Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:15])[CH3:14])=[C:8]2[CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:20]=[C:21]([Cl:24])[C:22]=1[F:23]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:15])[CH2:14][C:25]([C:19]2[CH:20]=[C:21]([Cl:24])[C:22]([F:23])=[C:17]([Cl:16])[CH:18]=2)([OH:30])[C:26]([F:28])([F:27])[F:29])=[C:8]2[CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4]
Reactant: O=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1sc(C(C)=O)c2c1CCC2
Solvent: C1CCOC1
Product: COC(=O)c1sc(C(=O)CC(O)(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)c2c1CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
Add a solution of LiHDMS (1M in THF, 75 mL, 75 mmol) to a suspension of 3-acetyl-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester (14.0 g, 62.5 mmol) in dry THF (200 mL) at −78° C. under N2. After stirring at room temperature for 1.5 h, add 1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (17.9 g, 68.7 mmol) in dry THF (100 mL) to the reaction mixture and stir the resultant mixture at the same temperature for additional 2 hours. Quench the reaction with saturated NH4Cl aqueous solution. Extract the aqueous mixture with EtOAc (100 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 15:1) to afford 3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-butyryl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester as an orange solid (27 g, 89.3%). MS (m/z): 486 (M+1).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([OH:11])[CH2:3][CH2:2]1
Reactant: O=C1CCOc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCOc2ccccc21
Reaction time: 1 h
Yield: 956.5 %

Procedure:
To a MeOH (250 ml) solution of 4-chromanone (16.6 g, 11 mmol), at 0° C., was added NaBH4 (5.5 g, 145 mmol) in 1 g portions over a 30 min. period. After complete addition the mixture was stirred for 1 h with spontaneous warming. The reaction was quenched with the slow addition of aq. NH4Cl (100 ml). The MeOH was removed in vacuo and the residue extracted with Et2O (2×100 ml). The organic layers were dried over MgSO4 and treated with activated carbon. After filtration the Et2O was removed in vacuo to yield 15.8 g of chroman-4-ol as a clear oil. HRMS (ESI+) calcd for C9H10O2 m/z 150.0681 (M+H)+. Found 150.0679.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH3:7][C:8]1([CH2:21][NH2:22])[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][CH2:10][O:9]1)=[CH:19][CH:18]=[CH:17][CH:16]=3.C(N(CC)CC)C.O1CCCC1>C(OCC)C>[CH3:1][N:2]([CH3:6])[C:3]([NH:22][CH2:21][C:8]1([CH3:7])[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][CH2:10][O:9]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: CC1(CN)OCCc2c1[nH]c1ccccc21
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
Dimethylcarbamic chloride (3.95 g) is added to a solution at 0° C. of 1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine (7.9 g, described in Example 3), triethylamine (3.7 g) and tetrahydrofuran (200 ml) over a period of 5 minutes. The mixture is stirred at 0° to 5° C. for 30 minutes and at 25° C. for 18 hours. Diethyl ether (200 ml) is added, the mixture is filtered and the filtrate is evaporated. The residue is crystallized from diethyl ether to obtain the title compound (9.0 g); mp 153°-155° C.; ir (CHCl3) 3450-3250 and 1635 cm-1 ; nmr(CDCl3) δ1.51(s) and 2.69(m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1N.N([O-])=O.[Na+].[ClH:17]>O.Cl[Cu]>[Cl:17][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc([N+](=O)[O-])c1N
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture consisting of 15.5 g (92.26 mmol) 2-methoxy-6-nitro-phenylamine, 31 ml water and 31 ml conc. HCl, a solution of 6.36 g (92.26 mmol) NaNO2 in 38 ml water is slowly added dropwise at −10° C.-0° C. After stirring for 0.5 h the mixture is slowly added to a solution of 11.88 g (120 mmol) CuCl in 93 ml conc. HCl. After completion of the addition stirring is continued for 1.5 h at room temperature and for 0.5 h at reflux temperature. The reaction mixture is allowed to cool to room temperature and is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 12.69 of the title compound as a crystalline solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[Cl:22])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[N:10]=[CH:11][N:12]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[Cl:22])[CH:14]=1)[C:4]#[C:5][CH3:6]
Reactant: Clc1cc(OC2CCCCC2Cl)ncn1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OC2CCCCC2Cl)ncn1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
In 1.2 ml of tetrahydrofuran was suspended 0.03 g of sodium hydride (60% in oil), to which 0.4 ml of a tetrahydrofuran solution containing 0.05 g of 2-butyn-1-ol was slowly added dropwise under stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, and 0.4 ml of a tetrahydrofuran solution containing 0.16 g of 4-chloro-6-(2-chlorocyclohexyloxy)pyrimidine was slowly added dropwise, followed by stirring at 0° C. for 3 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.15 g of 6-(2-butynyloxy)-4-(2-chlorocyclohexyloxy)pyrimidine (the present compound (166)).
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[O:9])=[C:6]([I:16])[C:5]([C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[O:18])=[C:4]([I:25])[C:3]=1[NH:26][C:27]([NH:29][C:30]1[C:35]([I:36])=[C:34]([C:37]([NH:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43])=[O:38])[C:33]([I:45])=[C:32]([C:46]([NH:48][CH2:49][CH:50]([OH:53])[CH2:51][OH:52])=[O:47])[C:31]=1[I:54])=[O:28].[OH-].[Na+].Br[CH2:58][CH2:59][OH:60]>O>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[O:9])=[C:6]([I:16])[C:5]([C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[O:18])=[C:4]([I:25])[C:3]=1[N:26]([CH2:58][CH2:59][OH:60])[C:27]([NH:29][C:30]1[C:35]([I:36])=[C:34]([C:37]([NH:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43])=[O:38])[C:33]([I:45])=[C:32]([C:46]([NH:48][CH2:49][CH:50]([OH:53])[CH2:51][OH:52])=[O:47])[C:31]=1[I:54])=[O:28]
Reactant: OCCBr
Reactant: O=C(Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCC(O)CO)c1c(I)c(NC(=O)N(CCO)c2c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c2I)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 60 h

Procedure:
N,N'-bis[2,4,6-triiodo-3,5-bis(2,3-dihydroxypropylaminocarbonyl)phenyl]-urea (2.0 g, 1.4 mmol) was dissolved in water (13 ml) containing 2 M NaOH (7 ml). 2-Bromoethanol (1 g, 8.4 mmol) was added and the mixture was stirred at ambient temperature for 60 h, treated with a strongly acidic ion exchange resin (Amberlyst 15) evaporated and purified by preparative HPLC. Yield: 1.45 g (70%) of the product as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3Br)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].[OH-:30].[K+]>O.O1CCOCC1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[CH:1]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[OH:30])[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3ccncc3Br)c3ccc(C#N)cc23)C1
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3ccncc3O)c3ccc(C#N)cc23)C1
Temperature: 100 °C
Yield: 101.7 %

Procedure:
A mixture of (S)-4-((3-bromopyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamic acid isopropyl ester (3.81 g, 7.05 mmol), potassium hydroxide (1.34 g, 23.9 mmol), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (230 mg, 479 μmol), tris(dibenzylideneacetone)dipalladium (110 mg, 120 μmol) in water (50 mL) and 1,4-dioxane (50 mL) is heated at 100° C. for one hour. Tris(dibenzylideneacetone)dipalladium (110 mg, 120 μmol) and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (230 mg, 479 μmol) are added and the mixture is heated for 3 h. The reaction is diluted with water and dichloromethane. The layers are then separated and the aqueous layer is washed with dichloromethane twice. The aqueous portion is acidified to pH 1-2 with a few drops of 5 M HCl and then neutralized to pH 7 with potassium carbonate. Ethyl acetate is added and the bi-layer is filtered. The organic phase is separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a brown residue. The residue is triturated with ether twice and dried under vacuum. It is then purified by flash chromatography eluting with 1% to 6% methanol in chloroform to obtain impure product (˜2.8 g). It is purified by preparative super critical fluid chromatography (column: ethylpyridine 20×150 mm (Princeton Chromatography, Inc.); flow rate: 70 mL/min @ 35° C. and 100 psi; eluent: 5-50% MeOH with 0.1% isopropylamine:carbon dioxide) to obtain the title compound as a white solid (548 mg, 20%). LC-ES/MS m/z 391.2 [M+H]+, TR=2.63 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23]CC1C=CC=CN=1)=[O:22].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>>[CH3:41][O:40][C:38](=[O:39])[CH2:37][O:19][C:12]1[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[C:16]2[C:11]=1[CH2:10][CH2:9][N:8]([CH:20]([CH2:6][C:7]1[CH:16]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:21](=[O:22])[NH2:23])[CH:7]2[CH2:6][C:5]1[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: COC(=O)CBr
Product: COC(=O)COc1ccc(OC)c2c1CCN(C(Cc1ccccn1)C(N)=O)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with methyl bromoacetate
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:35](=[O:37])[CH3:36])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1c(OC)cc(OC)cc1OC
Product: CCCCCC(CC(=O)Nc1cc(CNC(C)=O)ccc1C(C)(C)C)c1c(OC)cc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 144, but using N-(2-t-butyl-5-aminomethylphenyl)-3-(2,4,6-trimethoxyphenyl)octanamide (prepared as described in Preparation 72C) and acetic anhydride, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65](=[O:73])[NH:66][S:67]([CH:70]([CH3:72])[CH3:71])(=[O:69])=[O:68])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:52][CH2:51]5)[N:48]=[C:47]([CH:53]([CH3:55])[CH3:54])[C:46]=4[C:56](O)=[O:57])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl.Cl.[CH3:76][N:77]1[CH2:83][CH:82]2[NH:84][CH:79]([CH2:80][CH2:81]2)[CH2:78]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65]([NH:66][S:67]([CH:70]([CH3:72])[CH3:71])(=[O:68])=[O:69])=[O:73])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:51][CH2:52]5)[N:48]=[C:47]([CH:53]([CH3:55])[CH3:54])[C:46]=4[C:56]([N:84]4[CH:82]5[CH2:81][CH2:80][CH:79]4[CH2:78][N:77]([CH3:76])[CH2:83]5)=[O:57])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COc1ccc2c(c1)C=C(c1c(C(=O)O)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reactant: CN1CC2CCC(C1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(c1c(C(=O)N3C4CCC3CN(C)C4)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reaction time: 2 h
Yield: 36 %

Procedure:
HATU (65.0 mg, 0.171 mmol) was added to a stirring solution of 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1-cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxylic acid (78 mg, 0.114 mmol), 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (45 mg, 0.23 mmol), DIEA (80 μL, 0.456 mmol) in DMF (1 mL) at room temperature. The reaction was allowed to stir for 2 hours. The reaction was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (37 mg, 0.041 mmol, 36% yield) consistent by LCMS and NMR, with sufficient purity by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:29])[CH2:18][CH2:17][N:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:16]1[CH2:15][CH2:14][C:13]([F:29])([F:12])[CH2:18][CH2:17]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: Cc1ncc(C(CN)N2CCC(F)(F)CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2ccc(Cl)cc2Cl)N2CCC(F)(F)CC2)cn1

Procedure:
From 2,4-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:23]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]1=[O:34].O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH:23]3[CH2:27][CH2:26][N:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:24]3=[O:34])[CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1C(Br)CCN1c1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCN(c3ccccc3)C2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A solution of 60.1 mg (0.23 mmol) of the compound from example 1g in 1 ml of absolute DMF was mixed with 11 mg (0.23 mmol) of sodium hydride (50%) and stirred at RT for 1 h. Then 55.5 mg (0.23 mmol) of (+/−)-3-bromo-1-phenyl-2-pyrrolidinone were added, and the mixture was stirred at RT for 45 min. The reaction solution was mixed with 1 ml of water and extracted several times with EA. The combined EA extracts were dried over Na2SO4, filtered and concentrated. Purification of the resulting residue by chromatography on silica gel with CH2Cl2/methanol (92:8 to 85:15 in 35 min) as mobile phase afforded 52.2 mg of the title compound.
Reaction SMILES: C(OC(=O)[NH:6][C@@H:7]([C:17]1[S:18][C:19]([CH2:22][NH:23][C:24](=[O:44])[C@H:25]([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:26][C:27]([O:29][CH3:30])=[O:28])=[CH:20][CH:21]=1)[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])C=C.C1([SiH3])C=CC=CC=1.C(OCC)(=O)C.O>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:6][C@@H:7]([C:17]1[S:18][C:19]([CH2:22][NH:23][C:24](=[O:44])[C@H:25]([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:26][C:27]([O:29][CH3:30])=[O:28])=[CH:20][CH:21]=1)[CH2:8][O:9][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11]
Reactant: C=CCOC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(CNC(=O)[C@@H](NC(=O)OC)C(c2ccccc2)c2ccccc2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)NCc1ccc([C@H](N)CO[Si](C)(C)C(C)(C)C)s1)C(c1ccccc1)c1ccccc1

Procedure:
A solution of prop-2-en-1-yl{(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-[5-({[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}methyl)thiophen-2-yl]ethyl}carbamate (1.2 g, 1.841 mmol) in dichloromethane (18.4 mL) was treated with phenylsilane (6.3 mL, 5.52 mmol) and Pd(PPh3)4 (106 mg, 0.092 mmol) for 1 hour at room temperature. Ethyl acetate and water were added and the phases were separated. The organic phase was washed with brine, dried, and then concentrated under reduced pressure. The concentrate was purified on silica gel using 5%-65% ethyl acetate in hexane to afford the title compound. 1H NMR (CD3OD) δ 7.40-7.15 (11H, 6.79 (1H), 6.40 (1H), 4.98 (1H), 4.38 (1H), 4.21 (2H), 3.82 (1H), 3.70 (1H), 3.52 (3H), 0.91 (9H), 0.10 (6H).
Reaction SMILES: Cl[CH2:2][C@@:3]([OH:18])([CH3:17])[CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].C(N(CC)CC)C.[CH3:26][OH:27]>>[CH3:26][O:27][C:7](=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:14]([N:6]1[CH2:2][C@@:3]([OH:18])([CH3:17])[CH2:4][O:5]1)=[O:15]
Reactant: C[C@](O)(CCl)CON1C(=O)c2ccccc2C1=O
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C(=O)N1C[C@](C)(O)CO1

Procedure:
A solution of 2-[[(2R)-3-Chloro-2-hydroxy-2-methylpropyl]oxy]-1H-isoindole-1,3 (2H)-dione (3.3 g, 12.2 mmol) in methanol (25 ml) was treated with triethylamine (3.4 ml) and heated under nitrogen at reflux for 1 h. The mixture was concentrated to dryness and purified by chromatography eluting with a gradient from dichloromethane to 5% methanol in dichloromethane. The chiral purity of the product was enhanced by recrystallising twice from acetonitrile to give the sub-title compound as a colourless solid (1.92 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:21]2[NH:25][N:24]=NN=2)[CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[C:4]([C:21]2[O:28][C:26]([CH3:27])=[N:24][N:25]=2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnn[nH]4)cc(Br)cc32)cc1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(C)o4)cc(Br)cc32)cc1
Temperature: 130 °C
Yield: 28.1 %

Procedure:
A stirred mixture of 6-Bromo-1-[(4-methylphenyl)sulphonyl]-4-(1H-tetrazol-5-yl)-1H-indazole (300 mg, 0.615 mmol) and acetyl chloride (0.722 ml, 10.15 mmol) in toluene (10 ml) were heated under microwave irradiation at 130° C. for 20 mins. The reaction mixture was heated for a further 20 mins at 130° C. then evaporated to dryness. The resultant yellow solid was treated with methanol (10 ml), to give a beige solid and supernatant. The supernatant was pipetted off, the process repeated twice and the resultant solid dried under vacuum to give the title compound as a beige solid (75 mg).
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH:5](C(OC)=O)[CH2:4]1)#[N:2].O>CS(C)=O>[C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2cccc(F)c2)CCC1=O
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2cccc(F)c2)CCC(=O)CC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
A mixture of 1-cyano-1-(3-fluorophenyl)-3-methoxycarbonylcyclohexan-4-one (57, 51 g, 185 mmol), water (54.8 mL) and DMSO (840 mL) was heated and stirred at 150° C. for 3 hours, followed by stirring at room temperature overnight. The reaction mixture was evaporated and purified by chromatography on silica gel. Elution with ethyl acetate/heptane (5%:95% to 30%:70%) gave 28 g of desired material as a solid product. Rt=3.89 min (Method 3). Detected mass: 218.2 (M+H+).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:12]=[CH:11][C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=1>C(=S)=S>[Br:1][C:9]1[O:10][C:6]2[CH:5]=[C:4]([CH3:3])[CH:12]=[CH:11][C:7]=2[CH:8]=1
Reactant: Cc1ccc2ccoc2c1
Reactant: BrBr
Solvent: S=C=S
Product: Cc1ccc2cc(Br)oc2c1
Temperature: 150 °C
Yield: 98.8 %

Procedure:
A solution of bromine (8.4 g, 0.0525 mol) in carbon disulphide (75 cm3) was added dropwise to a stirred solution of 6-methylbenzofuran (7.64 g, 0.0516 mol) in carbon disulphide (125 cm3) at below 10° C. The solvent was removed and the residue was heated at 150° C. for 1.5 hr. under reduced pressure. The residue was subjected to column chromatography on silica using petroleum ether (b.p. 60°-80° C.) as the eluant. The solvent was removed from the appropriate fractions to give 2-bromo-6-methylbenzofuran (11.0 g, 0.051 mol; 98.2%) RF 0.80.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]1([CH3:9])[CH3:8].N1C=CC=CC=1.CO[C@](C1C=CC=CC=1)(C(F)(F)F)C(Cl)=O>ClC(Cl)C>[CH3:8][C:3]1([CH3:9])[C:2](=[O:1])[CH2:6][CH2:5][C:4]1=[O:7]
Reactant: CC1(C)C(=O)CC[C@@H]1O
Agent: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CC1(C)C(=O)CCC1=O
Reaction time: 8 h

Procedure:
The enantiomeric excess of 3 was assayed by 1H NMR of the corresponding Mosher's ester which was prepared by treatment of alcohol 3 (11 mg, 0.09 mmol) in dichloroethane (0.3 mL, Aldrich) with pyridine (27 μL, 0.33 mmol, Aldrich) and (R)-α-methoxy-α-trifluoromethyphenylacetic acid chloride (58 μL, 0.31 mmol, Fluka). The mixture was stirred overnight and then partitioned between water (10 mL) and ether (10 mL). The ether layer was washed with 1 M HCl (10 mL) and saturated NaHCO3 solution and then was dried (MgSO4), filtered and evaporated. 1H NMR analysis was done on the crude ester.