Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:36])[CH2:25][N:26]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[N:27]3)[CH2:20][CH2:19]2)[S:16][CH:17]=1)=O.Cl.[CH3:38][O:39][NH2:40]>CO>[CH3:38][O:39][N:40]=[C:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:36])[CH2:25][N:26]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]([F:33])([F:34])[F:35])=[N:27]3)[CH2:20][CH2:19]2)[S:16][CH:17]=1)[CH:10]=[CH:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)C=Cc3c(F)cccc3F)cs2)CC1
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=C(C=Cc1c(F)cccc1F)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 60 °C

Procedure:
A mixture of 3-(2,6-difluorophenyl)-1-[2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolyl]-2-propen-1-one (i.e. the product of Example 2, Step A) (0.25 g, 0.48 mmol) and methoxyamine hydrochloride (0.047 g, 0.58 mmol) in methanol (10 mL) was heated overnight at 60° C. The reaction was concentrated under reduced pressure, partitioned between dichloromethane and saturated sodium bicarbonate. The mixture was eluted from a Celite® extraction tube (ChemElute® diatomaceous earth-based liquid-liquid exchange cartridge) with dichloromethane and concentrated to provide 0.26 g of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([C:20](OC)=[O:21])[O:17][C:16]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[NH3:27]>CO>[O:26]=[S:2]1(=[O:1])[CH:7]=[CH:6][N:5]([C:8]2[C:9]([F:25])=[CH:10][C:11]([N:15]3[CH2:19][C@H:18]([C:20]([NH2:27])=[O:21])[O:17][C:16]3=[O:24])=[CH:12][C:13]=2[F:14])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@H]1CN(c2cc(F)c(N3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: N
Solvent: CO
Product: NC(=O)[C@H]1CN(c2cc(F)c(N3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reaction time: 1.5 h
Yield: 86 %

Procedure:
A solution of methyl (5R)-3-[4-(1,1-dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidine-5-carboxylate (Step 3, 0.090 g, 0.23 mmol) in methanol (2 mL) is treated with a solution of ammonia in methanol (2 mL of a 2.0M solution). The mixture is stirred for 1.5 h and concentrated. The residual solids are washed with methanol to provide 75 mg (86%) of the title compound as a white solid, MS (m/z) for C14H13F2N3O5S: [M+H]+=374; 1H NMR (300 MHz, d6-DMSO): δ 3.33–3.39 (m, 2H), 3.99–4.06 (m, 3H), 4.26 (t, 1H), 5.04–5.09 (m, 1H), 5.48 (d, 1H), 6.93 (d, 1H), 7.50 (d, 2H), 7.65 (s, 1H), 7.90 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[N:8]=[CH:7]1)(=[O:5])=[O:4].C([Li])CCC.CN([CH:24]=[O:25])C.[NH4+].[Cl-]>C1COCC1>[CH3:1][N:2]([CH3:15])[S:3]([N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[N:8]=[C:7]1[CH:24]=[O:25])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1cnc2c1CCCC2
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1c(C=O)nc2c1CCCC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
2-Formyl-4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide was prepared following a modification of the procedure found in the Journal of Medicinal Chemistry, 40; 14, 1997, 2205. To a solution of 4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide (2.67 g, 11.6 mmol) in dry THF (100 mL) under argon at −78° C. was added dropwise 2.5 M n-butyllithium in hexanes (7.0 mL, 17.5 mmol). The reaction was stirred at −78° C. for 1 hour, then DMF (1.1 mL, 13.9 mmol) was added dropwise, and the reaction was warmed to room temperature and stirred for 2 hours. Saturated NH4Cl (25 mL) was added, and the reaction mixture was concentrated, and then diluted with CH2Cl2 (500 mL) and distilled water (25 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were washed with brine (1×100 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (1:1 hexanes-EtOAc) provided 1.53 g (51%) of 2-formyl-4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide as a yellow solid. 1H NMR (CDCl3) δ 1.82-1.86 (m, 4H), 2.66-2.68 (m, 2H), 2.86-2.88 (m, 2H), 2.96 (s, 6H), 9.99 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[CH3:32])[N:25]([CH3:33])[CH:24]=2)[C:12]1=[O:34])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCOCC1.O>[CH3:33][N:25]1[C:26]2[C:31](=[C:30]([CH3:32])[CH:29]=[CH:28][CH:27]=2)[C:23]([CH2:22][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:21])[N:11]([C@@H:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:3]([OH:35])=[O:2])[C:12]2=[O:34])=[CH:24]1
Reactant: COC(=O)[C@H](c1ccccc1)n1c(=O)c2ccccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc2c1c(Cn1c(=O)n([C@H](C(=O)O)c3ccccc3)c(=O)c3ccccc31)cn2C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-phenyl-acetic acid methyl ester (100 mg, 0.21 mmol) in dioxane (2.5 ml) is added a solution of LiOH monohydrate (25 mg, 0.60 mmol) in H2O (2.5 mL). The solution is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, quenched with 4M HCl in dioxane (500 μL) and is concentrated. The resulting residue is purified by flash chromatography with 10% MeOH in dichloromethane as the eluent to afford the title compound. LCMS (ESMS): m/z 454.19 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:6]([C:7]#[N:8])=[C:5]([N+:14]([O-])=O)[CH:4]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28]N[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:14]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:6]=2[C:7]#[N:8])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc([N+](=O)[O-])c(C#N)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C#N)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To 1.32 g (5.92 mmol)of 4-methoxy-2,6-dinitrobenzonitrile dissolved in 8 mL dimethylformamide was added 2.2 g (2 eq., 11.83 mmol) piperazine-1-carboxylic acid tert-butyl ester. The mixture was heated to 50° C. and stirred overnight, then partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography, eluting with ethyl acetate/hexanes provided 1.48 g of 4-(2-cyano-5-methoxy-3-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][O:56][CH2:57][C:58](Cl)=[O:59]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:58](=[O:59])[CH2:57][O:56][CH3:55])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: COCC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: COCC(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 77 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and methoxyacetyl chloride as the starting materials in 77% yield. LCMS for C26H29ClN7O4 (M+H)+: m/z=538.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C@@H:10]([C:12]1[CH:21]=[CH:20][C:15]2[C:16](=[O:19])[O:17][CH2:18][C:14]=2[C:13]=1[CH3:22])[OH:11].[N:23]1([C:28]2[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH:27]=[N:26][N:25]=[N:24]1>>[OH:11][C@H:10]([C:12]1[C:13]([CH3:22])=[C:14]2[C:15](=[CH:20][CH:21]=1)[C:16](=[O:19])[O:17][CH2:18]2)[CH2:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:4]1[CH2:3][NH:2][S:34]([C:31]1[CH:30]=[CH:29][C:28]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)=[CH:33][CH:32]=1)(=[O:35])=[O:36]
Reactant: Cc1c([C@@H](O)CN2CCCC2CN)ccc2c1COC2=O
Reactant: O=S(=O)(Cl)c1ccc(-n2cnnn2)cc1
Agent: Cl
Product: Cc1c([C@@H](O)CN2CCCC2CNS(=O)(=O)c2ccc(-n3cnnn3)cc2)ccc2c1COC2=O

Procedure:
N-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-2-yl)methyl)-4-(1H-tetrazol-1-yl)benzenesulfonamide was prepared in a similar fashion to that described for the synthesis of EXAMPLE 13 starting from 5-41R)-2-(2-(aminomethyl)pyrrolidin-1-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride [INTERMEDIATE 3] and commercially available 4-(1H-tetrazol-1-yl)benzene-1-sulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=2[NH:20]C(=O)C(C)(C)C)=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[NH2:20][C:11]1[CH:12]=[C:13]([O:18][CH3:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=1[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:9]
Reactant: COc1cc(NC(=O)C(C)(C)C)c(C(=O)c2cccc(Br)c2)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(N)c(C(=O)c2cccc(Br)c2)cc1OC
Temperature: 25 °C

Procedure:
To a solution of N-{2-[(3-bromophenyl)carbonyl]-4,5-dimethoxyphenyl}-2,2-dimethylpropanamide (7.9 g, 18.9 mmol) in 1,4-dioxane (80 mL) was added concentrated HCl (9.55 g, 94.2 mmol). The mixture was refluxed for 2 hours. After cooling to room temperature, 1,4-dioxane was removed in vacuum and the residue was diluted with water (100 mL) and EtOAc (100 mL), then neutralized with NaHCO3 to pH=8. The mixture was extracted with EtOAc (80 mL×3). The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated under vacuum to afford (2-amino-4,5-dimethoxyphenyl)(3-bromophenyl)methanone. MS (M+H)=336 and 338.
Reaction SMILES: [Cl:1][C:2]1[C:20]([NH:21][C:22](=O)[CH2:23][NH2:24])=[CH:19][CH:18]=[C:17]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:24][CH2:23][CH2:22][NH:21][C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:26])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(NC(=O)CN)c3Cl)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(NCCN)c3Cl)c2n1
Reaction time: 0.25 h
Yield: 25.4 %

Procedure:
To a suspension of 8-[2,6-dichloro-3-glycylaminobenzyloxy]-2-methylquinoline (2.14 g) in tetrahydrofuran (21 ml) was dropwise added 2M borane-methylsulfide complex in tetrahydrofuran (5.48 ml) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 15 minutes at the same temperature and refluxed for 6 hours. After cooling, the mixture was adjusted to pH 1 with 1N hydrochloric acid and refluxed for 30 minutes. The mixture was neutralized with saturated sodium bicarbonate solution and extracted with chloroform. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (chloroform) to give 8-[3-[N-(2-aminoethyl)amino]-2,6-dichlorobenzyloxy]-2-methylquinoline (525 mg) as colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([N+:21]([O-])=O)[CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[H][H]>O1CCOCC1.[C].[Pd]>[ClH:1].[NH2:21][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: O=[N+]([O-])c1cc(CCCS(=O)(=O)c2ccc(Cl)cc2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc(CCCS(=O)(=O)c2ccc(Cl)cc2)ccc1O
Yield: 190.7 %

Procedure:
4-[3-(4-Chlorophenylsulfonyl)propyl]-2-nitrophenol (10.00 g, 28.11 mmol) was dissolved in 1,4-dioxane (100 ml), 4 N hydrochloric acid solution in 1,4-dioxane (8.43 ml, 33.73 mmol) and 10% palladium-carbon (1.0 g) were added, and the mixture was stirred for 4 hours in an atmosphere of hydrogen gas under 1 atmospheric pressure. The crystals precipitated in the reaction solution were dissolved by adding methanol, the reaction mixture was filtered, and then the resulting filtrate was concentrated under reduced pressure. By crystallizing the resulting residue from acetonitrile-ether, 2-amino-4-[3-(4-chlorophenylsulfonyl)propyl]phenol hydrochloride (9.71 g, 95%) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([F:28])[CH:22]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[C:11]3[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])=[C:23]([F:28])[CH:22]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)c(C#N)cnc2c(OC)c1OC
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2c(OC)c1OC
Yield: 67.2 %

Procedure:
A mixture of 0.279 g of 4-chloro-6,7,8trimethoxy-quinoline-3-carbonitrile, 0.177 g of 4-chloro-2-fluoroaniline, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was extracted with ethyl acetate, washed with water, dried and concentrated in vacuo. The solid thus obtained was chromatographed on silica gel eluting with hexanes-ethyl acetate 9:1 to 2:1. Solvent was removed from product fractions giving 0.261 g of 4-(4-chloro-2-fluoro-phenylamino)-6,7,8-trimethoxy-quinoline-3-carbonitrile as a yellow solid: mp 166-168° C.; mass spectrum (EI, m/e): M 387.0777.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH3:20])[C:13](=O)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH3:20])[C:13](=[S:23])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCn1c(-c2ccc(OC)c(OC)c2)cc(=O)n(C)c1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCn1c(-c2ccc(OC)c(OC)c2)cc(=S)n(C)c1=O
Yield: 71.1 %

Procedure:
A mixture of 6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-2,4(1H,3H)-pyrimidinedione (0.80 g) and phosphorus pentasulfide (1.8 g) in pyridine (18 ml) was refluxed for 15 hours with stirring. The reaction mixture was evaporated under reduced pressure. The residue was washed with 1N-hydrochloric acid and extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated in diisopropyl ether to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-4-thioxo-2(1H)-pyrimidinone (0.60 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[I:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>ClCCCl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:20])[NH:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:41]([I:40])[CH:42]=3)=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: Nc1cccc(I)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(I)c4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
A 50 ml round bottomed flask was charged with 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 2) (1.466 g, 4.15 mmol), a drop of DMF, and 1,2-dichloroethane (10 ml). Oxalyl chloride (2M in dichloromethane) (2.283 ml, 4.565 mmol) was slowly added and the mixture became a clear solution. Gas evolution was observed. The mixture was stirred for 17 hours at ambient temperature. Triethylamine (1.157 ml, 8.30 mmol) and 3-iodoaniline (0.524 ml, 4.358 mmol) were added to the acid chloride solution. The mixture was stirred for 1 hour at ambient temperature. The crude mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 2.094 g of the title compound as light brown solid (91%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:22]([O:24]C)=O)=[CH:11][C:10]=1[C:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl.C[Li].[CH3:36][Si](Cl)(C)C.[Cl-].[NH4+]>C1COCC1.C(OCC)C.O.CO>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:22](=[O:24])[CH3:36])=[CH:11][C:10]=1[C:26]([CH3:28])([CH3:27])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)c(OCc2ccccc2)c(C(C)(C)C)c1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1cc(-c2ccc(C)cc2)c(OCc2ccccc2)c(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
2 g (5.1 mmol) of methyl 6-benzyloxy-5-tert-butyl-4′-methyl-3-biphenylcarboxylate (Example 1,d) are dissolved in 30 mL of THF, 15 mL of methanol and 2 mL of water. 320 mg (7.7 mmol) of lithium hydroxide hydrate are added and the reaction medium is refluxed for 5 hours and then cooled. The medium is neutralized with a 1 N hydrochloric acid solution and the medium is then extracted with ethyl ether. A white powder is obtained (m.p.=196° C.), which is dissolved in 10 mL of ethyl ether and 5 mL of THF. The medium is cooled to −78° C., and 11 mL (11 mmol) of 1 N methyllithium solution are then added dropwise. The medium is stirred at this temperature for 3 hours and is then treated with 5 mL of trimethylsilyl chloride. The medium is hydrolysed with a saturated ammonium chloride solution and then extracted with ethyl ether. The residue obtained is purified by chromatography (eluent: 9 heptane/1 ethyl acetate). A yellow crystalline solid is obtained (m=1.1 g; yield=60%; m.p.=104° C.).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][N:18]([CH3:21])[C:19]#[N:20].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C1C(O)=CC=CC=1C.CO>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:17][N:18]([CH3:21])[C:19]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[NH:20].[CH3:17][N:18]([CH3:21])[C:19]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[NH:20]
Reactant: CSc1ccc(N)c(-c2ccccc2)c1
Reactant: CN(C)C#N
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: Cc1cccc(O)c1
Product: CSc1ccc(NC(=N)N(C)C)c(-c2ccccc2)c1

Procedure:
Reaction of 2-amino-5-methylthiobiphenyl hydrochloride (1.6 g) with N,N-dimethylcyanamide (0.83 g) in m-cresol (1 ml) at 80° C. for 6 hours yielded a colourless solid which was dissolved in methanol (50 ml) and treated with a solution of fumaric acid (0.61 g) in methanol (50 ml) to give N,N-dimethyl-N'-(5-methylthio-2-biphenylyl)guanidine hemifumarate as a colourless solid (m.p. 207° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH2:14])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])C.[OH-].[Li+]>C(O)C.O>[NH2:14][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CCOC(=O)c1cnc(SC)nc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ncc(C(=O)O)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a stirred solution of 4-amino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (24.0 g, 112.5 mmol, Salor) in ethanol (400 mL) and water (200 mL) was added lithium hydroxide (9.536 g, 225.0 mmol). The suspension was stirred at room temperature for 3 hours during which all the solids went into solution. The ethanol was removed in vacuo and additional water was added to make a total volume of 300 mL. The resulting solution was washed with 2×100 mL of ether which was discarded. To the aqueous solution was added concentrated hydrochloric acid (20 mL) to bring the pH of the aqueous solution to about pH 3 during which the desired product precipitated out. The product was filtered, washed with 25 mL of water, suction dried and then dried in a vacuum oven at 50° C. to give 20.6 g (98.8%) of the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[NH:8][C:7](=[S:23])[CH2:6][CH2:5]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCc2cc(Br)cc(F)c2N1
Solvent: Cc1ccccc1
Product: Fc1cc(Br)cc2c1NC(=S)CC2

Procedure:
To a suspension of 6-bromo-8-fluoro-3,4-dihydroquinolin-2(1H)-one (157-3, 2.00 g, 8.19 mmol) in toluene (50 mL) was added Lawesson's reagent (1.66 g, 4.10 mmol). After reflux for 2 h, toluene was distilled off to yield the crude product, which was then purified by flash chromatography on silica gel to obtain title compound (yellow solid). 1H NMR (DMSO-D6, 500 MHz) 6=12.14 (s, 1H), 7.46 (dd, J=2.0 Hz, JHF=10.0 Hz, 1H), 7.34 (s, 1H), 2.94 (d, J=8.0 Hz, 2H), 2.84 (d, J=8.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18]12([N:28]=[C:29]=[O:30])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.CCCCCC.CCOC(C)=O>C(Cl)Cl>[C:18]12([NH:28][C:29]([N:15]3[CH2:16][CH2:17][N:12]([C:6]4[C:5]5[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=[CH:8][CH:7]=4)[CH2:13][CH2:14]3)=[O:30])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (124 mg, 0.5 mmol) and 1-adamantyl isocyanate (89 mg, 0.5 mmol) in CH2Cl2 (5 mL) are reacted according to method C yielding the title product as a colorless solid after column chromatography with hexane-EtOAc.