Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:24]=[CH:23][C:16]([O:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])=[CH:15][CH:14]=1)[C:5]2=O.O.[NH2:27][NH2:28]>>[Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[C:6]([C:13]3[CH:24]=[CH:23][C:16]([O:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])=[CH:15][CH:14]=3)=[CH:7][NH:28][N:27]=2)[CH:3]=1
Reactant: NN
Reactant: N#CCCCOc1ccc(-c2coc3cc(O)c(Cl)cc3c2=O)cc1
Solvent: O
Product: N#CCCCOc1ccc(-c2c[nH]nc2-c2cc(Cl)c(O)cc2O)cc1
Yield: 71.6 %

Procedure:
This compounds was synthesised in the same manner as described above. 4-[4-(6-Chloro-7-hydroxy-4-oxo-4H-chromen-3-yl)-phenoxy]-butyronitrile (0.12 g, 0.34 mmol), Hydrazine hydrate (5 ml). The precipitate formed on quenching was filtered to give 4-{4-[3-(5-Chloro-2,4-dihydroxy-phenyl)-1H-pyrazol-4-yl]-phenoxy}-butyronitrile as a white solid (0.09 g, 71.6%); Rf 0.6 ethyl acetate/hexane (70/30)].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:22])[CH:28]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:17][CH:16]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Product: CC(C)(C)c1ccc(Cn2ccc3cc(-c4cccc(Cl)c4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (Step 1 of Example 34) and 3-chlorophenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 374. 1HNMR (400 MHz, DMSO-d6): δ 7.86 (d, 1H, J=1.53 Hz), 7.68 (dd, 1H, J=1.84 and 1.83 Hz), 7.61 (d, 1H, J=7.79 Hz), 7.43 (d, 1H, J=8.40 Hz), 7.36 (d, 1H, J=8.55 Hz), 7.55-7.54 (m, 2H), 7.46-7.41 (m, 2H), 7.34 (d, 1H, J=1.07 Hz), 7.31 (d, 2H, J=8.40 Hz), 7.13 (d, 2H, J=8.40 Hz), 6.53 (d, 1H, J=3.06 Hz), 5.40 (s, 2H), 1.30 (s, 9H), and 1.21 ppm (s, 9H).
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][S:20]([CH3:22])=[O:21])=[C:14]([NH:24][CH3:25])[CH:13]=1>O>[F:11][C:12]1[CH:13]=[C:14]2[C:15]([C:18](=[O:23])[C:19]([S:20]([CH3:22])=[O:21])=[CH:25][N:24]2[CH3:1])=[CH:16][CH:17]=1
Reactant: CNc1cc(F)ccc1C(=O)CS(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: Cn1cc(S(C)=O)c(=O)c2ccc(F)cc21
Temperature: 25 °C

Procedure:
A mixture of acetic anhydride (66.0 ml) and formic acid (45.0 ml) was stirred and heated at 50°-60° under nitrogen for 2 hours and then cooled to ambient temperature. 1-(4-Fluoro-2-methylaminophenyl)-2-methylsulphinylethanone (69.0 g), prepared in a similar manner to that described in Example 1, was added slowly below 30° and the mixture stirred for a further 2 hours. The mixture was cooled in an ice/salt bath to 0° and water (500 ml) added whilst maintaining the temperature below 30°. The mixture was filtered and the filtrate cooled in an ice/salt bath to 0°. Toluene (100 ml) and aqueous sodium hydroxide solution (specific gravity 1.5; 140 ml) were added sequentially, again maintaining the temperature below 30°. The mixture was stirred for 30 minutes at ambient temperature and the product collected by filtration, washed with water (200 ml), toluene (3×50 ml) and hexane (2×50 ml) and then dried at 50° in vacuo to give 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone, m.p.228.5°-230.5° (53.7 g).
Reaction SMILES: [NH:1]=[C:2]1[C:15]([NH:16][C:17]([NH:19][C:20]([O:22][CH3:23])=[O:21])=[S:18])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31].[H-].[Na+].S(OC)(O[CH3:38])(=O)=O.O>COCCOC>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:19][C:20]([O:22][CH3:23])=[O:21])[S:18][CH3:38])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)NC(=S)NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2Cl)C1=N
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2Cl)C1=N)SC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-imino-(o-chlorophenyl)methyl-4-(3-carbomethoxythioureido)benzophenone (4.52 g.; 0.01 mol) in 1,2-dimethoxyethane (50 ml.) there is added 57% sodium hydride (0.42 g.; 0.01 mol) (oil dispersion). The mixture is stirred at room temperature for one hour and there is then added dimethyl sulfate (1.26 g.; 0.01 mol). The mixture is stirred at room temperature for one hour and is poured into an excess of water. The suspension is filtered and the filter cake dried to afford 3-imino-(o-chlorophenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:26])[N:9]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:27]([O:31][CH3:32])(=[O:30])[CH2:28][SH:29]>>[CH3:32][O:31][C:27](=[O:30])[CH2:28][S:29][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[O:26])=[N:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCC(C(F)(F)F)CC1
Product: COC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCC(C(F)(F)F)CC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(4-trifluoromethyl-cyclohexyl)-urea (Example 204) and methyl thioglycolate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C1(C)C(C)=CC=CC=1>[OH:12][C:13]1[C:6]2[C:7](=[C:2]([CH3:1])[N:3]=[C:4]([CH3:9])[CH:5]=2)[N:8]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Cc1ccc(N)c(C)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cnc2c(C)nc(C)cc2c1O
Temperature: 25 °C
Yield: 29.2 %

Procedure:
A mixture of 2,6-dimethyl-3-aminopyridine (0.85 g) and diethyl ethoxymethylenemalonate (1.53 g) is heated at 135° C. in xylene (30 mL) for 2 h allowing for removal of ethanol. After the solvent is removed, the mixture is suspended in diphenyl ether (15 mL). The mixture is then heated to reflux with removal of ethanol for 30 min. The reaction mixture is cooled to room temperature and hexanes (20 mL) is added. The resulting precipitate is filtered, washed with diethyl ether (2×10 mL) and dried to give 0.5 g (30%) of the title compound as a brown solid. Physical chracteristics: MS (ESI+) m/z 247 (M+H)+; 1H NMR (DMSO) δ8.67, 7.97, 4.38, 2.85, 2.67, 1.40.
Reaction SMILES: C([NH:8][S:9]([C:12]1([C:15]#[CH:16])[CH2:14][CH2:13]1)(=[O:11])=[O:10])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:15]([C:12]1([S:9]([NH2:8])(=[O:11])=[O:10])[CH2:14][CH2:13]1)#[CH:16]
Reactant: C#CC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CC1(S(N)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of compound 81 (200 mg, 0.81 mmol) and TFA (0.3 mL) in DCM (5 mL) was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure and the crude material was purified by chromatography on silica gel (MeOH/DCM) to yield compound 82 in 70% yield.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([F:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=2)=[CH:11][C:10]=1[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:32]C(=O)OC(C)(C)C)[CH:29]=[CH:30][CH:31]=1)=O)(C)(C)C.CO.[ClH:42]>O1CCOCC1>[ClH:23].[ClH:42].[ClH:23].[NH2:32][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:10]2[CH:11]=[C:12]([NH:15][C:16]3[C:21]([F:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=3)[CH:13]=[CH:14][C:9]=2[NH2:8])[CH:31]=[CH:30][CH:29]=1.[ClH:23]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(Nc3nc(Cl)ncc3F)ccc2NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cccc(CCc2cc(Nc3nc(Cl)ncc3F)ccc2N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into the reaction flask was added tert-butyl [3-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyl}ethyl)phenyl]carbamate (0.32 g, 0.57 mmol), methanol (3 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (5 mL). The mixture was stirred at rt overnight and concentrated under vacuum to give the desired product as a HCl salt (220 mg, 98%). LCMS for C18H18ClFN5 (M+H)+: m/z=358.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)=[O:7].[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[C:14]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])[S:13][C:12]=12)=[O:7]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: O=C(c1cccs1)c1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cccs3)c2s1

Procedure:
The title compound (923 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 550 mg of 7-(thiophen-2-yl)carbonylimidazo[5,1-b]thiazole, 0.701 ml of tri-n-butylstannyl chloride, and 3.6 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12]([CH3:14])=O.C[OH:16]>[Pd]>[CH3:1][CH:2]1[CH:3]([CH2:10][CH2:11][CH2:12][CH3:14])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][C:7]1=[O:16]
Reactant: CO
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Agent: [Pd]
Product: CCCCC1C(C)C(=O)CCC1(C)C

Procedure:
The mixture of compounds obtained according to example 1 starting from β-ionone is dissolved in methanol and hydrogenated at atmospheric pressure and room temperture using 5% Palladium on charcoal as a catalyst.
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH2:31]([O:38][C:39]1[C:40]([NH:47][C:48]2[S:49][CH:50]=[C:51]([CH3:53])[N:52]=2)=[N:41][CH:42]=[C:43]([CH:46]=1)[CH:44]=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[ClH:54]>C1COCC1>[ClH:54].[ClH:54].[CH2:31]([O:38][C:39]1[C:40]([NH:47][C:48]2[S:49][CH:50]=[C:51]([CH3:53])[N:52]=2)=[N:41][CH:42]=[C:43](/[CH:44]=[CH:5]/[CH2:4][N:3]([CH3:25])[CH3:2])[CH:46]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1csc(Nc2ncc(C=O)cc2OCc2ccccc2)n1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1csc(Nc2ncc(/C=C/CN(C)C)cc2OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 51.3 %

Procedure:
A 25 mL round-bottomed flask was charged with [2-(dimethylamino)ethyl]triphenylphosphonium bromide (1114 mg, 2.69 mmol) and THF (5 mL). The reaction was cooled to 0° C. under nitrogen. Butyllithium (1.08 ml, 2.69 mmol) was added slowly and the reaction was stirred for 50 minutes. A solution of 5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)nicotinaldehyde (350 mg, 1.08 mmol) in THF (5 mL) was added and the reaction was stirred at ambient temperature for 1.5 hours. The reaction was partitioned between EtOAc and water. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified on a silica gel column (10 to 20% methanol in EtOAc with NH4OH) to afford the title compound (250 mg, 51.3% yield) after HCl salt formation. 1H NMR (DMSO-d6) δ 10.85 (bs, 1H), 10.49 (bs, 1H), 8.03 (d, 1H), 7.78 (s, 1H), 7.63 (d, 2H), 7.45-7.33 (m, 3H), 6.82 (m, 3H), 6.45 (m, 1H), 5.37 (s, 2H), 3.85 (m, 2H), 2.77 (d, 6H), 2.30 (s, 3H). Mass spectrum (apci) m/z=381.1 (M+H-2HCl).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40]>CN(C=O)C>[CH2:39]([N:41]([CH2:42][CH3:43])[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH3:40]
Reactant: CCNCC
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(F)c4)cc23)CC1
Temperature: 100 °C
Reaction time: 0.02 h
Yield: 21.6 %

Procedure:
To a solution of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-fluorophenyl)-1H-indazole-7-carboxamide (0.222 mmol) in DMF (4 mL) was added K2CO3 (61 mg, 0.444 mmol) and diethyl amine (115 uL, 1.11 mmol). The reaction mixture was heated to 100° C. overnight. The solution was filtered and the filtrate was purified by using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 80% B in 10 min, hold for 1 min where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (24.7 mg, 22% for 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:38]=[N:39][C:40]([CH3:43])=[N:41][CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:37]4[CH:38]=[N:39][C:40]([CH3:43])=[N:41][CH:42]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ncc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)cn1
Yield: 44.5 %

Procedure:
To a solution of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (61 mg, 0.13 mmol), 5-bromo-2-methylpyrimidine (18 mg, 0.11 mmol), PdCl2(PPh3)2 (6 mg, 10%) and aqueous solution of Cs2CO3 (2 mol/L, 0.13 mL) in 1,4-dioxane (1 mL) was heated to reflux overnight. The reaction was quenched with water. The organic layer was separated, dried and concentrated to give the residue, which was purified by column chromatography to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-methylpyrimidin-5-yl)phenyl)ethyl)-1,3-oxazinan-2-one (22 mg, 39%). 1H NMR (CDCl3): 1.42 (m, 1H), 1.48 (d, 3H), 1.67 (m, 1H), 1.71-1.99 (m, 4H), 2.11-2.41 (m, 3H), 2.52 (s, 3H), 2.72 (m, 1H), 3.53 (m, 2H), 5.62 (m, 1H), 6.89-7.04 (m, 4H), 7.15-7.33 (m, 4H), 8.70 (s, 2H). LC-MS Method 2 tR=1.184, m/z=450; 1H NMR (CDCl3) 1.20 (d, 1H), 1.27-1.40 (m, 1H), 1.49 (d, 3H), 1.59-1.70 (m, 1H), 1.71-2.07 (m, 4H), 2.11-2.33 (m, 3H), 2.70 (s, 3H), 2.90 (m, 1H), 3.46-3.61 (t, 2H), 5.67 (m, 1H), 6.90-7.11 (m, 4H), 7.26 (m, 4H), 8.57-8.83 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH2:15])(=[O:3])[CH3:2].[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2[nH]cc(CCN)c2c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
A suspension of 5-acetyl-1H-indole-3-ethanamine (1.0 g), phthalic anhydride (0.83 g) and sodium acetate (1.0 g) in acetic acid (15 ml) was heated at reflux for 3 h. On cooling the title compound was deposited as an off-white crystalline solid (1.5 g) m.p. 234°-5°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:19]=1)[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:17]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[OH:18])[CH:19]=1
Reactant: COc1ccc(O)cc1C=O
Reactant: COc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cc(O)ccc2OC)cc1
Yield: 99.4 %

Procedure:
To the Grignard reagent prepared from 4-bromoanisole (286 g) and magnesium turnings (38.5 g) in dry tetrahydrofuran (480 ml) was added, dropwise, with vigorous stirring, a solution of 5-hydroxy-2-methoxybenzaldehyde (100 g) in dry tetrahydrofuran (1 liter). The mixture was heated on a steam bath for 3 hours, cooled and decomposed with saturated ammonium chloride solution. The organic layer was removed and the aqueous extracted with ethyl acetate (twice). The combined organics were washed with water, dried with anhydrous magnesium sulphate and evaporated to dryness. The residue was stirred with water (4 liters), an the buff coloured solid collected and dried to give crude 1-(5-hydroxy-2-methoxyphenyl)-1-(4-methoxy- phenyl)-methanol (170 g, 99%), m.p. 62-68° . This carbinol (85 g) was dissolved in ethanol (700 ml) and 10% palladium on charcoal (10 g) added. The mixture was hydrogenated in a Parr apparatus at 45° until hydrogen uptake ceased. The mixture was filtered, the flltrate evaporated to dryness and the residue filtered through a column containing silica gel, eluting with dichloromethane, to give 2,4'-dimethoxy-5-hydroxydiphenylmethane (46 g, 58%), m.p. 56-58° (from petroleum spirit (60-80° )).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C@H:3]1[C:8]1[CH:9]=[CH:10][CH:11]=[N:12][CH:13]=1.[OH:14]N1C(=O)CCC1=O.C(N=C=NCCCN(C)C)C>>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]([OH:14])[CH2:4][CH:3]1[C:8]1[CH:9]=[CH:10][CH:11]=[N:12][CH:13]=1
Reactant: CN1C(=O)CC[C@H]1c1cccnc1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Product: CN1C(=O)C(O)CC1c1cccnc1

Procedure:
Hydroxycotinine hemisuccinate succinic ester was prepared by adding to 1 ml of cotinine hemisuccinate 14 mg of N-hydroxysuccinimide (Sigma) and 23 mg of 1-ethyl-3-(dimethylaminopropyl) carbodiimide (Sigma) and incubating at room temperature for 3 ]]ours.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15]>>[OH:15][CH2:14][CH:13]([NH:12][C:9](=[O:11])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:16][OH:17]
Reactant: O=C(O)CCc1ccccc1
Reactant: NC(CO)CO
Product: O=C(CCc1ccccc1)NC(CO)CO

Procedure:
The procedure of example 79c was followed, using 3-phenylpropionic acid and serinol. At the end of the reaction, the DMF was evaporated and CH2Cl2 was added to the residue. The white crystalline material was collected and gave pure N-(2-hydroxy-1-hydroxymethyl-ethyl)-3-phenyl-propionamide as a white solid (56%, MS: m/e=224.2 (M+H+)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)[N:9]2[CH3:24])[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:24][N:9]1[C:10]2[C:15](=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=2)[C:16]([CH3:19])([CH3:18])[CH2:17][CH:8]1[C:4]1[CH:3]=[C:2]([NH:25][C:26]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]2)[CH:7]=[CH:6][CH:5]=1
Reactant: NC1(C(=O)O)CC1
Reactant: CN1c2ccc(C(F)(F)F)cc2C(C)(C)CC1c1cccc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1c2ccc(C(F)(F)F)cc2C(C)(C)CC1c1cccc(NC2(C(=O)O)CC2)c1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
A solution of 2-(3-bromo-phenyl)-1,4,4-trimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (398.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(1,4,4-trimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (167.6 mg, 40%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 419.2.
Reaction SMILES: Cl[C:2]1[C:3](=[O:20])[N:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:21][O-:22].[Na+]>CO>[Cl:8][C:6]1[N:7]=[C:2]([O:22][CH3:21])[C:3](=[O:20])[N:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=1
Reactant: O=c1c(Cl)nc(Cl)cn1-c1ccnn1-c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)cn(-c2ccnn2-c2ccccc2)c1=O
Reaction time: 2 h
Yield: 58.6 %

Procedure:
To a solution of 3,5-dichloro-1-(1-phenyl-1H-pyrazol-5-yl)pyrazin-2(1H)-one (0.627 g) in methanol (15.0 mL) was added sodium methoxide (0.132 g) at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was concentrated and adjusted to pH 5-6 with 2N hydrochloric acid. The reaction mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (0.362 g).
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[C:13]2[O:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[ClH:20]>C(Cl)(Cl)Cl>[Cl:20][CH2:19][CH:2]([OH:1])[CH2:3][O:4][C:5]1[C:13]2[O:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cc2cccc(OCC3CO3)c2o1
Reactant: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2cccc(OCC(O)CCl)c2o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
There was dissolved 2.6 g (0.01 mole) of 7-(2,3-epoxypropoxy)-2-ethoxycarbonylbenzofuran obtained in Reference Example 9 in 15 ml of chloroform, and thereto 2 ml of concentrated hydrochloric acid was added. Thereafter, the mixture was vigorously stirred at room temperature for 15 minutes. After the chloroform layer was washed with water, the layer was dried with magnesium sulfate, and then the solvent was distilled away from the reaction mixture under reduced pressure. The resultant residue was purified by silica-gel column-chromatography (eluent:n-hexane:methylene chloride=1:1) to give the desired compound.