Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[C:12](#[N:16])[CH2:13][C:14]#[N:15].[BH4-].[Na+]>CC(O)C>[O:3]1[C:4]2([CH2:9][CH2:8][CH:7]([CH:13]([C:12]#[N:16])[C:14]#[N:15])[CH2:6][CH2:5]2)[O:11][CH2:1][CH2:2]1
Reactant: N#CCC#N
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: N#CC(C#N)C1CCC2(CC1)OCCO2
Reaction time: 2 h

Procedure:
The title compound was prepared by the method of Dunham et al. (Synthesis 2006 (4), 680). 1,4-Cyclohexanedione monoethylene ketal (3.15 g, 20.0 mmol) was dissolved in anhydrous 2-propanol (20 mL), treated with warm malononitrile (Aldrich, 0.70 mL, 11.1 mmol) via syringe, and the reaction was cooled in ice and treated with powdered sodium borohydride (Aldrich, 0.42 g, 11.1 mmol). After stirring for 2 h in ice, the reaction was quenched with water and acidified to pH 6 with 1N aqueous HCl, and the resulting suspension was extracted thrice with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a pale yellow oil, which was purified by flash column chromatography on silica gel (gradient elution, 30 to 80% EtOAc in hexanes) giving the title compound as a pale yellow crystalline solid.
Reaction SMILES: FC1C=C(CN)C=NC=1.[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[CH2:16][NH2:17].[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33]([NH:17][CH2:16][C:11]4[N:12]=[CH:13][CH:14]=[CH:15][N:10]=4)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:19][CH2:20]1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Reactant: NCc1ncccn1
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ncccn1
Yield: 58 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyrimidin-2-ylmethanamine to react with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 58% yield: mp 218-220° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.71 (d, J=4.9 Hz, 2H), 7.24-7.21 (m, 1H), 7.15-7.11 (m, 1H), 4.83 (d, J=4.4 Hz, 2H), 4.16-4.11 (m, 2H), 3.74-3.68 (m, 2H), 3.20 (d, J=7.1 Hz, 2H), 2.66 (s, 3H), 1.01-0.91 (m, 1H), 0.59-0.54 (m, 2H), 0.28-0.25 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.4, 162.5, 157.7, 157.1, 155.2, 152.7, 119.5, 117.6, 48.6, 45.5, 42.2, 42.1, 17.2, 8.9, 3.4; MS (ES+) m/z 373.3 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][C:13]([OH:15])=O)[C:2]1=2.C(OC(=O)C)(=[O:18])C>>[CH2:4]1[C:3]2=[CH:6][CH:7]=[CH:8][CH:9]=[CH:10][C:11]3=[C:2]2[N:1]([C:13](=[O:15])[CH2:12]3)[C:5]1=[O:18]
Reactant: O=C(O)CC1=CC=CC=Cc2cc[nH]c21
Reactant: CC(=O)OC(C)=O
Product: O=C1CC2=CC=CC=CC3=C2N1C(=O)C3
Temperature: 25 °C

Procedure:
A solution of ±1H-cycloocta[b]pyrrole-9-acetic acid, decahydro-2-oxo-, (3aα, 9β, 9aα)-; ±1H-cyloocta[b]pyrrole-9-acetic acid,decahydro-2-oxo, (3aα, 9α, 9aα)-; ±1H-cycloocta[b]pyrrole-9-acetic acid, decahydro-2-oxo-, (3aα, 9β, 9aβ) (2.8 g, 0.012 mol) in acetic anhydride is heated at reflux for 30 minutes and allowed to cool to room temperature overnight. The solution is concentrated at reduced pressure and the resulting solid is triturated with anhydrous diethyl ether. Sublimation (120° C., 0.1 mm) yields cycloocta[gh]pyrrolizine-2,4-(1H, 5H)-dione, octahydro-, (5aα, 10a α, 10bα)-; ±cycloocta[gh]pyrrolizine-2,4(1H,5H)-dione, octahydro-, (5aβ, 10aβ, 10bα)-; cycloocta[gh]pyrrolizine-2,4(1H,5H)dione,octahydro-, (5aα, 10aβ, 10bα)- with mp 121°-124° and 132°-134° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[Cl:17])=O.Cl.[C:19]([O-:22])(O)=O.[Na+]>C1COCC1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]([CH3:7])[CH:19]=[O:22])=[C:11]([Cl:17])[CH:12]=1
Reactant: O=C([O-])O
Reactant: CC(=O)c1ccc(Br)cc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (7.53 g) was added to a solution 2-chloro-4-bromoacetophenone (CAS Reg. No. 252561-81-2, 10.45 g) and (methoxymethyl)-triphenylphosphosium chloride (21.48 g) in THF (100 ml) at room temperature. The mixture was stirred for 1 h at room temperature. 25% aqueous HCl (90 ml) was added. The resulting mixture was stirred 1 h at room temperature and poured then carefully to a saturated aqueous NaHCO3 solution. After neutralization, the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:4) to give the title compound (8.1 g) as a yellow oil. MS (m/e, ISP neg. ion)=247.2 [M−H+].
Reaction SMILES: [CH:1]([Si:4]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:5][CH2:6][C:7]1[S:8][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:11]=1[CH3:12])([CH3:3])[CH3:2].Br[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH:1]([Si:4]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[O:5][CH2:6][C:7]1[S:8][C:9]([C:29]2[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=2)=[CH:10][C:11]=1[CH3:12])([CH3:2])[CH3:3]
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)sc1CO[Si](C(C)C)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)sc1CO[Si](C(C)C)(C(C)C)C(C)C

Procedure:
A mixture of triisopropyl{[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thien-2-yl]methoxy}silane (intermediate 116, 0.40 g) in 1,2-dimethoxyethane (12 ml) and water (6 ml) was treated with 4-bromo-trifluoromethoxybenzene (0.26 g), sodium carbonate (0.26 g) and tetrakis(triphenylphosphine)palladium (0) (0.120 g). The reaction mixture was stirred at reflux for 2 hours and then partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with further ethyl acetate and then the organic solutions combined and dried over magnesium sulfate. The crude product was purified by Si SPE using dichloromethane as eluent to give the title compound as a yellow gum.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][CH3:24])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][N:23]([CH3:24])[S:26]([CH3:25])(=[O:28])=[O:27])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CNC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
[(R)-6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methyl-amine hydrochloride (0.4 g, 1.13 mmol) was dissolved in 10 mL methylene chloride and 2.0 mL pyridine, and the mixture was cooled in an ice bath. Methanesulfonyl chloride (0.2 mL) was added dropwise, and the reaction mixture was stirred for 10 minutes at ice bath temperature, then allowed to warm to room temperature. The reaction mixture was quenched by addition of water, and was extracted with methylene chloride. The organic layer was washed with 1% aqueous HCl, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was eluted through silica gel at medium pressure with 1:1: EtOAc/hexanes to give 310 mg of N—[(R)-6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-N-methyl-methanesulfonamide, M+H=412.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:18]([CH3:20])[CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.O>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:18]([CH3:20])[CH3:19])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)c1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) solution of 1-iodo-3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (379 mg; 0.673 mmol) in anhydrous THF (6 ml) was treated dropwise with a 1.6N butyllithium solution in hexanes (1.05 ml; 1.680 mmol). The resulting mixture was additionally stirred at −78° C., under nitrogen, for 15 min. Water (0.2 ml) was then added and the reaction mixture was allowed to warm-up to rt. The resulting solution was diluted with ether (30 ml), the organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) gave the pure product 3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (229 mg; 78%). LC-MS: tR=0.92 min.; [M+H]+=438.43 g/mol.
Reaction SMILES: N[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8]2)[N:4]([CH2:21][C:22]#[C:23][CH3:24])[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26].N([O-])=O.[Na+].[PH2](O)=O.C(=O)([O-])[O-].[K+].[K+]>Cl.O>[C:17]([O:16][C:14]([NH:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([C:5]2[N:4]([CH2:21][C:22]#[C:23][CH3:24])[C:3]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:2][N:6]=2)[CH2:8]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc(N)c1C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: CC#CCn1c(C(=O)OCC)cnc1N1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3.00 g ethyl 5-amino-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-3-(but-2-ynyl)-3H-imidazole-4-carboxylate in 36 ml 2 M hydrochloric acid is cooled to 0° C. To this is added a solution of 0.60 g sodium nitrite in 2 ml of water and the reaction mixture is stirred for 1 h at 0° C. Then 8.4 ml hypophosphorous acid are added and the mixture is stirred for a further 14 h at 0° C. Then the reaction mixture is added to ice-cooled aqueous potassium carbonate solution and extracted with dichloromethane. The organic extracts are dried over sodium sulphate and evaporated down. The residue is dissolved in 8 ml dichloromethane, and 1.62 g di-tert-butyl carbonate are added. The solution is stirred for 2 h at ambient temperature, then evaporated to dryness and chromatographed on silica gel (cyclohexane/ethyl acetate 7:3->1:1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C@@H:8]([CH3:36])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:24]=[CH:25][C:26]5[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=5)[N:28]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:4][C:3]1=[O:37].C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C@@H:8]([CH3:36])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH2:24][CH2:25][C:26]5[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=5)[N:28]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:4][C:3]1=[O:37]
Reactant: C[C@@H](COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1)N1CCN(C)C(=O)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: C[C@@H](COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1)N1CCN(C)C(=O)C1
Temperature: 78 °C
Reaction time: 24 h
Yield: 43.3 %

Procedure:
Palladium (8.22 mg, 0.08 mmol) was added to (S)-1-methyl-4-[1-methyl-2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one (0.040 g, 0.08 mmol) and ammonium formate (0.146 g, 2.32 mmol) in ethanol (5 mL) at 20° C. The resulting suspension was stirred at 78° C. for 24 hours. The catalyst was filtered off through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give a yellow gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford (S)-1-methyl-4-[1-methyl-2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one (0.018 g, 44.8%), which was shown by chiral hplc to correspond to the first eluting isomer obtained in Example 55.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](/[Br:11])\[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([OH:14])=[O:13].[C:16]([C@@H:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)#[N:17]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](/[Br:11])\[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:14][C@H:18]([C:16]#[N:17])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:13]
Reactant: COC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, the product of Step B and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-bromo3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+9.5°±2.5° (c=0.3% in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[C:4]([O:6][CH:7]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH:17]=[CH:16]2)[C:8]([O:10]C)=[O:9])=[O:5].[Li+].[OH-].OO.OS([O-])(=O)=O.[K+]>C1COCC1>[Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[C:4]([O:6][CH:7]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH:17]=[CH:16]2)[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)OC(=O)c1c(Cl)cccc1Cl
Agent: O=S(=O)([O-])O
Agent: OO
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(OC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a solution of 1-{[2-(2,6-dichlorophenyl)-6-quinolinyl]methyl}-2-methoxy-2-oxoethyl 2,6-dichlorobenzoate 57 (0.113 g) in 10 ml THF are added, at 0° C., 1 ml of LiOH (1 M) and 0.5 ml of H2O2 (30%). The solution is then stirred at room temperature for 18 h. After addition of 10 ml KHSO4 (10%), the THF is evaporated. The aqueous phase is extracted with AcOEt (3×10 ml). The organic phases are washed with brine, dried over MgSO4 and evaporated under vacuum. The residue is triturated in pentane to give 2[(2,6-dichlorobenzoyl)oxy]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoic acid 93 as a white powder.
Reaction SMILES: COC(=O)[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](OC)=[O:13])Br.COC(=O)C(C1C=CC(Cl)=CC=1C(OC)=O)Br.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([OH:43])=[C:39]([CH:42]=1)[C:40]#[N:41].OC1C=CC=CC=1C#N>>[OH:13][C:12]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2[O:43][C:38]3[CH:37]=[CH:36][C:35]([Cl:34])=[CH:42][C:39]=3[C:40]=2[N:41]=1
Reactant: N#Cc1cc(Cl)ccc1O
Reactant: COC(=O)c1ccccc1C(Br)C(=O)OC
Agent: COC(=O)c1cc(Cl)ccc1C(Br)C(=O)OC
Agent: N#Cc1ccccc1O
Product: Oc1nc2c3cc(Cl)ccc3oc2c2ccccc12

Procedure:
The procedure was similar to step S19B, while the starting material was 24A in stead of 19A, and used 5-chloro-2-hydroxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[F:34][CH2:35][CH2:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][CH:39]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:42][C:41]1[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][F:34])=[CH:46][CH:45]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(OCCF)cc1
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCF)cc3)c3c(F)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 2-(3) and 4-(2-fluoroethyloxy)benzoyl chloride were treated in a manner similar to Example 2-(4), (5), (6) and (7) to give the titled compound as a colorless powder. APCI-Mass m/Z 467 (M+NH4). 1H-NMR (DMSO-d6) δ 3.15-3.41 (m, 4H), 3.65 (m, 2H), 4.01 (s, 2H), 4.12 (m, 1H), 4.22 (dd, J=4.7, 3.2 Hz, 1H), 4.53 (t, J=5.5 Hz, 1H), 4.63 (m, 1H), 4.78 (m, 1H), 5.09 (d, J=5.3 Hz, 1H), 5.16 (d, J=5.0 Hz, 1H), 5.21 (d, J=5.9 Hz, 1H), 5.36 (d, J=9.1 Hz, 1H), 6.74 (dd, J=11.4, 7.8 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 7.06 (dt, J=8.1, 5.2 Hz, 1H), 7.18 (d, J=8.6 Hz, 2H), 7.20 (s, 1H), 7.35 (d, J=8.4 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.C1(C)C=CC=CC=1.Br[CH2:21][CH2:22][C:23]([O:25]C)=[O:24]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:7]2=[N:8][CH:9]=1
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: COC(=O)CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCn1ccc2cc(Cl)cnc21
Temperature: 100 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of NaOH (5.19 g, 129.8 mmol) in water (10 mL) was added tetrabutylammonium bromide (0.35 g, 1.08 mmol), 5-chloro-1H-pyrrolo[2,3-b]pyridine (1.5 g, 9.83 mmol), toluene (60 mL) and methyl 3-bromopropanoate (9.8 g, 59 mmol). The reaction mixture was heated overnight at 100° C. The reaction was quenched with water, the layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. 3-(5-chloro-/H-pyrrolo[2,3-b]pyridin-1-yl)propanoate solution in THF was treated with NaOH and stirred at RT for 5 hours. The reaction mixture was diluted with water and the pH was adjusted to 1 with 1N HCl to crash out the product. The reaction was then filtered, azeotroped with acetonitrile and dried to give 3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)propanoic acid. (1.97 g, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=2.3 Hz, 1H), 8.09 (d, J=2.3 Hz, 1H), 7.64 (d, J=3.5 Hz, 1H), 6.46 (d, J=3.5 Hz, 1H), 4.46 (t, J=7.0 Hz, 2H), 2.82 (t, J=7.0 Hz, 3H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=225.3; tR=1.20 min.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[C:21](=O)[CH2:20][O:19][CH:18]([C:23]3[N:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[S:26][CH:27]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].B#B>O1CCCC1>[OH:2][CH2:1][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:23]3[N:24]=[C:25]([C:28]([F:29])([F:31])[F:30])[S:26][CH:27]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1
Reactant: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OCC2=O)cc1
Agent: B#B
Solvent: C1CCOC1
Product: CC(Cc1ccc(OCCO)cc1)N1CCOC(c2csc(C(F)(F)F)n2)C1
Reaction time: 0.5 h

Procedure:
1 g (0.0022 Mol) of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-5-one (diastereomer A) is dissolved in 6 ml of absolute tetrahydrofuran. At room temperature 15 ml (0.015 Mol) of a one molar solution of diborane in tetrahydrofuran is added dropwise within 15-20 minutes. During this the solution heated up to about 35°-40° C. After 30 minutes the mixture is evaporated to dryness and the remaining residue is dissolved in 40 ml of methanol and 2 ml of concentrated hydrochloric acid, and the mixture is left to stand for 30 minutes. While cooling in ice, the mixture is made alkaline with ammonia and is extracted several times by shaking with methylene chloride. The organic phase is dried over sodium sulphate and the base is purified on a silica gel column using toluene/ethyl acetate=7.5:2.5 as eluant.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:28])[C@H:10]([NH2:27])[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:8][C@H:9]([CH3:28])[C@H:10]([NH:27][C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[NH:32][CH:33]=[N:34]2)[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@@H](OCc1ccccc1)[C@H](Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 96.1 %

Procedure:
A mixture of (1R,2R)-2-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine (100 mg, 0.27 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (65 mg, 0.27 mmol) and DIPEA (240 μL, 1.35 mmol) in n-butanol (1 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound (128 mg, 96%). LCMS (Method J): RT 3.19 min [M+H]+ 494.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1.[CH3:38][N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:38][N:39]1[CH:43]=[C:42]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=4)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]3=[N:6][CH:7]=2)[CH:41]=[N:40]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(Cl)cc23)c1)C(=O)NCC(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(-c4cnn(C)c4)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of N2-[5-(5-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-N-(2,2,2-trifluoroethyl)valinamide 2-1a (200 mg, 0.360 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CA) (90 mg, 0.432 mmol), X-PHOS (30.9 mg, 0.065 mmol), palladium(II) acetate (9.69 mg, 0.043 mmol) in DMF (2 mL) was added phosphate tribasic (153 mg, 0.719 mmol) and water (0.4 mL). The mixture was evacuated then N2 purged 3 times and heated at 100° C. for overnight. After cooling the reaction was filtered and filtrate was loaded directly onto HPLC Reverse phase (C-18), eluting with acetonitrile/water (0.1% TFA), to give product 8-1a as a colorless foam. MS APCI: [M+H]+ m/z=602.1.