Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C@@H:14]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C@H:20]3[C@@H:15]2[CH2:16][CH2:17][CH2:18][N:19]3C(OC(C)(C)C)=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[C:37]([O:41][C:42]([NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@@H:46]1[C:51]([OH:53])=O)=[O:43])([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C.CCOC(OC(OCC)=O)=O>O>[C:37]([O:41][C:42](=[O:43])[NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@@H:46]1[C:51]([N:19]1[C@@H:20]2[C@@H:15]([C@H:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=32)[CH2:16][CH2:17][CH2:18]1)=[O:53])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)O
Agent: CCOC(=O)OC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CCC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 26.1 %

Procedure:
TFA (1 ml) was added to tert-butyl (4aR*,5R*,10bR*)-5-phenyl-3,4,4a,5,6,10b-hexahydrobenzo[h]-1,6-naphthyridine-1(2H)-carboxylate (195 mg, 0.54 mmol), and the mixture was stirred at room temperature for 3 min. Ice water was added to the reaction mixture, basified with 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 ml), (1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (131 mg, 0.54 mmol) and triethylamine (109 mg, 1.1 mmol) were added, DEPC (88 mg, 0.54 mmol) was added at 0° C., and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 6% aqueous sodium hydrogen carbonate solution and saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g), and eluted with hexane-ethyl acetate (9:1-4:1, v/v) to give the title compound (69 mg, 26%) as a colorless amorphous form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[NH:17][CH:18]=[C:19]([CH3:20])[C:12]=12.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[C:24]([NH2:29])[N:23]=1.Cl.[OH-].[Na+]>O>[Cl:21][C:22]1[N:23]=[C:24]([NH2:29])[N:25]=[C:26]([NH:8][C:6]2[CH:5]=[C:4]([F:9])[C:3]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]4[NH:17][CH:18]=[C:19]([CH3:20])[C:12]=34)=[C:2]([F:1])[CH:7]=2)[CH:27]=1
Reactant: Cc1c[nH]c2nccc(Nc3c(F)cc(N)cc3F)c12
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c[nH]c2nccc(Nc3c(F)cc(Nc4cc(Cl)nc(N)n4)cc3F)c12
Temperature: 100 °C

Procedure:
27 mg (0.10 mmol) of 2,6-difluoro-N1-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene-1,4-diamine and 23 mg (0.14 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 5 ml of water. 0.14 ml of 1 M hydrochloric acid is added, and the mixture is heated at 100° C. overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off and washed with water. The crude product is purified by preparative HPLC.
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][C:14](=[O:16])[CH3:15]>C(O)C.O.CN(C=O)C.[Fe]>[NH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[C:5]=1[NH:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Nc1c(Br)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)Nc1c(N)cccc1Br
Reaction time: 6 h

Procedure:
Iron powder (2.92 g, 52.32 mmol) and ammonium chloride (2.3 g, 43.6 mmol) in ethanol (40 mL) and water (20 mL) were added to a solution of N-(2-bromo-6-nitrophenyl)acetamide [Edlin et al., New Journal of Chemistry 1999, 23, 819–826] (2.26 g, 8.72 mmol) in DMF (20 mL) and the mixture was heated at reflux. After 6 h, the reaction was filtered through a celite pad, washed with acetone, and concentrated in vacuo to give the title compound. MS: m/z=231 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I>[Cl:9][C:4]1[N:3]=[C:2]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:11]2)[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: Fc1ccc(Cl)nc1Cl
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2nc(Cl)ccc2F)C1
Temperature: 105 °C
Yield: 22.3 %

Procedure:
A mixture of 2,6-dichloro-3-fluoro-pyridine (3.802 mmol, 631.1 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (3.992 mmol; 799.6 mg), potassium carbonate (7.605 mmol; 1051 mg), N,N′-Dimethylethylenediamine (0.3802 mmol; 33.52 mg; 0.0409 mL), and copper(I) iodide; (3.802 mmol; 724.1 mg) in 1,4-Dioxane (15 mL) was purged with Argon then sealed in a pressure tube and heated at 105° C. overnight. The reaction was cooled to room temperature, then filtered through Celite. The filtrate was concentrated and the residue was purified on silica eluted with 0 to 20% EtOAc in Heptane to afford tert-butyl N-[(3S)-1-(6-chloro-3-fluoro-2-pyridyl)-3-piperidyl]carbamate (279.2 mg, 22%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11](OCC)=[O:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1.C1C=CC=CC=1.C(O)C.Cl>CC1C=CC=CC=1.O(CC)CC.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][OH:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1
Reactant: CCOC(=O)C1CCc2cc(F)ccc2O1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: c1ccccc1
Product: OCC1CCc2cc(F)ccc2O1
Temperature: 15 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
To a stirred mixture of 50 parts of ethyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate and 540 parts of benzene were added dropwise, during a 1 hour-period, a mixture of 89 parts of a solution of sodium dihydro-bis(2-methoxyethoxy)aluminate in methylbenzene (3.4M) and 135 parts of benzene at reflux temperature and under nitrogen atmosphere. Upon completion, stirring was continued for 2.5 hours at reflux. After cooling to 15° C., the reaction mixture was decomposed by the dropwise addition of 24 parts of ethanol and 10 parts of water. The reaction mixture was poured onto ice water. Concentrate hydrochloric acid and 350 parts of 1,1'-oxybisethane were added. The organic layer was separated, washed with water, dried, filtered and evaporated. The oily residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 34 parts (85%) of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol as an oily residue (intermediate 7).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][C@@H:14]([C:16]([O-:18])=[O:17])[NH2:15])=[O:11])=[CH:8][CH:7]=1>C1COCC1.C1CCCCC=1.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][C@@H:14]([C:16]([O:18][C:6]([CH3:20])([CH3:7])[CH3:5])=[O:17])[NH2:15])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1

Procedure:
128 mg of Pd(OH)2 on carbon is added to a solution of 10-4 (1.28 g, 2.64 mmol) in 35 ml of THF and 10 ml of cyclohexene, and the reaction medium is heated under reflux for 45 minutes. The temperature is brought down to approximately 20° C. followed by filtering, rinsing with ethyl acetate and evaporating under reduced pressure until a dry extract is obtained (724 mg) corresponding to the expected deprotected product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][OH:23].Cl.N1C=CC=CC=1.C(OCCO)C>>[OH:23][CH2:22][C:21]1[C:20]([CH3:27])=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1c(N)cccc1CO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc(CO)c3C)c2cc1OC
Temperature: 139 °C
Yield: 91.6 %

Procedure:
A mixture of 0.248 g (1 mmol)of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.151 g (1.1 mmol) of 3-amino-2-methylbenzyl alcohol, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 6 hours; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.32 g (91.5%) of the desired product as light tan crystals. MP 123-125° C.; : mass spectrum (electrospray, m/e,): 349.9(M+H)+.
Reaction SMILES: C([O:4][C:5]([C:7]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[C:26]([F:42])[CH:25]=1)([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])C(OCC=C)=O)=[O:6])C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(O)=O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH:7]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:37])[CH3:38])=[C:26]([F:42])[CH:25]=1)[C:5]([OH:6])=[O:4])[CH3:22]
Reactant: C=CCOC(=O)C(CCCCC(=O)OCC)(Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)CCCCC(Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)C(=O)O
Temperature: 100 °C

Procedure:
4.2 g (6.88 mmol) of 1-allyl 7-ethyl 2-allyloxycarbonyl-2-(3,5-difluoro-4-triisopropylsilanyloxy-benzyl)heptanedioate, 39 mg (0.17 mmol) of palladium(II)acetate and 135 mg (0.52 mmol) of triphenylphosphine are stirred in 30 ml of dioxane under argon. A solution of 2.3 g (22.69 mmol) of triethylamine and 0.79 g (17.19 mmol) of formic acid in 20 ml of dioxane is then added dropwise, and the mixture is heated at 100° C. overnight. The cooled mixture is concentrated and the crude product is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, 3:1). 2.07 g (52% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[F:14][CH:15]([F:21])[C:16](OCC)=[O:17]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16](=[O:17])[CH:15]([F:21])[F:14])=[N:3][CH:4]=1
Reactant: CCOC(=O)C(F)F
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Br)cn1)C(F)F
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of 2,5-dibromopyridine (15.21 g, 64 mmol) in anhydrous toluene (150 mL) at −78° C. under nitrogen was added dropwise with n-BuLi (2.5 M in hexane, 25 mL, 62 mmol). Stirring was continued at −78° C. for 2 h, then ethyl difluoroacetate (11 g, 80 mmol) was added dropwise at −78° C. The mixture was stirred overnight while the temperature rose to room temperature. The mixture was partitioned between EtOAc and brine, the water layer was extracted with EtOAc, the combined organic extracts were dried and concentrated, flash chromatography on silica gel afforded 8.53 g of 1-(5-bromopyridin-2-yl)-2,2-difluoroethanone as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl.CN(C1C=CC=CN=1)C>[Si:21]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(O)c2)CC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(O[Si](C)(C)C(C)(C)C)c2)CC1
Yield: 84.6 %

Procedure:
The tert-butyl 4-(3-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.01 g, 14.58 mmol), tert-butyldimethylsilyl chloride (2.73 g, 18.22 mmol), triethylamine (4.01 g, 40.0 mmol) and a catalytic amount of dimethylaminopyridine (100 mg, 0.80 mmol) were mixed in dichloromethane (100 mL) at room temperature for 16 h. The solvent was removed at reduced pressure and the resulting semisolid dissolved in diethylether (100 mL). The solution was extracted with 1N aqueous hydrochloric acid (2×50 mL), extracted with saturated aqueous sodium bicarbonate (2×50 mL), and extracted with saturated with saturated aqueous ammonium chloride (2×50 mL). The solution was dried over sodium sulfate and solvent removed at reduced pressure. The tert-butyl 4-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.8 g, 12.33 mmol) was isolated as a clear colorless oil by preparative silica chromatography (5% ethyl acetate/95% hexanes). HRMS m/z 388.2305 (calcd for M−H 388.2302.)
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[N+:14]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1Cl)([O-:16])=[O:15]>C(O)C>[N+:14]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[NH:6][C:5]1[CH:7]=[CH:8][C:2]([OH:1])=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 50.2 g of p-hydroxyaniline and 38.7 g of sodium bicarbonate in 1.5 1 of ethanol was added dropwise 73 g of 3-nitro-4-chloropyridine in 2.0 l of ethanol. After stirring overnight at room temperature, the resulting solids were filtered, washed with water (2 l) and dried, 85.4 g.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=O)[NH2:27])=[CH:22][CH:21]=2)=[O:17])=[CH:11][CH:10]=1)[CH3:7]>CN(C=O)C>[CH2:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=2)=[O:17])=[CH:13][CH:14]=1)[CH3:7]
Reactant: CCOc1ccc(CC(=O)OCc2ccc(C(N)=O)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOc1ccc(CC(=O)OCc2ccc(C#N)cc2)cc1

Procedure:
65 g of POCl3 is added dropwise at 50° and while stirring to a solution, in 500 ml of DMF, of 31.3 g of p-carbamoylbenzyl p-ethoxyphenylacetate (obtainable by esterification). After stirring for a further hour, the mixture is poured onto ice and worked up in a customary manner to give p-cyanobenzyl p-ethoxyphenylacetate, m.p. 59°, c.p. -40°.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:7][C:5]=2[N:6]=1.[C:16]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[C:27]1[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=1)#[N:17].[I-].[K+]>C(#N)C.O.[OH-].[NH4+].C(OCC)(=O)C>[C:16]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[C:27]1[CH2:28][CH2:29][N:30]([CH2:14][CH2:13][CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:31][CH:32]=1)#[N:17]
Reactant: Cc1nc2cc(OCCCCl)ccc2s1
Reactant: N#Cc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: [I-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc2cc(OCCCN3CC=C(c4c[nH]c5ccc(C#N)cc45)CC3)ccc2s1
Yield: 37.6 %

Procedure:
A mixture of 2-methyl-5-(3-chloropropoxyl)-benzothiazole (3 g, 12.4 mmol), 5-cyano-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (3 g, 13.4 mmol) and a catalytic amount of potassium iodide in 50 ml of acetonitrile was stirred at 80° C. overnight. The reaction mixture was cooled, diluted with water, ammonium hydroxide and ethyl acetate. The two phases were separated and the aqueous phase was extracted with ethyl acetate twice. The organic phases were combined, washed with brined, dried over sodium sulfate and then concentrated under reduced pressure to a solid. This residual solid was subjected to a silica gel chromatography, eluting with 7% methanol in dichloromethane. Fractions shown to contain product were combined and concentrated to provide 2 g of the title compound in 35% yield as free base. The resulting free base was dissolved in methanol/dichloromethane and precipitated with excess HCl in ether. Recrystalization from ethanol give 1.8 g of the title compound as a light yellow solid. mp. 263-65° C. MS(CI) m+1=429. EA (C25H24N4 OS.1.7HCl): Theory: C, 61.21%; H, 5.28%; N, 11.42%. Found: C, 61.10%; H, 5.43%; N, 11.39%.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH:19]([F:21])[F:20])=[O:5])C.[OH-].[Li+].C(O)(=O)C>O1CCCC1.O>[F:21][CH:19]([F:20])[C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[S:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nc(C(F)F)c(C(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
3.0 g 4-Difluoromethyl-2-(4-methoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester were dissolved in 90 ml tetrahydrofuran. A solution of 2.29 g lithium hydroxide dissolved in 30 ml water was added and the reaction mixture stirred at room temperature overnight. Concentrated acetic acid were added until a pH of ˜6 was attained, then the tetrahydrofuran was removed in vacuo. The residual aqueous phase was extracted three time with portions of 100 ml ethyl acetate. The combined organic layers were dried over MgSO4. Then the solvent was removed in vacuo to obtain 2.73 g 4-difluoromethyl-2-(4-methoxy-phenyl)-thiazole-5-carboxylic acid as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:17]Cl.[CH3:20][O:21][C:22](=[O:35])[CH2:23][NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:17][N:24]([CH2:23][C:22]([O:21][CH3:20])=[O:35])[S:25]([C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)(=[O:27])=[O:26]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1ccc(Oc2ccccc2)cc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1cc(Oc2ccccc2)ccc1C(=O)OC)S(=O)(=O)c1ccc(C)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a mixture of 2-chloromethyl-4-phenoxy-benzoic acid methyl ester (17.8 g, 64.3 mmol) in DMF (100 mL) was added (toluene-4-sulfonylamino)-acetic acid methyl ester (15.65 g, 64.3 mmol), K2CO3 (17.78 g, 128.6 mmol) and then NaI (964 mg, 6.43 mmol). The resulting mixture was stirred at 50° C. overnight. After cooled, reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water (2×) and brine. It was dried over Na2SO4, filtered and concentrated. Crude residue was purified by silica gel chromatography to provide the title compound (14.34 g, 29.8 mmol). 1H NMR in CDCl3, δ in ppm: 7.86 (d, 1H, 8.8 Hz), 7.70 (d, 2H, J=8.4 Hz), 7.38-6.8 (m, 9H), 4.88 (s, 2H), 3.99 (s, 2H), 3.82 (s, 3H), 3.53 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[F:12][C:13]([F:23])([F:22])[S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[F:22][C:13]([F:12])([F:23])[S:14][C:15]1[CH:16]=[CH:17][C:18]([N:19]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[CH:20][CH:21]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(SC(F)(F)F)cc1
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(SC(F)(F)F)cc1
Yield: 70.3 %

Procedure:
In a manner similar to above, 1.6 g (0.01 mole) of 3,4,5,6-tetrahydrophthalic anhydride and 2.0 g (0.01 mole) of p-trifluoromethylthioaniline were treated to obtain 2.3 g of N-(p-trifluoromethylthiophenyl)-3,4,5,6-tetrahydrophthalimide (melting point, 112°-114° C.; 70% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH:6]1O)=[O:4].O=S(Cl)Cl.C1CCN2C(=NCCC2)CC1.CCOC(C)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][CH2:7][CH:6]=1)=[O:4]
Reactant: COC(=O)C1CC(CCOCc2ccccc2)CCC1O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1=CCCC(CCOCc2ccccc2)C1
Temperature: 55 °C

Procedure:
A solution of 5-(2-benzyloxy-ethyl)-2-hydroxy-cyclohexanecarboxylic acid methyl ester (Intermediate R2; 0.72 g, 2.48 mmol) in pyridine (10 mL) was treated with SOCl2 (0.73 mL, 12.4 mmol) at −20° C. The mixture was allowed to react for 15 minutes and was then warmed to 55° C. for 16 hours. The solvents were removed under vacuum and the residue was diluted in ether at 0° C. The solution was quenched with water, washed with 1M HCl, 5% NaOH and brine. The organic material was dried over MgSO4, filtered and freed of solvent. The mixture was diluted with benzene, and water was removed by azeotropic distillation under vacuum. The residue was dissolved in benzene (15 mL), and DBU (0.76 mL, 5 mmol) was added). The mixture was reacted for 30 minutes at room temperature. After work-up and chromatography on SiO2 with 20% EtOAc:Hx, 5-(2-benzyloxy-ethyl)-cyclohex-1-enecarboxylic acid methyl ester (Intermediate R3) was isolated (0.56 g (82%)).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:10][NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]3[N:19]([CH3:27])[C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]=2)[CH2:9][CH2:8][CH2:7]1)=O)C.[CH:28]([Mg]Cl)([CH3:30])[CH3:29]>C1COCC1>[CH3:29][CH:28]([CH3:30])[C:4]([C:6]1([CH2:10][NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]3[N:19]([CH3:27])[C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]=2)[CH2:7][CH2:8][CH2:9]1)=[O:3]
Reactant: CC(C)[Mg]Cl
Reactant: CCOC(=O)C1(CNc2cncc(-c3cc4ccccc4n3C)c2)CCC1
Solvent: C1CCOC1
Product: CC(C)C(=O)C1(CNc2cncc(-c3cc4ccccc4n3C)c2)CCC1
Reaction time: 0.75 h

Procedure:
To a solution of 1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid ethyl ester (Example 213b, 0.45 g, 1.21 mmol) in THF (150 mL) cooled with an ice-water bath is added iPrMgCl (2.0M in THF, 2.43 mL, 4.85 mmol) dropwise. After 45 min, the mixture is quenched with 1M aqueous NaHSO4 (5 mL), washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 3:2 to 1:1), followed by purification by RP HPLC on an Xbridge RP18 eluting with a gradient of acetonitrile in 0.1% aqueous NH4OH to give 2-methyl-1-(1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutyl)-propan-1-one.