Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:2]2[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1NC2CCC1C2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1C2CCC(C2)N1S(=O)(=O)c1ccc(OC)cc1
Yield: 69.7 %

Procedure:
To a solution of ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (664 mg, 3.92 mmol) in chloroform (8 ml) were added triethylamine (0.55 ml, 3.92 mmol) and 4-methoxybenzene sulfonyl chloride (892 mg, 4.32 mmol) while being cooled with ice. After a reaction at room temperature for 4 hours, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized (hexane/ethyl acetate), to give ethyl 2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (927 mg, 70%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:14][CH:13]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cccnc1Cl
Product: O=C(O)c1cccnc1NCc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of 2-chloronicotinic acid (30.0 g) and 4-chlorobenzylamine (45 ml) was heated at 120° C. for 3.5 hours. The mixture was cooled to ambient temperature and the solid obtained was washed with water and collected by filtration. The solid was boiled in methanol and filtered to give 2-(4-chlorobenzylamino)-nicotinic acid, m.p. 240°-242° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[NH:5][C:6]2[NH:7][CH2:8][CH:9]([CH:15]([OH:19])[CH:16]([OH:18])[CH3:17])[NH:10][C:11]=2[C:12](=[O:14])[N:13]=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>N1C=CC=CC=1>[CH2:24]([O:23][C:21]([N:10]1[CH:9]([CH:15]([OH:19])[CH:16]([OH:18])[CH3:17])[CH2:8][NH:7][C:6]2[NH:5][C:4]([NH2:3])=[N:13][C:12](=[O:14])[C:11]1=2)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.6 %

Procedure:
2-Amino-6-(1,2-dihydroxy-propyl)-5,6,7,8-tetrahydro-1H-pteridin-4-one dihydrochloride (1.63 g, 5.2 mmol) was dissolved in 50 mL of pyridine under a nitrogen atmosphere. To this solution was added benzyl chloroformate (1.93 ml, 13.5 mmol). The reaction mixture was degassed under vacuum and placed under an atmosphere of nitrogen. The mixture was stirred for 12 h at room temperature. The solvent was evaporated in vacuo and the residue purified by preparative RP-HPLC to give the sub-titled compound as a white solid (0.93 g, 48% yield). 1H NMR (DMSO-d6) δ 10.02 (s, 1H), 7.41-7.30 (m, 5H), 6.84 (s, 1H), 6.12 (s, 2H), 5.10-4.99 (m, 2H), 3.93 (d, J=6.0 Hz, 1H), 3.66 (dd, J=2.4 Hz, J=6.3 Hz, 1H), 3.56 (dd, J=4.8 Hz, J=12 Hz, 1H), 3.25 (d, J=10.5 Hz, 1H), 3.03 (dd, J=4.5 Hz, J=12.4 Hz, 1H), 1.26 (d, J=6.3 Hz, 1H). MS: ESI (positive): 376 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](O)=[C:8]([C:11]#[N:12])[CH:7]=[N:6][N:5]2[CH:13]=1.O=P(Cl)(Cl)[Cl:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([Cl:16])=[C:8]([C:11]#[N:12])[CH:7]=[N:6][N:5]2[CH:13]=1
Reactant: N#Cc1cnn2cc(Br)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnn2cc(Br)cc2c1Cl
Temperature: 75 °C
Yield: 47.7 %

Procedure:
To a 25 mL round bottom flask was added 6-bromo-4-hydroxypyrrolo [1,2-b]pyridazine-3-carbonitrile (16.5 g, 69.47 mmol) and POCl3 (85 mL, 0.88 mol) and the reaction mixture was stirred and heated at 75° C. for 3 hours. The POCl3 was removed under vacuum and the resulting residue was dissolved in CH2Cl2. The solution was cooled to 0° C. and saturated aq. NaHCO3 solution was added and the biphasic mixture was stirred vigorously while allowing to warm to rt. The organic layer was separated and concentrated and the obtained residue was purified by flash silica gel column chromatography to yield 8.5 g (29%) of the title compound as a yellow solid. HPLC (condition P): retention time=16.74 min. 1H NMR (400 MHz, CDCl3) δ ppm: 8.09 (1H, s), 7.94 (1H, d, 2.0 Hz), 7.06 (1H, d, 2.0 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH3:23])=[O:21])=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31]>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([S:32]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][CH2:3][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:19][CH:18]=3)[CH:14]=[C:15]2[C:20]([O:22][CH3:23])=[O:21])(=[O:33])=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 55.7 %

Procedure:
Sodium Hydride (60% dispersion, 444 mg) was added to a stirred solution of methyl 5-benzyloxyindole-2-carboxylate (2.08 g) in DMF (50 ml) at room temperature. After 1 hour, 3,4-dichlorobenzenesulphonyl chloride (2.72 g) was added. Stirring was continued for 2 hours after which the reaction mixture was partitioned between water and ethyl acetate. Combined organic extracts were dried and concentrated in vacuo and the residue purified by column chromatography using isohexane-20% ethyl acetate as eluent to give the desired product as a white solid (2.02 g, 56%). NMR: δ3.85 (s, 3H), 5.1 (s, 2H), 7.2 (m, 1H), 7.4 (m, 7H), 7.9 (s, 2H), 8.0 (d, 1H), 8.2 (s, 1H); m/z 489.8 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].[CH2:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)[CH3:37]>>[CH2:36]([N:38]1[CH2:39][CH2:40][N:41]([C:44]2[CH:50]=[CH:49][C:47]([NH:48][C:32]3[C:27]4[S:26][CH:25]=[C:24]([C:22]([NH:21][C:3]5[CH:4]=[C:5]([C:8](=[O:20])[NH:9][C:10]6[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=6)[CH:6]=[CH:7][C:2]=5[CH3:1])=[O:23])[C:28]=4[N:29]=[CH:30][N:31]=3)=[CH:46][CH:45]=2)[CH2:42][CH2:43]1)[CH3:37]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Product: CCN1CCN(c2ccc(Nc3ncnc4c(C(=O)Nc5cc(C(=O)Nc6cccc(C(F)(F)F)c6)ccc5C)csc34)cc2)CC1

Procedure:
The procedure of Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and 4-(4-ethylpiperazine-1-yl)aniline to obtain the title compound (see Table 1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19](Br)[C:18]([CH:22]=O)=[C:17]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:38][NH2:39]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19]2[NH:38][N:39]=[CH:22][C:18]2=[C:17]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:25]2)[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(Br)c2C=O)C1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc3[nH]ncc23)C1
Temperature: 90 °C
Reaction time: 15 h
Yield: 23 %

Procedure:
To a stirred solution of tert-butyl 3-{6-[2-(benzyloxy)phenyl]-2-bromo-3-formyl-4-pyridinyl}-1-piperidinecarboxylate (0.150 g, 0.272 mmol) in 1,4-dioxane (1 mL) was added hydrazine monohydrate (0.5 mL). The reaction mixture was stirred at 90° C. for 15 hrs. After cooled to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give tert-butyl 3-{6-[2-(benzyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-1-piperidinecarboxylate as a white solid (0.030 g, 23%). Then tert-butyl 3-{6-[2-(benzyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-1-piperidine-carboxylate was treated in a similar manner as that of the step (2) of Example 1-1 and then the step (3) of Example 1-1 to obtain 2-(4-Piperidin-3-yl-1H-pyrazolo[3,4-b]pyridin-6-yl)-phenol hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[OH-].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccccc1C(=O)Nc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A 9.1 g (0.04 mol) portion of 3'-hydroxy-2-methylbenzanilide was dissolved in a solution of 2.3 g (0.041 mol) of potassium hydroxide in 50 ml of ethanol, and 5.1 g (0.04 mol) of benzylchloride was added dropwise to the above solution with stirring at room temperature. After the addition, the reaction mixture was warmed and refluxed for 3 hours. The reaction mixture was poured into 200 ml of water and the precipitated product was filtered and washed with water and dried. The product was recrystallized from 90% methanol to obtain 7.5 g (60.5%) of white needles having a melting point of 114°-115° C.
Reaction SMILES: [CH2:1]([O:7][CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[C:25]1([C:31](=[O:35])[C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:1]([O:7][CH:8]1[CH2:9][C:10]([CH3:16])([CH3:17])[N:11]([C:32](=[O:33])[C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:35])[C:12]([CH3:15])([CH3:14])[CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOC1CC(C)(C)NC(C)(C)C1
Reactant: O=C(Cl)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCOC1CC(C)(C)N(C(=O)C(=O)c2ccccc2)C(C)(C)C1
Temperature: -10 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
24.1 g (0.1 mole) of 4-hexyloxy-2,2,6,6-tetramethylpiperidine are dissolved in 100 ml of absolute methylene chloride. To this solution are added 15.2 g (0.15 mole) of absolute triethylamine and the whole solution is cooled to -10° C. At this temperature a solution of 16.8 g (0.1 mole) of phenylglyoxylyl chloride in 100 ml of methylene chloride is slowly added dropwise. When this addition is complete, the reaction mixture is allowed to warm to room temperature and stirred for about 4 hours. Precipitated hydrochloride is removed by filtration and the solution is clarified by filtration over a small amount of silica gel and concentrated by evaporation, affording 28.4 g of 1-(4-hexyloxy-2,2,6,6-tetramethylpiperidino)-2-phenyl-ethane-1,2-dione as a yellow oil (stabiliser 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]=[CH2:16])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:23]([CH2:24][C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:32])[CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CO>[CH2:14]([N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:12][N:11]([CH2:18][C:19]2[N:23]([CH2:24][C:25]3[C:26]([Cl:32])=[CH:27][CH:28]=[CH:29][C:30]=3[Cl:31])[CH:22]=[N:21][CH:20]=2)[C:10]1=[O:13])[CH:15]=[CH2:16]
Reactant: ClCc1cncn1Cc1c(Cl)cccc1Cl
Reactant: C=CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(Cc2cncn2Cc2c(Cl)cccc2Cl)c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
41 mg (0.17 mmol) of the compound from Example 12A were dissolved in 2 ml of DMF, and 48 mg (0.17 mmol) of the compound from Example 40A and 85 mg (0.26 mmol) of cesium carbonate were added. The mixture was stirred at 80° C. for 16 h. After cooling to RT, the reaction mixture was diluted with 1 ml of methanol and directly purified chromatographically [Method 19]. This gave 4 mg (5% of theory) of the target compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].C(N(CC)CC)C.[CH2:19]([O:21][C:22](=[O:34])[C:23](=[CH:30]OCC)[C:24]([C:26]([F:29])([F:28])[F:27])=O)[CH3:20]>C(O)C>[F:27][C:26]([F:28])([F:29])[C:24]1[N:10]([C:4]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=2[Cl:2])[N:11]=[CH:30][C:23]=1[C:22]([O:21][CH2:19][CH3:20])=[O:34]
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Temperature: -10 °C
Reaction time: 8 h

Procedure:
2,4-Dichlorophenylhydrazine hydrochloride salt (15.68 grams, 0.068 mole) was dissolved in a minimum amount of ethanol and the solution was cooled to -10° C. Triethylamine (9.44 ml, 0.068 mole) was added followed by ethyl(ethoxymethylene)trifluoroacetoacetate (16.27 grams, 0.068 mole). The addition of this last reactant was made over thirty minutes, keeping the reaction temperature below -10° C. The reaction mixture was allowed to rise to room temperature overnight (about 16 hours). The solvent was removed in vacuo and the residue was dissolved in equal parts of ethyl acetate and water. The organic phase was separated, washed with 1N HCl, water, saturated sodium bicarbonate solution, water, and brine. It was then dried and evaporated to 7.85 grams of an oil which slowly crystallized. The 5-(trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester, was recrystallized from petroleum ether, mp=81°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[N+:17]([O-])=O)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH2:17])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
N-(4-Chlorophenyl)-5-chloro-2-nitrobenzamide (13.2 g, 42.4 mmol) and tin(II) chloride dihydrate (48 g, 213 mmol) were combined in ethyl acetate (90 mL) and the mixture was heated at 70° C. under a nitrogen atmosphere. After 15 minutes, the mixture was cooled to ambient temperature, then poured onto water (750 mL) and ethyl acetate (750 mL). The aqueous layer was adjusted to pH 8 with by addition of 1 N NaOH and a saturated NaHCO3 solution, and the layers were separated. The aqueous layer was further extracted with 500 mL of ethyl acetate. The combined organic extracts were washed with water (1 L), then brine (500 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 11.6 g (97% yield) of N-(4-chlorophenyl)-2-amino-5-chlorobenzamide as an bite solid; NMR (CDCl3) 7.7 (br s, 1), 7.2-7.5 (m, 6), 6.7 (d, 1), 5.5 (br s, 2) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[CH:3]=1.[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]2[CH:30]=[C:25]([OH:24])[CH:26]=[CH:27][CH:28]=2)[CH:3]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(C(F)(F)F)cc2F)n1
Reactant: OB(O)c1cccc(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(O)c2)n1
Reaction time: 15 h
Yield: 116.9 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine [1.47 g, 4.2 mmol, see Example 52, step 1], (3-hydroxy-phenyl)-boronic acid, (637 mg, 4.62 mmol), and Cs2CO3 (3.4 g, 10.5 mmol) in ethylene glycol dimethyl ether (20 mL) and water (4 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium(0) (243 mg, 0.21 mmol) at room temperature. After 15 h at 85° C., the mixture is diluted with water (50 mL), and extracted with EtOAc (2×50 mL). The extracts are dried (MgSO4), filtered through a pad of SiO2, and concentrated to afford 3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenol (2 g). LCMS: RT=2.32 minutes; MS: 408 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([O:16][CH3:17])=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].C[O-].[Na+].[CH:24](OCC)=O.Cl>COCCOC.O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:18]([OH:20])=[CH:19][CH:24]=[N:1]2)=[CH:4][C:5]=1[O:16][CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of 1-(2-Amino-4-benzyloxy-5-methoxy-phenyl)-ethanone (108 mmol, 29.3 g) in DME (700 ml) was added sodium methoxide (432 mmol, 23.35 g). The mixture was stirred for 30 minutes. Ethyl formate (540 mmol, 44 ml) was added and the mixture was stirred overnight. (Additional sodium methoxide may be needed if reaction is not complete as monitored by LC/MS.) After the reaction was completion, the mixture was diluted with water (40 ml) and acidified to neutral with 1M HCl. The precipitate was filtered and washed with water, dried in vacuo to afford 22 g (72%) of 7-benzyloxy-6-methoxy-quinolin-4-ol. 1H NMR (CDCl3): 10.7 (1H, br), 7.703 (1H, s), 7.493-7.461 (1H, t), 7.431-7.413 (2H, br d), 7.372-7.333 (2H, t), 7.296-7.283 (1H, d), 6.839 (1H, s), 6.212-6.193 (1H, d), 5.212 (2H, s), 3.965 (3H, s). LC/MS (M+l=282).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][C:11]=2[F:22])[CH2:5][C@H:4]1[OH:23].[O:24]=[C:25]1[NH:30][C:29]2[N:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:22][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[CH2:9][CH2:8][N:6]1[CH2:5][C@H:4]([OH:23])[C@H:3]([CH2:2][NH:1][CH2:35][C:32]3[CH:33]=[CH:34][C:28]4[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=4[N:31]=3)[CH2:7]1)=[N:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H](CN)[C@H](O)C3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@@H](O)C3)c2n1
Reaction time: 24 h
Yield: 66.9 %

Procedure:
To a stirred solution of (±)-cis-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.23 g, 0.72 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.14 g, 0.72 mmole). After 24 h, at RT was added NaBH(OAc)3 (0.23 g, 1.08 mmole). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.24 g, 66%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 4.21 (s, 2H), 4.12 (s, 3H), 3.52 (m, 4H), 3.33 (s, 4H), 3.21 (m, 2H), 3.09 (m, 2H), 2.98 (m, 2H). LC-MS (ES) m/e 499 (M+H)+.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[NH:19])[S:15][CH:16]=1)SC)#[N:2].[CH2:21]([NH2:24])[C:22]#[CH:23]>CO>[C:1]([NH:3][C:4]([NH:24][CH2:21][C:22]#[CH:23])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[NH:19])[S:15][CH:16]=1)#[N:2]
Reactant: CSC(=NCCSCc1csc(NC(=N)N)n1)NC#N
Reactant: C#CCN
Solvent: CO
Product: C#CCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N

Procedure:
A mixture of N-cyano-N'-{2-[(2-guanidinothiazol-4-yl)methylthio]ethyl}-S-methylisothiourea [prepared according to the procedure described in South Africa Pat. No. 78/2129] (3.0 g; 9.11 mmoles) and propargylamine (6.0 ml) in methanol (15 ml) was stirred and heated at reflux temperature under a positive pressure of nitrogen for 20 hours. The reaction mixture was evaporated under reduced pressure and the residue triturated with isopropanol and filtered to give product (1.5 g). Recrystallization from nitromethane gave the title compound, mp 146°-148°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C[Al](C)C.[CH3:13][C:14]1[N:18]=[C:17]([CH3:19])[N:16]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([C@@H:27]3[CH2:29][C@H:28]3[C:30](OCC)=O)[CH:21]=2)[N:15]=1>C1(C)C=CC=CC=1>[CH3:13][C:14]1[N:18]=[C:17]([CH3:19])[N:16]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([C@@H:27]3[CH2:29][C@H:28]3[C:30]3[S:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[N:1]=3)[CH:21]=2)[N:15]=1
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(C)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1nc([C@@H]2C[C@H]2c2nc3ccccc3s2)cc(-n2nc(C)nc2C)n1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
To 2-aminobenzenethiol (24.0 mg, 0.19 mmol, 1.1 eq.) dissolved in anhydrous toluene (5.0 mL) was added trimethylaluminium (2.0 M in toluene, 0.25 mL, 0.50 mmol, 3.0 eq.) under nitrogen at 0° C. dropwise. The reaction was stirred at a temperature between 10° C. to 20° C. for 30 minutes followed by the addition of ethyl trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropanecarboxylate (2-1) (50.0 mg, 0.165 mmol, 1.0 eq.) and the reaction was heated to 130° C. for 24 hours. The reaction was cooled to room temperature and quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrate to dryness. The resulting residue was purified by silica gel column chromatography (10-40% ethyl acetate in toluene) to afford trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropyl)benzo[d]thiazole (2-2) as a yellow glue. 1H NMR (300 MHz, CDCl3) δ 7.92 (br d, 1H, J=8.0 Hz), 7.81 (m, 1H), 7.64 (br s, 1H), 7.45 (m, 1H), 7.34 (m, 1H), 3.11 (ddd, 1H, J=9.7, 5.9, 3.9 Hz), 2.92-2.83 (m, 1H), 2.89 (s, 3H), 2.66 (s, 3H), 2.39 (s, 3H), 2.13-1.97 (m, 2H). LRMS m/z (M+H+) 363 found, 363 required.