Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[CH3:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH2:6][CH2:5]1.CCN(CC)CC.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:32][CH2:33][C:34]([N:22]1[CH2:23][CH2:24][N:19]([C:12]2[N:11]=[C:10]([N:7]3[CH2:8][CH2:9][CH:4]([CH3:3])[CH2:5][CH2:6]3)[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=2)[CH2:20][CH2:21]1)=[O:35]
Reactant: CC1CCN(c2nc(N3CCNCC3)ccc2[N+](=O)[O-])CC1
Reactant: O=C(Cl)CCl
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN(c2nc(N3CCN(C(=O)CCl)CC3)ccc2[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
A solution of 4-methyl-3′-nitro-6′-piperazin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl dihydrobromide (as prepared in Example 67, step (c), 0.28 g, 0.60 mmol) in CH2Cl2 (6 mL) was treated with Et3N (0.27 mL, 1.9 mmol) and cooled to 0° C. The mixture was treated with chloroacetyl chloride (53 μL, 0.66 mmol) as a solution in CH2Cl2 (2 mL) and stirred at 0° C. for 15 min then at room temperature for 30 min. The reaction was diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.18 g, 80%) as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.21 (d, 1H, J=9.2 Hz), 6.03 (d, 1H, J=9.2 Hz), 4.11 (s, 2H), 3.84-3.76 (m, 4H), 3.76-3.61 (m, 4H), 3.13-3.05 (m, 1H), 3.04-2.92 (m, 2H), 1.7-1.66 (m, 2H), 1.45-1.38 (m, 2H), 1.38-1.25 (m, 2H), 0.98 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C17H24ClN5O3, 382.1 (M+H), found 382.1.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([NH2:23])[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[C:27]([O:29][CH3:30])=[O:28]>O1CCCC1.C(N(CC)CC)C.ClCCl>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([NH:23][C:27](=[O:28])[O:29][CH3:30])[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)Cl
Reactant: CC(C)Oc1ccc(Oc2ccc(-c3cc(C(C)N)on3)cc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC(C)c1cc(-c2ccc(Oc3ccc(OC(C)C)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A solution of Example 17F (340 mg, 1.00 mmol) in tetrahydrofuran (5 mL) and triethyl amine (1.0 mL) was cooled to 0° C. To this was added methyl chloroformate (200 μL, 2.59 mmol) at 0° C. The mixture was stirred at room temperature for 30 minutes. The reaction was diluted with dichloromethane, which was washed with water (1×) and concentrated. The residue was purified on silica gel eluting with hexane and ethyl acetate gradient to give the desired product as a white solid (234 mg, 59%). MS (DCI): m/z 397 (M+H); 1H NMR (300 MHz, CDCl3) δ ppm 7.65-7.77 (m, 2H), 6.94-7.07 (m, 4H), 6.85-6.93 (m, 2H), 6.40 (s, 1H), 5.01-5.16 (m, 1H), 4.44-4.58 (m, 1H), 3.71 (s, 3H), 1.58 (d, J=6.99 Hz, 3H), 1.35 (d, J=6.25 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13](N)=[O:14]>O>[Br:11][C:7]1[CH:6]=[C:3]2[C:2](=[C:9]([Cl:10])[CH:8]=1)[N:1]=[C:13]([OH:14])[N:12]=[CH:4]2
Reactant: NC(N)=O
Reactant: Nc1c(Cl)cc(Br)cc1C=O
Solvent: O
Product: Oc1ncc2cc(Br)cc(Cl)c2n1
Temperature: 180 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A mixture of 2-amino-5-bromo-3-chlorobenzaldehyde (9.0 g, 38.6 mmol) and urea (34.7 g, 579 mmol) was heated to 180° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature, and the resulting precipitate was diluted with water (1 L) and stirred for 2 hours. The resulting precipitate was filtered, and the moisture trapped was completely removed by the co-evaporation with toluene three times. The title compound (9.0 g, 90%) was obtained as a yellow solid. MS (ES+) C8H4BrClN2O requires: 257, 259, found: 258, 260 [M+H]+.
Reaction SMILES: C1([SeH-](C2C=CC=CC=2)=[Se])C=CC=CC=1.[BH4-].[Na+].[O:17]1[C@H:19]2[C@:20]3([CH2:35][CH2:34][C@H:33]4[C@@H:24]([CH2:25][CH2:26][C:27]5[CH:28]=[C:29]([O:36][CH3:37])[CH:30]=[CH:31][C:32]=54)[C@@H:22]3[CH2:23][C@@H:18]12)[CH3:21].OO>C(O)C>[CH3:37][O:36][C:29]1[CH:30]=[CH:31][C:32]2[C@@H:33]3[C@H:24]([C@H:22]4[C@@:20]([CH2:35][CH2:34]3)([CH3:21])[C@H:19]([OH:17])[CH:18]=[CH:23]4)[CH2:25][CH2:26][C:27]=2[CH:28]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]3O[C@@H]3C[C@@H]12
Agent: OO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)C=C[C@@H]12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.9 g. of diphenyldiselenide is dissolved in 100 ml. of absolute ethanol and combined at room temperature with 500 mg. of sodium borohydride. After decolorization of the yellow solution, 2.5 g. of 16α,17α-epoxy-3-methoxy-1,3,5(10)-estratriene [B. Schoenecker et al., Z.Chem [Chemical News] 10 (6), (1910)] is added thereto, and the mixture is heated for 27 hours under reflux. After cooling to 0° C., 6 ml. of 30% H2O2 is added dropwise thereto, and the solution is gradually warmed to 50° C. After 2 hours, the solution is poured into ice water. The thus-precipitated product is vacuum-filtered, washed with water, taken up in methylene chloride, and dried over sodium sulfate. After the crude product has been chromatographed on silica gel with 5 - 7.5% acetone/hexane, 1.1 g. of 3-methoxy-1,3,5(10),15-estratetraen-17α-ol is isolated as an oily product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[Br:20][CH2:21][CH2:22]Br>CC(N(C)C)=O>[Br:20][CH2:21][CH2:22][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1
Reactant: BrCCBr
Reactant: Cc1cccc(Nc2ncnc3ccc(O)cc23)c1
Solvent: CC(=O)N(C)C
Product: Cc1cccc(Nc2ncnc3ccc(OCCBr)cc23)c1
Temperature: 80 °C
Yield: 47 %

Procedure:
Using an analogous procedure to that described in Example 39, except that DMA was used in place of DMF and that the reaction mixture was heated to 80° C. for 4 hours, 6-hydroxy-4-(3'-methylanilino)quinazoline was reacted with 1,2-dibromoethane to give 6-(2-bromoethoxy)-4-(3'-methylanilino)quinazoline in 47% yield, m.p. 129°-135° C.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][S:15][CH3:16])(C1C=CC(C)=CC=1)(=O)=O.[SH:17][CH2:18][CH2:19][CH2:20][OH:21].CC(C)([O-])C.[K+].O>C1COCC1>[CH2:20]([OH:21])[CH2:19][CH2:18][S:17][CH2:12][CH2:13][CH2:14][S:15][CH3:16]
Reactant: CSCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: OCCCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CSCCCSCCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.8 %

Procedure:
To a mixture of 3-methylthio-1-propanol tosylate (14.14 g, 54.3 mmol), and 3-mercapto-1-propanol (5.0 g, 54.3 mmol) in dry THF (300 mL) was added potassium tert-butoxide (8.51 g, 80.0 mmol) in one portion under a blanket of nitrogen, and the resulting mixture was stirred at room temperature for 24 hours. Water (10 mL) was added drop-wise to the reaction mixture to quench excess potassium tert-butoxide, and solvent was evaporated under reduced pressure. The resulting solid was washed with ether (3×100 mL), and filtered. The ether layer was washed with water (3×100 mL) and dried (Na2SO4). Solvent evaporation produced 8.7 g of a light yellow oil. This product was used for acryloylation without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][NH2:25])[N:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](Cl)=[O:36])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][NH:25][C:35](=[O:36])[CH2:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[N:13]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(=O)c2cccc(-c3ccccc3CN)n2)cc1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CC(=O)NCc2ccccc2-c2cccc(C(=O)Nc3ccc(OC)cc3)n2)cc1
Reaction time: 8 h
Yield: 96.9 %

Procedure:
39 mg (0.12 mmol) of 6-(2-Aminomethylphenyl)-pyridine-2-carboxylic acid-(4-methoxyphenyl)-amide were dissolved in 3 ml of dichloromethane, treated with 27 μl (0.144 mmol) of 4-methoxyphenylacetyl chloride and 19 mg (0.144 mmol) of DIPEA and the mixture was stirred overnight. It was diluted with 20 ml of dichloromethane and washed with an NaHCO3 solution. The organic phase was dried, concentrated and purified by RP-HPLC. 56 mg (78%) of the compound of Example 20 were obtained in the form of its trifluoroacetate.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][NH:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]([C:21]3[S:22][C:23]([CH3:30])=[C:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:25]=3)=[N:19][N:20]=2)=[CH:11][C:10]=1[CH3:31]>C1COCC1.CO.[Li+].[OH-]>[CH2:26]([C:24]1[CH:25]=[C:21]([C:18]2[O:17][C:16]([C:12]3[CH:13]=[C:14]([CH3:15])[C:9]([CH2:8][CH2:7][C:6]([NH:5][CH2:4][C:3]([OH:33])=[O:2])=[O:32])=[C:10]([CH3:31])[CH:11]=3)=[N:20][N:19]=2)[S:22][C:23]=1[CH3:30])[CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)CNC(=O)CCc1c(C)cc(-c2nnc(-c3cc(CC(C)C)c(C)s3)o2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2nnc(-c3cc(CC(C)C)c(C)s3)o2)cc(C)c1CCC(=O)NCC(=O)O

Procedure:
A solution of (3-{4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenyl}-propionylamino)-acetic acid methyl ester in THF (1 mL), MeOH (1 mL) and 2 N aq. LiOH solution (0.25 mL) is stirred at rt for 4 h. The precipitate that formes is collected, washed with water and dried under HV to give (3-{4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenyl}-propionylamino)-acetic acid (9 mg) as a white powder; LC-MS: tR=0.99 min, [M+1]=456.17.
Reaction SMILES: CS(C1OC2C=C(OC3C=CN=C(C(NC)=O)C=3)C=CC=2N=1)=[O:3].C1(CN)CCCCC1.[CH:32]1([CH2:38][NH:39][C:40]2[O:41][C:42]3[CH:48]=[C:47]([O:49][C:50]4[CH:55]=[CH:54][N:53]=[C:52]([C:56](NC)=[O:57])[CH:51]=4)[CH:46]=[CH:45][C:43]=3[N:44]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:38][NH:39][C:40]2[O:41][C:42]3[CH:48]=[C:47]([O:49][C:50]4[CH:55]=[CH:54][N:53]=[C:52]([C:56]([OH:3])=[O:57])[CH:51]=4)[CH:46]=[CH:45][C:43]=3[N:44]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Agent: NCC1CCCCC1
Product: O=C(O)c1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1

Procedure:
In Scheme 5, 4-(2-(methylsulfinyl)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide is aminated with cyclohexylmethanamine. The resulting 4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide is then hydrolyzed to form 4-[2-(cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid. 4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid then reacts with benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate, tert-butyl carbazate, and triethyl amine to form 4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbohydrazide. 4-(2-(Cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbohydrazide then reacts with trimethyl orthoformate to form a compound of the embodiments.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH2:14]([N:16]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[C:22]2[CH:25]=O)=[N:17]1)[CH3:15]>O1CCCC1.[Cl-].[NH4+]>[CH2:14]([N:16]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[C:22]2/[CH:25]=[CH:3]/[C:1]#[N:2])=[N:17]1)[CH3:15]
Reactant: CCn1cc2c(C=O)cccc2n1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCn1cc2c(/C=C/C#N)cccc2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (254 μL, 1.57 mmol) in tetrahydrofuran (6 mL) was added 60% sodium hydride (57.9 mg, 1.45 mmol) under ice-cooling, and the mixture was stirred at 0° C. for 15 min. To the mixture was added a solution of 2-ethyl-2H-indazole-4-carbaldehyde (210 mg, 1.20 mmol) in tetrahydrofuran (6 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 15 min. The reaction solution was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=15/85→50/50) to give the title compound (222 mg, yield 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]1([N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:34](=[O:35])[N:33]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)N(c1ccccc1)c1ccccc1

Procedure:
A solution of 1.03 g (3.90 mmole) of (S)-4-(benzyloxycarbonyl)piperazine-2-carboxylic acid (from Step A) in 12 ml. of DMF was treated with 0.788 g (7.79 mmole) of triethylamine at 25° C. With stirring 0.901 g (3.89 mmole) of diphenylcarbamoyl chloride was added in portions over 2 hours. After 16 hours the mixture was concentrated in vacuo to an orange oil which was chromatographed over an 88×2.5 cm LH 20 column with 11 ml. fractions of methanol. Fractions 35-43 were combined and concentrated to 1.136 g (64%) of pale yellow oil which contained a major spot by TLC (80:18:2 chloroform-methanol-ammonia water, Rf =0.45).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](NCC=C)=O)[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=O)C.[C:22](CC(N)=S)#[N:23]>CCO>[NH2:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([CH2:16][C:22]#[N:23])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1
Reactant: C=CCNC(=O)c1nc(-c2sc(NC(C)=O)nc2C)cs1
Reactant: N#CCC(N)=S
Solvent: CCO
Product: Cc1nc(N)sc1-c1csc(CC#N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Amino-4-methyl-1,3-thiazol-5-yl)-2-bromo ethanone, hydrobromide salt (Intermediate 2) (116.97 mg; 0.50 mmol; 1 eq.) and 2-cyanothioacetamide (Aldrich) (50.1 mg; 0.50 mmol; 1 eq.) are dissolved in EtOH (5 ml). The mixture is stirred at rt overnight. Solvents are evaporated, affording a yellow-orange solid which is purified by flash chromatography (CHCl3/EtOH gradient, from 50:1 to 10:1). (2′-amino-4′-methyl-4,5′-bi-1,3-thiazol-2-yl)acetonitrile is isolated as an orange solid. (71.6 mg; 61%). 1H NMR (DMSO-d6, 300 MHz) δ 2.41 (s, 3H), 4.62 (s, 2H), 7.87 (s, 1H), 9.23 (br s, 2H). M− (ESI): 235.04; M+ (ESI): 237.06. HPLC (method A), Rt: 1.16 min (purity: 98.3%).
Reaction SMILES: CS(O[C@@H:6]1[CH2:9][CH2:8][C@@H:7]1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])(=O)=O.[NH2:21][CH2:22][CH2:23][OH:24]>C(OCC)(=O)C>[F:18][C:17]([F:20])([F:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C@@H:7]1[CH2:8][CH2:9][C@H:6]1[NH:21][CH2:22][CH2:23][OH:24]
Reactant: NCCO
Reactant: CS(=O)(=O)O[C@@H]1CC[C@@H]1Oc1ccccc1C(F)(F)F
Solvent: CCOC(C)=O
Product: OCCN[C@@H]1CC[C@H]1Oc1ccccc1C(F)(F)F
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A mixture of C8 (500 mg, 1.61 mmol) and 2-aminoethanol (5 mL) was heated at 90° C. for 18 hours, then at 100° C. for an additional 24 hours. The reaction was cooled, diluted with ethyl acetate (100 mL) and washed with aqueous sodium hydroxide solution (1 M, 5×50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via HPLC (Column: Phenomenex Luna C18(2), 5 μm; Mobile phase A: 0.1% formic acid in water; Mobile phase B: 0.1% formic acid in methanol; Gradient: 5% to 100% B) afforded the title compound as a solid. Yield; 191 mg, 0.694 mmol, 43%. LCMS m/z 276.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.49 (br s, 1H), 7.56 (br d, J=7.6 Hz, 1H), 7.44-7.50 (m, 1H), 7.04 (br dd, J=7.6, 7.6 Hz, 1H), 6.92 (br d, J=8.4 Hz, 1H), 4.90-4.97 (m, 1H), 3.75-3.90 (m, 3H), 2.99-3.15 (m, 2H), 2.46-2.56 (m, 1H), 2.21-2.31 (m, 1H), 1.90-2.02 (m, 1H), 1.77-1.89 (m, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].F[C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH2:16].[Cl-].[NH4+]>CN(C)C=O>[NH2:16][C:15]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:14]=1[CH:9]([C:7]#[N:8])[C:10]([NH2:12])=[O:11]
Reactant: N#CCC(N)=O
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C(N)=O)c1ccc([N+](=O)[O-])cc1N
Temperature: 5 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
Potassium tert-butoxide (36 g, 0.32 mol) was added to a solution of 2-cyanoacetamide (27 g, 0.32 mol) in anhydrous N,N-dimethylformamide (700 mL), and a solution of 2-fluoro-5-nitroaniline (25 g, 0.16 mol) in anhydrous N,N-dimethylformamide (80 mL) was added dropwise thereto under ice-cooling. After the reaction mixture was stirred at 5° C. for 18 hours, it was poured into a saturated ammonium chloride aqueous solution (1.0 L) under ice-cooling. The whole was extracted with ethyl acetate (1.0 L). The organic layer was washed with water (500 mL), brine (300 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, toluene (100 mL) and dichloromethane (100 mL) were added to the residue. The precipitated solid was filtered off, and dried under reduced pressure to give the title reference compound (33 g) as a brown solid (yield 94%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:10][CH2:11][CH2:12][CH2:13][C:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:15]
Reactant: O=C(Cl)CCCCl
Reactant: c1ccc2c(c1)CCN2
Product: O=C(CCCCl)N1CCc2ccccc21

Procedure:
from 2,3-dihydro-1H-indole and 4-chlorobutanoyl chloride
Reaction SMILES: [I-].[Na+].C1OCCOCCOCCOCCOC1.C[O:19][C@H:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([CH2:26][N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])[CH2:21]1.BrB(Br)Br.ClCCl>ClCCl>[OH:19][C@H:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([CH2:26][N:27]2[C:28](=[O:37])[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]2=[O:36])[CH2:21]1
Reactant: CO[C@H]1CCC[C@H](CN2C(=O)c3ccccc3C2=O)C1
Agent: BrB(Br)Br
Agent: C1COCCOCCOCCOCCO1
Agent: [I-]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CCC[C@H](O)C1
Reaction time: 0.17 h
Yield: 66.6 %

Procedure:
Under a nitrogen atmosphere, a solution of sodium iodide (247 mg, 1.65 mmol) and 15-crown-5 (327 μl, 1.65 mmol) in dichloromethane (2.7 ml) was slowly dropped into a solution of trans-2-[(3-methoxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione (100 mg, 0.366 mmol) in dichloromethane (2 ml) at −40° C. After 10 minutes, a 1M-tribromoborane-dichloromethane solution (1.10 ml, 1.10 mmol) was added dropwise thereto. After 1 hour, the mixture thus obtained was slowly heated to be adjusted to 0° C. 2.5 hours after the start of the heating. After standing at room temperature for 14 hours, the reaction solution was poured onto ice and extracted with chloroform. The extract solution was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain trans-2-[(3-hydroxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione (63.2 mg, 67%).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:11][C:12]([CH3:14])=O>S(=O)(=O)(O)O>[CH3:11][C:12]1([CH3:14])[NH:10][C:1](=[O:9])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: NC(=O)c1ccccc1O
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Product: CC1(C)NC(=O)c2ccccc2O1
Yield: 47 %

Procedure:
A solution of salicylamide (4.14 g, 30.2 mmol) and conc. sulfuric acid (3 drops) in acetone (40 mL) was refluxed for 5 h. The reaction was concentrated and the residue taken up in ethyl acetate. The organic solution was washed with 1 N NaOH (2×), 1 N HCl (2×), H2O, then sat. aq. NaCl, dried (MgSO4) and concentrated to afford 2,2-dimethyl-4-keto-1,3-benzoxazine (2.50 g, 47%) as a white solid: 1H NMR (CDCl3, 300 MHz, ppm) 7.92 (d, 1H), 7.60 (bs, 1H), 7.47 (m, 1H), 7.06 (m, 1H), 6.92 (d, 1H), 1.65 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:13]2[CH2:14][CH2:15][CH:10]([OH:9])[CH2:11][CH2:12]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: Clc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1CCN(c2ncccc2Br)CC1
Temperature: 120 °C
Yield: 64.1 %

Procedure:
3-Bromo-2-chloropyridine (5.95 g, 30.92 mmol), 4-hydroxypiperidine (5 g, 49.43 mmol) and potassium carbonate (15.03 g, 108.75 mmol) were combined in DMF (200 ml) and heated to 120° C. overnight. The solvent was removed and the residues partitioned between EtOAc and water. The aqueous layer was re-extracted with EtOAc and the combined organics washed with water, dried and concentrated. The crude product was purified by column chromatography. Elution with 20-75% EtOAc/pet. ether yielded the product as a yellow oil (5.1 g). δH (CDCl3, 400 MHz): 1.60-1.61 (1H, m), 1.68-1.79 (2H, m), 2.01-2.07 (2H, m), 2.98-3.04 (2H, m), 3.64-3.69 (2H, m), 3.86-3.91 (1H, m), 6.74-6.77 (1H, m), 7.77-7.79 (1H, dd), 8.21-8.22 (1H, m).
Reaction SMILES: C(O[C:4]([C:6]1[CH2:13][N:12]2[N:8]([C:9](=[O:22])[CH:10]([NH:14]C(OC(C)(C)C)=O)[CH2:11]2)[C:7]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])=[O:5])C.[ClH:29].[C:30](O)(=O)[CH3:31]>>[ClH:29].[CH2:30]([C:4]([C:6]1[CH2:13][N:12]2[N:8]([C:9](=[O:22])[CH:10]([NH2:14])[CH2:11]2)[C:7]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])=[O:5])[CH3:31]
Reactant: C=CCOC(=O)C1=C(C(=O)OCC)CN2CC(NC(=O)OC(C)(C)C)C(=O)N12
Reactant: CC(=O)O
Agent: Cl
Product: C=CCOC(=O)C1=C(C(=O)CC)CN2CC(N)C(=O)N12
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, allyl 3-(ethyloxycarbonyl)-7-(R,S)-(t-butoxycarbonylamino)-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate (120 mg, 0.304 mmol) was combined with 3N hydrochloric acid in glacial acetic acid (5 ml) and the solution was stirred for 5 minutes then concentrated in vacuo. The resultant oil was dried in vacuo for 1.6 hours to yield allyl 3-(ethylcarbonyl)-7-(R,S)-amino-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate hydrochloride.