Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:5][O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH2:3][OH:4].C(Cl)(Cl)(Cl)Cl.O.I([O-])(=O)(=O)=[O:25].[Na+]>C(#N)C.CCOC(C)=O>[CH3:17][C:2]([CH3:1])([CH2:5][O:6][Si:7]([CH:8]([CH3:10])[CH3:9])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[C:3]([OH:25])=[O:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)[Si](OCC(C)(C)CO)(C(C)C)C(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)[Si](OCC(C)(C)C(=O)O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A solution of 2,2-Dimethyl-3-triisopropylsilanyloxy-propan-1-ol (1.39 g, 5.34 mmol) (Journal of the American Chemical Society, 123(39), 9687-9688; 2001) dissolved in ACN (14 ml), CCl4 (14 ml), and water (22 ml) was treated with sodium periodate (4.57 g, 21.4 mmol) and then RuCl3—H2O (33 mg, 0.16 mmol). After stirring at room temperature for approximately 2 hours, the reaction mixture was partitioned between DCM/water. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a black oil. Silica gel chromatography using 0-30% EtOAc in hexanes as eluant provided 1.23 mg (84%) of 2,2-dimethyl-3-triisopropylsilanyloxy-propionic acid. M−H=569.
Reaction SMILES: Cl.[S:2]1[C:6]([C@H:7]2[NH:12][CH2:11][C@H:10]([N:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14](Cl)=[O:15])[CH2:9][CH2:8]2)=[N:5][CH:4]=[N:3]1>C(Cl)Cl>[CH2:18]([O:17][N:13]1[C:14](=[O:15])[N:12]2[CH2:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C:6]1[S:2][N:3]=[CH:4][N:5]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)N(OCc1ccccc1)[C@@H]1CC[C@@H](c2ncns2)NC1
Agent: Cl
Solvent: ClCCl
Product: O=C1N2C[C@@H](CC[C@H]2c2ncns2)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a mixture of ((3R,6S)-6-(1,2,4-thiadiazol-5-yl)piperidin-3-yl)(benzyloxy)carbamic chloride HCl salt in dry DCM (15 mL) at 0° C. was added TEA (606 mg, 6.0 mmol). The mixture was stirred at rt for 2 hrs and then concentrated. The residue was purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to give (2S,5R)-6-(benzyloxy)-2-(1,2,4-thiadiazol-5-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (190 mg, 51%) as a yellow solid. ESI-MS (EI+, m/z): 317 [M+H]+, 1HNMR (500 M, CDCl3): δ 8.62 (s, 1H), 7.46-7.37 (m, 5H), 5.09 (d, J=11.2 Hz, 1H), 4.92 (d, J=11.2 Hz, 1H), 4.90 (br d, J=5.5 Hz, 1H), 3.35 (m, 1H), 2.88 (br d, J=6.0 Hz, 1H), 2.79 (d, J=12.0 Hz, 1H), 2.31-2.28 (m, 2H), 2.21-2.11 (m, 1H), 1.98-1.90 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:16][C:17]2[O:21][C:20]([C:22]([OH:24])=O)=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:16][C:17]2[O:21][C:20]([C:22]([Cl:27])=[O:24])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc2c(cc1Cc1ccc(C(=O)O)o1)C(C)(C)CCC2(C)C
Solvent: ClCCl
Product: Cc1cc2c(cc1Cc1ccc(C(=O)Cl)o1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution containing 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furoic acid 7 (20.15 g, 61.77 mmol) in methylene chloride (310 mL), thionyl chloride (45 mL, 617 mmol) is added. The reaction is refluxed for 5 hours and another batch of thionyl chloride (45 mL, 617 mmol) is added. The reaction is stirred overnight at room temperature. The solution is concentrated to a syrup and passed through a pad of silica gel (50 g), washed with 3% hexanes, and concentrated in vacuo to afford 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furoyl chloride 8 (17 g, 80% yield). NMR 1.26 (s, 6H), 1.28 (s, 6H), 1.68 (s, 4H), 2.25 (s, 3H), 4.00 (s, 2H), 6.11 (d, 1H), 7.10 (s, 1H), 7.11 (s, 1H), 7.41 (d, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[C:12](=[O:42])[C:13](=[CH:16][C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:21]=3[CH3:22])[CH2:14][CH2:15][C:4]=12)[CH3:2].C([O-])=O.[NH4+]>[Pd].C(O)(=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[C:12](=[O:42])[CH:13]([CH2:16][C:17]3[N:18]=[CH:19][NH:20][C:21]=3[CH3:22])[CH2:14][CH2:15][C:4]=12)[CH3:2]
Reactant: CCc1c2n(c3ccccc13)C(=O)C(=Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCc1c2n(c3ccccc13)C(=O)C(Cc1nc[nH]c1C)CC2
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 56.8 %

Procedure:
A mixture of 10-ethyl-8,9-dihydro-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (1.0 g), 10% palladium on carbon (0.25 g), and ammonium formate (0.5 g) in acetic acid (14 ml) was stirred at 90° C. for 1 hour and 45 minutes and cooled to room temperature. After filtration of the catalyst, the filtrate was evaporated in vacuo and the residue was suspended in 0.5N hydrochloric acid. The aqueous layer was washed twice with toluene, made basic with aqueous sodium bicarbonate solution, and extracted three times with chloroform. The chloroform layer was washed with water twice and brine, dried over anhydrous magnesium sulfate, and evaporated to give crystals. Recrystallization from chloroform-methanol gave 10-ethyl-8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (0.319 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]1([S:26][CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10]([C:23]3[CH:24]=[CH:25][C:20]([S:26][CH3:27])=[CH:21][CH:22]=3)[C:9]=2[CH:15]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Reactant: CSc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CSc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
A solution of 26.2 g (0.10 mol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (201), Table 2, Example 1a) in 25 ml (0.21 mol) of thioanisoie is added dropwise to a solution of 14.7 g (0.11 mol) of aluminium chloride in 15 ml (0.13 mol) of thioanisole at 35-40° C. The reaction mixture is thereafter stirred for 30 minutes at 30° C. and for 2 hours at 80° C., and then after cooling, c. 50 ml of water and then concentrated hydrochloric acid and methylene chloride are added cautiously in sufficient amount to form a homogeneous two-phase mixture. The organic phase is separated, washed with water, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 6.7 g (18%) of 5,7-di-tert-butyl-3-(4-methylthiophenyl)-3H-benzofuran-2-one, m.p. 125-131° C. (compound (108), Table 1).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[H-].[Na+].I[CH3:17].O>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:17])[C:10](=[O:12])[O:9][C:7](=[O:8])[C:6]=2[CH:13]=1
Reactant: CI
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)oc(=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
5-bromoisatoic anhydride (3 g, 12 mmol) was stirred in 50 mL of DMF at 0° C. and sodium hydride (60% dispersion in mineral oil) (0.4 g, 15 mmol) was added in portions, with stirring for 1 hour at room temperature. Iodomethane (0.8 mL, 12 mmol) was added drop wise and the reaction mixture was allowed to stir for 4 hours. Water (50 mL) was added slowly and 50 mL of Dichloromethane (DCM) was also added. A white solid precipitated out and was filtered off. The layers were separated layers. Aqueous layer extracted with DCM (2×25 ml). The combined organic layers were extracted with water (4×25 ml) and once with brine (25 ml). The organic layer was dried with MgSO4 and the solvent removed. The residue was purified by flash chromatography (0-3% MeOH/DCM) to afford 1.57 g of product. Yield 49%
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11](=[O:13])[NH2:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:14]([O:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20])[CH3:15]>>[C:4]([C:3]1[C:2]([NH:1][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[O:16][CH2:14][CH3:15])=[C:10]([CH:9]=[CH:8][CH:7]=1)[C:11]([NH2:12])=[O:13])(=[O:5])[NH2:6]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1cccc(C(N)=O)c1N
Product: CCOc1ccccc1C(=O)Nc1c(C(N)=O)cccc1C(N)=O

Procedure:
The title compound was prepared from 2-amino-3-carbamoylbenzamide and 2-ethoxybenzoyl chloride following the procedure of Preparation 5 and was obtained as colourless crystals (33%), m.p. 224-225° C.
Reaction SMILES: [H-].[Na+].C(=N/[OH:11])\C1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:32]([O:34]CC)=O)[CH2:24][CH2:23][C:22]3([O:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][O:25]3)[CH2:21][CH2:20]2)=[C:15]([C:37]#[C:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:14]=1>O1CCOCC1.CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[C:19]1([CH2:20][CH2:21][C:22]3([O:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][O:25]3)[CH2:23][CH2:24]1)[C:32](=[O:34])[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:37]2[OH:11]
Reactant: CCOC(=O)C#Cc1cc(Cl)ccc1C1(C(=O)OCC)CCC2(CC1)OCC(C)(C)CO2
Reactant: O/N=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC3(CC2)OCC(C)(C)CO3)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A stirred mixture of NaH (60% dispersion in mineral oil (0.39 mL, 9.3 mmol)) in 40 mL dioxane at room temperature, was treated with a mixture of (E)-benzaldehyde oxime (1.0 g, 8.6 mmol) in 40 mL DMF. The resulting mixture was stirred for 30 minutes. The mixture was then cooled to 0° C. and treated with a mixture of ethyl 4′-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)-5,5-dimethyl-spiro[1,3-dioxane-2,1′-cyclohexane]-4′-carboxylate (3.6 g, 7.8 mmol) in 30 mL DMF. The resulting mixture was stirred for 1 hour. The mixture was then carefully quenched with 10 mL H2O and brought to a pH of 5 by addition of 10% HCl. The mixture was extracted with ethyl ether (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 20-30% EtOAc to give 2.2 g of the product as a pale yellow solid. MS (m/z)=435 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=O.CCN(CC)CC>CN(C=O)C.O.CCO>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[CH2:20][O:11][C:10](=[O:12])[C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:24][CH:25]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc(C2=C(c3ccc(Cl)cc3)COC2=O)cc1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
To a stirred and cooled (−15° to −10° C.) solution of 2-(4-cyanophenyl)acetic acid (35 g, 217.18 mmol) in DMF (250 mL) was added potassium t-butoxide (95%, 25.66 g, 217.22 mmol) under argon in small portions keeping the temperature below −10° C. After the addition was complete a solution of 2-bromo-1-(4-chlorophenyl)ethanone (50.71 g, 217.18 mmol) in DMF (75 mL) was added slowly over 30 min. The reaction mixture was stirred for 1 hr keeping the temperature between −10° to 0° C. Et3N (12.0 mL, 86.1 mmol) was added at 0° C. and the reaction mixture was allowed to warm to room temperature over 1.5 hr. Then EtOH (70 mL) was added at room temperature and the reaction mixture was stirred for 10 min. The reaction mixture was cooled in an ice bath and water (300 mL) was added slowly. The light green precipitate formed was collected by filtration, washed thoroughly with water followed by hexanes. The solid thus obtained was dried in a vacuum oven overnight at 50° C. to obtain 4-(4-(4-chlorophenyl)-2-oxo-2,5-dihydrofuran-3-yl)benzonitrile (58.2 g, 91% yield) as a light green solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([C:16](=[O:18])[CH3:17])C(OCC)=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH2:19]>Cl>[O:18]=[C:16]([CH3:17])[CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]([NH2:2])=[O:19]
Reactant: O
Reactant: CCOC(=O)C(Cc1cccc(C#N)c1)C(C)=O
Agent: Cl
Product: CC(=O)CCc1cccc(C(N)=O)c1

Procedure:
38.2 g of ethyl 2-(3'-cyanophenylmethyl)-3-oxobutyrate was heated for 2 hours under reflux in 500 ml of concentrated hydrochloric acid. To the reaction solution was added 500 ml of water, followed by extraction three times with 500 ml portions of ethyl acetate. The organic phase was washed with water and dried with anhydrous sodium sulfate, after which the solvent was distilled off. The resultant 3-(3'-oxobutyl)benzoic acid was admixed with 500 ml of benzene and 17 ml of thionyl chloride and heated for 2 hours under reflux. The reaction solution was dropped into ice-cooled concentrated ammonia water and the resultant amide extracted three times with 500 ml portions of ethyl acetate. The organic phase was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off and the residue recrystallized from ethyl acetate-n-hexane to obtained 23.1 g of 3-(3'-oxobutyl)benzamide, melting point 122°-125° C.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[CH2:31]([C:33]1[S:34][C:35]([C:38]2([OH:45])[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]2)=[CH:36][N:37]=1)[CH3:32]>>[CH2:31]([C:33]1[S:34][C:35]([C:38]2([OH:45])[CH2:39][CH2:40][CH:41]([N:8]3[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=5)[N:18]([CH3:29])[N:17]=4)[CH2:11]3)[CH2:42][CH2:43]2)=[CH:36][N:37]=1)[CH3:32]
Reactant: CCc1ncc(C2(O)CCC(=O)CC2)s1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCc1ncc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(F)F)cc45)C3)CC2)s1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-(2-ethyl-thiazol-5-yl)-4-hydroxy-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:28](O)=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:42]([S:61][CH2:62][C@@H:63]([C:65]([NH2:67])=[O:66])[NH2:64])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:28]([NH:64][C@H:63]([C:65]([NH2:67])=[O:66])[CH2:62][S:61][C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:31][CH:32]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
1.20 g (2.07 mmol) of the compound from example 9A was dissolved in 48 ml dichloromethane. 0.750 g (2.07 mmol) S-Trityl-L-cysteinamide, 0.36 ml (2.07 mmol) N,N-diisopropylethylamine and 0.787 g (2.07 mmol) HATU were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 400 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.30 g (1.5 mmol, 56% of theory, 82% purity) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10](OC)=[O:11].NC1C=C(F)C=CC=1NC1SC2CCCCC=2C=1C(OCC)=O>>[F:18][C:16]1[CH:15]=[CH:14][C:3]2[NH:4][C:5]3[CH:9]=[CH:8][S:7][C:6]=3[C:10](=[O:11])[NH:1][C:2]=2[CH:17]=1
Reactant: COC(=O)c1sccc1Nc1ccc(F)cc1N
Agent: CCOC(=O)c1c(Nc2ccc(F)cc2N)sc2c1CCCC2
Product: O=C1Nc2cc(F)ccc2Nc2ccsc21

Procedure:
Methyl 3-(2-amino-4-fluoroanilino)-thiophene-2-carboxylate, m.p. 225°-230° C. (EtOAc).
Reaction SMILES: [CH2:1]([S:4][C@:5]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[C@H:7]([C:20]([O:22][CH3:23])=[O:21])[CH2:6]1)[CH:2]=[CH2:3].I[Si](C)(C)C.CO>C(#N)C>[CH2:1]([S:4][C@:5]1([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)[CH2:9][NH:8][C@H:7]([C:20]([O:22][CH3:23])=[O:21])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: C=CCS[C@]1(c2ccc(-c3ccccc3)cc2)CN[C@H](C(=O)OC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To an iced solution of (2S,4R)-1-benzyl 2-methyl 4-(allylthio)-4-(biphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (1.85 g, 3.79 mmol) in Acetonitrile (20 mL) was added Iodotrimethylsilane (0.810 mL, 5.69 mmol). The formed light brown solution was stirred at room temperature for 2 h. Cooled with ice bath, quenched with Methyl alcohol (7.68 mL, 190 mmol). The formed light brown solution was purified by prep-HPL, and the collected fractions were evaporated on speed-vac system. The yellow residue was taken up in DCM, washed with sat. Na2CO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (2S,4R)-methyl 4-(allylthio)-4-(biphenyl-4-yl)pyrrolidine-2-carboxylate (664 mg, 1.878 mmol, 49.5% yield) as a viscous oil. 1H NMR (500 MHz, MeOD) δ ppm 2.96-3.09 (m, 3 H) 3.15 (d, J=14.34 Hz, 1 H) 3.84 (d, J=12.21 Hz, 1 H) 3.96 (s, 2.5 H) 4.00 (s, 0.5 H) 4.04 (d, J=11.90 Hz, 1 H) 4.77 (dd, J=10.07, 3.05 Hz, 1 H) 5.02 (d, J=9.77 Hz, 1 H) 5.09 (d, J=17.09 Hz, 1 H) 5.54-5.68 (m, 1 H) 7.38 (t, J=7.48 Hz, 1 H) 7.44-7.54 (m, 4 H) 7.66 (d, J=7.32 Hz, 2 H) 7.71 (d, J=8.55 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][C:15]([OH:17])=[O:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18]O>S(=O)(=O)(O)O>[CH3:18][O:16][C:15](=[O:17])[CH2:14][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CO
Reactant: O=C(O)CC1(c2ccc(Cl)cc2)CCOCC1
Agent: O=S(=O)(O)O
Product: COC(=O)CC1(c2ccc(Cl)cc2)CCOCC1

Procedure:
A stirred solution of (4-{4-chloro-phenyl}-tetrahydro-pyran-4-yl)-acetic acid [3.3 g, Reference Example 21(a)] in anhydrous methanol (125 mL), under argon, was treated with concentrated sulfuric acid (8 drops). This mixture was stirred at reflux temperature for 5.5 hours then evaporated. The residue was treated with ethyl acetate (35 mL) and the resulting solution was washed three times with water (10 mL), then dried over magnesium sulfate and then evaporated to give the title compound (3.12 g) as a pale amber oil. LC-MS: RT=3.43 minutes, MS(ES+): 269 and 271(M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:25])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:24])[CH:13]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:14][S:15][C:16](=[O:18])[CH3:17])(C)(C)C.C(O)(=O)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:16]([S:15][CH2:14][CH:13]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:25])=[O:5])=[O:24])(=[O:18])[CH3:17]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
2.9 g. of the product from Example 80 is dissolved in a mixture of trifluoroacetic acid (17.5 ml.) and anisole (8.4 ml.). After one hour storage at room temperature, the excess trifluoroacetic acid is removed in vacuo and the residue is precipitated twice from ether-hexane to yield 2.1 g. of the named product. Rf : 0.4 (silica gel-benzene:acetic acid, 75.25).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:31][CH2:30][N:29]([C:4]([C:3]2[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:2]=2[I:1])=[O:6])[CH2:28][CH2:27]1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: Fc1cc(C(F)(F)F)ccc1N1CCNCC1
Product: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3F)CC2)c1

Procedure:
Example CN was prepared in analogy to Example 123 from 2-Iodo-5-methanesulfonyl-benzoic acid (example BQ) and 1-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine (example H). MS (m/e): 574.2 (M+NH4+, 100%).
Reaction SMILES: [F:1][C:2]1[C:10]([S:11]([N:14]2[CH2:19]CCC[CH2:15]2)(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.ClC1C(S(N2CC(C)CC(C)C2)(=O)=O)=CC(C(O)=O)=CC=1.ClC1C(S(N2CCOCC2)(=O)=O)=CC(C(O)=O)=CC=1.ClC1C(S(N2CCCC(C)C2)(=O)=O)=CC(C(O)=O)=CC=1.BrC1C(S(NCC2C=CC(Cl)=CC=2)(=O)=O)=CC(C(O)=O)=CC=1.CC1C(S(N2CCC(C)(C)CC2)(=O)=O)=CC(C(O)=O)=CC=1.CC1C(S(NC2C=C(Br)C=C(Br)C=2)(=O)=O)=CC(C(O)=O)=CC=1.CC1C(S(NCCCC2C=CC=CC=2)(=O)=O)=CC(C(O)=O)=CC=1.COC1C(S(N2CCC(C)CC2C)(=O)=O)=CC(C(O)=O)=CC=1.COC1C(S(N(C(C)C)C(C)C)(=O)=O)=CC(C(O)=O)=CC=1>>[F:1][C:2]1[C:10]([S:11]([N:14]([CH3:19])[CH3:15])(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)N2CCCCC2)c1
Agent: CC1CC(C)CN(S(=O)(=O)c2cc(C(=O)O)ccc2Cl)C1
Agent: CC1CCCN(S(=O)(=O)c2cc(C(=O)O)ccc2Cl)C1
Agent: COc1ccc(C(=O)O)cc1S(=O)(=O)N(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1cc(C(=O)O)ccc1F

Procedure:
4-fluoro-5-piperidinosulfonylbenzoic acid; 4-chloro-5-(3,5-dimethylpiperidinosulfonyl)benzoic acid; 4-chloro-5-morpholinosulfonylbenzoic acid; 4-chloro-5-(3-methylpiperidinosulfonyl)benzoic acid; 4-bromo-5-hexamethyleneiminosulfonylbenzoic acid; 4-bromo-5-(4-chlorobenzylaminosulfonyl)benzoic acid; 4-methyl-5-(4,4-dimethylpiperidinosulfonyl)benzoic acid; 4-methyl-5-(3,5-dibromophenylaminosulfonyl)benzoic acid; 4-methyl-5-(3-phenylpropylaminosulfonyl)benzoic acid; 4-methoxy-5-(2,4-dimethylpiperidinosulfonyl)benzoic acid; 4-methoxy-5-(4-biphenylethylaminosulfonyl)benzoic acid; 4-methoxy-5-(2-p-bromophenethylaminosulfonyl)benzoic acid; and 4-methoxy-5-di-i-propylaminosulfonylbenzoic acid.