Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:25]([O:29][C:30](=[O:38])[NH:31][CH2:32][C:33]1([F:37])[CH2:36][NH:35][CH2:34]1)([CH3:28])([CH3:27])[CH3:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:25]([O:29][C:30](=[O:38])[NH:31][CH2:32][C:33]1([F:37])[CH2:34][N:35]([C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]2[CH:16]=[N:17][C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:4]=3)=[N:14]2)[CH2:36]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCC1(F)CNC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 49.8 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.20 g, 0.56 mmol) was dissolved in DCM (10 mL). The reaction mixture was cooled to −60° C., at which temperature tert-butyl(3-fluoroazetidin-3-yl)methylcarbamate (0.127 g, 0.62 mmol), was added, followed by T3P (50% in EtOAc) (0.434 g, 0.67 mmol). DIPEA (0.144 g, 1.11 mmol) was then introduced slowly. The clear reaction mixture was stirred at −60° C. for a further 45 min. The reaction mixture was concentrated under reduced pressure to obtain crude product, which was purified by column chromatography (0-15% ethyl actetate-hexane) to afford 150 mg of (Z)-tert-butyl(1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-fluoroazetidin-3-yl)methylcarbamate (Yield 50%). 1H NMR (400 MHz, CDCl3, ppm) δ=9.7 (s, 1H); 8.63 (s, 2H); 7.94 (s, 1H); 7.24-7.21 (d, J=10.8 Hz, 1H); 5.67-5.64 (d, J=10.8, 1H); 4.41-4.16 (m, 4H); 3.76-3.54 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[S:16])[N:6]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:7]=1[NH2:8].[CH:18](OCC)(OCC)OCC>CCCCCCC>[CH:10]1([CH2:9][N:6]2[C:7]3[N:8]=[CH:18][NH:1][C:2]=3[C:3](=[O:17])[NH:4][C:5]2=[S:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1c(N)n(CC2CCCCC2)c(=S)[nH]c1=O
Reactant: CCOC(OCC)OCC
Solvent: CCCCCCC
Product: O=c1[nH]c(=S)n(CC2CCCCC2)c2nc[nH]c12
Temperature: 25 °C
Yield: 63 %

Procedure:
5,6-Diamino-1-cyclohexylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one, (1.44 g, 5.67 mmol) together with triethyl orthoformate (15 mL) was heated at 146° C. for 2 h and 10 minutes. The mixture was allowed to cool to ambient temperature and then further cooled on an ice-bath, followed by addition of heptane (5 mL). After filtration of the suspension and washing with heptane (20 mL), the obtained solid was dried in vacuo. Suspending the solid (1.2 g) in a hot mixture of 2-propanol (125 mL), water (5 mL) and tert-butyl methyl ether (25 mL) gave, after cooling and filtration, a white precipitate which was washed with further tert-butyl methyl ether (5 mL). The solid was dried in vacuo to give the title compound (0.95 g, 63%).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[H-].[Na+].Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)=[CH:14][CH:13]=1>COCCOC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[O:37])=[CH:34][CH:33]=2)=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(C(C)=O)C(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 28.4 g. of 2,4-pentanedione and 20 ml. of 1,2-dimethoxyethane is added to a suspension of 13.6 g. of sodium hydride in 220 ml. of 1,2-dimethoxyethane under argon. A solution of 28.7 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is stirred at room temperature for 12 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue is then chromatographed over silica gel to yield 3-{4'-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl} 2,4-pentanedione.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9]O>>[CH3:9][N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8]
Reactant: O=C1CCCCCN1
Reactant: CO
Product: CN1CCCCCC1=O

Procedure:
Thus after 2 times recycle of the distillation residue, an overall caprolactam yield of 91.2 mol % had been achieved based on the initial amount of M5FV. In the first cyclization pass, where still some methanol was present, 5.1 mol % of the unwanted by-product N-methyl caprolactam was formed. The approximated caprolactam yield per pass was 61.2% in the first pass, 66.5% in the second pass (first recycle of distillation residue) and 66.4% in the third pass (second recycle of distillation residue). Thus, it was proven that after distillative caprolactam recovery the remaining distillation residue can be successfully recycled to the cyclization reactor resulting in a high overall caprolactam yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[C:15]1([C@@H:21]2[CH2:23][C@H:22]2[C:24](=O)[CH3:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([C@@H:22]2[CH2:23][C@H:21]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:25])=[CH:6][CH:7]=1
Reactant: CC(=O)[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)[C@@H]1C[C@H]1c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 12, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and trans-1-(2-phenyl-cyclopropyl)-ethanone.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.Cl.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:22]([O:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:23])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1OC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of ethyl 2-hydroxybenzoate (0.5 g, 3.0 mmol) in CH2Cl2 (8 mL) was added 2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (0.8 g, 3.0 mmol), EDCl (0.63 g, 3.3 mmol) and dimethylaminopyridine (0.037 g, 0.3 mmol). The reaction was stirred (RT, 3 h) and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2 and the combined organic extracts were dried over MgSO4. The crude material was purified by silica chromatography (0-10% MeOH/CH2Cl2) to afford 1.2 g of ethyl 2-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)benzoate. Mass calculated for C235H27NO6=413.46; found: [M+Na]+=437.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([F:51])[C:49]=1F)[C:45]#[N:46]>>[C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:21]=[C:20]([O:22][C:49]3[C:42]([F:41])=[CH:43][C:44]([C:45]#[N:46])=[CH:47][C:48]=3[F:51])[CH:19]=[C:18]([O:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:29]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3c(F)cc(C#N)cc3F)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Yield: 64.9 %

Procedure:
Using 0.5 g (0.89 mmol) of {4-[3-[4-tert-Butoxycarbonylaminomethylphenoxy]-5-hydroxybenzoylamino]-cyclohexyl}carbamic acid tert-butyl ester and 3,4,5-trifluoro-benzonitrile (0.34 g, 2.22 mmol) and following the procedure of Example 42(b) afforded 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.38 (18H, d), 1.78 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 4.12 (2H, d), 6.74 (1H, d), 6.90 (1H, s), 7.02 (2H, d), 7.20 (2H, d), 7.28 (2H, d), 7.40 (1H, m), 8.08 (2H, d), 8.32 (1H, d).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8](=[O:29])[CH2:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:3]1[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([NH:39][CH2:40][C@H:41]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]1)=[O:38])=[O:31].[CH2:47](I)[CH3:48]>>[CH2:47]([N:43]1[CH2:44][CH2:45][CH2:46][C@H:41]([CH2:40][NH:39][C:37]([C@H:33]2[CH2:34][CH2:35][CH2:36][N:32]2[C:30]([C@@H:3]2[C@@H:2]([OH:1])[C@@H:6]([OH:7])[CH2:5][N:4]2[C:8](=[O:29])[CH2:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:31])=[O:38])[CH2:42]1)[CH3:48]
Reactant: O=C(NC[C@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1[C@@H](O)[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCI
Product: CCN1CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2[C@@H](O)[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Example 77, using (2R)-1-{(2S,3R,4S)-3,4-dihydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3S)-3-piperidylmethyl)pyrrolidine-2-carboxamide and ethyl iodide. The compound was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:7]=2[C:6]([O:15][CH3:16])=[CH:5][CH:4]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:17]([NH:24][CH:11]1[CH2:12][CH2:13][C:7]2[C:6]([O:15][CH3:16])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[CH2:9][CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(OC)c2c1CCC(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(OC)c2c1CCC(NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1,4-dimethoxy-5,6,8,9-tetrahydrobenzo-cyclohepten-7-one (670 mg) and benzylamine (0.5 ml) in toluene (60 ml) in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate was refluxed for 2 hours to remove water as the toluene azeotrope, and then the mixture was evaporated in vacuo. To the residue in methanol (60 ml) was added sodium borohydride (0.5 g) under nitrogen at 5° C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into ice-cold water and stirred for 30 minutes before adding ethyl acetate and brine. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate-methanol) over silica gel to afford N-benzyl-(1,4-dimethoxy-5,6,8,9-tetrahydrobenzcyclohepten-7-yl)amine (600 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2OCC)=[CH:4][CH:3]=1.[NH2:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>C1COCC1>[Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:9])=[O:10])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2[NH:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Reactant: CCC(N)CC
Solvent: C1CCOC1
Product: CCC(CC)Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Temperature: 50 °C

Procedure:
To a stirred solution of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (1 g, 2.56 mmol) in THF (20 ml) was added 3-aminopentane (0.596 ml, 5.12 mmol). The reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. The EtOAc solution was washed with 1M HCl(aq) and brine. The EtOAc solution was dried (MgSO4) and concentrated in vacuo. The residue was crystallized from toluene to give a solid; [M+H]+ 432.1. 1H NMR (DMSO) 0.9 (6H, t, 2×CH3), 1.5 (2H, m), 1.6 (2H, m), 3.0 (3H, s, CH3), 3.6 (3H, s, CH3), 3.9 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.2 (1H, d), 9.4 (1H, s), 10.1 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:18]([O-])(=[O:20])[CH3:19].[Na+]>C(OC(=O)C)(=O)C>[O:17]=[C:10]1[NH:9][C:8]([C:4]2[CH:3]=[C:2]([O:1][C:18](=[O:20])[CH3:19])[CH:7]=[CH:6][CH:5]=2)=[N:13][C:12]2[CH:14]=[CH:15][S:16][C:11]1=2
Reactant: CC(=O)[O-]
Reactant: O=c1[nH]c(-c2cccc(O)c2)nc2ccsc12
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cccc(-c2nc3ccsc3c(=O)[nH]2)c1
Temperature: 0 °C
Yield: 80.6 %

Procedure:
A mixture of 2-(3-hydroxy-phenyl)-3H-thieno[3,2-d]pyrimidin-4-one (28.58 g, 0.12 mol) and sodium acetate (1.1 eq., 0.13 mol, 10.56 g) in acetic anhydride (280 mL) was heated under reflux for 1.5 hours. The mixture was then cooled in ice-water and the grey solid collected by filtration, washed with water and dried to yield compound 4 (27.69 g, 82%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH2:18][C:19]([OH:21])=O)[N:11]=[C:12]([C:13]3[NH:14][CH:15]=[CH:16][N:17]=3)[C:5]=12.Cl.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][C:33]([CH3:38])([CH3:37])[CH2:32]2)=[CH:27][C:26]=1[O:39][CH3:40].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH2:18][C:19]([N:34]3[CH2:35][CH2:36][N:31]([C:28]4[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([O:39][CH3:40])[CH:27]=4)[CH2:32][C:33]3([CH3:38])[CH3:37])=[O:21])[N:11]=[C:12]([C:13]3[NH:17][CH:16]=[CH:15][N:14]=3)[C:5]=12
Reactant: COc1cc(N2CCNC(C)(C)C2)ccc1Cl
Reactant: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4c(N)ncnc43)C(C)(C)C2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
[4-Amino-3-(1H-imidazol-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]acetic acid dihydrochloride (100 mg, 0.2 mmol) and 1-(4-chloro-3-methoxyphenyl)-3,3-dimethylpiperazine dihydrochloride (100 mg, 0.3 mmol) were suspended in anhydrous DMF (2.5 mL). N,N-Diisopropylethylamine (0.32 mL, 1 mmol) was added at 0° C. and the mixture was stirred at room temperature until all solids dissolved to give a brown solution. HBTU (114 mg, 0.3 mmol) was added. After 2 h, the reaction mixture was poured slowly into a flask of vigorously stirred ice-water (100 mL). The resulting suspension was extracted with dichloromethane (100 mL) and washed with saturated NaHCO3 (100 mL), brine (100 mL) and evaporated. The residue was purified by flash column chromatography to afford 2-[4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-1-[4-(4-chloro-3-methoxyphenyl)-2,2-dimethylpiperazin-1-yl]ethanone as a light tan solid (45 mg) after evaporation and drying in vacuo. 1H NMR (400 MHz, d6-DMSO) δ 10.14 (d, 1H, J=3.6 Hz), 8.16 (s, 1H), 7.95 (d, 1H, d, J=3.6 Hz), 7.24 (s, 1H), 7.15 (s, 1H), 7.14 (d, 1H, J=8.8 Hz), 6.40 (d, 1H, J=2.4 Hz), 6.31 (dd, 1H, J=2.4 and 8.8 Hz), 5.29 (s, 2H), 3.90 (t, 2H, J=5.4 Hz), 3.84 (s, 3H), 3.46 (t, 2H, J=5.4 Hz), 3.30 (s, 2H), 1.38 (s, 6H). MS (ES) m/z 496.1 (M+H+).
Reaction SMILES: [OH-].[Na+].[C:3]1([C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][C:18]=2[OH:19])[CH:15]([C:20]([OH:22])=[O:21])[CH2:14][CH2:13]3)=[O:9])[S:7][CH:6]=[CH:5][CH:4]=1.[CH3:23]O>>[CH3:23][O:21][C:20]([CH:15]1[C:16]2[C:12](=[CH:11][C:10]([C:8](=[O:9])[C:3]3[S:7][CH:6]=[CH:5][CH:4]=3)=[C:18]([OH:19])[CH:17]=2)[CH2:13][CH2:14]1)=[O:22]
Reactant: O=C(c1cccs1)c1cc2c(cc1O)C(C(=O)O)CC2
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1CCc2cc(C(=O)c3cccs3)c(O)cc21

Procedure:
Analogously to the description in Example 2, 4.0 g of 5-thenoyl-6-hydroxy-indane-1-carboxylic acid methyl ester and 20 ml of 2N sodium hydroxide solution in 50 ml of methanol give 5-thenoyl-6-hydroxy-indane-1-carboxylic acid of melting point 183°-184° C (from ethyl acetate/petroleum ether).
Reaction SMILES: C[N:2]1CCOCC1.[C:8]1([CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)Cl>C(#N)C>[CH2:14]([S:15]([NH2:2])(=[O:17])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CN1CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: NS(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.1 %

Procedure:
To a solution of 5 (7.54 g, 0.0298 mole; see Example 5) and 4-methylmorpholine (9.04 g, 0.0894 mole, 9.83 mL) in 300 mL of anhydrous acetonitrile at 0° C. under N2 was added α-toluene-sulfonyl chloride (11.36 g, 0.0596 mole) in one portion. The solution was stirred at 0° C. for 1 hour and allowed to warm. to and stir at ambient temperature for 19 hours. The solution was filtered and evaporated. The crude residue was purified by flash chromatography on silica gel using a hexane, CH2Cl2: 4,1 to CH2Cl2 gradient system and afforded 12.05 g (99% yield) of product 6 as waxy reddish solid, mp 62-63° C. TLC (silica; CH2Cl2), Rf=0.45.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH:18]=[C:19]([O:22][CH2:23][C@@H:24]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH:26]([CH3:28])[CH3:27])[CH:20]=[CH:21][C:16]=2[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)C>ClCCl>[NH2:29][C@@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[C:9](=[O:37])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:17]=2[CH:18]=1
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(Cc3ccccc3)c2c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C[C@H](N)COc1ccc2c3ccncc3c(=O)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a solution of (S)-tert-butyl (1-((6-benzyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (35 mg, 0.070 mmol) in anhydrous dichloromethane (1 mL) was added a 2 M solution of HCl in diethyl ether (0.17 mL, 0.349 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to afford crude product which was purified by preparative TLC (ethyl acetate in petroleum ether) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-6-benzylbenzo[c][2,7]naphthyridin-5(6H)-one (10 mg, 0.024 mmol, 35% yield) as a light yellow solid. LC/MS (ESI) m/e 402.2 [(M+H)+, calcd for C25H28N3O2 402.2]; LC/MS retention time (method C): tR=1.77 min; HPLC retention time (method A): tR=5.54 min; HPLC retention time (method B): tR=6.17 min. 1H NMR (400 MHz CD3OD) δ ppm 9.61 (br. s., 1H), 8.87 (d, J=4.52 Hz, 1H), 8.53 (d, J=9.04 Hz, 1H), 8.47 (d, J=6.02 Hz, 1H), 7.28-7.38 (m, 5H), 7.15 (dd, J=8.91, 2.38 Hz, 1H), 7.04 (d, J=2.26 Hz, 1H), 5.72 (d, J=5.77 Hz, 2H), 4.27 (dd, J=10.54, 3.26 Hz, 1H), 4.10 (dd, J=10.42, 6.40 Hz, 1H), 3.69 (dd, J=6.65, 3.14 Hz, 1H), 1.68-1.81 (m, 1H), 1.57-1.67 (m, 2H), 1.00-1.05 (m, 6H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:26])(=[O:25])[N:16]=2)=[C:11]([OH:27])[C:10]2[S:28][C:29](S(C)(=O)=O)=[N:30][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:35]>>[NH2:35][C:29]1[S:28][C:10]2[C:11]([OH:27])=[C:12]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[S:17](=[O:25])(=[O:26])[N:16]=3)[C:13](=[O:14])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]=2[N:30]=1
Reactant: CS(=O)(=O)c1nc2c(s1)c(O)c(C1=NS(=O)(=O)c3ccccc3N1)c(=O)n2Cc1ccccc1
Reactant: N
Product: Nc1nc2c(s1)c(O)c(C1=NS(=O)(=O)c3ccccc3N1)c(=O)n2Cc1ccccc1
Yield: 99.2 %

Procedure:
The product of Example 146 (0.011 g, 0.02 mmol) was reacted with ammonia (0.5 M in dioxane, 1.3 mL, 0.64 mmol) in a pressure tube at 70° C. for 17 hours. The reaction was cooled and the resulting precipitate was collected by filtration and dried to give the title compound as a white solid (0.009 g, 100%). MS (ESI) m/z 452 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 5.43 (s, 2 H), 6.91 (s, 1 H), 7.07 (s, 1 H), 7.30 (m, 4 H), 7.52 (dd, J=24.27, 8.82 Hz, 2 H), 7.69 (t, J=7.54 Hz, 1 H), 7.85 (d, J=8.82 Hz, 1 H), 9.03 (br s, 1 H), 14.57 (brs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH2:29](O)[CH2:30][CH2:31][CH:32]=[CH2:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:33][CH2:32][CH2:31][CH:30]=[CH2:29])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Reactant: C=CCCCO
Product: C=CCCCN(c1cc2nn(-c3ccc(Cl)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Yield: 69 %

Procedure:
Synthesized under alkylation conditions by reacting 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (200 mg, 0.48 mmol) with 4-penten-1-ol (0.1 mL). Work up and purification afforded (i) (161 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=0.5 Hz, 1H), 7.56-7.48 (m, 4H), 7.37 (s, 1H), 5.88-5.66 (m, 2H), 5.03-4.93 (m, 2H), 3.73 (t, J=7.8 Hz, 2H), 3.05 (s, 3H), 3.01 (d, J=4.9 Hz, 3H), 2.49-2.37 (m, 1H), 2.15-2.05 (m, 2H), 1.85-1.62 (m, 2H), 1.15-1.04 (m, 2H), 1.04-0.93 (m, 1H), 0.67-0.52 (m, 1H). ESI-MS m/z calculated for [M+H]+: 487.2. found: 487.1.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][O:7][C:8]=1[CH3:9])(=O)[CH3:2].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(O)C>[C:16]1([NH:22][N:23]=[C:1]([C:4]2[C:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:6][O:7][C:8]=2[CH3:9])[CH3:2])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1c(-c2ccccc2)noc1C
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Product: CC(=NNc1ccccc1)c1c(-c2ccccc2)noc1C

Procedure:
A mixture of 80.4 g. (0.4 mole) of 4-acetyl-5-methyl-3-phenyl isoxazole, 39.4 ml. (0.4 mole) of phenyl hydrazine and 500 mg. toluenesulfonic acid in 400 ml. ethanol is stirred at room temperature for 48 hours. The resulting solid is filtered and washed with cold ether to give 1-(5-methyl-3-phenyl-4-isoxazolyl)-1-ethanone phenyl hydrazone; m.p. 129°-133°0 C.