Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2>[Pd].CC1C=CC(C(C)C)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Product: COc1ccc2c(O)cccc2c1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A mixture of 6-methoxy-1-tetralone (20.84 g, 118.3 mmol), 10% Pd/C (10.1 g), and p-cymene (500 mL) was heated at reflux for 60 hours. The suspension was cooled to room temperature and filtered through Celite. The solid was washed with ethyl acetate until UV clear and the combined organic solution was extracted with 1 N sodium hydroxide (3×200 mL). The combined aqueous layers were made acidic with 6N HCl and extracted with ethyl acetate (3×300 mL). The combined organic layers were dried over magnesium sulfate and filtered. Evaporation of the solvent and purification on a silica column (25% ethyl acetate-hexanes) yielded 17.02 g (83%) of the title compound as a light brown solid. An analytical sample was prepared by purification on a second silica column (40-60% dichloromethane-hexanes) to yield a white solid: mp 73-75° C.; 1H NMR (DMSO-d6): δ 3.85 (3H, s), 6.70-6.74 (1H, m), 7.06 (1H, dd, J=2.34 Hz, J=9.15 Hz), 7.20-7.27 (3H, m), 8.02 (1H, d, J=9.12 Hz), 10.01 (1H, s); MS (ESI) m/z174 (M-H)−.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1>CN1CCCC1=O.C(OCC)(=O)C>[F:27][C:26]([F:28])([F:29])[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])=[CH:20][CH:21]=1)([OH:34])[C:30]([F:31])([F:33])[F:32]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C(=O)C1
Reaction time: 14 h
Yield: 31.6 %

Procedure:
To a stirring solution of tert-butyl 3-oxopiperazine-1-carboxylate (9.99 mmol, 2 g) in dry N-methyl-2-pyrrolidinone (2 mL) was added sodium hydride (30.0 mmol, 1.198 g). The mixture was stirred at room temperature under nitrogen for 20 min before the addition of 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (10.99 mmol, 3.70 g). The mixture was stirred for a further 14 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (4×75 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with dichloromethane—3.5% methanol/96.5% dichloromethane gradient) to afford the title compound (1.44 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=[C:10]2[CH:9]=1)(C)(C)C.O.C(OCC)(=O)C>Cl>[C:17]1([C:15]2[N:16]=[C:10]3[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][N:11]3[N:14]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A suspension of (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-carbamic acid tert-butyl ester (8.5 g, 27.4 mmol) in hydrochloric acid (6 N in diethyl ether, 175 ml) is stirred overnight at room temperature. The suspension is diluted under cooling with water (ca 2 l) and ethyl acetate, the aqueous layer is washed once with ethyl acetate, made alkaline with 32% aqueous sodium hydroxide and extracted twice with ethyl acetate. The combined organic layers are dried with magnesium sulfate and the solvent is removed in vacuo affording 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (5.52 g, 95.9%) as a light pink solid. mp.: 212-213° C. MS: m/z=211.2 (M+H+).
Reaction SMILES: [CH:1]12[O:10][CH:2]1[CH2:3][C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O)(=O)=O.O.C(#[N:19])C>C(Cl)Cl>[NH2:19][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10]
Reactant: CC#N
Reactant: c1ccc2c(c1)CC1OC21
Agent: CS(=O)(=O)O
Solvent: O
Solvent: ClCCl
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: -20 °C

Procedure:
Indene oxide (117 g) diluted to a total volume of 600 mL in methylene chloride was diluted with acetonitrile (600 mL) and cooled to -20° C. Methanesulfonic acid (114 mL) was then added. The mixture was warmed to 25° C. and aged for 2 h. Water (600 mL) was added and the mixture heated at 45° C. for 5 h. The organic phase was separated and the aqueous phase further heated at reflux for 4 h with concentration to approximately 200 g/L. The solution was adjusted to pH 12.5 with 50% aqueous sodium hydroxide, and then cooled to 5° C. and filtered, dried in vacuo, to provide cis 1-amino-2-indanol.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]([OH:15])=O)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH3:20]>C1(C)C=CC=CC=1.ClCCl.O1CCCC1.O1CCOCC1>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]([NH2:20])=[O:15])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N
Reactant: O=C(O)c1c[nH]c2cc([N+](=O)[O-])ccc12
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)c1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 60 °C

Procedure:
250 mg 6-nitro-1H-indole-3-carboxylic acid are dissolved in 10 ml of toluene, combined with 3 ml of thionyl chloride and refluxed for 1 hour. Then the volatile constituents are eliminated in vacuo, the residue is taken up in dichloromethane and this is in turn eliminated in vacuo. Then it is taken up in 10 ml of tetrahydrofuran, combined with 6 ml of a 0.5 M solution of ammonia in dioxane and heated to 60° C. for 12 hours. The solvents are eliminated in vacuo, the residue is extracted from 1 N hydrochloric acid and the solid obtained is suction filtered and dried in vacuo.
Reaction SMILES: CC1C=CC(S(OCC2CC3C(C)=C(Cl)C=C(C(C)C)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:31]([CH2:34][CH:35]1[CH2:39][C:38]2[C:40]([CH3:48])=[C:41]([Cl:47])[CH:42]=[C:43]([CH:44]([CH3:46])[CH3:45])[C:37]=2[O:36]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>O1CCCC1.C(O)(C)C.O>[Cl:47][C:41]1[CH:42]=[C:43]([CH:44]([CH3:46])[CH3:45])[C:37]2[O:36][CH:35]([CH2:34][NH2:31])[CH2:39][C:38]=2[C:40]=1[CH3:48]
Reactant: Cc1c(Cl)cc(C(C)C)c2c1CC(CN=[N+]=[N-])O2
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3c(C)c(Cl)cc(C(C)C)c3O2)cc1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)cc(C(C)C)c2c1CC(CN)O2
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
Treatment of (±)-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (6.64 g, 16.8 mmol) with sodium azide (3.28 g, 50.4 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran. To a solution of (±)-2-(azidomethyl)-5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran (4.44 g, 16.71 mmol) in tetrahydrofuran (100 mL) was added triphenylphoshine (5.25 g, 20.05 mmol) followed by water (10 mL) and the reaction mixture was allowed to stir at room temperature for 12 h. The solvent was removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, 10% ammonium hydroxide in methanol:ethyl acetate 1:9) provided a colorless oil. The oil was re-dissolved in isopropanol (5 mL) and hydrogen chloride (20.0 mL, 1.0 N in diethyl ether) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 4.08 g (88%) of (±)-1-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp >225° C. (dec); Anal. calcd. for C13H18ClNOHCl: C, 56.53; H, 6.93; N, 5.07. Found: C, 56.56; H, 6.91; N, 4.94.
Reaction SMILES: [NH3:1].[N:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=[C:3]=[S:4]>CO>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([NH:2][C:3]([NH2:1])=[S:4])[CH:10]=[CH:9][C:8]=1[C:11]1[O:15][N:14]=[C:13]([CH3:16])[N:12]=1
Reactant: COc1cc(N=C=S)ccc1-c1nc(C)no1
Reactant: N
Solvent: CO
Product: COc1cc(NC(N)=S)ccc1-c1nc(C)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
Step I (2): Methanolic ammonia (3.33 mL, 23.3 mmol) was added to a flask charged with 5-(4-isothiocyanato-2-methoxyphenyl)-3-methyl-1,2,4-oxadiazole (1.28 g, 5.18 mmol) in MeOH (12 mL). After stirring at rt for 24 h, the reaction mixture was concentrated to dryness in vacuo to afford 1-(3-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)thiourea (1.368 g, 5.18 mmol, 100% yield). LC-MS (M+H)+ 265.2. 1H NMR (400 MHz, methanol-d4) δ ppm 7.94 (d, J=8.56 Hz, 1 H) 7.77 (d, J=2.01 Hz, 1 H) 7.06 (dd, J=8.31, 2.01 Hz, 1 H) 3.95 (s, 3 H) 2.40 (s, 3 H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:26])[NH:15][C:16]2[CH:17]=[C:18]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)[CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[NH:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:26])[NH:15][C:16]2[CH:17]=[C:18]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)[CH2:9]1
Reactant: NS(=O)(=O)c1cccc(NC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1cccc(NC(=O)N[C@@H]2CCNC2)c1
Reaction time: 24 h

Procedure:
A solution of 3-[3-((R)-1-benzyl-pyrrolidin-3-yl)-ureido]-benzenesulfonamide (25 g, 0.067 mol) in ethanol (250 mL) is purged with nitrogen, and palladium hydroxide (2.5 g, 20% w/w) is added. The suspension is purged with hydrogen and stirred under a positive pressure of hydrogen for 24 hours. Filtration though Celite® (filter material) and removal of solvent under reduced pressure gives the product as a colourless waxy solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:37].[N:38]12[CH2:45][CH2:44][CH:41]([CH2:42][CH2:43]1)[C@@H:40]([NH:46][C:47]([C:49]1[O:50][C:51]3[C:57](Br)=[CH:56][CH:55]=[CH:54][C:52]=3[CH:53]=1)=[O:48])[CH2:39]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:37].[N:38]12[CH2:43][CH2:42][CH:41]([CH2:44][CH2:45]1)[C@@H:40]([NH:46][C:47]([C:49]1[O:50][C:51]3[C:57]([C:2]4[CH:7]=[CH:6][C:5]([N:8]5[CH2:12][CH2:11][CH2:10][C:9]5=[O:13])=[CH:4][CH:3]=4)=[CH:56][CH:55]=[CH:54][C:52]=3[CH:53]=1)=[O:48])[CH2:39]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Reactant: O=C1CCCN1c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccc(N4CCCC4=O)cc3)c2o1

Procedure:
161.9 mg (0.67 mmol) of 1-(4-bromophenyl)-2-pyrrolidinone, 197.5 mg (0.78 mmol) of bis(pinacolato)diboron, 165.4 mg (1.69 mmol) of potassium acetate, 19.0 mg (0.03 mmol) of PdCl2(dppf), 200 mg (0.52 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A), 1.30 ml of 2 M sodium carbonate solution and a further 19.0 mg (0.03 mmol) of PdCl2(dppf) in 2.5 ml of DMF are reacted by general method D. Drying under high vacuum results in 166.6 mg (65% of theory) of the title compound.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7]>ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[S:15]([C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=1)(=[O:16])=[O:17])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 91.2 %

Procedure:
Diethylamine (0.815 mL, 576 mg, 7.86 mmol) was added in one portion to a solution of 4-nitrobenzenesulfonyl chloride (582 mg, 2.62 mmol) in dichloromethane (10 mL). The resultant solution was stirred at 23° C. for 14 hours and then washed twice with 1N HCl (15 mL). The organics were dried over magnesium sulfate and concentrated to provide N,N-Diethyl-4-nitro-benzenesulfonamide as an off-white solid (617 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31](/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38])=[CH:32][CH:33]=4)[N:28]([CH3:40])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.C([O-])=O.[NH4+].O1CCCC1>[Pd].C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:32][CH:33]=4)[N:28]([CH3:40])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)(=[O:15])=[O:16])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(/C=C/C(=O)O)ccc23)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(CCC(=O)O)ccc23)cc1

Procedure:
10% Palladium-on-carbon (10 mg) was added to a stirred solution of (E)-3-[3-{1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolyl]-2-propenoic acid (the compound of Example 58, 80 mg, 0.14 mmol) and ammonium formate (64 mg, 0.5 mmol) in a 1:1 mixture of tetrahydrofuran and ethanol (10 ml total). The mixture was stirred at reflux for 48 h. cooled, filtered through Arbocel™ and concentrated. The grey foam was purified by flash column chromatography (elution with 98% dichloromethane/2% methanol) giving the product as a white foam.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:22]([O:24][C:25](Cl)=[O:26])[CH3:23]>C1COCC1>[S:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:25]([O:24][CH2:22][CH3:23])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCc2ccsc2C1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Reaction time: 3.5 h

Procedure:
A solution of tert-butyl 4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate in dry THF was cooled to −78°, n-butyl lithium (1.5 eq.) was added slowly and reaction mixture stirred for 3-4 hrs. This reaction mixture was then added to the solution of ethylchloroformate (10 eq.) in dry THF at −78° C. Reaction mass wan then allowed to come at room temperature and stirred overnight. It was then cooled and quenched with ammonium chloride solution and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude was then purified using column chromatography to yield 6-tert-butyl 2-ethyl 4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxylate.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[N:12][C:13]2[NH:14][CH2:15][CH2:16][CH2:17][C:18]=2[CH:19]=1.[C:21]([N:29]=C=O)(=[O:28])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:21]([N:14]1[C:13]2[N:12]=[CH:11][C:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:2])=[O:20])=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:28])[NH2:29]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: COC(=O)c1ccncc1-c1cnc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: NC(=O)N1CCCc2cc(-c3cnccc3C(=O)O)cnc21
Yield: 54.7 %

Procedure:
To a solution of 3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-isonicotinic acid methyl ester (131 mg, 0.49 mmol) in DCM (30 mL) is added benzoyl isocyanate (107 mg, 0.73 mmol). The mixture is heated to reflux for 3 hrs. The solvent is then removed and the residue is dissolved in anhydrous MeOH (10 mL). Then K2CO3 (180 mg, 1.3 mmol) is added and the mixture is heated to reflux for 0.5 h. After cooling down, the organic solvent is evaporated. The residue is dissolved in water and washed with DCM. The water layer is separated and purified by neutral preparative HPLC to give 80 mg of 3-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-isonicotinic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][C:14]([O:16]CC)=O)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[NH4+:25].[OH-]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][C:14]([NH2:25])=[O:16])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)Cc1csc(-c2cccc(Br)c2)n1
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)Cc1csc(-c2cccc(Br)c2)n1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
Ethyl 2-(3-bromophenyl)-4-thiazolylacetate prepared by the process in Example 2 (10 g) in 75 ml of 28% NH4OH was stirred at room temperature. About 10 ml of dioxane was added to facilitate mixing. After 10 days, the crystalline product was filtered. The yield of product was 8.3 g, mp 150°-152° C. When recrystallized from alcohol, it melted 152°-154° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)C=CC=CC=1.[O-]CC.[Na+]>C(O)C>[F:11][C:10]([F:13])([F:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)C(F)(F)F)cc1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(=Cc2ccc(F)cc2)C(F)(F)F)cc1
Yield: 87 %

Procedure:
4'-Methoxy-2,2,2-trifluoroacetophenone (R. Fuchs: J. Org. Chem. 22, 993-994 (1957)) is reacted with triphenyl(4-fluorobenzyl)-phosphonium chloride (see Example 18) in ethanol in the presence of sodium ethoxide. 3,3,3-Trifluoro-1-(4-fluorophenyl)-2-(4-methoxyphenyl)-propene is obtained with a yield of 87%; b.p.: 138°-142° C./0.5 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@H:7]([NH:11][CH2:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]2[N:20]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:21]=[C:22]([C:23]([OH:25])=O)[C:14]=12)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[F:19][C:18]1[C:13]2[CH2:12][N:11]([C@H:7]([CH:8]([CH3:10])[CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:36])[C:23](=[O:25])[C:22]3=[CH:21][N:20]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=4)(=[O:28])=[O:27])[C:15]([C:14]=23)=[N:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@@H](C(=O)OC(C)(C)C)C(C)C)c(F)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(c(F)cnc42)CN([C@@H](C(=O)OC(C)(C)C)C(C)C)C3=O)cc1

Procedure:
Crude (R)-4-((1-tert-butoxy-3-methyl-1-oxobutan-2-ylamino)methyl)-5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid was heated in HATU (2.60 g, 7.19 mmol) and 4-methylmorpholine (1.091 g, 10.79 mmol) at reflux for 3 h. The reaction was incomplete by LC-MS. HATU (1.37 g, mmol, 3.79 mmol) and 4-methylmorpholine (1.091 g, 10.79 mmol) were added and the reaction mixture was stirred at reflux for 16 h. Following reaction, the mixture was washed with aqueous NaHCO3 (sat.) and extracted with DCM. The organics were washed with brine, dried over Na2SO4, and concentrated to a brown oil. Purification by silica column chromatography (EtOAc/DCM, 0-20%) afforded the title compound as a white foam. (0.933 g, 51.7%). 1H NMR (400 MHz, DMSO-d6) δ 0.80 (d, J=6.57 Hz, 3 H) 1.02 (d, J=6.57 Hz, 3 H) 1.39 (s, 9 H) 2.31-2.39 (m, 4 H) 4.77 (d, J=10.61 Hz, 1 H) 5.02 (d, J=7.58 Hz, 2 H) 7.46 (d, J=7.83 Hz, 2 H) 8.08 (d, J=8.34 Hz, 2 H) 8.29 (s, 1 H) 8.44 (d, J=2.78 Hz, 1 H). [M+H] calc'd for C25H28FN3O5S, 502; found, 502.3.
Reaction SMILES: [Si]([O:8][CH:9]([C:13]1[S:14][C:15]([C:18]2[N:23]=[C:22]([NH:24][C:25]3[CH:29]=[C:28]([CH:30]4[CH2:32][CH2:31]4)[NH:27][N:26]=3)[C:21]([Cl:33])=[CH:20][N:19]=2)=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11])(C(C)(C)C)(C)C.CCN(CC)CC>O1CCCC1.C(OCC)(=O)C>[Cl:33][C:21]1[C:22]([NH:24][C:25]2[CH:29]=[C:28]([CH:30]3[CH2:32][CH2:31]3)[NH:27][N:26]=2)=[N:23][C:18]([C:15]2[S:14][C:13]([CH:9]([OH:8])[C:10]([OH:12])=[O:11])=[CH:17][CH:16]=2)=[N:19][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)C(O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of 2-(tert-butyldimethylsilyloxy)-2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidin-2-yl)thiophen-2-yl)acetic acid (60 mg, 0.12 mmol, 1.0 equiv.) in tetrahydrofuran (10 mL) was added Et3N.3HF (0.06 mL, 0.36 mmol, 3.0 equiv.). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, the residue was purified by silica gel column chromatography (PE:EA=1:1) to afford 2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)-2-hydroxyacetic acid (Compound 219) (30 mg, 64.6%). LC-MS (m/z): 392.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.76 (m, 2H), 0.97-0.99 (m, 2H), 1.92-1.96 (m, 1H), 5.31 (s, 1H), 6.45 (s, 1H), 7.13 (d, J=3.2 Hz, 1H), 7.67 (d, J=3.6 Hz, 1H), 8.39 (s, 1H), 9.30 (s, 1H), 12.59 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=O.[CH3:22][C:23](=O)[CH2:24][C:25](=[O:27])[CH3:26]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:24]([C:25](=[O:27])[CH3:26])=[C:23]([CH3:22])[N:1]=[C:2]3[S:6][C:5]4[CH2:7][CH2:8][CH2:9][C:4]=4[C:3]=23)=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccc(C(=O)c2c(N)sc3c2CCC3)cc1
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccc(S(C)(=O)=O)cc1)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 31.1 %

Procedure:
To a stirred solution of 50 mg (0.15 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-methanesulfonyl-phenyl)-methanone (described above) in 2 ml acetic acid was added 0.011 ml (0.15 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 18 mg (30%) 1-[4-(4-methanesulfonylphenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a light brown solid. ES-MS m/e (%): 386 (M+H+, 100).