Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]([C:10]1[CH2:11][O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=2)([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].P(Cl)(Cl)(Cl)=O.C(OCC)C>C1(C)C=CC=CC=1>[C:20]1([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]([C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:19]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)CC(C)(O)C1=Cc2cc(-c3ccccc3)ccc2OC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(C)C1=Cc2cc(-c3ccccc3)ccc2OC1
Temperature: 0 °C

Procedure:
The whole of the solid obtained in Step C is dissolved in 70 ml of toluene and then treated with 1.25 ml (13.3 mmol) of phosphorus oxychloride. The mixture is refluxed for one hour. After returning to room temperature, the reaction mixture is poured onto 60 ml of ice-water and then mixed with 100 ml of diethyl ether. Customary treatment of the organic phase yields, after purification over a silica column (eluant: methylene chloride), 12.36 g of a yellow solid recrystallised from diisopropyl ether.
Reaction SMILES: C1(C[O:8][C:9]2[CH:14]=[C:13]([O:15]CC3C=CC=CC=3)[CH:12]=[CH:11][C:10]=2[NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[NH:23][C:24](=[O:29])[C:25]([F:26])([F:27])[F:28]
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1OCc1ccccc1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccc(O)cc1O)C(F)(F)F

Procedure:
A mixture of 1.5 grams (0.0036 mole) of, N-[2,4-bis(phenylmethoxy)phenyl]-2,2,2-trifluoroacetamide and 0.2 gram (catalyst) of 10% palladium on carbon in 125 mL of ethanol was treated with hydrogen gas in a Parr Hydrogenator, yielding 0.80 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:3]=1.O.[NH2:22][NH2:23]>C1COCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:22][NH2:23])[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:5]=1
Reactant: NN
Reactant: Fc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: NNc1nc(Cl)nc(Nc2ccc(F)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To a solution of the compound XVII (1.83 g, 6 mmol) in THF (10 mL) was added hydrazine monohydrate (0.84 mg, 17 mmol) and the mixture was stirred at room temperature over night. The mixture was concentrated to a volume of about 3 mL and diluted with ethyl acetate (50 mL) and water (10 mL). The organic phase was separated, rinsed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to afford the titled compound XXII (1.5 g, 83% yield, 92% purity): ESI/MS 319 (M+H), 317(M−H); 1H NMR (DMSO-d6): δ 10.40 (bs, 1H), 9.24 (bs, 1H), 8.08 (m, 1H), 7.42 (m, 2H), 4.43 (m, 2H)
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(N(CC)CC)C.[CH2:28]([N:30]([CH2:34][CH3:35])[C:31]([NH2:33])=[S:32])[CH3:29]>C(Cl)Cl>[CH2:28]([N:30]([CH2:34][CH3:35])[C:31]([S:32][CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4])=[NH:33])[CH3:29]
Reactant: CC1(C)S[C@@H]2C(NC(=O)CBr)C(=O)N2C1c1nnn[nH]1
Reactant: CCN(CC)C(N)=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=N)SCC(=O)NC1C(=O)N2C(c3nnn[nH]3)C(C)(C)S[C@H]12
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1.40 g (0.039 mole) of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml of methylene chloride is added 0.54 ml (0.039 mole) of triethylamine, followed by 0.52 g (0.039 mole) of N,N-diethylthiourea. Stirring is continued for a further 45 minutes, and then the solvent is decanted from the oil which has separated. The oil is triturated with ether, giving a white solid, which is filtered off. The yield is 1.28 g (76% of theory) of 6-(2-[N,N-diethylamidinothio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum (KBr disc) of the product shows absorption bands at 1780 cm-1 (β-lactam) and 1670 cm-1 (amide I). The NMR spectrum (DMSO-d6) shows absorption bands at 5.65 ppm (multiplet, C-5 and C-6 hydrogens), 5.15 ppm (singlet, C-3 hydrogen), 4.10 ppm (singlet, methylene hydrogens), 3.45 ppm (quartet, ethyl hydrogens), 1.60 ppm (singlet, C-2 methyl hydrogens), 1.10 ppm (triplet, ethyl hydrogens) and 1.00 ppm (singlet, C-2 methyl hydrogens).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:20](=[O:23])([O-])[O-:21].[Na+].[Na+]>O1CCCC1>[N:1]1[N:2]([C:10]2[C:11]([OH:19])=[C:12]([CH:13]=[C:14]([CH3:16])[CH:15]=2)[CH2:17][O:21][C:20](=[O:23])[CH2:11][CH:12]([CH3:17])[CH3:13])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(COC(=O)CC(C)C)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 205.4 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (10.0 g, 33 mmol) is suspended in a mixture of 2-isovaleric acid (8.4 g, 82 mmol) and tetrahydrofuran (75 g) and stirred at 70° C. for 30 minutes. Sodium carbonate (10.5 g, 99 mmol) is added. The reaction mixture is stirred at 60° C. for 15 minutes and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with an aqueous potassium carbonate solution (10%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 11.5 g of 3-Methyl-butyric acid 3-(2H-benzotriazol-2-yl)-2-hydroxy-5-methyl-benzyl ester.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].CCN=C=NCCCN(C)C.Cl.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:17]([NH:20][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][CH:15]=1)[CH2:18][CH3:19]
Reactant: CCCN
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a stirred solution of 1.06 g (5.0 mmol, 1 eq.) of 4-phenylaminobenzoic acid, prepared by the method of Portnaya, et al., Zhur. Obshchei. Khim., 30: 2693 (1960), n-propylamine (0.82 mL, 10.0 mmol, 2 eq.) and 0.061 g (0.5 mmol, 0.1 eq.) of DMAP in THF at 0° C. was added 1.05 g (5.5 mmol, 1.1 eq.) of EDCl. The mixture was stirred overnight while the bath melted. The mixture was poured into 150 mL of ethyl acetate and extracted with 50 mL each of water, 1N aqueous HCl, water, and saturated aqueous NaHCO3 solution. The ethyl acetate layer was then dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on SiO2 eluting with 1:1 ethyl acetate-hexanes to give 0.51 g (40%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 10.57 (bs, 2H), 7.21-7.41 (m, 9H), 3.96 (s, 2H), 2.75 (m, 2H), 1.64 (hextet, 2H), 0.92 (t, 3H). MS (DCl) m/e 255 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH:4]=1.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:4]=1
Reactant: COC(=O)CCc1cc(OC)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccnc(CCC(=O)O)c1
Temperature: 25 °C

Procedure:
41.95 g of methyl 3-(4-methoxypyridin-2-yl)propionate (starting material A2) are dissolved in 700 ml of tetrahydrofuran, and 217 ml of 1N sodium hydroxide solution are added. The mixture is stirred at room temperature until no more starting material is detectable by thin-layer chromatography (TLC). The mixture is neutralized using 217 ml of 1N hydrochloric acid solution, evaporated to dryness using a rotary evaporator and dried under high vacuum. The colorless residue is ground and extracted four times with dichloromethane/methanol (9:1). The combined extracts are evaporated to dryness. This gives 33.2 g of the title compound as a colorless powder of m.p. 131–132° C. The mass spectrum shows the molecular peak MH+ at 182 Da.
Reaction SMILES: [CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[F:48][C:49]([F:60])([F:59])[C:50]1[N:55]=[CH:54][C:53]([C@H:56]([NH2:58])[CH3:57])=[CH:52][CH:51]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:11]=[C:10]([C:21]([NH:58][C@@H:56]([C:53]2[CH:54]=[N:55][C:50]([C:49]([F:59])([F:48])[F:60])=[CH:51][CH:52]=2)[CH3:57])=[O:22])[CH:9]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C(F)(F)F)nc3)cc(C(=O)N(C)CC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylic acid (21 mg, 0.064 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (25 mg, 0.13 mmol), 1-hydroxybenzotriazole hydrate (9.9 mg, 0.064 mmol), and CH2Cl2 (3 mL) were added (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (18 mg, 0.097 mmol) (WO 2008/130481) and N,N-diisopropylethylamine (17 μL, 0.097 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 40-80% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C(O[CH:44]([CH2:47][OH:48])[CH2:45][OH:46])N=1.C(O)CCO.[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:46][CH2:45][CH2:44][CH2:47][OH:48])[CH:7]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: OCCCO
Solvent: C1CCOC1
Product: OCCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step 3 g) and propane-1,3-diol (1.1 g) in THF (50 ml) was added NaH (390 mg) slowly and the reaction was then allowed to stir at room temperature for 18 h. The reaction mixture was then partitioned between DCM (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow oil. Yield 2.9 g
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[CH:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][N:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:8]=1)(=O)=O.[Si:23]([O:40][CH2:41][C:42]#[CH:43])([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(NCC)C>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:23]([O:40][CH2:41][C:42]#[C:43][C:7]1[CH:20]=[CH:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][N:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:8]=1)([C:36]([CH3:37])([CH3:38])[CH3:39])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Oc1ccc2ncc3c(c2c1)CCCC3)C(F)(F)F
Reactant: C#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCC#Cc1ccc2ncc3c(c2c1)CCCC3)(c1ccccc1)c1ccccc1
Reaction time: 11 h
Yield: 96.9 %

Procedure:
To a mixture of Compound 277 (1.28 g, 3.86 mmol), 3-[(tert-butyldiphenylsilyl)oxy]propyne (Compound 278, 1.48 g, 5.02 mmol), and diethylamine (800 mL, 7.73 mmol) in dry degassed N,N-dimethylformamide (7.7 mL) was added copper (I) iodide (74 mg, 0.39 mmol) followed by bis(triphenylphosphine)palladium(II) chloride (135 mg, 0.19 mmol). After being stirred in the dark for 11 hours under argon, the mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (20 mL×2) and brine (20 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo, and the residue was purified by flash column chromatography (silica, 10 percent ethyl ether in dichloromethane) to give 1.78 g (97 percent) of Compound 279: Rf =0.39 (10 percent ethyl acetate in dichloromethane); IR (film) νmax 3048, 2932, 2857, 2227, 1589, 1568, 1502, 1428, 1370, 1112 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1 H, H6), 7.95 (d, J=8.6 Hz, 1 H, H4), 7.92 (d, J=1.5 Hz, 1 H, H1), 7.84-7.78 (m, 4 H, aromatic), 7.53 (dd, J=8.6, 1.5 Hz, 1 H, H3), 7.48-7.39 (m, 6 H, aromatic), 4.62 (s, 2 H, C≡CCH2O), 3.04 (t, J=5.8 Hz, 2 H, H10), 2.87 (t, J=5.8 Hz, 2 H, H7), 2.01-1.93 (m, 2 H, CH2), 1.93-1.85 (m, 2 H, CH2), 1.12 (s, 9 H, t-Bu); 13C NMR (125 MHz, CDCl3) δ 152.8, 145.6, 141.0, 135.6, 133.1, 130.6, 130.2, 129.7, 129.6, 127.6, 127.5, 127.2, 120.7, 88.4, 85.3, 53.2, 27.0, 26.7, 24.8, 22.2, 22.1, 19.2; MS (FAB+) m/e (rel intensity) 476 (M+H, 100), 418 (9), 388 (12), 220 (11), 197 (9); HRMS for C32H34NOSi (M+H), calcd 476.2410, found 476.2410.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].II.[I:14]([O-])(=O)=O.[Na+].O>C(O)(=O)C.S(=O)(=O)(O)O>[I:14][C:7]1[C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4](=[O:8])[NH:5][CH:6]=1
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Reactant: [O-][I+2]([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(I)c[nH]c(=O)c1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-3-nitro-2-pyridone (2.00 g, 13 mmol) in acetic acid (12 mL) and concentrated sulfuric acid (1.6 ml,) was added iodine (1.32 g) and sodium iodate (0.55 g). The mixture was heated at 75° C. for 2.5 hours and then stirred at rt overnight. Water (100 mL) was added, and the precipitated 5-iodo-4-methyl-3-nitro-2-pyridone was collected by filtration (2.97 g, 82%).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[CH:19]([O:22][CH2:23][C:24](Cl)=[O:25])([CH3:21])[CH3:20]>ClCCl>[CH:19]([O:22][CH2:23][C:24]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:25])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccccc1N
Reactant: CC(C)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)COC(C)C
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a solution of 4.90 g (33 mmol) of methyl anthranilate and 6.1 ml of triethylamine in 50 ml of dichloromethane was dropwise added a solution of 4.43 g (33 mmol) of isopropoxyacetylchloride in 20 ml of dichloromethane under chilling with ice for a period of 15 min. The resulting mixture was stirred over night at room temperature. The reaction mixture was washed sequentially with 5 % aqueous sodium carbonate, 3 N hydrochloric acid and 5% aqueous sodium carbonate, and then was dried over anhydrous sodium sulfate. The solvent was distilled off to leave 5.59 g of the desired compound as a residual pale brown oil. (Yield: 68.6 %)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:16]#N)=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[CH3:14])(C)(C)C.[OH2:19].[OH-:20].[Na+]>S(=O)(=O)(O)O>[NH2:7][C:8]1[C:9]([C:16]([OH:20])=[O:19])=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1cc(Cl)nc(C#N)c1NC(=O)OC(C)(C)C
Reactant: [OH-]
Reactant: O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc(Cl)nc(C(=O)O)c1N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(6-Chloro-2-cyano-4-methyl-pyridin-3-yl)-carbamic acid tert-butyl ester (3.72 g) was dissolved in concentrated sulfuric acid (19 mL) and stirred for 1 h at 100° C. The reaction mixture was cooled to room temperature and water (19 mL) was slowly added. The reaction mixture was warmed again to 100° C. and stirred at this temperature for 2 h. Water was added after cooling to room temperature, the mixture was cooled in an ice bath and the pH was adjusted to ˜14 by slow addition of solid sodium hydroxide. The aqueous solution was washed 2× with MTB-ether, the aqueous layer was then adjusted to pH ˜2 by addition of 5 M hydrochloric acid and extracted 3× with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum to afford 2.25 g of the title compound of the formula
Reaction SMILES: Cl[C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1.[CH3:26][NH:27][CH3:28].O>CC(N(C)C)=O>[CH3:26][N:27]([CH3:28])[C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1
Reactant: CNC
Reactant: O=C(c1cccs1)c1nc(NCc2cccnc2)nc2cc(Cl)sc12
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)c1cc2nc(NCc3cccnc3)nc(C(=O)c3cccs3)c2s1
Temperature: 170 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
A stirred solution of Example 5 (0.02 g, 0.052 mmol) in dimethylacetamide (1.5 ml) was treated with dimethylamine (2.0M in THF, 0.52 mmol). The solution was heated to 170° C. for 30 min in a microwave reactor. The cooled solution was poured onto stirred iced water (20 ml). After 15 min stirring, an orange solid was filtered. Recrystallisation from hot ethyl acetate gave the title compound in 42% yield, >95% purity. LC-MS m/z=396.0 [M+H]+; RT=2.97; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 3.13 (6H, s), 4.68 (2H, bd), 5.91 (1H, s), 7.26-8.61 (8H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[OH:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[CH3:32].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][S:28]([C:25]2[CH:26]=[CH:27][C:22]([OH:21])=[C:23]([CH3:32])[CH:24]=2)(=[O:30])=[O:29])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1N
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(Br)cc1NS(=O)(=O)c1ccc(O)c(C)c1
Reaction time: 1 h
Yield: 11.6 %

Procedure:
5-Bromo-2-methoxypyridin-3-amine (1.08 g, 5.32 mmol) was dissolved in THF (2.5 ml) and cooled with an ice bath. A solution of sodium bis(trimethylsilyl)amide (1 M in THF, 8 ml, 8 mmol) was added dropwise. Ten minutes later, 4-hydroxy-3-methylbenzene-1-sulfonyl chloride (1.65 g, 5.91 mmol, prepared according to JP 47015818 B4 19720511) in THF (3 ml) was added and the reaction mixture was allowed to reach room temperature. After stirring for 1 h, a saturated solution of sodium bicarbonate was added dropwise and the reaction mixture was extracted with dichloromethane (×3). The organic phase was dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The resulting residue was purified by reverse phase chromatography using SP1® Purification System (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give 230 mg (12% yield) of the title compound. Purity 100%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]([N+:14]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O1CCCC1>CO.[Pd]>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]([NH2:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1N
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(N)c(F)c1N
Yield: 108.4 %

Procedure:
A mixture of methyl 2,4-diamino-3-fluoro-5-nitrobenzoate (5) (40.0 g, 173.7 mmol) and 5% Pd/C (3.0 g, Type 487; 0.4 mol % Pd relative to starting material), in methanol (300.0 mL) and tetrahydrofuran (300.0 mL) was stirred at 2000 RPM, under hydrogen (˜3.5 bar), at 50° C. in a 1.5 L hydrogenation vessel. After 6 hours the vessel was purged with nitrogen and HPLC analysis indicated that no starting material remained. The mixture was then filtered under nitrogen pressure and the filter washed through with THF (160 mL), to give a clear yellow solution. The solvent was removed by rotary evaporation, to provide methyl 2,4,5-triamino-3-fluorobenzoate (9) 37.5 g (93.3% w/w by NMR) as a solid, yield ˜100%. 1H NMR (400 MHz, d6 DMSO) δ 3.69 (3H, s, NMe), 4.20 (2H, br s, NH2), 5.24 (2H, br s, NH2), 5.70 (2H, br s, NH2), 6.83 (1H, d, J 1, Ar—H). 13C NMR (100 MHz, d6 DMSO) δ 51 (CH3), 98 (C, d, J 5), 110 (CH, d, J 2), 125 (C, d, J 6), 131 (C, d, J 12), 133 (C, d, J 12), 139 (CF, d, J 225), 166 (C═O). vmax/cm-1 3480, 3461, 3373, 3356, 3280, 3163, 1679, 1655, 1314. MS APCI (+) m/z 200 (M+1) detected.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:33]=[CH:32][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C@H:22]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:21][CH2:20]4)=[C:10]([CH2:34][CH2:35][CH3:36])[CH:9]=2)[S:6][CH:7]=1)[CH3:2].O[Li].O>C1COCC1.O.CO>[CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:33]=[CH:32][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C@H:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21][CH2:20]4)=[C:10]([CH2:34][CH2:35][CH3:36])[CH:9]=2)[S:6][CH:7]=1)[CH3:2]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.5 %

Procedure:
To a solution of ethyl ((1S-5-{3-[4-(4-ethyl-1,3-thiazol-2-yl)2-propylphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (60 mg 0.12 mmol) (Example 147) in THF (3.0 mL) was added a solution of LiOH.H2O (20 mg, 0.48 mmol) in water (1.0 mL) and MeOH (1.0 mL), and the mixture was stirred for 12 h at rt. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with Et2O (3×). The aqueous phase was brought to pH 3 using HCl (1N aqueous solution), and then the aqueous layer was extracted with EtOAc. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give 36 mg (63%) of the title compound as a white solid. 1H NMR (300 MHz, CD3OD): δ 0.96 (t, 3H), 1.34 (t, 3H), 1.59-1.71 (m, 2H), 1.73-1.81 (m, 1H), 2.25-2.38 (m, 2H), 2.39-2.47 (m, 2H), 2.62-2.98 (m, 7H), 3.44-3.57 (m, 1H), 4.20 (t, 2H), 4.26 (t, 2H), 6.75 (d, 1H), 6.84 (s, 1H), 7.02 (d, 1H), 7.07 (s, 1H), 7.14 (d, 1H), 7.71 (s, 1H), 7.78 (d, 1H); LC-MS: RT=4.04 min, (M+H)+ 480.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1F>>[ClH:13].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:9][CH:6]1[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]2[O:12][CH:11]=[CH:10][C:5]1=2
Reactant: CN1CCC(O)c2ccoc2C1
Reactant: Fc1ccccc1Cl
Product: CN1CCC(Oc2ccccc2Cl)c2ccoc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 1-chloro-2-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.