Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.[CH2:13]([NH2:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.Cl>C(Cl)Cl>[C:15]1([CH2:14][CH2:13][NH:21][C:10](=[O:12])[CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)CCc1ccccc1I
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(CCc1ccccc1I)NCCc1ccccc1
Reaction time: 72 h
Yield: 120.9 %

Procedure:
To a solution of 2-iodobenzenepropionic acid (8 g, 0.029 mol) and phenethylamine (10.9 g, 0.090 mol) in methylene chloride (200 mL) was added N-ethyl-N-[3-(dimethylamino)propyl]carbodiimide hydrochloride (6.13 g, 0.032 mol) at room temperature. After 3 days, water (100 mL) and 2.5N HCl (50 mL) were added. The organic phase was separated, dried and concentrated to give an oil (13.3 g). The oil was chromatographed on silica gel and eluted with hexane: ethyl acetate (2:1) then hexane: ethyl acetate (1:1) to give a fraction containing a yellow solid 7.6 g (69%). Recrystallization from toluene (15 mL) and petroleum ether (150 mL) afforded 7.1 g of product, mp. 94.5°-95.5° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[C:17]([O:18]C)[C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.C(S)(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[C:17]([OH:18])[C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: COc1cccc2c3c(sc12)Nc1cc(F)ccc1N=C3N1CCN(C)CC1
Agent: CC(S)S
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN1CCN(C2=Nc3ccc(F)cc3Nc3sc4c(O)cccc4c32)CC1

Procedure:
In the same manner as in Example 62 and using 8-fluoro-4-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine, dichloromethane, ethanedithiol and aluminium chloride, 8-fluoro-4-hydroxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([C:21]2[CH:25]=[C:24]([CH:26]=O)[O:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30][CH2:29]1>ClCCl>[C:15]1([C:21]2[CH:25]=[C:24]([CH2:26][N:28]3[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30][CH2:29]3)[O:23][N:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cc(-c2ccccc2)no1
Reactant: OCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: OCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
Sodium triacetoxyborohydride (12.2 g) was added portionwise to a room temperature mixture of the compound prepared in Example 7 (5.00 g) and piperidin-4-ylmethanol (4.99 g) in dichloromethane (150 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed sequentially with a saturated aqueous sodium bicarbonate solution and brine. The organics were dried over anhydrous magnesium sulfate and concentrated to obtain the crude title compound (8.05 g), which was used without further purification having the following physical data.
Reaction SMILES: Br[C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1>C1COCC1>[CH3:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:15]1([OH:18])[CH2:16][CH2:17][C:12]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:13][CH2:14]1
Reactant: Cn1ccnc1Br
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: Cn1ccnc1C1(O)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from 2-bromo-1-methyl-1H-imidazole (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one in THF using the procedure described in Step A of Example 1.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)C(C)C)(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.O>[CH3:13][C:3]1[C:2]([O:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cccc(O)c1C
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(OS(C)(=O)=O)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a cooled (0° C.) solution of ethyl 3-hydroxy-2-methylbenzoate (116a, 2.4 g, 13 mmol) and N,N-diisopropylethylamine (5.8 mL, 33 mmol) in dichloromethane (50 mL) was added drop wise methanesulfonyl chloride (1.4 mL, 17 mmol). The reaction mixture was stirred at 0° C. for 30 minutes then diluted with water (20 mL) and extracted with dichloromethane (2×25 mL). The combined organic extracts were dried over magnesium sulfate, concentrated under vacuum, and purified by column chromatography (30% EtOAc/Heptane) to give ethyl 2-methyl-3-[(methylsulfonyl)oxy]benzoate (116b, 3.0 g, 88% yield) as a yellow oil.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:15]([OH:17])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[N:60]1[CH:65]=[CH:64][C:63]([N:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[CH:62][CH:61]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[C:22]1([CH2:21][O:20][C:18]([NH:1][C@H:2]([C:15]([N:69]2[CH2:70][CH2:71][N:66]([C:63]3[CH:64]=[CH:65][N:60]=[CH:61][CH:62]=3)[CH2:67][CH2:68]2)=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: c1cc(N2CCNCC2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1

Procedure:
To a mixture of 100 g (0.263 mol) of Z-Lys(Boc)-OH, 86.1 g (0.268 mol) of TBTU and 36.3 g (0.263 mol) of HOBt in 600 ml of dimethylformamide were added 43.0 g (0.263 mol) of 1-(4-pyridinyl)-piperazine and 47.2 ml (0.268 mol) of DIEA with stirring and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated down in vacuo and the residue divided between ethyl acetate and aqueous saturated sodium hydrogen carbonate solution. The aqueous phase was extracted twice more with a mixture of ethyl acetate/methanol (10/1, v/v) and the combined organic phases were washed once with saturated sodium hydrogen carbonate solution. The organic phase was, after drying over sodium sulphate, evaporated down in vacuo and the residue was taken up in 750 ml of ethyl acetate and washed four times with 100 ml of water, six times with 100 ml of 1% potassium hydrogen sulphate solution, once with 100 ml of water, twice with 100 ml of 3% aqueous ammonia solution and twice with 100 ml of water. The organic phase was evaporated down after drying over sodium sulphate. 120 g (87% of theory) of the desired product were obtained as an oil, which was used without further purification for the subsequent reactions.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([C@H:14]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](O)=[O:23])=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].[NH2:35][CH2:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43]([NH2:47])=[N:42][CH:41]=[CH:40]2.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([C@H:14]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](=[O:23])[NH:35][CH2:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43]([NH2:47])=[N:42][CH:41]=[CH:40]2)=[O:16])[C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NCc1ccc2c(N)nccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
A mixture of {[2-{2-(S)-Carboxy-pyrrolidin-1-yl}-1-(R)-(4-methoxybenzyl)-2-oxo-ethyl]-tert.-butoxycarbonyl-amino}-acetic acid ethyl ester (0.240 g), 6-aminomethyl-isoquinolin-1-ylamine (0.092 g), N-methyl morpholine (0.170 mL) and 0.160 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 8 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. Removal of the solvent in vacuo followed by purification of the remaining residue by silica chromatography (dichloromethane/methanol 80/20) gave 0.310 g (100%) of the title compound as a light yellow solid. (+)-APCI-MS: 634 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:8]2([NH:12]S(C(C)(C)C)=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>CO>[ClH:1].[Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:8]2([NH2:12])[CH2:9][O:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)S(=O)NC1(c2cccc(Cl)c2F)COC1
Agent: Cl
Solvent: CO
Product: NC1(c2cccc(Cl)c2F)COC1

Procedure:
A solution of 2-methyl-propane-2-sulfinic acid [3-(3-chloro-2-fluoro-phenyl)-oxetan-3-yl]-amide (940 mg, 2.46 mmol) and hydrochloric acid (4 N in dioxane, 0.922 ml, 3.69 mmol) in MeOH (5 mL) was stirred 30 min at 0° C. and concentrated. The material thus obtained was used without further purification in the next step. MS (UPLC-MS): 202/204 [M+H]+; tR (HPLC conditions f): 0.86 min.
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:3]([N:5]([CH2:14][C:15]1[C:20]2[N:21]=[CH:22][S:23][C:19]=2[CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:4].[CH2:36]([NH:43][C:44](=[O:54])[NH:45][C@H:46]([CH2:51][CH:52]=[CH2:53])[CH2:47][C:48](O)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[S:23]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:14][N:5]([CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:3]([CH:2]([NH:1][C:48](=[O:49])[CH2:47][CH:46]([NH:45][C:44]([NH:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:54])[CH2:51][CH:52]=[CH2:53])[CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:29][CH:30]=3)=[O:4])[C:20]=2[N:21]=[CH:22]1
Reactant: C=CC[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1cccc2scnc12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2scnc12)CC(OCC)OCC)NC(=O)NCc1ccccc1
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-N-benzothiazol-4-ylmethyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide in CH2Cl2 (50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-hex-5-enoic acid (1.6 g, 6.1 mmol), EDCI (1.17 g, 1.2 eq), HOBt (0.93 g, 1.2 eq), DIEA (2.13 mL, 12.2 mL) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 744 (M+H), 766 (M+Na)
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.[NH2:16][CH2:17][C:18]#[N:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O.C(N(CC)CC)C>[C:17]([CH2:18][NH:19][C:12]([C:3]1[C:2]([OH:1])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)=[O:14])#[N:16]
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: N#CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: N#CCNC(=O)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
8-hydroxyquinoline-7-carboxylic acid (0.51 g), aminoacetonitrile HCl (0.27 g), and triethylamine (0.38 ml) are dissolved in 10 mL dimethylformamide. EDC.HCl (0.54 g) and HOBt.H2O (0.38 g) are added and the reaction is stirred at room temperature for 2 days. The reaction is poured into 50 mL ice/H2O and stirred. After approximately 30 minutes, a solid is collected and dried. The desired product is recrystallized from ethyl acetate (0.12 g).
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:9]=2[CH2:8][CH2:7][C:6]1=[O:21])(=[O:4])[CH3:3].[CH3:22][CH2:23][CH2:24][CH2:25][CH:26]([OH:31])[CH2:27][CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[C:2]([NH:5][CH2:14][CH2:13][CH2:12][C:11]([C:10]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:9]=1[CH2:8][CH2:7][C:6]([O:31][CH:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH2:24][CH2:23][CH3:22])=[O:21])=[O:15])(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCCC(=O)c2ccc(Cl)cc2CCC1=O
Reactant: CCCCC(O)CCCC
Agent: Cl
Solvent: ClCCl
Product: CCCCC(CCCC)OC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
15 ml of concentrated hydrochloric acid are added to a solution of 10.00 g (0.034 mol) of 4-acetyl-11-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione in 90 ml of 5-nonanol and 50 ml of methylene chloride and the mixture is stirred at room temperature for 18 hours. The solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with ethyl acetate gives 1-butylpentyl 2-(4-acetamido-butyryl)-5-chlorohydrocinnamate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[C:16](O)(=[O:18])[CH3:17].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:18][C:16](=[C:11]1[C:12](=[O:14])[CH2:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:9][C:10]1=[O:15])[CH3:17]
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CC(O)=C1C(=O)CC(c2ccccc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 78.5 %

Procedure:
To a solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (1.5 g), acetic acid (0.73 g) and dimethylaminopyridine (0.12 g) in dimethylformamide (65 ml) was added dicyclohexylcarbodiimide (1.5 g), and the mixture was stirred at room temperature for 13 hours. Under reduced pressure, the solvent was evaporated, and to the residue was ethyl acetate. The solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 2-(1-hydroxyethylidene)-5-(2-chlorophenyl)cyclohexane-1,3-dione (1.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[C:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-phenyl-methanone and 103 mg of 4-Methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.78 (s, 3H), 6.83 (d, 2H, J=9.2 Hz), 7.39 (b, 1H), 7.49 (d, 2H, J=6.4 Hz), 7.68 (m, 4H), 8.85 (d, 2H, J=6.0 Hz), 9.96 (b, 1H). MS: m/z 447.0 (M++1).
Reaction SMILES: [CH2:1]([Si:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[C:4]#[CH:5])[CH3:2].[Li]CCCC.[F:15][CH2:16][C:17](=[O:19])[CH3:18]>C1COCC1>[F:15][CH2:16][C:17]([CH3:18])([OH:19])[C:5]#[C:4][Si:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:1][CH3:2]
Reactant: C#C[Si](CC)(CC)CC
Reactant: CC(=O)CF
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[Si](C#CC(C)(O)CF)(CC)CC
Temperature: -78 °C

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure B. A stirred solution of triethyl(ethynyl)silane (1.05 eq, 5.4 mL) in THF. at −78° C. was treated with n-BuLi (2.5 mol/L in hexanes, 1.1 eq) dropwise. The reaction was stirred for 15 minutes before addition of 1-fluoropropan-2-one (2.1 mL) then stirred for another hour at −78° C. whereupon it was slowly warmed to room temperature. The reaction was quenched with a saturated ammonium chloride solution then extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to give a clear oil. This crude intermediate was purified by ISCO with ELSD option (0-100% Heptane: Ethyl acetate over 25 minutes) to afford 1-fluoro-2-methyl-4-triethylsilyl-but-3-yn-2-ol. 1H NMR (400 MHz, MeOD) δ 4.81 (s, 1H), 4.36-4.27 (m, 1H), 4.24-4.14 (m, 1H), 1.45 (d, J=1.8 Hz, 3H), 1.06-0.97 (m, 9H), 0.65-0.55 (m, 6H).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(F)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-fluorobenzeneboronic acid. The title compound was obtained in 93% yield as yellow foam. MS (m/e): 500.2 (MH+, 100%).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([CH2:28][O:29][Si](C(C)(C)C)(C)C)[CH2:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][C:14]=1[CH:15]=[O:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][CH2:9][CH:10]([CH2:28][OH:29])[CH2:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][C:14]=1[CH:15]=[O:16]
Reactant: COc1cc(OCC(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)c(C=O)cc1-c1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OCC(CO)CO)c(C=O)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
Ex-13E: To a solution of 2-[3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propoxy]-4-methoxy-5-thien-2-ylbenzaldehyde (Ex-13D, 0.78 g, 1.41 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 3.0 mL, 2.9 mmol) and the mixture was stirred at room temperature for 30 min. The reaction was diluted with ethyl acetate (50 mL) and washed sequentially with a 50% ammonium chloride solution (30 mL), water (2×30 mL), brine (30 mL), dried over sodium sulfate and concentrated to a crude yellow solid. Silica gel chromatography afforded 0.37 g (99%) of 2-(3-hydroxy-2-hydroxymethylpropoxy)-4-methoxy-5-thien-2-ylbenzaldehyde as a pale yellow solid, mp 144–145° C. 1H-NMR (300 MHz, CDCl3) δ 10.33 (s, 1H), 8.10 (s, 1H), 7.38 (dd, 1H, J=3.6, 1.5 Hz), 7.30 (dd, 1H, J=5.1, 1.5 Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.59 (s, 1H), 4.35 (d, 2H, J=6.0 Hz), 4.02 (t, 4H, J=4.8 Hz), 3.96 (s, 3H), 2.33 (pentet, 1H, J=6.0 Hz), 1.89 (t, 2H, J=4.8 Hz). Anal. Calcd. for C16H18O5S: C, 59.61; H, 5.63; S, 9.95; Found: C, 59.34; H, 5.75; S, 9.82.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[O:12][N:11]=[C:10]([C:13]([CH3:23])([CH3:22])[CH2:14][O:15]C2CCCCO2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[O:12][N:11]=[C:10]([C:13]([CH3:23])([CH3:22])[CH2:14][OH:15])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(C)(C)COC2CCCCO2)no1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(C(C)(C)CO)no1
Yield: 85.7 %

Procedure:
A solution of 933.0 mg (2.74 mmol) of {3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-carbamic acid tert-butyl ester and 103.0 mg (0.41 mmol) of pyridinium p-toluenesulfonate in ethanol (8.0 mL) is stirred at 65° C. for 1 h. After this time, the reaction mixture is concentrated under reduced pressure. Purification by flash chromatography on silica gel using ethyl acetate/heptane provides 602.0 mg of the title compound. Yield: 85.7%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.3 (6H, s), 1.55 (9H, s), 2.35 (1H, t, J=8.0 Hz), 3.7 (2H, d, J=8.0 Hz), 6.5 (1H, s), 7.3 (1H, s).
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][C@@H:16]([CH:18]3[CH2:20][CH2:19]3)[C@H:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6]C=CC=2)[CH:4]=[CH:3][CH:2]=1.C(C1C=CC=C2C=1[N:45]([CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH:44]=C2)(O)=O>>[C:54]([O:53][C:51]([NH:50][CH2:49][CH2:48][CH2:47][N:45]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][C:1]=2[C:11]([N:13]2[CH2:17][C@@H:16]([CH:18]3[CH2:20][CH2:19]3)[C@H:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[CH:6]=[CH:44]1)=[O:52])([CH3:57])([CH3:56])[CH3:55]
Reactant: O=C(c1cccc2ccccc12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](C2CC2)C1
Reactant: CC(C)(C)OC(=O)NCCCn1ccc2cccc(C(=O)O)c21
Product: CC(C)(C)OC(=O)NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Yield: 5.4 %

Procedure:
1-(N-(3-t-butoxycarbonylaminopropyl)-7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine (0.13 g) was prepared from 0.125 g (4 mmol) of 3-(S)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine (Example 9) and 0.13 g (4.3 mmol) of 7-carboxy-N-(3-t-butoxycabonylaminopropyl)indole as described in Example 11. It was purified by chromatography (silica, acetone:hexanes, 3:7).
Reaction SMILES: [ClH:1].[I:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH2:11]([OH:13])[CH3:12]>>[ClH:1].[I:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6](=[NH:7])[O:13][CH2:11][CH3:12]
Reactant: CCO
Reactant: N#Cc1cccc(I)c1
Agent: Cl
Product: CCOC(=N)c1cccc(I)c1

Procedure:
Hydrogen chloride gas was bubbled into a solution of 3-iodobenzonitrile (2.00 g, 8.73 mmol) in 20 mL of absolute ethanol for 30 min at room temperature. The resultant solution was kept at room temperature for 48 h, and was then concentrated under reduced pressure. The residue was triturated with diethyl ether, collected and dried in vacuo to afford the product as a white powder.