Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.[OH2:17].C([O-])([O-])=[O:19].[Na+].[Na+]>CS(C)=O>[C:1]1([C:7](=[O:19])[C:8]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(#Cc1ccncc1)c1ccccc1
Reactant: O
Reactant: O=C([O-])[O-]
Agent: II
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(C(=O)c1ccncc1)c1ccccc1
Yield: 30 %

Procedure:
A solution of 4-(phenylethynyl)pyridine (2.25 g, 12.6 mmol) and powder iodine (1.60 g, 6.3 mmol) in DMSO (30 mL) is heated at 155° C. for 4 h. The reaction mixture is cooled and poured to H2O (100 mL). The aqueous is neutralized with powdered Na2CO3 to pH˜12 and extracted with EtOAc (2×100 mL). The combined organic extracts are washed sequentially with H2O (60 mL) and brine (60 mL), then dried and concentrated. The crude material is purified by chromatography (silica gel: EtOAc/hexane: 20/80) to afford the title compound (0.81 g, 30%) as an oil. MS (+) ES: 212 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>CN(C)C=O>[CH2:1]([N:8]1[C:18]2[C:13](=[C:14]([O:19][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2c(O)cccc2N1Cc1ccccc1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2c(OCCCN3CCN(c4ccccc4)CC3)cccc2N1Cc1ccccc1
Yield: 46.7 %

Procedure:
2.5 grams of 1-benzyl-5-hydroxy-3,4-dihydrocarbostyril and 0.48 g of 50% oily NaH are mixed with 30 ml of dimethyl formamide and stirred, then 4 g of 1-chloro-3-(4-phenylpiperazinyl)propane are added therein and warmed to 50°-60° C. for 2.5 hours. The reaction mixture is concentrated under a reduced pressure and the residue thus obtained is extracted with chloroform. After removing the chloroform by distillation, the thus obtained residue is recrystallized from ligroin to obtain 2.1 g of 1-benzyl-5-[3-(4-phenylpiperazinyl)-propoxy]-3,4-dihydrocarbostyril in the form of pale yellowish needle-like crystals with a melting point of 113° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[N:25]=[C:24]3[C:20]([NH:21][C:22](=[O:34])[N:23]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[C:19]([C:35]([NH2:37])=[O:36])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[Si](OCC1C=C(NC2N=C3C(NC(=O)N3C3C=CC=CC=3OC)=C(C(OCC)=O)N=2)C=CC=1)(C(C)(C)C)(C)C>CO.N>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[N:25]=[C:24]3[C:20]([NH:21][C:22](=[O:34])[N:23]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[C:19]([C:35]([NH2:37])=[O:36])[N:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3cccc(CO[Si](C)(C)C(C)(C)C)c3)nc21
Agent: CCOC(=O)c1nc(Nc2cccc(CO[Si](C)(C)C(C)(C)C)c2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Agent: N
Solvent: CO
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3cccc(CO)c3)nc21
Reaction time: 16 h
Yield: 91 %

Procedure:
2-(3-((tert-Butyldimethylsilyloxy)methyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide. Ethyl 2-(3-((tert-butyldimethylsilyloxy)methyl)phenyl-amino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. (0.180 g, 3.97 mmol) was dissolved in methanol (10 mL), saturated with ammonia gas, and reacted according to General Procedure G. After 16 h, the solution was condensed under reduced pressure to afford the title compound (0.153 g, 91%). MS (ESI) m/z 521.6. [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([NH:15][NH:16][C:17]([C@@H:19]1[CH2:25][CH2:24][C@@H:23]2[CH2:26][N:20]1[C:21](=[O:35])[N:22]2[O:27]CC1C=CC=CC=1)=[O:18])=[O:14])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([NH:15][NH:16][C:17]([C@@H:19]1[CH2:25][CH2:24][C@@H:23]2[CH2:26][N:20]1[C:21](=[O:35])[N:22]2[OH:27])=[O:18])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a solution of compound 286 (0.22 g, 0.44 mmol) in 10 mL of CH3OH was added 0.1 g of Pd—C (10%, wet). The mixture was hydrogenated at room temperature for 16 h. The catalyst was removed by filtration through a pad of celite. The filtrate was concentrated to afford compound 287 as a solid (0.15 g, 83%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([O:33][CH3:34])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:34][O:33][C:26]1[CH:25]=[C:24]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=2)[CH:29]=[CH:28][C:27]=1[N+:30]([O-:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 130 °C

Procedure:
Into a 5 mL microwave tube was charged tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.247 g, 0.800 mmol), 4-chloro-2-methoxy-1-nitrobenzene (0.100 g, 0.533 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.019 g, 0.027 mmol), sodium carbonate (0.113 g, 1.066 mmol) in water (0.889 ml) and dimethoxyethane (2.3 ml). The reaction mixture was heated at 130° C. for 20 minutes in a Biotage microwave reactor. The solids were filtered off and the filtrate was purified by reverse phase HPLC using 0.1% ammonium hydroxide. MS (DCI(+)) m/e 335.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:13][C:14](N)=[O:15].[OH-].[Na+].Cl>O>[Cl:12][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[Cl:11])[NH:1][C:14](=[O:15])[NH:13][C:4]2=[O:5]
Reactant: NC(N)=O
Reactant: Nc1cc(Cl)c(Cl)cc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(=O)c2cc(Cl)c(Cl)cc2[nH]1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
2-Amino-4,5-dichlorobenzoic acid (920 mg) and urea (2.75 g) were stirred at 160° C. After 6 hours the mixture was cooled to 100° C. and an equivalent volume of water was added while stirring was continued for 5 minutes. The formed precipitate was filtered off and washed with water to yield a solid cake that was suspended in a solution of 0.5 N NaOH in water. The suspension was heated to boil for 5 minutes and then cooled to r.t. The pH was adjusted to about 2 with HCl and the quinazoline-dione was filtered off. After washing with a mixture of water and methanol the product was dried in vacuo to yield 994 mg (94%) of a solid. 1H-NMR (DMSO-δ6) δ (ppm) 7.89 (s, 1H), 7.33 (s, 1H).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[CH2:7][C:8]1[C:16]2[S:15][N:14]=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>CS(C)=O>[C:1]([S:3][CH2:7][C:8]1[C:16]2[S:15][N:14]=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: ClCc1cccc2nnsc12
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)SCc1cccc2nnsc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 2.2 g of potassium thioacetate in 20 ml of absolute dimethyl sulfoxide, stirred at 20° C., is treated dropwise with stirring with a solution of 2.8 g of 7-chloromethylbenzo-1,2,3-thiadiazole in 10 ml of dimethyl sulfoxide, during which process the internal temperature rises to 37° C. The mixture is subsequently stirred overnight at room temperature and, on the following day, poured into ice-water and extracted using ethyl acetate. The extracts are washed five times with water, dried over sodium sulfate and evaporated. The residue which remains is distilled in vacuo, resulting in an oil of refractive index nD27 =1.6478.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.[CH3:14][CH:15]([CH3:34])[CH2:16][CH:17]([N:27]=[CH:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[C:18]12[O:25][CH2:24][C:21]([CH3:26])([CH2:22][O:23]1)[CH2:20][O:19]2>CCOCC>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([CH:28]([NH:27][CH:17]([C:18]23[O:25][CH2:24][C:21]([CH3:26])([CH2:22][O:23]2)[CH2:20][O:19]3)[CH2:16][CH:15]([CH3:34])[CH3:14])[C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[CH:7][CH:2]=1
Reactant: Brc1ccccc1Br
Reactant: CC(C)CC(N=Cc1nccs1)C12OCC(C)(CO1)CO2
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)CC(NC(c1ccc(Br)cc1)c1nccs1)C12OCC(C)(CO1)CO2
Reaction time: 1 h

Procedure:
To a solution of dibromobenzene (760 mg, 3.2 mmol) in dry ether was added 2.5 M solution of nBuLi in hexanes (1.3 mL, 3.2 mmol) at −30° C. After stirring for 1 h, a solution of [3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butyl]-thiazol-2-ylmethylene-amine (500 mg, 1.6 mmol) in 5 mL of dry ether was added slowly. The reaction mixture was allowed to stir at the same temperature for 2 h and then the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4. The solvent was evaporated in vacuo. The crude was flash column chromatographed using 2:1 hexanes:EtOAc as an eluant to get [(4-bromo-phenyl)-thiazol-2-yl-methyl]-[3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butyl]-amine as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:12]1[N:13]=[C:14]3[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]3=[N:16][CH:17]=1)[C:6]2=[O:11].C(N(CC)CC)C.[NH2:39][C@H:40]([CH:49]1[CH2:51][CH2:50]1)[C:41]([N:43]1[CH2:46][CH:45]([C:47]#[N:48])[CH2:44]1)=[O:42].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:47]([CH:45]1[CH2:46][N:43]([C:41](=[O:42])[C@H:40]([NH:39][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([N:5]4[CH2:4][C:3]5[C:7](=[CH:8][CH:9]=[CH:10][C:2]=5[Cl:1])[C:6]4=[O:11])[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=2)=[O:23])[CH:49]2[CH2:50][CH2:51]2)[CH2:44]1)#[N:48]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(N3Cc4c(Cl)cccc4C3=O)cnc21
Reactant: N#CC1CN(C(=O)[C@H](N)C2CC2)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(N3Cc4c(Cl)cccc4C3=O)cnc21
Reaction time: 16 h
Yield: 39.8 %

Procedure:
To a solution of 2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 0.17 mmol) in DMF (2.4 mL) was added triethylamine (73 μl, 0.52 mmol), 1-((R)-2-amino-2-cyclopropyl-acetyl)-azetidine-3-carbonitrile (31.2 mg, 0.17 mmol) and PyBOP (109 mg, 0.21 mmol) at room temperature. The reaction mixture was stirred for 16 h at the same temperature then poured into EtOAc (50 mL) and washed with water (4×50 mL). The organic extracts were dried (Na2SO4) and evaporated under vacuum. The crude residue was purified by column chromatography (SiO2, 23 g, Hex:EtOAc, 0% to 6:4, in 35 min) to afford 42 mg (39%) of 2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.FC1C=C(CN[C@]23CC[C@@H](C(C)=C)[C@@H]2[C@@H]2[C@@](C)(CC3)[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(C3C=CC(C(O)=O)=CC=3)=CC4)CC2)C=CN=1.[F:88][C:89]([F:99])([F:98])[C:90]1[C:91]([CH:96]=O)=[N:92][CH:93]=[CH:94][CH:95]=1>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][CH2:96][C:91]1[C:90]([C:89]([F:98])([F:88])[F:99])=[CH:95][CH:94]=[CH:93][N:92]=1)[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=Cc1ncccc1C(F)(F)F
Agent: C=C(C)[C@@H]1CC[C@]2(NCc3ccnc(F)c3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCc3ncccc3C(F)(F)F)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 42 %

Procedure:
The title compound was prepared in 42% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 3-trifluoromethylpyridine-2-carbaldehyde was used instead of 2-fluoropyridine-4-carboxaldehyde in Step 1. LCMS: m/e 689.6 (M+H)+, 4.12 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=8.83 (d, J=4.3 Hz, 1H), 8.28 (d, J=7.9 Hz, 1H), 7.93 (d, J=8.5 Hz, 2H), 7.72 (dd, J=5.0, 7.8 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 5.31 (dd, J=1.5, 6.1 Hz, 1H), 4.85 (s, 1H), 4.76 (s, 1H), 4.44 (d, J=16.2 Hz, 1H), 2.80 (dt, J=5.5, 11.0 Hz, 1H), 2.25-2.10 (m, 5H), 2.02 (dt, J=3.5, 12.1 Hz, 1H), 1.92-1.79 (m, 2H), 1.78 (s, 3H), 1.76-1.68 (m, 3H), 1.64-1.54 (m, 4H), 1.52-1.43 (m, 3H), 1.40 (br. s., 1H), 1.36 (s, 3H), 1.32-1.22 (m, 2H), 1.16-1.13 (m, 3H), 1.08 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: [CH:1]1([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][C@H:8]2[NH:23][C:24](OC2C=CC([N+]([O-])=O)=CC=2)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:36][C:37]1[C:38]([F:57])=[C:39]([C@:43]([C@@H:51]2[CH2:56][CH2:55][CH2:54][NH:53][CH2:52]2)([OH:50])[CH2:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH:40]=[CH:41][CH:42]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:36][C:37]1[C:38]([F:57])=[C:39]([C@:43]([C@@H:51]2[CH2:56][CH2:55][CH2:54][N:53]([C:24]([NH:23][C@H:8]3[C@H:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[O:14])[CH2:9]3)=[O:25])[CH2:52]2)([OH:50])[CH2:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH:40]=[CH:41][CH:42]=1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCNC1
Reactant: O=C(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CCCCC1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)N[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@H]2C2CCCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Half of the crude (3S,4S)-benzyl 4-cyclohexyl-3-((4-nitrophenoxy)carbonylamino)piperidine-1-carboxylate from Step 1 was added to a solution of (S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (29 mg, 2 equiv) and DIEA (15 μL, 3 equiv) in CH2Cl2 (2 mL). The mixture was stirred for 1 h at rt. LC-MS showed the reaction was complete. The mixture was concentrated and purified by preparative HPLC to afford (3S,4S)-benzyl 3-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-4-cyclohexylpiperidine-1-carboxylate (18.4 mg, 63%). LC-MS (3 min) tR=2.40 min., m/z 672 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C@H:13]3[CH2:16][C@H:15]([NH:17][C:18]4[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:25](OC)(OC)(OC)[O:26][CH3:27].C(O)(=O)CC>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C@H:13]3[CH2:16][C@H:15]([N:17]4[C:18]5=[N:19][CH:20]=[CH:21][CH:22]=[C:23]5[N:24]=[C:25]4[O:26][CH3:27])[CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(OC)(OC)OC
Reactant: Nc1cccnc1N[C@H]1C[C@H](Nc2cnc3ccc(Cl)cc3n2)C1
Solvent: CCC(=O)O
Solvent: O
Product: COc1nc2cccnc2n1[C@H]1C[C@H](Nc2cnc3ccc(Cl)cc3n2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
N2-(trans-3-((7-chloroquinoxalin-2-yl)amino)cyclobutyl)pyridine-2,3-diamine (118 mg, 0.346 mmol), tetramethyl orthocarbonate (922 μl, 6.92 mmol) and propionic acid (12.91 μl, 0.173 mmol) were combined under nitrogen. The reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with saturated ammonium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo to give the crude material as a off-white solid. It was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with a hexane to ethyl acetate gradient, to provide 7-chloro-N-(trans-3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)quinoxalin-2-amine (85 mg, 0.223 mmol, 64.5% yield). M+1: 380.9.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=1.[CH:14]#[C:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.CCCCCCC>C(#N)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:14]([C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=1)#[C:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCCC
Reactant: CC(=O)C1Oc2ccc(Br)cc2O1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCC#Cc1ccc2c(c1)OC(C(C)=O)O2
Yield: 99.9 %

Procedure:
A solution of 1-(5-bromobenzo[d][1,3]dioxol-2-yl)ethanone (4.13 g), copper (I) iodide (0.16 g), pent-1-yne (2.32 g), triphenylphosphine palladium chloride (1.19 g) and triethylamine (7 ml) in acetonitrile (40 ml) was stirred overnight at 50° C. Then 100 ml of heptane were added and the organic layer was washed successively with a 2M HCl solution and three times with water, dried over MgSO4 and concentrated. The crude reaction mixture was purified by flash chromatography on silica gel (eluant heptane/ethyl acetate 97/3) to give 3.91 g (22%) of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:17]=[N:18][CH:19]=[C:20](Cl)[C:21]=1[CH:22]=O.[C:25]([O:29][CH3:30])(=[O:28])[CH2:26][SH:27]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[CH:19]=[N:18][CH:17]=[C:16]3[S:27][C:26]([C:25]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=23)=[CH:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: O=Cc1c(Cl)cncc1Cl
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(Oc3ccc(Br)cc3)cncc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a solution of 4-bromophenol (4.94 g., 28.55 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen atmosphere was added dropwise a solution of potassium t-butoxide (1 M solution in THF, 28.6 mL, 28.6 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes, then a solution of Example 17A (2 g, 11.4 mmol) in anhydrous tetrahydrofuran (20 mL) was added and refluxed for 8 hours. The reaction mixture was allowed to cool to 25° C., methyl thioglycolate (1.23 mL, 13.7 mmol) was added and refluxed for 15 minutes. The cooled reaction mixture was diluted with ethyl acetate (300 mL) and partitioned with an ice cold solution of 1 N NaOH (3×75 mL). The organic layer was washed with brine (3×100 mL), dried (MgSO4) and solvents were removed under reduced pressure to obtain the crude product (4.2 g). This was purified by flash chromatography on silica gel eluting with 10% acetone-hexane to obtain the title compound (1.81 g) in 44% yield.
Reaction SMILES: [CH:1]([CH:3]([S:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[CH:12]1C=CC=CC=1.[S:18]([O:23]C)([O:21][CH3:22])(=[O:20])=[O:19]>O>[CH3:22][O:21][S:18]([O-:23])(=[O:20])=[O:19].[CH3:11][S+:10]([CH3:12])[CH:3]([CH:1]=[CH2:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(SC)c1ccccc1
Reactant: c1ccccc1
Reactant: COS(=O)(=O)OC
Solvent: O
Product: C=CC(c1ccccc1)[S+](C)C
Product: COS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 44 h

Procedure:
Methyl (vinylbenzyl) sulfide (13.59 g, 8.25×10−2 mol), benzene (45 ml), and dimethyl sulfate (8.9 ml, 9.4×10−2 mol) were combined in a 100 ml round bottomed flask equipped with a nitrogen inlet. The mixture was allowed to stir at room temperature for 44 hours, at which point two layers were present. Water (20 ml) was added and the top (benzene) layer was removed by pipette. The aqueous layer was extracted three times with 30 ml of diethyl ether and a vigorous stream of nitrogen was bubbled through the solution to remove residual volatile compounds. The product was used without further purification as a 35% (w/w) solution.
Reaction SMILES: [Mg].[O:2]=[C:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19](Cl)=[O:20].S(=O)(=O)(O)O>CCOCC.C(Cl)(Cl)(Cl)Cl.C(O)C>[C:3]([CH:4]([C:19](=[O:20])[CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:2])[CH3:10]
Reactant: Cc1ccccc1CC(=O)Cl
Reactant: CCOC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(C(C)=O)C(=O)Cc1ccccc1C
Reaction time: 8 h

Procedure:
This material was prepared according to the procedure of M. Viscontini and N. Merckling, Helvetica Chimica Acta, 35, 2280 (1952). To 2.65 parts of magnesium turnings was added 15 parts absolute ethanol at room temperature and 0.5 parts of carbon tetrachloride. As soon as the initial reaction subsides 100 parts of dry ether was added. The mixture was stirred without cooling until the reaction ceased, then 19.6 parts of ethyl 3-oxobutanoate in 20 parts of dry ether was added with ice cooling and good stirring. After the resulting precipitate dissolved, the solution was cooled in an ice-salt bath and 16 parts of 2-methylphenylacetyl chloride was slowly added. The mixture was allowed to stand overnight at room temperature and then combined with ice and sulfuric acid. The ether layer was separated, washed with water, dried over sodium sulfate and stripped to give ethyl 2-acetyl-4-(2-methylphenyl)-3-oxobutanoate as a crude oil.