Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])[N:19]([C:31]3[C:32]4[C@H:39]([CH3:40])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:18]2)[CH2:14][CH2:13]1)C1C=CC=CC=1.[ClH:41]>CO.C(Cl)Cl.CCOCC.[Pd]>[ClH:41].[ClH:41].[ClH:41].[CH3:40][C@H:39]1[C:32]2[C:31]([N:19]3[C:20]4[C:25](=[C:24]([CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:22][CH:21]=4)[C:15]4([CH2:16][CH2:17][NH:12][CH2:13][CH2:14]4)[CH2:18]3)=[N:36][CH:35]=[N:34][C:33]=2[CH2:37][CH2:38]1
Reactant: CC(C)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1[C@H](C)CC2
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)NCc1cccc2c1C1(CCNCC1)CN2c1ncnc2c1[C@H](C)CC2
Yield: 89 %

Procedure:
Ammonium formate (43 mg, 0.68 mmol) and 10% Pd/C (6 mg, 20% weight) was added to a solution of (R)—N-((1′-benzyl-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine (33 mg, 0.069 mmol) in MeOH (0.8 mL). The mixture was allowed to stir at reflux for 4 hours. After cooling, the reaction mixture was filtered through Celite. The filtrate was evaporated in vacuo. The residue was taken up in DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The crude residue was purified by column chromatography (5% 7 N ammonia in MeOH/DCM) to yield the free base, which was taken up in DCM and acidified with 2N HCl in Et2O. Evaporation of the solvents in vacuo gave (R)—N-((1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine trihydrochloride (24 mg, 89%) as a solid. LCMS (APCI+) m/z 392 [M+H]+; Rt=1.77 min.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:15].[C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)=[CH:20][C:19]=1[F:33])#[CH:17]>>[F:33][C:19]1[CH:20]=[C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:31]=[CH:32][C:18]=1[C:16]1[O:15][C:3]2[CH:4]=[CH:5][C:6]([CH2:8][C:9]3[N:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[CH:7][C:2]=2[CH:17]=1
Reactant: Oc1ccc(Cc2ncccn2)cc1I
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ncccn5)ccc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B3 and general procedure G from 2-iodo-4-(pyrimidin-2-ylmethyl)phenol (0.230 g, 0.74 mmol) and methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (0.220 g, 0.89 mmol). MS (ESI) m/z: Calculated: 431.2; Observed: 432.5 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].C(N(CC)CC)C.[CH2:17]([S:20](Cl)(=[O:22])=[O:21])[CH2:18][CH3:19].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:20]([CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21]
Reactant: Nc1ccc(F)cc1F
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenylamine (42, 3.0 mL, 29.8 mmol) in tetrahydrofuran (50 mL) were added triethylamine (9.13 mL, 65.5 mmol) and propane-1-sulfonyl chloride (2.90 mL, 25.8 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into 1 M HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the compound (72, 2.0 g, 28%) that was used in the next step.
Reaction SMILES: [N:1]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32][C@H:2]1[C:3]([N:5]([CH3:31])[C@@H:6]([C:17]([NH:19][C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:42][C@@H:43]([C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]([C:70]([NH2:72])=[O:71])[CH2:66][CH2:67][S:68][CH3:69])=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])[CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1.CC(O)=O.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[N:1]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32][C@H:2]1[C:3]([N:5]([CH3:31])[C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:42][C@@H:43]([C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]([C:70]([NH2:72])=[O:71])[CH2:66][CH2:67][S:68][CH3:69])=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])[CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Reactant: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 20 %

Procedure:
Condensation of BocPro-MeDTrp-PheOH (3.68 g.) and HDTrp-Leu-MetNH2 acetate salt (part B of Example 17, 3.32 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MeDTrp-Phe-DTrp-Leu-MetNH2 in 20% yield. De-t-butoxycarbonylation of BocPro-MeDTrp-Phe-DTrp-Leu-MetNH2 (1.00 g.) using trifluoroacetic acid in methyl ethyl sulfide and ethanedithiol gave HPro-MeDTrp-Phe-DTrp-Leu-MetNH2, which was isolated as the amorphous white solid phosphate salt monohydrate in 67% yield.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH3:26][O:27][C:28]1[N:29]=[CH:30][C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)=[N:32][CH:33]=1.NC1C=NC(OC)=CN=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH3:26][O:27][C:28]1[N:29]=[CH:30][C:31]([NH:34][C:35]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:36])=[N:32][CH:33]=1
Reactant: COc1cnc(NC(=O)Oc2ccccc2)cn1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: COc1cnc(N)cn1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)cn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenyl 5-methoxypyrazin-2-ylcarbamate (0.254 g, 1.2 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 2-amino-5-methoxypyrazine) in DMSO (2.5 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and was heated to 60° C. After 4 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated to a white solid. Trituration with diethyl ether provided the title compound as a white solid (365 mg, 75%). MS (APCI 10V) AP+ 486.25; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (t, J=5.46 Hz, 2H) 2.44 (t, J=5.46 Hz, 2H) 3.47 (t, J=5.46 Hz, 2H) 3.54 (t, J=5.46 Hz, 2H) 3.83 (s, 3H) 6.37 (s, 1H) 7.02-7.05 (m, 2H) 7.11 (d, J=7.8 Hz, 1H) 7.21 (d, J=8.57 Hz, 1H) 7.39 (dt, J=7.6 Hz, 2 Hz, 1H) 7.99 (d, J=1.6 Hz, 1H) 8.21 (dd, J=9.2 Hz, 2.7 Hz, 1H) 8.53 (m, 2H) 9.18 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)#[N:2].Cl.[OH-].[Na+].CCOCC>C1COCC1.ClCl>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1
Reactant: COc1cc2c(cc1OC)CN(CCC#N)CC2
Agent: Cl
Agent: ClCl
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CN(CCCN)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2-(2-cyanoethyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (5.70 g, 23.1 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0M, 81 mL, 81 mmol, 3.5 equiv) at room temperature. The mixture was stirred at reflux for 4.5 hours and then cooled to room temperature. Aqueous HCl (6N, 130 mL) was added cautiously at room temperature and stirring was continued for 2.5 hours at 55°-60° C. The mixture was cooled to 0° C., basified to pH 10-11 by addition of 6N aq. NaOH, and extracted with CH2 Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. To a solution of the residue in CH2 Cl2 (20 mL) was added HCl in ether (1.0M, 40 mL, 1.7 equiv). The resulting solution was added dropwise into ether (250 mL) with swirling. The precipitate was filtered and washed with ether (3×100 mL). This solid was taken up in water (50 mL), which was basified to pH 10 by addition of 1M aqueous NaOH, and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 5.10 g (88%) of white solid, which was characterized spectroscopically.
Reaction SMILES: C(N(CC)CC)C.C(O[CH:12]([CH2:17][CH3:18])[CH2:13][N+:14]([O-:16])=[O:15])(=O)C.[CH2:19]([SH:21])[CH3:20].Cl>C(#N)C>[CH2:19]([S:21][CH:12]([CH2:17][CH3:18])[CH2:13][N+:14]([O-:16])=[O:15])[CH3:20]
Reactant: CCC(C[N+](=O)[O-])OC(C)=O
Reactant: CCS
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCSC(CC)C[N+](=O)[O-]
Reaction time: 1 h
Yield: 86 %

Procedure:
2-Ethylthio-1-nitrobutane was prepared by dropwise addition of a solution of triethylamine (16.77 g., 0.166 mol) and acetonitrile (50 ml.) to a stirred solution of 2-acetoxy-1-nitrobutane (26.50 g., 0.164 mol) and ethanethiol (11.20 g., 0.164 mol) over 30 minutes at 0°-5° C. Upon complete addition, the resulting solution was stirred for 1 hour at 0°-5° C., and then was poured into dilute aqueous hydrochloric acid solution (500 ml.). The organics were extracted into methylene chloride (3×150 ml.) and the combined portions were washed with deionized water (2×200 ml.), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was distilled (1.5 Torr., 72°-75° C., internal) yielding a clear oil, 23.03 g., 86% yield. 1H-NMR (CDC13): δ 1.1, t, 3H, --CH3 ; 1.29, t, 3H, SCH2CH3 ; 2.5-2.85, m, 2H, --CH2 --; 2.6, q, 2H, SCH2 --; 3.28, m, 1H, CH; 4.5, d, 2H, --CH2NO2.
Reaction SMILES: C(N1C2C=CC=CC=2C2C1=CC=CC=2)C.C(Cl)(=O)C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:29](Cl)(=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl>[CH:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCC(=O)Cl
Agent: CCn1c2ccccc2c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Product: CCCCCCCC=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 234.2 %

Procedure:
To 7.83 g (40.1 mmol) of N-ethylcarbazole in 40 mL of CH2Cl2 are added 5.91 g (42.0 mmol) of benzoyl chloride and 5.88 g (44.1 mmol) of AlCl3. After stirring for 4 h at room temperature, 6.89 g (42.3 mmol) of octanoyl chloride and 5.92 g (44.4 mmol) of AlCl3 are added. This reaction mixture is stirred at room temperature for 4.5 h. Then, the reaction mixture is poured into ice-water. The products are extracted with CH2Cl2. The CH2Cl2 layer is washed with water, saturated NaHCO3 aq. solution and with brine, followed by drying over anhydrous MgSO4. Purification by column chromatography on silica gel with CH2Cl2-hexane(1:1) as eluent affords 12.7 g of a white solid (74.2%).
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: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: C=CCNC(=O)[C@H]1N(C(=O)OC(C)(C)C)CSC1(C)C
Agent: CC(C)(C)OC(=O)N1CSC(C)(C)[C@H]1C(=O)O
Agent: Cl
Solvent: C=CCN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
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: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH2:15][C:16](OC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH2:15][CH2:16][OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC1c2ccccc2-c2c(O)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCC1c2ccccc2-c2c(O)cccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
To a stirred solution of 277.5 mg (1.09 mmol) of the ester prepared in Example 14 in 5 mL of anhydrous THF at 0° C. was added dropwise 1.1 mL (1.1 mmol) of a 1M solution of lithium aluminum hydride in ether. The resulting mixture was stirred at 0° C. under nitrogen for 1.5 hours and then carefully quenched with Glaubers salt. The mixture was partitioned between EtOAc, ice, 2N HCl, and brine and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by PLC with CH2Cl2-EtOAc (10:1) to give 236.8 mg of the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[O:45]1[CH2:50][CH2:49][CH:48]([CH2:51][CH:52]=[O:53])[CH2:47][CH2:46]1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:52]([OH:53])[CH2:51][CH:48]2[CH2:49][CH2:50][O:45][CH2:46][CH2:47]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCC1CCOCC1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCOCC2)cc2cccnc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 57.4 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (5.0 g, 19.4 mmol) in dry tetrahydrofuran (125 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (18 mL, 29 mmol) to a 0° C. solution of diisopropylamine (4.4 mL, 31 mmol) in dry tetrahydrofuran (17 mL)] dropwise. The mixture was stirred at −78° C. for 5 min and then treated with (tetrahydro-pyran-4-yl)-acetaldehyde (3.7 g, 29 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 50% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanol as a colorless oil (4.3 g, 57%): LC/MS m/e calcd for C20H22N2O4S [M+H]+ 387.47, observed 387.1.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:13][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: BrC(Br)(Br)Br
Reactant: OC1CCC2(CC1)OCCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 17.4 grams (0.11 mole) of 1,4-dioxaspiro[4.5]decan-8-ol (prepared as in Step B of Example 8) and 46.2 grams (0.14 mole) of freshly recrystallized carbon tetrabromide in 100 mL of methylene chloride is cooled to about 0° C., and a solution of 32.3 grams (0.12 mole) of triphenylphosphine in 50 mL of methylene chloride is added dropwise. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 18 hours. After this time the reaction mixture is concentrated to about one quarter of the original volume. The concentrate is then passed through a pad of silica gel. Elution is accomplished with heptane. The eluate is concentrated under reduced pressure, yielding 8-bromo-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH3:17][SiH](C)C>C(Cl)Cl.CO>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH3:17])=[O:14]
Reactant: C[SiH](C)C
Reactant: Cc1cccc(NC(=O)CCC(=O)O)c1C
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCC(=O)Nc1cccc(C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 4-((2,3-dimethylphenyl)amino)-4-oxobutanoic acid (0.5 g, 2.26 mmol) in DCM (9 mL) and MeOH (2 mL) at room temperature was added 2.0 M diazomethyl)trimethylsilane (1.36 mL, 2.71 mmol) dropwise. The reaction was stirred at room temperature for 30 min and quenched with a solution of 20% AcOH in DCM). The mixture was concentrated and purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound as a white solid (0.52 g, 98% yield). LCMS, [M+H]+=236.4.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([O:25]CC)=[O:24])[N:21]=3)=[CH:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=3)=[CH:15][N:16]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(Cl)ccc4Cl)CC3)nc2)n1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(Cl)ccc4Cl)CC3)nc2)n1

Procedure:
The title compound was prepared in a similar manner as that described for Example 3 (step 5) from ethyl (5-{2-[4-(2,5-dichlorophenoxy)piperidin-1-yl]pyrimidin-5-yl}-2H-tetrazol-2-yl)acetate and aqueous NaOH.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[N:32][CH:33]=2)=[CH:22][C:5]=1[O:6][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])(=[O:3])[CH3:2]>O1CCOCC1.[OH-].[Na+]>[C:1]([C:4]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[N:32][CH:33]=2)=[CH:22][C:5]=1[O:6][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2cncnc2)ccc1C(C)=O)c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)c1ccc(OCc2cncnc2)cc1OC(CCC(=O)O)c1ccccc1C
Yield: 42.7 %

Procedure:
A solution of ethyl (RS)-4-[2-acetyl-5-(5-pyrimidinylmethoxy)phenoxy]-4-(2-methylphenyl)-butanoate (1.1 g) in dioxan (10 mL) and sodium hydroxide (5.3 mL; 1 M) is stirred at 25° C. for 45 minutes. The solution is evaporated, the residue is diluted with water, and brought to pH 6 by treatment with hydrochloric acid (2 M). The precipitate is extracted with ethyl acetate, washed with water, dried and evaporated. The residual oil is subjected to flash chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95:5 v/v), followed by trituration with diethyl ether to give (RS)-4-(2-acetyl-5-(5-pyrimidinylmethoxy)-phenoxy]-4-(2-methylphenyl)butanoic acid (0.44 g) in the form of a colourless solid, m.p.142-144° C. [NMR(CDCl3):- 2.2-2.7(4H,m),2.45(3H,s), 2.7 (3H,s),4.9(2H,q),5.5(1H,q),6.2-7.8(7H),8.7(2H,s), 9.2(1H,s)].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3/[CH:13]=[C:14]([C:17]4[N:18](C(OC(C)(C)C)=O)[CH:19]=[CH:20][CH:21]=4)[CH2:15][O:16]/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:16][CH2:15][C:14]([C:17]4[NH:18][CH:19]=[CH:20][CH:21]=4)=[CH:13]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1cccc1C1=C/C(=C2\C(=O)Nc3cc(F)ccc32)OC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cc(F)ccc2/C1=C1/C=C(c2ccc[nH]2)CO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl 2-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,5-dihydrofuran-3-yl]-1H-pyrrole-1-carboxylate (Example 37; 30 mg) in a mixture of trifluoroacetic acid (2 mL) and CH2Cl2 (10 mL) was stirred at room temperature for 16 hours. The mixture was evaporated to dryness, and re-dissolved in 1:1 THF/MeOH (4 mL). The solution was slowly added into diluted NaHCO3 solution (100 mL) with stirring. The precipitates were filtered, washed with water, and dried in vacuum to give (3E)-6-fluoro-3-[4-(1H-pyrrol-2-yl)furan-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as brown solid. Yield: 15 mg.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1CCO[CH:9]1[CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]([CH3:24])[C:15]1=[O:25]>>[CH3:24][C:16]1[C:15](=[O:25])[N:14]([CH2:13][CH:9]=[O:8])[C:23]2[C:18]([CH:17]=1)=[CH:19][CH:20]=[CH:21][CH:22]=2
Reactant: Cc1cc2ccccc2n(CC2OCCO2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2ccccc2n(CC=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into 3 mL of a 90% aqueous trifluoroacetic acid solution, 361 mg of 1-(1,3-dioxolan-2-ylmethyl)-3-methylquinolin-2(1H)-one was dissolved, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the reaction mixture was alkalified with an aqueous saturated sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The organic layer was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 354 mg of a pale yellow oily substance, (3-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde.