6-diamino-2-(2-(dimethylamino)ethyl)-4-methylisoindoline-1,3-dione (0.36 g, 1.37 mmol) and 4-chloro-2-methoxynicotinaldehyde (0.26 g, 1.51 mmol) in a mixture of methanol (8 mL) and acetic acid (0.4 mL) was heated at 50° C. for 14 h. After the end of reaction was established by TLC, the reaction mixture was concentrated under vacuum to dryness, and the crude product was subjected to the next step without further purification. Mass (ESI, positive) m/z 414.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:17]1([NH:23][C:24]([NH:16][C:13]2[CH:14]=[CH:15][C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc2oc(-c3ccccc3)nc2c1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To 2-phenylbenzo[d]oxazol-5-amine (75 mg, 0.36 mmol) in dichloromethane (2 mL) at room temperature was added phenyl isocyanate (43 μL, 0.39 mmol). The solution was stirred at room temperature for 16 h. The resulting precipitate was filtered off and washed with dichloromethane to afford 99.9 mg (85%) of the title compound (LCMS RT=6.45 min, MH+ 330.1)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C@@H:11]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:12]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:13]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=2)[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:57]O.[OH-].[Na+]>C1COCC1>[CH2:50]([O:49][C@H:11]1[C@H:12]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@@H:13]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@H:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=2)[C@@H:15]([OH:57])[C@@H:10]1[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CCc1ccc(Cc2cc(Cl)ccc2O[C@@H]2C=C(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(Cl)ccc2O[C@@H]2[C@@H](O)[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred 0° C. THF solution of ((1S,2S,3R,6R)-4-(benzyloxymethyl)-6-(4-chloro-2-(4-ethylbenzyl)phenoxy)cyclohex-4-ene-1,2,3-triyl)tris(oxy)tris(methylene)tribenzene (27, 150 mg, 0.196 mmol) was added dropwise BH3OEt2 (2M, 0.98 mL, 1.962 mmol). After stirring for 2 h at 0° C., the mixture was warmed to 25° C. and stirred overnight. H2O2 (30%, 4.2 mL) was added, followed by added aqueous NaOH solution (1M, 3.93 mL, 3.93 mmol) to the reaction mixture at 0° C. After complete addition, the reaction mixture was warmed to 25° C. and stirred for 3 h. The reaction was quenched by addition of dilute HCl (1N, 10 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were washed with water and brine prior to drying over anhydrous Na2SO4. The residue was purified by preparative TLC (EA:PE=1:8 v/v) to obtain 59 mg of (1S,2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-2-(4-ethylbenzyl)phenoxy)cyclohexanol (28).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[CH:16](OCC)=[O:17].CCO.O>CCOCC>[O:17]=[CH:16][CH:10]([C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)Cc1cc(C)cc(OC)c1
Reactant: CCOC=O
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C=O)c1cc(C)cc(OC)c1
Temperature: 0 °C
Yield: 60.5 %

Procedure:
To a solution of ethyl 3-methoxy-5-methylphenylacetate (3.0 g; 14 mmol; is from step (iv) above) and ethyl formate (1.9 g; 26 mmol) in ether (75 mL) was added Na (0.39 g; 17 mmol) in small lumps. The solution was cooled to 0° C. and EtOH (abs.; 0.24 mL) was then added. To the resulting slurry was added ether (100 μL), EtOH (5 mL) and water until the slurry was dissolved. The aqueous phase was collected, acidified to pH 2 (HCl/aq) and extracted with ether. The organic phase was washed with NaHCO3/aq, dried (Na2SO4), and evaporated to yield 2 g (59%) of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[CH2:22][N:21]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[CH2:20]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[CH2:22][N:21]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:20]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)CCN1Cc2ccc(-c3nc(-c4ccc(OC(C)C)c(Cl)c4)no3)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2noc(-c3ccc4c(c3)CN(CCC(=O)O)C4)n2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)isoindolin-2-yl)propanoate (21 mg, 0.048 mmol) in ethanol (1 ml) was added 2M aqueous NaOH (1 ml, 2.000 mmol). The reaction was stirred at room temperature under an atmosphere of nitrogen for approximately 4 hours. Reaction mixture was then acidified to a pH of I by addition of 2N HCl, at which time a precipitate formed. The solid was collected by filtration and washed with water (3×5 mL). The solid was then dried in a vacuum oven overnight to give 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)isoindolin-2-yl)propanoic acid as the hydrochloride salt (10.2 mg, 46.2%). LCMS (Table 1, Method c) Rt=1.86 min, m/z 428.20 (M+H)+. 1H NMR (400 MHz, DMSO) δ ppm 12.12 (m, 1H), 8.23 (s, 1H), 8.19 (d, 1H), 8.07 (d, 1H), 8.01 (dd, 1H), 7.68 (d, 1H), 7.41 (d, 1H), 4.83 (sept, 1H), 4.72 (s, 4H), 3.58 (t, 2H), 2.84 (t, 2H), 1.36 (d, 6H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.BrBr>C(Cl)(Cl)Cl.[Hg]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C=Cc2ccc(C(F)(F)F)cc2)cc1
Agent: BrBr
Agent: [Hg]
Solvent: ClC(Cl)Cl
Product: Fc1ccc(C#Cc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
12.4 g (47 mmol) of 4-fluoro-4'-trifluoromethylstilbene was dissolved in 80 ml of chloroform. While irradiating the solution with a light of 160W mercury lamp, a solution of 2.4 ml (47 mmol) of bromine in 20 ml of chloroform was dropwise added at 40° C. Then, stirring was continued for 30 minutes. After completion of the reaction, the solvent was distilled off to obtain a yellow oily substance. Without purification, this oily substance was dissolved in 100 ml of ethanol. While refluxing the solution under heating, a solution of 12.3 g of potassium hydroxide in 45 ml of water was dropwise added. After completion of the dropwise addition, refluxing under heating was continued for 3 hours. After completion of the reaction, ethanol was distilled off, and water was added to the residue. The mixture was extracted with diethyl ether and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 12.2 g of 4-fluoro-4'-trifluoromethyltolane as a yellow solid. Without purification, this yellow solid was used for the subsequent reaction.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([C:44]([F:47])([F:46])[F:45])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([C:44]([F:46])([F:45])[F:47])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:49][CH2:50]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1ccc(C(F)(F)F)cc1-c1cccc-3c1
Agent: [Pd]
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1ccc(C(F)(F)F)cc1-c1cccc-3c1
Solvent: CO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C(F)(F)F)cc1-c1cccc-3c1
Reaction time: 2 h
Yield: 75.5 %

Procedure:
A mixture of methyl (2S)-2-(tert-butoxy)-2-[(22S,24Z)-4,22,28-trimethyl-17-(trifluoromethyl)-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate (50 mg, 0.071 mmol), 10% Pd/C (7.53 mg, 7.07 μmol) in MeOH (2 mL) was stirred under a H2 balloon for 2 h. It was then filtered, concentrated and purified by biotage eluting with 20% EtOAc/hexane to isolate 38 mg of methyl (2S)-2-(tert-butoxy)-2-[(22S)-4,22,28-trimethyl-17-(trifluoromethyl)-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate as an off-white solid. LCMS (M+1)=709.3.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[N:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[N:43]=[N:42][CH:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cnnn4CCC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cnnn4CCC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propyl-1,2,3-triazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.54 g) was dissolved in methylene chloride (16.2 ml), and a solution of m-chloroperbenzoic acid (209 mg) in methylene chloride (10.8 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propyl-1,2,3-triazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 278) (0.35 g).
Reaction SMILES: [CH3:1][O:2][NH:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH3:15][C:16]1([CH3:26])[O:20][C:19](=[CH:21][C:22](O)=[O:23])[C:18](=[O:25])[O:17]1>>[CH3:15][C:16]1([CH3:26])[O:20][C:19](=[CH:21][C:22]([N:3]([O:2][CH3:1])[CH2:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][CH:6]=2)=[O:23])[C:18](=[O:25])[O:17]1
Reactant: CC1(C)OC(=O)C(=CC(=O)O)O1
Reactant: CONCc1cccc2ccccc12
Product: CON(Cc1cccc2ccccc12)C(=O)C=C1OC(C)(C)OC1=O
Yield: 56 %

Procedure:
O-Methyl-N-naphthalen-1-ylmethyl-hydroxylamine was reacted with (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic acid according to the method described for the preparation of compound 90-B to give the title compound as a pale yellow solid (0.826 g, 56% yield). 1HNMR (300 MHz, CDCl3) δ: 8.18 (1H, d, J=8.05 Hz), 7.85 (2H, t, J=9.15 Hz), 7.56–7.41 (4H, m), 6.40 (1H, s), 5.30 (2H, s), 3.43 (3H, s), 1.77 (6H, s).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[I:22]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(=O)(O)[O-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[C:5]([I:22])=[CH:4][N:3]=1
Reactant: II
Reactant: COC(=O)c1ccc2ccnc(O)c2c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(I)cnc(O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a mixture of methyl 1-hydroxyisoquinoline-7-carboxylate (1.0 g) and pyridine (40 mL) was added iodine (1.2 g), and stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and a 5% aqueous sodium thiosulfate solution. Then, the precipitate was collected by filtration to obtain methyl 1-hydroxy-4-iodoisoquinoline-7-carboxylate (1.1 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH:40][C:41]2[CH:46]=[C:45](B3OC(C)(C)C(C)(C)O3)[CH:44]=[C:43]([O:56][CH3:57])[CH:42]=2)(=[O:39])=[O:38])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:45]2[CH:46]=[C:41]([NH:40][S:37]([CH2:36][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=3)(=[O:38])=[O:39])[CH:42]=[C:43]([O:56][CH3:57])[CH:44]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(NS(=O)(=O)Cc2ccc(F)cc2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(NS(=O)(=O)Cc2ccc(F)cc2)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.27 mmol) were added 1-(4-fluorophenyl)-N-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (138 mg, 0.33 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (22 mg, 0.03 mmol) and 273 μl of a 2M aqueous solution of cesium carbonate in dioxane (5 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (0 to 80%, hexane-ethyl acetate) to give 155 mg (85% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: C[Si](C)(C)CCOC(=O)[NH:7][N:8]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]2[N:8]([NH2:7])[C:9]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:11]=2)[CH:14]=1
Reactant: C[Si](C)(C)CCOC(=O)Nn1c(-c2cccnc2)ccc1-c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nn1c(-c2cccnc2)ccc1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2,5-di-pyridin-3-yl-pyrrol-1-yl)-carbamic acid 2-trimethylsilanyl-ethyl ester (1 g, 2.6 mmol) is treated with a 1M solution of TBAF in THF (5.2 ml, 5.2 mmol). The resulting solution is stirred overnight under Ar at rt, then quenched with glacial acetic acid (0.3 ml, 5.2 mmol) and diluted with toluene. The resulting solution is passed through a short plug of silica gel and concentrated in vacuo to afford 2,5-Di-pyridin-3-yl-pyrrol-1-ylamine.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].C([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH2:17])C.Cl.C([BH3-])#N.[Na+].[OH-].[Li+].CO>CN(C)C=O.C(O)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:17][CH2:16][CH2:15][C:14]([OH:18])=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(CNCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
4-cyanobenzaldehyde (0.65 g; 5 mmoles) and β-alanine ethyl ester.HCl (0.76 g; 5 mmoles) were dissolved in N,N-dimethylformamide (10 ml) containing 1% acetic acid. After 10 min., sodiumcyanoborohydride (0.35 g; 5 mmoles) was added to the solution. The reaction mixture was stirred at room temperature for 12 hrs. and taken down to dryness under reduced pressure. The residue was treated with 1N lithium hydroxide/methanol (1:1; 20 ml) for 15 min. Methanol was removed and the pH of the remaining solution was adjusted to pH 5 with 50% acetic acid. The product was purified by HPLC using a linear gradient of acetonitrile/water/trifluoroacetic acid. The desired fractions was collected and lyophilized to give 0.81 g of white solid (79% yield). FAB-MS: MH+ =205.1.
Reaction SMILES: [N+]([O-])([O:3][CH2:4][C:5](=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)=O.O.O.O.C([O-])(=O)C.[Na+].O>CS(C)=O>[I:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5](=[O:14])[CH:4]=[O:3])=[CH:12][CH:11]=1
Reactant: O=C(CO[N+](=O)[O-])Cc1ccc(I)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=CC(=O)Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
3-(4-Iodophenyl)-2-oxopropyl nitrate (17) (450 mg) was dissolved in dimethylsulfoxide (20 mL) and to this was added sodium acetate trihydrate (211 mg, 1.55 mmol), and stirred for an hour at room temperature. To this was added water and the product was extracted with diethyl ether (×3). The organic layer was washed sequentially with water (×1), saturated aqueous solution of sodium bicarbonate (×1) and saturated brine (×1), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 3-(4-iodophenyl)-2-oxopropanal (18) as an orange solid (346 mg, <1.26 mmol, <90.1%), which was used in the next reaction without further purification.