Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([O:6][C:7]([CH3:14])([CH3:13])[C:8](OCC)=[O:9])=[C:4]([N:18]2[C:22](=[O:23])[N:21]([CH3:24])[N:20]=[N:19]2)[CH:3]=1.[BH4-].[Li+].CO.[OH-].[Na+]>CCOCC>[NH2:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([O:6][C:7]([CH3:13])([CH3:14])[CH2:8][OH:9])=[C:4]([N:18]2[C:22](=[O:23])[N:21]([CH3:24])[N:20]=[N:19]2)[CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1cc(F)c(N)cc1-n1nnn(C)c1=O
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: Cn1nnn(-c2cc(N)c(F)cc2OC(C)(C)CO)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
A solution of ethyl 2-(4-amino-5-fluoro-2-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenoxy)-2-methylpropanoate (5.60 g, 16.5 mmol, 1.00 equiv) in Et2O (155 mL) under argon was cooled to 0° C. The ice-cooled solution was charged with lithium borohydride (791 mg, 36.3 mmol, 2.20 equiv) followed by MeOH (1.540 mL), which resulted in the formation of a free-flowing precipitate. The reaction was stirred at 0° C. for 30 min, then the ice-bath was removed, and the reaction was stirred at ambient temperature for 1 h. At ambient temperature, the reaction was slowly quenched with aqueous 1 N NaOH (100 mL, 100 mmol, 6.00 equiv), which dissolved the free-flowing precipitate. The layers were separated, and the aqueous layer was extracted with DCM 2×. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to give 1-(5-amino-4-fluoro-2-(1-hydroxy-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one (4.60 g, 94%) as a white solid that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[C:14]3[CH2:15][NH:16][CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:20]1[CH2:23][C:22](=O)[CH2:21]1.C([BH3-])#N.[Na+].C(Cl)Cl.C(OCC)C.CO>CO.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[C:14]3[CH2:15][N:16]([CH:22]4[CH2:23][O:20][CH2:21]4)[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCNC3)c1=O
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Temperature: 48 °C
Yield: 33.7 %

Procedure:
Following Example 214b, 5-bromo-1-methyl-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one 126a (250 mg, 0.78 mmol), oxetan-3-one (600 mg, 8.3 mmol) were dissolved in methanol (8 mL). Sodium cyanoborohydride (148 mg, 3 mmol) and zinc chloride (165 mg, 1.5 mmol) in methanol (8 mL) was added, and the reaction was heated at 48° C. for 12 hours. Work-up and flash column chromatography (silica, 60:35:5 methylene chloride/diethyl ether/methanol) afford a 34% yield (100 mg) of 252a as a light green solid: MS (ESI+) m/z 382.1 (M+H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O:13]=[CH:14][C@@H:15]([C@H:17]([C@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])O.COS([O-])(=O)=O>O.S(=O)(=O)(O)O>[OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([O:8][C@@H:23]2[O:24][C@H:15]([CH2:14][OH:13])[C@H:17]([OH:18])[C@H:19]([OH:20])[C@H:21]2[OH:22])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: COS(=O)(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 0.17 h

Procedure:
100 mmol/l of glucose, 20 mmol/l of galactose and 2 mg/ml of galactosidase are incubated at 35° C. in a mixture of water and MMIm MeSO4 for 24 h. The reaction is stopped by boiling for 10 minutes at 100° C., the reaction solution is filtered (Minisart RC 4 Sartorius injection filter) and the concentration of the reaction components at this time is determined chromatographically (Aminex HPX-87H cation exchange column from BioRad with corresponding preparatory column, 0.006 M sulphuric acid as eluent with a flux of 0.8 ml/min and a column temperature of 65° C. Detection is accomplished using UV at 208 nm and using the refractive index).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:49])[C:22]1[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([S:30]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[O:41][Si](C(C)(C)C)(C)C)(=[O:32])=[O:31])[CH:23]=1>O1CCCC1>[CH3:19][O:20][C:21]([C:22]1[CH:27]=[C:26]([CH3:28])[C:25]2[O:41][C:35]3[C:36]([Cl:40])=[CH:37][CH:38]=[CH:39][C:34]=3[CH2:33][S:30](=[O:32])(=[O:31])[C:24]=2[CH:23]=1)=[O:49]
Reactant: COC(=O)c1cc(C)c(Br)c(S(=O)(=O)Cc2cccc(Cl)c2O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cccc(Cl)c1O2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of tetrabutyl ammonium fluoride (90 g, 0.283 mol) in tetrahydrofuran (250 mL) was added dropwise to a solution of compound of Example 1h (72 g, 0.135 mol) in tetrahydrofuran (350 mL) over a period of 25 min under nitrogen, at 5° C. The reaction mixture was stirred at 5° C. for 30 min. Solvent was removed under reduced pressure and water (250 mL) was added. The solid was filtered and washed with water (2000 mL). The crude product was purified by column chromatography (silica gel, methanol in chloroform) to obtain the title compound. Yield: 37.0 g (87%); 1H NMR (CDCl3, 300 MHz): δ 2.71 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 4.72 (s, 2H, CH2), 7.25 (d, 1H, Ar), 7.33 (d, 1H, Ar), 7.45 (d, 1H, Ar), 8.09 (s, 1H, Ar), 8.46 (s, 1H, Ar); MS: m/e (El) 352 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.O[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8582.6 %

Procedure:
The starting material was prepared as follows 4-Chloro-7-hydroxy-6-methoxyquinazoline (1.7 g, 0.08 mmol), (prepared as described for the starting material in Example 4), tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (20.17 g, 8.89 mmol), (prepared as described for the starting material in Example 15), and triphenylphosphine (2.97 g, 11.3 mmol) were added to dichloromethane (42.5 ml). Diisopropyl azodicarboxylate (1.91 ml, 9.70 mmol) was added and the reaction mixture stirred at ambient temperature for 1.5 hours and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 92/8) to give the product containing a single impurity. A second column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4) gave tert-butyl 4-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}piperazine-1-carboxylate (3.0 g, 99%) as a white solid.
Reaction SMILES: [Se](=O)=O.[OH2:4].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15](=[O:17])[CH3:16]>O1CCOCC1>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15](=[O:17])[CH:16]=[O:4]
Reactant: O
Reactant: COc1ccc(OC)c(C(C)=O)c1
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: COc1ccc(OC)c(C(=O)C=O)c1
Temperature: 60 °C

Procedure:
A mixture of 3.66 g (33 mmol) of selenium dioxide, 1 ml of water and 25 ml of dioxane is heated to 60° C. 5.4 g (30 mmol) of 2′,5′-dimethoxyacetophenone are added and the mixture is refluxed for 16 hours. The solvents are evaporated off (orange-coloured oil; 6 g) and the product obtained is purified by flash chromatography (dichloromethane) (3.1 g of yellow oil; 53%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.Cl>[F:16][C:2]([F:1])([F:15])[CH:3]([NH:14][S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(NC(Cc1c[nH]c2ccccc12)C(F)(F)F)c1ccccc1
Temperature: 45 °C
Reaction time: 18 h
Yield: 66.4 %

Procedure:
A mixture of 40 mg (0.18 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 30 μL (0.23 mmol) of benzenesulfonyl chloride in 1 mL of pyridine was warmed at 45° C. The reaction was monitored by TLC (ethyl acetate-hexanes (25:75)) indicating a new less polar product compared to amine. The mixture stirred for 18 hours at 45° C. and over the weekend at room temperature. The mixture was diluted with 7 mL of 1 N aqueous HCl and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with three 5 mL portions of 1 N aqueous HCl, 5 mL of brine, and three 5 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was adsorbed onto silica gel and chromatographed on silica gel using dichloromethane-hexanes (gradient 50-100%). The material from the column solidified from ether-hexanes to afford 44 mg (68%) of the title compound as an white solid, m.p. 121° C.-123° C., MS: m/z 367.08 (M−).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Clc1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-chloro-phenol to give [1-(4-chloro-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([O:4][C:5]([N:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:8]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:17]=[N:16][N:15]=2)=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:6])[CH3:3].[C:36]([Si:38]([CH3:41])([CH3:40])[CH3:39])#[CH:37]>C(NCC)C.C(Cl)Cl.[Cu]I>[CH3:1][C:2]([CH3:35])([O:4][C:5]([N:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:8]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:17]=[N:16][N:15]=2)=[CH:12][C:11]([C:37]#[C:36][Si:38]([CH3:41])([CH3:40])[CH3:39])=[CH:10][N:9]=1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cc1-c1nnnn1-c1cccc(F)c1F
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C#C[Si](C)(C)C)cc1-c1nnnn1-c1cccc(F)c1F
Temperature: 50 °C
Yield: 29.3 %

Procedure:
In a tube was placed N,N-di(1,1-dimethylethoxycarbonyl)-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-bromopyridin-2-amine (2.3 g, 4.1 mmol) in diethylamine (10 mL) with ethynyltrimethylsilane (1.5 g, 15.3 mmol) and the reaction was deoxygenated with a stream of nitrogen gas. To the mixture was added copper(I) iodide (554 mg, 2.9 mmol). The reaction vessel was sealed and warmed to 50° C. to achieve dissolution. To the mixture was added PdCl2dppf2.CH2Cl2 (190 mg, 0.06 eq). The reaction vessel was sealed and the mixture sonicated at 50° C. for 10 minutes. The reaction was diluted with methylene chloride, filtered through Celite™, concentrated, and purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give N,N-di(1,1-dimethylethoxycarbonyl)-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (713 mg, 1.2 mmol, 30%) as a yellow solid; LC-MS: m/e=471.3 [M-Boc+H].
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[C:14]([CH3:17])=[CH:15][S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C(=O)N([Br:25])C(=O)C1>CC(O)=O.C(Cl)(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[C:14]([CH3:17])=[C:15]([Br:25])[S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CCc2scc(C)c2C(C)C1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCc2sc(Br)c(C)c2C(C)C1
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
The product of step (b) (92 mg, 0.36 mmol) was dissolved in 4 mL of 1:1 HOAc/CHCl3 and treated with NBS (67 mg, 0.38 mmol). After stirring for ½ hour, the reaction was diluted with EtOAc (70 mL) was washed with water (3×30 mL) and 1M NaOH (2×30 mL). The organic solution was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (EtOAc/Hex) to give 90 mg of the sub-title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(O)C.[OH-].[K+].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCc1ccc(-c2ccc(O)c(F)c2)nc1
Reactant: CCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCc1ccc(-c2ccc(OCCCCCC)c(F)c2)nc1
Reaction time: 4 h
Yield: 65.4 %

Procedure:
2-(m-Fluoro-p-hydroxyphenyl)-5-heptylpyridine (2 g, 0.007 mol), ethanol (20 ml), potassium hydroxide (0.48 g, 0.008 mol) and n-hexylbromide (1.4 g, 0.008 mol) were heated under reflux with stirring for 4 hours, followed by cooling the resulting reaction fluid, adding water and toluene, transferring the mixture into a separating funnel, washing the resulting organic layer with 2N-NaOH aqueous solution, then washing it with water, distilling off the solvent under reduced pressure, recrystallizing the residue from ethanol, filtering off it in a refrigerator and drying it to obtain the objective final product 2-(m-fluoro-p-hexyloxyphenyl)-5-heptylpyridine (1.7 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[Cl-].[Li+].Cl.[CH2:31]([NH2:33])[CH3:32].C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH2:31]([NH:33][C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:27])[CH3:32]
Reactant: CCN
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 57.7 %

Procedure:
A suspension of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid with 1 eq. lithium chloride (54 mg, 0.133 mmol), ethylamine hydrochloride (44 mg, 0.534 mmole), diisopropyl-ethylamine (93 ul, 0.534 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 197 ul, 0.334 mmol) in tetrahydrofurane (3 ml) is stirred for 1.5 hours at 70° C. As no dissolution occurs after this time, ethylamine hydrochloride (87 mg, 1.07 mmol), diisopropylethylamine (186 ul, 1.07 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 99 ul, 0.167 mmol) are added and the mixture is stirred overnight at room temperature. The white suspension is diluted with ethyl acetate, washed once with water, once with sat. aqueous sodium bicarbonate solution, once with brine, dried with magnesium sulfate and the solvent is evaporated to dryness affording N4-ethyl-1-methyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (30 mg, 57.7%) as a white solid. mp.: 253-5° C. MS: m/z=390.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[CH:10][CH:9]=[C:8]([S:21]([N:24](CC1C=CC(OC)=CC=1)[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)(=[O:23])=[O:22])[CH:7]=2)#[N:2].C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[CH:10][CH:9]=[C:8]([S:21]([NH:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1)(=[O:23])=[O:22])[CH:7]=2)#[N:2]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OC)c(C#N)cnc3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccccc1-c1c(C#N)cnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A vial was charged with 3-cyano-N-(4-methoxybenzyl)-4-(2-methoxyphenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (23.3 mg, 0.043 mmol), DCM (0.5 mL), and TFA (0.25 mL). After 30 min, the mixture was diluted with MeOH and concentrated, and the crude product was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-5% MeOH/DCM) to give 3-cyano-4-(2-methoxyphenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (13.6 mg, 0.032 mmol, 75.0% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=12.99 (br. s., 1H), 9.35 (s, 1H), 8.50 (d, J=1.8 Hz, 1H), 7.98 (dd, J=1.9, 8.8 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.67-7.58 (m, 1H), 7.40 (dd, J=1.7, 7.5 Hz, 1H), 7.35-7.28 (m, 2H), 7.21 (dt, J=0.8, 7.5 Hz, 1H), 6.89 (d, J=4.6 Hz, 1H), 3.71 (s, 3H). m/z (ESI) 423.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[N:12]=2)[CH:4]=1)[CH3:2].[C:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:21])[CH3:20]>>[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:17][C:13]2[N:12]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: CC(=O)N1CCNCC1
Reactant: CCc1cc(-c2cccc(C=O)n2)c(C)[nH]c1=O
Product: CCc1cc(-c2cccc(CN3CCN(C(C)=O)CC3)n2)c(C)[nH]c1=O

Procedure:
5′-Ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carbaldehyde prepared in accordance with PREPARATION 11 is reacted with 4-acetylpiperazine as described in Method A, Example 123 to give the title compound. MS: m/e=355 (M+H).
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[N:5]=[C:6]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=2)[C:7]2[N:8]=[C:9]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[N:10](C(=O)C)[CH2:11][C:12]=2[N:13]=1.Br.OO>O.[Pd].C(O)=O.C1COCC1.CO>[Cl:33][C:28]1[CH:27]=[C:26]([NH:25][C:6]2[C:7]3[N:8]=[C:9]([NH:17][CH:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:10]=[CH:11][C:12]=3[N:13]=[CH:4][N:5]=2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CC(=O)N1Cc2nc(Cl)nc(Nc3ccc(F)c(Cl)c3)c2N=C1NC1CCN(C)CC1
Agent: [Pd]
Agent: Br
Agent: OO
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CO
Product: CN1CCC(Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
9 ml of 2N sodium hydroxide solution are added to a mixture of 9 g (0.019 mol) of (4), 81 ml of methanol and 9 ml of THF and the mixture is refluxed for 1 hour. Then 0.45 g of Pd/C (10%) are added and 4.5 ml of formic acid are added dropwise at boiling temperature. The mixture is refluxed for 24 hours, filtered off and evaporated down in vacuo to leave a residue. This is taken up in 90 ml of water and 7.2 ml of conc. hydrobromic acid and combined at ambient temperature with 3.9 ml of hydrogen peroxide (30%). The mixture is stirred for 5 hours at ambient temperature, then the product that crystallises out is filtered off and washed with water. The filter residue is dissolved in methanol, the free base is precipitated by the addition of 30 ml of water and 2N sodium hydroxide solution. Yield: 4.95 g (66%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([NH2:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(Cl)Cl.O.C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:27][CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NC(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 69 h
Yield: 91.3 %

Procedure:
4-Nitrobenzenesulfonyl chloride (2.51 g) was added to a methylene chloride solution (30 ml) containing benzhydrylamine (2.12 g) and triethylamine (1.62 g) under ice cooling, followed by stirring for 3 hours under ice cooling and for 69 hours at room temperature. Water (30 ml), 1 N hydrochloric acid (12 ml) and methylene chloride (5 ml) were added to the reaction mixture, followed by extraction and solution separation, and the aqueous layer was extracted again with methylene chloride (10 ml). The resulting extract was concentrated, and ethyl acetate (80 ml) and water (50 ml) were further added, followed by solution separation. The organic layer was washed in turn with saturated aqueous solution of sodium bicarbonate (10 ml) and water (25 ml), and concentrated. The resulting solid was washed with a mixed solution of ether (9 ml)/hexane (20 ml) and successively with hexane (10 ml), and dried under vacuum to obtain N-(4-nitrobenzenesulfonyl)benzhydrylamine (3.81 g; yield: 91.3%).
Reaction SMILES: [CH3:1][S-:2].[Na+].[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([C@@H:16]2[CH2:18][O:17]2)[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].O>C1COCC1>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([C@@H:16]([OH:17])[CH2:18][S:2][CH3:1])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H]2CO2)C1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
Sodium methyl mercaptide (296 mg, 4.2 mmol) was dissolved in THF (1.0 mL), and the mixture was stirred for 10 minutes at room temperature. (S)—(R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (300 mg, 1.41 mmol) was dissolved in THF (0.4 mL) and added to the mixture. The resulting solution was placed in a microwave reactor for 30 minutes at 100° C., then cooled to room temperature. Hexanes (3×10 mL) was added, followed by water (10 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in hexanes) to yield the title compound as a clear oil (207 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[N:4][CH:3]=1.C[N:12]1C(=O)CCC1.ClC(OCC(C)C)=O.[NH4+].[OH-]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:12])=[O:10])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Cl)n1
Reactant: CN1CCCC1=O
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1cncc(Cl)n1
Temperature: -20 °C
Yield: 33.7 %

Procedure:
A solution of 6-chloro-pyrazine carboxylic acid (2.00 g, 12.62 mmol) in DMF (7 mL) was cooled to −40° C. NMP (2.77 mL, 25.23 mmol) and isobutyl chloroformate 3.27 mL, 25.23 mmol) were added. The temperature was allowed to increase to −20° C. during 20 min and then NH4OH was added. A precipitate was rapidly formed and after 15 min it was filtered off and washed with water. Crystallization from EtOH gave the title compound (670 mg, 34%) as light-brown needles.