Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N+:17]([O-])=O)[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.O.O.Cl[Sn]Cl>C(O)C>[N:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH:11]=3)[NH2:17])[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2noc(N3CCC3)n2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2noc(N3CCC3)n2)cc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
To a stirred solution of 5-(azetidin-1-yl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (108) (1.4 g, 5.38 mmol) in ethanol (25 mL) was added SnCl2.2H2O (6.07 g, 26.90 mmol). The resulting solution was stirred for 20 min at reflux then cooled to room temperature and concentrated under vacuum. The residue was poured into saturated sodium hydroxide (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×250 mL), dried over anhydrous sodium sulfate, concentrated under vacuum and purified by flash chromatography (PE/EA=10:1) to afford 5-(5-(azetidin-1-yl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (109) (0.8 g, 65% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.28-7.36 (m, 2H), 7.12 (d, J=7.8 Hz, 1H), 4.32 (t, J=7.5 Hz, 4H), 3.69 (brs, 2H), 2.47-2.57 (m, 2H), 2.21 (s, 3H). MS m/z 231.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[CH3:13])[C:4](=[O:14])[NH:3]1.I[C:17]1[CH:25]=[CH:24][C:20]2[N:21]=[CH:22][S:23][C:19]=2[CH:18]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:23]1[C:19]2[CH:18]=[C:17]([N:3]3[C:2]([CH3:15])([CH3:1])[CH2:6][N:5]([C:7]4[CH:8]=[N:9][CH:10]=[CH:11][C:12]=4[CH3:13])[C:4]3=[O:14])[CH:25]=[CH:24][C:20]=2[N:21]=[CH:22]1
Reactant: Cc1ccncc1N1CC(C)(C)NC1=O
Reactant: Ic1ccc2ncsc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CC(C)(C)N(c2ccc3ncsc3c2)C1=O
Yield: 12.1 %

Procedure:
Using the same reaction conditions as described in example 14, 4,4-dimethyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-163b: 150 mg, 0.731 mmol) was reacted with 6-iodo-benzothiazole (248 mg, 0.950 mmol), 1,4-dioxane (10 mL), copper iodide (13 mg, 0.0682 mmol), trans-1,2-diamino cyclohexane (31 mg, 0.218 mmol) and potassium phosphate (387 mg, 1.825 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 30 mg of the product (12.14% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1[NH2:22])=[S:7])=[O:4].[CH3:23][O:24]C(NC(NC1C=CC(CCCC)=CC=1NC=O)=S)=O>>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][CH:19]([CH3:20])[CH3:21])=[O:17])=[CH:11][C:10]=1[NH:22][CH:23]=[O:24])=[S:7])=[O:4]
Reactant: CCCCc1ccc(NC(=S)NC(=O)OC)c(NC=O)c1
Reactant: COC(=O)NC(=S)Nc1ccc(NC(=O)OC(C)C)cc1N
Product: COC(=O)NC(=S)Nc1ccc(NC(=O)OC(C)C)cc1NC=O

Procedure:
By proceeding in a similar manner but substituting an equimolecular quantity of 1-methoxycarbonyl-3-(2-amino-4-isopropoxycarbonylaminophenyl)thiourea for the 1-methoxycarbonyl-3-(2-amino-4-n-butylphenyl)thiourea, there was obtained 1-methoxycarbonyl-3-(2-formamido-4-isopropoxycarbonylaminophenyl)thiourea, m.p. 194°-195° C. (with decomposition).
Reaction SMILES: [C:1]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[N+:16]([O-])=O)[C:12](=[O:19])[CH2:11][CH2:10]2)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:16][C:15]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=[O:19])=[CH:8][C:7]=1[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCCCC#Cc1cc2c(cc1N)C(=O)CC2

Procedure:
A mixture of 5-hex-1-ynyl-6-nitroindan-1-one (8.2 g, 31.8 mmol), NH4Cl (0.84 g) and Fe (8.88 g, 0.159 mol) in ethanol (97 ml) and water (32 ml) is heated at reflux for 45 minutes.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O:33]O)(C)(C)C.Cl[O-].[Na+]>ClCCl>[O:33]=[C:14]1[CH:15]=[C:16]2[C@:22]([CH3:23])([CH2:21][CH2:20][C@H:18]([OH:19])[CH2:17]2)[C@@H:24]2[C@@H:13]1[C@H:12]1[C@:27]([CH3:28])([CH2:26][CH2:25]2)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OO
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 2.5 °C
Yield: 67.4 %

Procedure:
Cholesterol (13, 1.93 gm, 0.005 mol) and tert-butyl hydroperoxide (4.2 ml of 70% aq. solution, 0.03 mol) were dissolved in dichloromethane (20 ml). The mixture was stirred vigorously, cooled to 0-5° C. and a dilute solution of sodium hypochlorite (15 ml, 5.25% available chlorine) was added slowly in the form of fine, small droplets during ten hours at 0-5° C. After completion of addition, the dichloromethane layer was separated, washed with water, aqueous sodium bisulfite solution (10%, 2×10 ml) and water. The organic solvent was evaporated under reduced pressure to yield a crude product, which was chromatographed on a silica gel column utilizing 20% acetone in petroleum-ether to afford 1.35 gm (67.5%) of 7-oxo-cholesterol (14) as a snow white solid having a melting point of 169-70° C.
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)[N:5]=2.[CH3:24][O-:25].[Na+]>CO>[CH:15]1([CH2:14][CH2:13][O:12][C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([O:25][CH3:24])[N:3]3[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:8]([NH2:11])[N:7]=2)[CH2:17][CH2:16]1
Reactant: Nc1nc(OCCC2CC2)nc2c1nc(Br)n2C1CCCCO1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1C1CCCCO1

Procedure:
A solution of 8-bromo-2-[(2-cyclopropylethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.867 g) in dry MeOH (14 mL) was treated with sodium methoxide solution (3.1 mL, 25 wt. MeOH) and was heated to reflux for 5 h. The reaction was concentrated under reduced pressure before being partitioned between EtOAc (100 mL) and ammonium chloride (100 mL). The organics were separated and aqueous was re-extracted with EtOAc (100 mL). The combined organics were washed with brine (100 mL), separated and dried using a hydrophobic frit. The organics were evaporated under reduced pressure to give the title compound as a brown foam (845 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][NH:6]2.Cl.CN(C)CCCN=C=NCC.[CH3:25][N:26]1[C:31](=[O:32])[CH:30]=[C:29]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:28]=[C:27]1[CH2:39][C:40]([O-])=[O:41].[Na+].O>CN(C)C=O.N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][N:6]2[C:40](=[O:41])[CH2:39][C:27]1[N:26]([CH3:25])[C:31](=[O:32])[CH:30]=[C:29]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:28]=1
Reactant: CC1(C)CNc2cccc(F)c21
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(CC(=O)N2CC(C)(C)c3c(F)cccc32)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
150 mg of 4-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole [reference example 2c] and 279 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 300 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2c of example 4c) in 5 ml of N,N-dimethylformamide and 5 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours and then 30 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by trituration from a mixture of ethyl acetate and diisopropyl ether, so as to give 260 mg of 2-[2-(4-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one, the characteristics of which are the following:
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:26][CH:27]2C[CH2:30][CH2:29][CH2:28]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.[CH:33]1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC=C(C(F)(F)F)C=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:26]1([N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=2)[C:13](=[O:14])[N:12]([CH3:33])[C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:32])=[CH:8][N:9]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(F)(F)F)c2)s1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: FC(F)(F)c1cccc(NCC2CCCC2)c1
Product: CN(C(=O)N(c1cccc(C(F)(F)F)c1)C1CCCC1)c1ncc(SCC(=O)O)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-trifluoromethyl-phenyl)ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-trifluoromethyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([S:13][CH3:14])=[N:10][C:9]=2[CH2:15][OH:16])=[CH:4][CH:3]=1.[F:17][C:18]([F:22])([F:21])[CH2:19]O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([S:13][CH3:14])=[N:10][C:9]=2[CH2:15][O:16][CH2:19][C:18]([F:22])([F:21])[F:17])=[CH:6][CH:7]=1
Reactant: CSc1nc(CO)c(-c2ccc(F)cc2)o1
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CSc1nc(COCC(F)(F)F)c(-c2ccc(F)cc2)o1
Reaction time: 2 h

Procedure:
A suspension of [5-(4-fluoro-phenyl)-2-methylsulfanyl-oxazol-4-yl]-methanol (4.15 g; 17.34 mmol) in dry toluene (100 ml) was treated with 2,2,2-trifluoroethanol (12.63 ml; 173.4 mmol), 1,1'-(azodicarbonyl)dipiperidine (5.03 g; 19.94 mmol) and tributylphosphine (4.97 ml; 19.94 mmol) and stirred for 2 hours. The reaction mixture is partitioned between ethyl acetate (150 ml) and dilute sodium chloride solution (150 ml). The organic phase is washed with saturated brine (30 ml), dried over sodium sulfate and concentrated to dryness. Purification by flash chromatography on silica gel using an ethyl acetate/hexane gradient (2%-30%) afforded the product as a colorless residue (3.0 g; 49%). HNMR (CDCl3): 7.65 (m, 2H), 7.18 (t, 2H, J=8.7 Hz), 4.72 (s, 2H), 4.01 (qt, 2H, J=8.6 Hz), 2.73 (s, 3H). Mass spectrum: m/e calculated (MH+)=322; observed (MH+)=322.
Reaction SMILES: [CH2:1]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[N:20]=[C:19]([C:11]2[S:10][C:9]([CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:13][CH:12]=2)[CH:18]=[CH:17][N:16]=1
Reactant: c1ccc(CCc2cccs2)cc1
Reactant: Clc1ncccn1
Product: Clc1nccc(-c2ccc(CCc3ccccc3)s2)n1

Procedure:
The title compound was prepared from 2-phenethyl-thiophene and 2-chloropyrimidine in a manner analogous to Example 255, Step 1. MS (M+H)+ 301.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=O)[C:10]3=[N:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:19]=1.FC1C=CC2CC[C:27]3[C:28](C(=O)C=2C=1)=[N:29][CH:30]=[CH:31][CH:32]=3>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[C:32]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:10]3=[N:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: COc1cnc2c(c1)CCc1cc(Cl)ccc1C2=O
Reactant: O=C1c2cc(F)ccc2CCc2cccnc21
Product: COc1cnc2c(c1)CCc1cc(Cl)ccc1C2=C1CCNCC1

Procedure:
By substituting in Preparative Example 2 step D, 8-chloro-3-methoxy-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-one for 9-fluoro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-one and employing basically the same methods as steps D through H of Preparative Example 2, one obtains 8-chloro-3-methoxy-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridine as a white solid (MH+ 340).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=2[O:20][CH3:21])[CH2:8][C:7](=[O:22])[NH:6]1)=[O:4].[H-].[Na+].[CH3:25]I.Cl>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]2[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[CH:14][C:15]=2[O:16][CH3:17])[CH2:8][C:7](=[O:22])[N:6]1[CH3:25])=[O:4]
Reactant: CI
Reactant: COC(=O)C1NC(=O)CC1c1c(OC)cc(OC)cc1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1C(c2c(OC)cc(OC)cc2OC)CC(=O)N1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
(+)-Methyl-5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2-carboxylate (1.7 g, 0.0055 mol) was dissolved in N,N-dimethylformamide (15 mL) and the solution cooled to 0° C. Sodium hydride (0.134 g, 0.0056 mmol) was added in portions over a period of 10 minutes and stirred for another 20 minutes at 0° C. Methyl iodide (0.514 mL, 0.0082 mol) was added dropwise and the reaction allowed to warm to room temperature in 1 hour. The reaction mixture was poured slowly over a mixture of crushed ice (20 g) and 1:1 hydrochloric acid solution (5 mL). The mixture was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield an oil. The oil was triturated with petroleum ether and the resulting solid was filtered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][CH:16]=[CH:15][CH2:14][N:13]2[C:19]([OH:21])=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:29][N:30]1[CH:34]=[C:33]([S:35](Cl)(=[O:37])=[O:36])[N:32]=[CH:31]1.Cl>O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16]([S:35]([C:33]3[N:32]=[CH:31][N:30]([CH3:29])[CH:34]=3)(=[O:37])=[O:36])=[CH:15][CH2:14][N:13]2[C:19]([OH:21])=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(S(=O)(=O)N2C=CC=CCN2C(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(S(=O)(=O)N2C=CC(S(=O)(=O)c3cn(C)cn3)=CCN2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 1-[(4-methoxyphenyl)sulfonyl]-diazepine-2-carboxylic acid (0.150 g, 0.48 mmol) is dissolved in water (10 mL) and p-dioxane (10 mL). The triethyl amine (0.27 mL, 1.9 mmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride (0.104 g, 0.58 mmol) are next added. The reaction mixture is stirred overnight at room temperature and then the solution is acidified with 1N HCl to pH~1, poured into water, and extracted with methylene chloride. The organic extracts are dried (Na2SO4) and concentrated down to an oil. The oil is purified by HPLC with a reverse phase column using 70% (95% water, 5% acetonitrile, 0.1% formic acid) and 30% (80% acetonitrile, 20% water) as the eluent.
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[CH:6]=[C:7](\[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14](/[C:7](/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6]\[CH:5]=[CH:4]\[C:3]([OH:22])=[O:2])=[CH:19][CH:18]=1
Reactant: COC(=O)/C=C/C=C(/c1ccccc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C\C=C\C(=O)O)c2ccccc2)cc1
Reaction time: 2.5 h
Yield: 69.7 %

Procedure:
In the manner described in Example 99, (2E,4Z)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid methyl ester (6.4 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (23 mL). After 2.5 hours the reaction was worked up in the usual fashion and the crude acid was crystallized from 2-propanol to yield 4.25 g of (2E,4Z)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid. A sample was recrystallized from 2-propanol to give the analytical specimen, mp 184°-185° C.
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.[NH:74]1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1.CC([O-])(C)C.[Na+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C1(C)C=CC=CC=1>[O:77]1[CH2:78][CH2:79][N:74]([C:2]2[CH:40]=[CH:39][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:4][CH:3]=2)[CH2:75][CH2:76]1
Reactant: C1COCCN1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(N3CCOCC3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 5 mL microwave vial were added ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate (50 mg, 0.08 mmol), RuPhos (4.0 mg, 0.008 mmol), RuPhos pre-catalyst (6.2 mg, 0.008 mmol), morpholine (10.3 μL, 0.12 mmol), NaOt-Bu (11 mg, 0.12 mmol) and toluene (0.85 mL). The vial was flushed with N2 then capped and placed in a heating block at 85° C. After 1.5 h, the mixture was cooled to RT. The mixture was diluted with EtOAc (10 mL) and washed with water (10 mL). The organic layer was dried with Na2SO4, filtered and concentrated to dryness. The residue was purified by reverse phase HPLC to afford the title compound. MS (ESI): mass calcd. for C37H40N4O4, 604.3; m/z found 605.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH:27]1([CH2:32][N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[CH:27]1([CH2:32][N:33]2[CH:37]=[C:36]([C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]5[CH:17]=[C:16]([N:18]6[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]6)[N:15]=[C:14]([NH2:25])[N:13]=5)[CH2:9]4)=[CH:4][CH:3]=3)[CH:35]=[N:34]2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC1(C)OB(c2cnn(CC3CCCC3)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
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: CO
Solvent: O
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(CC4CCCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(cyclopentylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.3 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. It was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (4.1 mg). LCMS (M+H)+: m/z=487.3.
Reaction SMILES: [H-].[Na+:2].CN(C)C=O.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)=[O:11].[H][H]>>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O-:18])=[CH:14][CH:13]=1)([O:9][CH3:8])=[O:11].[Na+:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([O-])cc1
Temperature: 0 °C

Procedure:
To a suspension of sodium hydride (one equivalent, 50% dispersion in mineral oil) in dimethylformamide (DMF) (100 ml per 50 mmole), cooled to 0° C., is added slowly methyl p-hydroxybenzoate (one equivalent). The reaction mixture is stirred under a nitrogen atmosphere until the evolution of hydrogen ceases. To the solution of sodium 4-carbomethoxyphenolate so produced, is added N,N-dimethylthiocarbamoyl chloride [(CH3)2N(CS)Cl] (one equivalent) in one portion. The resulting suspension is heated to 70° C. for 1-3 hours and then is poured into an aqueous solution (1%) of potassium hydroxide (large excess). The suspension is extracted twice with toluene-hexane (4:1 v/v). After drying over MgSO4, the organic extracts are filtered and evaporated to an oil. The oil is purified by chromatography over silica gel using 2% methanol in methylene chloride to give O-(4-carbomethoxyphenyl)dimethylthiocarbamate [p-CH3CO2C6H4O(CS)N(CH3)2 ]. (mp 97°-102° C.). This product is heated under a nitrogen atmosphere at 220° C. for 30-60 min. to give S-(4-carbomethoxyphenyl)-dimethylthiocarbamate [p-CH3CO2C6H4S(CO)N(CH3)2 ] which is crystallized from methanol. To S-(4-carbometoxyphenyl)dimethylthiocarbamate, dissolved in DMSO, is added 2 equiv. of sodium hydroxide (10% aqueous). The mixture is heated at 65°-85° C., and the alkyl bromide (1 equiv.) is added. Heating is continued for 2-4 hours after which the mixture is poured into a large volume of water. Upon acidification, a precipitate forms, which is collected by filtration. The (alkylthio)benzoic acid is crystallized from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.Br[C:17]([F:21])([F:20])[CH:18]=[CH2:19].[In].[I-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[C:17]([F:21])([F:20])[CH:18]=[CH2:19])=[CH:6][CH:7]=1
Reactant: C=CC(F)(F)Br
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: [I-]
Agent: [In]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.511 g, 1.92 mmol), 3-bromo-3,3-difluoro-propene (0.4977 g, 3.07 mmol), indium (0.357 g, 3.07 mmol) and sodium iodide (0.0142 g, 0.096 mmol) were combined in DMF (5 mL) and stirred at room temperature overnight. The reaction mixture was submitted to standard aqueous workup to afford the title compound, which was taken to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH3:16][C:17]([CH3:25])([CH:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1)[OH:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:21]1[CH2:22][CH2:23][CH2:24][CH:19]([C:17]([OH:18])([CH3:25])[CH3:16])[CH2:20]1)=[O:15]
Reactant: CC(C)(O)C1CCCNC1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Product: CC(C)(O)C1CCCN(C(=O)c2cnoc2-c2ccccc2Cl)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and dimethyl-3-piperidylmethanol (10.8 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (5.7 mg). Calcd for C18H21ClN2O3: 348.1241, found 348.1236.