Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[C:35]([CH:36]=O)=[CH:34][CH:33]=[C:32]([O:38][CH3:39])[N:31]=1.C([BH3-])#N.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:36][C:35]4[C:30]([O:29][CH3:28])=[N:31][C:32]([O:38][CH3:39])=[CH:33][CH:34]=4)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C=O)c(OC)n1
Reactant: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CNc2ccc(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)cn2)c(OC)n1
Temperature: 100 °C
Yield: 72.7 %

Procedure:
To 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (120, 60.0 mg, 0.150 mmol) in 2.0 mL of ethanol and 0.1 mL of acetic acid, 2,6-dimethoxy-pyridine-3-carbaldehyde (121, 120 mg, 0.75 mmol) and silica supported cyanoborohydride (0.40 g, 0.484 mmol) were added. The reaction was heated to 100° C. for 18 minutes at 300 Watts in microwave, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (122, 60 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:19])[C:8]3[NH:9][CH:10]=[N:11][C:12]=3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2=[N:4][N:3]=1.[Cl:20]N1C(=O)CCC1=O>C1COCC1>[Cl:20][C:10]1[NH:9][C:8]2[C:7](=[O:19])[N:6]3[C:2]([CH3:1])=[N:3][N:4]=[C:5]3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=2[N:11]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(C)nnc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Cl)[nH]c2c(=O)n2c(C)nnc12
Temperature: 70 °C
Yield: 18.7 %

Procedure:
To a solution of 3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (0.10 g, 0.38 mmol) in THF (5 mL) in a microwave reaction tube was added N-chlorosuccinimide (0.046 g, 0.42 mmol). The mixture was heated at 70° C. in a microwave oven for 20 min. After cooling to room temperature, it was purified using preparative LCMS to provide the product (0.021 g). 1HNMR (300 MHz, CD3OD): δ 4.39 (t, J=7.5 Hz, 2H), 2.46 (s, 3H), 1.91 (m, 2H), 1.39 (m, 4H), 0.92 (m, 3H). LCMS calculated for C12H16ClN6O (M+H): 295.1; found: 295.1.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:34]3[CH2:33][CH2:32][N:31]([C:28]4[CH:27]=[CH:26][C:25]([OH:24])=[CH:30][CH:29]=4)[CH2:36][CH2:35]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Oc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
DIPEA (12.15 mL, 69.78 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (10.35 g, 46.52 mmol) and 1-(4-hydroxyphenyl)piperazine (CAS 56621-48-8, 9.12 g, 51.17 mmol) in DMF (80 mL). The resulting solution was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, evaporated to dryness and the residue re-dissolved in DCM (250 mL). The solution was washed with water (200 mL), dried over MgSO4 and evaporated to afford crude product, which was triturated with diethyl ether. The resulting solid was collected by filtration and dried under vacuum to give 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]phenol (14.27 g, 84%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[O:14][CH3:15].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: OCCCCCCCCCl
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(OCCCCCCCCCl)c(OC)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 90.4 %

Procedure:
20.0 g (96.06 mmol) methyl(2E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate, 16.6 g (100.9 mmol) 8-chlor-1-octanol and 27.7 g (105.7 mmol) of triphenylphosphine were dissolved in 400 ml of tetrahydrofurane. The colourless solution was subsequently cooled to 0° C. and 46.0 g (105.7 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene was added dropwise thereto over a period of 25 minutes. The mixture was subsequently allowed to react for 4 hours at 0° C. The reaction mixture reduced in volume by evaporation. The resulting residue was added to a mixture of methanol and water (3:2) and was then extracted with a mixture of tert.-butyl-methylether:hexane 1:1. The tert.-butyl-methylether:hexane phase was washed repeatedly with water, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The crude product was recrystallised from 2-propanol yielded 30.8 g (90%) methyl(2E)-3-{4-[(8-chloroctyl)oxy]-3-methoxyphenyl}-2-propenoate as white crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][C:13]#[CH:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(N(CC)CC)C.CCOCC>[CH3:15][S:16]([O:1][CH2:2][CH2:3][N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:11])[CH2:12][C:13]#[CH:14])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCN(CCO)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C#CCN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of 700 mg of 10d in 1 ml of triethyl amine and 15 ml of ether was treated at 0° C. with 320 μl of methanesulfonyl chloride in 3 ml of ether. The reaction mixture was stirred for ½ h and then quenched by addition of 20 ml of water and the product was extracted into ether. The organic extract was washed with 1M aq. K2CO3 and once with water, dried and concentrated, to give 900 mg of 10e as a colorless oil, essentially pure according to TLC and NMR, which was used without further purification in the next step. Rf 0.40 (heptane/ethyl acetate 1/1).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][OH:7])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C1COCC1>[CH3:15][O:14][C:12](=[O:13])[CH2:11][O:7][CH2:6][CH2:5][O:4][CH2:1][CH:2]=[CH2:3]
Reactant: C=CCOCCO
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCCOCC(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
To a stirred solution of 2-allyloxy-ethanol 7 (10.9 mL, 100 mmol, 1.0 equiv.) in THF (200 mL) was carefully added NaH (60%, 4.8 g, 120 mmol, 1.2 equiv.) in small portions at room temperature. The reaction was then refluxed for 1 h (until H2 release ceased) then cooled to 0° C. Methyl bromoacetate (11.4 mL, 120 mmol, 1.2 equiv.) was then added dropwise. After 15 min at 0° C., the reaction was submitted to a EtOAc/H2O extraction. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered then evaporated under reduced pressure. Purification was achieved by Kugelrohr distillation under reduced pressure and provided 9.77 g (55%) of ester (8) as a colorless oil; bp=130-145° C. (water tap vacuum); 1H NMR (400 MHz, CDCl3) δ 5.91 (m, 1H), 5.28 (m, 1H), 4.99 (m, 1H), 4.19 (s, 2H), 4.02 (m, 2H), 3.76 (s, 3H), 3.75 (m, 2H), 3.64 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 171.1, 134.8, 117.3, 72.4, 71.2, 69.7, 68.9, 51.9; IR (neat) 1755 cm−1; HRMS (ESI, m/z) calcd. for C8H15O4 (MH+) 175.0964, found 175.0960.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:25]([C:20]2[NH:21][C:22]3[C:18]([CH:19]=2)=[CH:17][C:16]([Cl:15])=[CH:24][CH:23]=3)=[O:26])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc3cc(Cl)ccc3[nH]2)C1

Procedure:
69.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-chloro-1H-indole-2-carboxylic acid to give (R)-3-{[(5-chloro-1H-indole-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Pale yellow solid. MS 376.4 ([M−H]−)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH3:15].CCCCCC.C1(S(N([F:41])S(C2C=CC=CC=2)(=O)=O)(=O)=O)C=CC=CC=1>C1COCC1>[F:41][C:10]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[C:6]([CH3:15])[CH:7]=[CH:8][C:9]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COCOc1ccc(C)c(OCOC)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(C)c(OCOC)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of 2,4-bis(methoxymethoxy)-1-methyl-benzene (WO2012/076877 Intermediate 150, 2000 mg, 9.4233 mmol) in dry THF (20 mL) butyllithium 1.6M in hexane (6.77 ml, 10.84 mmol) was slowly added and the reaction mixture was stirred for 30 minutes at room temperature. The reaction was cooled to −15° C. and it was added (via cannulation) to a solution of N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (3565.8 mg, 11.308 mmol) in dry THF (10 mL) at −15° C. The reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with brine (5 ml) diluted with water (20 ml) and extracted with ethyl acetate (2×30 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 50 g as column and cyclohexane/ethyl acetate from 100:0 to 80:20 as eluent affording the title compound (1950 mg) as colourless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].C(O)(=[O:10])CC.CC(C)=O.[OH:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[OH:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19].[OH:5][C:2]([CH3:6])([CH3:1])[C:3]([NH2:4])=[O:10]
Reactant: CCC(=O)O
Reactant: CC(C)(O)C#N
Agent: CC(C)(O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(O)C(N)=O
Reaction time: 21 h

Procedure:
A suspension of 0.343 g (wet cell paste) Comamonas testosteroni 22-1 cells (ATCC PTA-1853) in 5.61 mL of 50 mM potassium phosphate buffer (pH 6.0) was placed into a 15-mL polypropylene centrifuge tube, then 51.0 mg of acetone cyanohydrin (0.10 M final concentration of acetone cyanohydrin in the suspension) was added and the resulting suspension mixed on a rotating platform at 25° C. Samples for analysis (0.180 mL) were mixed with 0.020 mL of 1.0 M propionic acid (HPLC external standard), centrifuged, and the supernatant analyzed by HPLC for acetone cyanohydrin, acetone, and 2-hydroxyisobutyric acid. After 21 h, the yields of 2-hydroxyisobutyric acid, 2-hydroxyisobutyramide, and acetone were 40.4%, 0%, and 34.5%, respectively, with 18.4% acetone cyanohydrin remaining.
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]([F:24])([F:23])[CH:7]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH:8]([OH:13])[C:9](OC)=[O:10].Br.[CH3:26][NH:27][C:28](NC)=[NH:29].C(O)(=O)C>C(O)C>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH:7]([CH:8]2[O:13][C:28]([NH:27][CH3:26])=[N:29][C:9]2=[O:10])[C:6]([F:24])([F:23])[F:5])=[CH:15]1
Reactant: COC(=O)C(O)C(c1c[nH]c2ccccc12)C(F)(F)F
Reactant: CNC(=N)NC
Agent: Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CNC1=NC(=O)C(C(c2c[nH]c3ccccc23)C(F)(F)F)O1
Temperature: 0 °C
Yield: 20.5 %

Procedure:
Sodium ethoxide (580 mg) was added to a solution of methyl 4,4,4-trifluoro-2-hydroxy-3-(indol-3-yl)butyrate (980 mg) and N,N′-dimethyl guanidine hydrogen bromide (630 mg) in ethanol (2.5 ml). The mixture was refluxed for 1.5 hours and then cooled. To the cooled reaction mixture was added ice water (20 ml). After the pH of the mixture was adjusted to 7 using acetic acid, the whole was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and then dried over magnesium sulfate. Concentration of the solution under the reduced pressure gave residue, which was subjected to silica gel chromatography. Eluent with ethyl acetate-hexane was collected and concentrated to provide the titled compound (218 mg).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:24]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[O:34][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Reactant: CC(C)(C)c1cccc(O)c1
Product: COC(=O)C(Oc1cccc(C(C)(C)C)c1)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Yield: 82.9 %

Procedure:
In a manner similar to Example 16, 7.54 g of methyl α-bromo-α-[p-(p-tert-butylphenoxy)phenyl]acetate was treated with 3.75 g of m-tert-butylphenol to yield 7.4 g of product as a pale yellow glass.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH:10]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[CH2:9][CH:8]=[N:7]1)=[S:5])[CH3:2].I[CH3:17]>CO>[CH3:17][S:5][C:4]([N:6]1[CH:10]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[CH2:9][CH:8]=[N:7]1)=[N:3][CH2:1][CH3:2]
Reactant: CI
Reactant: CCNC(=S)N1N=CCC1c1ccsc1
Solvent: CO
Product: CCN=C(SC)N1N=CCC1c1ccsc1
Temperature: 50 °C
Yield: 0.2 %

Procedure:
0.70 g (1 mol equiv.) 5-Thiophen-3-yl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide was dissolved in 14 mL methanol, 1.82 mL (10 mol equiv.) iodomethane was added and the reaction mixture was heated at 50° C. for 1 hour. Volatiles were removed in vacuo, the residue was taken up in dichloromethane and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (EtOAc:MeOH=9:1) afforded 0.48 g (64%) N-ethyl-5-thiophen-3-yl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 1.03 (t, J=7.3, 3H), 2.44 (s, 3H), 2.84 (ddd, J=18.1, 10.4, 1.5 Hz, 1H), 3.23-3.51 (m, 3H), 5.57 (t, J=10.4 Hz, 1H), 6.87 (br.s., 1H), 7.00 (d, J=4.8, 1H), 7.13 (d, J=3.0, 1H), 7.24 (dd, J=4.8, 3.0 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.Cl[C:17]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=[C:19]([Cl:27])[N:18]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:27][C:19]1[N:18]=[C:17]([NH:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=1
Reactant: Clc1cc2nccnc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CNc2nc(Cl)cc3nccnc23)C1

Procedure:
A solution of (S)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (100 mg, 0.5 mmol), 5,7-dichloropyrido[4,3-b]pyrazine (100 mg, 0.5 mmol) and DIPEA (77 mg, 0.6 mmol) in THF (5 mL) was stirred at room temperature for 4 hours. The volatiles were removed under reduced pressure, and the residue was treated with ethyl acetate, with brine, and concentrated to give the crude title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:29]([C:31]1[CH:32]=[C:33]([CH3:40])[C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1)#[N:30].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:37]([C:34]3[C:33]([CH3:40])=[CH:32][C:31]([C:29]#[N:30])=[CH:36][N:35]=3)=[O:38])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C#N)cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CO[C@@]1(C)C(F)(F)F
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(NC(=O)OC(C)(C)C)=N2)c1

Procedure:
To a solution of [(2R,5R)-5-(5-amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-di-hydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (2.2 g, 5.43 mmol) in DMF (20 ml) was added at 0-5° C. 5-cyano-3-methyl-pyridine-2-carboxylic acid (0.968 g, 5.97 mmol), EDC (1.095 g, 7.05 mmol), HOAt (1.182 g, 8.68 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was added to cold saturated NaHCO3 solution and the product was extracted with TBME. Combined TBME layers were washed with H2O and brine, dried over MgSO4, filtered and concentrated to obtain after crystallization from diisopropylether the title compound as colorless crystals: UPLC RtH5=1.472 min); ESIMS: 550; [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 11.11 (s, 1H), 10.11 (s, 1H), 8.79 (br s, 1H), 8.01 (s, 1H), 7.84 (m, 1H), 7.68 (dd, 1H), 7.21 (dd, 1H), 4.49 (d, 1H), 4.16 (d, 1H), 1.76 (s, 3H), 1.64 (s, 3H), 1.62 (s, 9H).
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.C([O:18][C:19](=[O:25])[C:20](OCC)=[O:21])C>O>[N+:13]([C:8]1[CH:7]=[C:6]([Cl:5])[CH:11]=[CH:10][C:9]=1[CH2:12][C:20](=[O:21])[C:19]([OH:25])=[O:18])([O-:15])=[O:14]
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
To a cooled mixture prepared by adding 13.6 g. of sodium to 300 ml. of ethanol is added a solution of 100 g. of 4-chloro-2-nitrotoluene and 84 g. of diethyloxalate in 150 ml. of ethanol while maintaining the temperature below 20° C. The resulting mixture is refluxed for one hour, cooled, 400 ml. of water added and the resulting mixture refluxed for 90 minutes. The ethanol is then evaporated to a small volume and the resulting precipitate contains tan and black material and the black material is mechanically separated and discarded and the remainder (filtrate plus tan precipitate) used in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:13]([O:17][C:18]([NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24](OS(C)(=O)=O)[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC>C(#N)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]1[CH2:22][CH2:23][C@@H:24]([O:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([NH2:1])=[N:3][CH:4]=[CH:5]3)[CH2:25][CH2:26]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Nc1nccc2cc(O)ccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2ccc3c(N)nccc3c2)CC1
Temperature: 120 °C
Yield: 7.8 %

Procedure:
A suspension of 1-amino-6-hydroxyisoquinoline (0.08 g, 0.5mmol), methane-sulfonic acid trans-4-tert-butoxycarbonylaminocyclohexyl ester (176 mg) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (270mg, ˜2.2 mmol/g loading) in acetonitrile (2ml) were heated at 120° C. over a period of 15 minutes using the microwave. The excess supported reagent was removed by filtration, washing with acetonitrile followed by methanol, and the filtrate evaporated to dryness under reduced pressure. Purification was achieved by prep-HPLC to give cis-[4-(1-aminoisoquinolin-6-yloxy)cyclohexyl]carbamic acid tert-butyl ester (14 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:15]([CH3:16])[N:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])[C:13]1=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]N(C1C=CC=CN=1)C.CO.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:15]([CH3:16])[N:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([O:21][CH3:25])=[O:20])[C:13]1=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1ccccn1
Reactant: C[C@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1OC(C)(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(C)(C)ON1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of (3S-trans)-2-[[3-(benzyloxycarbonyl)amino4-methyl-2-oxo-1-azetidinyl]oxy]-2-methylpropanoic acid (1.68 g, 5.0 mmol) (see example 29) in 10 ml of dry dichloromethane were added 4 dimethylaminopyridine (30 mg), dry methanol 0.81 ml, 210 mmol) and dicyclohexylcarbodiimide (1.13 g, 5.5 mmol) at 0° C. The reaction mixture was stirred for 3 hours at room temperature. The precipitate (dicyclohexylurea) was removed by filtration and the filtrate was evaporated in vacuo. The residue was taken up in ether, filtered, washed with aqueous buffer solution pH 4 (citrate/HCl), NaHCO3 solution, dried over MgSO4 and filtered. Evaporation in vacuo gave the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C[O-].[Na+].Br[C@H:11]([CH2:15][CH3:16])[C:12]([NH2:14])=[O:13]>C1(C)C=CC=CC=1.CO>[CH3:16][CH2:15][C@H:11]([N:1]1[C:2](=[O:6])[CH2:3][CH2:4][CH2:5]1)[C:12]([NH2:14])=[O:13]
Reactant: CC[C@@H](Br)C(N)=O
Reactant: O=C1CCCN1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC[C@@H](C(N)=O)N1CCCC1=O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of pyrrolidine-2-one (85 mg, 1 mmol) in 6 ml of toluene is added sodium methoxide (0. 19 ml of a 30% solution in MeOH, 1 mmol, 1 equiv.). The mixture is heated to 40° C. and concentrated to dryness under reduced pressure. The solid residue is taken up in 3 ml of tetrahydrofuran, cooled to 0° C. and (R)-2-bromobutyramide (IId) (optical purity >98%) (166 mg, 1 mmol, 1 equiv.) is added. The mixture is stirred for 1 h at 0° C. and further 16 h at room temperature. The mixture is then concentrated to dryness under reduce pressure.