Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:5]=[C:4]([CH:18]=[CH:19][CH3:20])[C:3]=1[OH:21].ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)Cl>[Cl:8][C:7]1[C:6]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:5][C:4]2[CH2:18][CH:19]([CH2:20][OH:27])[O:21][C:3]=2[C:2]=1[Cl:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC=Cc1cc(C(=O)c2ccccc2F)c(Cl)c(Cl)c1O
Solvent: ClCCl
Product: O=C(c1ccccc1F)c1cc2c(c(Cl)c1Cl)OC(CO)C2
Reaction time: 96 h

Procedure:
A mixture of 2,3-dichloro-6-propenyl-4-(2-fluorobenzoyl)phenol (62.5 g., 0.192 mole) and m-chloroperoxybenzoic acid (47.6 g., 0.22 mole) in 550 ml. of methylene chloride was stirred at room temperature for 24 hours. The precipitated m-chlorobenzoic acid was removed by filtration and the filtrate was washed successively with 5% aqueous sodium sulfite and 10% aqueous sodium bicarbonate. The methylene chloride was kept at room temperature for 4 days and then washed with 0.5N NaOH solution. After drying over MgSO4, the solvent was evaporated to give 45 g. of solid product, m.p. 148°-150° C.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1C=CC=CC=1>[CH2:25]([O:24][C:22]([CH:21]=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:23])[CH3:26]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CBr
Solvent: c1ccccc1
Product: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 80.4 %

Procedure:
To a solution of triphenylphosphine (26.20 g, 100 mmol) in benzene (150 ml) was added ethyl bromoacetate (16.70 g, 100 mmol) at 0-5° C. The mixture was kept at room temperature for 16 h. The resulting phosphonium salt was filtered, washed with benzene (100 ml), and dried. To a solution of the solid in water (200 ml) was added benzene (200 ml), followed by 10% NaOH solution (100 ml). The organic layer was separated, and the aqueous layer was extracted with benzene (200 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), concentrated to 50 ml in vacuo, and poured onto hexane (200 ml). The precipitate was filtered and dried to afford the desired phosphorane (28.00 g, 80%) as a colorless solid. mp 128-130° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=O)[C:15]=4[N:14]=3)=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH:29][C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)=[O:24])[C:15]=4[N:14]=3)=[C:9]([C:25]([F:26])([F:28])[F:27])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc(CN4CCCC4)cc3C(F)(F)F)nc12
Product: Cc1ccc(NC(=O)c2cccc3[nH]c(-c4ccc(CN5CCCC5)cc4C(F)(F)F)nc23)cc1

Procedure:
2-(4-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid 159 was coupled with p-toluidine 161 to produce 2-(4-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-N-p-tolyl-1H-benzo[d]imidazole-4-carboxamide (Compound 870) using the same general procedure outlined in Example 39. as the starting material. MS (ESI) calcd for C27H25F3N4O: 478.20; found: 479 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)nn1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)nn2)cc1
Temperature: 85 °C
Yield: 26.1 %

Procedure:
6-Chloro-pyridazin-3-ylamine (7 g, 54 mmol) was taken up in pyridine (54 mL) and TsCl (11.34 g, 59 mmol) was added. The solution was heated at 80-90° C. for 24 h. The solution was concentrated and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine (2×50 mL), dried over sodium sulfate and concentrated. Purification by silica gel chromatography (ethyl acetate/hexane) afforded the title compound (4 g, 26%). 1H NMR (DMSO-d6, 300 MHz): δ 2.4 (s, 3H), 7.4 (d, 3H), 7.54 (d, 1H), 7.8 (m, 3H), 12.5 (br, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH:15]1([NH2:18])[CH2:17][CH2:16]1.CO>>[CH:15]1([N:18]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[C:9]2=[O:14])[CH2:17][CH2:16]1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: NC1CC1
Solvent: CO
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Nitro-isochromen-1-one (5 g, 0.03 mol), cyclopropylamine (2 g, 0.04 mol) were refluxed in methanol (50 mL, 1 mol) for 2 hours and then room temperature stirring overnight. The resulting yellow solid was collected via filtration. The volatiles were removed under vacuum, the residue was purified via flash chromatography (120 g of silica gel, 0-20% EtOAc/Hexane) to give a yellow solid. MS m/z (M+H) 231.3.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[C@H:24]([C:25](O)=O)[CH2:23][C:22]3([CH2:32][CH2:31][N:30]([CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH2:29][CH2:28]3)[CH2:21]2)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.O.N.C[NH3+].F[P-](F)(F)(F)(F)F.N1([O:60][C:61](N(C)C)=[N+:62](C)C)C2C=CC=NC=2N=N1.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C@H:24]([CH2:25][C:61]([NH2:62])=[O:60])[CH2:23][C:22]3([CH2:28][CH2:29][N:30]([CH:33]([CH2:34][CH3:35])[CH2:36][CH3:37])[CH2:31][CH2:32]3)[CH2:21]2)=[CH:38][CH:39]=1)[CH2:6][C:2]1[NH:3][CH:4]=[CH:5][N:1]=1
Reactant: CCC(CC)N1CCC2(CC1)C[C@@H](C(=O)O)N(Cc1ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc1)C2
Reactant: CN(C)C(On1nnc2ncccc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)N1CCC2(CC1)C[C@@H](CC(N)=O)N(Cc1ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc1)C2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under an argon atmosphere, the compound (315 mg) obtained in Example 32(7) was dissolved in dimethylformamide (3 mL), and then 28% ammonia water (199 μL) and HATU (2-(1H-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methaneaminium) (337 mg) were added, followed by stirring at room temperature for 15 hours. After completion of the reaction, water (10 mL) and then an aqueous saturated sodium hydrogen carbonate were added, followed by extraction twice with dichloromethane (20 mL). The organic layers were combined, washed with saturated brine and then dried over anhydrous magnesium sulfate. After removing anhydrous magnesium sulfate by filtration, the filtrate was concentrated and the resultant residue was purified by silica gel column chromatography (CHROMATOREX NH (trade name), manufactured by Fuji Silysia Chemical Ltd.) (hexane:ethyl acetate=50:50→0:100→ethyl acetate:methanol=100:0→80:20) to obtain the title compound having the following physical properties (yield: 204 mg).
Reaction SMILES: [S:1]([Li])[Li].Cl.O=C1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:9]=2[C:8](=O)[O:7]1>O>[O:7]=[C:8]1[S:1][NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:9]1=2
Reactant: [Li]S[Li]
Reactant: O=C(O)c1ccc2[nH]c(=O)oc(=O)c2c1
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2[nH]sc(=O)c2c1

Procedure:
To a solution of Li2S (5.7 g, 0.124 mol) in H2O (1000 ml) cooled to 0° C. in an ice bath was added HCl (1M, 186 ml, 0.186 mmol) slowly with stirring. The ice bath was then removed, and 2,4-dioxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-6-carboxylic acid (8.1 g, 0.050 mol) was added slowly. The suspension was stirred for 1 h and was filtered. The filtrate was purged with N2 for 30 min, and H2O2 (30%, 7.0 ml) was added, stirred for 45 min. The pH of the reaction mixture was adjusted with 6M HCl to ˜5 and the resulting suspension was filtered. The solid was washed with H2O (×3) and was dried to yield 3-oxo-1,3-dihydrobenzo[c]isothiazole-5-carboxylic acid as an off-white solid. To a solution of 3-oxo-1,3-dihydrobenzo[c]isothiazole-5-carboxylic acid 4.2 g, 27.8 mmol) in acetone (100 ml) was added MeI (5.2 ml, 83.4 mmol) and K2CO3 (7.7 g, 55.6 mmol). The mixture was heated to 60° C. for 2 h, and was filtered and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 20%→30% EtOAc-hexane to yield Intermediate 9 as a yellow solid.
Reaction SMILES: [CH2:1]([C@:3]1([OH:19])[C:15]2[CH:14]=[C:13]3[N:9]([CH2:10][CH2:11][C:12]3=O)[C:8](=[O:17])[C:7]=2[CH2:6][O:5][C:4]1=[O:18])[CH3:2].[C:20]([NH:23][CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[C:27]([NH2:34])[CH:28]=[CH:29][CH:30]=2)[C:25]1=O)(=[O:22])[CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:20]([NH:23][CH:24]1[C:25]2=[C:11]3[CH2:10][N:9]4[C:13](=[CH:14][C:15]5[C@:3]([CH2:1][CH3:2])([OH:19])[C:4](=[O:18])[O:5][CH2:6][C:7]=5[C:8]4=[O:17])[C:12]3=[N:34][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([C:26]=32)[CH2:32][CH2:33]1)(=[O:22])[CH3:21]
Reactant: CC(=O)NC1CCc2cccc(N)c2C1=O
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2C(NC(C)=O)CC3
Reaction time: 24 h

Procedure:
361 mg of (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano-[3,4-f]indolizine-3,6,10(4H)-trione (hereinafter abbreviated as "trione") was added to the solution of 300 mg of the compound prepared in (4) above in 200 ml of toluene. The mixture was heated under reflux using a Deanstark apparatus for 10 minutes. To the mixture was added 1 mg of pyridinium-p-toluenesulfonate (hereinafter abbreviated as "PPTS") and the mixture was refluxed while stirring for a further 24 hours. After cooling, the residue obtained by removing toluene by concentration was suspended into 300 ml of chloroform-methanol (10:1) solvent. Insoluble substances were removed and the residue was powdered with methanol to obtain 336 mg of the title compound.
Reaction SMILES: [Cl-].O[NH3+].[C:4]([O:7][CH2:8]/[CH:9]=[CH:10]/[C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)(=[O:6])[CH3:5].C([N:27](CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>O.N1C=CC=CC=1.C(Cl)Cl.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:4]([O:7][CH2:8]/[CH:9]=[CH:10]/[C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:27])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)(=[O:6])[CH3:5]
Reactant: CC(=O)OC/C=C/[C@H]1CC[C@H](c2ccc(C=O)cc2)CC1
Reactant: CCN(CC)CC
Agent: [Cu+2]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC/C=C/[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reaction time: 1 h

Procedure:
A solution of 513 mg of hydroxylammonium chloride in 5 ml of water was placed while gassing with argon in a sulphonation flask provided with a mechanical stirrer and treated at room temperature with a solution of 2.0 g of p-[trans-4-(3-acetoxy-trans-1-propenyl)cyclohexyl]benzaldehyde in 10 ml of pyridine. The mixture was stirred for 1 hour and then treated in sequence with 350 mg of copper sulphate pentahydrate and a solution of 2.1 ml of triethylamine in 10 ml of methylene chloride. After the initially inky blue colour of the copper-pyridine complex had turned olive-green, a solution of 1.74 g of dicyclohexylcarbodiimide in 20 ml of methylene chloride was added. The mixture was subsequently stirred at room temperature for a further 3 hours and then filtered. The filtrate was poured into 100 ml of water and extracted three times with 100 ml of methylene chloride each time. The organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (2.75 g) on silica gel with toluene/ethyl acetate (vol. 9:1) gave 2.26 g (114%) of p-[trans-4-(3-acetoxy-trans-1-propenyl)cyclohexyl]benzonitrile as colourless crystals which still contained some dicyclohexylcarbodiimide as the sole impurity. This material was processed without additional purification. Rf-value (toluene/ethyl acetate vol. 9:1) 0.33.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>C1COCC1>[CH:18]([N:21]([CH:22]([CH3:24])[CH3:23])[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4])([CH3:20])[CH3:19]
Reactant: CC(C)NC(C)C
Reactant: O=C(CCl)N1CCCc2ccc([N+](=O)[O-])cc21
Solvent: C1CCOC1
Product: CC(C)N(CC(=O)N1CCCc2ccc([N+](=O)[O-])cc21)C(C)C
Temperature: 25 °C

Procedure:
A mixture of 1-(2-chloroacetyl)-7-nitro-1,2,3,4-tetrahydroquinoline (D8) (6.7 g, 26 mmol) and diisopropylamine (50 ml) in THF (50 ml) was heated at reflux for 5d then cooled to room temperature. Aqueous work-up yielded a crude oil which was purified by flash column chromatography. Elution with 0-5% methanol/DCM gave the title compound as a dark oil (6.56 g). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.62 (br, 1H), 7.91 (dd, 1H), 7.27 (d, 1H), 3.95 (m, 2H), 3.54 (s, 2H), 3.02 (sp, 2H), 2.87 (t, 2H), 2.02 (m, 2H), 1.02 (d, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([N:14]=[C:15]=[S:16])[N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH3:24][N:25]([CH3:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([N:25]([CH3:33])[CH3:24])=[CH:27][CH:28]=3)=[S:16])[N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: CN1C(=O)C(N=C=S)N=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CN(C)c1ccc(N)cc1
Solvent: ClCCl
Product: CN(C)c1ccc(NC(=S)NC2N=C(c3ccccc3)c3cc(Cl)ccc3N(C)C2=O)cc1

Procedure:
To a solution of 7-chloro-1,3-dihydro-3-isothiocyanato-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (INTERMEDIATE 7) (0.342 g, 1 mmol) in dichloromethane (20 ml) was added N,N-dimethyl-1,4-benzenediamine (0.136 g, 1 mmol). The reaction mixture was heated at reflux for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (0.167 g, 35%). 1H-NMR (CDCl3): δ 7.70-7.22 (m, 10H), 6.75 (d, J=8.8 Hz, 2H), 6.05 (d, J=7.6 Hz, 1H), 3.42 (s, 3H) and 2.98 (s, 6H). MS (ESI) (M+H)+=478.
Reaction SMILES: O1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[SH:27][CH2:28][CH2:29][OH:30].B(F)(F)F>>[O:30]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2][S:27][CH2:28][CH2:29]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: OCCS
Agent: FB(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CSCCO4)c(F)c2)C(=O)O1

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol) with 2-mercaptoethanol (1.2 mmol), BF3.etherate (catalytic) in tetrahydrofuran (10 ml) at 70-80° C. for 14 hours followed by silica gel column chromatographic purification to provide title compound in 52% yield.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:34]1[CH:38]2[CH2:39][NH:40][CH2:41][CH:37]2[CH2:36][N:35]1C(OC(C)(C)C)=O>CN(C=O)C>[CH2:34]1[CH:38]2[CH2:39][NH:40][CH2:41][CH:37]2[CH2:36][N:35]1[C:2]1[C:21]([C:22]2[CH:27]=[N:26][CH:25]=[N:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC3CNCC3C2)c(-c2cncnc2)c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of 6-chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 223.1, 100 mg, 0.253 mmol) in DMF (2 mL) were added K2CO3 (105 mg, 0.760 mmol) and tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (81 mg, 0.380 mmol). The RM was stirred at 110° C. for 4 h and then at 130° C. for 5 h. After removal of solvent under reduced pressure, the crude intermediate was treated with a mixture of TFA/DCM (1 mL/2 mL) at RT for 5 h. The solvent was evaporated off under reduced pressure to afford 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, a portion of which (100 mg, 0.213 mmol) was dissolved in anhydrous THF (2 mL) and was treated with KOtBu (71.6 mg, 0.638 mmol) and 2-bromoethanol (0.1 mL, 1.435 mmol). The RM was stirred at 70° C. overnight, the solvent was evaporated off under reduced pressure and the crude material was purified by preparative HPLC. The compound was lyophilized in water/MeCN to afford the title product. UPLC-MS (Condition 3), tR=0.77 min, m/z=515.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]([N:22]=[N+]=[N-])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]2[C:12]([CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:22]2)=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(C)cc(OCc3ccccc3)cc2[nH]1

Procedure:
The reaction was carried out in a manner similar to Reference Example 13 b) except for using 3.22 g of ethyl 3-(4-benzyloxy-2-methylphenyl)-2-azidopropenoate and 100 ml of toluene. Ethyl 6-benzyloxy-4-methyl-2-indolecarboxylate was thus obtained in the yield of 2.66 g.
Reaction SMILES: COC1C(Cl)=C(Cl)C2C(=O)CCCCC=2C=1.C[O:18][C:19]1[C:20]([Cl:34])=[C:21]([Cl:33])[C:22]2[C:28](=[O:29])[CH:27]([CH2:30][CH3:31])[CH2:26][CH2:25][CH2:24][C:23]=2[CH:32]=1>>[OH:18][C:19]1[C:20]([Cl:34])=[C:21]([Cl:33])[C:22]2[C:28](=[O:29])[CH:27]([CH2:30][CH3:31])[CH2:26][CH2:25][CH2:24][C:23]=2[CH:32]=1
Reactant: CCC1CCCc2cc(OC)c(Cl)c(Cl)c2C1=O
Agent: COc1cc2c(c(Cl)c1Cl)C(=O)CCCC2
Product: CCC1CCCc2cc(O)c(Cl)c(Cl)c2C1=O

Procedure:
By the process of Example VI, Step 2, but substituting for the 2-methoxy-3,4-dichloro-6,7,8,9-tetrahydro- 5H-benzocyclohepten-5-one used therein an equivalent amount of 2-methoxy-3,4-dichloro-6-ethyl-6,7,8,9-tetrahydro- 5H-benzocyclohepten-5-one and conducting the reaction as described in Example VI, Step 2, there is obtained 2-hydroxy- 3,4-dichloro-6-ethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten- 5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=4[O:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:28][CH3:29].Cl[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][O:25][C:23]1[CH:22]=[CH:21][C:20]2[N:16]([CH2:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:28][CH3:29])[CH:4]=4)[CH2:13][CH2:12]3)=[O:27])[C:17](=[O:26])[O:18][C:19]=2[CH:24]=1)[CH3:36]
Reactant: CCOC(=O)CCl
Reactant: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(O)ccc43)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)oc(=O)n2CC(=O)N1CCN(c2ccc(Cl)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-hydroxy-3H-benzooxazol-2-one (44) (300 mg, 0.72 mmol, 1 eq), ethyl chloroacetate (132 mg, 1.08 mmol, 1.5 eq), cesium carbonate (467 mg, 1.43 mmol, 2 eq) in DMF (2 ml) was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and purified by flash chromatography to provide (3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-acetic acid ethyl ester (45).
Reaction SMILES: [CH2:1]([N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1.O1CCOCC1>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C(=O)OC(C)(C)C)cc2)cc1NC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(CCNCc3ccccc3)cc2)cc1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of methyl 4′-[2-[benzyl(tert-butoxycarbonyl)amino)ethyl]-3-(isopropylamino)-4-biphenylcarboxylate (768 mg) in tetrahydrofuran (8 ml) was added 4N hydrogen chloride solution in 1,4-dioxane (8 ml) at 0° C., and the mixture was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and the residue was diluted with chloroform and water. The mixture was basified with aqueous solution of sodium hydroxide (1N) and the organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give methyl 4′-[2-(benzylamino)ethyl]-3-(isopropylamino)-4-biphenylcarboxylate (600 mg).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:44][OH:45])=[O:37])[CH2:32][CH2:31]1>ClCCl>[CH3:29][N:30]1[CH2:31][CH2:32][N:33]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:44][O:45][N:26]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:27]=[O:28])=[O:37])[CH2:34][CH2:35]1
Reactant: CN1CCN(C(=O)c2ccccc2CO)CC1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCN(C=O)OCc1ccccc1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
Triethylamine (6.50 ml) and octadecyl isocyanate (14.40 ml) were added to a solution of the syrup containing 2-(hydroxymethyl)phenyl 4-methylpiperazinyl ketone (9.83 g) in dichloromethane (100 ml). After being stirred for 14.5 hours at room temperature, the insoluble material was filtrated out under a vacuum. The filtrate was concentrated. The residue was purified by silica gel column chromatography (silica gel 225 g, chloroform:methanol=80:1), thereby yielding 12.00 g of the aimed compound as white solid.