Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:35])([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:5][CH:4]=1.[CH3:36][O:37][Na].CO.O>CO>[Cl:28][C:24]1[CH:23]=[C:22]([C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([OH:35])([C:6]4[CH:5]=[CH:4][C:3]([CH2:2][O:37][CH3:36])=[CH:8][CH:7]=4)[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[CH:11]=3)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CO[Na]
Reactant: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Solvent: CO
Solvent: O
Product: COCc1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3C)c2cncn2C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.2 %

Procedure:
A mixture of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (described in Example B14)(0.000397 mol) and MeONa/MeOH (0.000793 mol) in methanol (2 ml) was stirred at room temperature for 48 hours, poured out into H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.12 g) was purified by column chromatography over kromasil 10 μm (eluent: CH2Cl2/CH3OH/NH4OH; 97/3/0.1). The pure fractions were collected and the solvent was evaporated, yielding 0.04 g (20%) of (±)-4-(3-chlorophenyl)-6-[hydroxy[4-(methoxymethyl)phenyl](1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, as a white foam, MS (ESI) m/z:500, 502 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: O=C1CCC(c2cc(Cl)c(O)c(Cl)c2)=NN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2c(Cl)cc(C3=NNC(=O)CC3)cc2Cl)cc1

Procedure:
A mixture of 10 g. of 6-(3,5-dichloro-4-hydroxyphenyl)-4,5-dihydro-3(2H)pyridazinone, 7.6 g. of p-toluenesulfonic chloride, 4 g. of triethylamine and 50 ml. of dimethylformamide was stirred at 50° C. for 8 hours. Then, the reaction mixture was treated in the same manner as in Example 11 and recrystallized from dioxane-petroleum ether to give 3.8 g. of the desired product as prisms of m.p. 208° - 209° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:6]2[C:7]3[CH2:8][CH2:9][N:25]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:2]=3[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccnc1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 3-aminopyridine, the desired compound was obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.[N:19]1([C:25]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:26]=2[CH:27]=[CH:28][N:29]=[CH:30]3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:22]1[CH2:23][CH2:24][N:19]([C:25]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:26]=3[CH:27]=[CH:28][N:29]=[CH:30]4)[CH2:20][CH2:21]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: O=CCCCOc1nc2c(cc1F)CCC(=O)N2
Reactant: c1cc(N2CCNCC2)c2ccncc2c1
Product: O=C1CCc2cc(F)c(OCCCCN3CCN(c4cccc5cnccc45)CC3)nc2N1

Procedure:
The title compound was prepared by reductive amination of 4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde with 5-piperazin-1-yl-isoquinoline using a procedure similar to Example A1′. MS: APCI: M+1: 450.2 (Exact Mass: 449.22).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[NH:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])[CH3:5].O.Cl>C1COCC1.[OH-].[Na+].CO>[CH3:29][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[NH:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])([CH3:5])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1NCCCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(NC(=O)c1ccc2ccccc2c1NCCCc1ccccc1)C(=O)O
Yield: 51.8 %

Procedure:
6 mg 2-methyl-2-{[1-(3-phenyl-propylamino)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester in 0.2 ml THF, 40 μl of 2 M sodium hydroxide and 0.2 ml methanol were reacted at room temperature for 3 h. To the mixture 0.5 ml of water were added and the pH was adjusted to 3-4 with 2 M hydrochloride acid. The volatiles were then removed by freeze drying, the resultic residue was suspended in methanol and filtrated. Concentration of the filtrate yielded 3 mg of 2-methyl-2-{[1-(3-phenyl-propylamino)-naphthalene-2-carbonyl]-amino}-propionic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:19](=O)[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[NH:12]1.[Cl:21]C(OC(Cl)(Cl)Cl)=O>C1(C)C=CC=CC=1.ClCCCl>[Cl:21][C:19]1[N:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[F:1])[N:12]=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14]2
Reactant: O=c1c2c([nH]n1-c1cc([N+](=O)[O-])ccc1F)CCCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1

Procedure:
To a solution of 2-(2-fluoro-5-nitrophenyl)1,2,4,5,6,7-hexahydro-3H-indazol-3-one (66.87 g) in toluene (125 ml) and 1,2-dichloroethane (175 ml), there was added trichloromethyl chloroformate (71.57 g), and the resultant mixture was allowed to react in an autoclave at a temperature of 120° to 130° C. under a pressure of 25 kg/cm2, for 3 hours. After cooling, the solvent was removed by distillation. The residue was purified by silica gel column chromatography using a mixture of ethyl acetate and n-hexane (1 : 6) as an eluent to give 3-chloro-2-(2-fluoro-5-nitrophenyl)-4,5,6,7-tetrahydro-2H-indazole. m.p., 109.1° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.Cl[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1(C)C=CC=CC=1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH2:4][CH2:3]1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(CCN[C@H]2CC[C@H](O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(CCN[C@H]3CC[C@H](O)CC3)cc2)nc1

Procedure:
Heat a mixture of the phenol (121.2 mg, 0.52 mmol), 6-chloronicotinamide (121.0 mg, 0.77 mmol), and K2CO3 (213.5 mg, 1.55 mmol) in 3:1 DMF/toluene (6.0 mL) at 165° C. for 3 hours. Quench the reaction with a small amount of H2O and concentrate to dryness, using xylenes to remove DMF azeotropically. Dissolve the residue in MeOH and filter. Concentrate the filtrate and purify by flash chromatography, eluting with 75:15:10 EtOAc/CH2Cl2/2.0 M NH3 in MeOH, to afford the title compound (79.1 mg, 43%): MS ES+ 356.0 (M+H)+, HRMS calcd for C20H26N3O3 356.1974 (M+H)+, found 356.1959, time 0.34 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min], tR=5.81 min, 100% purity.
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].ClC(OCCCC)=O.Cl.C(N(CC)CC)C.Cl.[CH3:40][O:41][C:42](=[O:53])[C@H:43]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=1)[NH2:44].Cl>C(#N)C.CO.C(N(CC)CC)C>[CH3:40][O:41][C:42](=[O:53])[C@H:43]([CH2:45][C:46]1[CH:47]=[CH:48][C:49]([OH:52])=[CH:50][CH:51]=1)[NH:44][C:1](=[O:22])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: CCCCOC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Arachidonic acid (152 g, 0.5 mmol) and triethylamine (52 mg, 0.51 mmol) were dissolved in 3 ml of dry acetonitrile and chilled to −15° C., and 70 mg (0.51 mmol) of butyl chloroformate was added. After 30 min, the mixture free of the precipitated triethylamine hydrochloride was pipetted in a solution of tyrosine methyl ester hydrochloride (232 mg, 1 mmol) and 0.14 ml of triethylamine in 1 ml of methanol, stirring was continued for 15 min at −15° C., then the mixture obtained was allowed to warm to room temperature. After 2 h, 0.5 M HCl was added, and the mixture was extracted with ether (20 ml). The extract was washed with water, then dried with Na2SO4, and evaporated in vacuo. The residue was dissolved in 2 ml of chloroform and purified by column (2×2 cm) chromatography on aluminum oxide (basic, Brockmann II). Elution of the column with chloroform-methanol (9:1 v/v) and evaporation of the appropriate fractions gave 222 mg (95%) of desired N-arachidonoyl-L-tyrosine methyl ester as oil: TLC (system A) Rf 0.6.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[N:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:22]1[N:26]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1)CCC>>[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]3=[N:24][CH:23]=2)=[CH:7][C:6]=1[C:8]1[N:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: N#Cc1cccnc1-c1cc(Br)ccc1F
Product: N#Cc1cccnc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
2-(5-Bromo-2-fluorophenyl)nicotinonitrile (214 mg, 0.8 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.1 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol, then crystallisation from toluene, gave 2-[2-fluoro-5-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)phenyl]nicotinonitrile as a yellow solid: δH (400 MHz, CDCl3) 8.95 (1H, dd, J 5 and 2), 8.91 (1H, d, J 7), 8.17 (1H, dd, J 8 and 2), 8.13 (1H, s), 7.80 (1H, dd, J 7 and 2), 7.69-7.73 (1H, m), 7.46-7.55 (2H, m), 7.29 (1H, d, J 7); m/z (ES+) 383 (M++H).
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16]([BH3-])#[N:17].[Na+].Cl>CO.C(O)(=O)C>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][N:17]([CH2:16][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]
Reactant: CN(C)CCCN
Reactant: O=Cc1ccccc1
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCCN(Cc1ccccc1)Cc1ccccc1
Yield: 92 %

Procedure:
A solution of 10.22 g of 3-aminopropyldimethylamine in 100 ml of methanol was neutralized with 12 ml of glacial acetic acid and mixed with 100 g of benzaldehyde. To the stirred mixture, was added portionwise 8.38 g of sodium cyanoborohydride. The mixture was allowed to react at room temperature for 16 hours. The reaction mixture was adjusted to pH 1 with concentrated hydrochloric acid, and stripped of the methanol by distillation under reduced pressure. The residue was treated with 200 of ml of water and 200 ml of chloroform. The aqueous layer was separated and extracted with 200 ml of chloroform to remove the benzaldehyde. The aqueous layer was adjusted to pH 12 with sodium hydroxide and extracted twice with 200 ml of chloroform. The chloroform extract was dried over sodium sulfate and freed from the solvent by distillation under reduced pressure to yield 26 g (92% yield) of [3-(N,N-dimethylamino)propyl]dibenzylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:20]1([CH3:31])[CH:25]=[CH:24][C:23]([S:26]([O:29][NH2:30])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:20]1([CH3:31])[CH:21]=[CH:22][C:23]([S:26]([O-:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[NH2:30][N+:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(Cl)cc1)c1nccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)ON)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: N[n+]1ccc2ccccc2c1C(=O)c1ccc(Cl)cc1
Yield: 88.5 %

Procedure:
The 1-(4-chlorobenzoyl)-isoquinoline prepared as described above is reacted with O-(p-toluenesulfonyl)-hydroxylamine as described in paragraph 3 of Example 1. The 2-amino-1-(4-chlorobenzoyl)-isoquinolinium-p-toluene sulfonate is obtained with a yield of 88.5%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=2)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:24].C([O-])(O)=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:24])=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)nc2cc(C(C)(C)C)ccc2c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(Cl)nc2cc(C(C)(C)C)ccc2c1C
Temperature: 150 °C
Yield: 88 %

Procedure:
A mixture of 150 mg (0.52 mmol) 7-tert-butyl-2-hydroxy-4-methyl-quinoline-3-carboxylic acid ethyl ester and POCl3 (1 ml) was heated for 2 h at 150° C. Then the reaction solution was poured into iced water (15 ml) and made alkaline with a saturated aqueous NaHCO3 solution. It was then extracted with EE and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 140 mg (0.46 mmol, 88%) 7-tert-butyl-2-chloro-4-methyl-quinoline-3-carboxylic acid ethyl ester were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[N:16]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]=1[SH:22]>>[ClH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[N:18]3[CH2:19][CH2:20][CH2:21][N:16]=[C:17]3[S:22][CH2:2]2)=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Reactant: SC1=NCCCN1
Product: Cl
Product: NS(=O)(=O)c1cc(C2(O)CSC3=NCCCN32)ccc1Cl

Procedure:
5.2 g of 2,4'-dichloro-3'-sulfamoylacetophenone and 2.4 g of ground 3,4,5,6-tetrahydro-2-pyrimidine-thiol were reacted in the manner described in Example 12, the reaction mixture was precipitated with 200 ml of diethyl ether, the solvent was decanted and the oily end product was crystallized under warm ethyl acetate. Colorless crystalline solid body, melting point: 180° C. (decomposition).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=[O:9])=[N:4][N:3]=[N:2]1.[CH2:14]=[C:15]([CH3:17])[CH3:16].CS(O)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:15]([N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=[O:9])=[N:4]1)([CH3:17])([CH3:16])[CH3:14]
Reactant: O=Cc1ccccc1-c1nnn[nH]1
Reactant: C=C(C)C
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)n1nnc(-c2ccccc2C=O)n1

Procedure:
In an autoclave, 6.4 g (36.7 mmol) of 2-(tetrazol-5-yl)-benzaldehyde (Step 61.1) in 50 ml of toluene are heated at 110° C. for 1.5 hours with ≈3 g of isobutene and 0.432 ml of methanesulfonic acid. When cold the reaction mixture is diluted with 300 ml of ethyl acetate, washed four times with water and once with brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/ethyl acetate=4:1) and crystallization from hexane with a small amount of diethyl ether at −20° C. yield 2-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde; TLC: Rf=0.36 (hexane/ethyl acetate=10:1).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:11][C:10]=2[F:23])=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][CH:25]=2)[S:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[F:23])=[C:5]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][CH3:31])=[CH:28][CH:29]=2)[S:4][N:3]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(CC)cc2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(-c2snc(Cl)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl 3-(4-[[3-chloro-5-(4-ethylphenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate (20 mg, 0.04 mmol, 1.00 equiv, 90%), TFA (0.5 mL), CH2Cl2 (2 mL). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The crude product (2 mL) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, Sum, 19*100 mm; mobile phase, Water of 0.05% TFA and CH3CN (40% CH3CN up to 100% in 6 min, hold 100% in 2 min, down to 40% in 0.1 min, hold 40% in 1.9 min); Detector, UV 220&254 nm. This resulted in 10 mg (59%) of 3-(4-[[3-chloro-5-(4-ethylphenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoic acid as a brown solid. 1H NMR (400 MHz, CD3OD) δ 7.49 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 6.83 (d, J=9.2 Hz, 2H), 5.10 (s, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.75 (q, J=7.2, 15.2 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H18ClF2NO3S, 438.1 (M+H). found 438.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:12]([CH3:21])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>C1(O)CCCCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22]([O:24][CH:25]2[CH2:4][CH2:3][CH2:2][CH2:7][CH2:26]2)=[O:23])[N:12]([CH3:21])[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: OC1CCCCC1
Solvent: ClCCl
Product: Cn1c(C(=O)OC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxylate (28 mg, 0.07 mmol) from Example 36, Step A (Method B) in cyclohexanol (2 mL) and methylene chloride (1 mL) was added a catalytic amount of sodium hydride (60% in mineral oil, <5 mg). The mixture was stirred at rt for 2 hr and then poured into aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (3×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound. HPLC/MS: 463 (M+1), 465 (M+3); Rt=4.50 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Br:11][CH2:12][C:13](Br)=[O:14].O>CN(C=O)C.O1CCOCC1>[Br:11][CH2:12][C:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:14]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A solution of 4-aminobenzoic acid (5.0 g, 0.036 mol) in anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) was cooled to 0° C. in a 250 mL 3-necked flask which was fitted with a constant additional funnel. Bromoacetyl bromide (7.36 g, 3.2 mL, 100 mol %) was added dropwise, keeping the internal temperature between 0° C. and 2° C. After the addition was completed (~30 min), the reaction mixture was stirred overnight at rt. Water (100 mL) was added, and then the light crystalline compound which precipitated was filtered, washed with 5% HBr, washed several times with water (200 mL), and then dried in a vacuum oven for 20 h at 40°-45° C., affording 9.3 g (99%) of the title compound: mp 245°-246.7° C.; 1H NMR (DMSO-d6) δ10.6 (s, 1H, NH), 7.91 (d, 2H, J=8.8), 7.69 (d, 2H, J=8.4), 4.10 (s, 2H); 13C NMR (DMSO-d6) δ168.88, 165.38, 142.62, 130.53, 125.78, 118.62, 30.30; MS (EI, m/z) 257 (M+), 258.9 (M+ 2+). HRMS (EI) calcd for C9H8NO3Br 256.9686, found 256.9677. Anal. Calcd. for C9H8NO3Br: C, 41.88; H, 3.12; N, 5.43. Found: C, 41.97; H, 3.19; N, 5.42.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:17])[C:11](=[C:14]([Cl:16])[CH:15]=1)[CH:12]=[O:13].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Cl:16][C:14]1[CH:15]=[C:8]([Cl:7])[CH:9]=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]=1[CH:12]=[O:13]
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cc(Cl)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Potassium carbonate (9.4 g, 67.8 mmole) was added to a stirred solution of 4,6-dichlorosalicylaldehyde (10.8 g, 56.5 mmole) in dimethylformamide (80 ml). The resulting mixture was stirred at 60° for 30 minutes and treated with benzyl bromide (10.6 g, 62.1 mmole). This mixture was stirred one hour at 60° C. and then poured into ice water (1000 ml) to give the title compound (15.9 g, 100%) which melted at 98°-100° C. after recrystallization from hexane. pmr (CDCl3) δ 5.10 (2H, s), 7.33 (5H, s), 10.40 (H, s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH3:7].[Cl:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12]>CCOCC>[Cl-:8].[OH:13][CH:10]([CH2:11][OH:12])[CH2:9][N+:4]1[CH:5]=[CH:6][N:2]([CH3:1])[C:3]=1[CH3:7]
Reactant: Cc1nccn1C
Reactant: OCC(O)CCl
Solvent: CCOCC
Product: Cc1n(C)cc[n+]1CC(O)CO
Product: [Cl-]
Reaction time: 48 h
Yield: 98.2 %

Procedure:
1,2-Dimethylimidazole (9.61 g, 100 mmol) and 3-chloro-1,2-propanediol (11.05 g, 100.0 mmol) were stirred in a 130° C. oil bath for 48 h, after which the flask was placed under vacuum and stirring continued at 130° C. for another 48 h. The product was then stirred in refluxing ether for 24 h and filtered to afford a brown solid (20.29 g, 100%). 1H NMR: δH ppm (400 MHz; DMSO-d6) 2.60 (s, 3H) 3.20-3.33 (m, 1H) 3.36-3.49 (m, 2H) 3.78 (s, 3H) 4.08 (dd, J=14.11, 7.88 Hz, 1H) 4.27 (dd, J=14.11, 3.11 Hz, 1H) 5.14 (t, J=5.50 Hz, 1H) 5.50 (d, J=5.68 Hz, 1H) 7.63 (d, J=2.01 Hz, 1H) 7.66 (d, J=2.20 Hz, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].C[Si](C)(C)[N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>>[Cl-:1].[CH3:6][O:5][C:3](=[O:4])[CH2:2][N:11]1[CH:12]=[CH:13][N+:9]([CH2:2][C:3](=[O:4])[O:5][CH3:6])=[CH:10]1
Reactant: COC(=O)CCl
Reactant: C[Si](C)(C)n1ccnc1
Product: COC(=O)Cn1cc[n+](CC(=O)OC)c1
Product: [Cl-]
Temperature: 60 °C
Yield: 99.7 %

Procedure:
Methyl chloroacetate (2; 29.8 mL, 338.6 mmol, 2.0 eq) was added drop-wise to 1-(trimethylsilyl)-1H-imidazole (8; 25.0 mL, 169.3 mmol). The mixture was heated at 60° C. for 24 hours. The mixture was cooled to room temperature, washed with Et2O (3×500 mL) and dried in vacuo yielding 9 (41.97 g, 168.8 mmol, 99.7%) as a white solid.