Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][NH:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[C:27]([O:33]C)(=O)[CH2:28][C:29]([CH3:31])=O>C(Cl)Cl>[C:16]([CH:13]1[CH2:12][CH2:11][CH:10]([N:9]2[C:27](=[O:33])[CH2:28][C:29]([CH3:31])=[N:8]2)[CH2:15][CH2:14]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NNC1CCC(C(C)(C)C)CC1
Reactant: COC(=O)CC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=NN(C2CCC(C(C)(C)C)CC2)C(=O)C1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To the N′-(4-tert-butyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester (7.61 g) in CH2Cl2 (30 mL) was added TFA (10 mL). After 5 h at RT, the solvent was removed under reduced pressure. The residue was dissolved in glacial acetic acid (100 mL), methyl acetoacetate (4.46 g, 38.4 mmol) was added and the reaction was heated to 100° C. for 18 h. After allowing the reaction to cool to RT, the solvent was removed under reduced pressure. Flash chromatography of the residue (50% to 80% EtOAc/hexanes, silica gel) gave the two isomers of 2-(4-tert-butyl-cyclohexyl)-5-methyl-2,4-dihydro-pyrazol-3-one as pale yellow oils. Isomer 1: 2.67 g; TLC Rf 0.30 (silica gel, 1:1 EtOAc/hexanes); MS (ES+) m/z 237.0 (M+H+). Isomer 2: 0.66 g; TLC Rf 0.15 (silica gel, 1:1 EtOAc/hexanes); MS (ES+) m/z 237.4 (M+H+).
Reaction SMILES: BrBr.[CH2:3]=[CH:4][CH:5]=[CH2:6].[C:7]([O-:10])(=[O:9])[CH3:8].[K+].[C:12]([O-:15])(=[O:14])[CH3:13]>C(O)(=O)C>[C:7]([O:10][C:4]([CH3:3])=[C:5]([O:15][C:12](=[O:14])[CH3:13])[CH3:6])(=[O:9])[CH3:8]
Reactant: CC(=O)[O-]
Reactant: C=CC=C
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OC(C)=C(C)OC(C)=O

Procedure:
Halogen, e.g., bromine, and a conjugated diene, e.g., butadiene, are reacted in vapor phase, the reacted mass condensed and contacted with alkali metal acetate dissolved or dispersed in an acid, e.g., potassium acetate in glacial acetic acid, thus causing a reaction of formed dibromobutene-2 with the acetate to form diacetoxy-2-butene. The latter is hydrogenated to the corresponding diacetoxylated alkane. The diacetoxy alkane is hydrolyzed to the dihydroxy alkane, e.g., 1,4-butanediol. Alternately, the diacetoxy alkene can be hydrolyzed and the hydrogenation then conducted.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.I[CH3:14]>C1COCC1>[CH3:14][O:3][C:4]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CI
Reactant: COC(=O)C1(O)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(OC)CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
A 0° C. suspension of NaH (60% in mineral oil, 0.644 g, 16.09 mmol) (pre-washed with hexanes, 2×) in THF (10 mL) was treated slowly with a solution of methyl 1-hydroxycyclopentanecarboxylate (1.45 g, 10.06 mmol) in THF (10 mL), stirred at 0° C. for 15 min, treated with iodomethane (1.258 mL, 20.12 mmol), warmed to RT and stirred overnight. The mixture was poured into satd. NH4Cl, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford methyl 1-methoxycyclopentanecarboxylate (1.0 g, 63%). 1H NMR (400 MHz, CDCl3): δ 3.76 (s, 3H), 3.24 (s, 3H), 1.98-1.96 (m, 4H), 1.76-1.74 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.BrC1C=C(C(F)(F)F)C=CC=1.[Mg].[CH:25]([N:38]1[CH2:41][CH2:40][CH:39]1[C:42]#[N:43])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCOCC>[CH:25]([N:38]1[CH2:41][CH2:40][CH:39]1[C:42](=[NH:43])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N#CC1CCN1C(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)c1cccc([Mg]Br)c1
Agent: FC(F)(F)c1cccc(Br)c1
Agent: [Mg]
Solvent: CCOCC
Product: N=C(c1cccc(C(F)(F)F)c1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Suspend m-trifluoromethylphenylmagnesium bromide in ether by adding a solution of 18 g of m-bromobenzotrifluoride in 30 ml of ether to a stirred suspension of 1.94 g of magnesium turnings in 20 ml of dry ether. Upon completion of addition, allow the reaction mixture to cool to room temperature and add 7.95 g of 1-benzhydryl-2-cyanoazetidine.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:50])[C@@H:14]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([O:28][CH2:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[C:37](=[O:43])[NH:38][CH:39]3[CH2:42][CH2:41][CH2:40]3)=[O:31])[N:25]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3].[CH2:51](Cl)CCl.CO>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:50])[C@@H:14]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([O:28][CH2:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[C:37](=[O:43])[NH:38][CH:39]3[CH2:40][CH2:41][CH2:42]3)=[O:31])[N:25]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH3:51])=[O:18])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Product: CCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 150 mg 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid propyl ester in 3 ml DMF were added 42 mg EDC, 27 mg DMAP and 37 μl methanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 40 mg MS (ES+): m/e=710.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[Br:1][CH2:18][C:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:15]=1)=[O:19]
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
Bromine (80 mmol) was added dropwise over 5 min to a stirred solution of 4′-benzyloxyacetophenone (70 mmol) in 40 ml chloroform. This mixture was stirred for an additional 5 min and quenched with saturated sodium bicarbonate in water until the pH reached 7. The organic layers were combined, dried over MgSO4, and concentrated to dryness. The crude mixture was purified over a silica gel column and eluted with methylene chloride to yield 2-bromo-4′-benyloxyacetophenone. An Rf of 0.62 was observed when resolved by thin layer chromatography using methylene chloride. 1H nmr (δ, ppm, CDCl3), 7.97 (2H, δ, 9.2 Hz, O—Ar—C(O)), 7.43 (5H, m, Ar′CH2O—), 7.04 (2H, δ, 9.0 Hz, O—Ar—C(O)), 5.15 (2H, s, Ar′CH2O—), 4.40 (2H, s, CH2Br).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:26]([OH:27])=[CH:25][C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:35]=[O:36].C(NC(C)C)(C)C>ClCCl>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([C:18]3[C:26]([OH:27])=[CH:25][C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)([CH2:35][OH:36])[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=O
Reactant: Cc1ccc2c(c1)C(c1cc3c(cc1O)OCO3)C(=O)N2C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: Cc1ccc2c(c1)C(CO)(c1cc3c(cc1O)OCO3)C(=O)N2C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-5-methyl-1,3-dihydro-2H-indol-2-one (1.61 g, 3.60 mmol) and para-formaldehyde (0.43 g, 14.6 mmol) in dichloromethane (60.0 mL) was added diisopropylamine (7.20 mmol). After stirring at ambient temperature for 3 h, the reaction was quenched with saturated aqueous ammonium chloride (60.0 mL). The organic layer was separated and washed with water (3×100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexanes (20-60%) to afford the title compound (1.07 g, 63%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 10.09 (br, 1H), 7.37-7.16 (m, 12H), 6.99 (s, 1H), 6.87 (d, 1H), 6.62 (s, 1H) 6.54 (s, 1H), 6.37 (d, 1H), 5.87 (d, 2H), 4.45 (ABq, 2H), 2.33 (s, 3H); MS (ES+) m/z 480.4 (M+1).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]1)([O:15][CH3:16])=[O:14].[Cl:26][C:27]1[C:28]([CH:33]([NH2:50])[C:34]2[CH:43]=[C:42]3[C:37]([CH:38]=[CH:39][C:40]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[N:41]3)=[CH:36][CH:35]=2)=[N:29][CH:30]=[CH:31][N:32]=1>C1COCC1>[CH3:16][O:15][C:13]([C@H:17]1[CH2:18][CH2:19][C@H:20]([C:23](=[O:25])[NH:50][CH:33]([C:28]2[C:27]([Cl:26])=[N:32][CH:31]=[CH:30][N:29]=2)[C:34]2[CH:43]=[C:42]3[C:37]([CH:38]=[CH:39][C:40]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[N:41]3)=[CH:36][CH:35]=2)[CH2:21][CH2:22]1)=[O:14]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)CC1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A THF solution (15 mL) of CDI (1.2 g, 7.3 mmol) and trans-4-carbomethoxycyclohexane-1-carboxylic acid (1.2 g, 6.6 mmol) was stirred at 60° C. for 16 h. The reaction mixture was charged with C-(3-chloropyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (compound of Formula IV where Q1=2-phenylquinolin-7-yl) (2.3 g, 6.6 mmol) and stirred at 60° C. for 20 h. The reaction mixture was concentrated in vacuo, taken up in EtOAc, and washed with water (2×) and brine (1×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (20% EtOAc/Hexanes to 100% EtOAc) the desired product as an orange foam; 1H NMR (CDCl3, 400MHz) δ 1.48-1.55 (m, 4H), 1.95-2.06 (m, 4H), 2.17-2.24 (m, 1H), 2.26-2.33 (m, 1H), 3.66 (s, 3H), 6.77 (d, 1H, J=7.6 Hz), 7.36-7.41 (m, 1H), 7.45-7.55 (m, 3H), 7.72-7.77 (m, 1H), 7.81-7.89 (m, 2H), 8.11 (d, 2H, J=7.2 Hz), 8.20-8.25 (m, 1H), 8.39 (d, 1H, J=2.4 Hz), 8.60 (d, 1H, J=2.8 Hz); MS (ES+): m/z 515.0 [MH+]; HPLC: tR=3.1 min (Micromass Platform II, nonpolar—5 min).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
A suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and m-anisoyl chloride (0.4 g, 2.5 mmol) in THF 30 mL) was cooled to 5° C. Triethylamine (0.5 g, 4.8 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated, and the residue was stirred with 1N HCl (40 mL). The mixture was filtered, and the solid was slurried with hot ethanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-methoxy-benzamide (0.8 g, 93%) as a white solid: mp 244-246° C.; 1H NMR (DMSO-d6) δ 2.01-2.07 (m, 1H), 2.36-2.65 (m, 2H), 2.86-3.00 (m, 1H), 3.80 (s, 3H, CH3), 4.41-4.61 (m, 4H, 2CH2), 5.12-5.19 (dd, J=5.1 and 13.2 Hz, 1H, CH), 7.08-7.12 (m, 1H, Ar), 7.35-7.65 (m, 6H, Ar), 9.09 (t, J=5.6 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 31.17, 46.29, 51.59, 55.24, 112.41, 117.19, 119.44, 121.65, 128.31, 129.46, 130.67, 131.61, 134.68, 135.46, 140.12, 159.18, 166.08, 168.06, 171.00, 172.82; Anal. calcd. for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 64.62; H, 5.06; N, 10.23.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13]([O-])=[O:14]>>[Cl:8][C:5]1[S:4][C:3]2=[N:2][C:11]([CH2:10][Cl:9])=[CH:12][C:13](=[O:14])[N:7]2[CH:6]=1
Reactant: Nc1ncc(Cl)s1
Reactant: O=C([O-])CC(=O)CCl
Agent: Cl
Product: O=c1cc(CCl)nc2sc(Cl)cn12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
2-amino-5-chloro-thiazole hydrochloride (8 g) was reacted with 4-chloroacetoacetate (15.8 g) in polyphosphoric acid (40 g) under stirring at 110° C. for 1 hour. After cooling, dilution with water and neutralization with 35% NaOH, the precipitate was filtered and washed with water. Crystallization from isopropyl ether gave 2-chloro-7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 123°-125° C. (7.45 g), which was reacted with triphenylphosphine (9.42 g) in acetonitrile (100 ml) under stirring at reflux temperature for 10 hours. After cooling the precipitate was filtered and washed with acetonitrile to give (2-chloro-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl)-methyl-triphenylphosphonium chloride, m.p. 300°-310° C. dec. (10 g) which was suspended in dimethylsulfoxide (40 ml) and treated with potassium tert-butoxide (2.48 g) dissolved in dimethylsulfoxide (40 ml) at room temperature under stirring for 10 minutes. To the solution of the ylide so obtained 5 -formyl-2-methyl-thiazole (3.1 g) dissolved in dimethylsulfoxide (20 ml) was added and the reaction mixture was kept under stirring at room temperature for 15 minutes: after dilution with ice water and neutralization with NaH2PO4 the precipitate was filtered and crystallized from CH2Cl2 -methanol to give 3.4 g of 2-chloro-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 224°-226° C., NMR (CDCl3) δ ppm: 2.97 (s) (3H, --CH3), 6.61 (s) (1H, C-6 proton), 6.78 (d) (1H, β-ethenyl proton), 7.82 (d) (1H, α-ethenyl proton), 7.88 (s) (1H, C-3 proton), 8.02 (s) (1H, C-4 thiazolyl proton); JHαHβ =16 Hz.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[CH2:26][CH2:25][NH:24][CH2:23][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16]4)[N:12]=2)[CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[CH2:26][CH2:25][N:24]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:23][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16]4)[N:12]=2)[CH2:5][CH2:6]1
Reactant: Clc1ncccn1
Reactant: O=C1Cc2cc(-c3nc4c(c(N5CCOCC5)n3)CCNC4)ccc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1Cc2cc(-c3nc4c(c(N5CCOCC5)n3)CCN(c3ncccn3)C4)ccc2N1

Procedure:
Step 3—Synthesis of compound ud: 5-(4-Morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)indolin-2-one (0.083 g, 0.24 mmol), 2-Chloropyrimidine (0.0406 g, 0.354 mmol), N,N-Dimethylformamide (4.00 mL, 51.6 mmol) and N,N-Diisopropylethylamine (0.164 mL, 0.945 mmol) were combined and reaction mixture was microwaved on 300 watts, 120° C. for 30 minutes on a CEM microwave, and vacuum filtered. 1H NMR (400 MHz, DMSO) δ 10.60 (s, 1H), 8.44 (d, J=4.7, 2H), 8.24 (d, J=8.2, 1H), 8.20 (s, 1H), 6.92 (t, J=10.8, 1H), 6.70 (t, J=4.7, 1H), 4.82 (s, 2H), 3.98 (t, J=5.2, 2H), 3.77-3.69 (m, 4H), 3.57 (s, 2H), 3.47 (d, J=4.4, 4H), 2.75 (dd, J=8.8, 3.8, 2H). LC/MS-m/z+430.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH3:22][NH2:23]>CO>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:23][CH3:22])=[O:5]
Reactant: COC(=O)c1ccc(OCc2ccc(OC)cc2)cc1O
Reactant: CN
Solvent: CO
Product: CNC(=O)c1ccc(OCc2ccc(OC)cc2)cc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of methyl 2-hydroxy-4-[(4-methoxybenzyl)oxy]benzoate (500 mg, 1.73 mmol) in methanol (15 mL) was slowly added aqueous 40% methylamine (3 mL) at 0° C. After addition was complete the reaction mixture was kept on stirring at room temperature for 2 days. The volatiles were removed in vacuo to give the subtitled compound (500 mg).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][C@H:10]2[NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])=[O:6]>CO.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([NH:16][C@H:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=2)[CH2:12][CH2:11]1)=[O:25]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Method 1 LiOH (5 eq) was added to a suspension of (3R)-3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (B-01) (8.569 mmol, 1 eq) in methanol (35 ml) and water (8 ml), and the reaction mixture was stirred overnight at 25° C. Methanol was removed in vacuo and the residue was taken up in diethyl ether and water. The phases were separated and the aqueous phase was adjusted to pH 2 with 1N HCl. The aqueous phase was extracted with ethyl acetate (2×) and the combined organic phases were then dried over magnesium sulfate. After concentration, the desired product (3R)-3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid (E-01) was obtained. Yield: 93%
Reaction SMILES: [CH:1]([N:4]1[C:30](=[O:31])[C:29]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:27][CH3:28])[C:18]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][C:20]=4[C:11]3=[C:10]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:37][C:38](OC(C)=O)=[O:39].O.[NH4+].[OH-]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:38]([N:7]1[CH2:8][C:9]2[C:10]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[C:11]3[C:20]4[CH:19]=[C:18]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)[C:17]([O:27][CH3:28])=[CH:16][C:15]=4[CH2:14][CH2:13][N:12]3[C:29]=2[C:30](=[O:31])[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)(=[O:39])[CH3:37]
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(C)=O)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 32 mg of 10n in 200 μl of pyridine was treated with 30 μl of Ac2O and 1 mg of DMAP and was stirred at RT for 1 hr. Then, 2 ml of water was added and stirring was continued for 1 hr at RT. The mixture was made slightly alkaline by addition of conc. aq. NH4OH and was extracted with ethyl acetate. The organic layer was washed with a small amount of sat. NaCl, dried, concentrated and treated with diisopropyl ether, to give 30 mg of white crystalline 10p. Mp: 225-226° C.; Rf 0.40 (CH2Cl2/acetone 1/1). MS-ESI: [M+1] 541.12.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:15][C:16]1[C:24]2[O:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:18]2[CH:17]=[C:16]([CH3:15])[C:24]3[O:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Cc1cccc2c1OCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1OCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
0.396 g (2.24 mmol) 6-chloropyrimidine-4-carboxylic acid chloride and 0.328 g (2.46 mmol) aluminium trichloride in 10 mL DCM were stirred for 20 min at RT. Then 0.300 g (2.24 mmol) 7-methyl-2,3-dihydro-benzofuran in DCM were added dropwise to the reaction mixture and this was stirred for 1.5 h at RT. After the addition of water and DCM to the reaction mixture the phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution, dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: [CH:1]1([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[C:2]1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:41]I>C1COCC1.CCCCCC>[I:41][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[C:2]1
Reactant: II
Reactant: OCCCCCCOC1C#CCCCCC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: ICCCCCCOC1C#CCCCCC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a magnetically stirred solution of 6-(cyclooct-2-yn-1-yloxy)hexan-1-ol (126 mg, 0.566 mmol, 1 eq) in dry THF (1.5 ml) under Ar atmosphere, Imidazole (1.1 eq, 0.622 mmol, 42 mg) and Ph3P (1.3 eq, 0.736 mmol, 193 mg) were added. The solution was cooled to 0° C. and Iodine (0.680 mmol, 1.2 eq, 173 mg) was added in three portions. Solution was warmed to RT and stirred for 4 h. The reaction was monitored by TLC (hexane 100% as eluent), quenched by addition of a saturated solution of Na2SO3 (3 ml) and the phases were separated. The aqueous phase was extracted with Et2O and combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The obtained raw product was purified using a column of silica gel (40 g) and Hexane as eluent to obtain 3-[(6-iodohexyl)oxy]cyclooct-1-yne.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]2([NH2:29])[CH2:28][CH2:27][CH2:26]2)[N:21]=1>>[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]2([NH:29][C:15]([C:7]3[CH:6]=[N:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[C:9]([O:10][CH2:11][CH:12]4[CH2:13][CH2:14]4)[N:8]=3)=[O:17])[CH2:28][CH2:27][CH2:26]2)[N:21]=1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc(C2(N)CCC2)no1
Agent: Cl
Product: Cc1nc(C2(NC(=O)c3cnc(C4CC4)c(OCC4CC4)n3)CCC2)no1

Procedure:
The title compound was synthesized in analogy to Example 8e, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and 1-(5-methyl-1,2,4-oxadiazol-3-yl)-cyclobutanamine (CAN 1170897-128-5, 98.07 mg, 0.64 mmol) as starting materials, and isolated (50 mg, 31.67%) as off white solid; LC-MS (UV peak area, ESI) 99.91%, 370.0 (M+H).