Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1.Cl>C(O)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:31]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)CC(=O)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cc(-c3ccc(OC)cc3)n(-c3ccc(OC)cc3)n2)cc1
Temperature: 25 °C

Procedure:
A mixture of the 1,3-diketone obtained in step 1 (1.0 equiv.), 4-methoxyphenyl hydrazine (1.5 equiv.), conc. HCl aq. (catalytic amount) and ethanol was heated to reflux overnight. Cooled to rt and removed solvent in vacuo. Water and ethyl acetate were added. The organic layer was separated, washed with dil. HCI, brine, dried, filtered and the solvent was concentrated in vacuo to give the product 1-[1,5-bis(4-methoxyphenyl)pyrazol-3-yl]-4methoxybenzene.
Reaction SMILES: C(OC(N1[C@H](C(O)=O)C(C)(C)SC1)=O)(C)(C)C.C1(OP([Cl:34])(OC2C=CC=CC=2)=O)C=CC=CC=1.CCN(CC)CC.C(N)C=C.Cl.C(OC([N:54]1[C@H:58]([C:59](=[O:64])[NH:60][CH2:61][CH:62]=[CH2:63])[C:57]([CH3:66])([CH3:65])[S:56][CH2:55]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:34].[CH2:61]([NH:60][C:59]([C@@H:58]1[C:57]([CH3:66])([CH3:65])[S:56][CH2:55][NH:54]1)=[O:64])[CH:62]=[CH2:63]
Reactant: C=CCNC(=O)[C@H]1N(C(=O)OC(C)(C)C)CSC1(C)C
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)(C)OC(=O)N1CSC(C)(C)[C@H]1C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C=CCN
Solvent: CCOC(C)=O
Product: C=CCNC(=O)[C@H]1NCSC1(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of (R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester (105 kg, 402 mol) and ethyl acetate (690 L) was treated with diphenylchlorophosphate (113 kg, 422 mol) and was then cooled to 0° C. NEt3 (85.5 kg, 844 mol) was added while maintaining the temperature at 5° C., and the mixture was then held at this temperature for 2 h. The mixture was cooled to 0° C., and allylamine (24.1 kg, 422 mol) was then added while maintaining the temperature at 5° C. The mixture was warmed to 20° C. and was then quenched with 10 wt. % aqueous HCl (310 L). After separation ofthe layers, the organic fraction was washed with 8.6 wt. % aqueous Na2CO3 (710 L). After separation of the layers, the aqueous fraction was extracted with ethyl acetate (315 L). The combined ethyl acetate extracts containing AG-074278 were dried by azeotropic distillation at one atmosphere, while maintaining a minimum pot volume of approximately 315 L. The resulting suspension of (R)-4-Allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acid tert-butyl ester was cooled to 5° C. A 13 wt. % solution of anhydrous HCl (36.8 kg, 1008 mol) in ethyl acetate (263 L) was cooled to 5° C. and was then added to the (R)-4-Allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acid tert-butyl ester suspension while maintaining the temperature at 15° C. The resulting suspension was held at 20° C. for 19 h, and was then cooled and held at 5° C. for 2 h. The suspension was then filtered, using cold ethyl acetate for rinsing. The wet cake was dried under vacuum at 45° C. to give 90.5 kg (95.2%) of (R)-5,5-Dimethyl-thiazolidine-4-carboxylic acid allylamide hydrochloride as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.94 (app t, J=5.5 Hz, 1H), 5.82 (ddt, J=10.4, 17.2, 5.2 Hz, 1H), 5.19–5.25 (m, 1H), 5.10–5.14(m, 1H),4.38(ABq, JAB=9.8Hz, Δν=14.5Hz, 2H),4.08(s, 1H), 3.72–3.91 (m, 2H), 1.58 (s, 3H), 1.32 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.7, 132.2, 114.0, 67.9, 51.4, 43.5, 39.3, 25.3, 24.3; MS (CI) m/z 201.1070 (201.1062 calcd for C9H17N2OS, M+H+); elemental analysis calcd for C9H17ClN2OS: C, 45.65; H, 7.24; N, 11.83; Cl, 14.97; found: C, 45.41; H, 7.33; N, 11.69; Cl, 15.22.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][C:23]([NH:36][C:37](=[O:39])[CH3:38])([CH3:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=2)[NH:27][CH:26]=1>>[OH:6][C:5]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:7])[C:4]=1[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:26]1[NH:27][C:28]2[C:33]([C:25]=1[CH2:24][C:23]([NH:36][C:37](=[O:39])[CH3:38])([CH3:22])[CH3:35])=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=2
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Reactant: CC(=O)NC(C)(C)Cc1c[nH]c2cc(C)ccc12
Reactant: O=Cc1ccccc1
Product: CC(=O)NC(C)(C)Cc1c(C(C2=C(O)C(C)(c3ccccc3)C2=O)c2ccccc2)[nH]c2cc(C)ccc12

Procedure:
Using general procedure C, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with benzaldehyde and N-[1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethyl]-acetamide (from Example 1.2) to give the title compound as a pale yellow solid. MS: 505.5 ([M−H]−).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Br:31][CH2:32][CH2:33]Br>CN(C)C=O>[Br:31][CH2:32][CH2:33][N:19]1[C:18]([O:22][CH3:23])=[N:17][C:16]2[C:20]1=[N:21][C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])=[N:14][C:15]=2[NH2:24]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCBr)c2n1

Procedure:
The compound obtained in Example 2-1 step (v) (2 g), potassium carbonate (3.7 g) and 1,2-dibromoethane (0.6 ml) were added to dimethylformamide (20 ml), and the same manner to Example 2-13 step (i) was conducted to give the titled compound as a cream colored solid. Yield: 1.2 g (62%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][CH:10]=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20].O>C(#N)C>[CH:10]([NH:9][NH:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)(=[O:29])=[O:30])=[CH:7][CH:6]=1)=[O:11]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(NNC=O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: O=CNNc1ccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
15.1 g of 2-(4-aminophenyl)-1-formylhydrazine and 14 ml of triethylamine were dispersed in 50 ml of acetonitrile. To the dispersion, a solution containing 50 ml of acetonitrile and 22.1 g of 3-nitrobenzenesulfonyl chloride was added dropwise while stirring at room temperature. After heating at 60° C. for 2 hours, the reaction mixture was cooled and then poured into water. The resulting crystals were collected by filtration. 15 g of the object compound was obtained.
Reaction SMILES: [C:1]1(=[CH:6][C:7](=[O:9])[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]1([CH2:15][C:16](=[O:18])[CH3:17])CCC[CH:11]=1.C(CC(=O)C)(=O)C>C1C=CC=CC=1.CCCCCCC.[Cl-].[Zn+2].[Cl-]>[C:7]([CH:6]1[C:1]2([CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:17][C:16](=[O:18])[CH:15]=[C:10]1[CH3:11])(=[O:9])[CH3:8]
Reactant: CC(=O)CC1=CCCC1
Reactant: CC(=O)C=C1CCCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCCCC
Solvent: c1ccccc1
Solvent: CC(=O)CC(C)=O
Product: CC(=O)C1C(C)=CC(=O)CC12CCCC2
Yield: 2.1 %

Procedure:
In a Dean-Stark apparatus, a mixture of 1-cyclopentylidenepropan-2-one/1-cyclopentenylpropan-2-one (25:75, 600 g, 4.83 mol), acetylacetone (493 g, 4.83 mol), and zinc chloride (164.6 g, 1.21 mol) in benzene (500 ml) and heptane (500 ml) was heated at reflux for 2.5 d (44 ml water collected). The reaction mixture was poured into ice/water (1.5 l) and extracted with cyclohexane (0.6 l). The organic phase was washed with water (1 l), with a saturated aqueous solution of NaHCO3 (0.5 l), twice with a saturated aqueous solution of NaCl (1 l and 0.5 l), dried (100 g MgSO4), and concentrated (till 60° C./30 mbar). Vigreux-Distillation (0.08 mbar, bath temperature 180° C., head temp. 120-130° C.) of the crude product (615 g) followed by FC (2 kg SiO2, hexane/MTBE 2:1) gave 10-acetyl-9-methylspiro[4.5]dec-8-en-7-one (20.7 g, 2.1%). Boiling point: 150° C. (0.09 mbar).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:34]B(O)O>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:34])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CB(O)O
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Product: Cc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)[C@H](C(=O)N3CCC(F)(F)C3)C2)c(Cl)c1

Procedure:
The title compound was prepared in analogy to example 196 using (1R,2R,4R)-4-(2-chloro-4-bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 187 step 4) and methylboronic acid. White solid (19%). MS (EI): 500.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[CH:31]1([C:34]2[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=2)[NH2:37])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[C:34]([CH:31]4[CH2:33][CH2:32]4)[CH:35]=3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Nc1cccc(C2CC2)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)Nc3cccc(C4CC4)c3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 35.6 %

Procedure:
The title compound was prepared by following the same procedure as described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.150 g, 0.400 mmol), thionyl chloride (2.0 mL), 3-cyclopropyl aniline (0.079 g, 0.598 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.070 g of the desired product. 1HNMR (DMSO-d6): δ 0.66 (d, J=4.8 Hz, 2H), 0.93 (d, J=2.1 Hz, 2H), 1.57 (s, 6H), 1.92 (m, 1H), 3.10 (s, 2H), 6.77 (d, J=7.8 Hz, 1H), 7.18-7.48 (m, 7H), 9.69 (s, 1H), 11.13 (s, 2H); MS [M]+: 491.30.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([F:33])[CH:26]=1>O.CO>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[O:11][CH3:12])=[C:27]([F:33])[CH:26]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
1-(4-hydroxy-3-methoxyphenyl)ethanone (25.0 g, 0.15 mol) and potassium carbonate (15.4 g, 0.11 mol) were added to DMF (80 mL). 4-bromo-1-(bromomethyl)-2-fluorobenzene (50.2 g, 0.19 mol) was added to the mixture, and the mixture was stirred at room temperature for 2 hours and then stirred at 60° C. for 16 hours. Methanol (40 mL) was added to this reaction solution, which was stirred at 60° C. for 1 hour and then blended with water (200 mL). The precipitated crystals were filtered and washed with water and hexane. The crystals were vacuum-dried at 60° C. for 3 hours, yielding 1-[4-(4-bromo-2-fluorobenzyloxy)-3-methoxyphenyl]ethanone (52.7 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].COC(OC)OC.C([O-])=O.[NH4+:25].[CH3:26]O>O>[CH3:14][O:13][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH3:12])[N:1]=[CH:26][NH:25][C:4]2=[O:5]
Reactant: CO
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: O
Solvent: COC(OC)OC
Product: COc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 70 °C
Yield: 93 %

Procedure:
A suspension of 2-amino-4,5-dimethoxybenzoic acid (23.40 g), trimethoxymethane (52 mL), ammonium formate (30.00 g) and methanol (400 mL) was heated to 70° C. and refluxed for 4 h. After the reaction mixture was cooled to room temperature, 160 mL of water was added to the reaction. The mixture was filtered to afford the title compound as a yellow solid (22.70 g, 93.00%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, d6-DMSO) δ: 3.87 (s, 3H), 3.91 (s, 3H), 7.13 (s, 1H), 7.45 (s, 1H), 7.98 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5](=[O:13])[N:6]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:7]=1.[N:15]1([C:21](=[O:24])[CH:22]=[CH2:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[C:21]([N:15]1[CH2:20][CH2:19][N:18]([C:10](=[O:12])[CH2:9][CH2:8][N:6]2[CH:7]=[C:2]([Br:1])[C:3]([CH3:14])=[CH:4][C:5]2=[O:13])[CH2:17][CH2:16]1)(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)N1CCNCC1
Reactant: Cc1cc(=O)n(CCC(=O)O)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(C(=O)CCn2cc(Br)c(C)cc2=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.9 %

Procedure:
A mixture of 3-(5-Bromo-4-methyl-2-oxopyridin-1(2H)-yl)propanoic acid (112 mg, 0.43 mmol), 1-(piperazin-1-yl)prop-2-en-1-one (80 mg, 0.43 mmol), HATU (163 mg, 0.43 mmol) and Et3N (0.2 mL, 1.43 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via Isolera One (silica cartridge, 0-6% MeOH/DCM) to afford the desired product (22.8 mg, 14 yield). 1H NMR (300 MHz, CDCl3) δ: 7.73 (s, 1H), 6.55 (dd, J=10.5, 16.7 Hz, 1H), 6.46 (s, 1H), 6.32 (dd, J=1.8, 16.8 Hz, 1H), 5.75 (dd, J=1.8, 10.5 Hz, 1H), 4.20 (t, J=6.0 Hz, 2H), 3.4-3.6 (m, 8H), 2.86 (t, J=6.0 Hz, 2H), 2.22 (s, 3H). ESI-MS m/z: 382.05 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].C(N(CC)CC)C.[C:12](Cl)(=[O:19])[C:13]1C=CC=CC=1.C(O)(=O)[C:22](O)=[O:23]>C(OCC)(=O)C>[C:12]([O:3][CH:2]([CH3:4])[CH2:1][O:23][CH3:22])(=[O:19])[CH3:13]
Reactant: O=C(O)C(=O)O
Reactant: CC(C)=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCC(C)OC(C)=O

Procedure:
Into a four-necked flask equipped with a condenser, a stirrer and a thermometer, 174.5 parts of the resin obtained and 1,047 parts of acetone were charged to obtain a solution. To the solution, 19.7 parts of triethylamine was added and the resultant mixture was heated to 40° C. To the mixture, 18.3 parts of benzoyl chloride was added dropwise over 30 minutes and the resultant mixture was kept at 40° C. for 3 hours. The obtained mixture was mixed with 698 parts of ethyl acetate and 640 parts of 0.5% aqueous solution of oxalic acid. the resultant mixture was separate to obtain the organic layer and the aqueous layer. The organic later obtained washed with an aqueous solution of oxalic acid. The obtained organic layer was mixed with 698 parts of ethyl acetate, 698 parts of propylene glycol methyl ether acetate and 436 parts of water. The resultant mixture was stirred and separated to obtain the organic layer. The organic layer was washed four times with water and concentrated under reduced pressure. The residue was mixed with propylene glycol methyl ether acetate to concentrate under reduced pressure to obtain 543 parts of a propylene glycol methyl ether acetate solution containing the resin (the content of the solid: 33.7%). The resin obtained is called as A1.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([C@@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])[CH2:12][OH:13])C1C=CC=CC=1.[H][H].O>[Pd].CO>[NH2:10][C@@H:11]([C@@H:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH3:15])[CH2:12][OH:13]
Reactant: [H][H]
Reactant: C[C@H](OC(C)(C)C)[C@@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: C[C@H](OC(C)(C)C)[C@H](N)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a round bottom flask containing benzyl((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (5.27 g, 17.8 mmol) was added MeOH (100 mL). Solution was degassed with nitrogen for 15 min at which time palladium on carbon (0.95 g, 0.89 mmol) in MeOH (5 mL) was added. A hydrogen atmosphere was then inserted. Resulting reaction mixture allowed to stir 40 min at room temperature at atmospheric pressure when water (2 mL) was added and once again a hydrogen atmosphere was inserted at atmospheric pressure and the subsequent reaction mixture allowed to stir 18 hr at room temperature. The reaction mixture was filtered through a pad of celite and concentrated to a brown oil. Oil redissolved in toluene and concentrated to afford (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (2.5 g, 15.5 mmol, 87% yield) as a brown oil. LCMS m/z 162.1 (M+H)+, Rt 0.41 min (Mass ion only, no UV peak).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:8]=1.[CH3:23]O>>[CH3:15][CH2:7][CH2:8][CH:9]([CH3:16])[CH3:10].[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:23])=[O:12])=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:8]=1
Reactant: O=C(O)c1ccc(O)cc1-c1ccc(F)cc1
Reactant: CO
Solvent: O=S(=O)(Cl)Cl
Product: CCCC(C)C
Product: COC(=O)c1ccc(O)cc1-c1ccc(F)cc1
Yield: 65 %

Procedure:
Sulphuryl chloride (4.4 ml) was carefully added to a solution of 4-hydroxy-2-(4-fluorophenyl)benzoic acid (20.8 g, 0.0896 mol) (from Example 32) in methanol (220 ml) and the mixture heated at reflux for 16 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and aqueous NaHCO3 (pH ˜8). The organic phase was washed with water, brine, dried (MgSO4), filtered and evaporated to give a sticky brown solid which, on trituration with isohexane, gave methyl 4-hydroxy-2-(4-fluorophenyl)benzoate (14.34 g, 65% yield).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[S:11][CH:12]=[CH:13][C:14]=3[C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[C:4]2[CH:3]=[CH:2]1.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>>[CH2:22]([NH:24][C:25]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:1][CH:2]=[CH:3][C:4]=23)=[CH:16][CH:17]=1)=[O:26])[CH3:23]
Reactant: Nc1ccc(-c2ccsc2-c2ccnc3[nH]ccc23)cc1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2ccsc2-c2ccnc3[nH]ccc23)cc1

Procedure:
Following the procedure described in Example 1 with 4-[2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-thienyl]aniline and ethyl isocyanate provided the title compound. ESMS [M+H]+: 363.2
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[Br:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[C:36]([F:41])[CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:38][C:37]1[CH:39]=[CH:40][C:34]([Br:33])=[CH:35][C:36]=1[F:41])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c2cnccc2n1C
Reactant: Nc1ccc(Br)cc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(Br)cc2F)c2cnccc2n1C
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A degassed solution of 1-methyl-3-(nonafluorobutane-1-sulfonyloxy)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (800 mg, 1.58 mmol), 4-bromo-2-fluoroaniline (360 mg, 1.89 mmol), Pd2dba3 (144 mg, 0.16 mmol), Xantphos (182 mg, 0.32 mmol) and DBU (538 μl, 3.79 mmol) in toluene (8 ml) was subjected to microwave irradiation at 120° C. for 5 minutes. The reaction mixture was cooled to ambient temperature then diluted with ethyl acetate (100 ml). The resultant solution was washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo to give a solid residue. The solid residue was purified by flash chromatography (Si-PPC, pentane:ethyl acetate, gradient 100:0 to 60:40) to afford the title compound as a yellow solid (210 mg, 34%). LCMS (method B): RT=2.33 min, M+H=392/394.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([CH2:9][NH2:10])[OH:8].O>ClCCl>[OH:8][CH2:7][CH2:9][NH:10][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: NCCO
Reactant: C=C1CC(=O)O1
Solvent: ClCCl
Solvent: O
Product: CC(=O)CC(=O)NCCO
Reaction time: 2 h

Procedure:
To a solution of diketene (42.1 g, 0.5 mol) in dichloromethane (100 ml), ethanolamine (30.5 g, 0.5 mol) was added dropwise at 10°-20.C with stirring, and the reaction was carried out at room temperature for 2 hrs. After pouring H2O (200 ml) into the reaction solution, an aqueous layer was separated, washed thrice with dichloromethane and was obtained N-(2-hydroxyethyl)-3-oxobutanamide as an aqueous solution.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30](ON3C(=O)CCC3=O)=[O:31])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl>O.O1CCCC1>[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]3)=[O:31])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reaction time: 0.17 h
Yield: 85 %

Procedure:
Piperidine-4-carboxylic acid (15.00 g, 116 mmol) was added to a solution of sodium hydrogen carbonate (12.7 g, 151 mmol) in water (200 mL) and the mixture was stirred for 10 min. A solution of 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy-2,5-pyrrolidinedione (Fmoc-Osu; 46.9 g, 139 mmol) in tetrahydrofuran (400 mL) was added. The solution was stirred at room temperature for 20 h and then acidified to pH 1 with 3 M HCl (500 mL). The mixture was extracted with ethyl acetate (200 mL then 100 mL) and the combined organic layers were washed with saturated brine (3×100 mL), dried (Na2SO4), filtered and concentrated to approximately 100 mL. Crystallization occurred on concentration. The mixture was allowed to stand for 2 h, then the filtered off, washed with ethyl acetate and dried in a vacuum oven at give N-[(9H-fluoren-9-ylmethoxy)carbonyl]piperidine-4-carboxylic acid 85%) as a white solid, mp 187–189° C. e following can also be prepared by this procedure: