Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cc(Br)cc(C2OCCO2)c1
Yield: 99.8 %

Procedure:
A suspension of 3,5-dibromo-benzaldehyde (20.0 g, 75.8 mmol, 1.0 equiv; [CAS RN 56990-02-4]), ethane-1,2-diol (12.7 mL, 14.1 g, 227.3 mmol, 3.0 equiv) and p-toluene sulfonic acid monohydrate (0.29 g, 1.52 mmol, 0.02 equiv) in toluene (50 mL) was heated to reflux under Dean-Stark conditions for 1 h. The reaction mixture was extracted with ethyl acetate (3×200 mL), the combined organic phases washed with a sat. solution of sodium carbonate (4×50 mL) and dried over MgSO4. Removal of the solvent by evaporation under reduced pressure yielded 23.3 g (100%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 4.00-4.12 (m, 4H), 5.76 (s, 1H), 7.55-7.56 (m, 2H), 7.65-7.66 (m, 1H). MS (EI): 306.8 [M]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C@H:6]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:20][NH:21][C:22]([CH:24]2[CH2:26][CH2:25]2)=[O:23])[C:11]1=[O:27])[C:7]([OH:9])=O)(=[O:3])[NH2:2].S(Cl)(Cl)=O.N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[O:9]=[C:7]1[C@@H:6]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:20][NH:21][C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:11]2=[O:27])[CH2:5][CH2:4][C:1](=[O:3])[NH:2]1
Reactant: NC(=O)CC[C@@H](C(=O)O)N1C(=O)c2cccc(CNC(=O)C3CC3)c2C1=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC[C@H](N2C(=O)c3cccc(CNC(=O)C4CC4)c3C2=O)C(=O)N1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A suspension of (2S)-4-carbamoyl-2-{4-[(cyclopropanecarbonyl-amino)-methyl]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-butyric acid (1.4 g, 3.8 mmol) in dry CH2Cl2 (87 mL) was cooled to −40° C. with IPA/dry ice bath. Thionyl chloride (0.5 g, 4.1 mmol) was added dropwise, followed by pyridine (0.3 g, 4.1 mmol). The mixture was stirred at −40° C. for 30 minutes. Triethylamine (0.4 g, 4.2 mmol) was added dropwise, and the mixture was stirred at −30 to −40° C. for 3 hours. The mixture was filtered into ice water (150 mL). The aqueous layer was extracted with CH2Cl2 (40 mL), and the combined CH2Cl2 solution was washed with H2O (2×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the solid was slurried with ethanol (20 mL) to give cyclopropanecarboxylic acid {2-((3S)-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (1.0 g, 74%) as a white solid: mp 219-221° C.; Chiral HPLC: Daicel ChiralPak AD, 46×250 mm, 70/30 IPA/hexane, 0.6 mL/min, 19.76 min (98.5% ee); 1H NMR (DMSO-d6) δ 0.69-0.72 (m, 4H), 1.61-1.71 (m, 1H), 2.04-2.08 (m, 1H), 2.50-2.63 (m, 2H), 2.83-2.97 (m, 1H), 4.74 (d, J=5.7 Hz, 2H, CH2), 5.11-5.18 (dd, J=5.2 and 12.4 Hz, 1H, CH), 7.67-7.88 (m, 3H, Ar), 8.69 (t, J=5.6 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 6.41, 13.50, 21.96, 30.91, 37.74, 48.84, 121.84, 127.08, 131.51, 133.31, 134.76, 139.39, 166.92, 167.44, 169.78, 172.72, 173.09; Anal. calcd. for C18H17N3O5: C, 60.84; H, 4.82; N, 11.82. Found: C, 60.49; H, 4.76; N, 11.51.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:13])=[N:8][CH2:7][CH2:6]2.[BH4-].[Na+].Cl.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH3:13])[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN=C2C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)CCNC2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82627.6 %

Procedure:
6-methoxy-1-methyl-3,4-dihydroisoquinoline (54.0 g, 0.31 mmol) was added to a suspension of sodium borohydride(5.8 g, 138 mmol) in ethanol. The mixture solution was stirred for 1 hour at a room temperature, cooled to below 5° C., acidified with diluted hydrochloric acid, adjusted to alkali with sodium hydroxide solution, and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 45.4 g of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=2)[CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>C(N(CC)CC)C>[CH2:18]([NH:20][C:21]([N:6]1[C:2]([CH3:1])=[CH:3][C:4]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=2)=[N:5]1)=[O:22])[CH3:19]
Reactant: Cc1cc(Oc2cc(C)c([N+](=O)[O-])cn2)n[nH]1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2cc(C)c([N+](=O)[O-])cn2)cc1C
Yield: 19.3 %

Procedure:
Reaction of 5-methyl-3-(4-methyl-5-nitropyridin-2-yloxy)pyrazole with ethyl isocyanate was carried out in the presence of triethylamine in the same manner as in Example 130, to give a yellow viscous substance of N-ethyl-5-methyl-3-(4-methyl-5-nitropyridin-2-yloxy)pyrazole-1-carboxamide (yield: 19.3%). 1H-NMR (CDCl3, TMS, ppm): δ 1.23 (t, J=7.3 Hz, 3H), 2.65 (d, J=0.7 Hz, 3H), 2.70 (s, 3H), 3.40 (dq, J=5.9 and 7.3 Hz, 2H), 6.03 (q, J=0.7 Hz, 1H), 6.95 (s, 1H), 6.99 (br s, 1H), 8.92 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:13]2=[CH:14][CH:15]=[N:16][CH:17]=[C:12]2[C:5]2[C:6]([OH:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[O:3]1.[ClH:19].[N:20]1([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:19].[CH3:1][C:2]1([CH3:18])[C:13]2=[CH:14][CH:15]=[N:16][CH:17]=[C:12]2[C:5]2[C:6]([O:11][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[O:3]1
Reactant: Cc1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: Cc1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-methyl-10-[4-(piperidino)-butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-methyl-5H-[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])=[C:4]([CH:14]2[O:19]CCCO2)[CH:3]=1.[Li]CCCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:2]([B:25]([OH:30])[OH:26])=[CH:3][C:4]=1[CH:14]=[O:19]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN(C)CCOc1ccc(Br)cc1C1OCCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(B(O)O)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of [2-(4-bromo-2-[1,3]dioxan-2-yl-phenoxy)-ethyl]-dimethyl-amine (15 mmol) in dry THF (100 mL) was cooled to −78° C. and added n-BuLi (16.5 mmol) dropwise. The reaction was left for 30 min at −78° C. and added triisopropyl borate (22.5 mmol). The reaction was heated to room temperature, was added 2M HCl (aq, 50 mL) and was left for an additional, hour. The mixture was added 1M Na2CO3 to neutral pH and was extracted with EtOAc. The organic phase was washed with water, dried (Na2SO4) and evaporated in vacuo. Addition of EtOAc afforded beige crystals that was filtered of and was used without further purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[C:7]([C:22]([F:25])([F:24])[F:23])[CH:6]=1)[NH2:4].[CH3:26][O:27][CH2:28][C:29]1[CH:34]=[C:33]([C:35](O)=O)[CH:32]=[CH:31][C:30]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH3:44].C(Cl)CCl>CC#N.N1C=CC=CC=1>[CH3:26][O:27][CH2:28][C:29]1[CH:34]=[C:33]([C:35]2[O:1][N:2]=[C:3]([C:5]3[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([OH:14])=[O:13])=[C:7]([C:22]([F:24])([F:23])[F:25])[CH:6]=3)[N:4]=2)[CH:32]=[CH:31][C:30]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH3:44]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1C(F)(F)F
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)O)c(C(F)(F)F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 74 (0.112 g, 0.31 mmol) and Intermediate 3 (0.067 mg, 0.26 mmol) in MeCN (2 mL) was added EDC (0.069 g, 0.36 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with pyridine (2 mL) and heated at 150° C. in the microwave for 30 minutes. The reaction was repeated and combined to work up. The solvent was removed in vacuo and the residue dissolved in DCM. The mixture was washed with water and the organic phase passed through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by SCX chromatography. The material was treated with a 4N solution of HCl in dioxane (4 mL) and the resulting mixture was stirred at 70° C. for 18 hours. The solvent was evaporated in vacuo and the residue purified by preparative HPLC, affording the title compound as an orange oil. 1H NMR (CDCl3, 400 MHz) δ 8.98 (1H, br s), 8.50 (1H, s), 8.43-8.34 (2H, m), 8.14 (2H, d, J=8.0 Hz), 7.34-7.21 (4H, m), 7.12 (1H, d, J=7.4 Hz), 4.26-4.18 (4H, m), 3.56 (2H, s), 3.32 (3H, s), 2.62 (3H, s), 2.07 (3H, s). LC/MS (Method A): 526 (M+H)+. HPLC (Method F) Rt 3.74 min (Purity: 99.4%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH3:9])[CH:8]=1.Br.C(O)(=O)C>>[O:10]([C:6]1[C:7]([CH3:9])=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(Oc2ccccc2)c(C)c1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(O)ccc1Oc1ccccc1

Procedure:
4-methoxy-o-cresol and bromobenzene yield 5-methoxy-2-phenoxytoluene of b.p. 102°-104° C./0.035 Torr and m.p. 39°-42° C. and reaction with hydrobromic acid/acetic acid yields p-phenoxy-m-cresol; m.p. 96°-99° C.;
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6](I)=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[CH3:1][NH:2][C:3]([C:5]1[C:6]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[Cl:26])=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: OB(O)c1ccccc1Cl
Reactant: CNC(=O)c1cnc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)cc1I
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: COCCOC
Product: CNC(=O)c1cnc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)cc1-c1ccccc1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
A mixture of 480 mg (1.01 mmol) 4-(tert-butyl-dimethyl-silanyloxy)-4′-iodo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid methylamide, 174 mg (1.11 mmol) 2-chlorophenylboronic acid, 6 ml dimethoxyethane and 1 ml of a 2 M aqueous solution of sodium carbonate was deoxygenated by three freeze-thaw cycles. After addition of 60 mg (0.052 mmol) tetrakis(triphenylphosphine)palladium(0) the reaction mixture was stirred at 90° C. for 3 h. Cooling to room temperature was followed by dilution with water and extraction with ethyl acetate. The organic extract was washed with saturated aqueous sodium carbonate and sodium chloride solutions, dried with sodium sulfate and concentrated. Column chromatography afforded 425 mg (91.5%) of the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=[CH:11]1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)(=O)C(Cl)=O.ClCCl>[Br:1][C:2]1[S:3][C:4]([C:7]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:10][CH:11]=2)=[O:9])=[CH:5][N:6]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(O)c1cnc(Br)s1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1cnc(Br)s1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.9 %

Procedure:
A suspension of 2-Bromo-thiazole-5-carboxylic acid (98, 0.5 g, 0.002 mol) in oxalyl chloride (3 mL) was stirred at room temperature until it turned into a clear solution. Solvent was removed and the residue was dried over vacuum. A light yellow solid was obtained and was dissolved in dichloromethane (10 mL) and slowly added to a solution of 1H-Pyrrolo[2,3-b]pyridine (1, 0.34 g, 0.0029 mol) in dichloromethane (30 mL) at −10° C. To the mixture was then added aluminum trichloride (2.6 g, 0.019 mol) in one portion with vigorous stirring. The reaction was held at −10° C. for 30 minutes, then allowed to warm to room temperature. The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with ice-water and acidified with hydrochloric acid (10%) to pH 4. The solution was then extracted with dichloromethane. The organic layer was collected, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (99, 12 mg, 2%). MS (ESI) [M−H+]=369.09.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[F:17])[C:12]#[N:13])[C:4]1=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][CH:26]=2)[CH:20]=1>>[C:12]([C:11]1[CH:14]=[CH:15][C:16]([F:17])=[C:9]([CH:10]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:28]2[S:29][C:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:26][CH:27]=2)(=[O:31])=[O:32])[C:4]1=[O:18])#[N:13]
Reactant: N#Cc1ccc(F)c(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2cccnc2)s1
Agent: Cl
Product: N#Cc1ccc(F)c(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4cccnc4)s3)C2=O)c1

Procedure:
The title compound is prepared from 3-(S)-[(3-amino-2-oxo-pyrrolidin-1-yl)-methyl]-4-fluoro-benzonitrile hydrochloride as described in EXAMPLE 17, Part G substituting 5-pyridin-3-yl-thiophene-2-sulfonyl chloride in place of 4,6-dichlorobenzo[b]thiophene-2-sulfonyl chloride. The crude product is triturated with Et2O to give the title compound as a white solid
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH:7]=O)[CH2:4][O:3]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:17]([NH:24][OH:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:9][C:2]1([CH3:1])[O:6][C@@H:5](/[CH:7]=[N+:24](\[O-:25])/[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](C=O)O1
Reactant: ONCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OC[C@H](/C=[N+](\[O-])Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 54.6 %

Procedure:
1.50 g (11.53 mmol) (R)-2,2-Dimethyl-1.3-dioxolane-4-carboxaldehyde (Fluorochem, Hadfield, UK) was dissolved in 60 ml of DCM and treated with 1.64 g (11.53 mmol) sodium sulfate. The reaction mixture was flushed with argon and treated with a solution of 1.42 g (11.53 mmol) N-benzyl-hydroxylamine (prepared from the commercially available hydrochloride salt) in 20 ml of CH2Cl2. The reaction mixture was stirred under argon at RT for 16.5 h and then filtered. Silicagel was added to the filtrate is and preabsorbed, before being purified by chromatography on silicagel (gradient: Heptane/EtOAc 0%-100% in 30 min). Fr. 20-80 were collected and evaporated to dryness and dried under vacuum overnight to give 1.48 g of a white solid (˜100% pure by HPLC, Rt=1.43); ESI-MS: 236.2 [M+H]+(LC-MS 1))
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([CH2:7][NH:8][S:9]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:11])=[O:10])=[O:6].[Cl:18][C:19]([Cl:25])([S:23]Cl)[CH:20]([Cl:22])[Cl:21]>O.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.ClCCl>[CH3:3][O:4][C:5]([CH2:7][N:8]([S:23][C:19]([Cl:25])([Cl:18])[CH:20]([Cl:22])[Cl:21])[S:9]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:10])=[O:11])=[O:6]
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Reactant: COC(=O)CNS(=O)(=O)C1CCCCC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CN(SC(Cl)(Cl)C(Cl)Cl)S(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
A 1.2 g (0.03 mol) sample of sodium hydroxide in 1.2 ml water was added dropwise to a solution of 6.5 g (0.03 mol) N-(methoxycarbonylmethyl)cyclohexanesulfonamide, 7.0 g (0.03 mol) 1,1,2,2-tetrachloroethylsulfenyl chloride, 0.5 g. triethylbenzylammonium chloride in 100 ml dichloromethane. The resulting reaction mixture was stirred at about 25° C. for 3 hours, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give an oil residue. The residue was chromatographed through silica gel. Elution with 10% ethyl ether/hexane gave 2.5 g of the product as an oil. Elemental analysis for C11H17Cl4NO4S2 showed: %Cl, calc. 32.7, found 32; %S, calc. 14.8, found 15.1. The product is tabulated in Table I as Compound No. 2.
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:6]1)=[O:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]2=[O:33])=[CH:23][C:22]=1[F:34]>>[F:34][C:22]1[CH:23]=[C:24]([N:27]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]2=[O:33])[CH:25]=[CH:26][C:21]=1[NH:20][C:3]([C@@H:5]1[CH2:6][C@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[C@@H:8]([OH:10])[CH2:9]1)=[O:4]
Reactant: Nc1ccc(-n2ccncc2=O)cc1F
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccncc3=O)cc2F)C[C@@H]1O)c1ccc(Cl)s1

Procedure:
In analogy to example 1C, (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentanecarboxylic acid methyl ester (example 1B) was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyrazin-2-one (prepared from 2-fluoro-4-iodoaniline by reaction with 1H-pyrazin-2-one, Cu(I)I, N,N′-dimethylethylenediamine and cesium carbonate in dioxane at 120° C.) to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentyl}-amide. Yellow solid. MS: 477.0 ([M+H]+)
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:19][C:20]1[O:21][C:22]([CH3:44])([CH3:43])[CH:23]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[S:24](=[O:27])(=[O:26])[N:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:45]([N:49]1[CH2:54][CH:53]=[C:52](OS(C(F)(F)F)(=O)=O)[CH2:51][CH2:50]1)([CH3:48])([CH3:47])[CH3:46].C(=O)([O-])[O-].[Cs+].[Cs+]>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].CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.C1C=CC([C]2[C](C3C=CC=CC=3)[C](C3C=CC=CC=3)[C](C3C=CC=CC=3)[C]2C2C=CC=CC=2)=CC=1.[Fe].O1CCOCC1.O>[Si:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:19][C:20]1[O:21][C:22]([CH3:44])([CH3:43])[CH:23]([C:28]2[CH:29]=[CH:30][C:31]([C:52]3[CH2:51][CH2:50][N:49]([C:45]([CH3:46])([CH3:47])[CH3:48])[CH2:54][CH:53]=3)=[CH:32][CH:33]=2)[S:24](=[O:27])(=[O:26])[N:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2F)=NS(=O)(=O)C1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Fe]
Agent: [Pd]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2F)=NS(=O)(=O)C1c1ccc(C2=CCN(C(C)(C)C)CC2)cc1
Temperature: 62 °C
Reaction time: 0.67 h
Yield: 67.8 %

Procedure:
To a solution of [(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propyl]-{6,6-dimethyl-4,4-dioxo-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-2-yl}amine (300 mg), trifluoromethanesulfonic acid 1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl ester (208 mg) and cesium carbonate (519 mg) in 3:1 dioxane/water (4 ml) were added Pd(dba)2 (31 mg) and CTC-Q-Phos (75 mg), and the mixture was stirred at 62° C. for 40 min. After dilution with ethyl acetate, the mixture was washed with water, dried using a kieselguhr cartridge and concentrated. This was followed by purification by column chromatography (ethyl acetate/heptane). This gave the product (207 mg) with a molecular weight of 658.0 g/mol (C35H52FN3O4SSi).
Reaction SMILES: Br[C:2]1[C:3]2[N:19]=[CH:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[C:4]=2[C:5]([NH:10][C@@H:11]([CH:13]2[CH2:16][CH2:15][CH2:14]2)[CH3:12])=[N:6][C:7]=1[C:8]#[N:9].[CH3:31]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)(Cl)Cl.O>[CH:13]1([C@H:11]([NH:10][C:5]2[C:4]3[N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=4)[CH:18]=[N:19][C:3]=3[C:2]([CH3:31])=[C:7]([C:8]#[N:9])[N:6]=2)[CH3:12])[CH2:16][CH2:15][CH2:14]1
Reactant: CB(O)O
Reactant: C[C@@H](Nc1nc(C#N)c(Br)c2ncn(Cc3ccc(C(F)(F)F)cc3)c12)C1CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1c(C#N)nc(N[C@H](C)C2CCC2)c2c1ncn2Cc1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
To a vial containing (R)-7-bromo-4-((1-cyclobutylethyl)amino)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (65 mg, 0.14 mmol), methylboronic acid (16.3 mg, 0.3 mmol), 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride-chloroform adduct (11.1 mg, 0.014 mmol) and potassium phosphate (87 mg, 0.41 mmol) was added 1,4-dioxane (800 ul) and water (200 uL). The vial was evacuated and refilled with Ar (3×). The solution was heated to 120° C. for 10 minutes under microwave irradiation. The mixture was cooled to room temperature and quenched with saturated sodium bicarbonate and ethyl acetate. The organic layer was collected and concentrated. The residue was dissolved in DCM and purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to give (R)-4-((1-cyclobutylethyl)amino)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C22H22F3N5 [M+H]+ 414. found 414.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.CON(C)[C:23]([CH:25]1[CH2:29][CH2:28][O:27][CH2:26]1)=[O:24]>C1COCC1>[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:23]([CH:25]1[CH2:29][CH2:28][O:27][CH2:26]1)=[O:24]
Reactant: Fc1cccnc1
Reactant: CON(C)C(=O)C1CCOC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(c1ccncc1F)C1CCOC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.3 %

Procedure:
Diisopropylamine (605 μL, 4.30 mmol) was dissolved in THF (8 mL) and cooled to −78° C. nBuLi (1.72 mL, 2.5 M in hexanes, 4.30 mmol) was added and the resulting solution was stirred for 10 min, warmed to room temperature for 30 min and re-cooled to −78° C. 3-Fluoro-pyridine (370 μL, 4.30 mmol) was added drop-wise and the reaction mixture was stirred for 2 h. A solution of N-methoxy-N-methyloxolane-3-carboxamide (685 mg, 4.30 mmol) in THF (4.2 mL) was added drop-wise and the reaction mixture was warmed to room temperature and stirred for 15 min. The reaction mixture was quenched with sat aq NH4OAc (5 mL), diluted with EtOAc (50 mL), washed with water (2×25 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the title compound as a yellow gum (61.0 mg, 10%). LCMS (ES+): 196.0 (M+H)+.