Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:56][CH2:55][C@@:54]2([CH3:57])[C@H:4]([CH2:5][C@@H:6]([OH:60])[C@@H:7]3[C@@H:53]2[CH2:52][C@H:51]([OH:58])[C@@:50]2([CH3:59])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:49])[CH2:13][CH2:14][C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:30]([Cl:31])=[CH:29][C:28]([NH:32][C:33](=[O:44])[C:34]([O:36]CC4C=CC=CC=4)=[O:35])=[CH:27][C:26]=3[Cl:45])=[CH:20][C:19]=2[CH:46]([CH3:48])[CH3:47])=[O:16])[CH2:3]1.[H][H]>C(O)C.[C].[Pd]>[OH:1][C@@H:2]1[CH2:56][CH2:55][C@@:54]2([CH3:57])[C@H:4]([CH2:5][C@@H:6]([OH:60])[C@@H:7]3[C@@H:53]2[CH2:52][C@H:51]([OH:58])[C@@:50]2([CH3:59])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:49])[CH2:13][CH2:14][C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:26]([Cl:45])=[CH:27][C:28]([NH:32][C:33](=[O:44])[C:34]([OH:36])=[O:35])=[CH:29][C:30]=3[Cl:31])=[CH:20][C:19]=2[CH:46]([CH3:48])[CH3:47])=[O:16])[CH2:3]1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)OCc3ccccc3)cc2Cl)ccc1OC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)O)cc2Cl)ccc1OC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
4- {4-[(2-benzyloxy-1,2-dioxoethyl)amino]-2,6-dichlorophenoxy}-2-isopropylphenyl 3,7,12(3α,5β,7α,12α)-trihydroxycholan-24-oate (260 mg) and 26 mg of 10% palladium carbon in 50 ml ethanol are treated with hydrogen on a Parr shaker. Catalyst is removed by filtering through celite and the fitrate is stripped to give 4-{2,6-dichloro4-[(2-hydroxy-1,2-dioxoethyl) amino]phenoxy}-2-isopropylphenyl 3,7,12(3α,5β,7α,12α)-trihydroxycholan-24oate, as an amorphane monohydrate, m.p. 180°-92° (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([N:14]([CH2:16][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:18][CH:19]=C)[CH3:15])=[O:13])[C:6]2[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1)#[N:2].ClC1C=C(C=C(Cl)C=1)C(N(C[C@H](C1C=CC(F)=CC=1)CC=C)C)=[O:33]>>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([N:14]([CH2:16][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:18][CH:19]=[O:33])[CH3:15])=[O:13])[C:6]2[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1)#[N:2]
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(C#N)cc2c1CCC2)c1ccc(F)cc1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Cl)cc(Cl)c1)c1ccc(F)cc1
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(C#N)cc2c1CCC2

Procedure:
The compound was synthesized in an analogous way to that of Method 21b but using 6-cyano-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methylindane-4-carboxamide rather than 3,5-dichloro-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methylbenzamide (yield, 89%). 1H NMR (300 MHz, CDCl3): 0.9-4.2 (cm, 14H), 5.9 (s, <1H), 6.6-8.2 (cm, 6H), 8.0 (s, <1H), 9.8 (s, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=1[C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:3])[CH3:2].C1N2CN3CN(C2)CN1C3.O.[OH-].[Na+].FC(F)(F)[C:32](O)=[O:33]>>[C:1]([O:4][C:5]1[C:6]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:8]([OH:12])=[C:9]([C:10]=1[CH3:11])[CH:32]=[O:33])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)cc(O)cc1C(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C=O)c1C
Temperature: 0 °C

Procedure:
0.33 g of 4-acetoxy-3-t-butyl-5-methylphenol and 0.33 g of hexamethylenetetramine were dissolved in 2 ml of trifluoroacetic acid and the solution was heated under reflux for 15 minutes. After cooling to 0° C., the reaction solution was combined with water, neutralized with a 2N aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The organic layers were washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was dissolved in 5 ml of methanol and heated with 3.9 ml of 1N hydrochloric acid under reflux for one hour. The reaction solution was returned to room temperature and then combined with water, and the precipitated crystal was filtered off. After drying, 0.35 g of 5-acetoxy-4-t-butyl-2-hydroxy-6-methylbenzaldehyde was obtained as a white solid (72%).
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:41]2[N:42]=[C:43]([NH:46]C=O)[S:44][CH:45]=2)[C:9]([NH:11][CH:12]2[C:39](=[O:40])[N:14]3[C:15]([C:36]([OH:38])=[O:37])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH2:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl.C(=O)(O)[O-].[Na+]>CO>[CH:1]1([O:6][N:7]=[C:8]([C:41]2[N:42]=[C:43]([NH2:46])[S:44][CH:45]=2)[C:9]([NH:11][CH:12]2[C:39](=[O:40])[N:14]3[C:15]([C:36]([OH:38])=[O:37])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH2:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CN1CCN(CCCn2nnnc2SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NOC4C=CCC4)c4csc(NC=O)n4)[C@H]3SC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(CCCn2nnnc2SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NOC4C=CCC4)c4csc(N)n4)[C@H]3SC2)CC1
Yield: 28.4 %

Procedure:
A mixture of 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-[3-(4-methyl-1-piperazinyl)propyl]-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.1 g), methanol (85 ml) and conc.hydrochloric acid (0.6 ml) was stirred for 45 minutes at room temperature. The reaction mixture was adjusted to pH 4.5 with a saturated aqueous solution of sodium bicarbonate and then concentrated. The concentrate was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate and then subjected to column chromatography (CM-cephadex, H-type: 110 ml), eluted with 1%, 2%, 4% and 5% aqueous solution of sodium chloride The fractions containing the object compound were collected and adjusted to pH 4.3 with a saturated aqueous solution of sodium bicarbonate. The resulting solution was subjected to column chromatography (Non-ion adsorption resin, Diaion HP20 prepared by Mitsubishi Chemical Industries: 50 ml), eluting with water and 20% isopropyl alcohol. The fractions containing the object compound were collected and concentrated under reduced pressure. The concentrate was lyophilized to give 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-[3-(4-methyl-1-piperazinyl)propyl]-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(O[CH:10]=[C:11]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])C>CC(N(C)C)=O>[C:15]1([S:12]([C:11]([S:21]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])=[CH:10][NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:13])=[O:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1nccs1
Reactant: CCOC=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Solvent: CC(=O)N(C)C
Product: O=S(=O)(C(=CNc1nccs1)S(=O)(=O)c1ccccc1)c1ccccc1
Yield: 44.3 %

Procedure:
A solution of 2-aminothiazole (0.5 g) and 2-ethoxy-1,1-bis(phenylsulphonyl)ethene (1.76 g) in dimethylacetamide (20 ml) was heated at reflux for 3.5 hours. The solution was cooled and poured onto ice (200 g) and then the resulting buff precipitate was filtered off, washed with water and dried in vacuo over phosphorous pentoxide. Recrystallisation from ethyl acetate gave 1,1-bis(phenylsulphonyl)-2-(thiazol-2-ylamino)ethene (0.9 g), m.p. 189°-191° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:44]([O:46][CH2:47][CH:48]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][N:24]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])[C:44]([O:46][CH2:47][CH:48]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:54]=2[C:55]2[C:60]1=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:45])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CNCc3cc(F)ccc3F)N(C(=O)OC(C)(C)C)C2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CS[C@@H]2C[C@@H](CN(Cc3cc(F)ccc3F)C(=O)OCC3c4ccccc4-c4ccccc43)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To 3.19 g (6.67 mmol, 1 eq) (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 10 ml CH2Cl2 were added 1.35 ml (8.0 mmol, 1.2 eq) EtNiPr2, followed by 2.07 g (8.0 mmol, 1.2 eq) 9-fluorenylmethyl chloroformate and a catalytic amount of DMAP at 0° C. The solution was stirred at room temperature overnight, 5% NaHCO3 solution was added (pH 9), the layers were separated and the inorganic one was extracted with CH2Cl2. The combined organic layers were washed with 1M KHSO4 and brine, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography with EtOAc/hexane 1:3 as eluent yielding 3.81 g (82%) (2S,4R)-2-{[(2,5-difluoro-benzyl)-(9H-fluoren-9-ylmethoxy-carbonyl)-amino]-methyl}-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as white foam, which was subjected to the next reaction directly.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].C(=O)(O)[O-].[Na+].Cl[CH2:18][C:19](Cl)=[O:20]>O1CCCC1.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:19](=[O:20])[CH2:18][S:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CSc2cc([N+](=O)[O-])ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a stirred solution of 2-amino-5-nitrobenzenethiol (1.72 g, 10.11 mmol) in tetrahydrofuran (10 mL) was added sodium bicarbonate (2.80 g, 33.4 mmol) as a solution in water (40.0 mL). To this dark red solution was added 2-chloroacetyl chloride (0.885 mL, 11.12 mmol). The resulting mixture, which turned faint red, was then stirred at room temperature overnight. The mixture was then diluted with water and extracted three time with dichloromethane . The combined organics were dried, filtered, concentrated, and then chromatographed in 10% ethyl acetate in dichloromethane, giving the desired product (1.02 g, 48.0%). 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 8.24 (d, J=2.7 Hz, 1H), 8.07 (dd, J=9.0, 2.7 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 3.60 (s, 2H); MS-EI: (m/z, %) 210 (M+, 100), 181 (40), 131 (46).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([Br:26])=[C:14]([C:24]#[N:25])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.O1CCOCC1.CO[CH:42](OC)[CH2:43][NH2:44]>C(Cl)Cl>[CH2:1]([N:8]1[CH:42]=[CH:43][N:44]=[C:9]1[C:11]1[S:12][C:13]([Br:26])=[C:14]([C:24]#[N:25])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CN)OC
Reactant: N#Cc1c(Br)sc(C(=O)NCc2ccccc2)c1-c1ccc(Cl)cc1Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1c(Br)sc(-c2nccn2Cc2ccccc2)c1-c1ccc(Cl)cc1Cl
Temperature: 60 °C
Yield: 58.3 %

Procedure:
N-benzyl-5-bromo-4-cyano-3-(2,4-dichlorophenyl)thiophene-2-carboxamide (0.180 g, 0.386 mmol) was dissolved in DCM (2 mL) and phosphorus pentachloride (0.0884 g, 0.425 mmol) and 4.00 M of Hydrochloric acid in 1,4-dioxane (0.050 mL, 0.20 mmol) were added. The mixture was heated in a sealed vial at 60° C. for 2 hours. After cooling down to room temperature, aminoacetaldehyde dimethyl acetal (0.252 mL, 2.32 mmol) was slowly added. The mixture was heated at 60° C. for additional 1 hour. After cooling to room temperature, 4.00 M of Hydrochloric acid in 1,4-dioxane (1.0 mL, 4.0 mmol) was added and the mixture was heated at 60° C. for 2 hours and at room temperature overnight. Solvent was concentrated and the residue was diluted with EA, washed with saturated NaHCO3, brine, dried with Na2SO4, filtered and evaporated. The residue was purified using ISCO chromatography on silica gel, elution with 10-25% EA in hexanes to give the product (0.110 g, 58%). LCMS: (FA) ES+, 488, 490, 492. 1H NMR (300 MHz, d1-chloroform) δ: 7.28 (d, J=2.07 Hz, 1H), 7.26-7.15 (m, 5H), 7.11-7.08 (d, J=8.29 Hz, 1H), 6.85 (s, 1H), 6.73-6.70 (dd, J=6.97 Hz, 1.66 Hz, 2H), 4.85-4.70 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([BH3-])#N.[Na+].C=O.C(O)(=O)C>CO>[CH3:23][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]1[CH2:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2[nH]c3ccccc3c2C[C@H]2CCCCN2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCCC[C@@H]1Cc1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.4 %

Procedure:
To a solution of 1.1 g (3.8 mmol) of 2-phenyl-3-(piperidin-2(R)-ylmethyl)-1H-indole and 238 mg (3.8 mmol) of sodium cyanoborohydride in methanol (20 ml) at 0° C. was added a solution of formaldehyde (527 mg of a 37% w/w aqueous solution) and glacial acetic acid (0.5 ml, 8.7 mmol) in methanol (10 ml). After stirring at room temperature for 3 hr the reaction was evaporated in vacuo. The residue was partitioned between saturated potassium carbonate (20 ml) and EtOAc (20 ml), the organic layer separated, and the aqueous layer extracted with EtOAc (2×20 ml). The combined EtOAc layers were washed with water (50 ml), saturated sodium chloride (50 ml), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (SiO2; 5% MeOH in CH2Cl2+0.5% NH3) and the product recrystallised from Et2O/hexanes to afford 210 mg (0.7 mmol; 18%) of 3-(1-methylpiperidin-2(R)-ylmethyl)-2-phenyl-1H-indole as a white solid. (Found: C, 81.50; H, 7.98; N, 9.14; C21H24N2.0.25H2O requires C, 81.64; H, 7.99; N, 9.07%); mp 150° C. (from Et2O/hexane); [α]D23+80.0 (c 1.0 in CHCl3); δH (360 MHz; CDCl3) 0.96-1.14 (2H, m, aliphatics), 1.44-1.58 (4H, m, aliphatics), 2.06-2.16 (1H, m, aliphatic), 2.21-2.32 (1H, m, aliphatic), 2.46 (3H, s, CH3), 2.76-2.89 (2H, m, aliphatics), 3.47 (1H, dd, J 13.8 and 3.8, indole CHAHB), 7.14 (1H, m, indole H5), 7.20 (1H, m, indole H6), 7.33-7.38 (2H, m, aromatics), 7.43-7.47 (2H, m, aromatics), 7.57 (2H, d, J 7.1, aromatics), 7.65 (1H, d, J 7.8, aromatic), 8.05 (1H, br s, NH); m/z (ES+) 305 (M++H, 100%).
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)CCC>>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)([O-:9])=[O:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Product: N#Cc1csc([N+](=O)[O-])c1-c1nc2ccccc2s1

Procedure:
5-nitro-4-(benzo[d]thiazol-2-yl)thiophene-3-carbonitrile was prepared from 4-bromo-5-nitrothiophene-3-carbonitrile (0.16 g, 0.67 mmol) and 2-(tributylstannyl)benzo[d]thiazole (0.45 g, 1.07 mmol) according to protocol R. Retention time (min)=0.381, method [4], MS(ESI) 288.0 (M+H).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[CH3:11].C(=O)([O-])O.[Na+].[C:25]1([CH2:31][CH2:32][CH2:33][NH2:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH3:11][C:4]1([C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:18]#[N:19])[CH:5]2[CH:3]1[CH2:2][N:34]([CH2:33][CH2:32][CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]2=[O:8]
Reactant: NCCCc1ccccc1
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2cccc(C#N)c2)C2CN(CCCc3ccccc3)C(=O)C21
Temperature: 100 °C
Yield: 39.1 %

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-(3-cyanophenyl)-2-methylcyclopropanecarboxylate (Preparation 35, 170 mg, 0.62 mmol) in N,N-dimethylformamide (6.0 ml) at room temperature was added sodium hydrogen carbonate (52 mg, 0.62 mmol) followed by 3-phenylpropylamine (0.35 ml, 2.47 mmol). The mixture was heated at 100° C. for 6 h and under reflux for 5 h. After the mixture had cooled to room temperature, water (4 ml) was added and the aqueous layer was extracted with diethyl ether (3×4 ml). The combined ethereal extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude oil was purified by silica column chromatography eluting with a gradient of hexane:ethyl acetate (50:50 to 0:100) to afford the title compound (80 mg, 40%) as a colourless oil.
Reaction SMILES: [C@H:1]1([NH:11][C:12]([C@@H:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:21]=3)[CH2:16][N:15]2C(OC(C)(C)C)=O)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:1]1([NH:11][C:12]([C@@H:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:21]=3)[CH2:16][NH:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CN[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of (S)-2-tert-butyl 7-methyl 3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate (1.06 g, 2.28 mmol) in CH2Cl2 (22.8 mL) was added TFA (5.7 mL). The resulting reaction mixture was stirred at room temperature for 1 h and then quenched with sat. aq. NaHCO3 solution. The aqueous layer was extracted with EtOAc (3×), and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was then lyophilized from MeCN/H2O overnight to give the title compound (0.79 g, 2.18 mmol, 96%) as a light yellow solid. 1H NMR (DMSO-d6) δ 8.39 (d, J=8.6 Hz, 1H), 7.85-7.67 (m, 2H), 7.34 (d, J=7.9 Hz, 1H), 7.24-7.02 (m, 4H), 5.12-4.93 (m, 1H), 4.23-3.97 (m, 2H), 3.86 (s, 3H), 3.73 (dd, J=10.0, 4.7 Hz, 1H), 3.33 (br s, 1H), 3.18-3.05 (m, 1H), 3.03-2.88 (m, 1H), 2.86-2.63 (m, 2H), 2.02-1.83 (m, 2H), 1.81-1.64 (m, 2H); MS (ESI+) m/z 365.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](/[C:8](=[CH:13]\[C:14]1[CH:24]=[CH:23][C:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=2[CH:15]=1)/[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=2[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C(=C/c1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Yield: 103.9 %

Procedure:
To a slurry of (Z)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)acrylate (5000 mg, 14311 μmol) in 30 mL of MeOH was added [(1S,1S′,2R,2R′) Rh(duanphos)cod]BF4 (101.1 mg, 143.1 μmol) followed by an additional 15 mL of methanol. The mixture was purged with hydrogen 3 times and then sealed at 50 psi of H2. After 3 hours reaction the reaction was concentrated and purified by silica gel chromatography to provide (S)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoate (5000 mg, 99.43% yield) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Na+].[I-:15]>O1CCOCC1.[Cu]I>[I:15][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [I-]
Reactant: CCOC(=O)c1cc(Br)ccc1C
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(I)ccc1C
Temperature: 110 °C
Reaction time: 15 h
Yield: 88.4 %

Procedure:
To a solution of bromide 3 (39.0 g, 161 mmol) in 1,4-dioxane (150 mL) were added NaI (48.2 g, 321 mmol), CuI (1.6 g, 8.03 mmol) and N,N′-dimethylethyldiamine (1.8 mL, 16.1 mmol). The mixture was evacuated and backfilled with N2. The mixture was stirred at 110° C. for 15 h. The mixture was cooled to room temperature and filtered off through celite. The filtrated was evaporated under vacuum to remove solvent. The residue was diluted with EtOAc and washed with aq. 50% NH4Cl solution. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography to provide the titled compound 4 (41.3 g, 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:23]([O:25]CC)=[O:24])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:23]([OH:25])=[O:24])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2[nH]c(-c3cccc4ccccc34)nc2C(=O)O)cc1
Yield: 79.6 %

Procedure:
Ethyl 5-(4-methylphenyl)-2-(1-naphthyl)imidazole-4-carboxylate (4.5 g) was dissolved in ethyl alcohol (90 ml) and 1 M sodium hydroxide solution (38 ml) was added. The reaction mixture was refluxed under heating for 12 hr, and the mixture was concentrated under reduced pressure. To the obtained residue were added water and ethyl acetate, and the mixture was partitioned. The aqueous layer was filtered, and aqueous citric acid was added to the filtrate. The precipitated crystals were collected by filtration to give 5-(4-methylphenyl)-2-(1-naphthyl)imidazole-4-carboxylic acid (3.3 g), melting point 165° C. (decomposition).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22](O)=[O:23])[CH2:17]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C>ClCCl>[O:23]=[C:22]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:21][CH:18]1[CH2:19][CH2:20][N:16]([CH2:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]2=[O:1])[CH2:17]1
Reactant: O=C(O)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Reactant: C1CCNC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1CCN(CCc2ccccc2N2CCCCC2=O)C1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To (1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)acetic acid a14-1 (115 mg, 0.348 mmol, 1 eq) and pyrrolidine (32 μl, 0.382 mmol 1.1 eq) in dichloromethane (5 ml) are added dicyclohexylcarbodiimide (79 mg, 0.82 mmol, 1.1 eq), hydroxybenzotriazole (52 mg, 0.382 mmol, 1.1 eq) and diisopropylethylamine (131 μl, 0.731 mmol, 2.1 eq). The reaction mixture is stirred overnight at room temperature, then filtered and concentrated under reduced pressure. The residue is purified by reverse phase chromatography (gradient: CH3CN/H2O/NH4OH from 30/70/0.1 to 60/40/0.1) to afford 9 mg of 1-[2-(2-{3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]pyrrolidin-1-yl}ethyl)phenyl]piperidin-2-one 86 as a yellow oil.