Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Mg].BrN1C(=O)CCC1=O.O>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: Nc1ccccc1
Agent: O=C1CCC(=O)N1Br
Agent: [Mg]
Solvent: ClCCl
Solvent: O
Product: Nc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
According to a method described in Bumagin, N. A. and Luzikova, E. V. J. Organometallic Chem. 532, 271-273 (1997), 4-aminobiphenyl (18.0 g, 0.1 mol) was synthesized from 4-iode aniline and magnesium phenyl bromide and dissolved in methylene chloride (150 mL). The solution thus obtained was cooled down to 0° C. Into the solution, N-bromosuccinimide (19 g, 0.1 mol) was gradually added and stirred at the room temperature for 12 hours. After the reaction was completed, water (100 mL) was added therein to terminate the reaction. The resultant was extracted with chloroform (50 mL×3) and then washed with water (50 mL×5). The resultant was then dried with anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The resultant was purified via column chromatography (silica gel, chloroform/hexane (1:1 (v/v), Rf=0.2), thereby obtaining 3-bromo-4-aminobiphenyl (compound 4) in a form of an orange-tan solid. Then, 3-bromo-4-aminobiphenyl (compound 4) was recrystallized using hexane, thereby obtaining an orange-tan needle-like crystal (17.7 g, 72%).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:60]=[CH:59][C:14]([CH2:15][N:16]([CH2:49][CH2:50][O:51]CC3C=CC=CC=3)[C:17]3[CH:22]=[C:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:18]=3[CH:31]3[CH2:40][CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:37]=4)[CH2:32]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Cl)(Cl)Cl.CO>ClCCl.C(=O)(O)[O-].[Na+]>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:60]=[CH:59][C:14]([CH2:15][N:16]([C:17]3[CH:22]=[C:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:18]=3[CH:31]3[CH2:40][CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:37]=4)[CH2:32]3)[CH2:49][CH2:50][OH:51])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1N(CCOCc1ccccc1)Cc1ccc(OCCN3CCCCCC3)cc1)C2
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1N(CCO)Cc1ccc(OCCN3CCCCCC3)cc1)C2
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of [4-(2-azepan-1-ylethoxy)benzyl](2-benzyloxyethyl){5-(tert-butyldimethylsilyloxy)-2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]phenyl}amine (450 mg) in dichloromethane (23 ml) was added dropwise boron trichloride (1.0 M solution in dichloromethane) (4.2 ml) at −78° C., and the solution was stirred for 30 minutes. At −78° C., to the reaction solution was added methanol (2 ml), and the reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate. The solution was extracted with chloroform, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (240 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:9][C:10]1([CH3:17])[C:14]([CH3:16])([CH3:15])[O:13][BH:12][O:11]1>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:17])[C:14]([CH3:16])([CH3:15])[O:13][B:12](/[CH:2]=[CH:1]/[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[O:11]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C#Cc1cccnc1
Solvent: Cc1ccccc1
Product: CC1(C)OB(/C=C/c2cccnc2)OC1(C)C
Temperature: 50 °C
Yield: 49.8 %

Procedure:
An oven-dried round-bottom flask was cooled under N2 (g) and then charged with 3-ethynyl pyridine (104 mg, 1 mmol), toluene (4 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.73 mL, 5 mmol). The mixture was purged with argon for 15 min HRuCl(CO)(PPh3)3 (73 mg, 0.05 mmol) was then added and the reaction heated to 50° C. for 18 h. The reaction was quenched with NaHCO3 (sat.) (10 mL), extracted with EtOAc, and the organic layer washed with brine (10 mL) and then dried over MgSO4. The solvent was removed and the resulting residue purified by column chromatography (silica gel, Hexanes/EtOAc, 1:1) to give the title compound as a white solid (115 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H) 8.52 (d, 1H, J=4.8 Hz), 7.81 (d, 1H, J=7.8 Hz), 7.38 (d, J=18.6 Hz, 1H), 7.28-7.26 (m, 1H), 6.26 (d, 1H, J=18.5 Hz), 1.33 (s, 12H).
Reaction SMILES: [C:1]1([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=O)[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2>>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([N:18]=[C:10]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:8]3=[O:9])=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C1C(=O)N(c2ccccc2)c2ccccc21
Product: O=C1C(=Nc2ccc3[nH]ccc3c2)c2ccccc2N1c1ccccc1
Temperature: 140 °C
Yield: 13.9 %

Procedure:
1-phenylisatin (51.8 mg, 0.23 mmol) and 5-aminoindole (31 mg, 0.23 mmol) were mixed and heated at 140° C. for 2 h. The resulting crude product was purified by preparative TLC using ethyl acetate/hexane (6:4) as the eluent, giving the desired product as a yellow solid (10.8 mg, 14%). 1H NMR (400 MHz): δ 8.28 (s, 1H), 7.57 (t, J=7.7, 2H), 7.49–7.40 (m, 6H), 7.29–7.23 (m, 1H), 7.03 (dd, J 8.5, 1.7, 1H), 6.98 (d, J=7.6, 11H), 6.83 (d, J=8.0, 1H), 6.74, J=7.6, 1H), 6.59 (s, 1H); ESI-MS m/z found 338 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[CH:14]2)[CH3:6])[CH3:2].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:39][C@@H:40]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=3)[C:41](O)=[O:42])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:35][CH:33]2[C:34]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])[CH2:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][N:13]=[CH:14]3)=[O:42])=[CH:50][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2cnccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cnccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 76.8 %

Procedure:
According to the procedure described in the synthesis method of Compound III-5, (S)-1,1-diethoxy-N-(isoquinolin-5-ylmethyl)propan-2-amine (Compound IX-9)(1.98 g, 5.21 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (2.4 g, 5.21 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: n-hexane:ethyl acetate=7:3) to obtain the title compound (2.92 g, 76%).
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[NH2:6][C@@H:5]([CH:7]([CH3:9])[CH3:8])[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:3]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)[C@H](N)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 35.9 %

Procedure:
L-Valine methyl ester hydrochloride (9.9 g, 59.06 mmol) was added portionwise to a 1.0 M solution of phenylmagnesium bromide (108.8 g, 0.6 mol) in THF at 0° C. and heated at reflux for 20 h. After quenching with crushed ice and NH4Cl salt, the organic layer was separated, washed with brine and concentrated under reduced pressure. The resulting solid was treated with HCl (2.0 M, 100 ml) and then evaporated to dryness under reduced pressure. Impurities precipitated out as a white solid, when the amine hydrochloride salt was dissolved in hot MeOH and allowed to cool to room temperature. After removing the impurities by filtration, the filtrate was made basic with KOH (1.0 M) and the organics were extracted into diethyl ether (4×100 ml). Combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to obtain a crude product as a light brown solid. Purification over silica gel, eluting with a 1:4 and 1:1 mixture of ethyl acetate and petrol gave the title compound (2) (5.42 g, 36%) as a white solid. m.p. 90–92° C. (liti 94–95° C.). [α]D25=−107.92° (c, 0.0424 in CHCl3) (litii: −127.7° (c, 0.639 in CHCl3). δH 0.81 (3H, d, 3J=6.90 Hz, CH3), 0.85 (3H, d, 3J=7.20 Hz), 1.67 (1H, ds, 3J=1.80 and 6.90 Hz, CH-Me2), 3.76 (1H, d, 3J=2.10 Hz, CH—NH2), 7.04–7.58 (10H, m, Ar). δC 16.3 and 23.2 (CH3), 28.1 (CH—Me2), 60.4 (CH—NH2), 79.9 (C—OH), 125.7, 126.1, 126.5, 126.8, 128.2 and 128.6 (o-, m- and p-Ar), 145.1 and 148.2 (α-Ar. Anal. Calcld. for C17H21NO: C 79.96; H 8.29; N 5.48. Found: C 79.80; H 8.15; N 5.39. ir 3338 (OH and NH2). m/e (CI—CH4) 256 (MH+, 14%), 72 (100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[N:5]([C:6](=[O:9])[CH2:7][OH:8])[N:4]([CH:10]2[CH:17]3[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:19][CH:11]2[CH2:12]4)[CH2:16]3)[C:3]1=[O:20].[OH-].[Na+].[Br:24][C:25]1[CH:26]=[CH:27][C:28](F)=[N:29][CH:30]=1.O>CN(C)C=O>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([O:8][CH2:7][C:6]([N:5]2[C:2]([CH3:21])([CH3:1])[C:3](=[O:20])[N:4]2[CH:10]2[CH:11]3[CH2:12][CH:13]4[CH2:14][CH:15]([CH2:16][CH:17]2[CH2:18]4)[CH2:19]3)=[O:9])=[N:29][CH:30]=1
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)CO
Reactant: Fc1ccc(Br)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)COc1ccc(Br)cn1
Reaction time: 1 h
Yield: 10.2 %

Procedure:
Under an argon atmosphere, a solution of 4,4-dimethyl-1-(hydroxyacetyl)-2-(adamantan-2-yl)-1,2-diazetidin-3-one (14.0 mg, 0.0480 mmol) in N,N-dimethylformamide (0.5 mL) was added with sodium hydroxide (excess amount) and 5-bromo-2-fluoropyridine (26.4 mg, 0.150 mmol) at room temperature, and the resultant was stirred at the same temperature for 1 hour. The reaction solution was added with water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparatory Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (2.20 mg, 10.2%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:26])C(=O)C1>C(Cl)Cl>[Br:26][C:13]1[S:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)cs1
Solvent: ClCCl
Product: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)c(Br)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution (0.2 M) of ethyl 4-[(tert-butoxycarbonyl)amino]thiophene-2-carboxylate in DCM was cooled to 0° C. and treated with NBS (1.1 eq.) then stirred at 0° C. for 30 min. The mixture was quenched with aqueous Na2S2O3 (saturated solution) and extracted with AcOEt. The organic phase was washed with aqueous Na2S2O3 (saturated solution) and brine then dried and concentrated. The residue was purified by flash chromatography on silica gel (1:12 AcOEt/petroleum ether) to afford the title compound (48%) as a solid. 1H NMR (300 MHz, DMSO-d, 300 K) δ 1.32 (t, J=7.07 Hz, 3H), 1.50 (s, 9H), 4.32 (q, J=7.07 Hz, 2H), 7.81 (s, 1H), 9.13 (bs, 1H); MS (ES+) m/z 350, 352 (M+H)+;
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C([Li])CCC.[C:12]1([CH2:18][CH2:19]C(Cl)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(CCC(O)=O)C=CC=CC=1>O1CCCC1.S(Cl)(Cl)=O>[O:6]=[C:4]([CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:1]#[N:2]
Reactant: N#CCC(=O)O
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C(O)CCc1ccccc1
Agent: [Li]CCCC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: N#CCC(=O)CCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of cyanoacetic acid (1.0 g, 11.8 mmol) in tetrahydrofuran (20 mL) was cooled to −78° C. and treated with 1.6 M n-butyl lithium in hexanes (14.7 mL, 23.5 mmol). The mixture was warmed to −20° C. over 2 hours, cooled to −78° C. and treated with 3-phenylpropionyl chloride (prepared by refluxing a solution of 3-phenylpropionic acid (1.0 g, 6.7 mmol) in thionyl chloride (4 mL) for 3 hours, evaporating and drying). The mixture was stirred at −78° C. for 1 hour and 20% hydrochloric acid added until the pH=3. The mixture was diluted with diethyl ether, washed with saturated sodium bicarbonate, and the organic layer separated and concentrated. The crude product was purified by flash chromatography on silica gel using 0-50% ethyl acetate/hexanes to provide the title compound. MS (ESI) m/e 191 (M+H+NH3).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([CH2:15][CH3:16])([OH:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25].C(N(CC)CC)C.[OH-].[K+]>C1C=CC=CC=1>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([CH2:15][CH3:16])([OH:14])[C:7]1[CH:8]=[CH:9][C:10]([O:13][C:27](=[O:28])[NH:26][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:12]=1
Reactant: CCC(O)(c1ccc(O)cc1)c1cccc(C(F)(F)F)c1
Reactant: CCCCN=C=O
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)Oc1ccc(C(O)(CC)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C

Procedure:
8.9 g. of 3-trifluoromethyl-4'-hydroxy-α-ethyl-benzhydrol, 3.3 g. of n-butyl-isocyanate and 0.06 ml. of triethyl amine in 45 ml. of dry benzene are heated up to 50° C. under stirring, and the reaction mixture is kept at the same temperature for one additional hour. The progress of the reaction is monitored by thin layer chromatography. When the reaction is complete, the mixture is cooled to room temperature, the benzene solution is shaken with a 5% aqueous potassium hydroxide solution and washed to neutral with water. The organic phase is dried over anhydrous magnesium sulfate, filtered, and the solvent is distilled off under reduced pressure. The solid residue is crystallized from a mixture of ethyl acetate and n-hexane. 11.4 g. of the named compound are obtained, melting at 99° to 100° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[F:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=2)[N:3]=1
Reactant: CCCCCCCCC1CCc2cc(-c3ccc(O)cc3)nc(F)c2C1=O
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cc3c(c(F)n2)C(=O)C(CCCCCCCC)CC3)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1-fluoro-3-(4-hydroxyphenyl)-7-octyl-6,7-dihydro-5H-isoquinolin-8-one are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1-fluoro-3-[4-(octyloxy)phenyl]-7-octyl-6,7-dihydro-5H-isoquinolin-8-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NC[CH2:22][CH2:23][N:24]([CH3:26])C.Cl.CN1CCOCC1.N1CCC1>C(Cl)Cl>[N:24]1([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH3:15])[CH2:23][CH2:22][CH2:26]1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC1
Temperature: 0 °C
Yield: 59.8 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)pentanoic acid (17.0 g, 78.25 mmol), which is commercially available, and EDC hydrochloride (18.00 g, 93.90 mmol) was mixed in DCM (300 mL). To the mixture was NMM (20.65 mL, 187.79 mmol) added. The mixture was cooled to 0° C. and azetidine (6.33 mL, 93.90 mmol) was added. The resultant mixture was stirred at 0° C. for 30 min. and at rt over night. The reaction mixture was washed with NaHCO3 (saturated, 2×300 mL) and brine (300 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified via Biotage (gradient; DCM/iso-propanol, 99:1 to 90:10, KP-SIL 340 g column). The solvent was removed under reduced pressure to give the title compound (12.0 g, 60%). 1H NMR (400 MHz, CD3OD) δ 0.92, 1.20-1.76, 2.30, 3.89-4.26, 4.26-4.46, 5.16. LCMS (M+H)+: 257.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([C:28](O)=[O:29])=[CH:25][C:24]=2[CH:31]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:28]([C:26]3[O:27][C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:31][C:24]=4[CH:25]=3)=[O:29])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2cc3cc(Cl)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.1 %

Procedure:
To a solution of N1-(4-methoxybenzoyl)-1,2-benzenediamine (200 mg, 0.826 mmol) in methylene chloride (5 mL) was added 5-chlorobenzofuran-2-carboxylic acid (162 mg, 0.826 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (316 mg, 1.65 mmol), and 4-dimethylaminopyridine (10 mg, 0.083 mmol). The resulting solution was stirred at room temperature for 6 h. The resulting precipitate was collected via vacuum filtration to provide 209 mg (60%) of the title compound as an amorphous off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[C:5]([CH3:18])=[CH:4][N:3]=1.[F:19][C:20]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:23]([NH2:24])=[C:22]([O:30][CH3:31])[CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)CCC>[F:19][C:20]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:23]([NH:24][C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH3:17])[CH:9]=3)[C:5]([CH3:18])=[CH:4][N:3]=2)=[C:22]([O:30][CH3:31])[CH:21]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Reactant: Cc1cnc(Cl)nc1-c1cn(C)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Temperature: 125 °C

Procedure:
A mixture of 3-(2-chloro-5-methylpyrimidin-4-yl)-1-methyl-1H-indole (Intermediate 80, 350 mg, 1.36 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 265 mg, 1.43 mmol) and p-toluenesulfonic acid (284 mg, 1.49 mmol) in 2-pentanol (25 mL) was heated at 125° C. for 24 h. The mixture was then cooled and concentrated in vacuo. The resulting gum was used without further purification; m/z: ES+ MH+ 240.13.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:24])[CH:3]=1.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.C(OCC)C>[F:24][C:4]1[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[S:36])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[CH:8]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 28.6 %

Procedure:
To a solution of morpholine-4-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (50 mg) in N,N-dimethylformamide (1.0 ml) was added phenylacetyl isothiocyanate (42 mg), followed by stirring at room temperature for 22 hrs. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were concentrated to give a solid, which was suspended in diethyl ether. The solid was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (22 mg, 0.043 mmol, 29%) as colorless solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[OH:18].[CH2:19]1N2CN3CN(C2)CN1C3.O.Cl>C(O)(=O)C.O>[C:10]([C:9]1[C:4]([CH2:3][NH:2][CH3:19])=[C:5]([OH:18])[CH:6]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CC(C)(C)c1cc(O)c(CN)c(C(C)(C)C)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CNCc1c(O)cc(C(C)(C)C)cc1C(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 1.25 g (4.60 mmol) of the product of Example 19 (as the hydrochloride salt) in 10 mL of acetic acid-water (11:3) was added 0.75 g (5.35 mmol) of hexamethylenetetramine. The mixture was refluxed for 3 h then treated with 6 mL of water and 3 mL of conc. hydrochloric acid. Heating was continued for 10 min at which point the reaction mixture was cooled and concentrated in vacuo to remove the acetic acid. The residue was partitioned between EtOAc and water, and the aqueous layer was separated and extracted. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The product was purified on a silica gel flash chromatography column eluted with 5% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.