Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]=1[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH:40]=O)[CH:32]=1.FC(F)(F)C(O)=O.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]=1[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[CH2:40][CH2:39][CH2:38][CH2:37][C:33]1[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCCc1cccnc1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCNCc2ccccc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reaction time: 48 h
Yield: 72.4 %

Procedure:
A mixture of benzyl-{2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethyl}amine (700 mg) and 4-pyridin-3-yl butyraldehyde (314 mg) were solvated in 30 mL dry methanol to which ca. 2 g powdered 3 Å molecular sieves were added. The pH of this mixture was adjusted to 5 by the addition of trifluoroacetic acid and then 441 mg sodium cyanoborohydride was added and the mixture atirred at room temperature. After 48 hours, the mixture was filtered through diatomaceous earth, concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 96:4:0; then 96:4:1) to give the title compound (676 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]1[CH:14]=O)[CH3:2].Br.[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[N:28]=[N:27][C:26]([CH2:29]P(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:25]2)[CH:21]=[CH:22][CH:23]=1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[N:28]=[N:27][C:26]([CH:29]=[CH:14][C:4]3[N:3]([CH2:1][CH3:2])[C:7]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)=[N:6][N:5]=3)=[N:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccc(-n2nnc(C[PH](c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCn1c(C=O)nnc1-c1ccncc1
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCn1c(C=Cc2nnn(-c3cccc(Cl)c3)n2)nnc1-c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-carbaldehyde (56.4 mg, 0.279 mmol) was dissolved in dimethylformamide (2 mL) and added to a vial containing 2-(3-chloro-phenyl)-5-[(triphenyl-λ5-phosphanyl)-methyl]-2H-tetrazole hydrobromide (165.1 mg, 0.307 mmol) dissolved in dimethylformamide (2 mL). After addition of DBU (84.9 mg, 0.558 mmol), the vial was capped and the reaction was allowed to stir at room temperature for two hours. It was then heated at 80° C. for 1.5 hours. After cooling, water was added and an aqueous workup was done extracting with ethyl acetate three times. The combined organic layers were washed with water twice, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by an SPE tube (5% MeOH/CH2Cl2) to yield the title compound as a white solid. 1H NMR (CDCl3) δ (ppm): 8.84 (d, 2H), 8.22 (m, 1H), 8.10 (d oft, 1H), 8.04 (d, 1H), 7.67 (d, 1H), 7.64 (m, 2H), 7.51 (m, 2H), 4.27 (q, 2H), 1.51 (t, 3H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[NH:45]1[CH2:50][CH2:49][CH:48]([C:51]2[C:52](=[O:57])[NH:53][N:54]=[CH:55][CH:56]=2)[CH2:47][CH2:46]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:45]2[CH2:46][CH2:47][CH:48]([C:51]3[C:52](=[O:57])[NH:53][N:54]=[CH:55][CH:56]=3)[CH2:49][CH2:50]2)=[O:34])[CH2:18][CH2:17]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]nccc1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21)N1CCC(c2ccn[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.5 %

Procedure:
Triethylamine (37 μL, 0.50 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (70 mg, 0.167 mmol) and 4-nitrophenyl chloroformate (34 mg, 0.167 mmol) in tetrahydrofuran (1 mL) at 0° C. After 15 min, a solution of 4-piperidin-4-ylpyridazin-3(2H)-one (30 mg, 0.167 mmol) in dichloromethane (1 mL) and triethylamine (49 μL, 0.67 mmol) were added and the mixture allowed to warm to ambient temperature. After 4 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate (3×). The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (51 mg). MS 551.2152 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:21]([Si:18]([CH3:20])([CH3:19])[O:1][CH:2]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CCC(O)Cc2ccccc2)N1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Reaction time: 24 h
Yield: 92.7 %

Procedure:
To a solution of 5-(3-hydroxy-4-phenyl-butyl)-pyrrolidin-2-one (4.3 g, 18.43 mmol) in DMF (86 mL) was added tert-butyldimethylsilyl chloride (3.06 g, 20.3 mmol) followed by imidazole (2.5 g, 37 mmol) and DMAP (225 mg). The reaction mixture was stirred for 24 h and was quenched with saturated aqueous ammonium chloride. The aqueous solution was washed with EtOAc (3×) and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2) to yield 5.94 g of 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one. 1H NMR (CDCl3) δ 7.26-7.10 (m, 5H), 5.68 (m, 1H), 3.83 (m, 1H), 3.54 (m, 1H), 2.69 (m, 2H), 2.30-2.16 (m, 3H), 1.66-1.35 (m, 5H), 0.82 (s, 9H), −0.06 (d, 3H), −0.2 (d, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:32])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[C:23]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:20]([CH:13]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=2)=[O:32])=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(-c3ccccc3)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: O=C(Nc1nc(CO)cs1)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Yield: 48.5 %

Procedure:
A solution of 2-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-thiazole-4-carboxylic acid ethyl ester (prepared in Example 1B-d, 150 mg, 0.33 mmol) in diethyl ether (3 mL) at 0° C. under nitrogen was slowly treated with lithium aluminum hydride powder (16 mg, 0.44 mmol). The resulting reaction mixture continued to stir at 0° C. and was then allowed to gradually warm to 25° C. The reaction mixture was then stirred at 25° C. over a period of 64 h. The reaction mixture was slowly quenched by the dropwise addition of water (5 mL). The resulting reaction mixture was partitioned between water and ethyl acetate, and the layers were separated. The aqueous layer was further extracted with ethyl acetate (1×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/2 hexanes/ethyl acetate) afforded 2-biphenyl-4-yl-3-cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-propionamide (65 mg, 48%) as a white solid: mp 102-104° C.; EI-HRMS m/e calcd for C24H26N2O2S (M+) 406.1715, found 406.1711.
Reaction SMILES: ClS(C1C=CC(C(O)=O)=CC=1)(=O)=O.CC1CNCC(C)N1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.[CH3:36][CH:37]1[NH:42][CH:41]([CH3:43])[CH2:40][N:39]([S:44]([C:47]2[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[CH2:38]1>>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:51](=[O:52])[C:50]2[CH:54]=[CH:55][C:47]([S:44]([N:39]3[CH2:38][CH:37]([CH3:36])[NH:42][CH:41]([CH3:43])[CH2:40]3)(=[O:46])=[O:45])=[CH:48][CH:49]=2)=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC1CN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC(C)N1
Agent: CC1CNCC(C)N1
Agent: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: CC1CN(S(=O)(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC(C)N1

Procedure:
1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 570 mg of 2,6-dimethylpiperazine via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 119 mg of 4-(3,5-dimethylpiperazin-1-ylsulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3,5-dimethylpiperazin-1-ylsulfonyl)benzamide. MS (Q1) 485.4 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:49]=[CH:48][C:45]([CH:46]=[O:47])=[CH:44][C:43]=1Br>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:43]5[CH:44]=[C:45]([CH:48]=[CH:49][C:42]=5[F:41])[CH:46]=[O:47])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: O=Cc1ccc(F)c(Br)c1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C=O)ccc3F)cn2)cc1

Procedure:
In the same manner as Step A in Example 1-D-26, using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (215 mg) and 4-fluoro-3-bromo-benzaldehyde (113 mg) instead of 2-(4-bromo-phenyl)-[1,3]dioxolane, a crude product of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-benzaldehyde was obtained as a colorless solid (260 mg). Using a crude product (130 mg) of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-benzaldehyde, in the same manner as Step B in Example 1-D-26, using 1-ethylpiperazine (0.05 ml) instead of 1-methylpiperazine, a crude product of 5-{7-[5-(4-ethyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine was obtained as a colorless solid (57 mg). Using a crude product (57 mg) of 5-{7-[5-(4-ethyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine, according to the above Deprotection method 2, 5-{7-[5-(4-ethyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-ylamine was obtained as a colorless powder (26 mg, 68%).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:18]I.Cl>CN(C)C=O>[CH3:18][O:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1
Reactant: CI
Reactant: NC(=O)NC1CCC(O)c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCC(NC(N)=O)c2ccccc21
Reaction time: 8 h

Procedure:
A 2.0 g sample of 1,2,3,4-tetrahydro-4-hydroxy-1-naphthylurea (cis/trans) is stirred in 10 ml of dry dimethylformamide and one equivalent of sodium hydride in mineral oil added at 0° C under a nitrogen atmosphere. After the addition is completed, 1.2 equivalents of methyl iodide is added and the reaction mixture stirred overnight. The mixture is carefully poured on ice, neutralized with hydrochloric acid and the title compound collected by filtration. Evaporation of the filtrate to dryness and washing the residue with water affords additional title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[C:35]1([CH:41]([OH:44])[CH2:42][CH3:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:44][CH:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:42][CH3:43])=[CH:18][CH:17]=1
Reactant: CCC(O)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1)c1ccccc1
Yield: 99.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-phenyl-1-propanol (35 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 92%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]4[N:36]=[CH:37][CH:38]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][CH:38]=[C:12]23)[CH2:9][CH2:10]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-{(4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (27.7 g) in tetrahydrofuran (200 mL) was added 3M hydrochloric acid (200 mL), and the mixture was stirred at 60° C. for 15 hr. The mixture was allowed to cool to room temperature, diluted with ethyl acetate, and neutralized with 8M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was crystallized using ethyl acetate, and the resulting solid was collected by filtration, and dissolved in tetrahydrofuran (100 mL). This solution was added dropwise to a solution of lithium borohydride (2M tetrahydrofuran solution, 37 mL) in tetrahydrofuran (150 mL) at −5° C. over 30 min. After stirring for 1.5 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (21.1 g, 84%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]([C:21](=[O:24])[CH2:22][CH3:23])[N:13]=[C:14]([C:18]([O-:20])=O)[C:15]([O-:17])=[O:16].O>C1COCC1>[OH:20][C:18]1[C:14]([C:15]([OH:17])=[O:16])=[N:13][N:12]([CH3:11])[C:21](=[O:24])[C:22]=1[CH3:23]
Reactant: CCC(=O)N(C)N=C(C(=O)[O-])C(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(O)c(C(=O)O)nn(C)c1=O
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 47.3 %

Procedure:
To a solution of LiHMDS (331 mL, 331 mmol, 1 M solution in THF) in THF (430 mL) at −78° C. was added a solution of 2-(2-methyl-2-propionylhydrazono)malonate (21.40 g, 82.86 mmol) in THF (10 mL). The resulting mixture was slowly warmed to −40° C. over 1 hour and stirred for 1.5 hours at −40° C. To the reaction mixture was added water (500 mL) at −40° C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, quenched with 6 N aqueous HCl at 0° C., and acidified to pH 1 to 2. The resulting mixture was stirred for 16 hours at room temperature. The precipitates were filtered off and triturated with CH2Cl2 to afford 7.21 g (47%) of the desired product. The filtrate was extracted with EtOAc (3×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was triturated with CH2Cl2 to afford additional 3.56 g (23%) of the desired product. The aqueous layer was extracted again with EtOAc (3×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was triturated with CH2Cl2 to afford additional 1.32 g (9%) of the desired product. A total of 12.09 g (79%) of the desired product was obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9]C(=O)[C:7]2=[O:14].[OH:17]O.Cl>[OH-].[Na+]>[NH2:9][C:10]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:1])([F:16])[F:15])=[CH:5][C:6]=1[C:7]([OH:14])=[O:17]
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(OC(F)(F)F)cc1C(=O)O
Temperature: 17 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
5-Trifluoromethoxy-1H-indole-2,3-dione (3.48 g, 15.0 mmol) was dissolved in 2N aqueous sodium hydroxide (90 ml) and cooled to 17° C. before adding 30% aqueous hydrogen peroxide solution (2.75 ml, 27 mmol) dropwise over 20 minutes. The mixture was stirred at room temperature for 1 hour before adding concentrated hydrochloric acid (7 ml). The resulting brown precipitate was filtered off and dried in vacuo at 50° C. for 66 hours to give the title compound (1.83 g) as a brown solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH2:19]O)[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].CCN(S(F)(F)[F:27])CC>C(Cl)Cl>[CH2:1]([C:3]1([CH2:18][CH2:19][F:27])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCF)OCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a stirred solution of compound 1 (136 mg, 0.5 mmol) in CH2Cl2 (2 mL) at −40° C. under argon, DAST (396 μL, 3.0 mmol, 6.0 eq) was slowly added in a dropwise manner. The resulting mixture was allowed to warm to room temperature and stirred for one hour before being cooled to 0° C. and quenched with MeOH (1 mL). The mixture was stirred an additional thirty minutes at room temperature, and then saturated NaHCO3 (10 mL) was added dropwise. The resulting aqueous layer was extracted three times with CH2Cl2. The combined organic phases were dried with Na2SO4, concentrated, and purified by column chromatography using 5:95:EtOAc:Hexane to give a yellow-white solid (45 mg, 33%): mp 118–119° C. 1HNMR (CDCl3, δ TMS): 0.88 (t, 3H), 1.37 (t, 3H), 1.94 (m, 2H), 2.29 (m, 2H), 2.78 (m, 2H), 2.86 (q, 2H), 3.99 (m, 2H), 4.57 (qq, 2H), 7.03–7.38 (m, 3H, Ar—H), 7.65 (br, 1H, NH). MS−: m/z 310 (MCl−), 274 ([M−H]−). Anal. (C17H22NOF): C, H, N.
Reaction SMILES: Br[C:2]1[C:11]2[O:10]C[N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:6]=2[CH:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][N:22]=1>>[ClH:20].[C:16]([C:4]1[CH:3]=[C:2]([C:24]2[CH:23]=[N:22][C:21]([Cl:20])=[CH:26][CH:25]=2)[C:11]([OH:10])=[C:6]([CH2:7][NH:8][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:5]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)c1cc(Br)c2c(c1)CN(C(C)(C)C)CO2
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2ccc(Cl)nc2)c1O
Product: Cl

Procedure:
The title compound was prepared as a white solid using the procedure described in Example 1 from 8-bromo-3,6-di-tert-butyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (Intermediate 1) and 2-chloropyridine-5-boronic acid [purchased from Frontier Scientific].
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.Cl.C(O)C>[Fe].O>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[CH:5]=[C:6]2[S:10][C:9]([NH2:11])=[N:8][C:7]2=[C:12]([NH2:14])[CH:13]=1
Reactant: Nc1nc2c([N+](=O)[O-])cc(OC(F)(F)F)cc2s1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1nc2c(N)cc(OC(F)(F)F)cc2s1

Procedure:
The procedure is as Example 7, starting with 6-trifluoromethoxy-4-nitro-2-benzothiazolamine, iron powder, concentrated hydrochloric acid and ethanol having a water content of 50% (vol./vol.). After purification on a column of silica with a mixture of cyclohexane and ethyl acetate (10:90 by volume) as eluant, a white solid (1.5 g) is recovered, which solid is recrystallized in toluene (130 cc) to obtain 6-tri-fluoromethoxy-2,4-benzothiazolediamine (1 g), m.p. 206° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C=CC=CN=1.[CH2:29]=[C:30]1[O:34][C:32](=[O:33])[CH2:31]1>C1COCC1>[CH2:1]([O:8][C:9](=[O:21])[CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:32](=[O:33])[CH2:31][C:30](=[O:34])[CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNCC(=O)OCc2ccccc2)cc1
Reactant: C=C1CC(=O)O1
Agent: Oc1ccccn1
Solvent: C1CCOC1
Product: COc1ccc(CN(CC(=O)OCc2ccccc2)C(=O)CC(C)=O)cc1
Yield: 78.9 %

Procedure:
Prepared according to the representative procedure (Method B) using (4-methoxy-benzylamino)-acetic acid benzyl ester (910 mg, 3.19 mmol), 2-hydroxypyridine (304 mg, 3.20 mmol) in THF (25 mL), and ketene dimer (1.0 mL, 16 mmol). Purification by flash chromatography on SiO2 (1:4 EtOAc/hexanes) gave keto ester 54e (930 mg, 78%) as a colorless oil. Due to the presence of enol tautomers and amide rotamers, the NMR spectra of this compound is extremely complex and so line listing is not provided. Rf=0.28 (33% EtOAc/hexanes); IR (neat) 1747, 1720, 1646 cm−1; LRMS (ESI) Calcd. for C21H23NO5 [M+H] 370, found 370; HRMS (ESI) Calcd. for C21H23NO5 [M+H] 370.1654, found 370.1655.