Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH3:16])=[O:7].C(=O)([O-])O.[Na+]>O>[Br:1][C:12]1[C:11]([O:14][CH3:15])=[CH:10][C:9]([CH3:16])=[C:8]([C:6](=[O:7])[C:5]2[C:4]([Cl:3])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])[CH:13]=1
Reactant: BrBr
Reactant: COc1ccc(C(=O)c2c(Cl)cccc2Cl)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1Br
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of bromine (0.25 ml in 3 ml of trichloromethane) is added dropwise to a stirred solution of 2,6-Dichloro-4'-methoxy-2'-methyl-benzophenone (1.5 g; 5 mmol in 5 ml of trichloromethane), followed by 15 minutes of stirring at 20° C. The mixture is shaken with water, sodium hydrogencarbonate solution and water. The organic phase is dried and evaporated. The residue is purified by chromatography (flash column filled with 30 g of silicagel, elution with petrolether/ethylacetate changing from 20:1 to 9:1, 8:2, 7:3 (v/v). After evaporation, the residue crystallises when treated with petrolether/toluene to give white crystalls (0.45 g; 24% y); mp. 159° C.
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[S:12][C:3]=12
Reactant: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Cl
Temperature: 25 °C
Yield: 73 %

Procedure:
A mixture of 1.22 g (4.49 mmol) of 4-hydroxy-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 20 mL of phosphorous oxychloride is heated at reflux temperature for 3 hours, then cooled to room temperature. The solid is collected by filtration, then washed with hexane followed by water. The solid is dried to give 947 mg (73%) of a dark brown solid, mp softens at 270° C.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][C:4]([C:7]#[N:8])=[CH:3]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C@@H:2]3[CH2:6][CH2:5][C:4]([C:7]#[N:8])=[CH:3]3)[CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: N#CC1=CC(Br)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CC1=C[C@H](N2CCN(c3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
To a stirred solution of 3-bromocyclopent-1-enecarbonitrile (3 g, 17.44 mmol) in N,N-dimethylformamide (25 ml) was added 1-(4-fluorophenyl)piperazine (3.14 g, 17.44 mmol) followed by the addition of triethylamine (7.29 ml, 52.3 mmol) in a dropwise manner at 0° C. The reaction mixture was stirred at 25° C. for 3 h. The progress of reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue was then diluted with ethyl acetate (100 ml) and washed with water (4×30 ml). The organic layer was dried over sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column over silica gel (100-200 mesh) using 20% ethyl acetate in hexane as eluent to obtain the title compound (2.7 g, 57.1%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[CH:20]=1>CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Br:18])[CH:20]=2)[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(Br)c1
Reactant: C[C@H]1C[C@H](O)CCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C[C@H]1C[C@H](Oc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Dissolve 4-hydroxy-trans-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 1 (preparation 2, 3.03 g, 14.07 mmol) in 1-methyl-2-pyrrolidinone (50 mL), treat with 95% sodium hydride (0.33 g, 12.93 mmol), stir and beat at 70° C. After 1 hr., add 1-bromo-3-fluoro-benzene (1.73 mL, 15.5 mmol), stir, and heat at 100° C. After 16 hr., cool to ambient temperature and quench with water (100 mL). Extract with 4:1 hexane:ethyl acetate (2×100 mL), combine the organic layers and wash with aqueous NaCl solution (75 mL), dry over sodium sulfate, filter and concentrate. Purify the residue by silica gel flash chromatography eluting with 4:1 hexanes:ethyl acetate to obtain of the title compound (2.42 g, 46%). 1H NMR (CDCl3): 7.1 (m, 3H), 6.8 (m, 1H), 4.55 (m, 1H), 4.5 (m, 1H), 4.1 (m, 1H), 2.95 (m, 1H), 2.1 (m, 1H), 1.95 (m, 1H), 1.7 (m, 1H), 1.5 (m, 1H), 1.45 (s, 9H), 1.2 (d, 3H).
Reaction SMILES: [ClH:1].NC(=O)[C@@H](N[C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])C1C=CC=CC=1.Cl.[NH2:35][C@H:36]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37]([O:39][CH3:40])=[O:38]>>[ClH:1].[NH2:30][C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:35][C@H:36]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:37]([O:39][CH3:40])=[O:38])=[O:32])=[CH:18][C:19]=2[F:31])[CH:29]=[CH:28][N:27]=1
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Reactant: COC(=O)[C@H](N)c1ccccc1
Agent: Cl
Product: COC(=O)[C@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Yield: 51.1 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with (R)-methyl 2-amino-2-phenylacetate, hydrochloride salt (Aldrich, 30 mg, 0.10 mmol) in a manner similar to that which is described in Step C of Example 1 to give (R)-methyl 2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylacetate, hydrochloride salt (25 mg, 51% yield). 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 9.03 (d, 1H, J=7.0 Hz), 7.96 (d, 1H, J=7.0 Hz), 7.77-7.88 (m, 3H), 7.42 (m, 7H), 6.71 (d, 1H, J=7.5 Hz), 6.12 (s, 1H), 5.44 (d, 1H, J=7.0 Hz), 3.63 (s, 3H), 3.44-3.38 (m, 2H); MS(ESI+) m/z 453.29 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:19][CH:20]=C)[C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[O:6][CH2:5][CH2:4][O:3]1.[O:22]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[CH2:19][CH:20]=[O:22])[O:3][CH2:4][CH2:5][O:6]1
Reactant: C=CCC(CCCC1(C)OCCO1)C(=O)N1CCOC1=O
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(CCCC(CC=O)C(=O)N2CCOC2=O)OCCO1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-4 (4.0 g, 13.5 mmol), sudan III (10 mg) and CH2Cl2 (350 mL) at -78° C. under argon was bubbled ozone until red solution changed to yellow-orange. The solution was purged with argon for 30 minutes. PPh3 (5.28 g, 20.3 mmol) was added followed by the removal of the cooling bath. After 3.0 h, the reaction was concentrated. Flash chromatography (silica, 20%-50% EtOAc/hexanes) gave 2-5 as a yellow oil.
Reaction SMILES: [Na].Cl[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH2:25][CH2:26][CH3:27])=[C:8]([C:10]2[NH:11][C:12](=[O:23])[C:13]3[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=3[N:15]=2)[CH:9]=1.[CH2:28]([OH:30])[CH3:29]>>[CH2:28]([O:30][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH2:25][CH2:26][CH3:27])=[C:8]([C:10]2[NH:11][C:12](=[O:23])[C:13]3[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=3[N:15]=2)[CH:9]=1)[CH3:29]
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: CCO
Agent: [Na]
Product: CCCOc1ccc(COCC)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1

Procedure:
Sodium (0.15 g, 0.0013 mol) was added portionwise to ethanol (40 ml) over 1 hour. 5-(5-Chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.5 g, 0.0013 mol) was then added to the solution and, after 3 days at room temperature, the solvent was removed by evaporation under vacuum. The residual solid was suspended in water (50 ml) and the suspension extracted with ethyl acetate (3×30 ml). The extracts were then combined, dried (Na2SO4) and evaporated under vacuum to give a green solid. Chromatography on silica gel (6 g) using a methanol in dichloromethane elution gradient gave, after crystallisation of the required product from a hexane-ethyl acetate mixture, the title compound as a white solid (0.2 g, 39%) m.p. 89°-90° C. Found: C,65.87; H,7.57; N,14.66. C21H28N4O3 requires C,65.60; H,7.34; N,14.57%.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:23]([NH:25][O:26][CH3:27])=[O:24])=[N:5][C:6](S(C)=O)=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2].C([N:39]1[CH2:43][CH2:42][C@@H:41]([NH2:44])[CH2:40]1)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:3]1[C:4]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:23]([NH:25][O:26][CH3:27])=[O:24])=[N:5][C:6]([NH:44][CH:41]2[CH2:42][CH2:43][NH:39][CH2:40]2)=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(S(C)=O)nc(N(C)CC(C)(C)C)c2C#N)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccc(C)c(Nc2nc(NC3CCNC3)nc(N(C)CC(C)(C)C)c2C#N)c1

Procedure:
3-{5-Cyano-6-[(2,2-dimethyl-propyl)-methyl-amino]-2-methanesulfinyl-pyrimidin-4-ylamino}-N-methoxy-4-methyl-benzamide (33 mg) and 1-N-Boc-3-(R)-aminopyrrolidine (30 mg), DIEA (0.2 mL) and p-dioxane (2 mL) were heated in a sealed tube at 75° C. for overnight. After the removal of the solvent in vacuo, the product was purified by silica gel column chromatography and treated with TFA/DCM (1:1) in order to remove the Boc-group. The product was then converted to hydrochloride salt by treating it with hydrochloric acid (1 M in ether) (Yield: 20 mg). MS (m/z): 567 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Product: c1cn(-c2nc(NCc3ccc4c(c3)OCO4)c3c4c(sc3n2)CCCC4)cn1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:6]([CH2:7][CH3:8])=[CH:5][S:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:12]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:6]([CH2:7][CH3:8])=[CH:5][S:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=1
Reactant: CCc1csc(CCc2ccnc(NC(=O)OC(C)(C)C)c2)c1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1csc(CCc2ccnc(N)c2)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
tert-Butyl N-{4-[2-(3-bromo-4-ethyl-2-thienyl)ethyl]-2-pyridyl}carbamate (1.34 g, 4.04 mmol) dissolved in dichloromethane (40 ml) was added with trifluoroacetic acid (40 ml) at 0° C. and stirred at 0° C. for 3 hours. The reaction solution was concentrated under reduced pressure, neutralized with saturated sodium hydrogencarbonate and extracted with chloroform, and then the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=3:1→1:1→ethyl acetate only) to obtain 524 mg (56%) of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:12][OH:13])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:3][CH:2]([OH:1])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of t-butyl N-(2,3-dihydroxypropyl)carbamate (9.0 g, 47 mmol) in CH2Cl2 (75 mL) was added t-butyldimethylsilyl chloride (7.80 g, 51.7 mmol), triethylamine (7.86 mL, 56.4 mmol) and DMAP (230 mg). The solution was stirred at rt overnight. After diluting with CH2Cl2 (50 mL), the solution was washed with water (2×100 mL), dried over MgSO4 and concentrated. The residual oil was distilled by Kugelrohr under vacuum to give the desired product (13.6 g, 95%). MS (DCI) m/z 306 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl.Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:11]([CH3:10])(=[O:13])=[O:12])[CH:6]=[C:7]([I:9])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(F)cc(I)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc(F)cc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Dissolve 3-fluoro-5-iodoaniline (600 mg, 2.53 mmol) (prepared as described in published PCT International Application WO96/23783 A1, published Aug. 8, 1996), methanesulfonyl chloride (896 mg, 7.83 mmol), triethylamine (1.91 g, 18.9 mmol), and N,N-dimethylamino-4-pyridine (31 mg, 0.253 mmol) in CH2Cl2 (10 mL) and stir at room temperature overnight. Dilute with 1.00N aqueous HCl (20 mL) and extract into ethyl acetate. Dry (MgSO4) and concentrate organics to a yellow solid. Dissolve solid in THF (50 mL) and add 1.0M tetrabutylammonium fluoride (2.8 mL). Heat to reflux for 3.5 h. Cool to room temperature, dilute with H2O, and extract into ethyl acetate. Dry (MgSO4) and concentrate organics. Chromatograph on silica gel (40 g), eluting with 20% to 35% ethyl acetate/hexanes affords 618 mg (78%) of the title compound as a white solid. MS (ES) 314 (M−H); HPLC shows 100% purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]2=[CH:12][C:11]=1[C:19]([OH:21])=O.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([O:35][NH2:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH2:31][CH:32]([O:35][NH:36][C:19]([C:11]2[CH:12]=[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][N:14]3[C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:21])[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(ON)CC1
Reactant: O=C(O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(ONC(=O)c2cc3ccncn3c2Nc2ccc(I)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
7-(2-Fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (190 mg, 0.48 mmol), 4-aminooxy-piperidine-1-carboxylic acid tert-butyl ester (154 mg, 0.72 mmol), HOBt (106 mg, 0.79 mmol), EDCI hydrochloride (150 mg, 0.79 mmol) and DIPEA (120 μL, 0.72 mmol) were suspended in DMF (5 mL). The reaction was stirred at RT for 1 hour, during which time the reagents dissolved. The reaction mixture was concentrated in vacuo, the resultant residue dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethylacetate in cyclohexane) to yield the title compound as a brown solid (180 mg, 65%). LCMS (Method B): RT=3.69 min, M+H+−tBu=540 (100%), M+H+−Boc=496 (95%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]#[N:13])[C:9]([NH2:11])=[O:10])=[C:4]([N+:14]([O-])=O)[CH:3]=1>C(O)(=O)C.C1(C)C=CC=CC=1.[Zn]>[NH2:13][C:12]1[NH:14][C:4]2[C:5]([C:8]=1[C:9]([NH2:11])=[O:10])=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2
Reactant: N#CC(C(N)=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: NC(=O)c1c(N)[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 31.9 %

Procedure:
2-(4-Bromo-2-nitrophenyl)-2-cyanoacetamide (Reference compound 1-1, 0.60 g, 2.1 mmol) was dissolved in acetic acid (7.0 mL) and toluene (3.5 mL), and the whole was stirred at 90° C. Zinc powder (0.97 g, 15 mmol) was added portionwise to the solution while keeping at 90° C., and then the reaction mixture was stirred at room temperature for 45 minutes. Ice-water (30 mL) was added to the reaction mixture, and the whole was extracted with ethyl acetate (30 mL). The organic layer was washed with brine (30 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the mixture of the title reference compound (0.17 g) as a brown solid (yield 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:22])[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.C[O:24][C:25](=[O:48])[C@H:26]([C@@H:45]([CH3:47])O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([O:22][C@H:45]([CH3:47])[C@@H:26]([C:25]([OH:48])=[O:24])[NH2:27])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: COc1ccccc1C1(O)c2ccccc2-c2ccccc21
Product: COc1ccccc1C1(O[C@H](C)[C@H](N)C(=O)O)c2ccccc2-c2ccccc21

Procedure:
from 9-(2-methoxyphenyl)-9H-fluoren-9-ol (Example 3k) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:12])[CH3:11])=[N:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CC#N>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:2]=1)(=[O:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1nn(CC(=O)OC(C)(C)C)c2ccccc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(1H-indazol-3-yl)ethanone [4498-72-0](2 g, 12.46 mmol) in CH3CN (50 mL) was added K2CO3 (3.97 g, 28.7 mmol) and tert-butyl 2-bromoacetate (2.58 mL, 17.48 mmol). The reaction mixture was stirred at 90° C. overnight. The reaction mixture was filtered, the residue was washed with CH3CN and the filtrate was concentrated under vacuum. The material thus obtained was used directly in the next step without further purification. MS: 275 [M+H]+; tR (HPLC conditions d): 3.78 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]([CH:22]=[CH:23][C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]3[CH2:32][CH3:33])=[O:25])=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]([CH:22]=[CH:23][C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]3[CH2:32][CH3:33])=[O:25])=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1CCCCN1C(=O)C=Cc1c(-c2cccc(N)c2)nn2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1CCCCN1C(=O)C=Cc1c(-c2cccc(NS(C)(=O)=O)c2)nn2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 24.8 %

Procedure:
Methanesulfonyl chloride (0.59 g) was added dropwise to a stirred solution of 1-[3-{2-(3-amino-phenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer) (1.20 g) and triethylamine (0.52 g) in methylene chloride (7.2 ml) with ice-cooling. After being stirred at room temperature for 6 hours, the reaction mixture was washed twice with water and once with saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (22 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give crystals of 1-[3-{2-(3-methanesulfonamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer) (0.36 g).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.Cl[CH2:18][C:19](=[O:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:18][C:19](=[O:21])[CH3:20])[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: CC(=O)CCl
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CN1C(=O)C2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.5 %

Procedure:
To a mixture of 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (822 mg, 3.42 mmol), chloroacetone (0.429 ml, 5.12 mmol) in DMF (10 ml) was added K2CO3 (1.42 g, 10.3 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water and saturated aqueous NaCl, dried and concentrated in vacuo to give a crude solid. The crude residue was triturated with hexane/ethyl acetate (3:1), collected by filtration, rinsed with hexane/ethyl acetate (3:1) and dried to afford 2-chloro-5-(2-oxopropyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (737 mg, 2.48 mmol, 73% yield) as a pale brown solid. MS [M+H] found 297.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1.CCN(CC)CC.[Cl:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:26][CH2:27][CH2:28][CH2:29][C:30]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1)=[O:31]
Reactant: N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCl)N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a stirred slurry of benzyl N-[(1S,3R)-3-aminocyclohexyl]carbamate, 18e, (0.97 g, 3.41 mmol) in CH2Cl2 (34 mL), was added Et3N (1.00 mL, 7.15 mmol), followed by 4-chlorobutanoyl chloride (0.40 mL, 3.58 mmol). After stirring at room temperature, the mixture was diluted with CH2Cl2, washed with 1N HCl (2×), 1N NaOH (2×), and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 1.07 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[N:14][CH:13]=[C:12](Cl)[C:9]=2[C:10]#[N:11])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[N:14][CH:13]=[C:12]3[NH:18][N:19]=[C:10]([NH2:11])[C:9]=23)=[CH:6][CH:7]=1
Reactant: N#Cc1c(Cl)cncc1-c1ccc(N)cc1
Reactant: NN
Solvent: O
Product: Nc1ccc(-c2cncc3[nH]nc(N)c23)cc1
Temperature: 25 °C

Procedure:
The product from Example 1C (1.4 g) in hydrazine hydrate (10 mL) was heated at 110° C. for 3 hours, cooled to room temperature, and partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with 8% methanol in CH2Cl2 to provide 0.5 g of the title compound as a yellow solid. MS (ESI(+)) m/e 225 (M+H)+.