Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13]([OH:18])(=[O:17])/[CH:14]=[CH:15]/[CH3:16].Cl>O1CCCC1>[C:7]1([CH:15]([CH3:16])[CH2:14][C:13]([OH:18])=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccccc1
Reactant: C/C=C/C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(CC(=O)O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
As presented in the following reaction formula, n-butyllithium (n-BuLi; 428 mL, 1.07 mol) was added dropwise at −78° C. to −65° C. to a mixture of bromobenzene (166 g, 1.07 mol) in tetrahydrofuran (THF; 500 mL), followed by stirring at −78° C. for 0.5 hours. Then, (E)-but-2-enoic acid (46 g, 0.53 mol) was added dropwise to the resulting mixture. After the completion of reaction, the mixture was treated with hydrochloric acid so that the pH thereof was adjusted to 1.0, and then extracted twice with 500 mL of dichloromethane (DCM). The combined organic phase was dried and concentrated with magnesium sulfate to give a crude product, which was purified by column chromatography (using 300 g of silica gel (product of Merck Co., Ltd.) to give 3-phenylbutanoic acid (52 g, yield: 60%) as a yellow liquid.
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][CH2:11][C@H:12]([NH:24][C:25](=[O:41])[C@@H:26]([NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=1)[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[F:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:14]([CH2:13][C@@H:12]([NH:24][C:25](=[O:41])[C@@H:26]([NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=1)[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:11][CH2:10][C:9]([OH:42])=[O:8])[CH2:15][CH2:16]2
Reactant: [H][H]
Reactant: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)OCc2ccccc2)CN2CCc3cc(F)ccc32)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)CN2CCc3cc(F)ccc32)c1
Reaction time: 8 h

Procedure:
The title compound of Example 42 (200 mg, 0.348 mmol) and 10% Pd/C were treated with MeOH (2 mL) and the atmosphere in the reaction was switched to hydrogen. After stirring overnight, the atmosphere in the reaction was switched back to nitrogen and the reaction was filtered through celite. Removal of solvent and drying afforded a white solid (168 mg, 94); HPLC-MS calcd. for C27H34FN3O4 (M+H+) 484.3, found 484.4.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH2:9]1[CH2:11][CH:10]1[CH2:12][NH2:13].[CH3:14][C:15]1[N:16]=[C:17]([N:23]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)[C:24]2=[O:40])[S:18][C:19]=1[C:20](O)=[O:21]>>[CH:10]1([CH2:12][NH:13][C:20]([C:19]2[S:18][C:17]([N:23]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=4)[C:24]3=[O:40])=[N:16][C:15]=2[CH3:14])=[O:21])[CH2:11][CH2:9]1
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: NCC1CC1
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCC1CC1
Yield: 15 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 2-cyclopropylmethylamine to react with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a white powder in 15% yield: mp 184-186° C.; 1H NMR (300 MHz, CDCl3) δ 7.32 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 5.70 (s, 1H), 4.48 (s, 2H), 4.08 (t, J=8.4 Hz, 2H), 3.46 (t, J=8.4 Hz, 2H), 3.24-3.20 (m, 2H), 2.58 (s, 3H), 1.03-0.92 (m, 1H), 0.55-0.44 (m, 2H), 0.29-0.27 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.3, 156.9, 155.5, 152.7, 148.9, 134.4, 129.7, 121.4, 120.4, 117.6, 47.3, 44.8, 42.0, 41.8, 17.1, 10.6, 3.5; MS (ES+) m/z 455.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18]>O1CCCC1.O>[C:17]([C:7]1[CH:6]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:4]=[CH:3][C:2]=1[F:1])([OH:19])=[O:18]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)ccc1F
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 4-fluorobenzotrifluoride (75 ml) in tetrahydrofuran (570 ml) under a nitrogen atmosphere and at a temperature of approximately -60° C. was added butyl lithium (25N, 200 ml) over a period of one hour. The reaction mixture was stirred at from -70° to -60° C. for four hours and then was poured over an excess of dry ice. After fifteen minutes the excess dry ice was evaporated and the solvent removed to leave a residue. The residue was taken up in water (500 ml) and sodium hydroxide (1N, 30 ml) prior to washing with ethyl acetate (2×300 ml). The aqueous phase was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2x300 ml). Finally, the combined organic extracts were washed with water (500 ml), dried and then evaporated to yield a crude residue which, upon recrystallisation from toluene/hexane, gave the title compound as a solid (77 g, 0.37 mol, 81% yield).
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:19]=[C:20]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:21]=[C:22]([CH3:24])[CH:23]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:20]3[CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]([F:17])[CH:19]=3)=[O:32])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: Cc1cc(F)cc(-c2oc(C)nc2C(=O)O)c1
Product: Cc1cc(F)cc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-5-methyl-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.O>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a stirred mixture of 6-chloropyridine-3-sulfonyl chloride (1 g, 4.717 mmol) in anhydrous dichloromethane (5 mL) was added triethylamine (790 μl, 5.66 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (945 mg, 4.717 mmol). The mixture was stirred at room temperature overnight and then poured into water. The resulting solids were collected by filtration to yield 1.7 g (99%) of tert-butyl 4-(6-chloropyridine-3-sulfonamido)piperidine-1-carboxylate as a white solid. 1H-NMR (CDCl3, 300 MHz): δ 9.82 (s, 1H), 8.11 (dd, 1H), 7.43 (d, 1H), 4.62 (d, 1H), 3.91 (m, 2H), 3.36 (m, 1H), 2.80 (m, 2H), 3.97 (m, 1H), 1.81 (m, 2H), 1.40 (s, 9H), 1.18 (m, 2H); LCMS: MS (m/z): 376 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH2:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C(=O)([O-])O.[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[NH:1]([C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23])[C@H:2]([C:6]([NH2:8])=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: C[C@@H](O)[C@H](N)C(N)=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(N)=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
11.8 g (0.1 mol) of L-threonine amide and 16.8 g (0.2 mol) of sodium hydrogencarbonate were added to 350 ml of water to obtain a solution. 17.9 g (0.105 mol) of benzyloxycarbonyl chloride was added slowly to the solution under vigorous stirring at a temperature of up to 20° C. over a period of 30 min. The mixture was stirred at room temperature for additional 5 h and a solid thus formed was filtered, washed and dried to obtain 21.4 g (yield: 85.0 %) of impure solid Z-L-Thr-NH2. 85 ml of water was added to the solid product and heated to 73° C. to obtain a solution. A small amount of an insoluble matter was filtered out and the filtrate was left to cool to room temperature and then cooled to 10° C. in an ice/water bath. Crystals thus formed were filtered and dried at a temperature of up to 40° C. under an aspirator vacuum to obtain 20.0 g of Z-L-Thr-NH2.1/2H2O. The filtration time was 2 min.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:28][C:29]([F:44])([S:40]([OH:43])(=[O:42])=[O:41])[C:30]([F:39])([F:38])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33].[C:45]1([CH3:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[F:44][C:29]([F:28])([S:40]([O-:43])(=[O:42])=[O:41])[C:30]([F:38])([F:39])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33].[CH3:51][C:45]1[CH:50]=[CH:49][C:48]([S+:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:47][CH:46]=1
Reactant: Cc1ccccc1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 2 °C
Reaction time: 1 h

Procedure:
Into a four-necked flask were charged 5.06 parts of diphenylsulfoxide and 50.6 parts of toluene, and the mixture was cooled to 2° C. Then, 10.5 parts of trifluoroacetic anhydride and 7.50 parts of perfluorobutanesulfonic acid were added and the mixture was stirred at the same temperature for 60 minutes. After standing, the lower layer was concentrated and diluted with 100 parts of chloroform. The obtained chloroform solution was washed 11 times with 50 parts of ion-exchange water and concentrated to give 12.0 parts of 4-methylphenyldiphenylsulfonium perfluorobutanesulfonate, which is referred to herein as PAG4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][C:28]=3[O:37][CH3:38])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:46].O1CCOCC1.CCOCC>CO>[ClH:46].[ClH:46].[F:45][C:42]1[CH:43]=[CH:44][C:39]([CH:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][C:28]=3[O:37][CH3:38])[CH2:19][CH2:18]2)=[O:16])=[CH:40][CH:41]=1
Reactant: COc1ccc2ccccc2c1CCCCN1CCN(C(=O)C(c2ccc(F)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2ccccc2c1CCCCN1CCN(C(=O)C(c2ccc(F)cc2)C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.1 g of 1-t-Butoxycarbonyl-4-(1-(4-fluorophenyl)-2-{4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin-1-yl}-2-oxoethyl)piperidine was dissolved in 10 ml of methanol, and 10 ml of 4M hydrogen chloride/1,4-dioxane solution was added, followed by stirring at room temperature for 2 hours. After concentration of the reaction solution under reduced pressure, to the residue was added ether, followed by stirring at room temperature. The precipitated crystals were filtered and washed with ether to give 1.7 g of 4-(1-(4-fluorophenyl)-2-{4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin-1-yl}-2-oxoethyl)piperidine dihydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[N:13]=[C:14]4[N:19]([C:20](=[O:24])[C:21]=3[O:22]C)[CH2:18][CH2:17][O:16][C:15]4([CH3:26])[CH3:25])[N:9]=[CH:8]2)=[CH:4][CH:3]=1.B(Br)(Br)Br.S(C)C>ClC(Cl)C>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[N:13]=[C:14]4[N:19]([C:20](=[O:24])[C:21]=3[OH:22])[CH2:18][CH2:17][O:16][C:15]4([CH3:26])[CH3:25])[N:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: COc1c(-c2cn(Cc3ccc(F)cc3)cn2)nc2n(c1=O)CCOC2(C)C
Agent: BrB(Br)Br
Solvent: CSC
Solvent: CC(Cl)Cl
Product: CC1(C)OCCn2c1nc(-c1cn(Cc3ccc(F)cc3)cn1)c(O)c2=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a solution of 2-(1-(4-fluorobenzyl)-1H-imidazol-4-yl)-3-methoxy-9,9-dimethyl-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (0.042 g, 0.109 mmol, 1.0 equiv) in dichloroethane (1.1 mL) under a nitrogen atmosphere, was added BBr3.SMe2 (0.137 g, 0.437 mmol, 4.0 equiv). The reaction was then heated to 80° C. (oil bath). After stirring 1 h, the reaction was cooled to ambient temperature and cautiously quenched with water (5 mL). The mixture was poured into saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by reverse phase preparatory HPLC to provide the title compound (0.017 g, 42% yield) as a pale gray solid. 1HNMR (400 MHz, CDCl3) δ ppm 11.34 (s, 1H), 7.59 (d, J=1.01 Hz, 1H), 7.42 (d, J=1.51 Hz, 1H), 7.20 (dd, J=8.69, 5.16 Hz, 2H), 7.05-7.13 (m, 2H), 5.16 (s, 2H), 3.95-4.08 (m, 4H), 1.58 (s, 6H); LCMS (ES+, (M+H)+) m/z 371.24.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8](=[O:17])[C:7]1=[O:18].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[O:17]=[C:8]1[C:7](=[O:18])[NH:6][CH2:11][CH2:10][N:9]1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CN1CCN(Cc2ccc(OC)cc2OC)C(=O)C1=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN1CCNC(=O)C1=O
Temperature: 25 °C
Yield: 77.4 %

Procedure:
A mixture of 10.5 g of methyl [4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin-1-yl]acetate, 42 ml of trifluoroacetic acid and 21 ml of anisole was refluxed for 4 hours. The reaction mixture was cooled to room temperature and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=6:1) to obtain 4.5 g of methyl (2,3-dioxopiperazin-1-yl)acetate as colorless crystals.
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: CC(=O)c1c(-c2ccccc2)noc1C
Reactant: NNc1ccccc1
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° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][OH:35])[CH2:31][CH2:32]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ncnn2c(C3CCN(CCO)CC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.2 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (38 mg, 0.065 mmol) in 95% aqueous ethanol (300 μL) was added concentrated hydrochloric acid (6 μL). The reaction was stirred (rt) for 48 h. The mixture was basified (pH 9) with, the addition of saturated aqueous NaHCO3 solution and was evaporated to remove volatiles. The aqueous mixture was extracted with ethyl acetate (3×20 mL) and the combined organics were washed with brine, dried (Na2SO4) and concentrated. The crude material was triturated with Et2O to afford 18 mg (61%) of the desired product as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 7.94 (s, 1 H), 7.85 (d, 1 H), 7.64 (s, 1H), 7.54 (s, 1 H), 7.46-7.33 (m, 5 H), 7.20 (d, 1 H), 6.63 (s, 1 H), 5.70 (s, 2 H), 3.60-3.51 (m, 2 H), 3.18-3.08 (m, 1 H), 3.06-2.98 (m, 2 H), 2.46 (t, 2 H), 2.14 (t, 2H), 2.02 (d, 2 H), 1.82-1.68 (m, 2 H); ES-MS m/z 468.34 [M+H]+, HPLC RT (min) 0.82.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O[C:5](=O)[C:4]=1[C:16]([O:18][CH3:19])=[O:17].[C:20]1([N:26]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][CH2:31]C3=O)=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[K+].Cl>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:31]2[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=3)[C:5]=2[C:4]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Reactant: COC(=O)c1c(SC)cc(-c2ccccc2)oc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2ccccc2)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 7 h
Yield: 54.9 %

Procedure:
A mixture of methyl 4-(methylthio)-2-oxo-6-phenyl-2H-pyran-3-carboxylate (276 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 7 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 234 mg (55%) of methyl 8-(methylthio)-2,6-diphenyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[F:22]C1C=C(F)C=CC=1C(O)=O>>[CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: CCOP(=O)(C=C1NCCN(C)c2ccccc21)OCC
Product: CCOP(=O)(C=C1NCCN(C)c2cc(F)ccc21)OCC

Procedure:
The starting material (8-fluoro-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]-diazepin-5-ylidenemethyl)phosphonic acid diethyl ester was prepared in an analogous fashion to (1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester, as described in Example 1 by replacing 2-fluorobenzoic acid with 2,4-difluorobenzoic acid.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[H-].[Na+].[F:41][C:42]([F:58])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:43](=[O:51])[CH2:44]P(=O)(OC)OC>ClCCl.C1COCC1>[F:41][C:42]([F:58])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:43](=[O:51])/[CH:44]=[CH:2]/[C@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16]
Reactant: COP(=O)(CC(=O)C(F)(F)c1ccccc1)OC
Reactant: N#CCCCCCCN1C(=O)OC[C@@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#CCCCCCCN1C(=O)OC[C@@H]1/C=C/C(=O)C(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of alcohol 2-3 (480 mg) in dichloromethane (10 mL) was added Dess-Martin periodanane (1 g) and the mixture was stirred at room temperature for 1 h and concentrated. The residue was co-evaporated with toluene several times, resuspended in ethyl acetate and was allowed to sit at 5° C. overnight. The mixture was filtered and the filtrate was concentrated to give the crude aldehyde 7-[(4S)4-formyl-2-oxo-1,3-oxazolidin-3-yl]heptanenitrile (2-5) which was used directly. To a suspension of NaH (168 mg) in THF was added dimethyl 3,3-difluoro-2-oxo-3-phenylpropylphosphonate (1.1 g) dropwise at 0° C. and the mixture was stirred at the temperature for 30 min. To the mixture was added crude aldehyde 2-5 in THF via a cannula and the mixture was stirred at room temperature for 5 h and quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate and the organic layer was dried and concentrated. The residue was purified by flash chromatography to give the desired product 2-4. 1H NMR (400 MHz, acetone-d6): δ 7.70–7.55 (m, 5H), 7.08 (dd, 1H), 6.95 (d, 1H), 4.70 (m, 1H), 4.52 (t, 1H), 3.30 (m, 1H), 3.00 (m, 1H), 2.48 (t, 2H), 1.70–1.25 (m, 8H).
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[C:11]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=2[CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[C:10]([CH3:26])[O:9][N:8]=1.CCO.[OH-].[Na+]>O>[CH3:6][C:7]1[C:11]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=2[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[C:10]([CH3:26])[O:9][N:8]=1
Reactant: CCOC(=O)CCc1ccc(O)cc1-c1c(C)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(O)ccc1CCC(=O)O
Reaction time: 16 h
Yield: 43.7 %

Procedure:
To a 10 mL RB flask fitted with magnetic stirrer was charged with 3 mL of tetrahydrofuran. To the stirred solvent were added ethyl 3-[2-(3,5-dimethyl-1,2-oxazol-4-yl)-4-hydroxy phenyl]propanoate (0.10 g, 0.35 mmol), ethanol (3 mL) and sodium hydroxide (0.015 g, 0.0.35 mmol) in water (0.5 mL). The reaction mixture was stirred at room 16 h. After completion of the reaction, the solvent was removed, the sodium salt was washed with diethyl ether (5 mL); the aqueous layer was acidified with 1N HCl to pH 2.0 and extracted with ethyl acetate (5 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to obtain the product (0.04 g, yield: 44.4%).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH:7]([CH:11]([C:16](=[O:29])[NH:17][CH:18]([C:23](=[O:28])[NH:24][CH:25]1[CH2:27][CH2:26]1)[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH:9]=[CH2:10])(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[CH:25]1([NH:24][C:23]([CH:18]([NH:17][C:16]([CH:11]([CH:7]([CH2:8][CH:9]=[CH2:10])[C:6]([OH:30])=[O:5])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:29])[C:19]([CH3:21])([CH3:22])[CH3:20])=[O:28])[CH2:27][CH2:26]1
Reactant: C=CCC(C(=O)OC(C)(C)C)C(CC(C)C)C(=O)NC(C(=O)NC1CC1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCC(C(=O)O)C(CC(C)C)C(=O)NC(C(=O)NC1CC1)C(C)(C)C
Reaction time: 8 h

Procedure:
2-[1-(1-Cyclopropylcarbamoyl-2,2-dimethyl-propylcarbamoyl)-3-methyl-butyl]-pent-4-enoic acid-tert-butyl ester (2.05 g, 4.83 mmol) was dissolved in dichloromethane (7 ml) and TFA (7 ml). The mixture was allowed to stand at 0°-5° C. overnight then solvent was evaporated under reduced pressure, azeotroping with three times toluene to provide the title compound as a white solid which was recrystallised from ethyl acetate. Yield: 1.81 g (74%). 1H-NMR; δ (CD3OD), 8.19 (1H, br s), 7.95 (1H, d, J=9.2 Hz), 5.72 (1H, m), 4.98 (2H, m), 4.19 (1H, d, J=9.3 Hz), 2.76 (1H,m), 2.56 (2H, m) 2.23 (1H, m), 1.59 (1H, m), 1.37 (1H, m), 0.96 (9H, s), 0.87 (3H, d,J=6.5 Hz), 0.81 (3H, d, J=6.6 Hz), 0.68 (2H, m) and 0.43 (2H, m).