Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([C:15]([C:17]2[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=2[F:35])[CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[O:16])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[O:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41](=[O:45])[C:42](O)=[O:43].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:35][C:34]1[CH:33]=[CH:32][C:19]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[CH:18][C:17]=1[C:15]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:42](=[O:43])[C:41]([C:37]2[O:36][CH:40]=[CH:39][CH:38]=2)=[O:45])[CH2:10][CH2:9]1)=[O:16]
Reactant: O=C(O)C(=O)c1ccco1
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(C(=O)N1CCCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)c1ccco1
Temperature: 25 °C
Reaction time: 60 h
Yield: 34 %

Procedure:
4-(3-(1,4-diazepane-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one TFA salt (320 mg, 0.65 mmol), 2-(furan-2-yl)-2-oxoacetic acid (563 mg, 4 mmol), DIPEA (1 ml, 6 mmol), and HATU (510 mg, 1.34 mmol) were mixed in DMF (30 ml). After the resulting reaction mixture was stirred at room temperature for 60 h, the reaction mixture was partition between DCM and water (100 ml each). The aqueous phase was extracted with DCM (100 ml), and the combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=1:3) to afford the desired product (111 mg, 31%) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:3]=1.[CH2:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1)[CH2:24][CH3:25]>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[N:3]=[C:2]([S:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH2:23][CH2:24][CH3:25])=[CH:28][CH:29]=3)[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[N:5]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-c2nc(Cl)cc(N3CCN(C)CC3)n2)cc1
Reactant: CCCOc1ccc(S)cc1
Product: CCCOc1ccc(Sc2cc(N3CCN(C)CC3)nc(-c3ccc(OC)cc3)n2)cc1

Procedure:
In the same manner, the above prepared 4-chloro-2-(4-methoxyphenyl)-6-(4-methyl-1-piperazinyl)-pyrimidine is reacted with p-propoxythiophenol to afford 2-(4-methoxyphenyl)-6-(4-methyl-1-piperazinyl)-4-(4-propoxyphenylthio)-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[C:13]1(B(O)O)=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]1([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[OH:1])[C:6]([O:8][CH3:9])=[O:7])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=1
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: OB(O)C1=CCCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(O)c(C2=CCCCCC2)c1
Temperature: 100 °C
Reaction time: 17 h
Yield: 44 %

Procedure:
To a stirred solution of methyl 4-hydroxy-3-iodobenzoate (1.4 g, 5.0 mmol) (commercially available from Aldrich) in DMF (15 mL) at 23° C. was added (Z)-cycloheptenylboronic acid (0.74 g, 5.3 mmol, commercially available from Combi-Blocks), potassium carbonate (2.1 g, 15 mmol), followed by tetrakis(triphenylphosphine)palladium (0.58 g, 0.50 mmol). The mixture was heated to 100° C. The reaction was then stirred for 17 hours and then cooled to room temperature. The reaction was diluted with brine and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-20% EtOAc in hexanes) to yield 78.7A as a colorless oil (0.55 g, 44% yield).
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:46])=[CH:41][C:40]=1[N+:53]([O-])=O>>[NH2:53][C:40]1[CH:41]=[C:42]([S:45]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[O:46])[CH:43]=[CH:44][C:39]=1[O:38][CH3:37]
Reactant: COc1ccc(S(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: COc1ccc(S(=O)c2ccccc2)cc1N
Yield: 89 %

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of (4-methoxy-3-nitrophenyl)-phenyl sulfoxide, the title compound is obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH3:34])=[C:6]([NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[S:20]([N:23]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[C:28]=2[CH3:33])COC)(=[O:22])=[O:21])=[O:14])[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])#[N:2].Cl>C1COCC1>[C:1]([CH2:3][C:4]1[C:5]([CH3:34])=[C:6]([NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[S:20](=[O:22])(=[O:21])[NH:23][C:27]2[O:31][N:30]=[C:29]([CH3:32])[C:28]=2[CH3:33])=[O:14])[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])#[N:2]
Reactant: COCN(c1onc(C)c1C)S(=O)(=O)c1ccsc1C(=O)Nc1c(C)cc(C)c(CC#N)c1C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2C)c(C)c1CC#N
Temperature: 65 °C

Procedure:
To a solution of N2-(3-cyanomethyl-2,4,6-trimethylphenyl)-3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarboxamide (2.29 g, 4.56 mmol) in THF (10 mL) was added concentrated hydrochloric acid (5 mL). The reaction was heated at 65° C. for 2 hours, then allowed to cool to room temperature. The mixture was poured into ice water (100 mL), extracted with ethyl acetate (3×100 mL), washed with saturated sodium chloride (150 mL), dried (MgSO4), then concentrated. The residue was purified by reverse-phase HPLC (20-80% acetonitrile in water). Acetonitrile was removed in vacuo. The aqueous layer was extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with saturated sodium chloride (200 mL), then with saturated sodium bicarbonate (3×200 mL). The organic layer was washed with saturated sodium chloride (200 mL), dried (MgSO4), then concentrated. The residue was purified by reverse-phase HPLC (20-80% acetonitrile in water). Acetonitrile was removed in vacuo. The aqueous layer was extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with saturated sodium chloride (200 mL), then with saturated sodium bicarbonate (3×200 mL). The organic layer was washed with saturated sodium chloride (200 mL), dried (MgSO4), then concentrated. The residue was dissolved in water (300 mL) and lyophilized to give N2-(3-cyanomethyl-2,4,6-trimethylphenyl)-3-[(3,4-dimethyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxamide, Na-salt (0.45 g, 21%) as a white powder, mp 153-173° C. 1H NMR (400 MHZ, DMSO-d6δ7.69 (d, J=4.76 Hz, 1H), 7.35 (d, J=5.16 Hz, 1H), 7.02 (s, 1H), 3.90 (s, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.13 (s, 3H), 1.95 (s, 3H), 1.55 (s, 3H) IR (KBr) 3449, 2249, 1623, 1421, 1121 cm−1.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:4]=[N:3][CH:2]=1>C(O)(C)C.[Pd]>[N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:4]=[N:3][CH:2]=1
Reactant: OCCCCC#Cc1cncnc1
Agent: [Pd]
Solvent: CC(C)O
Product: OCCCCCCc1cncnc1
Yield: 88.1 %

Procedure:
A solution of 25.3 g of 6-(5-pyrimidinyl)-5-hexyn-1-ol in 300 ml of isopropanol was hydrogenated over a total of 2.1 g of 10% palladium on carbon added in two portions. The residue was distilled to yield 22.8 g (88%) of 5-pyrimidinehexanol, bp 185°-196° C./0.35 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[O:21]1[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:26]([C:23]1[CH:24]=[CH:25][O:21][CH:22]=1)=[O:27]
Reactant: O=C(Cl)c1ccoc1
Reactant: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1N
Product: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1NC(=O)c1ccoc1
Yield: 35 %

Procedure:
The title compound was prepared in a manner substantially the same as example 20 by coupling (2S,3R)-2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylamine with 3-furoyl chloride in 35% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:33][C:34]1[C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=[CH:36][N:35]=1>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:39]4[C:34]([CH3:33])=[N:35][CH:36]=[CH:37][CH:38]=4)=[O:41])=[CH:3][CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1ncccc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To a stirred solution of 1.0 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 3 ml of N,N-diisopropylethylamine in 100 ml of methylene chloride is slowly added 600 mg of 2-methylpyridine-3-carbonyl chloride dissolved in 15 ml of methylene chloride. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with water and the organic layer washed well with water. The organic layer is dried(MgSO4), filtered and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate:hexane to give 800 mg of the desired product as a pale yellow residue. M+ =422.
Reaction SMILES: N[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:4][N:3]=1.N([O-])=O.[Na+].P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ncc(N2CCOCC2)nc1N1CCOCC1
Agent: O=N[O-]
Agent: [Na+]
Product: Clc1ncc(N2CCOCC2)nc1N1CCOCC1

Procedure:
This product is obtained by treating the 2-amino-3,5-dimorpholinopyrazine with sodium nitrite by the method described in the preceding procedure, Step C, and then with phosphorus oxychloride by the method described in Preparation 13, Step B.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])C.[K+].BrC1CC1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18]>CS(C)=O.[Cl-].[Na+].O>[CH:5]1([S:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH3:11])[CH2:2][CH2:1]1
Reactant: Cc1ccccc1S
Reactant: CC(C)(C)[O-]
Agent: BrC1CC1
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccccc1SC1CC1
Temperature: 100 °C
Reaction time: 9.5 h

Procedure:
Potassium t-butoxide (994 mg) and bromocyclopropane (2.92 g) were added to a solution of 2-methylbenzenethiol (1.05 g) in dimethyl sulfoxide (10 mL), and the mixture was stirred at 100° C. for 9.5 hours. The reaction solution was cooled to room temperature and brine was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 1-(cyclopropylsulfanyl)-2-methylbenzene as an orange oil (1.41 g, quant.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])=[CH:4][C:3]=1[C:19]1[C:20](=[O:46])[N:21]([CH2:44][CH3:45])[C:22]2[C:27]([CH:28]=1)=[CH:26][N:25]=[C:24]([NH:29][C:30]([C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1C(OC(C)(C)C)=O)=[O:31])[CH:23]=2.Cl.CO>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])=[CH:4][C:3]=1[C:19]1[C:20](=[O:46])[N:21]([CH2:44][CH3:45])[C:22]2[C:27]([CH:28]=1)=[CH:26][N:25]=[C:24]([NH:29][C:30]([C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)=[O:31])[CH:23]=2
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC(=O)[C@@H]3CCCN3C(=O)OC(C)(C)C)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC(=O)[C@@H]3CCCN3)cc21
Temperature: 50 °C
Yield: 27.8 %

Procedure:
A mixture of (S)-tert-butyl 2-((3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamoyl)pyrrolidine-1-carboxylate (115 mg, 0.177 mmol) in dioxane (3 mL) was treated with 1.25 N HCl in MeOH (2.8 mL, 3.5 mmol) and heated at 50° C. for 2 h. The mixture was concentrated to dryness, treated with satd. NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure and the aqueous residue treated with satd. NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford (S)—N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)pyrrolidine-2-carboxamide (27 mg, 30% yield). MS (ESI) m/z: 549.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11](=[O:15])[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:16][CH3:17].[CH3:18]O>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11](=[O:15])[C:12]([O:14][CH3:18])=[O:13])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(C(=O)C(=O)O)cc([N+](=O)[O-])c1O
Reactant: CO
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.42 g of 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid are dissolved in 25 ml of dry N,N-dimethylformamide, treated at room temperature with 50 mg of 4-dimethylaminopyridine and 920 mg of dry methanol, subsequently cooled to 0° with an ice-bath and 2.27 g of N,N-dicyclohexylcarbodiimide are added thereto. After 10 minutes the ice-bath is removed and the reaction mixture is stirred for a further 1 hour at room temperature. The mixture is subsequently evaporated. The residue is dissolved in ethyl acetate, whereupon insoluble urea is filtered, the filtrate is washed four times with water, dried over sodium sulfate, filtered and evaporated. There is obtained methyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate of m.p. 155°-157° (from methylene chloride/ether).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=1>CN(C)C=O>[Br:8][C:12]1[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:11]=1[O:10][CH3:9]
Reactant: COC(=O)c1ccc(OC)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(OC)s1
Reaction time: 1 h
Yield: 75.4 %

Procedure:
NBS (903 mg, 5.07 mmol) was added in portions to a 5 mL sealed tube reactor containing methyl 5-(methyloxy)-2-thiophenecarboxylate (0.73 g, 4.23 mmol) in N,N-Dimethylformamide (DMF) (20 mL) at room temperature and the reaction stirred for 1 hour. Additional NBS (249 mg) was added and after 1 h at room temperature the product was partitioned between CHCl3 and H2O. The organic layer was dried with Na2SO4, adsorbed onto silica and purified via column chromatography (0-25% EtOAc/Hexanes) affording the title compound (825 mg, 3.19 mmol, 75%): LC-MS (ES) m/z=252 (M+H)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15]1>>[CH2:23]([O:22][C:20]([CH:16]1[CH2:17][CH2:18][CH2:19][N:14]([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:15]1)=[O:21])[CH3:24]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)C1CCCNC1
Product: CCOC(=O)C1CCCN(S(=O)(=O)c2cccc(C(=O)O)c2)C1

Procedure:
The intended compound (7.12 g, 92%) was produced as a colorless solid according to the method of Reference Example 1 but using 3-(chlorosulfonyl)benzoic acid (5.00 g) and ethyl piperidine-3-carboxylate (7.04 mL) as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[C:16]([F:26])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].[OH-].[Li+].C1COCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:26])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CCOC(=O)c1cc(F)c(Oc2cnc(OCC(C)C)c(Cl)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COc1ncc(Oc2cc(F)c(C(=O)O)cc2F)cc1Cl
Yield: 100.6 %

Procedure:
Ethyl 4-[(5-chloro-6-isobutoxypyridin-3-yl)oxy]-2,5-difluorobenzoate (Preparation 38, 150 mg, 0.389 mmol) and lithium hydroxide (250 mg, 10.44 mmol) were dissolved in water (2.5 mL) and THF (2.5 mL) and stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (10 mL), washed with water (10 mL) and aqueous HCl (2 M, 10 mL), then was dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a white solid (140 mg, 100%):
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1)=[O:19])C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:29][C:26]3[CH:27]=[CH:28][C:23]([CH:21]4[CH2:22][CH:20]4[C:18]([OH:19])=[O:17])=[CH:24][C:25]=3[F:30])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(F)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SC2CCCC2)c(F)c1
Yield: 101.7 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.040 g, 0.17 mmol) obtained in Step C of Preparation Example 8 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.040 g, 0.17 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.067 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Fc1ccc(S)c(F)c1
Reactant: Fc1ccc(I)c(Br)c1
Product: Fc1ccc(Sc2ccc(F)cc2Br)c(F)c1

Procedure:
Prepared from 2,4-difluoro-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:25])[CH:11]([C:20]1(O)[CH2:23][CH2:22][CH2:21]1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:8][N:9]1[C:20]2([CH2:23][CH2:22][CH2:21]2)[CH:11]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NOCc1ccccc1)C1(O)CCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NC1C(=O)N(OCc2ccccc2)C12CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(Benzyloxy)-N2 -(t-butoxycarbonyl)-α-(1-hydroxycyclobutyl)glycinamide (3.50 g, 10 mmole) in 200 ml of dry tetrahydrofuran at 0° C. under argon was treated with 2.4 ml (15 mmole) of diethylazodicarboxylate, then with a solution of triphenylphosphine (5.2 g, 20 mmole) in 50 ml of tetrahydrofuran over 10 minutes, and the mixture stirred at 0° C. for one hour. The yellow color persisted so an additional 0.52 g (2 mmole) of triphenylphosphine was added. After 15 minutes, evaporation in vacuo gave an oil. Trituration with 100 ml of hexane:ethyl acetate (2:1) gave a white solid which was filtered. Chromatography of the filtrate on 800 ml of LPS-1 gave product fractions [Rf=0.8 in hexane:ethyl acetate (1:1)] contaminated with a close-running impurity which was removed by trituration with isopropyl ether, giving the product as a white solid, 1.07 g, melting point 156°-157° C.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)[C:3]#[CH:4].C([Li])CCC.[F:23][C:24]([F:31])([F:30])[C:25](OCC)=[O:26].CCCCCC.C(OCC)C>O1CCCC1.O>[F:23][C:24]([F:31])([F:30])[C:25](=[O:26])[C:4]#[C:3][C:2]([CH3:17])([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:14])([F:15])[F:16])=[CH:8][CH:7]=1)[CH3:1]
Reactant: C#CC(C)(C)Oc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C#CC(=O)C(F)(F)F)Oc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.47 g (6 mmol) of 1-(1,1-dimethyl-2-propynyloxy)-4-trifluoromethoxybenzene in 25 ml of tetrahydrofuran cooled to -78° C. is added 2.4 ml of n-butyllithium (2.5M in hexanes). The solution is maintained with stirring for 1 hour. The mixture is treated with 1.70 g (12 mmol, 1.43 ml) of ethyl trifluoroacetate at -78° C. and is allowed to warm to room temperature. After stirring for 1 hour, the mixture is diluted with water and is extracted with ethyl ether (3 times). The combined ethereal extracts are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to give a light oil. Flash chromatography using hexane:ethyl ether (65:35) affords the title compound: IR (film) 2215, 1740 cm-1 ; NMR (CDCl3) δ1.73 (6H, s), 7.16 (4H, m).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:3]1[NH:19]C(=O)OCC1C=CC=CC=1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34](I)=[N:35][CH:36]=1.C(O)(C(F)(F)F)=O>O.CO>[NH2:19][C@@H:3]1[C:2](=[O:1])[N:8]([C:34]2[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][N:35]=2)[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:4]1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: Clc1ccc(I)nc1
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1N=C(c2ccccc2)c2ccccc2N(c2ccc(Cl)cn2)C1=O

Procedure:
Intermediate B-16 was prepared from benzyl 2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate and 5-chloro-2-iodopyridine according to the procedure described for Intermediate B-15. RT=2.430 min (H2O/CH3OH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=3 min, wavelength=220 and 254 nm); MS(ES):m/z=363.12 [M+H+].