Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:30])[N:8]2[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1)#[N:2].C(C1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=C(F)C=1)#N.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1>ClCCl>[NH2:22][CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][N:8]2[C:9]3[C:10](=[C:11]([F:13])[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:5]=[CH:6][C:7]2=[O:30])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c(C#N)cc(F)cc32)CC1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c(F)cc(C#N)cc32)CC1
Agent: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(F)c2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Yield: 92 %

Procedure:
A mixture of tert-butyl {1-[2-(5-cyano-7-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate and tert-butyl {1-[2-(7-cyano-5-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediates 173 and 174, 170 mg, 0.41 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 120 mg (92% yield) of the mixture of regioisomers as an oil. This mixture was carried on without further purification to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C@@H:29]([OH:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C@@H:29]([OH:36])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)(=[O:26])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: O=C(O)c1ccc(S(=O)(=O)C[C@@H](O)c2ccccc2)cc1Cl
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)C[C@@H](O)c2ccccc2)cc1Cl

Procedure:
119 mg of (S)-styrene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (S)-methyl 2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate. 230 mg of (S)-methyl-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate was hydrolyzed via Procedure M to give (S)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid. 180 mg of (S)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid was reacted via Procedure R to give (S)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-phenylethylsulfonyl)benzamide. MS (Q1) 527.0 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:54]=[CH:53][CH:52]=[CH:51][C:3]=1[CH2:4][C:5]1([O:49][CH3:50])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:18]=[C:17]3[C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)=[O:13])[CH2:6]1.[SiH](CC)(CC)CC>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:54]=[CH:53][CH:52]=[CH:51][C:3]=1[CH2:4][C:5]1([O:49][CH3:50])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[C:17]3[C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)=[O:13])[CH2:6]1
Reactant: COC1(Cc2ccccc2F)CCCC(NC(=O)c2ccc3c(c2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC1(Cc2ccccc2F)CCCC(NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-(3-(2-fluorobenzyl)-3-methoxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide was stirred in neat TFA at room temperature for 10 minutes, and then Et3SiH (5 equiv.) was added. The reaction mixture was stirred at room temperature for 5 minutes, and then concentrated. The product was obtained and purified by reverse phase HPLC. Two diastereomers obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[CH3:25][O:26][C:27]([C:29]1[CH:30]=[C:31](OB(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28].C(N(CC)CC)C>C(OCC)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=4)[C:27]([O:26][CH3:25])=[O:28])[CH2:20]3)=[O:18])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CNC(=O)C1CCCNC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(N2CCCC(C(=O)NCc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.1 %

Procedure:
N-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]methyl]piperidine-3-carboxamide hydrochloride (123 mg, 0.318 mmol) was suspended in diethyl ether. The suspension washed sequentially with a 0.1 mol/L aqueous sodium hydroxide solution and brine and was dried over magnesium sulfate. The solvent was then evaporated and the resulting residue was dissolved in dichloromethane (10 mL). To this solution, 3-(methoxycarbonyl)phenylboric acid (114 mg, 0.636 mmol), molecular sieves 4 Å (300 mg), copper (II) acetate (122 mg, 0.636 mmol) and triethylamine (0.222 mL, 1.59 mmol) were added and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction mixture was filtered through Celite and a saturated aqueous sodium bicarbonate solution was added to the filtrate. The mixture was extracted with ethyl acetate. The extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=2:1->0:1) gave 20.1 mg (13%) of the desired compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([F:26])[CH:3]=1.Cl.[CH2:28]([N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][C:33](O)=[O:34])[CH3:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:28]([N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:15](=[O:16])[NH:17][CH2:18][CH3:19])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:10][CH2:9]2)=[C:4]([F:26])[CH:3]=1)=[O:34])[CH3:29]
Reactant: CCN(CC)CCC(=O)O
Reactant: CCNC(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)CCN(CC)CC)cc2F)CC1
Reaction time: 18 h
Yield: 58.6 %

Procedure:
A mixture of 2-[4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-N-ethyl-2-phenyl-acetamide (22 mg, 0.06 mmol), 3-diethylaminopropionic acid hydrochloride (13 mg, 0.07 mmol) and PyBroP (34 mg, 0.07 mmol) in DCM (2 mL) was treated with iPr2NEt (0.032 mL, 0.19 mmol). After 18 h, the mixture was washed with satd. aq. NaHCO3 and brine, dried (MgSO4), and concentrated to give an oil, which was purified by PTLC to give a beige solid (17 mg, 56%). MS (ESI): mass calcd. for C27H38FN5O2, 483.62. m/z found, 484.4 [M+H]+. 1H NMR (CDCl3): 11.15 (s, 1H), 7.38-7.37 (m, 1H), 7.36-7.35 (m, 1H), 7.33-7.32 (m, 3H), 7.31-7.28 (m, 1H), 7.13-7.09 (m, 2H), 6.85 (t, J=9.0, 1H), 3.88 (s, 1H), 3.38-3.33 (m, 2H), 3.06-3.04 (m, 4H), 2.79-2.76 (m, 1H), 2.69-2.65 (m, 4H), 2.59-2.58 (m, 4H), 2.50-2.47 (m, 1H), 1.40-1.38 (m, 1H), 1.35-1.32 (t, J=7.3, 1H), 1.77-1.22 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1>CO>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1
Reactant: Cc1cccc(CCOc2ccccc2)n1
Solvent: CO
Product: CC1CCCC(CCOc2ccccc2)N1

Procedure:
2-Methyl-6-(2-phenoxyethyl)pyridine (0.19 mmol, 0.04 g) and Adam Catalyst (0.09 mmol, 0.02 g) in MeOH was stirred at rt under a hydrogen balloon overnight. The reaction mixture was filtered through diatomaceous earth and concentrated in vacuo to provide the desired product 2-methyl-6-(2-phenoxyethyl)piperidine in 30% conversion. This crude residue was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: C1COCCN1
Product: Cc1ccccc1-c1cc2c(N3CCOCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C23H20FN5O3, 433.2
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:15][N:14]1[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[C:12]1=[O:13]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1CC(=O)c1ccccn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(-c2ccccn2)cc2onc(-c3ccccc3)c2c1=O

Procedure:
A mixture of 20.1 g. (0.0627 mole) of 3-phenyl-5-(2-pyridylcarbonylmethyl)-N-methyl-isoxazole-4-carboxamide and 200 ml. of 2M sulfuric acid is refluxed for 24 hours. The mixture is cooled and made basic with 2N sodium hydroxide and then extracted with methylene chloride. The methylene chloride layer is washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting solid is purified by column chromatography to give 5-methyl-3-phenyl-6-(2-pyridyl)-isoxazolo[4,5-c]pyridin-4-(5H)-one; m.p. 160° to 162° C.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH3:17])[N:15]=1)[C:10]([OH:12])=[O:11].C([O-])(O)=O.[Na+].[CH2:23](O)[CH3:24]>>[CH2:23]([O:11][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([O:16][CH3:17])[N:15]=[C:7]([Cl:6])[CH:8]=1)[CH3:24]
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc(Cl)nc(OC)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Sulfuric acid (1 mL) is added to a suspension of 2-chloro-6-methoxy-isonicotinic acid (4.16 g, 22.2 mmol) in ethanol (20 mL). The clear solution is stirred at 70° C. for 18 h. The mixture is neutralised by adding sat. aq. NaHCO3 solution and then extracted three times with EA (3×250 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give 2-chloro-6-methoxy-isonicotinic acid ethyl ester (4.32 g) as a white solid; LC-MS: tR=1.00 min, [M+1]+=215.89.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=O>C(Cl)Cl>[C:2]([S@@:5](/[N:7]=[CH:8]/[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]1)=[O:6])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(/C=N/[S@@](=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a round bottomed flask charged with a magnetic stir bar was added (S)-2-methylpropane-2-sulfinamide (20.46 g, 169 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (30 g, 141 mmol), DCM (300 mL), and Ti(OEt)4 (59.0 ml, 281 mmol). The solution was stirred at room temperature for 3 h before it was quenched with brine (80 mL). The solution was stirred for 30 minutes before filtering. The filter cake was washed with DCM and the filtrate was placed in a separatory funnel and washed with water. The organics layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue solidified to the title compound (29 g, 92 mmol, 65.1% yield) m/z 217.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.C(=O)([O-])[O-].[Na+].[Na+].Br[CH:19]1[CH2:24][CH2:23][O:22][C:20]1=[O:21].Cl>O.C(OC(=O)C)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[C:19]3([CH2:24][CH2:23][O:22][C:20]3=[O:21])[S:11][C:4]=2[CH:3]=1
Reactant: O=C1OCCC1Br
Reactant: O=C(O)c1ccc(Cl)cc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1OCCC12Sc1cc(Cl)ccc1C2=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 8.3 %

Procedure:
In 200 ml of water were dissolved 14.2 g of 4-chlorothiosalicylic acid and 20 g of sodium carbonate, and 19.1 g of α-bromo-γ-butyrolactone was added dropwise to the solution under ice-cooling. After stirring the solution at room temperature for 6 hours, 35 ml of concentrated hydrochloric acid was added to the reaction solution at room temperature to acidify. After stirring at room temperature for 3 hours, the precipitate was collected, washed with water and dried, resulting in crude α-[(2-carboxy-5-chlorophenyl)thio]-γ-butyrolactone. The crude product was dissolved in 150 ml of acetic anhydride and 30 ml of triethylamine, and heated under a stream of nitrogen at 130° C. for 10 minutes. The reaction solution was evaporated to dryness under reduced pressure, and the resulting residue was chromatographed on a column of activated carbon and silica gel. Recrystallization from ethanol of the resultant crude crystals yielded 1.60 g of 6-chloro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione as colorless needles. Melting point: 157°-158° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)N(C2CC2)CCC3(C)C)=[CH:7][CH:6]=1)[CH3:2].[CH2:29]([O:31][C:32](=O)[C:33]1[CH:38]=CC(I)=CC=1)C>C(N(CC)CC)C.[Cu]I.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>[CH3:29][O:31][C:32]1([C:20]2[CH:15]=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:28])=[CH:6][CH:7]=3)=[CH:22][CH:21]=2)[CH2:33][CH2:38]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCN3C2CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61, 100.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 141.0 mg, 0.51 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (109 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 135.0 mg (90%) of the title compound as an orange solid.
Reaction SMILES: [NH3:1].C([O:4][C:5]([C:7]1[N:8]=[C:9]2[C:14]([CH2:15][CH2:16][CH3:17])=[C:13]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[C:20]3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[N:25]=3)[N:12]=[CH:11][N:10]2[CH:31]=1)=O)C>CCO>[F:30][C:26]1[N:25]=[C:24]([C:20]2[N:19]([CH2:18][C:13]3[N:12]=[CH:11][N:10]4[CH:31]=[C:7]([C:5]([NH2:1])=[O:4])[N:8]=[C:9]4[C:14]=3[CH2:15][CH2:16][CH3:17])[CH:23]=[CH:22][N:21]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: N
Reactant: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncn2cc(C(=O)OCC)nc12
Solvent: CCO
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncn2cc(C(N)=O)nc12
Temperature: 90 °C

Procedure:
Ammonia gas is passed through a stirred solution of 7-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-8-propyl-imidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester (110, above) (1 mmol) in EtOH (7 ml) in a sealed tube for 20 minutes at 0° C. The tube is then sealed and heated at 90° C. for 2 days. The solvent is evaporated and the residue (128) is used directly in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>ClCCl>[Cl:24][C:19](=[O:21])[CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: O=C(O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a stirred mixture of 29 parts of 1-[(phenylmethoxy)carbonyl]-4-piperidinepropanoic acid and 520 parts of dichloromethane were added dropwise 14.9 parts of thionyl chloride. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was evaporated, yielding 28.3 parts (91.5%) of (phenylmethyl) 4-(3-chloro-3-oxopropyl)-1-piperidinecarboxylate as a residue (int. 34).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[NH:22][N:21]=1>>[N:13]1([C:11]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([N:22]4[C:23]5[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=5[C:20]([C:19]([F:18])([F:30])[F:29])=[N:21]4)=[CH:3][CH:4]=3)[CH2:10][CH2:9]2)=[O:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(N1CCCC1)C1(c2ccc(I)cc2)CC1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Product: O=C(N1CCCC1)C1(c2ccc(-n3nc(C(F)(F)F)c4c3CCCC4)cc2)CC1

Procedure:
The title compound was prepared from 1-{[1-(4-iodophenyl)cyclopropyl]carbonyl}pyrrolidine and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 19.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.Cl[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: ClCc1cccnc1
Agent: Cl
Product: CCOC(=O)N1CCC(c2cn(Cc3cccnc3)c3ccccc23)CC1
Reaction time: 16 h
Yield: 89.4 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 16 hours, starting with 11 g (40 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 7.2 g (44 mmol) of 3-chloromethyl-pyridine hydrochloride. After standard work-up, 13 g of a crude oil was obtained. This crude was precipitated with ethyl ether affording 10.8 g (90% of yield) of a white solid.
Reaction SMILES: C=O.[C:3]([O:6][C:7](=[O:9])[CH3:8])(=O)[CH3:4].[C:10]1(O)[CH:15]=CC=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[C:7]([O:6][C:3]1[CH:12]=[CH:11][CH:10]=[CH:15][CH:4]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccccc1
Agent: C=O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccccc1

Procedure:
In order to fully achieve the objects of this invention and optimize the formation of paraformaldehyde, it is essential that acetic anhydride be metered into the reaction mixture at a rate such that there is sufficient acetic anhydride present to selectively react with one of the toluene oxidation products, (phenol) to give phenyl acetate but not enough acetic anhydride to convert the other oxidation product (formaldehyde) to methylene diacetate, under reaction conditions. This may conveniently be accomplished by careful control of the amount of acetic anhydride introduced into the reaction as the oxidation process is monitored, e.g., by conventional chromatographic techniques.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][N:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]=[CH2:32])=[CH:25][CH:24]=2)N)=[CH:18][CH:17]=1.CC([O-])=O.[Na+]>C1(C)C=CC=CC=1.CC(O)=O>[Cl:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][N:21]2[C:23]3[C:24](=[CH:25][C:26]([O:29][CH2:30][CH:31]=[CH2:32])=[CH:27][CH:28]=3)[C:6]([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:7]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(=O)CSC(C)(C)C
Reactant: C=CCOc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=CCOc1ccc2c(c1)c(SC(C)(C)C)c(C(=O)OCC)n2Cc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A solution of ethyl 3-(t-butylthio)-2-oxopropanoate (18.6 g), 1-(4-chlorobenzyl)-1-(4-allyloxyphenyl)hydrazine hydrochloride (26.3 g), and NaOAc (15 g) in 300 mL toluene and 150 mL HOAc was stirred at room temperature under nitrogen for 16 hours then at 70° C. for 2 hours. The mixture was cooled, poured onto H2O, extracted (3×) with EtOAc and, the organic layers then washed successively with sat'd. NaHCO3 and brine. After drying over MgSO4, the solution was filtered and evaporated, and the residue chromatographed (silica gel; hexane/EtOAc 4:1) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:17])=[O:10]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1Br
Temperature: 0 °C
Yield: 98 %

Procedure:
A solution of o-bromophenylacetic acid (5 g, 23.2 mmol) in dry methanol (40 mL) containing concentrated sulphuric acid (1 mL) was heated to reflux for 6 hours. The reaction mixture was cooled, then poured into ice water (100 mL) and extracted with ethyl acetate (30 mL×2). The organic layers were combined, washed successively with water (20 mL×2), saturated sodium bicarbonate solution (40 mL×2) and brine. And then the organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo to give methyl 2-(2-bromophenyl)acetate as a pale yellow liquid (5.2 g, 98%). 1H NMR (300 MHz, CDCl3): δ 7.57 (d, J=7.8 Hz, 1H), 7.34-7.22 (m, 2H), 7.17-7.11 (m, 1H), 3.80 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][OH:12]>CO.[Ni]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([CH2:11][OH:12])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c(CO)cccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Cc1c(N)cccc1CO
Yield: 90.2 %

Procedure:
A solution of 2-methyl-3-nitrobenzenemethanol (10.0 g, 59.8 mmol) in methanol is treated with Raney Nickel and shaken under hydrogen gas (50 psi) in a Parr Shaker. The solution is filtered through Celite and evaporated. Recrystallization of the residue from isopropyl ether gives pure 3-amino-2-methylbenzenemethanol (7.4 g, 90%), mp=106-108° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10]Cl.[Na+].[I-:14]>CC#N>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][I:14]
Reactant: [I-]
Reactant: Nc1ccc(Cl)cc1C(=O)CCl
Agent: [Na+]
Solvent: CC#N
Product: Nc1ccc(Cl)cc1C(=O)CI
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.2 %

Procedure:
To a solution of 11.208 g (54.93 mM) of 2'-amino-2,5'-di-chloroacetophenone in 281 ml of CH3CN is added 24.7 g (165 mM) of NaI, and the mixture is stirred at room temperature for 2.5 hr. and concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with aqueous Na2S2O3, and brine in order, dried and concentrated to give 16.1 g (Yield: 99.2%) of 2'-amino-5'-chloro-2-iodoacetophenone as crystals.