Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:22]4[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:24](N(CC)CC)C.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>ClCCl.[OH-].[Na+]>[O:23]=[C:15]1[CH2:16][C@@H:17]2[C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18]2)[N:14]1[CH:11]1[CH2:12][CH2:13][N:8]([C:2]2([CH3:1])[CH2:3][CH2:4][N:5]([C:32]([O:34][C:35]([CH3:37])([CH3:24])[CH3:36])=[O:33])[CH2:6][CH2:7]2)[CH2:9][CH2:10]1
Reactant: CCN(CC)CC
Reactant: CC1(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CCNCC1
Reactant: CC(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CC1
Reaction time: 2 h
Yield: 48.4 %

Procedure:
A solution of (3aR,7aS)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-indol-2-one (100 mg, 0.31 mmol) and triethylamine (0.044 mL, 0.31 mmol) in dichloromethane (5 mL) was added with isopropyl chloroformate (0.313 mL, 1M solution in toluene, 0.31 mmol) dropwise at 0° C. and stirred for 2 hours. Diluted with dichloromethane (60 mL) and 1 N NaOH (10 mL) was added. The phases were separated and aqueous phase was extracted with dichloromethane (2×15 mL). The combined organic phases were washed with brine, concentrated in vacuo and the residue was purified by preparative LC/MS (high pH) to provide the title compound (63 mg, 49.6%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.85 (s, 3H), 1.19 (d, J=6.25 Hz, 6H), 1.21-1.43 (m, 6H), 1.48-1.87 (m, 10H), 1.87-2.00 (m, 1H), 2.04-2.18 (m, 2H), 2.28 (d, J=6.64 Hz, 1H), 2.32 (d, J=7.03 Hz, 1H), 2.88 (t, J=12.70 Hz, 2H), 2.97 (t, J=8.59 Hz, 1H), 3.20-3.35 (m, 2H), 3.39-3.58 (m, 2H), 3.90 (t, J=12.30 Hz, 1H), 4.76-4.93 (m, 1H). MS (M+1): 406.2.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[O:10][C:7]2=[N:8][CH:9]=1.C=O.[C:20]([O-])([O-])=O.[K+].[K+]>C(O)=O>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH3:20])[O:10][C:7]2=[N:8][CH:9]=1
Reactant: Clc1cnc2oc([C@@H]3CCCN3)cc2c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: O=CO
Product: CN1CCC[C@H]1c1cc2cc(Cl)cnc2o1

Procedure:
A 200 mg (0.80 mmol) sample of 5-chloro-2-(2-(S)-pyrrolidinyl)-furo[2,3-b]pyridine dihydrochloride, from Example 13c above, was dissolved in 4 mL of 88% formic acid and 8 mL of 37% aqueous formaldehyde and heated at reflux for 1 hour. The reaction mixture was cooled, poured into saturated K2CO3, and the mixture was extracted with CH2Cl2. The extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on silica gel, eluting with 100:0 to 95:5 CHCl3 :MeOH. The product was converted to the salt by treatment with HCl/ether to give 140 mg of title compound: 1H NMR (D2O, 300 MHz) δ 2.29-2.38 (m, 2H), 2.49-2.68 (m, 2H), 2.95 (br s, 3H), 3.44 (m, 1H), 3.84 (m, 1H), 4.84 (m, 1H), 7.22 (s, 1H), 8.22 (d, 1H, J=2.3 Hz), 8.36 (d, 1H, J=2.4); MS m/z: 237 (M+H)+, 254 (M+NH4)+ ; Anal. Calcd for C12H13N2OCl.1.0 HCl.0.3 H2O: C, 51.74; H, 5.28; N, 9.73. Found: C, 51.74; H, 5.28; N, 10.16.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[Cl:1][C:2]1[C:7]([CH:9]2[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1I
Reactant: OB(O)C1CC1
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1ncccc1C1CC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-chloro-3-iodopyridine (2.39 g, 9.98 mmol), cyclopropylboronic acid (860 mg, 10 mmol) and potassium carbonate (4.14 g, 30.0 mmol) in 1,4-dioxane (50 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.16 g, 1.00 mmol). The reaction mixture was stirred at 120° C. for 4 hours, then diluted with ethyl acetate (50 mL) and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (Gradient: 10% to 30% ethyl acetate in petroleum ether) to afford the product as a colorless oil. Yield: 1 g, 6 mmol, 60%. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J=4.7, 1.8 Hz, 1H), 7.24-7.28 (m, 1H), 7.14 (br dd, J=7.6, 4.8 Hz, 1H), 2.12-2.21 (m, 1H), 1.04-1.11 (m, 2H), 0.67-0.72 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:36]([NH:35][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:37])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]#[C:6][C:7]1([OH:20])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH3:2]>[Pd].O.C(O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1([OH:20])[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:11][CH2:12]1)[CH3:2]
Reactant: CCOC(=O)C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
Palladium on carbon (5%, 1 g) in water (10 ml) was added to a solution of 1,1-dimethylethyl 4-(3-ethoxy-3-oxo-1-propynyl)-4-hydroxy-1-piperidinecarboxylate (from step (i) above; 14.6 g, 0.046 mol) in ethanol (200 ml) and the mixture was shaken under hydrogen (45 psi) for 90 minutes. The mixture was filtered through a glass fibre pad and the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3](Cl)(=[O:6])[CH2:4][CH3:5].[OH2:8].S(=O)(=O)(O)O.C[CH2:15][O:16][CH2:17][CH3:18]>>[CH3:15][O:16][C:17]([CH:18]([C:3](=[O:6])[CH2:4][CH3:5])[C:3](=[O:6])[CH2:4][CH3:5])=[O:8]
Reactant: O
Reactant: CCC(=O)Cl
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Product: CCC(=O)C(C(=O)CC)C(=O)OC
Temperature: 5 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of 6.5 g (50 mmol) of methyl propionyl acetate in 100 mL of ether was treated with 1.19 g (50 mmol) of sodium hydride and the mixture was stirred for 2 hours. The mixture was then cooled to 5° C. and 6.93 g (6.51 mL. 75 mmol) of propionyl chloride was added dropwise over 5 minutes. The reaction mixture was stirred overnight at room temperature and then poured into cold water. This mixture was acidified with sulfuric acid and the product was extracted into ether, washed with water and dried. Evaporation gave the desired product, sufficiently pure for use in the following reaction, in 88% yield. 1H-NMR (CDCl3) δ 1.08 (6H, t, J=7), 2.58 (4H, q, J=7), 3.66 (1H, s), 3.74 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O-:14])=[O:13]>C(#N)C>[C:8]([C:7]1[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])(=[O:22])=[O:23])=[O:26])=[N:3][C:4]([CH3:11])=[CH:5][C:6]=1[CH3:10])#[N:9]
Reactant: Cc1cc(C)c(C#N)c(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: CC#N
Product: Cc1cc(C)c(C#N)c(NC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 0.5 g (3.4 mmol) 2-amino-4,6-dimethyl-3-pyridinecarbonitrile [Archiv. Pharm., 288, 174 (1955)] in 20 ml of acetonitrile was added 1.3 g (5.7 mmol) o-nitrobenzenesulfonyl isocyanate. The mixture was then heated to reflux (80°) for four hours followed by stirring at ambient temperature overnight. A crystalline product was collected, 0.5 g, m.p. 174°-176° dec. An infrared spectrum (nujol mull) exhibited absorptions at 1700, 1720 and 2240 cm-1 ; and a proton magnetic resonance spectrum (90 MHz NMR) exhibited absorptions at 2.5 (s, 3H), 2.6 (s, 3H), 7.05 (s, 1H), 7.7 (s br, NH), 7.8 (m, 3H), 8.4 (m, 1H), 9.7 (s br, NH) ppm indicating the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1.I[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:38]3[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=3)=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1
Reactant: Cn1ccc(I)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-iodo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 23 Step 9. LC-MS Method 2 tR=1.58 min, m/z=501, 479, 421.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([C:18]#[N:19])[C:5](=O)[N:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[C:15]#[N:16])[CH:7]=1.[OH2:21].[NH2:22][NH2:23].O1CCCC1>C(O)C>[NH2:19][C:18]1[C:4]2[C:5](=[O:21])[N:6]([C:8]3[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=3[C:15]#[N:16])[CH:7]=[C:2]([Br:1])[C:3]=2[NH:23][N:22]=1
Reactant: N#Cc1cccc(F)c1-n1cc(Br)c(Cl)c(C#N)c1=O
Reactant: NN
Reactant: O
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cccc(F)c1-n1cc(Br)c2[nH]nc(N)c2c1=O
Temperature: 90 °C

Procedure:
A solution of 5-bromo-4-chloro-1-(2-cyano-6-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step F (4.35 g) and hydrazine monohydrate (0.658 mL) in ethanol (32 mL)/tetrahydrofuran (64 mL) was heated at 90° C. for 1 hr. To the reaction mixture was added hydrazine monohydrate (0.5 mL), and the mixture was heated at 90° C. for 30 min. The solvent was evaporated under reduced pressure, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.12 g).
Reaction SMILES: [CH3:1][C@H:2]1[C@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15]([F:27])([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.[H][H]>CCOC(C)=O.C(O)C.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[F:27][C@@:15]12[C@:14]3([CH3:28])[C:8](=[CH:9][C:10](=[O:11])[CH2:12][CH2:13]3)[CH2:7][CH2:6][C@H:5]1[C@H:4]1[C@@:18]([CH3:25])([C@@:19]([OH:24])([C:20](=[O:21])[CH2:22][OH:23])[C@H:2]([CH3:1])[CH2:3]1)[CH2:17][C@@H:16]2[OH:26]
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Reactant: [H][H]
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Yield: 95.5 %

Procedure:
In a 1000 mL round-bottomed flask was suspended dexamethasone (10 g, 25.48 mmol) in EtOAc (400 mL) and ethanol (100 mL) and tris(triphenylphosphine)rhodium(I)chloride (Wilkinson's catalyst, 2.5 g, 2.70 mmol) was added together with a magnetic stirrer bar. The mixture was vigorously stirred in a hydrogen atmosphere (1 atm) at room temperature for 1 week and another 1.0 g of the catalyst was added. The reaction was allowed to proceed for another week and the resulting mixture was concentrated in vacuo to obtain a solid that was suspended in DCM (100 ml) and the suspension was filtered. The obtained solid was washed with 3 portions of DCM (50 ml) and dried on the sinter in air, yielding 9.6 g of the target compound as an off white solid. APCI-MS m/z: 395 [MH+].
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]#[CH:5].[ClH:7].[CH2:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:18]1[N:19]=[CH:20][CH:21]=[C:22]2[C:26]([CH3:27])=[C:25]([CH3:28])[NH:24][C:23]=12>O1CCCC1>[ClH:7].[CH:3]([N:24]1[C:23]2=[C:18]([N:9]3[CH2:10][CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:8]3)[N:19]=[CH:20][CH:21]=[C:22]2[C:26]([CH3:27])=[C:25]1[CH3:28])=[C:4]=[CH2:5]
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nccc2c1C
Reactant: C#CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C=Cn1c(C)c(C)c2ccnc(N3CCc4ccccc4C3)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 6.6 %

Procedure:
Sodium hydride (60%; 80 mg, 1.80 mmol) and propargyl bromide (35.6 μl, 1.40 mmol) were added at 0° C. to a solution of 7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine hydrochloride (92.3 mg, 0.33 mol) prepared in Example 468 in anhydrous tetrahydrofuran (10 ml). The reaction mixture was stirred for 12 hours at room temperature. Ice was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=1/1, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 32.5 mg of the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19]C1.[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:21]([CH:20]([CH3:22])[CH2:19][CH:10]1[CH2:9][CH:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:13][CH2:12][C:11]1=[O:14])#[N:17]
Reactant: C1CCNC1
Reactant: COc1ccc(CC2CCC(=O)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CC2CCC(=O)C(CC(C)C#N)C2)cc1

Procedure:
4-(4-Methoxybenzyl)cyclohexanone (10.25 g) was heated at reflux in toluene (500 ml) containing pyrrolidine (16 ml) and toluene-4-sulphonic acid (0.1 g). Water in the condensate was collected in a Dean and Stark apparatus. After 2 hours the solvent was removed by distillation until the reaction volume was approximately 100 ml. Ethanol (250 ml) and methacrylonitrile (20 ml) was added and the mixture heated at reflux for 16 hours, after which the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1M citric acid and saturated sodium carbonate solution. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give 2-(2-cyanopropyl)-4-(4-methoxybenzyl)cyclohexanone (10.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]([NH2:20])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18](=[S:30])[NH2:20]
Reactant: NC(=O)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC(=S)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
A mixture of 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid amide (1.8 g, 6.0 mmol), Lawesson's reagent (4.85 g, 12.0 mmol), toluene (150 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and the obtained reside was purified by column chromatography eluting with 20-50% (v/v) ethyl acetate in n-heptane to afford 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carbothioic acid amide (1.4 g, 4.5 mmol).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8](N2[C@@H](C(C)C)COC2=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:27]O.[OH-].[Li+]>O1CCCC1.O>[CH:1]1([CH2:6][C@H:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]([OH:9])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OO
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-4-(S)-isopropyl-oxazolidin-2-one (1.88 g, 4.72 mmol) in tetrahydrofuran (73 mL) and water (22 mL) cooled to 0° C. was treated with a 30% aqueous hydrogen peroxide solution (2.1 mL) and lithium hydroxide (394 mg, 9.4 mmol). The reaction was stirred at 0° C. for 1 h. At this time, the reaction was quenched with a saturated aqueous sodium sulfite solution (16 mL) followed by the addition of a 0.5N aqueous sodium bicarbonate solution (50 mL). The tetrahydrofuran was then removed in vacuo. The residue was diluted with water (40 mL) and extracted with methylene chloride (3×20 mL). The aqueous layer was then acidified to pH=2 with a 5N aqueous hydrochloric acid solution and extracted with ethyl acetate (4×25 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (928 mg, 70%) as a white solid: mp 75.1-78.3° C.; [α]23589=−50.3° (c=0.100, chloroform); EI-HRMS m/e calcd for C14H16Cl2O2 (M+) 286.0527, found 286.0535.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Cc1ccc(Br)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(C)nc2)CCN(C)C1
Temperature: 80 °C
Yield: 14.8 %

Procedure:
A mixture of 5-Ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (156 mg, 0.69 mmol), 5-bromo-2-methyl-pyridine (100 mg, 0.58 mmol), dichlorobistriphenylphosphine palladium (II) (12 mg, 0.017 mmol) and TBAF.3H2O (548 mg, 1.74 mmol) were added to a reaction vessel and the contents heated at 80° C. for 5 min in microwave. After completion of starting material (as monitored by TLC & LCMS), the reaction mixture was poured into water (25 mL) and the desired compound extracted with EtOAc (3×50 mL). The organic layer was dried over sodium sulfate, concentrated under vacuum and purified by reverse phase chromatography to obtain 27 mg of 2,8-dimethyl-5-(6-methyl-pyridin-3-ylethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and mg of 5-[1-fluoro-2,2-bis-(6-methyl-pyridin-3-yl)-vinyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm): 8.58 (s, 1H), 7.98 (s, 1H), 7.58 (d, 1H), 7.20 (d, 1H), 7.10 (d, 2H), 7.0 (d, 1H), 6.96 (d, 1H), 6.82 (d, 1H), 3.62 (m, 2H), 2.90-2.70 (m, 4H), 2.60 (s, 3H), 2.50 (s, 3H), 2.40 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.Cl.[NH2:27][C@@H:28]([C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[C:46]([Br:51])[CH:45]=1)[CH2:29][N:30]([CH3:43])[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:27][C@@H:28]([C:44]3[CH:49]=[C:48]([F:50])[CH:47]=[C:46]([Br:51])[CH:45]=3)[CH2:29][N:30]([CH3:43])[S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: Nc1ncc([C@H]2CC[C@H](O)[C@@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Reactant: CN(C[C@@H](N)c1cc(F)cc(Br)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(Br)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (300 g, 95% assay, 815.8 mmol) and (S)—N-(2-amino-2-(3-bromo-5-fluorophenyl)ethyl)-N-methyl-2-nitrobenzenesulfonamide hydrochloride (397.7 g, 848.5 mmol) in DMF (2.5 kg) was added DIPEA (421.8 g, 3263.4 mmol), followed by EDCl (312.8 g, 1631.7 mmol) and HOAt (222.1 g, 1631.7 mmol). After the reaction mixture was stirred at 25° C. for 18 hours, the reaction temperature was lowered to 10° C. before IPAC (3.5 kg) and water (4.0 kg) was added. The mixture was stirred for 10 minutes and then the layers were separated. The aqueous layer was extracted with IPAC (2.5 kg). The combined organic layers were washed successively with 10% aqueous Na2CO3 (4.5 kg) and water (2×4 kg), and then concentrated under vacuum (<100 mbar) at 40-45° C. to give 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(N-methyl-2-nitrophenylsulfonamido)ethyl)-2-fluorobenzamide as a foam (670 g, assay purity is 93%), which was used in next step without further purification. ESI-MS (m/z): 763.1216, 765.1161 ([M+H]+, 100). Mp=115-117° C. HPLC (method A), retention time=10.57 min. 1H NMR (400 MHz, CDCl3): 8.11 (t, J=8 Hz, 1H), 7.99 (m, 1H), 7.91 (s, 1H), 7.59-7.72 (m, 5H), 7.35 (s, 1H), 7.19 (d, J=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 5.46 (br. s, 1H), 4.77 (br. s, 2H), 4.48-4.55, 4.35-4.42 (m, 1H), 3.93 (q, J1=12 Hz, J1=16 Hz, 1H), 3.73-3.82 (m, 1H), 3.33 (q, J1=4 Hz, J1=12 Hz, 1H), 3.00 (s, 3H), 2.78-2.85 (m, 1H), 2.31-2.37 (m, 1H), 2.12-2.20 (m, 1H), 1.84-1.96 (m, 2H), 1.60-1.71 (m, 1H), 1.47-1.56 (m, 1H).