Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=O.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[OH:27][CH2:26][C:25]([NH:24][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:14]=1[F:13])([CH3:29])[CH3:28]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
WSC HCl (7.68 g, 40 mmol) was added to a mixture of 2,4-difluorobenzoic acid (6.32 g, 40 mmol), 2-amino-2-methyl-1-propanol (3.56 g, 40 mmol) and HOBt (5.40 g, 40 mmol) in methylene chloride (150 ml), and stirred at room temperature for 3 hours. The reaction mixture was concentrated, dilutedwith ethyl acetate andwashed with saturated aqueous NaHCO3, 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively, dried over MgSO4 and concentrated under a reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (6.20 g; 68%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:3]=1.[Cl:29]N1C(C)(C)C(=O)N(Cl)C1=O.O>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C:3]=1[Cl:29]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)cc(N)c2F)c1F
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CC#N
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Cl)c(N)c2F)c1F
Temperature: 25 °C
Yield: 228.3 %

Procedure:
Benzyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (2.07 g, 5.12 mmol) was slurried in acetonitrile (20 mL) in a scintillation vial. 1,3-Dichloro-5,5-dimethylhydantoin (554 mg, 2.181 mmol) was added as a solid, and the reaction mixture was stirred at reflux for 1 h. After cooling to room temperature, water (40 mL) was added to precipitate the product. The solid was collected on a Buchner funnel and washed with water. Drying under vacuum at 55° C. gave a white solid (2.187 g, 97%): 1H NMR (400 MHz, CDCl3) δ 7.50-7.41 (m, 2H, aromatic), 7.41-7.20 (m, 5H, aromatic), 5.42 (s, 2H, CH2Ph), 4.92 (br s, 2H, NH2), 3.97 (d, J=1.2 Hz, 3H, OMe); 19F{1H} NMR (CDCl3) δ −128.19 (d, J=33.9 Hz, F2′), −137.79 (d, J=33.8 Hz, F5).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[CH:7]([CH:9]=[CH2:10])=O>O1CCCC1>[CH:9]([CH:10]1[O:6][CH2:5][CH:2]([CH3:1])[CH2:3][O:4]1)=[CH2:7]
Reactant: CC(CO)CO
Reactant: C=CC=O
Solvent: C1CCOC1
Product: C=CC1OCC(C)CO1

Procedure:
This invention provides a process for producing tetrahydrofuran by (1) the condensation of 2-methyl-1,3-propanediol with acrolein to form 2-vinyl-5-methyl-1,3-dioxane; (2) the conversion of the 2-vinyl-5-methyl-1,3-dioxane under hydroformylation conditions to 3-(5'-methyl-1',3'-dioxane)propionaldehyde; and (3) hydrogenation of the propionaldehyde derivative under acidic conditions to yield tetrahydrofuran.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH:11]([N:13]1[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:14]1)=[O:12].[ClH:25].[NH4+].[Cl-]>>[ClH:25].[CH:11]([N:13]1[CH2:18][CH2:17][N:16]([C:8](=[O:10])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:15]([CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:14]1)=[O:12]
Reactant: O=CN1CCNC(CN2CCCC2)C1
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: O=CN1CCN(C(=O)Cc2ccccn2)C(CN2CCCC2)C1

Procedure:
The compound was prepared by coupling of 2-pyridinylacetic acid with 4-formyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine; mp: (HCl salt) 125-128° C.; 1H NMR (free base, 200 MHz, CDCl3) δ1.5-1.7 (4H, m), 2.1-3.6 (10H, m), 3.7-4.9 (5H, m), 6.9-7.3 (2H, m), 7.6 (1H, m), 8.0 (1H, m), 8.6 (1H, m); MS (FAB) 317 (M+H)+; Anal. Calcd. for C17H24N4O2.2HCl.NH4Cl: C, 46.11; H, 6.83; N, 15.82. Found: C, 46.37; H, 6.51; N, 16.35.
Reaction SMILES: [CH:1]([CH2:3][C:4](O)=[O:5])=[CH2:2].OC1C2N=NNC=2C=CC=1.Cl.[NH2:18][CH2:19][CH2:20][C:21]1[C:25]2[CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=[CH:29][C:24]=2[O:23][CH:22]=1>ClCCl>[C:4]([NH:18][CH2:19][CH2:20][C:21]1[C:25]2[CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=[CH:29][C:24]=2[O:23][CH:22]=1)(=[O:5])[CH2:3][CH:1]=[CH2:2]
Reactant: COC(=O)c1ccc2occ(CCN)c2c1
Reactant: C=CCC(=O)O
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: C=CCC(=O)NCCc1coc2ccc(C(=O)OC)cc12
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Vinylacetic acid (1 mmol), 1-ethyl-3-(3-dimethylaminopropyl-3-ethyl)carbodiimide hydro-chloride (E.D.C.) (1.1 mmol) and hydroxybenzotriazole (HOBT) (1.1 mmol) are dissolved in dichloromethane (30 ml) in a flask cooled to −20° C. After 30 minutes, the compound obtained in Step A of Example 63 (1 mmol), dissolved in dichloromethane (20 ml), is added dropwise. The reaction mixture is stirred for 30 minutes at −20° C. and then overnight at ambient temperature. The dichloromethane is evaporated off and the residue is purified by chromatography on a silica gel column.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:41][CH:42]([CH3:51])[C:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44]>ClCCl>[C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)=[O:9])[CH2:47][CH2:46]1)(=[O:44])[CH:42]([CH3:51])[CH3:41]
Reactant: CC(C)C(=O)N1CCNCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.4 %

Procedure:
To a stirred mixture of 4-formylbenzoic acid (1.5 g, 10 mmol) in anhydrous dichloromethane (30 mL) was added triethylamine (2.52 g, 25 mmol), 1-hydroxybenzotriazole (1.5 g, 11 mmol), followed by 1-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride (2.1 g, 11 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C. and 2-methyl-1-(piperazin-1-yl)propan-1-one (2.12 g, 11 mmol) was added in portion-wise. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated citric acid (100 mL×2), followed by saturated sodium bicarbonate (100 mL×2), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 4-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde (2 g, yield 70%) as a light yellow oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.15 (d, 6H), 2.80 (brs, 1H), 3.39-3.80 (m, 8H), 7.58 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 10.07 (s, 1H); LC-MS (ESI) m/z: 289 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2
Reactant: [H][H]
Reactant: FC(F)(F)c1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: FC(F)(F)c1cccc(CC2c3ccccc3CCc3ccccc32)c1
Reaction time: 17 h

Procedure:
Add 5-(3-trifluoromethyl-benzylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.145 g, 0.41 mmol), to a mixture of 10% Pd/C (0.04 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (4.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite. Evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrated the filtrate to give the title product. MS (m/e): 352 (M+); GC retention time=7.11 min.
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH:11]=2)[N:7]=[C:6]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][N:26]=2)(=[O:24])=[O:23])[C:5]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42].[CH2:43]([OH:46])[CH2:44][OH:45].Cl>O>[OH:45][CH2:44][CH2:43][O:46][C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH:11]=2)[N:7]=[C:6]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][N:26]=2)(=[O:24])=[O:23])[C:5]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]
Reactant: OCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(-c3nnn[nH]3)c2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccnc(-c3nnn[nH]3)c2)nc1OCCO
Temperature: 85 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
6.2 g of sodium hydroxide were added to 15 g (26 mmol) of 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazole-5-yl)-pyridine-4-yl]-pyrimidine-4-yl]-amid and 75 ml of ethylene glycol. The mixture was heated to 85° C. for 5 hr. Then 55 ml of de-ionized water were added and thereafter 55 ml of 3 N hydrochloric acid were added dropwise. The mixture was allowed to cool down to 20° C. and was stirred for 1 hr. The solid was filtered off and dried at 70° C., 2000 Pa for 18 hr. There were obtained 16.2 g (103%) of 5-isopropyl-pyridine-2-sulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazole-5-yl)-pyridine-4-yl]-pyrimidine-4-yl]-amide with a HPLC purity of 92% (w/w). 80 ml of dioxane and 80 ml of ethanol were added to this solid. At a temperature of 60° C., gaseous ammonia was introduced into the liquid until pH=9 to 10. The resulting suspension was allowed to cool down to 20° C. and was stirred at 20° C. for 20 hr and thereafter at 0° C. for 2.5 hr. Then the solid was filtered off and dried at 70° C., 2000 Pa for 18 hr. There were obtained 14.2 g of mono ammonium salt with a HPLC purity of 96.2% (w/w). The solid was heated (reflux) in 70 ml of methanol, cooled down slowly to 20° C. and stirred at 20° C. for 19 hr and thereafter at 0° C. for 2 hr. Then the solid was filtered off and dried at 70° C., 2000 Pa for 19 hr. There were obtained 11.5 g (66% of theory) of 5-isopropyl-pyridine-2-sulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazole-5-yl)-pyridine-4-yl]-pyrimidine-4-yl]-amide sodium salt (1:2) with a HPLC purity of 98.6% (w/w).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[F-].[K+]>C1COCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:15]1[CH:16]=[CH:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=1
Reactant: COc1ccccc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 97.6 %

Procedure:
2-Bromoanisole (98 mg, 0.52 mmol) reacted with 4-trifluoromethylphenylboronic acid (145 mg, 0.76 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (90 mg, 1.55 mmol) in THF at room temperature for 3 h to give the title compound (128 mg, 97%). 1H-NMR (300 MHz, CDCl3): δ 13C{1H}-NMR (100 MHz, CDCl3): δ. GC/MS(EI): m/z (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].C(=O)([O-])[O-].[K+].[K+].[OH:27][C:28]1[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][N:29]=1>CN(C)C=O.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:34][C:32]3[CH:31]=[CH:30][NH:29][C:28](=[O:27])[CH:33]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: Oc1ccnc(O)c1
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=c1cc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A solution of 4-(chloromethyl)phenyl 4-chloro-3-(trifluoromethyl)phenyl ether (500, mg, 1.557 mmol), potassium carbonate (500 mg, 3.62 mmol) and 2,4-dihydroxypyridine (350 mg, 3.15 mmol) in N,N-dimethylformamide (DMF) (5 mL) was heated at 60° C. for overnight, then cooled to rt and diluted with acetonitrile. Solid suspension was removed by filtration, concentrated. Purification via Biotage-C18 system afforded the title product (310 mg) as a white solid. LC-MS (ESI): m/z 396 [M+H]+; 3.48 min (ret time).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][CH:12]([CH3:24])[CH2:13][CH:14]([C:17]1[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[CH2:15][NH2:16]>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:16][CH2:15][CH:14]([C:17]1[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[CH2:13][CH:12]([CH3:24])[CH3:11])=[O:6]
Reactant: Cc1ccccc1C(=O)O
Reactant: Cc1ccc(C(CN)CC(C)C)cn1
Product: Cc1ccc(C(CNC(=O)c2ccccc2C)CC(C)C)cn1

Procedure:
From 2-methylbenzoic acid and 4-methyl-2-(6-methylpyridin-3-yl)-pentylamine. LCMS (MH30 ): m/z=311.0, tR (minutes, Method A)=1.31
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:37]3[CH:38]=[CH:39][C:34]([CH:32]=[O:33])=[CH:35][CH:36]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc(C=O)cc3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 8A) (2.85 g, 4.86 mmol) and 4-formylphenylboronic acid (1.094 g, 7.30 mmol) in N,N-dimethylformamide (36.5 ml) was added saturated aqueous bicarbonate solution (12.16 ml) followed by bis(triphenylphosphine)palladium dichloride (0.239 g, 0.341 mmol). The mixture was heated to 70° C. for 2 hours, cooled to room temperature, and quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 70% ethyl acetate in hexane, to afford the title compound. MS ESI(+) m/z 564.5 [M+H]+.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:17])[CH:6]=[C:7]([CH2:15][CH3:16])[CH:8]([CH3:14])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH3:3].[CH2:18](O)[CH2:19]CC>C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:17])[CH:6]=[C:7]([CH2:15][CH3:16])[CH:8]([CH3:14])[CH2:9][CH:10]=[C:11]([CH3:12])[CH3:13])[CH2:3][CH2:18][CH3:19]
Reactant: CCCCO
Reactant: CCOC(=O)C=C(CC)C(C)CC=C(C)C
Agent: [Na]
Solvent: CC(=O)O
Product: CCCCOC(=O)C=C(CC)C(C)CC=C(C)C
Temperature: 100 °C
Yield: 73 %

Procedure:
A solution of 100 mg of sodium in 85 ml of n-butanol is placed in a flask filled with nitrogen and cooled to ca 5° C. At this temperature, 20 g (0.09 mol) of 3-ethyl-4,7-dimethyl-2,6-octadienoic acid ethyl ester are added. The mixture is then warmed to 60° C for 5 hours and to 100° C for 3 hours. For the working-up, the mixture is acidified with a few drops of glacial acetic acid and then the major part of the n-butanol is distilled off on a rotary evaporator. The residue is taken up in n-hexane, washed twice with sodium bicarbonate solution and three times with water, dried over sodium over sodium sulphate and evaporated. The crude product (19.3 g) is fractionally distilled. There are obtained 16.4 g (73%) of pure 3-ethyl-4,7-dimethyl-2,6-octadienoic acid n-butyl ester of boiling point 90°-92° C/0.04 mm Hg; nD 20 = 1.4677.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:15](=[O:17])[CH3:16])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (5 g, 25.2 mmol) was added to aluminum chloride (16.8 g, 126.2 mmol) in dichloromethane (200 ml) under nitrogen. The mixture was allowed to stir at room temperature for 1 hour. Acetyl chloride (9 ml, 126.2 mmol) in dichloromethane was added drop wise and the reaction was allowed to proceed at room temperature overnight. Next day the reaction was cooled to 0° C. and quenched with methanol (˜500 ml) until the reaction turned clear. The reaction was concentrated under vacuum and resuspended in water (300 ml). The pH was adjusted to 4 with 7N sodium hydroxide solution and then extracted with ethyl acetate (300 ml×3). The combined organic layers were extracted with saturated sodium potassium tartrate and brine and dried with Na2SO4. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 1-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)-ethanone (5.2 g, 87% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.48 (s, 3H), 8.41 (s, 1H), 8.57 (s, 1H), 8.58 (s, 1H). MS: m/z 241.0 (M+H+).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:6]=[CH:7][C:8]=1[C:9]1[CH2:14][CH2:13]S[C:11](=[O:15])[CH:10]=1)C.C(N)(=[O:29])C>>[O:29]=[C:11]1[CH:10]=[C:9]([C:8]2[CH:3]=[CH:4][C:5]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:6][CH:7]=2)[CH2:14][CH2:13][O:15]1
Reactant: CCc1cc(N2C[C@H](CNC(C)=O)OC2=O)ccc1C1=CC(=O)SCC1
Reactant: CC(N)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(=O)OCC3)cc2)C(=O)O1

Procedure:
N-((5S)-3-(3-ethyl-4-(2-oxo-5,6-dihydrothiapyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide and N-(5S)-3-(3-hydroxy-4-(2-oxo-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide are excluded.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7]2.[CH:20](OC(=O)C)=[O:21]>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:20]=[O:21])[CH2:7]2
Reactant: CC(=O)OC=O
Reactant: CCOC(=O)CNC1CCc2c(F)cc(F)cc2C1
Solvent: ClCCl
Product: CCOC(=O)CN(C=O)C1CCc2c(F)cc(F)cc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A solution of ethyl [(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino]acetate (7.15 g, 25.6 mmol) in 20 mL of methylene chloride under argon was cooled to approximately 0° C. Acetic formic anhydride (9.7 mL, 67.3 mmol) was cooled to 0° C. and added over 5 to 10 minutes. The mixture was stirred at 0° C. for 2 hours and then allowed to warm to room temperature. The solvent was removed by co-evaporation with toluene (3×50 mL). Crystallization of the residue under high vacuum gave ethyl [(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(formyl)amino]acetate (7.68 g, 25.0 mmol).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[K+].Cl>C(O)C.O>[OH:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(-c2ncccc2O)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1csc(-c2ncccc2O)n1
Yield: 92.4 %

Procedure:
To a solution of ethyl 2-(3-hydroxy-2-pyridyl)-4-thiazolecarboxylate (350 mg) dissolved in ethanol (7 ml) at 80° C. was added a solution of potassium hydroxide (436 mg) in water (5.5 ml) and the mixture was allowed to react at the same condition for 30 minutes. Then the reaction mixture was nuetralized with 1N--HCl under ice-cooling. The resulting solids were sucked off and dried to give yellowish crystals of 2-(3-hydroxy-2-pyridyl)-4-thiazolecarboxylic acid (287 mg, 92%), m.p. above 300° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1coc(C2CCCN2)c1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccco2)cc1

Procedure:
The title compound, white solid, m.p. 58° C. and MS: m/e=291 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-furan-2-yl-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1[CH:13]=[C:12]([CH:14]=O)[CH:11]=[N:10][CH:9]=1>C(Cl)(Cl)Cl>[N:8]1[CH:13]=[C:12]([CH:14]=[N:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:11]=[N:10][CH:9]=1
Reactant: Nc1ccccn1
Reactant: O=Cc1cncnc1
Solvent: ClC(Cl)Cl
Product: C(=Nc1ccccn1)c1cncnc1
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
A solution of 2-aminopyridine (11.314 g, 120.3 mmol) and pyrimidine-5-carboxaldehyde (14.0 g, 129.6 mmol) in chloroform (300 mL) was stirred at room temperature for 15 min. The volatiles were then removed under reduced pressure (1 h at 75° C.) to yield a yellow solid. The crude solid was dissolved in chloroform (300 mL) and the solution was stirred for 15 min. The volatiles were then removed under reduced pressure (1 h at 75° C.) to yield a yellow solid. The crude solid was again dissolved in chloroform (300 mL), the solution was stirred for 15 min, and the volatiles were removed under reduced pressure (1 h at 85° C.) to yield a yellow solid. This solid was dried in a vacuum oven overnight at 80° C. to yield 22.090 g (99.8%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](=[CH:24]\[CH:25]([CH3:27])[CH3:26])/[C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:28]1[CH:32]=[N:31][N:30]=[C:29]1[NH2:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](=[CH:24]\[CH:25]([CH3:26])[CH3:27])/[C:18]([CH3:23])([CH3:22])[C:19]([NH:33][C:29]4[S:28][CH:32]=[N:31][N:30]=4)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: CC(C)/C=C(\c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)O
Product: CC(C)/C=C(\c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)Nc1nncs1
Yield: 25 %

Procedure:
Example 139 was prepared from (E)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoic acid (105 mg, 0.29 mmol) and 1,3,4-thiadiazol-2-amine using General Coupling Method B to give 30 mg (25% yield). MS found: (M+H)+=450.