Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:22])([F:21])[C:4]1[C:19]([Cl:20])=[CH:18][C:7]2[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=1.[CH3:23][C:24]([CH3:28])(O)[C:25]#[N:26].[O:29]1[CH2:34]CC(=O)C[CH2:30]1.CC(N(C)C)=O>C(OCC)(=O)C.O>[Cl:20][C:19]1[C:4]([C:3]([F:21])([F:2])[F:22])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:24]4([C:25]#[N:26])[CH2:28][CH2:34][O:29][CH2:30][CH2:23]4)[CH2:14][CH2:13]3)[C:7]=2[CH:18]=1
Reactant: O=C1CCOCC1
Reactant: CC(C)(O)C#N
Reactant: O=c1[nH]c2cc(C(F)(F)F)c(Cl)cc2n1C1CCNCC1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC1(N2CCC(n3c(=O)[nH]c4cc(C(F)(F)F)c(Cl)cc43)CC2)CCOCC1
Temperature: 60 °C

Procedure:
5-Trifluoromethyl-6-chloro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D64, 850 mg) was converted to the free base using SCX then combined with acetone cyanohydrin (400 mg), tetrahydropyran-4-one (500 mg) magnesium sulphate (1.5 g) and dimethylacetamide (2.5 ml), and the mixture heated under a slow stream of argon for 18 h at 60° C. To the cooled mixture were added water and ethyl acetate. The organic layer was dried over MgSO4, filtered and evaporated, and the residue was crystallised from diethyl ether to afford the subtitle compound, 160 mg.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4](C)=[CH:3]1.O=O.[O:13]=[O+][O-].[OH2:16]>>[CH3:7][C:6]([CH3:8])([CH2:9][C:2](=[O:1])[CH3:3])[CH2:5][C:4]([OH:13])=[O:16]
Reactant: O
Reactant: O=[O+][O-]
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: O=O
Product: CC(=O)CC(C)(C)CC(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of 15.8 g of isophorone in 110 ml of water was cooled down to 0° C. Then a stream of oxygen which contains about 4 percent of ozone was introduced until the suspension was saturated with ozone. The entire matter was now heated to 95° C. and was boiled for 3 hours under reflux. The 3,3-dimethyl-5-oxo-hexanoic acid was subsequently isolated by evaporation of water under vacuum.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[CH:16]=[CH:15]2.C(N(CC)CC)C>O1CCCC1>[CH3:21][N:17]1[C:18]2[C:14](=[CH:13][C:12]([NH:11][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cn1ccc2cc(N)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1ccc2cc(NC(=O)Oc3ccccc3)ccc21
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
To a solution of phenyl chloroformate (2.21 ml; 17.4 mM) in dry tetrahydrofuran (30 ml), cooled in a carbon tetrachloride/solid carbon dioxide bath, was added 5-amino-1-methylindole (D3) (2.31 g; 15.8 mM) followed by triethylamine (2.40 ml; 17.4 mM). The mixture was stirred for 45 min at -20° C. (bath temp.), then evaporated and the residue was dissolved in ethyl acetate, washed with brine, dried and evaporated to give the title compound (4.29 g; 100%), m.p. 103°-107° C. (EtOAc/petrol).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[Br:13]Br.O>C(O)(=O)C>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([Br:13])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: BrBr
Reactant: NC(=O)Nc1sccc1C(N)=O
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1sc(Br)cc1C(N)=O
Reaction time: 1.5 h

Procedure:
2-[(Aminocarbonyl)amino]-3-thiophenecarboxamide (1.0 g) was dissolved in acetic acid (20 ml) and a solution of bromine (0.35 ml) in acetic acid (5 ml) was added over 5 minutes with rapid stirring. The mixture was stirred for 90 minutes and then added to water (50 ml). The product was filtered off and washed with water and dried under vacuum (0.55 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[N:28]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1.[NH2:57][CH:58]1[CH:63]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[CH:65]=2)[CH2:62][CH2:61][N:60]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH2:59]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([NH:57][CH:58]3[CH:63]([C:64]4[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[CH:65]=4)[CH2:62][CH2:61][N:60]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH2:59]3)=[O:36])[CH:33]=2)[N:28]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2)C(N)C1
Reactant: O=C(O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2)C(NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate (HATU) (88 mg, 0.231 mmol) was added to a suspension of 3-bromo-1-trityl-1H-indazole-5-carboxylic acid (100 mg, 0.21 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of tert-butyl 3-amino-4-(3-fluorophenyl)piperidine-1-carboxylate (62 mg, 0.21 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [CH:1](/[C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=[N:14][C:13]=2[NH2:23])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=[N:14][C:13]=2[NH2:23])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc2ccccc2c2cc(/C=C/c3ccccc3)cnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nc2ccccc2c2cc(CCc3ccccc3)cnc12
Reaction time: 3 h

Procedure:
To a solution of (E)-2-styrylbenzo[f][1,7]naphthyridin-5-amine (Example 32) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacua and the crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-phenethylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (CDCl3): δ 8.54 (d, 1H), 8.32 (d, 1H), 8.10 (dd, 1H), 7.63 (dd, 1H), 7.51 (m, 1H), 7.03-7.32 (m, 6H), 6.16 (bs, 2H), 3.11 (t, 2H), 2.97 (t, 2H). LRMS [M+H]=300.1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.CN[C@@H]1CCCC[C@H]1NC.[CH3:41][OH:42]>[Cu]I>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([O:42][CH3:41])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Reactant: CO
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Product: COc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cn1
Temperature: 150 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (Example 1, 0.060 g, 0.14 mmol) in 2 mL of methanol under an atmosphere of nitrogen was added trans-N,N′-dimethylcyclohexane-1,2-diamine (6.0 mg, 0.042 mmol) and copper(I) iodide (6.0 mg, 0.033 mmol). The mixture was heated at 150° C. for 15 h in a sealed pressure vessel, cooled to rt, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 417.0 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 9.41 (s, 1H), 8.68 (s, 1H), 8.60-8.54 (m, 1H), 8.36-8.28 (m, 2H), 8.09 (s, 1H), 8.05 (s, 1H), 7.40-7.38 (m, 1H), 6.66 (d, J=8.3 Hz, 1H), 4.58 (br s, 1 H), 4.47 (s, 2H), 4.09 (br s, 1H), 3.90 (s, 3H), 2.61 (br s, 1H), 2.30-2.27 (m, 1H), 2.05-1.92 (m, 4H), 1.40-1.32 (m, 2H).
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[O:13]=[C:14]1[C:20]2[S:21][CH:22]=[CH:23][C:19]=2[CH:18]([NH2:24])[CH2:17][CH2:16][CH2:15]1.[CH2:25]([NH2:28])[C:26]#[CH:27]>C(Cl)Cl>[CH2:25]([NH:28][C:1]([NH:24][CH:18]1[C:19]2[CH:23]=[CH:22][S:21][C:20]=2[C:14](=[O:13])[CH2:15][CH2:16][CH2:17]1)=[O:2])[C:26]#[CH:27]
Reactant: NC1CCCC(=O)c2sccc21
Reactant: C#CCN
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: C#CCNC(=O)NC1CCCC(=O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sample of 11 grams of carbonyl diimidazole in 50 ml. of methylene chloride is stirred and an equivalent amount of 5,6,7,8-tetrahydro-8-oxo-4H-cyclohepta[b]thiophen-4-amine in 50 ml. of methylene chloride is added. After one hour, 3.74 grams of propargylamine in 50 ml. of methylene chloride is added. The mixture is stirred at room temperature for 3 hours and the title compound is collected by filtration.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5](=[O:40])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([O:29]COCCOC)=[C:21]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:20]=2)=[O:18])=[CH:8][CH:7]=1)[CH3:2].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:41])[C:5](=[O:40])[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[C:23]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:22]([OH:29])=[C:21]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:20]=2)=[O:18])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(OCCCCC(=O)c2cc(C(C)(C)C)c(OCOCCOC)c(C(C)(C)C)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(=O)c1ccc(OCCCCC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 31 h
Yield: 78.8 %

Procedure:
4-Hydroxy-alpha-oxobenzeneacetic acid ethyl ester (1.44 g) and 55% sodium hydride (0.36 g) in dimethylformamide (30 mL) was stirred for 20 minutes and then treated with 5-bromo-1-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy) methoxy]phenyl]pentanone (3.4 g) in dimethylformamide (6 mL). The mixture was stirred at room temperature for 20 hours and then after an additional 4 hours at 50° C., it was worked up as in Example 20. The residual oil was purified by HPLC (ethyl acetate-toluene; 1:17) to give 2.7 g of 4-[5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy) methoxy]phenyl]-5-oxopentyloxy]-alpha-oxobenzeneacetic acid ethyl ester as an oil. A solution of the above 4-[5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy) methoxy]phenyl]-5-oxopentyloxy]-alpha-oxobenzeneacetic acid ethyl ester (2.1 g) was dissolved in dichloromethane (20 mL) containing trifluoroacetic acid (1.1 mL) was stirred at room temperature for 31 hours, then saturated sodium bicarbonate solution was added (25 mL). The separated organic layer was dried (MgSO4) and evaporated and the crude product was purified by HPLC (ethyl acetate-hexane; 4:21). Trituration of the resulting material with hexane afforded 1.4 g of 4-[5-[3,5-bis(1,1-dimethylethyl) -4-hydroxyphenyl]-5-oxopentyloxy]-alpha-oxobenzeneacetic acid ethyl ester, mp 95°-96° C.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]2[NH:14][C:13]3[C:18](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20][C:12]=3[C:11]=2[CH:10]=1)C1C=CC=CC=1.C(OCC)(=O)C.C(O)=O>[Pd].C(N(CC)CC)C>[OH:8][C:9]1[CH:17]=[CH:16][C:15]2[NH:14][C:13]3[CH:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20][C:12]=3[C:11]=2[CH:10]=1
Reactant: CCOC(=O)C=C1CCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Temperature: 50 °C
Reaction time: 0.03 h
Yield: 49.7 %

Procedure:
The E/Z mixture of ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate (7.5 g, 21.59 mmol) and 10% Pd/C (50% wet; 1.13 g, 10.58 mmol) were taken up in ethyl acetate (60 mL, 613 mmol). The suspension was degassed 3× with N2 and followed with pre-activation of the catalyst with the addition of formic acid (2.48 mL, 64.8 mmol). The mixture was allowed to stir for 1-2 min. Triethylamine (9.03 mL, 64.8 mmol) was charged portion-wise maintaining the temperature <35° C. Upon complete addition of triethylamine, the mixture was stirred for about 5-10 minutes followed with heating to 50° C. The reaction progression was followed by HPLC to monitor the complete consumption of starting material (i.e., E/Z mixture of ethyl 2-(7-benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate) and the debenzylated intermediate. Approximately after 4 h at 50° C., the solution was cooled to about 20° C., the Pd/C was removed via vacuum filtration and rinsed with ethyl acetate (30 mL). To the filtrate was added water (75 mL) and the biphasic mixture was partitioned. The organics were washed with water (2×60 mL), concentrated under vacuum with a bath temp of 40° C. to a minimum stir volume, chased with ethyl acetate (1×37.5 mL) and further concentrated under vacuum to a minimum stir volume. Ethyl acetate (11 mL) was charged to the crude mixture and the resulting solution was heated to 60° C. Heptanes (34 mL) were charged maintaining the internal temperature at 60° C. The solution was slowly cooled to 10° C. and held for 30 min. The slurry was filtered, the filter cake rinsed with heptanes (2×52.5 mL) and the solids dried in the vacuum oven set to 40° C. to afford the title compound (2.78 g, 74.5% yield) as light beige solids.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]2[C:15](=[O:16])OC(C)(C)OC2=O)=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]=[CH:9][CH:10]=[C:15]2[OH:16]
Reactant: CC1(C)OC(=O)C(=CNc2ccc(Cl)nc2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Oc1ccnc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
To the heated Dowtherm A (200 mL) at 200° C. was added 5-((6-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.5 g, 12.4 mmol) and then stirred for additional 5 min. After cooling to r.t., PE was added. The precipitate was collected, and dried in vacuo to afford 6-chloro-1,5-naphthyridin-4-ol as off-white solid in 42% yield (0.94 g). m/z 183 (M+H)+
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C:6]1([S:12](Cl)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([CH3:29])[C:23]=1[S:24][CH2:25][N+:26]([O-:28])=[O:27])[NH2:20].O>O1CCCC1>[CH3:29][C:22]1[CH:21]=[C:19]([NH:20][S:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:14])=[O:13])[CH:18]=[C:17]([CH3:16])[C:23]=1[S:24][CH2:25][N+:26]([O-:28])=[O:27]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N)cc(C)c1SC[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)cc(C)c1SC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.7 %

Procedure:
0.75 g (7.49 mmol) of calcium carbonate and then 1.0 g (5.66 mmol) of benzenesulphonyl chloride are added to a solution, maintained under a nitrogen atmosphere, of 0.80 g (3.77 mmol) of 3,5-dimethyl-4-[(nitromethyl)thio]aniline in 30 ml of anhydrous tetrahydrofuran. After stirring for 3 days at room temperature, the reaction medium is poured into water and extracted with methylene chloride. The combined organic extracts are washed with water, dried over sodium Sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) to give 0.9 g (68%) of N-[3,5-dimethyl-4-[(nitromethyl)thio]phenyl]benzenesulphonamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1.[C:12]([N:19]1[CH:23]=NC=N1)(N1C=NC=N1)=[O:13].NC1[CH:39]=[CH:38][C:28]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=2)=[CH:27][C:26]=1[F:40].C(Cl)Cl>ClCCCl.CCOC(C)=O>[C:8]([C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH:1][C:12]([NH:19][C:23]2[CH:39]=[CH:38][C:28]([O:29][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=3)=[CH:27][C:26]=2[F:40])=[O:13])[CH:3]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: N#Cc1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: O=C(n1cncn1)n1cncn1
Reactant: CC(C)(C)c1cc(N)ncn1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(C#N)c3)cc2F)ncn1
Temperature: 65 °C
Reaction time: 72 h
Yield: 52.4 %

Procedure:
To a solution of 6-amino-4-tert-butylpyrimidine (150.0 mg; 0.99 mmol) in anhydrous 1,2-dichloroethane (1.9 mL) was added 1,1′-carbonyldi(1,2,4-triazole) (195.4 mg, 1.19 mmol, 1.2 eq), and the reaction mixture was stirred at 65° C. for 3 days. A solution of 4-(4-amino-3-fluorophenoxy)pyridine-2-carbonitrile (227.4 mg; 0.99 mmol, 1.0 eq) in anhydrous 1,2-dichloroethane (1.9 mL) was then added, and the reaction mixture was heated at 65° C. for 5 h. The reaction was diluted with EtOAc, and the organic layer was washed with water and brine, dried over sodium sulfate, and evaporated under reduced pressure to give a crude oil. Trituration from DCM afforded the title compound (211 mg, 52%) as a white solid. 1H-NMR (DMSO-d6) δ 10.37 (broad s, 1H), 10.08 (broad s, 1H), 8.75 (d, J=1.2 Hz, 1H), 8.59 (d, J=5.4 Hz, 1H), 8.25 (t, J=9.3 Hz, 1H), 7.73 (d, J=2.7 Hz, 1H), 7.59 (s, 1H), 7.37 (dd, J=12.0, 2.7 Hz, 1H), 7.24 (dd, J=5.4, 2.4 Hz, 1H), 7.08 (ddd, J=9.0, 2.7, 1.5 Hz, 1H), 1.26 (s, 9H); LC-MS m/z 407 [M+H]+, RT=3.17 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH:26]([OH:28])[CH3:27])[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:30](OC(=O)C)(=[O:32])[CH3:31]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:30]([O:28][CH:26]([C:23]1[S:24][CH:25]=[C:21]([C:19](=[O:20])[NH:18][C@@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=3[CH3:29])=[N:11]2)[N:22]=1)[CH3:27])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(C(C)O)n3)n2)ccc(C#N)c1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)cs1
Temperature: 0 °C
Yield: 80 %

Procedure:
N—((S)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxyethyl)thiazole-4-carboxamide (0.1 g, 0.233 mmol) and DMAP (2.87 mg, 0.023 mmol) were added into a flask under nitrogen atmosphere. Pyridine was added, the mixture cooled to 0° C. and acetic anhydride (0.023 ml, 0.244 mmol) was added dropwise. The mixture was slowly heated to RT and stirred. After 2.5 h the mixture was evaporated. The product was purified with Flash-chromatography. Yield 80%. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 1.59 (dd, 3H), 2.15 (d, 3H), 2.56 (d, 3H), 4.33 (dd, 1H), 4.43 (dd, 1H), 4.60 (m, 1H), 6.03-6.11 (m, 1H), 6.43 (d, 1H), 7.50-7.58 (m, 3H), 7.77-7.88 (m, 1H), 8.05 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(=[O:10])[CH:8]=[CH2:9].[C:26]1([CH:33]=[CH:32][C:30](O)=[CH:29][CH:28]=1)[OH:27].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:23][C:30]2[CH:32]=[CH:33][C:26]([OH:27])=[CH:28][CH:29]=2)=[O:22])=[CH:19][CH:18]=1)(=[O:10])[CH:8]=[CH2:9]
Reactant: Oc1ccc(O)cc1
Reactant: C=CC(=O)OCCCCOc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CC(=O)OCCCCOc1ccc(C(=O)Oc2ccc(O)cc2)cc1
Reaction time: 0.33 h
Yield: 66.5 %

Procedure:
Oxalyl chloride (10 ml) is added at 0° C. to (2) (5 g; 19 mmol), and the mixture is stirred until the evolution of gas subsides (20 min). The excess oxalyl chloride is removed by distillation in a water-pump vacuum, the acid chloride is taken up in toluene (10 ml), the toluene solution is added at 0° C. to a solution of hydroquinone (10.5 g; 95 mmol) in pyridine (10 ml) and toluene (5 ml), and the mixture is subsequently stirred at room temperature for 24 hours. The reaction mixture is then transferred into water (200 ml), and the mixture is extracted twice with dichloromethane (50 ml each time). The organic extracts are dried using calcium chloride, hydroquinone (50 mg) is added to the filtrate, and the mixture is evaporated in a water-pump vacuum. The residue is chromatographed on silica gel (toluene/ethyl acetate (5:1), giving 4.5 g (66%) of (3).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[NH:5][N:4]=1.C(=O)(O)[O-].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19]>O>[C:8]([C:6]1[NH:5][N:4]=[C:3]([N:2]([CH3:1])[C:18](=[O:19])[O:20][CH3:21])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CNc1cc(C(C)(C)C)[nH]n1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)N(C)c1cc(C(C)(C)C)[nH]n1
Yield: 64.2 %

Procedure:
70 g of 3-(N-methylamino)-5-t-butylpyrazole as prepared in Reference Example was dissolved in 1.5 l of water together with 46 g of sodium bicarbonate, and 52 g of methyl chloroformate was added dropwise to the aqueous solution over 1.5 hours at 10° C. The mixture was allowed to react at 10° C. for 1 hour. After completion of the reaction, the solid product was collected by filtration, washed with water and hexane and dried to obtain 62 g of methyl N-(5-tert-butyl-3-pyrazolyl)-N-methylcarbamate.
Reaction SMILES: [F:1][CH:2]1[CH2:5][NH:4][CH2:3]1.[CH3:6][N:7]1[C:11]([C:12](=[O:29])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:22]=3)[CH:19]=2)=[C:10]([C:30](O)=[O:31])[CH:9]=[N:8]1>>[N:23]1([C:21]2[N:22]=[C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:12]([C:11]4[N:7]([CH3:6])[N:8]=[CH:9][C:10]=4[C:30]([N:4]4[CH2:5][CH:2]([F:1])[CH2:3]4)=[O:31])=[O:29])=[CH:19][N:18]3[N:20]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: FC1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Product: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1

Procedure:
Using 3-fluoro-azetidine and 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Off-white solid (150 mg, 76%). MS: m/z=429 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](CCCO)=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:19].[CH3:20][CH2:21][CH2:22]CCC>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:21]([Cl:19])([CH3:22])[CH3:20])[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCc1ccccc1OCc1ccccc1
Reactant: CCCCCC
Reactant: Cl
Product: CC(C)(Cl)c1cccc(OCc2ccccc2)c1

Procedure:
A mixture of 200 g. (0.826 mole) of 3-benzyloxybenzene-2-propanol in 50 ml. of hexane and 1 l. of concentrated hydrochloric acid is shaken for 15 minutes in a 2 l. separatory funnel. The organic layer is removed and washed with saturated sodium bicarbonate. The neutralized organic extract is dried over magnesium sulfate and evaporated to give a quantitative yield of the title compound as an oil.