Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH3:2]C(C)([O-])C.[K+].[O:8]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.CCCCCC>[O:8]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:2])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of methyltriphenylphosphium bromide (7.85 g, 22 mmol) in THF (10 mL) was added potassium tert-butoxide (1.0M solution in THF, 22 mL). After 30 minutes, 4-phenoxybenzaldehyde (3.96 g, 20 mmol) was added to the above mixture. The reaction was diluted with equal volume of hexane after 20 minutes and filtered through silica gel. The residue was rinsed and washed with 20% ether in hexane. Concentration of the filtrate gave the crude product as an off white solid which was used without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]([F:16])=[C:14]2[C:9]([C:10]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:24][CH2:23]4)=[C:18]([F:33])[C:11]=3[C:12](=O)[O:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>ClC1C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:15]([F:16])=[C:14]2[C:9]([C:10]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:24][CH2:23]4)=[C:18]([F:33])[C:11]=3[C:12](=[S:43])[O:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC1CCC(c2ccc3c(c2F)c(=O)oc2c(F)c(OCCCC)ccc23)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Clc1ccccc1
Product: CCCCCC1CCC(c2ccc3c(c2F)c(=S)oc2c(F)c(OCCCC)ccc23)CC1
Yield: 65.3 %

Procedure:
11.7 g (25.6 mmol) of 3-butoxy-4,7-difluoro-8-(4-pentylcyclohexyl)-benzo[c]chromen-6-one and 11.4 g (28.2 mmol) of Lawesson's reagent were refluxed for 16 hours in 130 ml of chlorobenzene. The solution was subsequently filtered through silica gel and evaporated, and the crude product was purified by crystallisation from MTB ether, giving 7.9 g (65%) of 3-butoxy-4,7-difluoro-8-(4-pentylcyclohexyl)benzo[c]chromene-6-thione as yellow crystals.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C.O>C(#N)C.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.[Cu]I>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:14]#[C:13][CH2:12][OH:15])=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.5 %

Procedure:
To a solution of methyl 4-iodobenzoate (20 g, 76 mmol), propargyl alcohol (5.55 g, 99.0 mmol) and triethylamine (20 mL) in acetonitrile (200 mL) was added dichlorobis(triphenylphosphine)palladium(II) (1.55 g, 2.21 mmol), followed by CuI (454 mg, 2.38 mmol). The reaction mixture was stirred at room temperature for 24 h. Water was added and the aqueous solution was washed with EtOAc (3×). The organic solutions were combined, dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (9:1 hexanes:EtOAc to 4:1 hexanes:EtOAc) provided 4-(3-hydroxy-prop-1-ynyl)-benzoic acid methyl ester (12.65 g).
Reaction SMILES: O[C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.FC(F)(F)C(O)=O.C(Cl)Cl.CO.[H][H]>[Pd]>[C:18]1([C@@H:2]2[CH2:6][NH:5][C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1CC(O)(c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](c2ccccc2)CN1

Procedure:
1-tert-Butyl 2-methyl (2S)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxylate (0.32 g, 0.0010 mol) was treated with trifluoroacetic acid (1.00 mL, 0.0130 mol) and methylene chloride (1.00 mL, 0.0156 mol) at rt for 4 h. The solvents were evaporated and the residue was dissolved in methanol (5.0 mL, 0.12 mol). Palladium (50.0 mg, 0.000470 mol) was added under nitrogen and the resulting mixture was hydrogenized with a hydrogen-gas-filled-balloon for 3 h. The mixture was filtered and the filtrate was concentrated to give the desired product, which was directly used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.C(O)(=O)C.[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>O.CN(C)C(=O)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[CH2:19][CH2:18]1
Reactant: CC(=O)NCC1CCNCC1
Reactant: BrCC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: CC(=O)NCC1CCN(CC2COc3ccccc3O2)CC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A mixture of 12.6 parts of 2-(bromomethyl)-2,3-dihydro-1,4-benzodioxin, 11 parts of N-(4-piperidinylmethyl)acetamide acetate (1:1), 15 parts of sodium carbonate, 0.1 parts of sodium iodide and 135 parts of N,N-dimethylacetamide was stirred overnight at 75° C. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 1,1'-oxybisethane and 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.2 parts (21.0%) of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]acetamide; mp. 137.9° C. (intermediate 89).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O.O1CCOCC1>[C:1]([CH2:2][CH2:3][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])#[N:4]
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Reactant: C=CC#N
Solvent: C1COCCO1
Solvent: O
Product: N#CCCn1c(C(=O)OCc2ccccc2)cc2ccccc21
Temperature: 80 °C

Procedure:
1.6 ml of Triton B at 40% in water and 4 ml of acrylonitrile are mixed in 40 ml of dioxane, and 9.44 g of benzyl 2-indolecarboxylate are then added with stirring. The mixture is heated at 80° C. for 24 hours and is then poured into 500 ml of ice-cold water. The precipitate formed is filtered off, taken up in EtOAc and this solution is then dried over Na2SO4 and concentrated to give 10.1 g of the expected compound, which crystallizes: m.p.=98-100° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14](I)=[CH:13][C:12]=3[Cl:19])=[N:10][C:6]=2[C:5]([F:20])=[CH:4][N:3]=1.[C:21](=[O:28])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:22].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([O:23][C:21](=[O:28])[NH:22][C:14]1[CH:15]=[C:16]([Cl:17])[C:11]([C:9]2[S:8][C:7]3[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([F:20])[C:6]=3[N:10]=2)=[C:12]([Cl:19])[CH:13]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(N)=O
Reactant: Fc1cnc(Cl)c2sc(-c3c(Cl)cc(I)cc3Cl)nc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(-c2nc3c(F)cnc(Cl)c3s2)c(Cl)c1
Temperature: 100 °C
Yield: 51.9 %

Procedure:
To 4-chloro-2-(2,6-dichloro-4-iodophenyl)-7-fluorothiazolo[5,4-c]pyridine (579 mg, 1.3 mmol), in toluene (12 mL) and water (2 mL), was added tert-butyl carbamate (221 mg, 1.9 mmol), XantPhos (72.9 g, 0.13 mmol) and K3PO4 (534 mg, 0.34 mmol). The resulting mixture was degassed with argon for 10 minutes, Pd2(dba)3 (57.7 mg, 0.063 mmol) was added and the reaction mixture was heated at 100° C. for 18 hours in a sealed vial. After cooling to room temperature, the reaction mixture was filtered through Celite® washing with EtOAc (5 mL). The filtrate was partitioned between water and the organic layer separated. The aqueous phase was further extracted with EtOAc (×2). The combined organic layers were dried (MgSO4), filtered concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-100% DCM in cyclohexane to afford the title compound as a white solid (303 mg, 54% yield). LCMS (Method D): RT=4.86 min, m/z: 448.0 [M+H+].
Reaction SMILES: [OH:1][C@@H:2]([C@@H:7]([OH:19])[CH:8]1[CH2:10][N@@:9]1[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])[C:3]([O:5][CH3:6])=[O:4].[CH3:20]S(N)(=O)=O>CC(O)(C)C.O>[OH:1][C@H:2]([C@@H:7]([OH:19])[CH:8]1[CH2:10][N@@:9]1[C@@H:11]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:3]([O:5][CH2:6][CH3:20])=[O:4]
Reactant: CS(N)(=O)=O
Reactant: COC(=O)[C@@H](O)[C@@H](O)C1C[N@@]1[C@H](C)c1ccccc1
Agent: CCOC(=O)[C@H](O)[C@@H](O)C1C[N@]1[C@H](C)c1ccccc1
Agent: COC(=O)[C@@H](O)[C@@H](O)C1C[N@]1[C@H](C)c1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)[C@H](O)[C@@H](O)C1C[N@@]1[C@H](C)c1ccccc1
Reaction time: 24 h

Procedure:
To a solution of (2S,3S)-methyl 2,3-dihydroxy-3-((R)-1-((R)-1-phenylethyl)aziridin-2-yl)propanoate (3.3 g, 13.3 mmol) in t-BuOH/H2O (60 mL, 0.2 M/60 mL, 0.2 M) were added AD-mix α (33 g, 1000 w/w %) and methanesulfonamide (1.9 g, 19.9 mmol, 1.5 equiv) at 0° C. The reaction mixture was stirred for 24 hrs and quenched with water. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine, dried over MgSO4, filtered through a pad of celite, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (2/3) to afford the title product (diastereomeric mixture, ratio=7/1). Yield: 2.3 g (62%); yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.CCN(C(C)C)C(C)C.Cl[C:31]1[N:36]=[CH:35][N:34]=[C:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:32]=1[CH3:44].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:31]4[N:36]=[CH:35][N:34]=[C:33]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C:32]=4[CH3:44])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1c(Cl)ncnc1C(=O)OC(C)(C)C
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)OC(C)(C)C)c3C)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.20 g (0.73 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 0.14 mL (0.80 mmol) DIPEA were placed in 3.0 mL DMF. 0.17 g (0.74 mmol) tert. butyl 6-chloro-5-methyl-pyrimidine-4-carboxylate were added and the reaction mixture was stirred for 3 h at RT. The reaction mixture was mixed with water and extracted with DCM. The organic phase was dried, filtered and concentrated to dryness by rotary evaporation. The residue was combined with diisopropylether and the precipitated solid was suction filtered and dried.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](OS(C(F)(F)F)(=O)=O)[CH:27]=1)=[O:7].[C:50](=[NH:63])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[F:48][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:46])([F:45])[F:47])[CH:43]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N:63]=[C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:27]=1)=[O:7]
Reactant: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(OS(=O)(=O)C(F)(F)F)c3)C2)CCO1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(N=C(c4ccccc4)c4ccccc4)c3)C2)CCO1
Temperature: 80 °C
Reaction time: 22 h
Yield: 72 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-methyl-3-trifluoromethanesulfonyloxybenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine (0.10 g), benzophenone imine (30.5 mg), cesium carbonate (62 mg), palladium acetate (3 mg), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (12.7 mg) in toluene was stirred at 80° C. under nitrogen atmosphere for 22 hours. After cooling, water and ethyl acetate were added to the mixture and the organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (NH-DM1020, Fuji Silysia Chemical Ltd.) with a mixture of hexane and ethyl acetate (3:1) as eluent to give (2R)-1-[3,5-bis(trifluorometh yl)benzoyl]-2-[3-(diphenylmethyleneamino)-4-methylbenzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine (75 mg) as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([C:14]([NH:16][NH:17][C:18]2[N:19]=[C:20]3[CH:26]=[CH:25][N:24](S(C4C=CC(C)=CC=4)(=O)=O)[C:21]3=[N:22][CH:23]=2)=O)[CH2:10][CH2:9]1)(C)(C)C.C(OC(N[C@@H]1CC[C@H](C(O)=O)CC1)=O)(C)(C)C.O=S(Cl)[Cl:57].C([O-])([O-])=O.[Na+].[Na+].Cl>CO.O1CCOCC1>[ClH:57].[C:14]1([C@@H:11]2[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]2)[N:19]2[C:20]3[CH:26]=[CH:25][NH:24][C:21]=3[N:22]=[CH:23][C:18]2=[N:17][N:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)cnc32)cc1
Reactant: O=S(Cl)Cl
Agent: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n32)CC1
Temperature: 90 °C

Procedure:
A round-bottomed flask was charged with cis-tert-butyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclohexylcarbamate (0.415 g, 0.785 mmol, prepared using A from cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid [AMRI] and Preparation #9), 1,4-dioxane (9 mL) and SOCl2 (0.115 mL, 1.57 mmol). The resulting mixture was heated at about 90° C. for about 1 h and then allowed to cool to ambient temperature. To the reaction mixture was added aqueous Na2CO3 (5 N, 7.85 mL, 15.7 mmol) and the reaction mixture was heated at about 90° C. for about 5 h. MeOH (5 mL) was added to the reaction mixture and the resulting mixture was heated at about 90° C. for about 16 h and then allowed to cool to ambient temperature. The layers were separated and the organic layer was concentrated under reduced pressure. To the residue was added 1,4-dioxane (10 mL) followed by HCl (4 M in 1,4-dioxane, 5 mL, 20.0 mmol). The resulting suspension was heated at about 60° C. for about 1 h and then allowed to cool to ambient temperature. The solid was collected by vacuum filtration, washed first with 1,4-dioxane (1 mL) then Et2O (50 mL) to yield the crude product cis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanamine hydrochloride (0.42 g, 98%, 84% purity). A portion of the crude HCl salt (0.075 g) was further purified by RP-HPLC (Table 2, Method g) to give cis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanamine (0.044 g) with 3 equiv NH4OAc as an excipient. LC/MS (Table 2, Method a) Rt=0.92 min; MS m/z: 257 (M+H)+.
Reaction SMILES: O1C=CN=C1Cl.[CH2:7]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH2:29].C(N(C(C)C)C(C)C)C>CN(C=O)C.O.ClCCl>[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH:29][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CN
Agent: Cl
Agent: Clc1ncco1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxazolyl chloride (4.0 mL, 45.9 mmol) and several drops of DMF were added to a solution of dichloromethane (5 mL) containing 4-benzyloxybenzoic acid (2.29 g, 10.0 mmol) under ice-cooling, and then dichloromethane (2.5 mL) was further added thereto. The mixture was stirred at room temperature for 2.5 hours, and the solvent was evaporated. The resulting residue was dissolved in dichloromethane (20 mL), and glycine methyl ester hydrochloride (1.39 g, 11.1 mmol) and N-ethyl-N,N-diisopropylamine (4.4 mL, 25.2 mmol) were added thereto under ice-cooling. The mixture was stirred at room temperature for 18 hours, and then water was added thereto to terminate the reaction. The mixture was extracted with dichloromethane, and the organic layers were combined and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate, 3:4 to 0:1, v/v) to give N-[4-(benzyloxy)benzoyl]glycine methyl ester. Then, 1.66 g of this ester was dissolved in a solvent mixture of methanol (8 mL) and THF (8 mL). To the resulting mixture, 20% palladium hydroxide-carbon (168 mg) was added. The mixture was vigorously stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite and then concentrated to give 1.19 g of the title compound (white powder, yield: 85%).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:15][CH:16]=[CH2:17].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Si:18]([O:1][C:2]1[C:3]([CH2:15][CH:16]=[CH2:17])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[CH2:12][CH:13]=[CH2:14])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCc1cc(C(=O)OC)cc(CC=C)c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCc1cc(C(=O)OC)cc(CC=C)c1O[Si](C)(C)C(C)(C)C
Yield: 97.2 %

Procedure:
The product of Step B (3.1 g, 13.36 mmol) was treated with tert-butyldimethylsilyl chloride (2.22 g, 1.1 equiv), triethylamine (3 mL) and DMAP (0.1 equiv) in dichloromethane overnight. The mixture was concentrated and flash chromatographed with 5% and then 10% ethyl acetate in hexane to furnish 4.5 g (97%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:13])[CH3:12].O>ClCCCl>[C:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Solvent: O
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 50 °C
Yield: 73 %

Procedure:
2-Oxindole (3 g) was suspended in 1,2-dichloroethane and slowly treated with 3.2 mL of acetyl chloride. The resulting suspension was heated to 50° C. for 5 hours, cooled, and poured into water. The resulting precipitate was collected by vacuum filtration, washed copiously with water and dried under vacuum to give 2.9 g (73% yield) of the title compound as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][C@@H:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:19]([CH3:21])[CH3:20].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:17][C@@H:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 94.4 %

Procedure:
A mixture of N-[(benzyloxy)carbonyl]glycine (, 2.4 g, 11.5 mmol), tert-butyl D-valinate hydrochloride (2.4 g, 11.4 mmol) and N-methylmorpholine (2.53 ml, 22.9 mmol) in DCM (20 ml) was stirred at room temperature. TBTU (4.79 g, 14.9 mmol) was added and the mixture was stirred for three days. The solvent was removed under reduced pressure. Water was added and the mixture was extracted two times with toluen. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography using DCM:EtOAc:aceton 4:1:1 as eluent to give 3.92 g (94%) of the title compound. NMR (500 MHz, CD3COOD) 0.88-0.99 (m, 6H), 1.48 (s, 9H), 2.08-2.19 (m 1H), 3.85 (ABq, 2H), 4.24 (d, 1H), 5.12 (ABq, 2H), 7.28-7.41 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=O)[NH:6]2.Cl.[OH-].[Na+].O>C1COCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: O=C1Cc2c(Br)cccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Brc1cccc2c1CCN2
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A mixture of 4-bromooxindole (2.77 g, 0.01 mol) and a solution of BH3 in THF (2 M, 40 mL) was stirred at room temperature overnight. The mixture was cooled to 0° C. and diluted with 30 mL of methanol, followed by addition of 12 N HCl (7.5 mL). The resulting mixture was stirred at room temperature for 1 hour, adjusted to pH 8-9 with 10% aqueous NaOH. Water was added to the mixture and extracted with ethyl acetate (3×100 mL). The organic layer was dried and concentrated to get the crude product which was washed through a silica gel column (ethyl acetate in petroleum ether (10%). The crude product was dissolved in 10% HCl (3×10 mL). The aqueous layer was adjusted to pH7 with NaHCO3, extracted with ethyl acetate (3×20 mL). The organic layer was dried and concentrated to get 4-bromoindoline (1.16 g, 45%) as an oil. LCMS: 200 [M+1]+. 1H-NMR (400 MHz. DMSO-d6) δ 2.90 (t, J=8.8 Hz, 2H), 3.46 (t, J=8.8 Hz, 2H), 5.86 (s, 1H), 6.43 (m, 1H), 6.64 (m, 1H), 6.83 (t, J=8.0 Hz, 1H).