Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[CH:34][CH:33]=3)[CH:7]=2)[N:13]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.6) (0.202 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.18 g, 80%). MS (ISP) 462.0 [(M+H)+]; mp 226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])=[O:8])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([N:9]2[CH2:10][CH2:11][CH2:12][C:13]2=[O:14])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)NCCCC(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)N2CCCC2=O)cc1

Procedure:
20.0 g. of 4-(p-methoxybenzoylamino)butyric acid, 50 ml. of toluene and 9.2 ml. of thionyl chloride are heated at reflux for 2 hours and then the mixture is treated with decolorizing charcoal and evaporated. The residue is dissolved in methylene chloride and chromatographed over neutral aluminum oxide. The 1-(p-methoxybenzoyl)-2-pyrrolidinone, which is eluted with methylene chloride, is recrystallized from alcohol and has a melting point of 119°-120° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([S:8]([NH:19][CH:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Br)ccc1Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(NC1CCC(O)CC1)c1cc(Br)ccc1Cl
Reaction time: 18 h

Procedure:
5-Bromo-2-chloro-benzenesulfonyl chloride (1.0 g, 3.45 mmol) (Intermediate E, Step 1) and pyridine (2 ml) are added to a stirred suspension of trans-4-aminocyclohexanol (2.0 g, 17.2 mmol) suspended in DCM (20 ml). After 18 h, the solvents are removed and the residue is partitioned between aq. 1M HCl and ethyl acetate. The organic extract is dried over Mg2SO4 and the solvent is removed. The residue is purified by chromatography on silica, eluting with ethyl acetate:hexane (1:1 to 1:0) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[C:6]([OH:18])[N:5]=[C:4]([SH:19])[N:3]=1.[OH-].[Na+].I[CH3:23].Cl>O.CN1CCCC1=O>[OH:18][C:6]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[C:2]([OH:1])[N:3]=[C:4]([S:19][CH3:23])[N:5]=1
Reactant: CI
Reactant: Cc1cccc(C(=O)Nc2c(O)nc(S)nc2O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CSc1nc(O)c(NC(=O)c2cccc(C)c2)c(O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
28.6 g of N-(4,6-dihydroxy-2-mercapto-pyrimidin-5-yl)-3-methyl-benzamide in 280 ml of water were cooled to 0° C. With cooling, 10.3 g of sodium hydroxide were added, and the mixture was stirred at 0° C. for 30 min. Then a solution of 6.4 ml of iodomethane in 108 ml of N-methylpyrrolidin-2-one was added. After completion of the reaction (6 h), the mixture was acidified with 6 N hydrochloric acid, and the precipitate filtered off and dried. 21.3 g of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C.C(OC(C)C)(C)C>>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1ccc([N+](=O)[O-])c2[nH]ncc12
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CC(C)OC(C)C
Product: CN(C)C=Cc1ccc([N+](=O)[O-])c2[nH]ncc12
Yield: 94.8 %

Procedure:
17.7 g of 4-methyl-7-nitro-1H-indazole [Chem. Ber. 37: 2556 (1904)] and 68.0 g of tertbutoxybis(dimethylamino)methane are heated to 80° C. for 45 minutes, combined with diisopropyl ether, suctioned off, and washed with diisopropyl ether, thus producing 22.0 g of N,N-dimethyl-N-[2-(7-nitro-1H-indazol-4-yl)ethenyl]amine, mp 255° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([C:18]([O-:20])=[O:19])[C:13]([O:15]CC)=[O:14].NC(N)=[S:23].[OH-].[Na+].Cl>C(O)C>[SH:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([C:18]([OH:20])=[O:19])[C:13]([OH:15])=[O:14]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(CCCCCCCCCCBr)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(CCCCCCCCCCS)C(=O)O

Procedure:
Reflux a solution of ethyl 2-(10-bromo-decyl)malonate (5.5 mmole) and thiourea (6.6 mmole) in 95% ethanol (25 mL) for 5 hours and then add an aqueous NaOH (2.0 M, 25 mL) and reflux for another 15 hours. Then, add an aqueous HCl (2.0 M) until the solution becomes acidic (approximately pH ˜2). Extract the reaction mixture with ether three times and wash and dry the combined organic layers with saturated NaCl solution with MgSO4. The product, 2-(10-mercaptodecyl)-propanedioic acid, can then be obtained by removal of solvent under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[N:14][N:13]([CH3:16])[C:12]=3[CH:17]=2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[N:14][N:13]([CH3:16])[C:12]=3[CH:17]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: Cn1nnc2ccc(C(=O)c3ccc(Cl)cc3)cc21
Agent: [BH4-]
Agent: [Na+]
Product: Cn1nnc2ccc(C(O)c3ccc(Cl)cc3)cc21

Procedure:
The keto compound (c) is reduced with sodium borohydride, yielding the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][C:9](=O)[CH2:8]1.O>CCOCC.O1CCCC1.C(OCC)(=O)C>[O:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: O=C1COc2ccccc2CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)CNCCO2
Yield: 90.5 %

Procedure:
To the suspension of lithium aluminium hydride (15.2 g, 0.4 mol) in 600 mL of ether was added a solution of 4,5-dihydro-1,4-benzoxazepin-3(2H)-one (16.3 g, 0.1 mol) in 60 mL of tetrahydrofuran at room temperature. After being heated with stirring under reflux overnight, water was added dropwise to quench the reaction at 0° C., The resulting mixture was diluted with ethyl acetate, and then filtered by a pad of celite. The filtrate was concentrated under reduced pressure, followed by the addition of hydrochloric acid ethyl acetate solution. The hydrochloride was collected by filtration, washed with ethyl acetate then ether, and then dried in vacuo to give 13.5 g of product. MS obsd. (ESI+) [(M+H)+] 150.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[N:13]([O-])=O.[Na+].C(OCC)C.[F:22][B-:23]([F:26])([F:25])[F:24].[H+]>>[F:22][B-:23]([F:26])([F:25])[F:24].[C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([N+:1]#[N:13])=[C:3]([CH3:12])[CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1cc(C)c(N)cn1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)Nc1cc(C)c([N+]#N)cn1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
The N1-(5-amino-4-methyl-2-pyridyl)acetamide (8.00 g, 48.4 mmol) obtained in (B) was dissolved in tetrafluoroboric acid (160 ml) and slowly added dropwise with an aqueous solution (40 ml) of sodium nitrite (3.51 g, 50.8 mmol) at −20° C. under nitrogen atmosphere. The reaction mixture was further stirred at −10° C. for 1 hour and added with diethyl ether (800 ml), and the deposited white solid was collected by filtration and washed with diethyl ether to obtain the title compound (14.7 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([OH:16])[C:6]=2[CH:17]=1.[Br:18][CH2:19][CH2:20]O>C1C=CC=CC=1.S(=O)(=O)(O)O>[Br:18][CH2:19][CH2:20][O:16][CH:7]1[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: OCCBr
Reactant: OC1c2ccccc2CCc2ccc(Cl)cc21
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: Clc1ccc2c(c1)C(OCCBr)c1ccccc1CC2
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a solution of 3-chloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol (3.52 g, 0.014 mol, prepared similarly as described in Fr.M. 2165, 1963; Chem.Abstr. 60, 14523 (1963)) and 2bromoethanol (2.5 g, 0.02 mol) in benzene (80 ml), concentrated sulfuric acid (0.85 ml) was added dropwise. The reaction mixture was stirred for 1.5 h, diluted with 50 ml of benzene and washed with water (30 ml), 0.6 N NaHCO3 (20 ml) and 2×30 ml of water. The benzene solution was dried (MgSO4) and the solvent was evaporated under vacuum to give a residue which was crystallised from a mixture of cyclohexane and n-hexane. 3.9 g (77%) of 5-(2-bromoethoxy)-3-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:19]C#N)=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1.[BH4-].[Na+].O>CO>[NH2:1][C:2]1[S:3][C:4]([SH:19])=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[N:6]=1
Reactant: CC(C)(C)OC(=O)NCCSCc1nc(N)sc1SC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCSCc1nc(N)sc1S
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a stirred solution of 2-amino-4-(2-t-butyloxycarbonylaminoethylthiomethyl)-5-thiocyanato-1,3-thiazole (2.83 g, 8.19 mmol) in methanol (30 mL) at room temperature was added sodium borohydride under nitrogen (0.93 g, 24.6 mol) and stirring was continued for 1 hour. After addition of water, stirring was continued until gas evolution subsided and the aqueous solution was washed with methylene chloride to remove impurities. Aqueous thiolate solution was neutralized with dilute hydrochloric acid and the product was extracted with ethyl acetate (all manipulations were performed under nitrogen to prevent formation of disulfide). Organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford pale orange foam of title product (1.72 g) which was used f6r further steps without further purification. 1H NMR (CDCl3) δ 1.40 (s, 9H), 2.60 (m, 2H), 3.20 (m, 2H), 3.65 (s, 2H), 5.40 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:15][N:16]3C(OC(C)(C)C)=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:15][NH:16]3)=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1nn(C(=O)OC(C)(C)C)c2cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1n[nH]c2cc(-c3ccc(N)cc3)ccc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a stirred solution of 1-tert-butyl 3-ethyl 6-(4-nitrophenyl)-1H-indazole-1,3-dicarboxylate (879 mg, 2.14 mmol) in ethanol (40 Ml), was added SnCl2 (2.4 g, 10.7 mmol) and the mixture was stirred at 80° C. for 3 h. The mixture was cooled to room temperature and saturated sodium bicarbonate aqueous solution was added. The organic layer was extracted three times and the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated in ethyl acetate and hexane to give ethyl 6-(4-aminophenyl)-1H-indazole-3-carboxylate (442 mg).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C@@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13]
Reactant: CC1=Nc2ccc(F)c(F)c2OC1
Solvent: Cc1ccccc1
Product: C[C@H]1COc2c(ccc(F)c2F)N1
Reaction time: 23 h
Yield: 97.9 %

Procedure:
To an argon-purged pressure-resistant glass vessel (100 mL) equipped with a magnetic stir bar, RuCl[(R)-daipena][(R)-dm-segphos] (2.8 mg, 2.3 μmol) and KO(t-Bu) (13.2 mg, 0.118 mmol) were added, and the vessel was purged with argon again. To this vessel, a toluene (0.9 mL) solution containing 7,8-difluoro-3-methyl-2H-1,4-benzoxazine (84.9 mg, 0.464 mmol) and being degassed by the freeze-pump-thaw technique in advance was added by pressure transfer using a cannula. An operation in which hydrogen was introduced into the pressure-resistant vessel up to 0.8 MPa and then released was repeated 10 times to completely substitute the inside with hydrogen. Then, hydrogen was introduced up to 2.0 MPa, and the vessel was starred in a water bath at 40° C. for 23 hours. After hydrogen was released, the solution was concentrated under reduced pressure, and the residue was purified through a silica gel short path column (hexane:ethyl acetate=1:1) to obtain (S)-7,8-difluoro-3,4-dihydro-3-methyl-2H-1,4-benzoxazine (84.1 mg, 98%). A result of an analysis was conducted by high performance liquid chromatography (column: CHIRALCEL OD-H, mobile phase: hexane:IPA=98:2, 1 mL/min) showed that the optical purity of this product was 98% ee.
Reaction SMILES: C(Cl)(=O)C.[OH:5][C@@:6]([CH3:14])([C:10]([F:13])([F:12])[F:11])[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].N1C=CC=CC=1.O.[OH-].[Li+]>C1(C)C=CC=CC=1.C(Cl)Cl.CN(C=O)C.O.C(OCC)(=O)C>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:7](=[O:8])[C@:6]([OH:5])([CH3:14])[C:10]([F:13])([F:12])[F:11]
Reactant: Nc1ccccc1Cl
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccccc1Cl)C(F)(F)F
Temperature: 80 °C
Reaction time: 15 h
Yield: 82.5 %

Procedure:
Acetyl chloride (11.7 ml, 164 mmol) was added dropwise to a stirred solution of the (R)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (10 g, 63 mmol) in toluene (100 ml) cooled in an ice bath. The mixture was then heated to 80° C. and the suspension dissolved to yield a clear solution. After 2 h the reaction mixture was cooled and then concentrated to yield a slight brown oil. This oil was then redissolved in DCM (140 ml) and DMF (4 drops) was added followed by oxalyl chloride (6 ml, 69 mmol). The solution bubbled vigorously and the reaction mixture was left to stir. After 15 h, this reaction mixture was added slowly to a stirred solution of 2-chloroaniline (8.7 g, 68 mmol) and pyridine (5.5 ml, 68 mmol) in DCM (150 ml). After 15 h stirring at room temperature, the resultant mixture was concentrated and the residue dissolved in methanol (500 ml). A solution of lithium hydroxide monohydrate (7.8 g, 0.19 mol) in water (120 ml) was then added and the mixture was stirred for 4 h. The mixture was then concentrated and the residue acidified to pH 2 (by addition of concentrated hydrochloric acid). Ethyl acetate(150 ml) was added and the mixture washed with water (2×100 ml) and brine, dried and evaporated to dryness. The residue was purified by flash column chromatography using 6:1, iso-hexane: ethyl acetate to yield the title compound as a white solid (13.8 g, 52 mmol). NMR: 1.6 (s, 3H), 7.1-7.25 (m, 1H), 7.3-7.4 (m, 1H), 7.55 (dd, 1H), 7.8 (s, 1H), 8.0 (dd, 1H), 9.7 (brs, 1H); MS: 266.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:34])[CH2:18][O:19][CH2:20][C:21]([NH:23][C:24]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:22])[CH:13]=[CH:14][CH:15]=1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:24]([NH:23][C:21](=[O:22])[CH2:20][O:19][CH2:18][C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:11]=2)=[O:34])=[C:25]([CH:29]=1)[C:26]([OH:28])=[O:27]
Reactant: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Br)c1
Reactant: OB(O)c1ccsc1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccsc2)c1

Procedure:
Using the same method as in Example 19-(ii), 3-thiopheneboronic acid was reacted with the 2-[((2-[(3-bromophenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 19-(i) to give 5-chloro-2-([(2-([3-(thiophene-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 82%).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[C:1]([NH:9][C:10]([NH:20][CH:12]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC1CCCCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(NC(=S)NC1CCCCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl isothiocyanate (7.40 mL, 54.0 mmol) was added to a solution of cyclooctanamine (6.25 g, 49.1 mmol) in 200 mL of chloroform. The mixture was stirred at ambient temperature overnight. The solvents were removed in vacuo to give the title compound as a viscous light yellowish oil. MS m/z: 291.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]([CH2:24][C:25]([NH2:27])=O)[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]([CH2:24][C:25]#[N:27])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(-c2nc3c(-c4ccccc4)nn(CC(N)=O)c3c(=O)n2-c2ccc(Cl)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1ccc(-c2nc3c(-c4ccccc4)nn(CC#N)c3c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetamide (10.0 mg, 0.020 mmol) and POCl3 (0.5 mL) is heated at 100° C. for 30 minutes. Upon completion, excess POCl3 is removed under reduced pressure. The residue is purified by preparative LC/MS to provide the title compound; HPLC-MS calculated for C28H22ClN5O (M+H+) 480.1. Found 480.1.
Reaction SMILES: [Cl:1][O-].[Na+].[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[N:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[OH-].[Na+]>[Cl:1][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[OH:4])[C:12](=[O:15])[NH:11][N:10]=[CH:9]2
Reactant: [O-]Cl
Reactant: O=c1[nH]ncc2ccc(O)cc12
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]ncc2cc(Cl)c(O)cc12
Reaction time: 2 h

Procedure:
Sodium hypochlorite solution (10% w/v chlorine, 175 ml) was added to a stirred solution of 7-hydroxy-1(2H)-phthalazinone (10 g, 0.062 mol) in aqueous sodium hydroxide (2N, 140 ml), and the stirring was continued for two hours. An excess of sodium metabisulphite was added to the reaction mixture, and the precipitate was recrystallised from ethanol to give 6-chloro-7-hydroxy-1(2H)-phthalazinone, m.p. > 340° (decomp), which was purified via the acetyl derivative m.p. 190°-192° as described in Example 4(i).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38](O)=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].[C:50]1([C:102]2[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=2)[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[NH:56][C:57]([O:59][CH:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][N:68]([CH3:101])[C:69](=[O:100])[CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][N:75]([C:86]2[CH:91]=[CH:90][C:89]([N:92]([CH3:99])[C:93](=[O:98])[CH2:94][CH2:95][NH:96][CH3:97])=[CH:88][CH:87]=2)[C:76](=[O:85])[O:77][CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[CH2:62][CH2:61]1)=[O:58]>>[C:50]1([C:102]2[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=2)[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[NH:56][C:57]([O:59][CH:60]1[CH2:61][CH2:62][N:63]([CH2:66][CH2:67][N:68]([CH3:101])[C:69](=[O:100])[CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][N:75]([C:86]2[CH:87]=[CH:88][C:89]([N:92]([C:93](=[O:98])[CH2:94][CH2:95][N:96]([C:38](=[O:39])[CH2:37][O:36][C@@H:28]3[C:25]4([CH2:26][CH2:27][N:22]([CH2:21][CH2:20][C@:11]5([C:13]6[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=6)[O:10][CH2:9][N:8]([C:6](=[O:7])[C:5]6[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:3]([C:2]([F:49])([F:1])[F:48])[CH:4]=6)[CH2:12]5)[CH2:23][CH2:24]4)[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29]3)[CH3:97])[CH3:99])=[CH:90][CH:91]=2)[C:76](=[O:85])[O:77][CH2:78][C:79]2[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=2)[CH2:64][CH2:65]1)=[O:58]
Reactant: CNCCC(=O)N(C)c1ccc(N(CCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)C(=O)OCc2ccccc2)cc1
Reactant: O=C(O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(C(=O)OCc1ccccc1)c1ccc(N(C)C(=O)CCN(C)C(=O)CO[C@H]2Cc3ccccc3C23CCN(CC[C@@]2(c4ccc(F)cc4)CN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CO2)CC3)cc1
Yield: 76.7 %

Procedure:
The compound (111 mg, 0.16 mmol) obtained in Example 1j and the compound (133 mg, 0.17 mmol) obtained in Example 97e were used to give the title compound (180 mg; yield, 73%) as a white solid according to the method described in Example 11e.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([F:13])[C@H:9]1[C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([F:13])[C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H]1C(=O)O
Yield: 95 %

Procedure:
A solution of (2R,3R)-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (70.0 mg, 0.216 mmol) in MeOH (10 mL) was hydrogenated at RT (1 atm) over Pd/C 10% (35 mg, 50% w/w) for 48 h. The reaction mixture was filtered through a 0.45 microns filter and concentrated under reduced pressure to give the crude title compound (>95% purity by 1H-NMR) as a white solid. MS (LC/MS): 232 [M−H]+; tR (HPLC conditions b): 2.26 min. This material was used in the next reaction step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][NH:14][C:15](=[O:24])[CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1.[NH4+].[Cl-]>[Fe]>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:11]#[C:12][CH2:13][NH:14][C:15](=[O:24])[CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[C:2]([F:1])[CH:28]=1
Reactant: O=C(CN1CCC(O)CC1)NCC#Cc1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1ccc(Oc2ccncc2C#CCNC(=O)CN2CCC(O)CC2)c(F)c1

Procedure:
The title compound was prepared by the reduction N-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(4-hydroxypiperidin-1-yl)acetamide (33 mg, 0.077 mmol) in a manner similar to that of Step E of Example 35 using Fe (powder, 67 mg, 1.21 mmol), NH4Cl (128 mg, 2.42 mmol). The product (30 mg, 100%) was obtained as a yellow oil which was used directly in the subsequent step. MS (ESI+): m/z 399.27 (M+H)+.