Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[CH3:41][O:42][CH2:43][CH2:44][CH2:45][NH2:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][NH:46][CH2:45][CH2:44][CH2:43][O:42][CH3:41])=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COCCCN
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COCCCNCc1ccc(-n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)c(OC)c3)c3c(N)ncnc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), 3-methoxypropylamine (0.024 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of 3-methoxypropylamine (0.1 mL, 1 mmol) and sodium triacetoxyborohydride (0.085 g, 0.40 mmol) were added and the mixture was shaken for 3 days. Acetic acid (0.1 mL) was added and the reaction mixture was shaken for 4 days. An additional portion of sodium triacetoxyborohydride (0.100 g, 0.470 mmol) was added and the reaction mixture was shaken for 16 h. 1N NaOH (1 mL) was added and the reaction mixture was concentrated, dissolved in DMF (2 mL), filtered through a syring-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile-0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 18.0-19.7 min was collected, concentrated, and lyopholized to afford N1-{4-[4-amino-1-(4-{[(3-methoxypropyl)amino]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.009 g, 0.014 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.93 (1H, s), 8.33-8.38 (2H, m), 8.18-8.20 (2H, m), 7.97-8.01 (1H, m), 7.87-7.91 (1H, m), 7.73-7.76 (1H, m), 7.54-7.64 (5H, m), 7.31-7.45 (2H, m), 3.95 (3H, s), 3.85-3.89 (2H, m), 3.38 (2H, s), 2.55-2.68 (2H, m), and 1.70-1.74 (2H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.58 min. MS: MH+ 624.2.
Reaction SMILES: Cl.NO.C([N:7](CC)C(C)C)(C)C.[Br:13][C:14]1[C:15]([NH:20][C:21]([NH:23]C(OCC)=O)=S)=[N:16][CH:17]=[CH:18][CH:19]=1>CO.C(O)C>[Br:13][C:14]1[C:15]2[N:16]([N:7]=[C:21]([NH2:23])[N:20]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ncccc1Br
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2c(Br)cccn2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of hydroxylamine hydrochloride (17.4 g, 25.0 mmol) and N,N-diisopropylethylamine (26.0 mL, 14.9 mmol) in a mixture of methanol (70 mL) and ethanol (70 mL) was added N-(3-bromo-2-pyridinyl)-N′-carboethoxy-thiourea. The mixture was stirred for 2 hours at room temperature then heated to 60° C. for 18 hours. The suspension was cooled to room temperature, filtered and rinsed with methanol, water then methanol. 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was isolated as an off-white solid (8.41 g, 70%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.58 (d, J=6.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 6.80 (t, J=7.0 Hz, 1H), 6.25 (s, 2H). MS=213, 215 (MH)+.
Reaction SMILES: [NH2:1][N:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]1=[NH2+:9].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[Cl:23][CH2:24][C:25](OC)=O.C(=O)([O-])[O-].[K+].[K+]>CCO>[Cl:23][CH2:24][C:25]1[N:9]=[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[N:2]2[N:1]=1
Reactant: Cc1cccc(=[NH2+])n1N
Reactant: COC(=O)CCl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cccc2nc(CCl)nn12
Temperature: 80 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A suspension of 1-amino-6-methylpyridin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate (520 mg, crude product from the previous step, 1.61 mmol), methyl 2-chloroacetate (700 mg, 7.80 mmol) and potassium carbonate (444 mg, 3.22 mmol) in EtOH (10 m L) was stirred at 80° C. for 16 h. After cooled to room temperature, the reaction mixture was concentrated and purified by silica gel column chromatography (eluting with EtOAc in PE, a gradient from 17% to 30% v/v) to give the title compound (290 mg, yield 84%). ESI MS: m/z 182, 184 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([C:17]#[N:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)#[N:2].[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1.C(OCC)C>[C:1]([CH:3]([CH3:19])[CH2:4][N:5]1[CH2:10][CH2:9][C:8]([C:17]#[N:18])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)#[N:2]
Reactant: N#CCCN1CCC(C#N)(c2ccccc2)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CI
Product: CC(C#N)CN1CCC(C#N)(c2ccccc2)CC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(2-cyanoethyl)-4-cyano-4-phenyl-piperidine (2.81 g, 11.7 mmol) dissolved in tetrahydrofuran(110 mL) was cooled to −20° C. under an atmosphere of nitrogen and 1 M lithium bistrimethylsilylamide in tetrahydrofuran (12.3 ml) was added by syringe. The clear solution was allowed to stir for 30 min. and then methyl iodide (0.80 mL, 12.9 mmol) was added by syringe. This reaction mixture was stirred for 5 minutes and then warmed to room temperature and stirred for 30 minutes. The reaction was diluted with diethyl ether and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and the solvent removed to give an oil. This residue was purified by preparative centrifugal chromatography using a 5-50% ethyl acetate/hexane gradient to give the title compound which was used as is.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][O:13]C(=O)[N:11]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([O:27]CC)=[O:26])=[C:18]3[N:17]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CO.C1COCC1.O.[OH-].[Li+]>O>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]([NH:11][C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[C:18]3[N:17]=2)[CH2:14][OH:13])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3C(=O)OC[C@@H]3c3cc(F)cnc3OC)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(F)cc1[C@@H](CO)Nc1ccn2ncc(C(=O)O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
To a solution of (S)-ethyl 5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (311 mg, 0.77 mmol) in a 1:1:1 mixture of MeOH:THF:H2O (15 mL) was added lithium hydroxide monohydrate (97.6 mg, 2.32 mmol). The mixture was stirred at ambient temperature for 16 hours and then at 50° C. for 19 hours, then concentrated to ⅓ volume, diluted with water (30 mL) and acidified to pH 4-5 with 1N HCl. The resulting precipitate was collected by filtration, washed with water and Et2O then dried under reduced pressure to afford (S)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (121 mg, 45% yield) as a white powder. MS (apci) m/z=347.9 (M+H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)#[N:10].C(N(CC)CC)C>O1CCCC1.O>[CH2:1]([NH:8][S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]#[N:10])[CH:12]=1)(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(S(=O)(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzylamine (1.17 g, 10 mmol) was added to a solution of 3-cyanobenzene sulphonyl chloride (2 g, 10 mmol) and triethylamine (3.45 ml, 25 mmol) in tetrahydrofuran (30 ml) and the mixture stirred at room temperature for 18 hours. The mixture was diluted with water (30 ml), and extracted with ethyl acetate (50 ml). The organic extract was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a solid, 2.53 g.
Reaction SMILES: [Cl:1][C:2]1[C:8]([N:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:12]N1C(=O)CCC1=O>CN(C=O)C>[Br:12][C:5]1[CH:6]=[CH:7][C:8]([N:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[C:3]=1[NH2:4]
Reactant: CN(C)c1cccc(N)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CN(C)c1ccc(Br)c(N)c1Cl
Temperature: 0 °C
Reaction time: 48 h
Yield: 93.5 %

Procedure:
12.8 g of 2-chloro-3-dimethylaminoaniline is dissolved in 180 ml of DMF and stirred at 0° C. A solution of 13.4 g of N-bromosuccinimide in 80 ml of DMF is slowly added dropwise, so that the temperature does not rise above 2° C. The mixture is stirred for 5 hours at 0° C. and then at RT. After 48 hours, 700 ml of ice-water is added. The white precipitate is filtered off and the aqueous phase is extracted three times with 200 ml of diethyl ether. The organic phases are dried, filtered, and evaporated down. 17.5 g of 2-bromo-6-chloro-5-dimethylaminoaniline is obtained as a brown oil and used further without any additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=3)(=[O:26])=[O:27])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.8 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 4-nitro benzenesulfonyl chloride (292 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12g as a solid (120 mg, 33.3%). HPLC: 97% (Rt=7.76 min).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:37])=[C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[O:29])[CH:25]=2)[NH:20][C:19](=[O:38])[C:18]=1[C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:37][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[C:19](=[O:38])[NH:20]2)=[CH:25][C:24]=1[NH:27][C:28]([NH:30][C:31]1[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccs2)c(=O)[nH]c2cc(Cl)c(NC(=O)Nc3ccncc3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1)Nc1cc2c(OCCC3CCCCN3)c(-c3cccs3)c(=O)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-{2-[7-chloro-2-oxo-6-(3-pyridin-4-yl-ureido)-3-thiophen-2-yl-1,2-dihydroquinolin-4-yloxy]-ethyl }-piperidine-1-carboxylic acid tert-butyl ester in methylene chloride is added trifluoroacetic acid and the mixture stirred at room temperature. After 30 minutes, the mixture is concentrated in vacuo, resolvated in 10% ammonium hydroxide in methanol and concentrated once again. Purification by flash chromatography on silica gel gives the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[C:11]([O:12][CH3:13])=[CH:10][S:9][C:8]=1[CH3:14])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:13][O:12][C:11]1[C:7]([N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:24](=[O:25])[CH2:23][Cl:22])=[C:8]([CH3:14])[S:9][CH:10]=1
Reactant: O=C(Cl)CCl
Reactant: CCOCCNc1c(OC)csc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOCCN(C(=O)CCl)c1c(OC)csc1C

Procedure:
To a well stirred mixture of 6,05 g (0.03 mol) N-(2-ethoxyethyl)-4-methoxy-2-methyl-thiophene-3-amine, 4.15 g (0.03 mol) of K2CO3, 10 ml of water and 100 ml of CH2Cl2 is added dropwise without cooling the solution of 3.4 g (0.03 mol) of chloroacetyl chloride in 10 ml of CH2Cl2. After the exothermic reaction (27°) has subsided, stirring is continued for a further hour at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH3:19][CH2:20][N:21](C(C)C)[CH:22]([CH3:24])[CH3:23].CC[O:30]C(C)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:20][CH2:19][O:30][CH2:23][C@@H:22]2[CH3:24])[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1Cc2nc(Cl)nc(Cl)c2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)C2
Temperature: 35 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (1.61 g, 5.54 mmol) and DIPEA (1.1 mL, 6.21 mmol) at room temperature (20° C.) in DCM (10 mL) was added 3-S-methyl morpholine (0.98 g, 9.65 mmol). The reaction mixture was heated to 35° C. and stirred for 24 h. The reaction was diluted with DCM and Sat. NaHCO3. The organic layer was rinsed (brine), dried (anhydrous Na2SO4) and concentrated in vacuo. The desired product was isolated by flash chromatography (silica, 50 g, 0-30% EtOAc in petroleum ether (40-60) over 40 min) as a white solid (1.80 g, 5.07 mmol, 82% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.Cl.[F:37][C:38]1([F:44])[CH2:43][CH2:42][CH2:41][NH:40][CH2:39]1.C(N(CC)CC)C>C1COCC1.O>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([N:40]4[CH2:41][CH2:42][CH2:43][C:38]([F:44])([F:37])[CH2:39]4)[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: FC1(F)CCCNC1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCCC(F)(F)C2)c(C#N)c1-c1ccc(OCCO)cc1

Procedure:
At RT, 150 mg (0.20 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), 64 mg (0.41 mmol) of 3,3-difluoropiperidine hydrochloride and 57 μl (0.41 mmol) of triethylamine were stirred in 3 ml of THF for 2 h. The reaction mixture was then diluted with about 1 ml of water and about 3 ml of THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 90 mg (71% of theory) of the target compound.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[C:11]2[S:15][CH3:16])[CH:7]=[CH:6][C:5]=1[O:17][CH3:18].[OH-].[Li+].O.Cl>O1CCCC1>[CH3:18][O:17][C:5]1[CH:6]=[CH:7][C:8]([N:10]2[CH:14]=[N:13][N:12]=[C:11]2[S:15][CH3:16])=[CH:9][C:4]=1[C:3]([OH:19])=[O:2]
Reactant: COC(=O)c1cc(-n2cnnc2SC)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2cnnc2SC)cc1C(=O)O
Yield: 95.9 %

Procedure:
Stir a mixture of 2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid methyl ester (0.28 g, 3.5 mmol), lithium hydroxide (0.041 g, 3.8 mmol), and 25% water in tetrahydrofuran (20 mL) overnight. Add 1N hydrochloric acid (3.9 mL) dropwise to pH 3. Concentrate to remove the tetrahydrofuran and collect the precipitate by vacuum filtration. Wash the filter cake twice with water and hexane, and dry in vacuo overnight to give 0.89 g of 2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid as a solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2].[CH:12]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=1)=O.[CH2:28]([N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37](O)[CH:38]=2)[C:33](C)=CC1(C)C)[CH3:29].C(C1C=CC(OCC(O)=O)=CC=1)=O>CO>[CH2:1]([NH:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]2[C:12]([C:14]3[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=3)=[C:36]3[C:37]([O:11][C:6]=2[CH:5]=1)=[CH:38]/[C:39](=[N:30]/[CH2:28][CH3:29])/[C:34]([CH3:33])=[CH:35]3)[CH3:2]
Reactant: O=Cc1ccc(OCCCCC(=O)O)cc1
Reactant: CCNc1cc(O)ccc1C
Reactant: CCN1c2cc(O)ccc2C(C)=CC1(C)C
Agent: O=Cc1ccc(OCC(=O)O)cc1
Solvent: CO
Product: CC/N=c1/cc2oc3cc(NCC)c(C)cc3c(-c3ccc(OCCCCC(=O)O)cc3)c-2cc1C
Yield: 17 %

Procedure:
Dye 10 (shown below) was prepared using the procedure described in Example 4 except that 3-(ethylamino)-4-methylphenol and 5-(4-formylphenoxy)pentanoic acid substituted for 1-ethyl-2,2,4-trimethyl-1,2-dihydroquinolin-7-ol and 2-(4-formylphenoxy)acetic acid. Yield: 17%. λabs=524 nm (in methanol), λem=541 nm (in methanol).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:25]=[CH:24][C:14]([CH2:15][NH:16]C(=O)OC(C)(C)C)=[CH:13][C:12]=2[O:26][CH3:27])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[F:28][CH:2]([F:1])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:25]=[CH:24][C:14]([CH2:15][NH2:16])=[CH:13][C:12]=2[O:26][CH3:27])=[CH:5][CH:4]=1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1OCc1ccc(C(F)F)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CN)ccc1OCc1ccc(C(F)F)nc1
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a stirred solution of tert-butyl 4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzylcarbamate (7.32 g, 18.56 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (15 mL, 194.70 mmol). After 2 h, the reaction mixture was concentrated, and the residue was dissolved in water (75 mL). The acidic solution was extracted with diethyl ether (50 mL). The aqueous phase was retained and made basic with concentrated ammonium hydroxide solution (50 mL). The basic aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 4.54 g (83%) of (4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxyphenyl)methanamine as a yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH:23]4[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH:19]3[CH2:20][O:21][CH2:22]4)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:34].CCOCC>O1CCOCC1>[ClH:34].[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH:23]4[CH2:24][NH:25][CH2:26][CH:19]3[CH2:20][O:21][CH2:22]4)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2C(=O)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1C2CNCC1COC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
3-Oxa-7,9-diaza-bicyclo[3.3.1]nonane-7,9-dicarboxylic acid 7-tert-butyl ester 9-(9H-fluoren-9-ylmethyl) ester (1.29 g, 2.76 mmol) was dissolved into a 4N solution of HCl in 1,4-dioxane (10 mL). The resulting mixture was stirred at RT for 1.5 hours, and then concentrated under vacuum to give a colorless oil. The oil was taken up with Et2O (20 ml) and a precipitation occurred. The precipitate was filtered off, washed with Et2O (2×) and dried under vacuum to give the title compound as a white powder (1.06 g, 92%). 1H NMR (300 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.22 (s, 1H), 7.90 (d, J=7.3 Hz, 2H), 7.64 (d, J=7.4 Hz, 2H), 7.47-7.31 (m, 4H), 4.61-4.44 (m, 2H), 4.31 (t, J=6.0 Hz, 1H), 4.07 (s, 1H), 4.02-3.84 (m, 3H), 3.62-3.53 (m, 1H), 3.51-3.37 (m, 3H), 3.09-2.90 (m, 2H). HPLC (max plot) 97.4%; Rt 2.94 min. UPLC/MS: (MS+) 351.3 ([M+H]+).
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][C:8]#[N:9])(=[O:5])[OH:4])[CH3:2].[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH2:7][C:8]#[N:9])(=[O:4])[O:5][CH2:10][CH2:11][OH:12])[CH3:2]
Reactant: CCP(=O)(O)CCC#N
Reactant: OCCO
Solvent: Cc1ccccc1
Product: CCP(=O)(CCC#N)OCCO
Yield: 88.9 %

Procedure:
441 g (3.0 mol) of ethyl(2-cyanoethyl)phosphinic acid (produced as in Example 5) are at 85° C. dissolved in 400 ml of toluene and admixed with 248 g (4 mol) of ethylene glycol and esterified at about 100° C. in a distillation apparatus equipped with water trap during 4 h. On completion of the esterification the toluene and excess ethyl glycol is removed in vacuo to leave 510 g (89% of theory) of 2-hydroxyethyl ethyl(2-cyanoethyl)phosphinate as colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: N#Cc1ccc(CBr)cc1
Product: Cc1nc(-c2ccn(Cc3ccc(C#N)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 4-bromomethyl-benzonitrile as described in Example 49 and isolated as a white solid (0.065 g, 46% 1H NMR (400 CDCl3) δ 3.60 (s, 1H), 8.55-8.57 (m, 1H), 7.71 (d, J=8 Hz, 1H), 7.64 (d, J=8 Hz, 2H), 7.46 (s, 1H), 7.26-7.31 (m, 3H), 6.90 (d, J=4 Hz, 1H), 6.11-6.16 (m, 1H), 5.41 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=415.2; Rt=1.15 min; HRMS (M+H)+=415.14.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([CH3:18])[CH:12]=[CH:11][N:10]=1.[CH2:19]([OH:21])[CH3:20].Cl.C(OC(=O)C)(=O)C>[Fe].C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([NH:15][C:19](=[O:21])[CH3:20])=[C:13]([CH3:18])[CH:12]=[CH:11][N:10]=1
Reactant: CCO
Reactant: Cc1ccnc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(C)ccnc1-c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 68 %

Procedure:
To a mixture of 2-(2,4-dichloro-phenyl)4-methyl-3-nitro-pyridine (29; 1.15 g, 4.05 mmol), 10 mL of ethanol, 2.5 mL of water, and 0.5 mL of a concentrated HCl solution at 85° C. was added iron powder (1.37 g, 24.6 mmol). The grey suspension was stirred for 1 h, allowed to cool, and filtered through CELITE® 521 and the residual pad was washed well with methanol. The filtrate was concentrated, and the reddish-orange residue was partitioned between 50 mL of ethyl acetate and 50 mL of a saturated aqueous NaHCO3 solution. The organic layer was washed with 50 ML of a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to a yellow oil. To the oil was added 10 mL of toluene and acetic anhydride (0.41 mL, 4.35 mmol), and the yellow solution was stirred at 100° C. for 23 h then concentrated to a dark yellow residue. Column chromatography (50→66% EtOAc/hexanes) afforded of N-[2-(2,4-dichloro-phenyl)-4-methyl-pyridin-3-yl]-acetamide (30; 0.815 g; 68%) as an off-white solid.