Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:15][C:16]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[Cl:28])=[N:25][C:24]([Cl:29])=[CH:23][CH:22]=2)=[O:17]>CC(C)=O>[C:1]([O:4][CH2:15][C:16]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[Cl:28])=[N:25][C:24]([Cl:29])=[CH:23][CH:22]=2)=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: O=C(CCl)c1cnc2ccc(Cl)nc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CC(=O)OCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.8 %

Procedure:
To a solution of acetic acid (0.32 mL, 5.5 mmol) and N,N-diisopropylethylamine (0.87 mL, 5.0 mmol) in acetone (20 mL) was added 2-chloro-1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (0.26 g, 0.96 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with satd. aq. sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/ethyl acetate) to afford the desired product (0.12 g, 42%) as a white solid. ESI MS m/z 299 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH2:26][C@@H:27]3[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][NH:28]3)=[N:22][C:21]=2[CH:34]=1>>[N:1]1([C:6]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:7]=2[C:8]([N:28]2[CH2:29][CH2:30][CH2:31][C@@H:32]([CH3:33])[C@H:27]2[CH2:26][NH:25][C:23]2[O:24][C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:34][C:21]=3[N:22]=2)=[O:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1ccc(-n2ccnc2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-n2ccnc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 2-(1H-imidazol-1-yl)-5-methylbenzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 464 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH2:29]([O:31][C:32]1[C:37]([NH:38][S:39]([C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[C:44]([CH3:49])[CH:43]=2)(=[O:41])=[O:40])=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:35]2[CH:36]=[C:37]([NH:38][S:39]([C:42]3[CH:47]=[CH:46][C:45]([OH:48])=[C:44]([CH3:49])[CH:43]=3)(=[O:41])=[O:40])[C:32]([O:31][CH2:29][CH3:30])=[N:33][CH:34]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CCOc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(O)c(C)c1
Yield: 30.6 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) was treated with N-(2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-hydroxy-3-methylbenzenesulfonamide (149 mg, 0.34 mmol), 2M cesium carbonate (340 μl, 0.68 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.02 mmol) according to the method described in Example 3 to give 47 mg (27% yield) of the title compound. Purity 85%.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][C:9]=3[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:6]=2[NH:5][CH2:4]1.Cl.[CH3:28][N:29]([CH3:45])[CH2:30][CH2:31][O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37]([C:42](O)=[O:43])=[CH:36]2.CCN=C=NCCCN(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.N>CC(N(C)C)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])=[CH:15][C:9]=3[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:6]=2[N:5]([C:42]([C:37]2[NH:38][C:39]3[C:35]([CH:36]=2)=[CH:34][C:33]([O:32][CH2:31][CH2:30][N:29]([CH3:45])[CH3:28])=[CH:41][CH:40]=3)=[O:43])[CH2:4]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3cc(NC(=O)OC(C)(C)C)ccc43)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A mixture of 222 (75 mg, 0.20 mmol), 5-[2-(dimethylamino)ethoxy]indole-2-carboxylic acid hydrochloride (73 mg, 0.26 mmol), EDCI (152 mg, 0.79 mmol) and TsOH (5 mg, 0.03 mmol) in DMA (1.5 mL) was stirred at room temperature for 1 h, then poured into dilute aqueous NH3. The precipitate was collected, washed with water, and dissolved in CH2Cl2 (250 mL). The solution was dried, filtered, concentrated under reduced pressure to a small volume, and then diluted with i-Pr2O to give tert-butyl 1-(chloromethyl)-3-{5-[2-(dimethylamino)ethoxy]indol-2-carbonyl}-5-nitro-1,2-dihydro-3H-benzo[e]indole-7-carbamate (223) (91 mg, 75%) as a yellow solid: mp (THF/CH2Cl2/hexane)>250° C.; 1H NMR [(CD3)2SO] δ 11.67 (d, J=1.6 Hz, 1H), 9.85 (s, 1H), 9.12 (s, 1H), 8.69 (d, J=1.9 Hz, 1H), 8.14 (d, J=9.2 Hz, 1H), 7.79 (dd, J=9.2, 2.0 Hz, 1H), 7.41 (d, J=−8.9 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 7.15 (d, J=1.7 Hz, 1H), 6.93 (dd, J=8.9, 2.4 Hz, 1H), 4.90 (t, J=10.2 Hz, 1H), 4.67 (dd, J=10.9, 2.4 Hz, 1H), 4.58-4.51 (m, 1H), 4.16-4.03 (m, 4H), 2.66 (t, J=5.8 Hz, 2H), 2.24 (s, 6H), 1.53 (s, 9H). Anal. (C31H34ClN5O6) C, H, N.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:48][O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[CH2:56][CH2:57][NH2:58]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:58][CH2:57][CH2:56][C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=4[O:49][CH3:48])=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: COc1ccccc1CCN
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCCc2ccccc2OC)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-(2-methoxy-phenyl)-ethylamine (Fluka) to give the title compound. HR-MS (ES, m/z) calculated for C44H53Cl2N6O4 [(M+H)+] 799.35, observed 799.3496.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17](S(CC)(=O)=O)[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:32])[N:4]([CH3:33])[C:3]1=[O:34].[Cl:35]C1C=C([N+]([O-])=O)C=CC=1Cl.C(N(CC)CC)C>CN(C)C=O>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=3[Cl:35])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:32])[N:4]([CH3:33])[C:3]1=[O:34]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: CCS(=O)(=O)N(CCCN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(N2CCN(CCCNc3ccc([N+](=O)[O-])cc3Cl)CC2)cc(=O)n(C)c1=O
Yield: 155.7 %

Procedure:
A mixture consisting of 0.4 g of Compound 158 obtained in Example 99-(1), 0.4 g of 3,4-dichloro-nitrobenzene, 0.43 ml of triethylamine and 6 ml of dimethylformamide was treated in a manner similar to Example 99-(2), thereby obtaining 0.55 g of 1,3-dimethyl-6-{4-[3-(2-chloro-4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:36])([CH3:35])[C@@H:17]([O:27][Si](C(C)(C)C)(C)C)[CH2:18][CH2:19]2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:36])([CH3:35])[C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 96 h
Yield: 49.7 %

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethylchola-5,7-dien-24-oic acid methyl ester (0.50 g) is dissolved in 5 ml of dry THF and 0.48 g of tetra-butylammoniumfluoride hydrate and 0.4 g of pulverised molecular sieve is added and the mixture is stirred for 4 days. After column chromatography and crystallization from methanol/water and methanol, the title compound (195 mg) is isolated. Melting point: 124-128° C. 1H-NMR (CDCl3, 400 MHz): δ=5.91 (1H, m); 5.53 (1H, m); 3.67 (3H, s). 3.4 (1H, m). MS: Calculated: 414.6. Found 414.3.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[F:13][C:14]1[CH:15]=[C:16]([CH2:38][N:39]2[CH2:42][CH:41]([C:43]([O:45][CH3:46])=[O:44])[CH2:40]2)[CH:17]=[CH:18][C:19]=1[C:20]1[S:21][C:22]2[C:27]([N:28]=1)=[CH:26][CH:25]=[C:24]([C:29]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[CH2:30])[N:23]=2>CS(C)=O.C1COCC1>[F:13][C:14]1[CH:15]=[C:16]([CH2:38][N:39]2[CH2:40][CH:41]([C:43]([O:45][CH3:46])=[O:44])[CH2:42]2)[CH:17]=[CH:18][C:19]=1[C:20]1[S:21][C:22]2[C:27]([N:28]=1)=[CH:26][CH:25]=[C:24]([C:29]1([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH2:1][CH2:30]1)[N:23]=2
Reactant: C=C(c1ccc(F)cc1)c1ccc2nc(-c3ccc(CN4CC(C(=O)OC)C4)cc3F)sc2n1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccc(F)cc6)CC5)nc4s3)c(F)c2)C1
Reaction time: 0.5 h

Procedure:
To a solution of potassium tert-butoxide (0.080 g, 0.71 mmol) and trimethylsulfoxonium iodide (0.16 g, 0.71 mmol) in 2 mL DMSO was added slowly dropwise a solution of methyl 1-((3-fluoro-4-(5-(1-(4-fluorophenyl)vinyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate (0.170 g, 0.36 mmol) in 2 mL THF, with 1 mL rinse. The solution became colored. After 30 min, the reaction mixture was quenched with sat'd aq. NH4Cl and EtOAc. The organic layer was washed with water, then brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The material was treated with DCM and adsorbed onto 1.5 g silica gel and passed through a Redi-Sep® pre-packed silica gel column (12 g) using 0-100% EtOAc/hexane. The product-containing fractions were concentrated to afford methyl 1-((3-fluoro-4-(5-(1-(4-fluorophenyl)-cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate as a yellow solid. MS (ESI) m/z: calculated: 491.2; Observed: 492.1 (M++1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5]([C:6]3[C:7](=[C:11]([C:14]([O:16]CC)=[O:15])[NH:12][CH:13]=3)[NH:8][CH:9]=2)=[N:4][N:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CO.C1COCC1.[Li+].[OH-]>O>[O:1]=[C:2]1[C:10]2[C:5]([C:6]3[C:7](=[C:11]([C:14]([OH:16])=[O:15])[NH:12][CH:13]=3)[NH:8][CH:9]=2)=[N:4][N:3]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1[nH]cc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1[nH]cc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c12
Temperature: 45 °C

Procedure:
Ethyl 3-oxo-2-phenyl-2,3,5,7-tetrahydropyrazolo[3,4-d]pyrrolo[3,4-b]pyridine-6-carboxylate was dissolved into a mixture of methanol, THF and H2O (1:1:1, 0.2 M). LiOH (5 eq.) was added and the reaction was heated at 45° C. for 17 hours. After cooling to room temperature the reaction was concentrated to dryness. 10% HCl (aq.) was added and the precipitate was collected, affording the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.87-7.21 (m, 1H) 7.25-7.52 (m, 2H) 7.60-7.85 (m, 1H) 8.13 (br. s., 3H) 11.56-11.92 (m, 1H) 12.90-13.17 (m, 1H)
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:13][C:14]([CH:16]1[CH2:19][N:18]([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17]1)=O.[OH-].[Na+]>O>[CH:20]([N:18]1[CH2:19][CH:16]([CH2:14][OH:13])[CH2:17]1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 108.6 %

Procedure:
To an anhydrous tetrahydrofuran solution (100 mL) of lithium aluminum hydride (1.14 g, 29.93 mmol), a tetrahydrofuran solution (50 mL) of 1-benzhydrylazetidin-3-carboxylic acid methyl ester (Oakwood Products, Inc.: Code No. W07L) (2.00 g, 7.16 mmol) was added dropwise over 10 minutes under ice cooling and stirring, and the reaction mixture was stirred for 3.5 hours. While the reaction mixture was stirred again under ice cooling, water (1.14 mL), a 4N-aqueous solution of sodium hydroxide (1.14 mL) and water (4.50 mL) were added to the reaction liquor, and the mixture was stirred for 20 minutes. Precipitated insoluble matter was removed through separation by filtration, and the obtained mother liquor was concentrated under reduced pressure to obtain the title compound (1.97 g, over yield) as an oily matter.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[NH:13][C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:32](Br)[CH:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)CC>[CH2:32]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[NH:13][C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[O:9])[CH2:2][CH2:3]1)[CH:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCC=Cc1ccccc1
Reactant: O=C1Nc2cccnc2N(C(=O)CN2CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Product: O=C1Nc2cccnc2N(C(=O)CN2CCN(CC=Cc3ccccc3)CC2)c2ccccc21

Procedure:
5.05 gm of 5,11-dihydro-11-[(1-piperazinyl)acetyl]-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one, 1.6 gm of sodium carbonate and 3.7 gm of cinnamyl bromide were refluxed in 80 ml of n-propanol for 3.5 hours. After evaporation, the residue was dissolved in chloroform/water. The organic phase was dried with sodium sulfate, the chloroform was distilled off, and the residue was purified on a silica gel column. After recrystallization from ethyl acetate.
Reaction SMILES: C[N:2]([CH3:19])/[CH:3]=[CH:4]/[C:5](=O)[CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[NH2:20][C:21]1[NH:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[C:22]=1C#N>CC(O)=O>[O:16]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:17])[N:7]1[CH2:6][C:5]1[N:25]2[N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)[C:22]([C:21]#[N:20])=[C:19]2[N:2]=[CH:3][CH:4]=1
Reactant: CN(C)/C=C/C(=O)CN1C(=O)c2ccccc2C1=O
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Solvent: CC(=O)O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(CN3C(=O)c4ccccc4C3=O)ccnc12
Temperature: 120 °C
Yield: 39.1 %

Procedure:
A mixture of (E)-2-(4-(dimethylamino)-2-oxobut-3-enyl)isoindoline-1,3-dione (600 mg, 2.33 mmol) and 5-amino-3-(4-phenoxy phenyl)-1H-pyrazole-4-carbonitrile (642 mg, 2.33 mmol) in 20 mL of HOAc was stirred and heated to 120° C. for 15 hr. The mixture was concentrated and suspended in 30 mL of solvent (PE/EA=4/1). The mixture was filtered and the solid was purified by pre-TLC (DCM/EA=50/1) to give 430 mg (40%) of 7-((1,3-dioxoisoindolin-2-yl)methyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a solid. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J=4.4 Hz, 1H), 8.05 (d, J=8.8 Hz, 2H), 7.96-7.90 (m, 1H), 7.88-7.85 (m, 2H), 7.50 (d, J=4.4 Hz, 1H), 7.46-7.37 (m, 2H), 7.21-7.09 (m, 5H), 5.32 (s, 2H). MS (ESI) m/e [M+1]+ 472.1.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([O:16][C:17](=[O:33])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][NH2:32])=[CH:25][CH:24]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:9]([O:16][C:17](=[O:33])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][NH:32][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[CH:25][CH:24]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C(NCCCCc1ccc(OCCNCc2ccccc2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 42.8 %

Procedure:
Benzyaldehyde (0.74 ml, 7.31 mmol) was added to a solution of 4-[4-(2-aminoethoxy)phenyl]butylcarbamic acid benzyl ester (15) (5.00 g (˜50% purity by NMR), 7.30 mmol) dissolved in anhydrous dichloroethane (50 mL). The resulting solution was stirred at ambient temperature for 7 h. Sodium triacetoxyborohydride (4.10 g, 19.35 mmol) was added slowly and the reduction continued for 60 h. The reaction was quenched with aqueous sodium bicarbonate (50 mL) and then extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed sequentially with water and brine, and dried over anhydrous sodium sulfate. A white solid precipitated out during the drying and collected by dissolving it in dichloromethane and then filtering off the solid sodium sulfate. The filtrate was concentrated and dried under vacuum to give 16 (1.35 g, 43%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.45-1.62 (m, 4H), 2.54 (t, 2H), 3.07-3.22 (m, 4H), 3.88 (s, 2H), 4.10 (t, 2H), 4.73 (br, 1H), 5.09 (s, 2H), 6.79 (d, 2H), 7.04 (d, 2H), 7.28-7.39 (m, 10H); m/z (ESI) 433 [C27H32N2O3+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21]#[N:22].[OH:23]O.[OH-].[NH4+].CO>O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21]([NH2:22])=[O:23]
Reactant: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C#N
Reactant: OO
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(N)=O
Reaction time: 10 h

Procedure:
A mixture of 5-amino-3-methylsulfanyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole-4-carbonitrile (2.7 g, 7.35 mmol), 30% hydrogen peroxide (10 ml), ammonium hydroxide (90 ml), methanol (70 ml) and water (15 ml) was stirred in a pressure reactor for 10 hours. The mixture was filtered and washed with water to give an off-white solid. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated to recover more product as an off-white solid. Both portions of off-white solid were combined to give 1.400 g of the desired title compound which was identical to the first title compound of Preparation B.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][CH2:27][NH:28][OH:29])[CH:21]=4)[C:16]3=[O:30])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([N:35]=[C:36]=[O:37])(C)C>O1CCOCC1.C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][CH2:27][N:28]([C:36]([NH2:35])=[O:37])[OH:29])[CH:21]=4)[C:16]3=[O:30])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=C1c2ccc(OCCNO)cc2CCN1Cc1ccc(-c2ccc(F)cc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)N(O)CCOc1ccc2c(c1)CCN(Cc1ccc(-c3ccc(F)cc3)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4'-fluoro-4-biphenylylmethyl)-6-[2-(N-hydroxyamino)ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (~22.5 mmol) in 1,4-dioxane (50 ml) and methylene chloride (30 ml), is added trimethylsilylisocyanate (3.36 ml). The reaction mixture is stirred at room temperature overnight and is subsequently diluted with H2O (500 ml). The resulting solution is extracted with EtOAc (2×400 ml) and the combined EtOAc portions washed with 2N HCl (800 ml), saturated NaCl solution (800 ml), dried over MgSO4, and concentrated in vacuo. The resulting solid is recrystallized from EtOAc/hexanes to give 2-(4'-fluoro-4-biphenylylmethyl)-6-[2-(N-aminocarbonyl-N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline, m.p. 171°-172°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([N:19]1[CH2:33][CH2:32][CH2:31][C@H:20]1[C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([OH:27])=O)=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[NH3:42]>O1CCCC1.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([N:19]1[CH2:33][CH2:32][CH2:31][C@H:20]1[C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:42])=[O:27])=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzyloxycarbonyl-isoleucyl-prolyl-proline (4.5 g) is dissolved in a mixture of tetrahydrofuran (30 ml) and triethylamine (1.4 ml). The solution is chilled in a -5° cooling bath and isobutyl chloroformate (1.6 ml) is added. The solution is allowed to warm to room temperature (10 minutes) and concentrated aqueous ammonia (10 ml) is added. After four hours stirring at room temperature, the reaction is concentrated in vacuo, diluted with ethyl acetate and washed sequentially with saturated sodium bicarbonate, water, 0.1 N hydrochloric acid and water. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to give the title compound.