Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][O:19][C:20]([N:22]4[CH2:25][CH2:24][CH2:23]4)=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:34]([O:37][CH:38](Br)[CH3:39])(=[O:36])[CH3:35]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH:38]([O:37][C:34](=[O:36])[CH3:35])[CH3:39])=[O:27])=[C:15]([CH2:18][O:19][C:20]([N:22]4[CH2:25][CH2:24][CH2:23]4)=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC(C)Br
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(COC(=O)N4CCC4)CS[C@H]23)cs1
Agent: [Na+]
Product: CC(=O)OC(C)OC(=O)C1=C(COC(=O)N2CCC2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound obtained in Example 8 and 1-bromoethyl acetate were reacted, whereby the title compound was obtained.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]1([CH2:22][C:23]2[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[OH:1][CH:2]([CH2:3][O:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:24]=1)[CH2:4][N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: Oc1cccc(CN2CCCCC2)c1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CC(O)COc1cccc(CN2CCCCC2)c1
Temperature: 130 °C
Yield: 100.1 %

Procedure:
A mixture of 2-(oxiranylmethyl)-1H-isoindole-1,3-(2H)-dione (9.10 g) and 3-(1-piperidinylmethyl)phenol (8.55 g) was heated at 130° C. under nitrogen for 10 minutes. The resulting mixture was dissolved in chloroform (100 ml), washed with 1N sodium hydroxide (2×25 ml), dried (MgSO4) and evaporated to give the title compound as a gum (17.65 g). T.l.c. system B, Rf 0.60.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(C(OC)=O)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:14]([O-:16])=[O:15])[CH2:6]1)=[O:4].[Cl-].[Li+].O>CS(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:14]([O-:16])=[O:15])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(=O)OC)Cc2cccc([N+](=O)[O-])c2C1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1Cc2cccc([N+](=O)[O-])c2C1
Yield: 67.7 %

Procedure:
A mixture of 4.84 g dimethyl-4-nitroindane-2,2-dicarboxylate (0.0167 mol), 0.84 g lithium chloride (0.0198 mol), 1.1 mL water, and 18 mL dimethylsulfoxide was heated to 160 C under nitrogen for two hours. It was then allowed to cool and the dimethylsulfoxide was removed under high vacuum. The residue was purified on silica (10%-100% CH2Cl2 in hexanes) to give 2.5 g white solid (65%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[N:12]O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.O.[BH4-].[Na+]>CO.Cl[Ni]Cl>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][NH2:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(C=NO)c[nH]c2c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(CN)c[nH]c2c1

Procedure:
To a mixture of 6-methyl-1H-indole-3-carbaldehyde oxime (0.66 g) and NiCl2.6 H2O (0.97 g) in methanol (60 ml) was added at 22° C. sodium borohydride (3.04 g) in portions. The suspension was filtered and the filtrate evaporated. The residue was partitioned between aqueous NH3 (1%) and ethyl acetate, the organic layer was dried and evaporated to the give the crude title compound as a yellow semi solid (0.68 g).
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OC)=O.[F:14][CH:15]1[C:22](=O)[CH2:21][CH:20]2[N:24](C(OCC3C=CC=CC=3)=O)[CH:16]1[CH2:17][O:18][CH2:19]2>O1CCCC1>[F:14][CH:15]1[CH:22]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:21][CH:20]2[NH:24][CH:16]1[CH2:17][O:18][CH2:19]2
Reactant: O=C1CC2COCC(C1F)N2C(=O)OCc1ccccc1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC1CC2COCC(N2)C1F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of NaH (273 mg, 11.4 mmol) in tetrahydrofuran (30 mL) at 0° C. was added dropwise a solution of methyl 2-dimethoxyphosphorylacetate (2.1 g, 11.4 mmol) in tetrahydrofuran (10 mL). The reaction was stirred at 70° C. for 1 hour and then cooled to 0° C. again. To the reaction mixture was added a solution of benzyl 6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 100c (1.7 g, 5.7 mmol) in tetrahydrofuran (8 mL). The reaction was allowed to warm up to room temperature and stirred 2 hours. After being quenched with 1 N HCl, the solvent was evaporated under reduced pressure. Ethyl acetate (20 mL) was added. The mixture was washed with water, brine, dried over Na2SO4 and evaporated to dryness. The crude mixture was purified on silica gel, eluted with 0 to 20% EtOAc in hexanes, to give the desired product benzyl (7Z/E)-6-fluoro-7-(2-methoxy-2-oxo-ethylidene)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 100d (1.8 g, 89%). MS: calc'd (MH+) 350, measured (MH+) 350.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([N:33]3[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]3)[CH:24]=1)=[O:21])=[CH:15][CH:14]=[CH:13]2.Cl[C:40]1[N:45]=[CH:44][N:43]=[C:42]([NH:46][C:47](=[O:49])[CH3:48])[CH:41]=1>C1(C)C=CC=CC=1>[CH3:38][C:36]1[N:35]=[CH:34][N:33]([C:25]2[CH:24]=[C:23]([NH:22][C:20]([C:16]3[C:17]4[C:12](=[CH:11][C:10]([O:9][C:40]5[CH:41]=[C:42]([NH:46][C:47](=[O:49])[CH3:48])[N:43]=[CH:44][N:45]=5)=[CH:19][CH:18]=4)[CH:13]=[CH:14][CH:15]=3)=[O:21])[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=2)[CH:37]=1
Reactant: CC(=O)Nc1cc(Cl)ncn1
Reactant: Cc1cn(-c2cc(NC(=O)c3cccc4cc(O)ccc34)cc(C(F)(F)F)c2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(Oc2ccc3c(C(=O)Nc4cc(-n5cnc(C)c5)cc(C(F)(F)F)c4)cccc3c2)ncn1
Temperature: 110 °C
Reaction time: 50 h

Procedure:
Anhydrous tripotassium phosphate (848 mg, 4.0 mmol) is added to a stirred solution of 6-hydroxy-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-1-naphthalenecarboxamide (411 mg, 1.0 mmol) in toluene (40 mL) under an argon atmosphere at 110° C. N-(6-Chloro-4-pyrimidinyl)-acetamide (252 mg, 1.5 mmol) is added and the mixture is stirred at 110° C. for a further 50 hours. The solvent is evaporated off under reduced pressure and the residue is washed with a saturated aqueous solution of NH4Cl and dried. The crude product is purified by recrystallisation from methanol to afford the title compound as a beige solid, m.p.: 291-293° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22].CCN(C(C)C)C(C)C>C1COCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9]3[CH:10]=[CH:11][C:2]([F:1])=[C:3]([CH:8]=3)[C:4]([O:6][CH3:7])=[O:5])=[O:36])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1ccc(C#Cc2ccc(C(=O)Cl)cc2)cc1
Reactant: CCCCCCNc1ccc(F)c(C(=O)OC)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCN(C(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 128 %

Procedure:
To a solution of methyl 2-fluoro-5-(hexylamino)benzoate (185 mg; 0.73 mmol) in THF (15 mL) were added 4-[(4-butylphenyl)ethynyl]benzoyl chloride (260 mg; 0.88 mmol), DIEA (0.15 mL; 0.88 mmol) and DMAP (20 mg). The mixture was stirred at 60° C. under N2 atmosphere for 1 hour. It was then diluted with DCM (100 mL), washed with HCl 0.1N (50 mL) and a saturated solution of NaHCO3 (100 mL). The organic layer was dried over magnesium sulfate, filtrated and the solvent was removed under reduced pressure to give 480 mg of a brown solid. Purification by flash chromatography on silicagel (c-Hex/EtOAc, 90:10) gave 170 mg (45.3%) of the title compound as a white solid. HPLC, Rt: 6.14 min (purity=99.5%). LC/MS: M+(ESI): 514.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: OB(O)c1ccncc1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(OC3CCOCC3)nc(Cl)nc21
Temperature: 75 °C
Reaction time: 3 h
Yield: 50.5 %

Procedure:
To a solution of 2-chloro-5-iodo-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), pyridin-4-ylboronic acid (1.1 equiv), tetrakis(triphenylphosphine)palladium(0) (0.1 equiv) in a 5:1 mixture of 1,4-dioxane and water (0.17 M) was added sodium carbonate (2.1 equiv). The reaction was stirred at 75° C. for 3 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (magnesium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-90%) ethyl acetate (with 10% 1N ammonia in methanol) in hexane) to give the title compound (50.5% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.06 (s, 9 H) 0.82-0.91 (m, 2 H) 1.74 (dtd, J=12.74, 8.37, 8.37, 3.71 Hz, 2 H) 2.01-2.16 (m, 2 H) 3.50-3.63 (m, 4 H) 3.69-3.83 (m, 2 H) 5.50 (tt, J=7.91, 3.81 Hz, 1 H) 5.59 (s, 2 H) 7.72 (d, J=6.25 Hz, 2 H) 8.12 (s, 1 H) 8.60 (d, J=6.25 Hz, 2 H); MS (ESI) m/z 461.0 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.CO[C:43]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH:44]=1>O1CCCC1>[C:43]1([O:18][CH2:17][CH2:16][C:13]2[N:14]([CH3:15])[C:10]([S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[C:11]([CH:19]([CH3:21])[CH3:20])[N:12]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH:44]=1
Reactant: COC1=CCCCCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(CCOC2=CCCCCCC2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A solution of the compound 22 (690 mg, 2 mmol) and p-toluenesulfonic acid hydrate (400 mg, 2.1 mmol) in a mixture of tetrahydrofuran (10 mL) - toluene (100 ML) was concentrated under reduced pressure. The residue was dried on an oil bath at 55° C. for 40 minutes. The residue was dissolved in toluene (100 mL), and 1-methoxycyclooctene (1.84 g, 10 mmol) was added thereto. The reaction mixture was heated with reflux over 1 hours and concentrated to a small quantity. After cooling down at room temperature, triethylamine (0.4 mL) was added thereto. The reaction mixture was purified by chromatography on an alumina column (eluate: hexane - ethyl acetate (15:1)) to give the compound 47 (790 mg, 87%). Mp 73-74° C. PMR (CDCl3 -0.1% d5 -Py): δH1.24 (6 H, d, J 4.6 Hz, (CH3)2C), 3.13 (2 H, t, J 4.2 Hz, CH2 -Im), 3.08 (1 H, m, (CH3)2CH), 3.51 (3 H, 8, NCH3), 3.96 (2 H, t, J 4.2 Hz, OCH2), 4.51(1 H, t, J 5.6 Hz, =CH), 6.77 (2 H, d, J 2 Hz, arom-H), 7.09 (1 H, t-like, arom-H). IR(KBr)cm-1 : 3436, 3056, 1659, 1568, 1533, 1500, 1160, 1094. Elementary analysis (for C23H30N2Ocl2S) Calcd. : C, 60.91% H, 6.67% N, 6.18% S, 7.07% Cl, 15.63% Found: C, 60.74% H, 6.69% N, 5.94% S, 6.83% Cl, 15.43%
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:28])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][C:18]=3[CH:25]3[CH2:27][CH2:26]3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].C[N+](C)(C)CC1C=CC=CC=1.[CH3:43][S:44]([CH2:46][S:47][CH3:48])=[O:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:28])[C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[C:46](\[S:44]([CH3:43])=[O:45])/[S:47][CH3:48])=[CH:19][C:18]=3[CH:25]3[CH2:27][CH2:26]3)=[CH:14][CH:15]=2)=[CH:29][CH:30]=1
Reactant: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1
Reactant: CSCS(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CS/C(=C/c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1)S(C)=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
N-(4-Chlorophenethyl)-4-(2-cyclopropyl-4-formylphenoxy)benzamide (160 mg, 0.381 mmol) was diluted with THF (3 mL) followed by the addition of N,N,N-trimethyl(phenyl)methanaminium hydroxide (0.0866 ml, 0.191 mmol) and methylsulfinyl(methylthio)methane (94.7 mg, 0.762 mmol). The reaction was heated to 70° C. and stirred for 2 hours. The reaction was cooled and loaded directly onto a silica gel column, eluting with ethyl acetate to yield (Z)—N-(4-chlorophenethyl)-4-(2-cyclopropyl-4-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)benzamide (100 mg, 49.9% yield).
Reaction SMILES: [CH3:1][C:2]([NH2:7])([CH3:6])[CH2:3][S:4][CH3:5].[C:8](Cl)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(N(CC)CC)C>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]([NH:7][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:6])[CH2:3][S:4][CH3:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CSCC(C)(C)N
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
In tetrahydrofuran (300 ml) was dissolved 23.86 g (200 mmol) of 1,1-dimethyl-2-(methylthio)ethylamine, and 103.4 g (200 mmol) of a 30% solution of carbobenzoxy chloride in toluene and then a solution of 24.29 g (240 mmol) of triethylamine in tetrahydrofuran were slowly dropped thereinto under ice-cooling. After the resulting mixture was stirred at room temperature for 3 hours, the triethylamine hydrochloride precipitated was filtered under reduced pressure and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 36.35 g (yield 72%) of benzyl 1,1-dimethyl-2-(methylthio)ethylcarbamate.
Reaction SMILES: COC([CH:5]1[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:7][C:6]1=[O:14])=O.OCC1CC(CO)C[C:18]1=[O:24].[OH:25][CH2:26]C1C(CO)CCC1=O>>[CH3:26][O:25][C:18]([CH:7]1[CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:5][C:6]1=[O:14])=[O:24]
Reactant: O=C1CCC(CO)C1CO
Reactant: O=C1CC(CO)CC1CO
Reactant: COC(=O)C1CCC(=O)C1C(=O)OC
Product: COC(=O)C1CC(=O)C(C(=O)OC)C1

Procedure:
2,4-Bis(methoxycarbonyl)cyclopentanone (Compound 1A-A) is prepared as a mixture with 2,3-bis(methoxycarbonyl)cyclopentanone (Compound 1-Aa), e.g., by the process described in J. Org. Chem., 47, 2379 (1982). By converting the mixture into 2,4-bis(hydroxymethyl)cyclopentanone and 2,3-bis(hydroxymethyl)cyclopentanone, the two compounds can be separated from each other by silica gel column chromatography.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)([CH3:5])[CH2:3][NH2:4].C(N(C(C)C)CC)(C)C.[CH3:21][C:22]([O:25][C:26]([N:28]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[N:29]([C:37]1[C:42]([F:43])=[C:41](Cl)[N:40]=[C:39]([Cl:45])[N:38]=1)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:27])([CH3:24])[CH3:23].CCOCC>CN(C=O)C>[CH3:24][C:22]([O:25][C:26]([N:28]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[N:29]([C:37]1[C:42]([F:43])=[C:41]([NH:4][CH2:3][C:2]([CH3:1])([N:6]2[CH2:7][CH2:8][O:9][CH2:10][CH2:11]2)[CH3:5])[N:40]=[C:39]([Cl:45])[N:38]=1)[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[O:27])([CH3:21])[CH3:23]
Reactant: CC(C)(CN)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCC(C)(C)N2CCOCC2)c1F
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a stirred solution of commercially-available [2-methyl-2-(4-morpholinyl)propyl]amine (0.158 g, 1.00 mmol) in DMF (10 mL) under a nitrogen atmosphere at 0° C., was added diisopropylethylamine (0.19 mL, 1.1 mmol) followed immediately by tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.497 g, 1.00 mmol). The reaction was allowed to reach room temperature and was stirred overnight. Then ether was added, and the mixture was washed with water. The aqueous layer was back extracted with ether, and the combined organics were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (5-60% ethyl acetate in hexanes, 1% triethylamine) to provide tris(1,1-dimethylethyl)2-(2-chloro-5-fluoro-6-{[2-methyl-2-(4-morpholinyl)propyl]amino}-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate as a clear oil (0.578 g, 94%). LCMS: (M+H)+=619.4.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH3:15])=[O:5].[OH-].[Na+].Cl[CH:24]([F:26])[F:25]>C(COC)OC.O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([O:12][CH:24]([F:26])[F:25])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH3:15])=[O:5]
Reactant: FC(F)Cl
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OC(F)F
Temperature: 60 °C

Procedure:
To a solution of 2,6-dichloro-5'-hydroxy-4'-methoxy-2'-methyl-benzophenone (1.0 g; 3.2 mmol) in dimethoxyethane (7 ml) a solution of sodium hydroxide(0.6 g; 15 mmol) in water (1 ml) is added. The mixture is-heated to 60° C. with stirring, then a stream of chlorodifluoromethane is introduced for 20 minutes. After further stirring for 1.5 hours the solvent is evaporated. The residue is extracted with a mixture of trichloromethane and water. The organic phase is separated, dried and the solvent is evaporated. For purification, a flash column with silicagel (30g) is used (elution with mixtures of petrolether/ethylacetate 9:1, then 8:2, then 7:3 (v/v)). The resulting compound forms white crystals (0.6 g; 5.8% y); mp. 126°-128° C.
Reaction SMILES: C[NH:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]([C:10]1[C:11](=[O:20])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:9])=O.Cl.[CH3:22]N(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:22][O:6][C:4](=[O:5])[CH2:3][NH:2][C:7]([C:10]1[C:11](=[O:20])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc2ccccc2oc1=O
Reactant: CNCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1cc2ccccc2oc1=O
Reaction time: 0.5 h

Procedure:
To a round bottom flask containing methyl-glycine (89 mg, 1.00 mmol), 3-carboxy coumarine, anh. DCM (25 ml), under Ar, N′-(3 dimethylaminopropyl)-N-ethyl-carbodiimide hydrochloride (EDC) (479 mg, 2.50 mmol) and DMAP (489 mg, 4.00 mmol) were added at room temperature. The resulting mixture was stirred for 1 h 30 min (total conversion was observed by TLC). Then, DCM (20 ml) was added and the solution was washed successively with aq. NaHCO3 (10 ml, sat) and brine (10 ml). The organic phase was dried (Na2SO4), filtered and concentrated. The resulting orange solid obtained was purified by flash LC (silica gel, grad hex:EtOAc 1:1 to 2:1) to give the title compound (445 mg, quant) as a colourless oil. Rf=0.08 (Hex/EtOAc 1:1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[Br-:11].[Br-].O1CCOCC1>CCOCC>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: [Br-]
Reactant: CC(C)c1ccccc1O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of 2-isopropylphenol (12) (2.0 g, 14.6 mmol) in 15 ml of Et2O at 0° C. was added dioxane dibromide (3.62 g, 14.6 mmol, 1 eqv). The, solution was allowed to stir for 30 min at rt. The reaction mixture was washed with sat. NaCl and 10% NaHCO3. The Et2O phase was concentrated in vacuo and then vacuum distilled (142-145° C., 20 mm Hg) to yield 2.07 g of a clear oil (66%) which solidified upon standing: 1H NMR (500 MHz, CDCl3) δ 1.23 (d, J=3.7 Hz, 6H), 3.16 (m, 1H), 4.84 (s, 1H), 6.61 (d, J=8.6 Hz, 1H), 7.15 (d, J=11.0 Hz, 1H), 7.28 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 22.33, 27.17, 113.24, 116.99, 129.34, 129.50, 136.91, 151.81; LRMS (EI) (M+, 214/216).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:19][CH:18]=1>>[ClH:1].[C:8]1([C:6]2[N:5]=[C:4]3[CH2:13][CH2:14][CH2:15][C:3]3=[C:2]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:21][CH:22]=3)[CH:7]=2)[CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: Clc1cc(C2=CCCC2)nc2c1CCC2
Product: Cl
Product: NC(=O)Cc1ccc(Nc2cc(C3=CCCC3)nc3c2CCC3)cc1
Yield: 28.8 %

Procedure:
Following general procedure A2, 4-chloro-2-(cyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.100 g, 0.45 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.081 g, 0.54 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.048 g, 29%) as a light yellow solid. MW=420.38. 1H NMR (DMSO-d6, 500 MHz) δ 13.47 (s, 1H), 9.69 (s, 1H), 7.52 (s, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 6.92-6.88 (m, 1H), 6.71-6.68 (m, 1H), 3.42 (s, 2H), 3.12 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H), 2.61-2.54 (m, 4H), 2.19 (quin, J=7.5 Hz, 2H), 1.95 (quin, J=7.5 Hz, 2H); APCI MS m/z 384 [M+H]+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([CH2:7][C:8](OCC)=[O:9])#[N:6]>>[C:5]([CH2:7][C:8]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:9])#[N:6]
Reactant: CCOC(=O)CC#N
Reactant: NC1CC1
Product: N#CCC(=O)NC1CC1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
To a flask charged with cyclopropylamine (12.3 g, 215.3 mmol) was added ethyl cyanoacetate (9.8 g, 86.1 mmol). The reaction was stirred at 45° C. for 1.5 hour, cooled and concentrated under reduced pressure to give 10.7 g title compound (˜100%) as a light yellow solid. 1H NMR (300.132 MHz, CDCl3) δ 6.20 (bs, 1H), 3.34 (s, 2H), 2.75 (m, 2H), 0.83 (m, 2H), 0.59 (m, 2H).