Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21].S([O-])(O[O-])(=O)=[O:23].[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:9])=[O:23])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21]
Reactant: O=S(=O)([O-])O[O-]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(SC)cc2F)n1
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(S(C)=O)cc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.5 %

Procedure:
To a solution of methyl 6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxylate (150 mg, 0.479 mmol) in DCM (3.0 mL) was added potassium peroxymonosulfate (147 mg, 0.958 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The solution was partitioned between EtOAc and water. The organic layer was dried, filtered. The filtrate was concentrated and then purified by silica gel column chromatography using CombiFlash® (0 to 100% EtOAc in hexanes) to give the sub-title compound as a white powder (37 mg, 23%). LCMS calc. for C14H11F3NO3S (M+H)+: m/z=330.0. Found: 330.2.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Si:9]([O:26][CH2:27][C@@H:28]([N:32]1[C@H:37]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[C@@H:36]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=2)[CH2:35][C@@:34]([C:53](=[CH2:58])[C:54]([O:56][CH3:57])=[O:55])([CH3:52])[C:33]1=[O:59])[CH:29]1[CH2:31][CH2:30]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O>[Si:9]([O:26][CH2:27][C@@H:28]([N:32]1[C@H:37]([C:38]2[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=2)[C@@H:36]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=2)[CH2:35][C@@:34]([C:53]2([C:54]([O:56][CH3:57])=[O:55])[CH2:2][CH2:58]2)([CH3:52])[C:33]1=[O:59])[CH:29]1[CH2:30][CH2:31]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: C=C(C(=O)OC)[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1([C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N([C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C3CC3)C2=O)CC1
Reaction time: 0.25 h

Procedure:
To a suspension of trimethylsulfoxonium iodide (39 mg, 0.18 mmol) in DMSO (0.71 mL) was added a suspension of 60% sodium hydride in mineral oil (7.1 mg, 0.18 mmol). After being stirred 15 min, a solution of methyl 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acrylate (66 mg, 0.089 mmol; Example 270, Step B) in DMSO (0.71 mL) was added and the mixture was stirred at rt for 3 h. The reaction was quenched (ice cold sat. NH4Cl), extracted (2×EtOAc), and washed (brine×3). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 10% and 20% EtOAc/Hex) provided the title compound as a colorless film.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[BrH:16]>>[BrH:16].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(-c2ccnc(Cl)c2)cc1
Agent: Br
Product: Oc1ccc(-c2ccnc(Cl)c2)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-(4-methoxyphenyl)pyridine (4.6 g) and 48% aqueous hydrobromic acid solution is heated under reflux for 3.5 hours and allowed to cool back to room temperature. The precipitate that appears is separated by filtration, washed with water and dried under reduced pressure to give 4.9 g of 2-chloro-4-(4-hydroxyphenyl)pyridine hydrobromide as a yellow solid used without further purification.
Reaction SMILES: [CH2:1]([N:5]([CH2:41][CH2:42][CH2:43][CH3:44])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[C:31]([O:33]CC2C=CC=CC=2)=[O:32])[N:11]([CH2:13][CH2:14][C:15]2C=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]>CCOC(C)=O.[Pd]>[CH2:13]([N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:1][CH2:2][CH2:3][CH3:4])[N:9]=[C:10]1[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[C:31]([OH:33])=[O:32])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCN(CCCC)C(=O)c1cn(CCc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)C(=O)c1cn(Cc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)O)n1
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a solution of 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1-phenethyl-1H-imidazol-2-yl)isophthalate (100 mg, 0.17 mmol) in EtOAc (5 mL) was added Pd/C (10%). The reaction mixture was stirred under H2 atmosphere for 6 h, filtered through a small pad of CELITE® and washed thoroughly with MeOH. The solvents were removed in vacuo to provide the title compound (75 mg, 89%), which was used without further purification. MS(ESI+) m/z 506.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.CCOC(C)=O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1Cl)c1cccc(F)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-chloro-1-(3-fluoro-benzoyloxy)-4-nitro-benzene (10 g, 35.5 mmol) was suspended in 50 mL acetic acid and 150 mL EtOAc in a 500 mL flask. Iron (9.9 g (177.5 mmol) was added to this suspension, and the mixture stirred at rt overnight. The reaction mixture was filtered through a thin pad of Celite®. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 aq solution, followed by EtOAc extraction. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 15% EtOAc/hexanes yielding 3-Chloro-4-(3-fluoro-benzyloxy)-phenylamine as a brown solid [8.5 g, 95%, TLC Rf=0.4, 30% EtOAc/HEX. (3:7)]. 1H-NMR (DMSO-d6) δ 4.94 (s, 2H), 5.00 (s, 2H), 6.40 (dd, 1H), 6.60 (s, 1H), 6.87 (d, 1H), 7.10-7.18 (m, 1H), 7.20-7.28 (m, 2H), 7.37-7.44 (m, 1H).
Reaction SMILES: C(O)C.[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]#[N:10].Cl.[NH2:12][OH:13].[OH-].[Na+]>ClCCl.O>[OH:13][NH:12][C:9]([C:5]1[S:4][CH:8]=[CH:7][CH:6]=1)=[NH:10]
Reactant: N#Cc1cccs1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: N=C(NO)c1cccs1
Temperature: 80 °C
Yield: 88 %

Procedure:
To an ethanol (5 mL) solution of 2-thiophenecarbonitrile (525.5 mg, 5 mmol), 5 M hydroxylamine hydrochloride (1.1 mL) and 1 M sodium hydroxide (5.5 mL) were added. After the reaction mixture was heated at 80° C. for 3 h, water and dichloromethane were added. The organic layer was dried, concentrated and triturated with hexanes to give a white solid 625.8 mg (88%). 1H NMR (DMSO-d6), δ(ppm): 9.6 (s, 1H), 7.46 (m, 2H), 7.05 (t, 1H), 5.93 (bs, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:27]=[CH:28][N:29]=[C:2]([N:34]4[CH2:35][CH2:36][CH:31]([CH3:30])[CH2:32][CH2:33]4)[CH:3]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Reactant: CC1CCNCC1
Product: CC1CCN(c2cc(C(=O)Nc3ccc(OCCN4CCOCC4)c4ccccc34)ccn2)CC1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and 4-methylpiperidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.26 (d, 1H), 8.22 (m, 1H), 7.84 (m, 1H), 7.57 (m, 2 H), 7.45 (d, 1H), 7.39 (s, 1H), 7.13 (d, 1H), 7.05 (d, 1H), 4.41 (d, 2H), 4.31 (t, 2H), 3.60 (t, 4 H), 2.88 (m, 4H), 2.57 (m, 4 H), 1.68 (m, 4H), 1.11 (m, 1H), 0.95 (d, 3 H). MS: 475.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:17][CH2:18]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC2CCN(Cc3ccc(OC)cc3)CC2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN2CCC(Oc3ccc(C(=O)O)cc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 3-chloro-4-(1-(4-methoxybenzyl)piperidin-4-yloxy)benzoate (0.04 g, 0.10 mmol) in methanol (0.5 mL) at room temperature was added 2 N sodium hydroxide (0.25 mL, 0.50 mmol) and the resulting mixture was stirred at room temperature overnight. After this time 2 N hydrochloric acid (0.3 mL, 0.60 mmol) was added and the mixture was concentrated under reduced pressure to afford 3-chloro-4-(1-(4-methoxybenzyl)piperidin-4-yloxy)benzoic acid as a crude solid which was used without further purification. MS (ESI): 376.1 (M+1).
Reaction SMILES: [CH:1]1([CH:7]([OH:27])/[CH:8]=[CH:9]/[CH:10]2[CH2:17][CH2:16][CH:15]3[CH:11]2[CH2:12]/[C:13](=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])/[C:14]3=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].CO>O>[C:23]([CH2:22][CH2:21][CH2:20]/[CH:19]=[C:13]1/[C:14](=[O:18])[CH:15]2[CH:11]([CH2:12]/1)[CH:10](/[CH:9]=[CH:8]/[CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[OH:27])[CH2:17][CH2:16]2)([OH:25])=[O:24]
Reactant: COC(=O)CCC/C=C1\CC2C(/C=C/C(O)C3CCCCC3)CCC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCC/C=C1\CC2C(/C=C/C(O)C3CCCCC3)CCC2C1=O
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 6-[(E)-3-cyclohexyl-3-hydroxyprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (12.7 mg), prepared as described in Example 1 and in the form of (±)-6β-[(E)-3-cyclohexyl-3α-hydroxyprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)methyl(5E,13E)-(9S,15S)-6a-oxo-6,9-methano-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanorprosta-5,13-dienoate, lithium hydroxide (21.5 mg), methanol (2 ml), and water (0.7 ml) was left to stand at the ambient temperature for 1 hour. The mixture was then diluted with water (5 ml) and washed with dichloromethane. The aqueous layer was separated and acidified to pH 3 by treatment with aqueous hydrochloric acid (2N). The acidic solution was extracted with dichloromethane, and this extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to give 3-[(E)-4-carboxybutylidene]-6-[ (E)-3-cyclohexyl-3-hydroxyprop-1-enyl]bicyclo[3,3,0]octan-2-one (6.6 mg), in the form of (±)-3-[(E)-4-carboxybutylidene]-6β-[(E)-3-cyclohexyl-3α-hydroxyprop-1-enyl]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-(5E,13E)-(9S,15S)-6a-oxo-6,9-methano-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanorprosta-5,13-dienoic acid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:33]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:27]5[C:22]4=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][CH:16]=3)=[N:13][CH:14]=2)O1.Br[C:36]1[CH:37]=[CH:38][C:39]([C:42]2[S:43][C:44]3[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=3[N:46]=2)=[N:40][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH:23]1[C:22]2[N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:12]4[N:13]=[CH:14][C:9]([C:36]5[CH:41]=[N:40][C:39]([C:42]6[S:43][C:44]7[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=7[N:46]=6)=[CH:38][CH:37]=5)=[CH:10][CH:11]=4)=[CH:16][CH:17]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccc(-c2nc3ccccc3s2)nc1
Reactant: CC1(C)OB(c2ccc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2sc(-c3ccc(-c4ccc(-c5ccc(-n6c7ccccc7c7ccccc76)cc5)nc4)cn3)nc2c1
Temperature: 80 °C
Yield: 71.8 %

Procedure:
A mixture of 7 (0.841 g, 1.89 mmol), 9 (0.549 g, 1.89 mmol), tetrakis(triphenylphosphine)palladium(0) (109 mg, 94.2 μmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) was degassed with argon for about 20 min while stirring. The stirring reaction mixture was then maintained under argon at about 80° C. for about 18 h. Upon confirming consumption of the starting materials by TLC (SiO2, CH2Cl2), the mixture was cooled to RT and poured over CHCl3 (300 mL). The organics were then washed with sat. NaHCO3, H2O and brine, dried over MgSO4, filter and concentrated in vacuo. Purification of the crude product via flash chromatography (SiO2, 100% CH2Cl2 to 49:1 CH2Cl2-acetone) provided 19 (0.72 g, 72%) as a light yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+].C([O-])(=[O:17])C.[Na+].Cl>O>[OH:17][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CC(=O)[O-]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(CO)cc1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A solution of 9.00 g (39.3 mmol) of p-bromomethylphenylacetic acid, 3.14 g (78.6 mmol) of sodium hydroxide and 3.54 g (43.2 mmol) of sodium acetate in 40 ml of water was stirred for 4 hours at 100° C. At the end of this time, it was cooled to room temperature and then acidified with 2N aqueous hydrochloric acid. It was then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was recrystallized from a mixture of ethyl acetate and methylene chloride to give 3.60 g (yield 55%) of the title compound, melting at 136°-137° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[CH2:24]([N:26]=[C:27]=[S:28])[CH3:25]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:26]([CH2:24][CH3:25])[C:27]2=[S:28])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCN=C=S
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: CCn1c(=O)c2cnc3c(OC)cccc3c2n(C2CCCC2)c1=S
Yield: 33.8 %

Procedure:
1-Cyclopentyl-3-ethyl-7-methoxy-2-thioxo-2,3-dihydro-1H-pyrimido[5,4-c]quinolin-4-one (12 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) (prepared as described in Example 1) and ethyl isothiocyanate (0.4 mmol) following a procedure similar to general procedure C. LCMS: m/z 356 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 7.74 (d, 1H), 7.53 (t, 1H), 7.21 (d, 1H), 5.03 (p, 1H), 4.09 (s, 3H), 4.07 (q, 2H), 2.42 (m, 2H), 2.08 (m, 4H), 1.64 (m, 2H) and 1.34 (t, 3H).
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[NH2:32][CH:33]([CH2:45][CH3:46])[C@@H:34]([C:36]1[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[O:38][N:37]=1)[OH:35]>>[N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([NH:32][C@H:33]([C:34]([C:36]2[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[O:38][N:37]=2)=[O:35])[CH2:45][CH3:46])=[O:12])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCC(N)[C@H](O)c1noc(C(F)(F)F)n1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1noc(C(F)(F)F)n1

Procedure:
It is similarly prepared according to general procedure given for Example 2 above but using 4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyric acid and (S)-2-Amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound with trifluoroacetic acid.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[CH2:17]([O:19][C:20]([C:22]1[N:23]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[CH:35][CH:34]=2)[C:24]2[C:29]([C:30]=1[Cl:31])=[CH:28][C:27](Br)=[CH:26][CH:25]=2)=[O:21])[CH3:18].[NH4+].[Cl-].Cl>CCOCC.[Cl-].[Cl-].[Zn+2].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].[Cu]I.CN1CCCC1=O.C1COCC1>[CH2:17]([O:19][C:20]([C:22]1[N:23]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH:40]([CH3:41])[CH3:42])=[CH:37][CH:38]=2)[C:24]2[C:29]([C:30]=1[Cl:31])=[CH:28][C:27]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1)=[CH:26][CH:25]=2)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c(Cl)c2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1c(Cl)c2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 75.3 %

Procedure:
t-BuLi (3.25 mL of 1.5M solution in pentane) was added dropwise at −78° C. to Et2O (5 mL). To the resulting solution was added, via syringe, a solution of 2-bromo-5-(trifluoromethyl)pyridine (550 mg, 2.43 mmol) in Et2O (2.5 mL). Stirring at −78° C. was continued for 20 min after which the cold reaction mixture was transferred via cannula to a cooled (−78° C.) 1M solution of ZnCl2 in Et2O (5.25 mL, 5.35 mmol). The reaction was allowed to warm to room temperature and left to stir for 3 h. THF (10 mL) was then added and the resulting solution was transferred via cannula to a mixture of 5-bromo-3-chloro-1-(4-isopropoxyphenyl)-1H-indole-2-carboxylic acid ethyl ester (see Example 35, Method 1, step (b)) (531 mg, 1.22 mmol), Pd(dppf)Cl2 (118.4 mg, 0.145 mmol), CuI (56.2 mg, 0.295 mmol) and N-methylpyrrolidine-2-one (2.5 mL) under argon. The reaction was heated at 80° C. for 6 h, poured into NH4Cl (aq. sat., 50 mL) and extracted with t-BuOMe (3×25 mL). The combined organic extracts were washed with brine, dried (Na2SO4), then filtered through a Celite® pad and the filter cake was washed with t-BuOMe. The solvent was removed and the residue dissolved in dry Et2O and HCl (4M in dioxane; 360 μL, 1.4 mmol) was added. After stirring for 10 min, solvents were removed by evaporation and the residue was twice recrystallised from EtOH to yield the sub-title compound (462 mg, 75%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[C:17]([C:18]([N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:16][N:15]=[C:14]2[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:29]=[C:30]([CH3:31])[C:13]=12>CN(C)C=O>[CH2:1]([O:8][C:12]1[C:17]([C:18]([N:20]([CH3:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])=[CH:16][N:15]=[C:14]2[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:29]=[C:30]([CH3:31])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1nn(-c2ccccn2)c2ncc(C(=O)N(C)c3ccccc3)c(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccn2)c2ncc(C(=O)N(C)c3ccccc3)c(OCc3ccccc3)c12
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a solution of benzyl alcohol (0.40 g, 3.7 mmol) in N,N-dimethylformamide (10 mL), sodium hydride (0.16 g, 40 mmol, 60% oil) was added at room temperature, and the resulting mixture was stirred at the same temperature for 30 minutes. To the solution, a solution of 4-chloro-N,3-dimethyl-N-phenyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (1.0 g, 2.8 mmol) in N,N-dimethylformamide (10 mL) solution was added at room temperature, and stirred at 100° C. for 11.5 hours. The mixture was concentrated under reduced pressure, and the residue was poured into water. Organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification of the resulting residue by silica gel chromatography (hexane:chloroform:ethyl acetate=2:1:1 to 1:1:1 to 1:2:2) gave the title compound (0.99 g, 80% yield).
Reaction SMILES: [CH3:1][CH:2]([N:8]([CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15]CC)[C:9](=[O:12])[CH2:10][Cl:11])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].C(O)CO.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][CH:2]([N:8]([CH2:13][CH:14]1[O:15][CH2:20][CH2:19][O:18]1)[C:9](=[O:12])[CH2:10][Cl:11])[CH2:3][CH2:4][CH:5]([CH3:6])[CH3:7]
Reactant: CCOC(CN(C(=O)CCl)C(C)CCC(C)C)OCC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: CCO
Product: CC(C)CCC(C)N(CC1OCCO1)C(=O)CCl

Procedure:
N-(1,4-Dimethylpentyl)-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), ethylene glycol (2 grams) and trace amounts of toluenesulfonic acid were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux until no more ethanol was given off. After this time sodium carbonate (1 gram) was added to the mixture with stirring and the resulting mixture was distilled to yield the desired product N-(1,4-dimethylpentyl)-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide having a boiling point of 200° to 205° C. at 1 mm of Hg pressure.
Reaction SMILES: [Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@@H:6]([C:12]3[CH2:16]C[CH2:14][C:13]=3[CH3:17])[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl>>[Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@H:6]([C:12]([CH3:16])=[C:13]([CH3:17])[CH3:14])[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CC1=C([C@H]2CN(C)CCc3cc(Cl)c(O)cc32)CCC1
Agent: Cl
Product: CC(C)=C(C)[C@@H]1CN(C)CCc2cc(Cl)c(O)cc21

Procedure:
(R)-7-chloro-8-hydroxy-3-methyl-1-(2-methyl-1-cyclopentenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. of hydrochloride 249°-251° C. (dec.).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1>CN(C)C1C=CN=CC=1.O1CCCC1.ClCCl>[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([N:2]([CH3:3])[CH3:1])=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CNC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepared according to the method described in Example 24a) from 1-(3-is dimethylaminopropyl)-3-ethylcarbodiimide 4-hydrochloride (2.15 g), 4-dimethylaminopyridine (3.82 g), a 2M solution of dimethylamine in tetrahydrofuran (10 ml) and a solution of 3-bromophenylacetic acid (2.15 g) in dichloromethane (100 ml). The mixture was stirred overnight at room temperature. The reaction mixture was washed with 2M hydrochloric acid (3×100 ml), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The sub-title compound was obtained as an oil (2.89 g).