Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Oc1cc(F)ccc1F
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCOc1cc(F)ccc1F
Yield: 92.5 %

Procedure:
2,5-Difluorophenol (23 g, 0.172 mol) was dissolved in dry, distilled ethanol (300 ml) under a stream of nitrogen. 1-Bromohexane (31.75 g, 0.193 mol, 1.2 eq) and potassium carbonate (133 g, 0.964 mol, 5.5 eq) were added and the reaction mixture was stirred vigorously under reflux for 4 days. Dichloromethane (300 ml) was added to the straw coloured mixture, which was then filtered through a bed of celite to remove the potassium carbonate. The filtrate was washed with water (3×100 ml), and dried with magnesium sulphate. Removal of the solvent in vacuo yields 34.07 g of pale brown oil. This was distilled under reduced pressure to yield a colourless oil (29.22 g, 77%), bp 70° C. @ 0.7 mmHg; (Found: C, 67.35; H, 7.55. C12H16OF2 requires C, 67.3; H, 7.53; O, 7.47; F, 17.76%); vmax(film)/cm−1 3090 (C—H unsat.), 2932 (C—H aliph.), 1832 (C═C); δH(300 MHz; CDCl3) 0.90 (3H, t, 3J(H,H)=7 Hz, —CH3), 1.33 (4H, m, 2×—CH2—), 1.35 (2H, septet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 1.81 (2H, quintet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 3.98 (2H, t, 3J(H,H)=7 Hz, —CH2CH2O—Ar), 6.56 (H, dddd, 3J(H,F)=10.8, 4J(H,F)=5.3, 4J(H,H)=2.4, 5J(H,H)=0.7 Hz, C6H), 6.67 (H, dddd, 3J(H,F)=10.8, 3J(H,H)=9.0, 4J(H,F)=5.3, 4J(H—H)=2.4 Hz, C4H), 6.99 (H, dddd, 3J(H,F)=10.8, 3J(H,H)=9.0, 4J(H,F)=5.3, 5J(H,H)=0.7 Hz, C3H); m/z 214 (M+, 19%), 130 (M+-alkoxy chain, 100%), 43 (56%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([Cl:18])=[CH:10][C:9]3[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]#[N:31])[CH:25]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(Cl)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3cc(N4CCC4)c(Cl)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from {5-azetidin-1-yl-4-chloro-2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert. -butyl ester (Example M50) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (66 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:21]C(=O)OC(C)(C)C)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:21]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC(=O)OC(C)(C)C)c(C)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(C)ccc32)cc1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl (5-methyl-1-tosyl-1H-indol-4-yl)carbamate (10.5 g, 26.2 mmol) in DCM (197 mL) was added TFA (65.5 mL), and the mixture was stirred at room temperature. After 20 minutes the reaction was concentrated, dissolved in EtOAc, washed with sat. aq. NaHCO3, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-70% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 301.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3S(C3C(C)=CC(C)=CC=3C)(=O)=O)=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12].[OH-].[Na+].Cl.C(=O)(O)[O-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: COCOc1ccc(-c2ccc3cnn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCOc1ccc(-c2ccc3cn[nH]c3c2)cc1OC
Temperature: 45 °C

Procedure:
Unpurified 6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole (under argon) was dissolved in THF (20 mL) and was treated with 1N NaOH in MeOH (70 mL degassed by bubbling through argon for 3 to 5 min). The mixture was heated to 45° C. for 1 h and allowed to cool. The mixture was neutralized by addition of 1N HCl (50 mL) followed by saturated sodium bicarbonate (200 mL). The product was extracted into ethyl acetate (350 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole. Purification by silica gel chromatography (500 mL silica, 20% ethyl acetate in benzene (1.8 L), 30% ethyl acetate in benzene (1.8 L)) gave 6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (1.19 g, 31%): 1H NMR (CDCl3) δ 7.80 (s, 1H), 7.69 (d, 1H, J=8.5 Hz), 7.52 (s, 1H), 7.29 (d, 1H, J=8.5 Hz), 7.16 (s, 1H), 7.13 (s, 1H), 7.08 (s, 1H). MS (ES) [m+Na]/z Calc'd 337, found 337; [m+Cl−]/z Calc'd 349, found 349.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:5]=1)[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([S:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[NH:6][N:5]=1)[CH3:2]
Reactant: CCSc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCSc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-1-(3-(Ethylthio)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (40.6 mg, 0.070 mmol) was dissolved in TFA (1 mL) and triethylsilane (0.017 mL, 0.104 mmol) was added. The reaction mixture stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, diluted with DMSO (1 mL), filtered, and purified by mass-triggered reverse phase HPLC. The fractions containing pure product were concentrated in vacuo to give (R)-1-(3-(ethylthio)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea, which was obtained as the trifluoroacetic acid salt. MS ESI calc'd. For C17H19N5OS [M+1]+ 342. found 342. 1H NMR (500 MHz, DMSO-d6) δ 13.13 (s, 1H), 9.09 (s, 1H), 8.65 (s, 1H), 7.73 (s, 1H), 7.61 (s, 1H), 7.33 (d, J=4.4 Hz, 4H), 7.22 (dt, J=4.1, 8.6 Hz, 1H), 4.94-4.77 (m, 1H), 3.10 (q, J=7.3 Hz, 2H), 1.39 (d, J=7.0 Hz, 3H), 1.27 (t, J=7.3 Hz, 3H). Examples 80-81 (Table 13) were prepared according to Scheme 8 following similar procedures described for Example 79 using the appropriate sodium thiol, which can be achieved by those of ordinary skill in the art of organic synthesis. Example 81 was obtained as the trifluoroacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([OH:20])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH2:21][C:22]([NH:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)=[O:23].[CH2:39](Br)[CH:40]=[CH2:41]>>[CH2:41]([O:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:12]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:21][C:22]([NH:24][CH:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26]3)=[O:23])[CH:7]([CH2:6][C:5]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:13]=2[CH:14]=1)[CH:40]=[CH2:39]
Reactant: C=CCBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CCC2
Product: C=CCOc1cc2c(cc1OC)CCCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide with allylbromide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH2:23]([NH:30][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:4][N:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(Cl)ncc1-c1nnn[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Nc1nc(NCc2ccccc2)ncc1-c1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 10.1 %

Procedure:
In a microwave tube, 2-chloro-5-(1H-tetrazol-5-yl)pyrimidin-4-amine (200 mg, 1.0 mmol) was dissolved into 3 mL of dioxane and DIPEA (1.5 mmol, 1.5 eq.). After the addition of benzylamine (5.0 mmol, 5.0 eq.), the tube was capped and irradiated in a CEM Discover microwave reactor to 120° C. for a total of 60 minutes in three 20 minutes intervals. LC/MS was taken every 20 minutes to follow the disappearance of starting material. After the complete consumption of the starting material, the reaction was cooled to room temperature and a precipitate formed. This solid was collected by filtration, washed several times with water, then with hot EtOAc. It was dried under vacuum to afford 27 mg of desired product. This material was carried forward without further purification. MS (EI) for C12H12N8: 269 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=1>C(O)CCC>[Cl:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccnc1Cl
Reactant: C1CNCCN1
Solvent: CCCCO
Product: Clc1cccnc1N1CCNCC1
Temperature: 23 °C
Yield: 71.8 %

Procedure:
A solution of piperazine (29.1 g, 338 mmol), 2,3-dichloropyridine (5.00 g, 33.8 mmol), and n-butanol (220 mL) was refluxed for 3 days. The reaction mixture was cooled to 23° C. and concentrated under reduced pressure. The residue was slurried with ethyl acetate and water. The ethyl acetate layer was poured off and dried over sodium sulfate, filtered, and concentrated to afford 4.8 g (72% yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.83 (m, 4H), 3.15 (m, 4H), 6.97 (dd, 1H, J=4.5, 7.5 Hz), 7.77 (dd, 1H, J=1.5, 7.5 Hz), 8.21 (dd, 1H, J=1.5, 4.5 Hz)); MS (ESI) m/e 198 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][C@@:15]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)([CH2:20][N+:21]([O-])=O)[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:33])([CH3:4])([CH3:3])[CH3:2].Cl>CN(C)C=O.[Zn]>[C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][C@:15]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)([C:16]([F:19])([F:18])[F:17])[CH2:20][N:21]=2)=[CH:9][C:8]=1[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: Cc1cc(C2=NC[C@@](c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a vigorously stirred suspension of zinc (0.060 g, 0.913 mmol) in dimethylformamide (2.0 ml) was added a solution of 4-[(R)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (0.190 g, 0.365 mmol) in dimethylformamide (2.0 ml). The resulting mixture was warmed to 80° C. and 37% aqueous hydrochloric acid (3.0 ml) was added very slowly to minimize the foaming. After stirring for 2 hours the reaction was cooled to room temperature and quenched by adding a pH 7 buffer solution. The mixture was extracted with dichloromethane; the organic layer was washed with water (3×) and brine. The crude product was purified by flash chromatography (6% ethyl acetate in cyclohexane) to afford 4-[(R)-4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-benzoic acid tert-butyl ester as a pale yellow oil (0.050 g, 29%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:20]1[O:21][C:16]([CH3:17])([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[O:18][CH2:19]1
Reactant: OCCO
Reactant: CC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(Cc2ccc(OCc3ccccc3)cc2)OCCO1

Procedure:
A solution of 1-(4-benzyloxyphenyl) propan-2-one (5 g), ethylene glycol (1.4 g) and a trace amount of 4-toluenesulphonic acid, in benzene (100 ml) was heated under reflux with azetropic removal of water for 2 hours. The solvent was evaporated, the residue dissolved in ethyl acetate, washed with 1.2 N sodium bicarbonate solution, dried (MgSO4) and evaporated to give a light brown oil which crystallised on standing (6.1 g) m.p. 58°-62°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](Cl)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][C:19]([N:28]([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:12])[NH:14][CH2:15][CH:16]2[CH2:17][CH2:18][C:19]([N:28]([CH3:30])[CH3:29])([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The chloroformic acid 4-nitrophenyl ester (913.5 mg, 4.53 mmole) dissolved in abs. DCM (15 ml) was slowly added dropwise while cooling in ice water to a solution of (4-aminomethyl-1-phenylcyclohexyl)-dimethylamine (1 g, 4.3 mmole) in abs. DCM (15 ml) and pyridine (766 μl, 9.49 mmole). The reaction mixture was then stirred for 20 hours at RT. The red reaction mixture was worked up by washing with water (3×10 ml), with 1M HCl (3×10 ml) and with 1M NaOH (2×10 ml). The organic phase was dried with Na2SO4 and then concentrated by evaporation. The residue was a mixture of the diastereoisomers of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid 4-nitrophenyl ester (1.25 g, reddish-brown oil, 73%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]([C:18]([O:20]CC)=[O:19])[C:5]2=[O:23].Cl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:23]
Reactant: CCOC(=O)c1cn(-c2cccs2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2cccs2)c2cc(F)c(F)cc2c1=O
Yield: 72.8 %

Procedure:
To ethyl 6,7-difluoro-1-(2-thienyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.6 g) are added 90% acetic acid (3 ml) and conc. hydrochloric acid (0.8 ml), and the mixture is refluxed for one hour. After allowing to cool, the precipitated crystals are separated by filtration, and washed with water, ethanol and ether in this order to give 6,7-difluoro-1-(2-thienyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.4 g) as colorless crystals, m.p. 245°-246° C.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].C(#N)C.Cl[CH:9]([C:15]([C:17]([F:20])([F:19])[F:18])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N(CC)CC)C>>[CH3:2][C:1]1[S:3][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([C:17]([F:18])([F:20])[F:19])[N:4]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(C)nc1C(F)(F)F
Temperature: 76 °C

Procedure:
A solution of thioacetamide in acetonitrile (6.66 mol), prepared as in Example 1, is placed in a flask. Ethyl 2-chloro-4,4,4-trifluoroacetoacetate (5.06 mol) is added and an exotherm is observed. Triethylamine (13.64 mol) is added and the mixture is heated to reflux (approx. 76° C.) for one hour. The resulting solution is cooled. Ethyl 2-methyl-4-(trifluoromethyl)-thiazole-5-carboxylate may be isolated by standard means.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:15][C@@H:14]([O:16]CC=C)[CH2:13][N:12]2[CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:9][C:8](=[O:33])[NH:7]1.OCC1COCCN1C(OC(C)(C)C)=O.C(OC(N1CCOCC1C(O)=O)=O)(C)(C)C.CCN(C(C)C)C(C)C.ClCCOC=O.[BH4-].[Na+]>C1COCC1.CO>[F:37][C:35]1[CH:34]=[C:4]([CH:3]=[C:2]([F:1])[CH:36]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:15][C@H:14]([OH:16])[CH2:13][N:12]2[CH:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:33])[NH:7]1
Reactant: C=CCO[C@@H]1C[C@H]([C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)N(C(c2ccccc2)c2ccccc2)C1
Agent: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Agent: CC(C)(C)OC(=O)N1CCOCC1CO
Agent: O=COCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Reaction time: 1.5 h
Yield: 81 %

Procedure:
Step L (1): tert-Butyl 3-(hydroxymethyl)morpholine-4-carboxylate. To a solution of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (4.7 g, 20.35 mmol) in THF (120 mL) were added Hunig's base (6.6 g, 50.875 mmol). Then chloroethylformate (2.65 g, 24.4 mmol) was added at 0° C. After stirring from 0° C. to rt over 1.5 h, NaBH4 (3.1 g, 81.4 mmol) was added and after 15 min, MeOH (20 mL) was added slowly at 0° C. After stirring at rt for 1 h, THF and MeOH was removed and ethyl acetate (600 mL) was added and the mixture was washed with NaHCO3, H2O, and dried (Na2SO4), and concentrated in vacuo. 3.56 g of product was obtained as the title compound (81% yield): 1H NMR (CDCl3, 500 MHz) δ 1.46 (9H, s), 2.03 (1H, brd s), 3.17 (1H, m), 3.46 (1H, m), 3.56 (1H, m), 3.72-3.86 (4H, m), 3.91 (1H, d, J=10 Hz), 3.99 (1H, brd s).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([NH2:10])(=[O:9])[CH:7]=[CH2:8].N12CCCCC1C=NCCC2>C(#N)C>[C:6]([CH2:7][CH2:8][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:9])[NH2:10]
Reactant: C=CC(N)=O
Reactant: c1c[nH]cn1
Agent: C1=NCCCN2CCCCC12
Solvent: CC#N
Product: NC(=O)CCn1ccnc1
Temperature: 80 °C

Procedure:
A stirred mixture of 3.4 g (49.9 mmoles) of imidazole, 3.55 g (49.9 mmoles) of acrylamide, and 7.6 g (49.9 mmoles) of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBu) in 100 mL of sieve dried acetonitrile was heated at 80° C. under nitrogen for 2.0 hours. The mixture was let cool, where upon the product crystallized out of the solution.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CS([C:19]1[N:24]=[CH:23][C:22]2=[CH:25][CH:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=3)[N:21]2[N:20]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:37][S:34]([C:30]1[CH:29]=[C:28]([C:27]2[N:21]3[C:22]([CH:23]=[N:24][C:19]([NH:15][C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[N:14]=4)=[N:20]3)=[CH:25][CH:26]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:35])=[O:36]
Reactant: CN1CCN(Cc2cccc(N)n2)CC1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(C)(=O)=O)c3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN1CCN(Cc2cccc(Nc3ncc4ccc(-c5cccc(S(C)(=O)=O)c5)n4n3)n2)CC1

Procedure:
Into a microwave vial, 6-(4-Methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (0.149 g, 0.722 mmol), 2-Methanesulfinyl-7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.110 g, 0.328 mmol), N,N-Diisopropylethylamine (0.126 mL, 0.722 mmol), and 1-Methoxy-2-propanol (0.5 mL, 5 mmol) were added. The reaction was microwaved on 300 watts, 180° C. for 4 hours. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give [7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amine a yellow solid (20 mg, 10%). LCMS (E/I+) 478.8 (M+H). NMR 1H (DMSO-d6)-9.16 (s, 1H), 8.81 (d, 1H, J=7.82), 8.78 (s, 1H), 8.46 (dd, 1H, JJ=1.89, 5.36 Hz), 7.83-7.95 (m, 2H), 7.78 (t, 1H, J=7.57 Hz), 7.58 (d, 1H, J=5.05 Hz), 7.19 (dd, 1H, JJ=5.05, 6.94 Hz), 7.15 (d, 1H, J=5.05 Hz), 3.80 (s, 2H), 3.40-3.51 (m, 2H), 2.93-3.11 (m, 4H), 2.81 (s, 3H), 2.34-2.60 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][CH:18]1[NH:23][CH:22]([CH3:24])[CH2:21][N:20]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:19]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:31][C:28]1[CH:27]=[CH:26][C:25]([N:20]2[CH2:19][CH:18]([CH3:17])[NH:23][CH:22]([CH3:24])[CH2:21]2)=[CH:30][CH:29]=1
Reactant: CC1CN(c2ccc(N)cc2)CC(C)N1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Product: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Temperature: 100 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
An amount of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.5 g, 1.77 mmol) in 5 mL of N,N′-dimethylformamide is added [4-(3,5-dimethylpiperazin-1-yl)phenyl]amine (0.44 g, 2.13 mmol). The mixture reaction is stirred at 100° C. for 3 h. Mass spectroscopy suggested the completion of reaction. Solvent is subsequently evaporated under high-pressure vacuum to brown solid. The solid is stirred in ether, filtered and washed with a small amount of methanol, excess amount of ether and hexane, and dried in oven overnight to give 0.65 g (80.0% yield) of yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[CH:22][C:23]=2[C:24](=[O:34])[NH:25][C:26]2([C:32]#[N:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.CS(O)(=O)=[O:37].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:32]([C:26]1([NH:25][C:24]([C:23]2[CH:22]=[N:21][N:12]3[C:13]([C:14]4[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=4)=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:9]=[N:10][C:11]=23)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[O:37])[NH2:33]
Reactant: CS(=O)(=O)O
Reactant: N#CC1(NC(=O)c2cnn3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)cnc23)CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: NC(=O)C1(NC(=O)c2cnn3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)cnc23)CCCCC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
To a solution of the compound obtained in Example A1 (70 mg) in methylene chloride (1.0 mL) were added methanesulfonic acid (84 μL) and a few drops of water, and the mixture was stirred at room temperature overnight and at 35° C. for 4 hours. To the reaction mixture was added successively an aqueous saturated sodium hydrogencarbonate solution and methylene chloride. After stirring, the organic layer was separated and concentrated in vacuo. The resultant crude product was purified by column chromatography on silica gel (solvent; chloroform/methanol=100/0 to 95/5) to give 3-[N-(1-carbamoylcyclohexyl)carbamoyl]-6-(2-chlorophenyl)-7-(4-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (18 mg; yield: 25%) as a pale yellow solid.