Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15](=[O:30])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)=[CH:19][C:18]=1[F:29])=O)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[F:29][C:18]1[CH:19]=[C:20]([N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)[CH:21]=[CH:22][C:17]=1[NH:16][C:15]([C@H:9]1[CH2:10][C@@H:11]([O:13][CH3:14])[CH2:12][NH:8]1)=[O:30]
Reactant: CO[C@@H]1C[C@H](C(=O)Nc2ccc(-n3ccc(C)n3)cc2F)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1CN[C@@H](C(=O)Nc2ccc(-n3ccc(C)n3)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Boc-amine 3 (˜0.6 g, 1.427 mmol) was dissolved in 25% TFA in dichloromethane. The mixture was stirred at ambient temperature for 2 h. The solvents were removed and the residue dried under vacuum to give 4 as a tan oil (˜0.450 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]3[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]2=[O:17])=[N:6][CH:5]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COC(=O)c1ccc(N)nc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(N2C(=O)c3ccccc3C2=O)nc1
Yield: 59 %

Procedure:
A solution of 6-aminonicotinic acid methyl ester (1.1 g, 7.2 mmol) and phthalic anhydride (1.2 g, 7.9 mmol) in anhydrous toluene was heated at reflux overnight in a Dean-Stark apparatus until no more water was collected. The reaction mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate (50 mL) and was washed with brine and water. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give 6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-nicotinic acid methyl ester (1.2 g, 60%), which was directly used in the next step without further purification. 1H NMR (300 MHz, d-DMSO) δ 9.12 (d, J=1.5 Hz, 1H), 8.52 (dd, J=2.1, 8.4 Hz, 1H), 8.03-7.92 (m, 4H), 7.72 (d, J=7.8 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)=[CH:9][CH:10]=2)[CH:5]([C:18]([O:20]CC)=O)[C:4]1=[O:23])[CH3:2].[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27].Cl.C(Cl)Cl>C1C=CC=CC=1>[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH:27][C:18]([CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)[CH:7]=2)[N:3]([CH2:1][CH3:2])[C:4]1=[O:23])=[O:20]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)C1C(=O)N(CC)c2ccc(C3(C)OCCO3)cc21
Agent: Cl
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2F)c2cc(C3(C)OCCO3)ccc21
Yield: 80 %

Procedure:
A mixture of 1.0 g. (3.1 mmoles) of ethyl 1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate and 809 mg. (6.3 mmoles) of 2,4-difluoroaniline in 40 ml of benzene was heated to reflux through a soxhlet filled with 4A sieves for 45 minutes. The reaction mixture was cooled and poured into a mixture of 400 ml. 2N hydrochloric acid and 100 ml. of methylene chloride. The organic layer was separated, dried over magnesium sulfate and concentrated to give 1.24 g. of a solid residue. Recrystallization from diisopropyl ether--methylene chloride gave 1.0 g. of product (80% yield), m.p. 166°-170° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][CH2:14][CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1)=[O:12].[OH-].[Na+]>C(O)C.O>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[CH2:15][CH2:14][N:13]1[C:3](=[O:2])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:11]1=[O:12]
Reactant: COC(=O)c1ccccc1NC(=O)NCCC1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c2ccccc2c(=O)n1CCC1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
A white mixture of 2-[3-(2-[1,3]dioxolan-2-yl-ethyl)-ureido]-benzoic acid methyl ester (0.50 g, 1.70 mmol) and 1N sodium hydroxide (2.0 mL) in ethanol (10 mL) was warmed until all the solids had gone into solution. The resulting colorless solution was cooled to ambient temperature and stirred for 30 minutes. Concentration yielded a colorless foam which was dissolved in water (15 mL); after 15 minutes, a white crystalline solid formed. The white crystalline solid was collected and dried to yield 3-(2-[1,3]dioxolan-2-yl-ethyl)-1H-quinazoline-2,4-dione (0.19 g, 43%). 1NMR CDCl3 δ7.92 (dd, J=1, 8 Hz, 1H), 7.67-7.61 (m, 1H), 7.22-7.15 (m, 2H) 4.88 (t, J=4 Hz, 1H), 4.00 (t, J=7 Hz, 2H), 3.89-3.71 (m, 4H), 1.93-1.86 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.Cl.C[CH:22]1[N:27]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH2:26][CH2:25][N:24]([CH2:37][CH:38]([NH:42]C(=O)C2C=CC(C)=CC=2)[CH:39]([CH3:41])[CH3:40])[CH2:23]1>C(Cl)Cl>[Cl:36][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[Cl:35])[CH2:28][N:27]1[CH2:26][CH2:25][N:24]([CH2:37][C@H:38]([NH:42][S:15]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:39]([CH3:41])[CH3:40])[CH2:23][CH2:22]1
Reactant: Cc1ccc(C(=O)NC(CN2CCN(Cc3ccc(Cl)c(Cl)c3)C(C)C2)C(C)C)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)NS(=O)(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 66.9 %

Procedure:
Triethylamine (21 ml, 0.15 mmol) and 4-fluorobenzenesulfonyl chloride (29 mg, 0.15 mmol) were added to a solution of 1-(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine (50 mg, 0.15 mmol) [prepared as described in Example 1 above] in methylene chloride (1.5 ml). The reaction mixture was stirred for 2 h, then concentrated. Purification by flash chromatography with 20:1 methylene: methanol as the eluant gave N-{1-(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-fluorobenzenesulfonamide (49 mg) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(O)C.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.P(=O)(O)(O)O>C(Cl)Cl>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: COc1ccc(CN)cc1
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(CNc2nc(Cl)cc(Cl)n2)cc1
Reaction time: 18 h

Procedure:
A 27.5 g portion of 2,4,6-trichloropyrimidine was suspended in a mixed solvent of 200 ml ethanol and 200 ml methylene chloride, to which, under ice-cooling, was subsequently added dropwise 30 ml of 4-methoxybenzylamine. After 19 hours of stirring at the same temperature, 10 ml of 4-methoxybenzylamine was further added dropwise and the mixture was stirred for 18 hours. The reaction solution was mixed with 200 ml of 0.5 N phosphoric acid aqueous solution and extracted with chloroform, and then the organic layer was washed with saturated brine. After drying with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the thus obtained residue was applied to a silica gel chromatography and developed with a chloroform-hexane (3:1) mixed solvent to obtain 13.3 g of 4,6-dichloro-2-(4-methoxybenzyl)aminopyrimidine and further developed with a chloroform-ethyl acetate (1:3) mixed solvent to obtain 24.2 g of 2,6-dichloro-4-(4-methoxybenzyl)aminopyrimidine. 2,6-Dichloro-4-(4-methoxybenzyl)aminopyrimidine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:20]([O:22]CC)=[O:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:20]([OH:22])=[O:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)n(-c2ccc(F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2ccc(F)cc2)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
23.0 g (66.7 mmol) of the compound of Example 35A are provided in 100 ml of 1,4-dioxane, 100 ml (200 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 50° C. for 2 h. The mixture is concentrated, a conc. aqueous hydrogen chloride solution is subsequently added until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is stirred in a little diethyl ether, collected by filtration and dried under high vacuum. 17.8 g (84% of theory) of the title compound are obtained.
Reaction SMILES: C([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]([C:22]([OH:24])=[O:23])[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])C(C)C.[C:25]([O:29][C:30]([NH:32][C@H:33]([C:44]([OH:46])=O)[C@@H:34]([CH3:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:11]([C@H:10]([C:22]([OH:24])=[O:23])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:44]([C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[C@H:34]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:43])=[O:46])[CH2:17][CH:18]([CH3:21])[CH3:19])(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CCCCNCC(C)C)C(=O)O)cc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nε-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-O-benzyl-L-threonine (93 mg, 0.3 mmol). The final product was triturated with ether to yield 195 mg (98%) of the desired material.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:26][CH2:25][CH2:24]1.CCN(CC)CC>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:23]2[CH2:26][CH2:25][CH2:24]2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example B5), azetidine and Et3N in DMSO at 23° C. according to the general procedure C. Obtained as a yellow solid (6.925 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[C:3]=1[C:17](=[O:19])[NH2:18].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>CCO.N1CCCCC1>[C:17]([C:3]1[C:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:25][C:24]1[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=1)(=[O:19])[NH2:18]
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1c(Nc2ccc(C(=O)O)cc2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2ccc(C(=O)O)cc2)n[nH]c1N=Cc1ccc(O)cc1

Procedure:
4-((5-amino-4-carbamoyl-1H-pyrazol-3-yl)amino)benzoic acid was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (325 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 4-((4-carbamoyl-5-((4-hydroxybenzylidene)amino)-1H-pyrazol-3-yl)amino)benzoic acid as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([OH:10])=[O:9].[CH3:11][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[ClH:1].[CH3:11][O:9][C:8]([C@H:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[NH2:2])=[O:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N[C@@H]1CCC[C@@H]1C(=O)O
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)[C@H]1CCC[C@H]1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(1S,2R)-2-Amino-cyclopentanecarboxylic acid hydrochloride (126 mg, 0.76 mmol) was dissolved in a 1:1 mixture of benzene and methanol (8 mL). The mixture was cooled to 0° C. A 2.0 M solution of (trimethylsilyl)diazomethane in hexanes (0.57 mL, 1.14 mmol) was added and the reaction was stirred at 25° C. for 30 min. The mixture was concentrated and dried in vacuo. The crude product was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[S:29](Cl)(=[O:31])=[O:30].C(Cl)Cl>CN(C)C=O>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[S:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(NS(=O)(=O)c2c(Cl)cccc2Cl)ccc1Oc1cncc(Cl)c1
Yield: 14 %

Procedure:
The title compound was prepared using the procedure described in Example 3, beginning with 0.1 g of the aniline of Example 1 and 2,6-dichlorobenzenesulfonyl chloride and using dimethylformamide as solvent in place of CH2Cl2. After workup, 0.024 g (14%) of the title sulfonamide was obtained
Reaction SMILES: IC.[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([CH:18]=[C:19]2[N:23]([CH3:24])[C:22](=[S:25])[NH:21][C:20]2=[O:26])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])[CH3:5].[CH:27](N(C(C)C)CC)(C)C>C(O)C.O>[CH3:6][C:4]([C:7]1[CH:8]=[C:9]([CH:18]=[C:19]2[N:23]([CH3:24])[C:22]([S:25][CH3:27])=[N:21][C:20]2=[O:26])[CH:10]=[C:11]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:12]=1[OH:13])([CH3:3])[CH3:5]
Reactant: CN1C(=S)NC(=O)C1=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CI
Solvent: O
Product: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N1C
Temperature: 25 °C
Yield: 69.3 %

Procedure:
Iodomethane (1.2 mL, 19 mmols) is added to a stirred suspension of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1-methyl-2-thioxo-4-imidazolidinone (4.0 g, 12 mmols) and diisopropylethylamine (2.4 mL, 14 mmols) in ethanol (50 ml) and the mixture is stirred under an inert atmosphere at room temperature. After 18 hours the mixture is stirred in water (300 mL) for an hour and the product is filtered off, washed three times with water, and dried. Recrystallization from ethyl acetate gave the pure 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1,5-dihydro-1-methyl-2-(methylthio)-4H-imidazol-4-one (3.0 g), mp 177°-179° C., retaining 0.25 equivalents of solvent of crystallization.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:13])=O.CN(C)C=O>ClCCl>[Cl:13][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: CSc1nccc(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1nccc(CCl)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 13.69 g of [2-(methylthio)pyrimidin-4-yl]methanol obtained in stage a) in 250 mL of dichloromethane are added dropwise 7.67 mL of thionyl chloride, followed by 3.91 mL of N,N-dimethylformamide. The reaction mixture is stirred at room temperature for 15 hours and concentrated under reduced pressure. The residue is taken up in diisopropyl ether and the solid formed is filtered off and dried to give 10.28 g of 4-(chloromethyl)-2-(methylthio)pyrimidine, the characteristics of which are as follows:
Reaction SMILES: N#N.[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([C:18](Cl)=[O:19])[N:17]=2)[O:8][CH2:7][CH2:6][O:5]1.[N-:21]=[N+:22]=[N-:23].[Na+]>CC(C)=O.O>[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([C:18]([N:21]=[N+:22]=[N-:23])=[O:19])[N:17]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(CCCCc2nc(C(=O)Cl)co2)OCCO1
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(CCCCc2nc(C(=O)N=[N+]=[N-])co2)OCCO1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), this crude 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-oxazole-4-carbonyl chloride was dissolved in acetone (18.0 mL). The solution was cooled to 0° C. and a solution of sodium azide (314 mg, 4.79 mmol) in H2O (2.0 mL) was added over 1 h. The reaction mixture was stirred at 0° C. for 1.5 h then at rt for 45 min. The mixture was concentrated under reduced pressure (coevaporation with toluene) then dissolved in CH2Cl2 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.89 min [M+H]+=281.38.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([Cl:11])[CH:3]=1.[NH:12]([C:14](=[S:16])[NH2:15])[NH2:13].O=P(Cl)(Cl)Cl>O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:16][C:14]([NH2:15])=[N:12][N:13]=2)=[C:4]([Cl:11])[CH:3]=1
Reactant: NNC(N)=S
Reactant: O=C(O)c1ccc(Br)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Nc1nnc(-c2ccc(Br)cc2Cl)s1
Temperature: 78 °C
Reaction time: 3 h
Yield: 44.1 %

Procedure:
A stirred mixture of 4-bromo-2-chlorobenzoic acid (2 g, 8.49 mmol) and hydrazinecarbothioamide (1.161 g, 12.74 mmol) was cooled under nitrogen in an ice-bath. POCl3 (2.375 mL, 25.5 mmol) was then added dropwise. On completion of addition, the reaction mixture was warmed to 78° C. and left to stir for 3 hours. The reaction mixture was allowed to cool to room temperature then cooled further in an ice-bath. Quenching by addition of ice-water (50 mL) resulted in a solid/gum-like mass. This material was sonicated for 1.5 hours and the resulting suspension was diluted with a further 50 mL water and slurried for 16 hours. The suspension was filtered under vacuum and the solid rinsed with water, then re-suspended in saturated NaHCO3(aq) (100 mL). The suspension was slurried for 30 minutes then filtered under vacuum and rinsed with water to afford the crude product as an off-white solid. The crude product was pre-absorbed onto silica gel and purified by flash chromatography using a gradient from 0-10% MeOH/DCM over 30 minutes to afford the title compound as a pale yellow/off-white solid (1.087 g, 44% yield). LC-MS: Rt 1.09 min; MS m/z 292.0 [M+2H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, J=8.59 Hz, 1H), 7.91 (d, J=2.02 Hz, 1H), 7.68 (dd, J=8.59, 2.02 Hz, 1H), 7.51 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCOCC>[OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[CH2:19]([NH3+:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(O)c1
Reactant: NCc1ccccc1
Solvent: CCOCC
Product: CC(C(=O)[O-])c1ccc(-c2ccccc2)c(O)c1
Product: [NH3+]Cc1ccccc1

Procedure:
2-(2-hydroxy-4-biphenylyl)propionic acid (140 mg.) in ether (5 ml.) was mixed with benzylamine (62 g.) in ether (5 ml.). The precipitate was collected, washed with ether, dried in vacuo and recrystallised for absolute alcohol/ether to give benzylammonium 2-(2-hydroxy-4-biphenylyl)propionate, m.p. 183°-185° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:16]([C:18]2[CH:19]=C([CH:25]=[CH:26][CH:27]=2)C(OC)=O)[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-:28].[Na+].Cl.[CH2:31]1[CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:1][C:2]1[C:3]([CH:16]([C:18]2[CH:19]=[C:35]([CH:31]=[CH:32][C:33]([OH:28])=[O:34])[CH:25]=[CH:26][CH:27]=2)[CH3:17])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc(C(C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1cc2c(cc1C(C)c1cccc(C=CC(=O)O)c1)C(C)(C)CCC2(C)C

Procedure:
A solution of the product of Example 19 (2.5 g, 6.4 mmol) and sodium hydroxide (2.5 g) in THF (50 ml) is refluxed for 4 h, acidified to pH 1 (concentrated HCl), extracted with ethyl acetate and washed with water. After drying, the organic phase is concentrated on a rotary evaporator under vacuum at 40° C. and the product is washed with heptane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:41]=[CH:42][CH:43]=1)[CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:39]=[O:40])[N:36]([CH3:38])[N:37]=1>O1CCCC1>[Cl:27][C:28]1[CH:29]=[C:30]([CH:41]=[CH:42][CH:43]=1)[CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:39]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:9]=2)[OH:40])[N:36]([CH3:38])[N:37]=1
Reactant: Cn1nc(NCc2cccc(Cl)c2)cc1C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(F)cnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2cc(NCc3cccc(Cl)c3)nn2C)c2cc(F)cnc21
Temperature: -20 °C

Procedure:
5-Fluoro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (146, 0.33 g, 0.79 mmol) and 1.5 mL of tetrahydrofuran were combined in a round bottom flask and cooled to −20° C. Isopropylmagnesium chloride (400 μL, 2.0 M in tetrahydrofuran, 0.8 mmol) was added dropwise and the reaction stirred and brought to −5° C. The reaction was cooled to −20° C. and 5-(3-chloro-benzylamino)-2-methyl-2H-pyrazole-3-carbaldehyde (145, 0.090 g, 0.36 mmol) in tetrahydrofuran was added and the reaction stirred and brought to 0° C. The reaction was concentrated under vacuum, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, then brine. The organic layer was separated and dried over sodium sulfate, filtered and the filtrate purified by silica gel flash column chromatography eluting with a gradient of 5-80% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound. MS (ESI) [M+H+]+=542.7, 543.95.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[CH3:8].[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:7][C:5]1[S:6][C:2]([NH:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([CH3:18])=[CH:10][CH:11]=2)=[C:3]([CH3:8])[N:4]=1
Reactant: Cc1ccc(CCN)cc1
Reactant: Cc1nc(C)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(CCNc2sc(C)nc2C)cc1
Temperature: 160 °C
Reaction time: 48 h
Yield: 13.2 %

Procedure:
To a solution of 5-bromo-2,4-dimethyl-1,3thiazole (1.00 g, 5.21 mmol) in DMSO (5 mL) was added 2-(p-tolyl)ethylamine (1.06 g, 7.81 mmol) and potassium carbonate (1.1 g, 7.9 mmol). The reaction mixture was stirred for 6 d at ambient temperature and for 2 d at 160° C. under a nitrogen atmosphere. After cooling to ambient temperature it was diluted with ethyl acetate (20 mL) and washed with aqueous sodium carbonate (saturated, 20 mL) and water (20 mL). Drying over sodium sulfate, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=70:30 to 0:100) afforded the title compound (170 mg, 13%) as a light brown solid. MS m/e: 247.0 [M+H]+.