Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1C=C2[C:16](=[CH:17][CH:18]=1)C=C(N1C=CC=[CH:21][C:20]1=[O:25])C=C2.[CH3:26][CH2:27]N(CC)CC>>[CH3:26][CH2:27][O:25][CH2:20][CH3:21].[CH3:7][CH2:8][CH2:9][CH2:18][CH2:17][CH3:16]
Reactant: O=c1ccccn1-c1ccc2cc(CCO)ccc2c1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Product: CCCCCC
Product: CCOCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.4 %

Procedure:
Methanesulfonyl chloride (0.01 mL, 0.136 mmol, 1.2 equiv.) was added dropwise via a syringe to a stirred, −30° C. solution of 1-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-1H-pyridin-2-one (Example 80A, 30 mg, 0.113 mmol) and Et3N (0.024 mL, 0.17 mmol, 1.5 equiv.). After two hours stirring at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous Na2CO3. The organic extract was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from Et2O/hexane (20 mg, 52% yield). This mesylate (20 mg, 0.058 mmol), (2R)-2-methylpyrrolidine (14.9 mg, 0.058 mmol, 3.0 equiv.), and cesium carbonate (19 mg, 0.058 mmol) in anhydrous acetonitrile (3.5 mL) were stirred in a sealed tube at 60° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (97:3:trace, dichloromethane/methanol/NH4OH). Fractions containing product were combined and concentrated under reduced pressure to provide the free base. This free base was dissolved in Et2O and HCl gas was bubbled in to precipitate the hydrochloride salt of the title compound. 1H NMR (CD3OD, 300 MHz) δ 8.08-7.96 (m, 2H), 7.93 (s, 2H), 7.76-7.66 (m, 2H), 7.60-7.51 (m, 2H), 6.70 (d, J=9 Hz, 1H), 6.56 (dt, J=1, 6 Hz, 1H), 3.83-3.68 (m, 2H), 3.64-3.49 (m, 1H), 3.43-3.18 (m, 4H), 2.43-2.30 (m, 1H), 2.22-2.02 (m, 2H), 1.84-1.69 (m, 1H), 1.49 (d, J=6 Hz, 3H). MS (DCl-NH3) [M+H]+ at 333.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.N[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[C:21]([C:28]([O:30][CH3:31])=[O:29])[N:22]=[CH:23]2.[N:32]1C=CC=CC=1>>[CH3:31][O:30][C:28]([C:21]1[N:22]=[CH:23][C:24]2[C:19]([CH:20]=1)=[C:18]([C@H:4]1[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][CH:7]3[C:6](=[NH:32])[S:5]1)[CH:27]=[CH:26][CH:25]=2)=[O:29]
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: COC(=O)c1cc2c(N)cccc2cn1
Reactant: c1ccncc1
Agent: [I-]
Product: COC(=O)c1cc2c([C@@H]3SC(=N)C4Cc5ccccc5CN43)cccc2cn1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo-[3,4-b]isoquinolinium iodide (22.4 g) is added to a solution of 5-amino-3-methoxycarbonylisoquinoline (13 g) in pyridine (400 cc). The suspension gradually changes to a solution. After stirring for 3 days at a temperature of the order of 20° C., the mixture is concentrated to dryness under reduced pressure (20 m Hg; 2.7 kPa) at 60° C. The residue is dissolved in methylene chloride (500 cc) and the solution is washed with a N aqueous sodium hydroxide (3×300 cc) and then with water. The solution is dried over sodium sulphate and filtered and the filtrate is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is recrystallised from acetonitrile (500 cc). After filtration, washing with diisopropyl ether and drying, (S)-3-[(3-methoxycarbonylisoquinol-5-yl)]-imino-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinoline (12.8 g) is obtained, as a pale yellow solid, m.p.=200° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([CH:27]=[CH:26][C:25]([O:29][CH3:30])=[O:28])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2C(F)(F)F)CC1
Product: COC(=O)C=Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1

Procedure:
4-(5-Bromo-3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (a) above (3.7 g, 9.0 mmol) reacted with methyl acrylate under the conditions of Example 183d to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 316 (M−Bu+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(=O)([O-])O.[Na+].[C:12]1([CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:23]3[C:24]([NH2:27])=[N:25][O:26][C:22]=3[CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O1CCCC1>O>[C:12]1([CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:23]3[C:24]([NH:27][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[N:25][O:26][C:22]=3[CH:21]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1noc2cc(OCc3ccccc3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1noc2cc(OCc3ccccc3)ccc12
Reaction time: 18 h

Procedure:
8.8 ml (0.092 mol) of ethyl chloroformate and 10.6 g (0.126 mol) of sodium hydrogen carbonate are added to a solution of 10.1 g (0.042 mol) of 6-(phenylmethoxy)-1,2-benzisoxazol-3-amine in 100 ml of a 9:1 mixture of tetrahydrofuran and water. The mixture is stirred for 18 hours and then the solvent is evaporated off and the residue is treated with dichloromethane and water. The organic phase is decanted off, dried over sodium sulphate and concentrated under reduced pressure. After crystallization from isopropyl alcohol and recrystallization from n-butanol, 11.5 g of product are obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C(Cl)Cl>[ClH:24].[CH2:1]([N:8]([CH2:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH2:9][CH2:10][Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1[nH]cnc1CN(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1[nH]cnc1CN(CCCl)Cc1ccccc1
Product: Cl
Temperature: 44 °C
Reaction time: 8 h

Procedure:
To a solution of Intermediate 1D (0.94 g, 3.24 mmol) in DCM (30 mL) was added thionyl chloride (0.95 mL, 12.96 mmol). The resulting mixture was stirred at 44° C. overnight and allowed to cool to ambient temperature. The mixture was concentrated under reduced pressure, azeotroped with acetonitrile and dried under vacuum overnight to give Intermediate 1E in quantitative yield as a white solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)(=[O:32])=[O:31]>>[ClH:1].[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]2[N:13]([CH3:25])[C:12]3[CH:26]=[CH:27][C:9]([N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]5[CH:39]=[CH:40][C:34]([CH2:33][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:35][CH:36]=5)[N:7]=4)[CH3:28])=[CH:10][C:11]=3[N:15]=2)=[CH:19][CH:20]=1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccc(F)cc1)n2C)c1ccnc(Cl)n1
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Product: CN(c1ccc2c(c1)nc(NCc1ccc(F)cc1)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-chloro-pyrimidin-4-yl)-N2-(4-fluoro-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (99 mg, 0.25 mmol) and 4-[(methylsulfonyl)methyl]aniline (46 mg, 0.25 mmol) as a white solid (69 mg, 48%). 1H NMR (300 MHz, d6-DMSO) δ 9.20 (s, 1H), 7.76-7.80 (m, 3H), 7.41-7.46 (m, 3H), 7.23 (d, J=8.4 Hz, 3H), 7.09-7.17 (m, 3H), 6.84 (dd, J=8.4 and 1.8 Hz, 1H), 5.63 (d, J=6.0 Hz, 1H), 4.57 (d, J=5.7 Hz, 2H), 4.34 (s, 2H), 3.57 (s, 3H), 3.43 (s, 3H), 2.85 (s, 3H). MS (ESI) m/z=546 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26](C(OC(C)(C)C)=O)[N:25]=1.C(O)(=O)C>CC(N(C)C)=O>[F:21][C:13]([F:22])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:4]1[N:3]=[C:2]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(F)c3n2)nc1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(F)cccc23)n[nH]1
Temperature: 100 °C
Yield: 4 %

Procedure:
To 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoroquinazoline (295 mg, 0.90 mmol) in DMA (2.2 mL) were added tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate and acetic acid (0.12 mL), and the mixture was heated at 100° C. for 6.5 h. The mixture was allowed to cool to rt and was purified by preparative reverse-phase HPLC using an ammonium acetate modifier. A later eluting fraction was treated with saturated aq NaHCO3 and concentrated under reduced pressure. The aqueous residue was extracted with DCM (3×30 mL) and the combined extracts were washed with saturated aq NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM, whereupon a precipitate formed, which was collected by filtration to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a colorless solid (13 mg, 4%). 1H NMR (300 MHz, DMSO-d6) δ 12.23 (br s, 1H), 10.86 (br s, 1H), 8.67 (s, 1H), 8.52 (d, J=9 Hz, 1H), 8.00-8.02 (m, 2H), 7.77 (m, 1H), 7.63 (m, 1H), 5.97 (s, 1H), 2.17 (s, 3H). LCMS (ESI) m/z 389 (M+H)+.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O)(=O)CCCCCCCCCCCCCCC>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)O
Yield: 55 %

Procedure:
Using the procedure described in Example 1 and substituting therein 20 g. of a purified commercial grade of oleic acid (cis-9 -octadecenoic) acid for the palmitic acid and employing 5 g. of catalyst and adjusting the deuterium flow rate to 150 ml./minute, there is obtained after 15 days of exchange a 55% yield of stearic acid of 99 atom % D.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:10][C:11]=2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)[S:10][C:11]=2[C:12]([N:25]([O:26][CH3:27])[CH3:24])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylic acid (850 mg, 2.57 mmol) in DMF (11.9 mL) was added N,O-dimethylhydroxylamine hydrochloride (852 mg, 8.74 mmol), HATU (1.95 g, 5.14 mmol) and diisopropylethylamine (2.42 mL, 13.9 mmol) and the resulting solution was stirred at room temperature overnight. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (3×30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→80/20) to give 775 mg of the title compound as a yellow solid (80% yield). LC/MS (FA) ES+ 374. 1H NMR (400 MHz, CDCl3) δ: 8.72-8.70 (m, 2H), 7.84-7.82 (m, 2H), 7.37-7.34 (m, 2H), 7.25-7.22 (m, 2H). 4.56 (s, 2H), 3.70 (s, 3H), 3.37 (s, 3H).
Reaction SMILES: N1C=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)C=1.[NH:18]1C(B(O)O)=CC=[N:19]1>>[NH:18]1[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)=[CH:4][CH:5]=[N:19]1
Reactant: O=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Reactant: OB(O)c1ccn[nH]1
Product: O=Cc1ccc2c(-c3ccn[nH]3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of 3-(pyridin-3-yl)-1H-indazole-6-carbaldehyde, except substituting 1H-pyrazole-5-boronic acid (25 mg, 0.22 mmol), the title compound was prepared as a beige solid (5.3 mg, 13%). 1H NMR (400 MHz, CD3OD) δ ppm 10.13 (s, 1H), 8.44-8.32 (br. m, 1H), 8.14 (s, 1H), 7.78 (d, J=1.8 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H); MS ESI 213.0 (100) [M+H]+, calcd for [C11H8N4O+H]+ 213.07.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[C:9]([C:11](O)=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.Cl.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27].C(N(CC)CC)C.C1COCC1>S(Cl)(Cl)=O>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[C:9]([C:11]([NH:27][CH2:26][C:25]([F:29])([F:28])[F:24])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: NCC(F)(F)F
Reactant: Nc1ncnn2cc(C(=O)O)c(-c3ccc([N+](=O)[O-])cc3)c12
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncnn2cc(C(=O)NCC(F)(F)F)c(-c3ccc([N+](=O)[O-])cc3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
A solution 4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (495 mg, 1.73 mmol) in thionyl chloride (15 mL) was heated (50° C.) for 3 h. Upon cooling to rt the reaction mixture was concentrated to dryness. The resulting acid chloride intermediate was combined with 2,2,2-trifluoro-ethylamine hydrochloride salt (587 mg, 4.33 mmol), triethylamine (1.15 ml, 8.66 mmol), and THF (8 mL). The reaction was stirred for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and then washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was tritureated with ethyl acetate and methanol to afford the desired product (490 mg, 74%). 1H-NMR (300 MHz, DMSO-d6) 8.77 (t, J=6.2 Hz, 1H), 8.29 (s, 1H), 8.23 (d, J=8.9 Hz, 2H), 7.97 (s, 1. H), 7.59 (d, J=8.9 Hz, 2H), 3.91-3.99 (m, 2H); ES-MS m/z 381.1 (MH)+; HPLC RT (Method B) 2.33 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[C:13]([NH:14][C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)=S)=[CH:12][CH:11]=[CH:10][N:9]=1.[S]>[Hg]=O.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[N:14]=[C:15]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1
Reactant: CCOC(=O)N1CCC(NC(=S)Nc2cccnc2NCc2ccco2)CC1
Agent: O=[Hg]
Agent: [S]
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2nc3cccnc3n2Cc2ccco2)CC1
Yield: 79 %

Procedure:
A mixture of 74 parts of ethyl 4-[[[2-[(2-furanylmethyl)amino]-3-pyridinyl]aminothioxomethyl]amino]-1-piperidinecarboxylate, 96 parts of mercury (II) oxide, 0.1 parts of sulfur and 800 parts of ethanol was stirred and refluxed for 3 hours. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding 52.5 parts (79%) of ethyl 4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl ]amino]-1-piperidinecarboxylate; mp. 149.2° C. (intermediate 32).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:17]3[N:26]=[C:25]([NH:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[N:33](C(OC(C)(C)C)=O)[N:32]=[CH:31]5)[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:33]1[C:34]2[C:30](=[CH:29][C:28]([NH:27][C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[C:17]([C:13]4[CH:12]=[C:11]([NH:10][C:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[O:9])[CH:16]=[CH:15][CH:14]=4)[N:26]=3)=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: CN1CCN(C(=O)Nc2cccc(-c3nc(Nc4ccc5c(cnn5C(=O)OC(C)(C)C)c4)c4ccccc4n3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)Nc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)CC1

Procedure:
To tert-butyl 5-(2-(3-(1-methylpiperazine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (165 mg, 0.22 mmol) was added a solution of 1:1 TFA:CH2Cl2 (6 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and left under high vacuum for several hours. The crude product was purified by prep HPLC (method 25-50—70 mins) to afford N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-4-methylpiperazine-1-carboxamide. (88 mg, 69%)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CO.N>CN(C=O)C>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][S:25][CH2:24][CH2:23]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: ClCCCN1CCSCC1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CN(C)CC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Yield: 39.7 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1000 mg, 4.25 mmol), 4-(3-chloro-propyl)-thiomorpholine (764 mg, 2,13 mmol), DMF (20 ml), and K2CO3 (2.34 g, 17 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant DCM:MeOH:NH3 (95:5:1) to give the title compound (320 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 6.86 (d, 2H), 3.99 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.79-2.64 (m, 8H), 2.55 (t, 2H), 2.40 (s, 2H), 2.16-2.04 (m, 2H), 2.01-1.82 (m, 4H), 1.97 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:10][C:5]2=[CH:4][CH:3]=1.[C:15]1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]([O-:47])([O-])=[O:45].[K+].[K+]>CO.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:12]([NH:11][C:9]1[S:8][C:6]2[C:5]([N:10]=1)=[CH:4][CH:3]=[C:2]([C:44]([O:47][CH3:15])=[O:45])[N:7]=2)([CH3:14])[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: CC(C)Nc1nc2ccc(Cl)nc2s1
Reactant: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(NC(C)C)sc2n1
Temperature: 25 °C
Yield: 726.3 %

Procedure:
A solution of 5-chloro-N-isopropylthiazolo[5,4-b]pyridin-2-amine (2.06 g, 9.05 mmol, 1.0 eq.), Pd(OAc)2 (0.2084 g, 0.928 mmol, 0.1 eq.), 1,3-bis(diphenylphosphino)propane (0.3775 g, 0.915 mmol, 0.1 eq.) and K2CO3 (1.90 g, 13.7 mmol, 1.5 eq.) in MeOH (24 mL) and DMF (12 mL) was stirred under an atmosphere of CO inside a bomb (42 psi) at 92° C. overnight. After cooling to room temperature, the reaction mixture was filtered through Celite and rinsed with MeOH. The filtrate was concentrated in vacuo, diluted with EtOAc and water. The layers were separated, and the organic layer was washed with brine and 10% aqueous LiCl, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography using CH2Cl2:MeOH (10:0.1) as eluent afforded methyl 2-(isopropylamino)thiazolo[5,4-b]pyridine-5-carboxylate as a white solid (1.67 g, 74% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:23]([O:22][C:20]([N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[C:3]1[C:2]([NH:1][C:33]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][N:27]=2)=[O:34])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)c1cccc(N)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cnccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)c2cnccn2)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 58.4 %

Procedure:
A solution of methyl 3-amino-2-(bis(tert-butoxycarbonyl)amino)benzoate 13 (3.8 g, 10.4 mmol), pyrazine-2-carboxylic acid 10 (1.54 g, 12.5 mmol), HATU (7.9 g, 20.8 mmol) and DIPEA (2.68 g, 20.8 mmol) in DMF was heated at 50° C. for 12 h. The reaction mixture was poured into H2O and the resulting precipitate was collected by filtration and dried under vacuum. The crude residue was purified by flash chromatography to give 14 (2.87 g, 58% yield)
Reaction SMILES: [H-].[Na+].C(=N[OH:6])C.[Cl:7][C:8]1[C:17]([Cl:18])=[C:16]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([N+]([O-])=O)=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:9]=1[O:10][CH:11]([OH:13])[CH3:12]>CN(C=O)C>[Cl:7][C:8]1[C:17]([Cl:18])=[C:16]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([OH:6])=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:9]=1[O:10][CH:11]([OH:13])[CH3:12]
Reactant: CC=NO
Reactant: CC(O)Oc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)Oc1ccc(C(=O)c2ccc(O)cc2)c(Cl)c1Cl
Reaction time: 0.17 h

Procedure:
Dry DMF (40 ml.) was cooled in an ice bath to 10°-15° C. Sodium hydride (7.2 g., 0.15 mole) was then added. The suspended mixture was stirred for 10 minutes and acetaldoxime (11.8 g., 0.2 mole) was added portionwise. After stirring for another 10 minutes the compound from Example 1 (17.8 g., 0.05 mole) in 30 ml. dry DMF was added dropwise. When the addition was completed, the ice bath was removed and the reaction mixture was stirred at room temperature for 21/2 hours. The mixture was poured into ice water and was filtered. The filtrate was acidified with concentrated HCl to obtain a precipitate. The crude solid was purified from aqueous ethanol to yield 11 g. (67%), m.p. 169°-170° C.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1.[H-].[Na+].[Cl-].[CH2:30]([NH2:33])[C:31]#[CH:32]>CN(C)C=O.O>[CH2:30]([NH:33][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1)[C:31]#[CH:32]
Reactant: C#CCN
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNc1cc(C)n(C)c(=O)c1C(=O)C=Cc1cccc(OCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To a solution of 0.71 g of 4-hydroxy-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone in 5 ml of dimethylformamide was added 0.090 g of sodium hydride (60% oily), and this was stirred at room temperature for 1 hour. 0.46 g of paratoluenesulfonyl chloride was added thereto, this was stirred at room temperature for 4 hours, then, 0.60 g of propargylamine was added, and this was stirred at room temperature overnight. To the reaction solution was added water, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 0.080 g of 4-propargylamino-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (13b)] as a yellow crystal.