Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>CCOCC>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[N:3][CH:4]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution containing 2-bromo-5-methylpyridine (1.42 g, 8.23 mmol) in ether (15 mL) at −78° C. was treated with n-butyllithium (5.14 mL, 1.6 M in hexanes) dropwise, stirred at −78° C. for 1 hour, treated with tributyltin chloride (3.35 mL, 12.35 mmol), stirred at 0° C. for 4 hours, quenched with saturated ammonium chloride solution and partitioned between ether and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on neutral alumina eluting with 10% ethyl acetate in dichloromethane to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=1[CH3:18].[OH-].[Na+]>CCO.O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[CH3:18]
Reactant: COC(=O)c1ccc(-c2ccccc2O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2′-hydroxy-2-methylbiphenyl-4-carboxylate (3 g; 12.38 mmol; 1 eq.) in EtOH (90 mL) at RT was treated with sodium hydroxide (7.43 mL; 5 M; 37.15 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to give a brown solid. It was taken up in water (250 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2. Then it was concentrated and extracted with EtOAc giving the title compound as an orange oil. It was purified by flash chromatomatography eluting with EtOAc:cHex (1:1) affording the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 12.88 (br s, 1H), 9.49 (s, 1H), 7.81-7.75 (m, 2H), 7.24-7.18 (m, 2H), 7.05-7.02 (m, 1H), 6.94-6.84 (m, 2H), 2.16 (s, 3H). LC/MS (Method B): 227.2 (M−H)−. HPLC (Method A) Rt 3.26 min (Purity: 95.1%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][CH2:18][CH2:19][OH:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[OH-].[Na+]>ClCCl.O>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:20][CH2:19][CH2:18][CH2:17][C:9]1[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: OCCCc1nc2ccccc2n1Cc1ccccc1
Reactant: BrCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: BrCCCCCOCCCc1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 20.9 %

Procedure:
A mixture of 1-(phenylmethyl)-2-benzimidazolepropanol (3.0 g), 1,5-dibromopentane (7.77 g), TAB (0.5 g) and 40% sodium hydroxide (5 ml) in dichloromethane (10 ml) was stirred at room temperature for 6 h under nitrogen. The mixture was diluted with water (100 ml) and extracted with dichloromethane (2×30 ml). The dried extracts were evaporated in vacuo to give an oil. Purification by FCC eluting with hexane-ether (10:0→0:10) gave the title compound as a colourless oil (0.98 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:20])[CH2:18]Cl)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(C1C=CC(C2CCNCC2)=CC=1)CCC.ClCC(Cl)=O.[N+:42]([C:45]1[CH:50]=[CH:49][C:48]([NH:51][C@H:52]2[CH2:57][CH2:56][C@H:55]([OH:58])[CH2:54][CH2:53]2)=[CH:47][C:46]=1[C:59]([F:62])([F:61])[F:60])([O-:44])=[O:43]>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:20])[CH2:18][O:58][C@H:55]3[CH2:56][CH2:57][C@H:52]([NH:51][C:48]4[CH:49]=[CH:50][C:45]([N+:42]([O-:44])=[O:43])=[C:46]([C:59]([F:60])([F:61])[F:62])[CH:47]=4)[CH2:53][CH2:54]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C2CCN(C(=O)CCl)CC2)cc1
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Agent: CCCCc1ccc(C2CCNCC2)cc1
Agent: O=C(Cl)CCl
Product: CCCCc1ccc(C2CCN(C(=O)CO[C@H]3CC[C@H](Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1

Procedure:
1-[4-(4-Butyl-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-butyl-phenyl)-piperidine (also known as 1-[4-(4-butyl-phenyl)-piperidin-1-yl]-2-chloroethanone) was prepared with a 72% yield from 4-(4-butyl-phenyl)-piperidine (prepared in accordance with Example 9) and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 1-[4-(4-butyl-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from the 1-chloracetyl-4-(4-butyl-phenyl)-piperidine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (36% yield). The structure was confirmed using Protocol II-A. Calculated mass=548; observed mass=548; HPLC retention time=4.92 min.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]([CH3:29])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:17]([C:9]1[CH:8]=[CH:7][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:11]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)[N:10]=1)=[O:19])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[CH3:29]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(C2CCCC2)c(OCC2CC2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CCCC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39 b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0, Example 33 d) as starting materials, MS (LC/MS): 385.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1)=[O:11].[CH2:22]([NH2:25])[CH2:23][CH3:24].O>O1CCCC1>[CH2:22]([NH:25][C:19](=[O:21])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[NH:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[CH:17][CH:16]=1)[CH2:23][CH3:24]
Reactant: O=C(O)Cc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reactant: CCCN
Solvent: O
Solvent: C1CCOC1
Product: CCCNC(=O)Cc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
1.5 g of 4-(2,3-dichlorophenylcarbamoyl)phenyl acetic acid was dissolved in 30 ml of anhydrous tetrahydrofuran. While cooling the solution with ice water, 0.75 g of N,N'-carbonyldiimidazole was added thereto, and the mixture was stirred for 30 minutes. Thereafter, 0.27 g of n-propylamine was added thereto. The mixture was returned to room temperature and stirred for 5 hours. After completion of the reaction, the reaction solution was poured into 200 ml of water. The resulting crystals were collected by filtration, washed with water and dried, and then recrystallized from benzene-hexane to obtain 1.5 g of desired N-n-propyl-4-(2,3-dichlorophenylcarbamoyl)phenylacetamide. The yield was 88.8%, and the melting point of this compound was from 177° to 178° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: FC(F)(F)Oc1cccc2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(OC(F)(F)F)cccc5s4)cc3CC[C@@H]12
Yield: 77.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-trifluoromethoxybenzothiazole (117 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 141 mg (77%) of the title compound as a white solid. mp 168°-173°. FDMS: m/e=478. α[D]589 =+57.89 (c=0.59, chloroform).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37]C)=[O:36])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:22](=[O:29])[CH2:23][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)[CH2:18][C:17]4[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>O1CCOCC1.O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([OH:37])=[O:36])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:22](=[O:29])[CH2:23][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)[CH2:18][C:17]4[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)Cn1ccnc1)Cc1cc(F)ccc1-3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)Cn1ccnc1)Cc1cc(F)ccc1-3
Temperature: 60 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
Methyl 14-cyclohexyl-3-fluoro-6-(1H-imidazol-1-ylacetyl)-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate was dissolved in a solution of dioxane: H2O (1:1) (0.1 M) and to that solution aqueous KOH (3 eq, 5 N) were added. The solution was stirred at 60° C. for 3 h. The solvent was evaporated in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters SYMMETRY prep. C18, 7 μm, 19×300 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (41%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14](O)=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[Cl-].C[NH3+].[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([NH:32][CH3:31])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1
Reactant: Nc1ncc(-c2ccc(OCC(=O)O)cc2)cc1-c1nc2ccccc2s1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)COc1ccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-[6-amino-5-(1,3-benzothiazol-2-yl)pyridin-3-yl]phenoxyacetic acid (20 mg, 0.050 mmol) in DMF (1.0 mL) were added methylammonium chloride (4 mg, 0.06 mmol), TBTU (19 mg, 0.060 mmol) and DIEA (0.05 mL, 0.3 mmol). The mixture was left to stir at rt for 30 min. Purification via MDP afforded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.67 (d, J=4.8 Hz, 3H), 4.51 (s, 2H), 7.04-7.10 (m, 2H), 7.45-7.52 (m, 1H), 7.54-7.59 (m, 1H), 7.63-7.68 (m, 2H), 7.97 (s, 2H), 8.10 (d, J=7.8 Hz, 1H), 8.13-8.17 (m, 2H), 8.48 (d, J=2.3 Hz, 1H). MS (ES+): m/z=391.10 (100) [MH+]. HPLC: tR=3.20 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH2:8][CH2:9][NH2:10])[N:7]=1)[CH3:2].O.[C:49]([O:53][CH2:54][CH3:55])(=[O:52])[CH:50]=O>O1CCCC1>[CH2:1]([C:3]1[N:4]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:5]2[CH:50]([C:49]([O:53][CH2:54][CH3:55])=[O:52])[NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc(CCN)cn1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
2-Ethyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole (7.48 g) is dissolved in tetrahydrofuran (60 ml) to which is added ethyl glyoxylate hydrate (1.56 g). The reaction mixture is stirred overnight at room temperature and then refluxed for one hour. The solution is evaporated and the residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-[2'-(1 -trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (5.54 g) as a foam, characterized as its oxalate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7]([CH2:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.[NH2:14][CH:15]1[C:29](=[O:30])[N:17]2[C:18]([C:26]([OH:28])=[O:27])=[C:19]([CH2:22][N:23]=[N+:24]=[N-:25])[CH2:20][S:21][C@H:16]12>>[N:1]1[CH:2]=[CH:3][C:4]([S:7]([C:9]#[C:10][C:11]([NH:14][CH:15]2[C:29](=[O:30])[N:17]3[C:18]([C:26]([OH:28])=[O:27])=[C:19]([CH2:22][N:23]=[N+:24]=[N-:25])[CH2:20][S:21][C@H:16]23)=[O:13])=[O:8])=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)CCS(=O)c1ccncc1
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)C#CS(=O)c3ccncc3)[C@H]2SC1

Procedure:
398 mg. of 3-(4-pyridylsulfinyl)propionic acid and 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 143 mg. of 7-[3-(4-pyridylsulfinyl)propinamido]-3-azidomethyl-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[NH3:18]>O1CCOCC1.O>[C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][S:8]([NH2:18])(=[O:10])=[O:9])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: NS(=O)(=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
2-Phthalimidoethanesulfonyl chloride (2.0 g) was added portion wise to a solution of 0.5 M of ammonia in dioxane (15 ml) and the solution obtained this way was stirred at room temperature. After 48 hours the reaction mixture was poured in water (50 ml) causing the title compound to precipitate. The product was collected by filtration. Yield: 1.52 g (83%) of a solid. 1H-NMR (DMSO-δ6) δ (ppm) 7.92-713 (m, 4H), 7.06 (s, 2H), 6.88-3.93 (m, 2H), 3.37-3.30 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([SH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([S:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)S
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CSC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 82.7 %

Procedure:
To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-mercapto-3-methylbutanoic acid (4.5 g, 18.05 mmol) in THF (60 mL) was added a solution of methyl 2-bromoacetate (3.04 g, 19.85 mmol) in THF (10 mL) followed by DIPEA (9.46 mL, 54.1 mmol). The resulting mixture was stirred at rt for 4.5 h. The reaction mixture was concentrated in vacuo to remove most of the solvent, and the residue was diluted with EtOAc and sat. aq. NaHCO3 solution. The aqueous layer was acidified with 1N HCl solution to adjust the pH to 2-3. The resulting aqueous layer was extracted with EtOAc (2×). The organic layers were combined and dried over MgSO4. The filtrate was concentrated in vacuo to give the title compound as solid (4.8 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ 6.93 (d, J=9.0 Hz, 1H), 4.10 (d, J=9.5 Hz, 1H), 3.62 (s, 3H), 3.41 (s, 2H), 1.39 (s, 9H), 1.33 (s, 3H), 1.27 (s, 3H); MS (ESI+) m/z 266.0 (M-55)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:15][C:16]1[C:17]([NH2:21])=[N:18][O:19][N:20]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([C:8]([NH:21][C:17]2[C:16]([CH3:15])=[N:20][O:19][N:18]=2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ncc(Cl)cc1C(F)(F)F
Reactant: Cc1nonc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nonc1NC(=O)c1ncc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
300 mg (1.33 mmol) of 5-chloro-3-(trifluoromethyl)pyridine-2-carboxylic acid and 132 mg (1.33 mmol) of 4-methyl-1,2,5-oxadiazol-3-amine are dissolved at RT in 10 ml of CH2Cl2, and 0.19 ml (1.33 mmol) of triethylamine, 32 mg (0.27 mmol) of DMAP and 1.27 g (2.00 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added. The reaction mixture is stirred at RT for 20 h and then washed twice with 10 ml each time of water. The organic phase is dried over Na2SO4 and concentrated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield: 250 mg (61%).
Reaction SMILES: Br[C:2]1[C:3]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[NH2:21][C:22]1[CH:34]=[CH:33][C:25]([CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CCOC(C)=O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:3]2[C:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=3)=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3)[S:5][C:4]=2[CH:15]=1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(Nc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Yield: 15 %

Procedure:
To a large microwave vial (10-20 mL) was added 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (350 mg, 1.00 mmol), ethyl 4-aminocinnamate (383 mg, 2.00 mmol) and K3PO4 (425 mg, 2.00 mmol). 1,4-dioxane (6.0 mL) was then added followed by chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct (RuPhos palladacycle, 73.0 mg, 0.10 mmol) and the reaction was subjected to microwave irradiation at 120° C. for 3 h. Upon completion the reaction mixture was transferred to round bottom flask with EtOAc and concentrated in vacuo. The resulting material was partitioned between water and EtOAc and separated, the aqueous layer was then further extracted with EtOAc (3×) and the combined organic layers were passed through a phase separator to remove water and concentrated in vacuo. The crude material was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)amino)phenyl)acrylate (69.0 mg, 0.15 mmol, 15% yield) as a white solid. LC/MS (m/z, MH+): 460.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH3:26])[CH:20]=[CH:21][C:22]=1[C:23]([OH:25])=[O:24]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:16][C:17]1[CH:18]=[C:19]([CH3:26])[CH:20]=[CH:21][C:22]=1[C:23]([OH:25])=[O:24])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: Cc1ccc(C(=O)O)c(N)c1
Product: Cc1ccc(C(=O)O)c(NC(=O)CCCCNC(=O)OC(C)(C)C)c1

Procedure:
For the preparation of the starting material, 5-[1-(t-butoxy)formamido]valeric acid and 3-amino-p-toluic acid are coupled to give 3-[5-(1-t-butoxyformamido)valeramido]-p-toluic acid, m.p. 212° C., and the latter is coupled with β-alanine benzyl ester to give N-[3-[5-(1-t-butoxyformamido)valeramido]-p-toluoyl]-β-alanine benzyl ester, m.p. 112°-113° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][C:9](=[O:13])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:14])(=O)[CH3:2].C(O)(=O)C.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:14][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:13])[CH2:10][O:11][C:12]=2[C:4]=1[CH:1]([N:29]1[CH2:28][CH2:27][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:31][CH2:30]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)c1c(O)ccc2c1OCC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(c1c(O)ccc2c1OCC2=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
A solution of 7-acetyl-6-hydroxybenzofuran-3(2H)-one (0.60 g, 3.1 mmol) in methylene chloride (25 mL) was added with acetic acid (0.25 mL) and N-Boc-piperazine (0.64 g, 3.4 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C., and then added portionwise with sodium triacetoxyborohydride (0.84 g, 4.1 mmol). After completion of the addition, the ice bath was removed to allow the reaction mixture to warm to room temperature, and the mixture was stirred at the same temperature for 20 hours. The reaction mixture was extracted with methylene chloride, and then the organic layer was successively washed with water, saturated aqueous sodium hydrogencarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (100:0→97:3)) to obtain tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperazine-1-carboxylate (0.74 g, 90%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4](=[O:7])[CH:3]1[O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1.[CH3:22][C@H:23]([NH2:26])[CH2:24][CH3:25]>C1COCC1>[CH:23]([NH:26][C:4](=[O:7])[CH:3]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:19])([F:18])[F:20])[CH:10]=1)[C:2]([CH3:21])([CH3:1])[CH2:6][OH:5])([CH2:24][CH3:25])[CH3:22]
Reactant: CC[C@H](C)N
Reactant: CC1(C)COC(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)CO

Procedure:
(±)-4-(4,4-Dimethyl-2-oxo-tetrahydrofuran-3-yloxy)-2-trifluoromethylbenzonitrile (66.00 g, 221 mmol) was combined with 330 mL dry THF and the (S)-(+)-2-butylamine (total of 64.5 g, 882 mmol), and the reaction mixture was heated at 40-60° C. in a sealed vessel for 124 h. The amber sol'n was concentrated under vac (35-40° C.) to an amber gum. The gum was redissolved in 500 m ethyl acetate “EtOAc” and conc'd again. The gum was redissolved in 500 mL “EtOAc” and passed through a pad of silica. The silica was washed with 500 mL EtOAc and the combined filtrate was concentrated under vac to a pale amber gum.