Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:6]=1[CH:17]([CH3:19])[CH3:18])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH:17]([C:6]1[CH:7]=[C:8]([CH:14]([CH3:16])[CH3:15])[CH:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1)([CH3:19])[CH3:18]
Reactant: NC(N)=S
Reactant: CC(C)c1cc(C(C)C)c(C(=O)CBr)c(C(C)C)c1
Solvent: CCO
Product: CC(C)c1cc(C(C)C)c(-c2csc(N)n2)c(C(C)C)c1
Yield: 25.5 %

Procedure:
A mixture of 2-bromo-1-(2,4,6-triisopropylphenyl)ethanone (13.9 g, 42.7 mmol) and thiourea (3.24 g, 42.6 mmol) in 95% EtOH (60.9 mL) was heated at reflux overnight. The solution was concentrated and added with water (100 mL), saturated aqueous Na2CO3 (10 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure, which was purified by column chromatography on silica gel (33% EtOAc in hexanes as eluant) to give 4-(2,4,6-triisopropylphenyl)thiazol-2-amine (3.28 g) as white solids in 25% yield: 1H NMR (500 MHz, CDCl3) δ 7.03 (s, 2 H), 6.22 (s, 1 H), 4.75 (bs, 2 H), 2.89 (m, 1 H), 2.68 (m, 2 H), 1.27-1.14 (m, 18 H).
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[Li]C(C)(C)C.[C:13](=[O:15])=[O:14]>CCOCC.CCCCC>[Br:7][C:6]1[C:2]([C:13]([OH:15])=[O:14])=[CH:3][S:4][CH:5]=1
Reactant: O=C=O
Reactant: Brc1cscc1Br
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: O=C(O)c1cscc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To a solution of 3,4-dibromothiophene (15 g, 62 mmol) in 80 mL ether under a positive nitrogen atmosphere was added dropwise 75 mL 1.7M t-BuLi in pentane at below -73° C. and the resulting reaction solution was stirred at -78° C. for 0.5 h. After that, the ether solution was poured into dry ice and extracted with water. The aq solution was washed with ether and then acidified with concentrated HCl. The solid was filtered and air-dried to give 9 g of 4-bromo-3-thiophenecarboxylic acid, yield 70.3%.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])[CH3:3].CN1CCOCC1.[C:23]1(=[O:42])[N:27]([C@@H:28]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:29](O)=[O:30])[C:26](=[O:37])[C:25]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:24]12.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:26]1(=[O:37])[N:27]([CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:29]([NH:7][C@@H:6]([C:5]([O:4][CH2:2][CH3:3])=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:30])[C:23](=[O:42])[C:24]2=[CH:41][CH:40]=[CH:39][CH:38]=[C:25]12
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](Cc1ccccc1)NC(=O)C(CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of L-phenylalanine ethyl ester hydrochloride salt (998 mg., 4.3 mmol) in dimethylformamide (10 mL.) was added with 4-methylmorpholine (575 μl, 529 mg., 5.2 mmol.). After stirring at room temperature for 5 minutes, the solution was cooled to 0° C. and treated successively with (S)-2-phthalimido-6-hydroxyhexanoic acid (1.002 g., 3.6 mmol.), hydroxybenzotriazole (582 mg., 4.3 mmol.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (770 mg., 4.0 mmol.). The resulting mixture was stirred at 0° C. for 0.5 hour and at room temperature for 1.5 hours. The solution was partitioned between ethyl acetate and water and the organic extract was washed successively with 0.5N hydrochloric acid, water, 50% saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give 1.63 g. of essentially pure title product as an oil/foam. TLC (1:1--acetone:hexanes) Rf =0.30.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[C:6]([C:11]3[S:15][C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[OH:29][CH2:28][CH2:30][NH:31][CH:2]1[C:10]2[C:5](=[C:6]([C:11]3[S:15][C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH:23]=4)[C:21]#[N:22])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NCCO
Reactant: CC(C)Oc1ccc(-c2ccc(-c3cccc4c3CCC4O)s2)cc1C#N
Product: CC(C)Oc1ccc(-c2ccc(-c3cccc4c3CCC4NCCO)s2)cc1C#N

Procedure:
Prepared using General Procedure 20 from 5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile and ethanolamine. LCMS-ESI (m/z) calculated for C25H26N2O2S: 418.2; found 419.1 [M+H]+, tR=2.73 min.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@@H:5]1[OH:11])(C)=[CH2:2].[O:12]=[O+][O-].O=O>C(Cl)Cl.CO>[OH:11][C@H:5]1[CH2:6][C@H:7]([CH3:10])[CH2:8][CH2:9][C@H:4]1[C:1](=[O:12])[CH3:2]
Reactant: C=C(C)[C@H]1CC[C@@H](C)C[C@@H]1O
Reactant: O=[O+][O-]
Agent: O=O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)[C@@H]1CC[C@@H](C)C[C@@H]1O
Temperature: 25 °C
Yield: 67 %

Procedure:
To the (1S,2R,5R)-2-Isopropenyl-5-methyl-cyclohexanol (2.07 g, 13.42 mmol) in DCM (67 mL) and MeOH (1.6 mL) at −78° C. was bubbled ozone/oxygen gas until the reaction mixture was turned blue and the excess ozone was flushed off with oxygen, Dimethyl sulfide (4.9 mL) was added at the same temperature, slowly warmed up to room temperature, stirred for over night, concentrated, purified on column chromatography using 10-20% EtOAc/hexane to give (1R,2S,4R)-1-(2-Hydroxy-4-methyl-cyclohexyl)-ethanone (1.40 g, 67%) as an oil. NMR 1H (CDCl3, 400 MHz): 4.29-4.27 ppm (m, 1H); 2.40-2.35 ppm (m, 1H); 2.19 ppm (s, 3H); 1.91-1.73 ppm (m, 5H); 1.05-0.91 ppm (m, 2H); 0.88 ppm (d, 3H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[O:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(Oc2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(phenoxy)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 69% overall yield. FDMS m/e=366 (M+ of free base). α[D]589 =-14.29(c=0.5, methanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Si:21]([CH2:24][Mg]Cl)([CH3:23])[CH3:22].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(O)(=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(C[Si](C)(C)C)c([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A solution of (2-methoxy-5-nitro-phenyl)-carbamic acid tert-butyl ester (1.80 g, 6.71 mmol) in THF (50 mL) was added ((trimethylsilyl)methyl)magnesium chloride (2.47 g, 16.8 mmol) at −70° C. under nitrogen gas. The solution was then stirred at −70° C. for one hour. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.05 g, 13.4 mmol) in THF (30 mL) was added, the reaction was warmed to 0° C. The reaction was allowed to stir at 0° C. for another hour. The reaction mixture is poured into an aqueous solution of acetic acid (50 mL, 5%). The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave brown oil. Flash chromatography (80/20 hexanes/ethyl acetate) afforded (2-methoxy-5-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester (1.50 g, 63%) as a light oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([F:33])[CH:26]=1>>[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[C@@H:12]2[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])=[C:27]([F:33])[CH:26]=1
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Reactant: CC1(C)CCNC(=O)[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C1
Product: COC(=O)c1ccc(CN([C@@H]2CC(C)(C)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1

Procedure:
4-Chloro-N-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 4-bromomethyl-3-fluoro-benzoic acid methyl ester analogous to Example 2c to yield 4-{[(4-chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid methyl ester: MS: m/e=497.4 (MH+).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10](=[O:12])[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=2[CH:18]=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10](=[O:12])[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=2[CH:18]=1
Reactant: CCOC(=O)c1cc2cc(CO)ccc2oc1=O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2cc(CCl)ccc2oc1=O

Procedure:
A mixture of 1 g of ethyl 6-hydroxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (3.9 mmol) and 10 ml of thionyl chloride is refluxed for 3 h. The solution obtained is evaporated under reduced pressure. The residue is re-suspended in 10 ml of dry toluene and the solvent is evaporated off under reduced pressure. The last two steps are repeated twice. The residue obtained is taken up in chloroform and the organic phase is washed three times with 0.1 N HCl solution and then dried over MgSO4. The solvent is removed by distillation under reduced pressure and the residue is recrystallized from CHCl3/Petroleum ether.
Reaction SMILES: COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH3:27][O:28][C:29]([N:31]1[CH2:34][CH:33]([N:35]2[CH2:40][CH2:39][CH:38]([N:41]3[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[NH:43][C:42]3=[O:50])[CH2:37][CH2:36]2)[CH2:32]1)=[O:30].C(Cl)(=O)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>>[CH3:27][O:28][C:29]([N:31]1[CH2:34][CH:33]([N:35]2[CH2:40][CH2:39][CH:38]([N:41]3[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]([S:56]([CH3:55])(=[O:58])=[O:57])[C:42]3=[O:50])[CH2:37][CH2:36]2)[CH2:32]1)=[O:30]
Reactant: COC(=O)N1CC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)C1
Reactant: CS(=O)(=O)Cl
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CC(=O)Cl
Product: COC(=O)N1CC(N2CCC(n3c(=O)n(S(C)(=O)=O)c4ccccc43)CC2)C1

Procedure:
Example 12 was repeated except that 1-[1-(1-methoxycarbonylpiperidin-4-yl) piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-methoxycarbonylazetidin-3-yl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one which was prepared by the method of Referential Example 3, and the acetyl chloride was replaced with methanesulfonyl chloride. The title compound was obtained as a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[C:5]1=[O:23])([CH3:3])[CH3:2].[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>C1COCC1.C([O-])(O)=O.[Na+]>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:26][CH2:25][C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22]2)=[O:14])[C:5]1=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Reactant: C=CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CCC(=O)OC(C)(C)C)CC2)c2ccccc21
Yield: 15.8 %

Procedure:
A mixture of 3-isopropyl-2-oxo-N-(piperidin-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide (0.50 g, 1.58 mmol, Step2), tert-butyl acrylate (0.340 mL, 2.37 mmol) and iPrNEt (0.275 mL, 2.37 mmol) in THF (20 mL) was refluxed for 18 h. After cooling, the reaction mixture was diluted with sat. NaHCO3 aq. (100 mL), extracted with CH2Cl2 (100 mL) for three times. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a column of silica gel eluted with MeOH/CH2Cl2 (1:20→1:10) and then NH-silica gel eluted with EtOAc/hexane (1:5→1:2) to give 0.111 g (16%) of title compound as colorless syrup.
Reaction SMILES: Br[Mg][C:3]1[CH:11]=[CH:10][C:6]2[CH2:7][CH2:8][O:9][C:5]=2[CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1COCC1.CCOCC>[O:9]1[C:5]2[CH:4]=[C:3]([C:12](=[O:14])[CH3:13])[CH:11]=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: Br[Mg]c1ccc2c(c1)OCC2
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)OCC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of bromo(2,3-dihydro-1-benzofuran-6-yl)magnesium (prepared from 6-bromo-2,3-dihydro-benzofuran (2.50 g, 12.56 mmol) and Mg (0.336 g, 13.8 mmol)) in THF (10 mL) was dropwise added to a solution of acetic anhydride (2.40 mL, 25.4 mmol) in Et2O (10 mL) held at −78° C. The reaction mixture was stirred at −78° C. for 1 h before the temperature was allowed to reach −10° C. over a period of 1 h. The reaction mixture was quenched by the addition of NH4Cl (aq, saturated, 20 mL) and the resulting mixture was extracted twice with Et2O (2×10 mL). The organic extracts were pooled, washed with NaOH (aq, 5%, 10 mL) and brine (10 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20-50% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:13]1([CH2:12][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH2:15][CH2:14]1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1cc2cc(OCC3CC3)ccc2[nH]1

Procedure:
To a solution of 7.3 g 5-hydroxy-indole in 130 ml of dry acetone are added 10.5 ml bromomethyl cyclopropane and 22.7 g anhydrous potassium carbonate. The mixture is heated to reflux for 24 h and an additional amount of 5 ml bromomethyl cyclopropane are added. The mixture is heated to reflux for additional 4 days. The mixture is filtered and the solvent is removed under reduced pressure. The residue is dissolved in dichloro methane and washed with an aqueous solution of hydrochloric acid (2 M), 10% aq. NaHCO3 and water. The organic layer is dried and the solvent is removed under reduced pressure. After purification by column chromatography (silica gel; toluene, acetone 95:5), 9.62 g, 94%) of the title compound are obtained as an oil. 1H-NMR (CDCl3): 0.36 (m, 2H, cyclopropyl CH2), 0.64 (m, 2H, cyclopropyl CH2), 1.30 (m, 1H, cyclopropyl CH), 3.83 (d, 2H, J=7.0 Hz, CH2O), 6.45 (s, 1H, aromatic), 6.90 (dd, 1H, aromatic), 7.09-7.27 (m, 3H, aromatic), 8.05 (bs, 1H, NH). 13C-NMR (CDCl3): 3.1 (2 cyclopropyl CH2), 10.4 (cyclopropyl CH), 74.2 (CH2O), 101.2, 101.6, 104.0, 104.6, 149.8 (aromatic)
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([NH:12][C@H:13]([C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[O:11])[CH2:2]1.[CH:48]([N:51](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN>CN(C=O)C.CCO>[O:42]1[C:41]2[CH:45]=[CH:46][C:38]([S:35]([N:30]([CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:29][C@@H:28]([OH:47])[C@@H:13]([NH:12][C:10](=[O:11])[O:9][C@@H:3]3[C@H:4]4[C@H:5]([O:6][CH2:7][CH2:8]4)[O:1][CH2:2]3)[CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][CH2:22][C:23]([NH:51][CH3:48])=[O:25])=[CH:26][CH:27]=3)(=[O:36])=[O:37])=[CH:39][C:40]=2[O:44][CH2:43]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC(=O)CCCOc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
A solution of 35 mg (0.052 mmol) of 4-(4-{(2S,3R)-2-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)butanoic acid and 27 μL (0.16 mmol) of N,N-diisopropylethylamine in 1 mL of anhydrous DMF was treated with 49 mg (0.13 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU). The resulting solution was stirred at RT for 15 minutes and was then treated with 0.5 mL of 8M MeNH2 in EtOH. After 18 hours TLC indicated the reaction to be complete. The solution was concentrated to dryness at reduced pressure and the residue subjected to flash chromatography (SiO2, 95:5 CH2Cl2/MeOH) to afford 22 mg (61%) of the desired compound as a white powder. 1H NMR (CDCl3): 7.37 (d, 1H), 7.22 (s, 1H), 7.13 (d, 2H), 6.92 (d, 1H), 6.82 (d, 2H), 6.13 (s 2H), 5.67 (m, 2H), 5.05 (m, 2H), 4.00 (m, 3H), 3.88 (m, 3H), 3.72 (m, 2H), 3.24-2.71 (m, 11H), 2.40 (t, 2H), 2.16 (m, 2H), 1.88 (m, 1H), 1.67 (m, 1H), 1.53 (m, 1H), 0.94 (m, 6H). MS(ESI): 692(M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[NH:17][C:18](=[S:22])[NH:19][C:20]=2[CH3:21])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]([S:22][CH3:23])[NH:19][C:20]=2[CH3:21])[CH:8]=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1[nH]c(=S)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)[nH]1
Yield: 29.9 %

Procedure:
By following the same procedure as in Example 10 using 0.32 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline, 10 ml of dry acetone, 0.15 g of potassium carbonate, and 0.15 g of methyl iodide and recrystallizing the product from cyclohexane, 0.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthioimidazole was obtained.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[OH:28][C:29]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN(C1C=CN=CC=1)C.O1CCOCC1>[I:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]([C:5]2[CH:17]=[CH:18][C:2]([N:32]3[CH2:33][CH2:34][C:29]([OH:28])([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:30][CH2:31]3)=[N:3][CH:4]=2)=[O:7])[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccc(N3CCC(O)(c4ccccc4)CC3)nc2)cc1I
Yield: 65 %

Procedure:
A solution of 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide (100 mg, 0.26 mmol), a catalytic amount of DMAP, diisopropylethyl amine (0.14 mL, 8.1 mmol), 4-hydroxy-4-phenyl piperidine (140 mg, 8.1 mmol) in 5 mL in dioxane was heated at 95° C. in a sealed tube for about 48 h. The reaction mixture was then cooled and partitioned between EtOAc and aq. saturated Na2CO3. The organic layer was then collected, dried over Na2SO4 filtered and concentrated. The residue was chromatographed with a silica gel column and 20-100% EtOAc in hexanes to afford the product (90 mg. Yield: 65%). HRMS m/z calcd for C24H24N3O2I [M+H]+: 514.0986. Found: 514.0987.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27]([OH:29])=O)[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH:42][C@H:43]1[CH2:47][CH2:46][NH:45][CH2:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27]([N:45]4[CH2:46][CH2:47][C@H:43]([OH:42])[CH2:44]4)=[O:29])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: O[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)N1CC[C@H](O)C1
Reaction time: 4 h
Yield: 37.4 %

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.2 mmol), (S)-3-hydroxypyrrolidine (35 mg, 0.4 mmol), HATU (152 mg, 0.4 mmol) and DMAP (73 mg, 0.6 mmol) in DMF (2 mL) was stirred for 4 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic phases were washed with saturated NaCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (50 mg).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:4]2[CH2:3]1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)O)ncn2-c2ccccc2C1=O

Procedure:
A solution of 14.26 g (0.05 mol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate and 2.2 g (0.055 mol) of sodium hydroxide in 100 ml of ethanol and 20 ml of water is heated to boiling under reflux for 45 minutes and subsequently treated with 55 ml of 1 N hydrochloric acid and 50 ml of water. After distillation of the ethanol, the resulting crystal slurry is filtered off under suction, washed with water and dried. There is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of melting point 287°.