Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCC[C@H]1C(O)=O.[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1.N1(C2C=CC(CC(C(O)=O)C(O)=O)=CC=2)C=NC=N1.[CH3:41][C:42]1([CH3:50])[O:47][C:46](=[O:48])[CH2:45][C:44](=[O:49])[O:43]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C(O)C.C(O)(C)C>[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][CH:45]3[C:46](=[O:48])[O:47][C:42]([CH3:50])([CH3:41])[O:43][C:44]3=[O:49])=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: O=Cc1ccc(-n2cncn2)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)C(Cc1ccc(-n2cncn2)cc1)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Solvent: CC(C)O
Product: CC1(C)OC(=O)C(Cc2ccc(-n3cncn3)cc2)C(=O)O1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
L-Proline (1.81 g, 15.6 mmol) was added to a stirring, heterogeneous mixture of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (13.5 g, 78.0 mmol, Intermediate 82: step a) and 2,2-dimethyl-1,3-dioxane-4,6-dione (11.2 g, 78.0 mmol) in ethanol (520 mL) at 23° C. After 1.5 hours, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (19.7 g, 78.0 mmol) was added in one portion. After 16 hours, the ethanol was removed by rotary evaporation at 35° C. to afford a yellow solid. Isopropanol (300 mL) was added and the heterogeneous mixture was stirred for 10 minutes at 23° C. The mixture was filtered and the filter cake was washed with isopropanol (150 mL). The solids were collected and dried under vacuum to provide the titled compound as a white solid.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][O:8][C:7]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[O:15][C:14]([CH3:24])([CH3:23])[CH2:13][CH2:12][C:11]=3[C:10]2=[O:25])[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][CH:5]1[CH2:9][O:8][C:7]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[O:15][C:14]([CH3:23])([CH3:24])[CH2:13][CH2:12][C:11]=3[C:10]2=[O:25])[O:6]1
Reactant: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(CN=[N+]=[N-])O1)C2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(CN)O1)C2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4′-(azidomethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one (0.012 mg, 0.035 mmol) in THF (1.0 mL) is added triphenylphosphine (0.033 mg, 0.13 mmol). The mixture is stirred at room temperature for 3 hour followed by addition of water (50 μL). The reaction is then stirred for another 16 hour at room temperature and solvent is removed under reduce pressure to yield a reside of 4′-(aminomethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one as confirmed by LC/MS, which indicates the product, which has a molecular weight of 315 Da, is present in the crude residue along with triphenylphosphine oxide (a side product from the triphenylphosphine).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][Br:8])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[Br-:8].[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][N+:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: c1ccncc1
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)C[n+]2ccccc2)cc1
Product: [Br-]
Temperature: 60 °C
Yield: 94 %

Procedure:
64 g (0.3 mol) of 4-methylphenacyl bromide in 80 ml acetone were initially taken and heated to 60° C. 24 g (0.3 mol) of pyridine were then slowly added dropwise. The reaction mixture was stirred for a further hour at 60° C. and cooled to room temperature. The precipitated solid was filtered off and washed with acetone. After drying, 82.5 g (corresponding to a yield of 94%) of the title compound were obtained in the form of a yellow powder. The purity of the product was more than 99%.
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([SH:7])[N:4]=[C:3]1[CH3:8].[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([CH2:30]Cl)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[CH3:32]N(C=O)C>>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([CH:30]([S:7][C:5]3[N:4]=[C:3]([CH3:8])[NH:2][CH:6]=3)[CH3:32])=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Reactant: Cc1nc(S)cn1C
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(SC(C)c2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)c[nH]1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
Dissolve 1,2-dimethyl-1H-imidazole-4-thiol (450 mg, 1.8 mmol, prepared as described in J. Heterocyclic Chem. 1998, 35, 141) in anhydrous DMF (3 mL). Add sodium hydride (55 mg, 1.4 mmol, 60% dispersion in mineral oil) portionwise over 2 min at room temperature under a nitrogen atmosphere. Stir the yellow solution for 5 min, then add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.9 mmol) in anhydrous DMF (3 mL) at room temperature over 2 min. Heat the mixture at 45° C. for 16 h under a nitrogen atmosphere. Cool the mixture to room temperature and quench with 10% aqueous sodium chloride (10 mL). Extract the mixture with EtOAc (2×30 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (7:3 to 1:1 gradient) to obtain 3-tert-butoxycarbonyl-7-chloro-6-(1,2-dimethyl-1H-imidazol-4-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (160 mg, 42%). MS (ES+) m/z: 422.0 (M+H)+.
Reaction SMILES: [H-].[Na+].S([NH:13][N:14]=[C:15]([CH2:17]P(OCC)(OCC)=O)[CH3:16])(C1C=CC(C)=CC=1)(=O)=O.[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1>C1COCC1.CN(C=O)C>[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][C:29]([C:32]2[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CCOP(=O)(CC(C)=NNS(=O)(=O)c1ccc(C)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(-c3ccccc3)cc2)[nH]n1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a stirred mixture of NaH (1.98 g, 0.049 mol, 60% oil dispersion) in dry THF (30 mL) was added a suspension of diethoxyphosphorylacetone tosyl hydrazone (8.97 g, 0.024 mol; N Almirante Syn. Lett. 1999, 302.) in a mixture of THF (35 mL) and DMF (5.0 mL) dropwise over 15 min. The yellow suspension was stirred at 0-5° C. for 30 min and was treated with a 4-biphenyl carboxaldehyde (3.10 g, 0.0169 mol) in dry THF (30 mL) at 0-5° C. over 15 min. The orange solution was heated and stirred at reflux for 4 h and stirred at ambient temperature overnight. The mixture was poured into 5% aq. NaH2PO4 (350 mL) and extracted with EtOAc (2×200 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated to a yellow semi-solid. This material was triturated with hot EtOAc (20 mL) and filtered. The solid was washed with EtOAc (2×10 mL) and dried under high vacuum to give the title compound (2.61 g, 47%): HRMS Calculated for C16H15N2: m/z 235.1235. Found: 235.1230.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:31][C:32]([O:34]CC)=[O:33])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:16][C:15]=3[CH:30]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:1].[C:2]1([N:8]([CH2:31][C:32]([OH:34])=[O:33])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:16][C:15]=3[CH:30]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: N=C(N)c1ccc(NCc2nc3cc(C(=O)N(CC(=O)O)c4ccccc4)ccc3s2)cc1
Yield: 75 %

Procedure:
Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 75% of theory, C24H21N5O3S (459.53) Rf value: 0.14 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid) ##EQU4##
Reaction SMILES: Br[CH:2]([S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:20]1[CH2:29][C:30](=[S:32])[NH2:31].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:5]1([C:3]2[N:31]=[C:30]([CH2:29][N:20]3[C:19](=[O:18])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:28])[S:32][C:2]=2[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(c1ccccc1)C(Br)Sc1ccccc1
Reactant: NC(=S)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2)c(Sc2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To a solution of 2-bromo-1-phenyl-2-(phenylthio)ethanone (3.2 g) in N,N-dimethylformamide (25 mL) was added 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanethioamide (2.3 g) and the mixture was stirred at room temperature for 3 hr. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound as white crystals (yield 3.0 g, yield 71%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:17]1=[O:27].[CH3:36][N:37]=[C:38]=[O:39].C(N(CC)CC)C>C(Cl)Cl>[CH3:36][NH:37][C:38]([N:24]1[CH2:25][CH2:26][CH:21]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH2:15][C:14]3[C:13]([Cl:28])=[CH:12][C:11]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)=[CH:10][C:9]=3[Cl:8])[C:17]2=[O:27])[CH2:22][CH2:23]1)=[O:39]
Reactant: CN=C=O
Reactant: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(F)cc4)cc3Cl)C2=O)CC1
Yield: 106.7 %

Procedure:
Treat a solution of (R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-1-piperidin-4-yl-pyrrolidin-2-one trifluoroacetic acid (Preparation 29) (0.10 g, 0.19 mmol) in CH2Cl2 (3 mL) with methyl isocyanate (21 mg, 0.36 mmol) and triethylamine (0.07 mL, 0.48 mmol). Stir the reaction overnight at room temperature. Quench the reaction with 1N HCl and extract with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute pure product. Remove the solvent to afford 0.097 g (84%) of product. MS (m/e): 478 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][C@@H:5]([C:18]([O:20]C)=[O:19])[CH2:4][CH2:3]1.O[Li].O.Cl>C1COCC1.O.CO>[CH3:1][C@H:2]1[N:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][C@@H:5]([C:18]([OH:20])=[O:19])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H]1CC[C@H](C(=O)O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 119 %

Procedure:
To a solution of 3-methyl 1-(phenylmethyl) (3S,6R)-6-methyl-1,3-piperidinedicarboxylate (15 g, 51.5 mmol) in THF/water/CH3OH (10/5/1, 480 mL) was added LiOH.H2O (2.59 g, 61.8 mmol), and the reaction mixture was stirred at room temperature for about 1 hour. The mixture was acidified with 1N HCl until the pH was ˜5, and then concentrated in vacuo. The resulting residue was extracted with EtOAc (2×300 mL) and CHCl3 (2×300 mL), and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to afford the crude title compound (17 g). LC-MS (ES) m/z=278 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.O=C1[N:47]([ClH]P([ClH]N2CCOC2=O)=O)[CH2:46]CO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:28])[F:26])=[N:20][C:21]([C:22](=[O:24])[NH:47][CH3:46])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Yield: 98.6 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), methylamine hydrochloride (36.5 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-methylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 8a (150 mg, yield 98.6%) as a white solid.
Reaction SMILES: [N+](=[CH2:3])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[CH2:18]([N:25]1[CH2:30][C@@H:29]([OH:31])[CH2:28][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[C@H:26]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCOCC>[CH2:18]([N:25]1[CH2:30][C@@H:29]([O:31][CH3:3])[CH2:28][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[C@H:26]1[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=[N+]=[N-]
Reactant: COC(=O)[C@H]1C[C@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: CCOCC
Product: COC(=O)[C@H]1C[C@H](OC)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.2 %

Procedure:
Diazomethane was generated (from 5 g of Diazald) and distilled together with ether into a mixture of 2-benzyl 3-methyl(2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (0.60 g, 0.0016 mol) and around 1 g of silica gel in 10 mL of ether. After distillation, the mixture was stirred at rt overnight. The mixture was diluted with methylene chloride, filtered to remove silica gel. The filtration was concentrated to dry and the resulting residue was applied on column, eluting with 0 to 40% EtOAc in Hexane, to yield the methyl ether compound (20 mg, 3.2%). MS (ESI): (M+H)+=398.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:13]([CH:22]([CH3:24])[CH3:23])[C:12](=[O:25])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].IC.[Li+].[CH3:29][CH:30]([N-]C(C)C)[CH3:31].[CH2:36](Br)C=C>C1COCC1>[CH2:31]([C@@:11]1([CH3:36])[CH2:10][C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:13]([CH:22]([CH3:23])[CH3:24])[C:12]1=[O:25])[CH:30]=[CH2:29]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)N1C(=O)CC[C@H](c2ccc(F)c(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C=CCBr
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2ccc(F)c(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)C1=O
Temperature: -78 °C
Reaction time: 16 h

Procedure:
A solution of (5R,6S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropylpiperidin-2-one (0.50 g, 1.32 mmol; Example 390, Step C) in anhydrous THF (3 mL) was degassed by bubbling argon through the solution for 15 minutes. LHMDS (1 M in THF that was degassed by bubbling argon through the solution for 15 minutes) (1.64 mL, 1.64 mmol) was added to the lactam solution at −15° C. dropwise while keeping the temperature below −8° C. After 15 minutes at −15° C. iodomethane (0.085 mL, 1.354 mmol) was added. Thirty five minutes later freshly prepared LDA (3.29 mmol) in THF (1 mL) was added to the reaction mixture. After 30 minutes the reaction mixture was cooled to −78° C. and allyl bromide (0.398 mL, 4.60 mmol) was added slowly while keeping the temperature at or below −68° C. The reaction mixture was allowed to warm as the cold bath warmed. After 16 hours the reaction mixture temperature was 18° C. The reaction was quenched with MeOH (0.5 mL), washed with 10 mL of 50% brine/water, brine, dried (Na2SO4), decanted and concentrated in vacuo to provide a yellow oil. Purification by flash chromatography on silica gel (eluent: 5-15% EtOAc/hexanes, gradient elution) provided the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:22](=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:22])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
7.12 g (30 mmol) of tyrosine-tert-butyl ester is dissolved in 28 ml of anhydrous N,N-dimethylformamide and mixed at 50° C. under argon with 1.21 g (31 mmol) of sodium hydride dispersion (60% in mineral oil). The batch is allowed to stir for 15 minutes, then 4.4 g (31 mmol) of methyl iodide is added, the reaction temperature is allowed to increase to room temperature and it is stirred for another hour. For working-up, the batch is taken up in ethyl acetate and shaken out several times against aqueous sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate, filtered and concentrated by evaporation. The residue is chromatographed for purification on silica gel with hexane/diethyl ether/ triethylamine.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[NH2:24].NC1C=C(C=CC=1N)C(N)=O>>[O:6]([C:7]1[CH:14]=[CH:13][C:10]([C:11]2[NH:24][C:23]3[CH:22]=[CH:21][C:20]([S:25]([NH2:28])(=[O:26])=[O:27])=[CH:19][C:18]=3[N:17]=2)=[CH:9][CH:8]=1)[C:5]1[CH:15]=[CH:16][CH:2]=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1N
Agent: NC(=O)c1ccc(N)c(N)c1
Product: NS(=O)(=O)c1ccc2[nH]c(-c3ccc(Oc4ccccc4)cc3)nc2c1

Procedure:
This compound was prepared according to the methods described in Example 22 and Scheme 3, substituting 4-phenoxybenzaldehyde for 4-(4-fluoro-phenoxy)-benzaldehyde, and 3,4-diaminobenzene sulfonamide for 3,4-diaminobenzoic acid amide.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([C:10]1[S:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:9])[C:4]([O:6][CH3:7])=[O:5].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:15][C:12]1[S:11][C:10]([C:8](=[O:9])[CH:3]([NH:2][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([F:16])=[CH:18][CH:19]=2)[C:4]([O:6][CH3:7])=[O:5])=[CH:14][CH:13]=1
Reactant: COC(=O)C(N)C(=O)c1ccc(Cl)s1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of methyl 2-amino-3-(5-chlorothiophen-2-yl)-3-oxopropionate hydrochloride (6.0 g), 4-fluorobenzoyl chloride (4.23 g) and sodium hydrogen carbonate (11.2 g) in ethyl acetate (100 ml) and water (10 ml) was stirred at room temperature for 2 hours. The organic layer was collected, washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with diethyl ether to obtain methyl 3-(5-chlorothiophen-2-yl)-2-(4-fluorobenzoylamino)-3-oxopropionate (7.3 g) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH:33]([CH3:34])[CH3:35])[CH:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: CC(C)Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K37) (265 mg, 0.75 mmol) in xylene (15 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light brown solid (230 mg, 70%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I([Cl:15])(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[C:9]([Cl:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Product: Cc1ccc(C(C)(C)C)cc1Cl
Temperature: 70 °C
Reaction time: 24 h
Yield: 62.3 %

Procedure:
A solution of 2 g (13.49 mmol) of 4-tert-butyltoluene is mixed with 5.65 g (13.49 mmol) of benzyltrimethylammonium tetrachloroiodate and stirred at 70° C. for 24 hours. After cooling, the precipitate is filtered off with suction and the filtrate is concentrated. The resulting residue is purified over silica gel (mobile phase: cyclohexane). 1.53 g (8.4 mmol) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[C:4](I)[CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[C:4]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C#N)c1ccc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(C#N)c1ccc(Cl)cc1C#C[Si](C)(C)C

Procedure:
2-(4-Chloro-2-iodophenyl)propanenitrile (0.620 g, 2.13 mmol), (trimethylsilyl)acetylene (0.451 mL, 3.19 mmol), copper(I) iodide (0.0144 mL, 0.425 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.149 g, 0.213 mmol), and TEA (20 mL) were stirred at 70° C. for 3 hours. The reaction was monitored by LC-MS. The solution was filtered through a plug of Celite, and the filtrate was concentrated under vacuum. The residue was purified by silica flash chromatography, 0-15% EtOAc/hexanes. MS m/e=262 (M+H)+.