Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([O:47]C)=[O:46])=[CH:41][C:40]=4[F:49])[C:33]([F:38])=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].O>O1CCOCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([OH:47])=[O:46])=[CH:41][C:40]=4[F:49])[C:33]([F:38])=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:50])[CH:4]=[C:3]([C:2]([F:52])([F:51])[F:1])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(OC)cc2F)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(F)c(-c2ccc(C(=O)O)cc2F)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2,6′-difluoro-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (50 mg, 0.067 mmol), lithium hydroxide monohydrate (28 mg, 0.67 mmol), water (1 mL) and 1,4-dioxane (2 mL) were stirred at room temperature for 2.5 hours. LCMS of aliquot indicated formation of the desired product and complete consumption of starting material. Crude mixture was acidified (1N HCl, aq.). Volatiles were removed under reduced pressure. Pot residue was dissolved in MeCN and purified by a reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v). Corresponding fractions were pooled and evaporated in vacuo to afford a mixture. The resulting mixture was extracted with EtOAc. The separated organic phases were back washed w/water, separated, dried/Na2SO4, filtered and evaporated to afford the title compound. LCMS (ESI) calc.=733.13; found=734.14 (M+1)+. 1H NMR (CDCl3, 500 MHz, 1:1 mixture of atropisomers): δ 7.95 (t, J=6 Hz, 1H), 7.89-7.83 (m, 2H), 7.73 (s, 0.5H), 7.71 (s, 1H), 7.68-7.64 (m, 2H), 7.62 (s, 0.5H) 7.58 (t, J=7 Hz, 0.5H), 7.53 (t, J=7.5 Hz, 0.5H), 7.42 (d, J=8 Hz, 0.5H), 7.39 (d, J=8 Hz, 0.5H), 7.31-7.23 (m, 1H), 6.89 (d, J=4 Hz, 0.5H), 6.87 (d, J=3.5Hz, 0.5H), 5.61 (d, J=8 Hz, 0.5H), 5.29 (d, J=8 Hz, 0.5H), 5.05 (d, J=16 Hz, 0.5H), 4.93 (d, J=16 Hz, 0.5H), 4.16 (d, J=16.5 Hz, 0.5H), 3.94 (d, J=16 Hz, 0.5H), 3.89 (s, 1.5H), 3.87 (s, 1.5H), 3.85-3.72 (m, 1H), 0.59 (d, J=7 Hz, 1.5H), 0.43 (d, J=6 Hz, 1.5H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][NH2:11])[CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][NH:11][S:20]([CH3:19])(=[O:22])=[O:21])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccnc(NCCN)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccnc(NCCNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a cooled (0° C.) solution of N-(4-methyl-2-pyridyl)ethane-1,2-diamine (683 mg, 4.52 mmol) in dichloromethane (25 ml) were added triethyl amine (1.26 ml, 9.06 mmol) followed by methanesulfonyl chloride (370 μl, 4.78 mmol). The mixture was stirred at room temperature for two hours and washed with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated to give 1.04 g of a yellow oil (4.57 mmol, 95%) MS(ESI) m/z=230.1 [M+1]+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:13][CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].N[C@@H:16](C(C)C)CO>>[ClH:1].[ClH:1].[NH2:3][C@@H:4]([CH:13]([CH3:16])[CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:10][CH2:11]1)=[O:7]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: CC(C)[C@H](N)CO
Agent: Cl
Product: CC(C)[C@H](N)[C@H](O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, starting with (S)-2-amino-3-methylbutan-1-ol in the first step (A1).
Reaction SMILES: C1(COC([NH:11][NH:12][C:13]([NH:15][NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=2)=[O:14])=O)C=CC=CC=1.CO.[ClH:29].CCOCC>[Pd]>[ClH:29].[NH:12]([C:13]([NH:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:14])[NH2:11]
Reactant: O=C(NNC(=O)OCc1ccccc1)NNC(=O)c1ccc(O)c(O)c1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NNC(=O)NNC(=O)c1ccc(O)c(O)c1

Procedure:
A solution of 3.60 g (10.0 mmol) of 3,4-dihydroxybenzoic acid, 2-[[2-[(phenylmethoxy)carbonyl]hydrazino]carbonyl]hydrazide in 90 ml of dry methanol containing 1.67 ml (20.0 mmol) of concentrated hydrochloric acid was hydrogenated in the presence of 0.36 g of 10% palladium on charcoal for 15 minutes. After the removal of the catalyst by filtration and of the solvent by evaporation in vacuo, the crude solid (2.61 g) was stirred with a few ml of dry ether; yield: 2.41 g.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][CH3:21])=[C:4]([CH:6]=[C:7]([F:19])[C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]1)[NH2:5].[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][C:29]([C:31]2([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32]2)=[O:30])=[CH:25][C:24]=1[N:40]=[C:41]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][C:29]([C:31]2([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32]2)=[O:30])=[CH:25][C:24]=1[NH:40][C:41]1[N:20]([CH3:21])[C:3]2[C:2]([F:1])=[C:8]([N:9]3[CH2:14][CH2:13][CH:12]([C:15]([F:16])([F:18])[F:17])[CH2:11][CH2:10]3)[C:7]([F:19])=[CH:6][C:4]=2[N:5]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1c(N)cc(F)c(N2CCC(C(F)(F)F)CC2)c1F
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(F)c(N3CCC(C(F)(F)F)CC3)c(F)c21

Procedure:
The title compound was prepared in analogy to Example 76 using 3,5-difluoro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (186 mg, 0.60 mmol), N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (200 mg; 0.60 mmol), DIC (76 mg, 0.60 mmol) and DMF (3 mL).
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:17]#[N:18])=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C>[CH2:31]([N:6]1[C:5]([C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=2)[C:17]#[N:18])=[O:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]1=[O:11])[CH:30]([CH3:33])[CH3:32]
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CC(C)(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC(C)C)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a stirred mixture of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (Compound 1) (1.19 g, 4 mmol) and powdered anhydrous potassium carbonate (662 mg, 4.8 mmol) in DMF (20 mL), was added 2-iodo-2-methylpropane (460 μL, 4 mmol). The mixture was then stirred in an oil bath (50-60° C.) for overnight and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to afford 500 mg (35%) of 3-(3-isobutyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (78) as a white solid. m.p. 200-201° C.; 1H-NMR (200 MHz, CDCl3) δ 0.80 (3H, d, J=3.2 Hz), 0.83 (3H, d, J=3.2 Hz), 1.12 (3H, d, J=7.0 Hz), 1.23 (3H, d), J=7.0 Hz), 1.90 (1H, m), 2.25 (1H, m), 2.53 (3H, s), 2.93 (1H, dd, J=14.2 Hz, J=7.4 Hz), 3.75 (1H, dd, J=14.2 Hz, J=7.4 Hz), 7.80 (1H, s), 7.92 (1H, s), 8.03 (1H, s), 9.03 (1H, s); m/z (EI) 353 (M+).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7](=[C:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:11][OH:12])([CH3:9])[CH3:8].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([O:12][CH2:11][C:10](=[C:7]([CH3:9])[CH3:8])[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)=CCC(CO)=C(C)C
Reactant: CCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCC(=O)OCC(CC=C(C)C)=C(C)C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
In a nitrogen atmosphere, 64.0 g of butyryl chloride was added dropwise to a mixture of 94.1 g of 2-isopropylidene-5-methyl-4-hexenol (3) having a purity of 81.1% and an α,β-isomer purity of 98.1%, 50 g of pyridine and 500 ml of acetonitrile over 55 minutes which was stirred under cooling with ice. The reaction mixture was stirred for 2 hours under cooling with ice. To the reaction mixture was added an aqueous solution of saturated sodium bicarbonate, followed by extraction with diethyl ether. The diethyl ether solution was subjected to work-up including washing, drying and concentration to obtain 131.22 g of the crude product. The crude product was purified by distillation under reduced pressure to obtain, as the intended product, 23.54 g of a fraction having a purity of 92.8% and an α,β-isomer purity of 97.0% and 82.05 g of a fraction having a purity of 92.2% and an α,β-isomer purity of 98.3%. The yield of fractions including the other fractions was 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[C:32]#[CH:33].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:33]#[C:32][C:26]3[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=3[Cl:24])=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1
Reactant: C#Cc1cc(Cl)ccc1Cl
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C#Cc1cc(Cl)ccc1Cl
Yield: 18.6 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-32, 0.050 g, 0.11 mmol), 1,4-dichloro-2-ethynylbenzene (Intermediate-23, 0.029 g, 0.16 mmol), TBAF (0.101 g, 0.33 mmol), bis(triphenylphosphine)palladium(IT) chloride (0.005 g, 0.04 mmol) and DMSO (3.0 mL) at 80° C. to afford 0.010 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.89 (s, 3H), 7.49-7.56 (m, 3H), 7.59-7.73 (m, 6H), 12.90 (br s, 1H); MS (m/z): 487.95 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].ClC1C=CC=CC=1.[C-]#N.[Na+].[CH3:24][NH:25]CCNC>[Cu]I.O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:24]#[N:25])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: O
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Example 1) (99.1% purity, 5.0 g, 0.02 mol) and chlorobenzene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and powdered sodium cyanide (powdered just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57 g, 0.003 mol) and N,N′-dimethylethylenediamine (1.51 g, 0.017 mol) were added. The mixture was heated at reflux (about 130° C.) for 4.5 h and then cooled to 25° C., and water (20 mL) was added over 5 minutes, and the resulting mixture was stirred for 30 minutes. The mixture was filtered, and the solid collected was washed with water (2×10 mL) and chlorobenzene (10 mL), and then dried to a constant weight in a vacuum-oven at 50° C. to give the title compound (3.6 g) as an off-white solid melting at 202-203° C.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[CH2:13]([O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)C>CN(C=O)C>[CH3:13][O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:3][C:4]1=[O:12]
Reactant: CCOC(=O)CCCCCCCBr
Reactant: O=c1[nH]c2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)oc2ccccc21

Procedure:
The product is produced as described in example 1 from 3.0 g. of NaH (80% suspension in mineral oil), 13.5 g. of benzoxazolin-2-one, 200 cc. of DMF, 23.7 g. of 8-bromocaprylic acid ethyl ester and 3.0 g. of NaJ. Eluant in chromatographic purification: hexane/ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:13])([CH3:12])[C:5](=[O:11])[NH:6]2.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[F:1][C:2]1[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:13])([CH3:12])[C:5](=[O:11])[NH:6]2
Reactant: O=[N+]([O-])O
Reactant: CC1(C)C(=O)Nc2cccc(F)c21
Agent: O=S(=O)(O)O
Product: CC1(C)C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Reaction time: 0.5 h

Procedure:
To a solution of 4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (4.1 g) in concentrated sulfuric acid (60 mL) was added dropwise a mixture of fuming nitric acid (0.99 mL) and concentrated sulfuric acid (10 mL) over 30 min at −30° C. The reaction mixture was stirred between −30° C. to 0° C. for 30 min, and poured into ice. The resulting solid was collected by filtration, washed with water, and dissolved in ethyl acetate. The obtained solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:16][CH3:17])=[O:7])=[CH:4][N:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cl)nc1
Yield: 84 %

Procedure:
6-Chloronicotinic acid (1.6 g, 10.0 mmol) was dissolved in ethanol. Concentrated sulfuric acid (0.5 ml) was added to the solution, and the mixture was refluxed overnight. The reaction solution was concentrated under the reduced pressure. The residue was diluted with methylene chloride and was then washed with water, followed by drying over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (development system, n-hexane:ethyl acetate=5:1) to give ethyl 6-chloronicotinate 1.6 g (yield 84%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7]C(=O)[C:5]2=[O:13].[OH-].[K+].OO.C(OCC)(=[O:20])C>CO>[NH2:7][C:8]1[C:9]([CH3:11])=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[C:5]([OH:13])=[O:20]
Reactant: Cc1cc(Cl)cc2c1NC(=O)C2=O
Reactant: CCOC(C)=O
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Cl)cc(C(=O)O)c1N
Reaction time: 16 h

Procedure:
The 5-chloro-7-methyl-1H-indole-2,3-dione (25.0 g, 0.13 mol), potassium hydroxide (8.4 g, 0.15 mmol) and 30% hydrogen peroxide (21.6 g, 0.18 mol) were mixed together in methanol (300 mL) at 0° C. for 2 h followed by 16 h at room temperature. The solution was poured into ethyl acetate (500 mL) and extracted with I N hydrochloric acid (3×200 mL) followed by brine (1×50 mL). The solution was dried over sodium sulfate and solvent removed at reduced pressure. The 2-amino-5-chloro-3-methylbenzoic acid (18.0 g, 0.10 mmol) was isolated as a yellow solid (75% yield). HRMS m/z 185.0238; calcd 185.0244.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH2:37])[CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:50].Cl.N>ClCCl.C(O)C>[ClH:1].[ClH:50].[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH:37][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: NCCN1CCCC(CCCCN2CCCC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: Cl
Agent: N
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCO
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCC(CCCCN3CCCC3)C2)c2ccccc21
Yield: 35 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[4-(pyrrolidin-l-yl)butyl]-piperidin-l-yl]ethanamine in a yield of 35% of theory. The colourless dihydrochloride melted at 170°-172° C.; RF 0.69 (HPTLC ready-made silica gel plates 60 F254 for Nano-TLC, Messrs Merck; eluant: dichloromethane/ethanol/conc. ammonia 65/30/5 v/v/v).
Reaction SMILES: C(O[C@H:9]([CH3:31])[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([Cl:28])=[N:22][C:23]=3[Cl:27])[C@H:15]([OH:29])[C@@H:14]1[OH:30])=[O:11])C1C=CC=CC=1.[C:32]([O:36]CCC(O)=O)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][CH2:31][CH2:9][C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([Cl:28])=[N:22][C:23]=3[Cl:27])[C@H:15]([OH:29])[C@@H:14]1[OH:30])=[O:11])([CH3:35])([CH3:34])[CH3:33]
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)(C)OCCC(=O)O
Product: CC(C)(C)OCCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared as described for (R)-2-benzyloxy-N-[(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (Example 181, Step 1), by replacing (R)-2-benzyloxy-propionic acid with 3-tert-butoxypropionic acid.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2]1.[OH:18]S(O)(=O)=O.N#N>>[CH:2]([OH:18])([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCC1CO1
Reactant: O=S(=O)(O)O
Agent: N#N
Product: CCCCCCCCCCCCCCCC(O)O
Yield: 95 %

Procedure:
120 grams of random, internal epoxyhexadecane was placed in a glass-lined autoclave with 40 ml. of 10% H2SO4. The mixture was heated to 150° C. for 3 hours under 300 psi N2. Upon cooling, the product solidified in the autoclave. The aqueous portion was decanted, and the solid was dissolved in hot hexane. The solution was dried over anhydrous, MgSO4, filtered, and cooled. The resulting crystals were removed by filtration to yield approximately 95% of pure random, internal vicinal hexadecane diol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([NH2:28])[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:36][CH:37]1[CH2:40][CH:39]([S:41](Cl)(=[O:43])=[O:42])[CH2:38]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([NH:28][S:41]([CH:39]3[CH2:40][CH:37]([O:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:38]3)(=[O:43])=[O:42])[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)C1CC(OCc2ccccc2)C1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Yield: 49.3 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Intermediate (I-5d), 8-Amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (I-5c: 350 mg, 0.7 mmol) in pyridine (3 mL) was reacted with 3-benzyloxy-cyclobutanesulfonyl chloride (273 mg, 1.05 mmol) to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane) afforded 250 mg of the product (45.3% yield).
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([CH2:30][C:31]5[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=5)=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(Cc5ccc(Cl)cc5)o4)ccc3C)csc12
Reactant: N
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(Cc5ccc(Cl)cc5)o4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-{5-[5-(4-chloro-benzyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.11 g, 0.20 mmol) (from Example 41 supra) in 2-propanol (15 mL) for 20 min. The mixture was heated in a microwave reactor at 140° C. for 5.5 hours. The reaction mixture was concentrated. The residue was washed with hot methanol, filtered and dried to give 4-amino-3-{5-[5-(4-chloro-benzyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.07 g, 64%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]=[C:8]([CH3:23])[CH2:9][C:10]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])=[O:11].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[O:7]=[C:8]([CH3:23])[CH:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])=[O:11]
Reactant: ClCc1ccccc1
Reactant: C=CC(C)(CCC=C(C)C)OC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CC(C)(CCC=C(C)C)OC(=O)C(Cc1ccccc1)C(C)=O

Procedure:
Potassium carbonate (3.92 g, 0.028 mol), 3,7-dimethyl-1,6-octadien-3-yl 3-oxo-butyrate (4.80 g, 0.030 mol), benzyl chloride (4.80 g, 0.038 mol) and acetone (15 mL) are placed in a 50 mL round-bottomed flask fitted with a magnetic stirrer, condenser and argon inlet. The mixture is heated to reflux for 18 h. The cooled mixture is filtered and concentrated by rotary evaporation. The resulting oil is purified on silica gel to yield the desired compound. Structure is confirmed by thin layer chromatography and 1H and 13C NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6](N)=[N:5][CH:4]=1.[C:9]([Cu])#[N:10]>>[CH3:1][O:2][C:3]1[S:7][C:6]([C:9]#[N:10])=[N:5][CH:4]=1
Reactant: N#C[Cu]
Reactant: COc1cnc(N)s1
Product: COc1cnc(C#N)s1
Yield: 30 %

Procedure:
5-methoxythiazol-2-amine (2.6 g, 20 mmol) was reacted with CuCN (4 g, 44 mmol) according to the procedure as described in Example 61, Step A to give the title compound as brownish oil (0.84 g, 30%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:5]=1[C:6]#[N:7])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH2:21]([O:12][C:9]1[CH:10]=[CH:11][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:8]=1)[C:6]#[N:7])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: CCOc1ccc(O)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(OCC)c(C#N)c1

Procedure:
25 g of 2-ethoxy-5-hydroxybenzonitrile (153.2 mmol) (example 36A) and potassium carbonate (63.52 g, 459.6 mmol) are initially charged in 750 ml of acetone, 19.9 ml of allyl bromide (229.8 mmol) are added, and the mixture is stirred under reflux overnight. The mixture is filtered off and concentrated giving a mobile orange oil.