Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[S:5].[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>N1C=CC=CC=1>[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([NH:2][NH:3][C:4]([NH2:6])=[S:5])=[O:11]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: NNC(N)=S
Agent: Cl
Solvent: c1ccncc1
Product: NC(=S)NNC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Thiosemicarbazide hydrochloride (2.55 g, 20.0 mmol) was mixed to pyridine (20 ml), and 2,4-dichlorobenzoyl chloride (2.81 ml) was added thereto. The mixture was stirred at a room temperature for 14 hours. The solvent was distilled off. Water was added to the resulting residue, and the mixture was stirred. The precipitate was separated by filtration. 2,4-Dichlorobenzoylthiosemicarbazide (2.11 g, 8.00 mmol) obtained from the precipitate by through circulation drying was mixed to toluene (25 ml), and methanesulfonic acid (0.78 ml) was added to the mixture. The resulting mixture was heated and stirred for 6 hours. The mixture was allowed to cool to a room temperature. Then, the precipitate was separated by filtration, neutralized with water and 25% ammonia water, and stirred for 30 minutes. The precipitate was separated by filtration, washed with water, and subjected to through circulation drying to give the title compound (1.14 g, 58%) as a white substance.
Reaction SMILES: C([O:8][C:9](=[O:27])[CH2:10][C@@H:11]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH2:23]([NH:22][C:20](=[O:21])[C@H:11]([CH2:10][C:9]([OH:27])=[O:8])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:24][CH2:25][CH3:26]
Reactant: [H][H]
Reactant: CCCCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCNC(=O)[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
5.09 g of Compound 6 obtained in Synthesis Example 5 was dissolved in 15 mL of ethyl acetate, 0.656 g of 5% palladium carbon (50% moisture content) was added thereto, and then the inside of the reaction system was substituted with hydrogen, and the reaction system was stirred at room temperature overnight and subjected to hydrogenolysis. The 5% palladium carbon was filtered off, and washed with ethyl acetate. Then, the organic layers were combined, distilled under reduced pressure to remove ethyl acetate, and then dried under vacuum, thereby to give 4.05 g of Compound 7.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][CH2:8][O:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[C:13]([NH2:22])[N:12]([CH3:23])[N:11]=2)=[CH:4][CH:3]=1.[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].[OH-:40].[K+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:22]([S:36]([C:33]2[CH:34]=[CH:35][C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:31][CH:32]=2)(=[O:37])=[O:40])[C:13]2[N:12]([CH3:23])[N:11]=[C:10]([O:9][CH2:8][CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=3)[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: [OH-]
Reactant: Cc1ccc(-c2c(OCCOc3ccc(F)cc3)nn(C)c2N)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(-c2c(OCCOc3ccc(F)cc3)nn(C)c2N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 79.7 %

Procedure:
To 3-[2-(4-fluorophenoxy)ethoxy]-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-ylamine (Preparation 26) (105 mg) in dichloromethane (20 ml) at room temperature was added 4-tert-butylbenzenesulfonyl chloride (2 g), tetrabutylammonium hydrogen sulfate (75 mg) and potassium hydroxide (690 mg), the mixture was sonicated for 3 hrs. The reaction was partitioned between 2N aqueous hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water, then brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel, eluting with a solvent gradient of pentane:ethyl acetate (39:1 to 4:1), to yield the title compound as a glass (180 mg).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Br)([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=O)C.C1COCC1.[NH3:23]>C(O)C>[NH2:23][C:11]([C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1)([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: N
Reactant: COC(=O)C(C)(Br)c1ccc(OC(C)=O)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)C(C)(N)c1ccc(O)cc1
Temperature: 25 °C

Procedure:
10 g of methyl 2-(4-acetoxyphenyl)-2-bromopropionate, 50 mL of THF and 30 mL of ethanol are introduced into a Woulff bottle at ambient temperature. The mixture is saturated with gaseous ammonia and stirred for one night at ambient temperature. The insoluble matter is filtered and purified over a silica column with 90/10 dichloromethane/methanol to yield the product (5 g; Yd=77%).
Reaction SMILES: [CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6](=[O:38])[CH2:5]1)[CH:2]=C.O=C1N2C(CC=C2C(OCC2C=CC=CC=2)=O)C1.[N+:57]([CH2:60][CH2:61][SH:62])([O-:59])=[O:58].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:57]([CH2:60][CH2:61][S:62][CH:2]1[CH2:1][CH:4]2[N:7]([C:6](=[O:38])[CH2:5]2)[CH:8]1[C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])([O-:59])=[O:58]
Reactant: C=CCC1CC(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])CCS
Agent: O=C(OCc1ccccc1)C1=CCC2CC(=O)N12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1C(SCC[N+](=O)[O-])CC2CC(=O)N21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An ethyl acetate solution of 4-allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemthyl)azetidin-2-one (37) (1.46 g) was ozonolysed and cyclized as described in Example 53. The crude product (13) was dissolved in dry dimethylformamide (5 ml) and a solution of 2-nitroethanethiol (0.30 g) in dimethylformamide (2 ml) was added, followed by powdered potassium carbonate (0.19 g). The reaction was stirred at room temperature for 2 hours and the solvent was then stripped off under high vacuum. The residue was partitioned between ethyl acetate and brine and the organic phase was separated, dried over sodium sulphate and concentrated. It was chromatographed on silica gel 60 (<230 mesh) eluting with ethyl acetate/60°-80° petroleum ether 3:7 grading to 7:3, and fractions containing the required products were rechromatographed on the same support using ethyl acetate/60°-80° petroleum ether 4:6. This gave two isomers of benzyl 3-(2-nitroethylthio)-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (122) and (123). The less polar compound was the 2α, 3α-isomer (122) (0.025 g); νmax (CHCl3) 3020, 2960, 1770, 1750sh and 1560 cm-1 ; τ(CDCl3) 2.66(5H, s, phenyl), 4.82(2H, s, benzyl CH2), 5.60(2H, t J7 Hz, CH2NO2), 5.65(2H, d, J61/2 Hz, C2-H), 5.9-6.4(2H, m, C3-H and C5-H), 6.70(1H, dd J15 and 41/2 Hz, C6-H), 6.94 and 6.96(2H, 2t J7 Hz, SCH2), 7.26(1H, dd J15 and 2 Hz, C6-H), 7.41(1H, dt J13 and 6 Hz, C4-H), and 8.44(1H, ddd J13, 9 and 7 Hz, C4-H); (M+ at m/e 350. C16H18N2O5S requires 350). The more polar product was the 2β, 3α-isomer (123) (0.010 g); νmax (CHCl3) 3000, 2940, 1770, 1740 and 1560 cm-1 ; τ(CDCl3) 2.65(5H, s, phenyl), 4.72 and 4.89 (2H, ABq J12 Hz, benzyl CH2) 5.64(2H, t J61/2 Hz, CH2NO2), 5.89(1H, d J7 Hz, C2-H), 6.1-6.5(2H, m, C3-H and C5-H), 6.7-7.1(3H, m, C6-H and SCH2 ), 7.18(1H, dd J15 and 21/2 Hz, C6-H), 7.73(1H, dt J12 and 6 Hz, C4-H) and 8.09(1H, td J12 and 10 Hz, C4-H); M+ m/e 350. C16H18N2O5S requires 350).
Reaction SMILES: [CH3:1][C:2]([CH3:59])([CH3:58])[C@H:3]([N:44]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[N:51]=2)[C:45]1=[O:57])[C:4]([NH:6][C@@H:7]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:25]C(=O)OCC1C=CC=CC=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=[O:5].Cl>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[NH2:25][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[C@@H:9]([OH:36])[CH2:8][C@@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([N:44]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[N:51]=2)[C:45]1=[O:57])[C:2]([CH3:1])([CH3:58])[CH3:59])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1ccc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)cc2)nc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(C[C@H](N)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 74D (0.033 g, 0.041 mmol) in a mixture of ethyl acetate (0.25 mL) and methanol (0.25 mL) was treated with Pd(OH)2 on carbon (0.009 g, 20% Pd by wt.) and HCl solution (0.041 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filtered through a bed of celite® and rinsed with methanol. The solvent was concentrated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[O:27]1[CH:28]=[CH:29][C:25]([C:23]2[N:16]3[C:17]([CH:18]=[N:19][C:14]([NH:13][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)=[N:15]3)=[C:20]([CH3:21])[N:22]=2)=[CH:26]1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccoc3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccoc4)n3n2)cc(OC)c1OC
Yield: 50.5 %

Procedure:
In a similar manner as described for Example 9, N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-3-furamide (Intermediate 37) (211 mg, 0.53 mmol), and 1,2,4-triazole (220 mg, 3.18 mmol) in pyridine (4 mL) and phosphorous oxychloride (0.15 mL, 1.60 mmol) gave 7-(3-furyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (102 mg, 51%) as a yellow solid. 1H NMR (CDCl3): δ8.78 (s, 1H), 8.56 (s, 1H), 7.52 (t, J=1.65 Hz, 1H), 7.20 (d, J=1.65, 1H), 6.87 (s, 2H), 6.82 (s, 1H), 3.90 (s, 6H), 3.87 (s, 3H), 2.60 (s, 3H). MS m/z 381 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([CH3:8])=[CH:4][C:3]=1[F:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a solution of 1-Bromo-2-fluoro-4-methyl-benzene (5.35 g, 28.30 mmol) in concentrated sulfuric acid (25 ml) was added concentrated nitric acid(9 ml) dropwise while maintaining an internal reaction temperature below 20° C. The reaction mixture was stirred at 0° C. for 10 minutes and poured into ice water. The resulting mixture was extracted three times with ether. The combined ether extracts were washed with brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 2 to 3% ethyl acetate in hexanes give 1-Bromo-2-fluoro-4-methyl-5-nitro-benzene as a white solid (5.21g, 78%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=2)[CH:5]=[N:6][CH:7]=1.[OH:19]O>C(Cl)Cl.C[Re](=O)(=O)=O>[Br:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=2)[CH:5]=[N+:6]([O-:19])[CH:7]=1
Reactant: OO
Reactant: Clc1cccc(Cl)c1-n1cc2cncc(Br)c2n1
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: [O-][n+]1cc(Br)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.4 %

Procedure:
To a solution of 7-bromo-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (3.43 g, 10 mmol) and methyltrioxorhenium (249 mg, 1.0 mmol) in DCM (35 mL) was added hydrogen peroxide (30% aq., 1.95 mL, 20 mmol) and the resulting mixture stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM and sodium bicarbonate (sat. aq.). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% methanol in DCM) to afford the title compound as a beige solid (1.7 g, 47% yield). LCMS (Method D): RT=2.46 min, m/z: 360 [M+H+].
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]1[O:14][C:13]2[CH:12]=[CH:11][C:9](N)=[CH:8][C:7]=2[O:6]1.[BrH:15].[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>O.CC(C)=O>[Br:15][CH:17]([CH2:18][C:9]1[CH:11]=[CH:12][C:13]2[O:14][CH2:5][O:6][C:7]=2[CH:8]=1)[C:16]([O:20][CH3:21])=[O:19]
Reactant: C=CC(=O)OC
Reactant: Br
Reactant: Nc1ccc2c(c1)OCO2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(Br)Cc1ccc2c(c1)OCO2
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 54 %

Procedure:
A solution of sodium nitrite (27.7 g) in water (40.0 ml) was added dropwise to a mixture of 3,4-methylenedioxyaniline (50 g), aq. HBr (47%, 125 ml) and acetone (500 ml) at 0°-5° C., followed by stirring for 20 minutes at 5° C. To the solution was added methyl acrylate (197 ml). The resultant solution was warmed to 32° C. to which cuprous oxide (Cu2O) (0.5 g) was added in small portions with vigorous stirring. The mixture generates nitrogen gas due to exothermic reaction. After completing the generation of nitrogen gas, the reaction mixture was further stirred for an hour and concentrated under reduced pressure. Water was poured into the reaction mixture and the mixture was extracted with ether. The ethereal layer was washed with H2O, dried (MgSO4) and distilled off under reduced pressure to give methyl 2-bromo-3-(3,4methylenedioxyphenyl)propionate (56.2 g, 54%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.CC([O-])(C)C.[K+].C(O[C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[C:37]3[C:32](=[CH:33][C:34](F)=[CH:35][CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH2:24][CH2:23]1)=[O:21])(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:51][C:52]2[CH:57]=[CH:56][C:55]([N:58]3[CH2:62][CH2:61][CH2:60][CH2:59]3)=[CH:54][CH:53]=2)=CC=1)([O-])=O>CS(C)=O.O>[N:58]1([C:55]2[CH:56]=[CH:57][C:52]([NH:51][C:20]([N:22]3[CH2:23][CH2:24][CH:25]([C:28]4[C:37]5[C:32](=[CH:33][C:34]([O:8][CH2:7][CH:4]6[CH2:5][CH2:6][O:1][CH2:2][CH2:3]6)=[CH:35][CH:36]=5)[N:31]=[CH:30][N:29]=4)[CH2:26][CH2:27]3)=[O:21])=[CH:53][CH:54]=2)[CH2:59][CH2:60][CH2:61][CH2:62]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: O=C(Nc1ccc(N2CCCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(N2CCCC2)cc1)N1CCC(c2ncnc3cc(OCC4CCOCC4)ccc23)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
A mixture of (tetrahydro-pyran-4-yl)-methanol (0.2 mmol), KOtBu (0.2 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 65b, in DMSO (1 mL), was stirred at 80° C. for 1 h. It was then diluted with water and extracted with DCM. The combined extracts were washed with water, brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude product was then treated with 3M HCl/MeOH (2 mL) and stirred at rt for 2 h and then concentrated in vacuo. The crude deprotected intermediate was dissolved in a mixture of DCM:MeOH (1:1; 2 mL) and neutralized with excess Et3N and treated with (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride (0.11 mmol), prepared by the method as outlined in Example 74a, at rt overnight. It was then concentrated in vacuo and the crude product was dissolved in DCM and washed with water thrice, then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was then purified by Preparative TLC (silica gel; DCM:MeOH, 9.5:0.5) followed by a further purification by Preparative HPLC to obtain 1.5 mg (3%) of the title compound. 1H-NMR (300 MHz, CDCl3+CD3OD): 9.05 (s, 1H), 8.09 (m, 1H), 7.52-7.23 (m, 6H), 4.30 (m, 2H), 4.03-3.94 (m, 4H), 3.75-3.50 (m, 8H), 3.48-3.38 (m, 2H), 2.30-2.18 (m, 4H), 2.17-2.00 (m, 2H), 1.97-1.85 (m, 2H), 1.75 (m, 2H), 1.55-1.41 (m, 2H). LC/MS (ESI): 516.2 (MH)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@:34]4([CH3:39])[CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH:40]1([CH:43]=O)[CH2:42][CH2:41]1>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@:34]4([CH3:39])[CH2:38][CH2:37][CH2:36][N:35]4[CH2:43][CH:40]4[CH2:42][CH2:41]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@]4(C)CCCN4)ncn3)cccc2s1
Reactant: O=CC1CC1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@]4(C)CCCN4CC4CC4)ncn3)cccc2s1

Procedure:
(2S)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-2-methylpyrrolidine-2-carboxamide (Example 57) was reacted with cyclopropanecarboxaldehyde (Aldrich) under the conditions of Example 3(d) to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 611 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].[CH3:15][C:16]1[N:20]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)[N:19]=[CH:18][C:17]=1[C:31]([NH:33][C:34]1[CH:35]=[N:36][C:37]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[C:38]([CH3:40])[CH:39]=1)=[O:32].ClCCl>O>[CH3:8][N:9]([CH3:14])[S:10]([N:44]1[CH2:43][CH2:42][CH:41]([C:37]2[N:36]=[CH:35][C:34]([NH:33][C:31]([C:17]3[CH:18]=[N:19][N:20]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)[C:16]=3[CH3:15])=[O:32])=[CH:39][C:38]=2[CH3:40])[CH2:46][CH2:45]1)(=[O:12])=[O:11]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCNCC1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(S(=O)(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
Triethylamine (73 μl) and dimethylsulfamoyl chloride (56 μl) were added to a mixture of 5-methyl-N-[5-methyl-6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (222 mg) described in Reference Example 171 and dichloromethane (10 ml), stirred at room temperature for 6.5 hours, triethylamine (146 μl) and dimethylsulfamoyl chloride (56 μl) were added and stirred at room temperature for 7.5 hours. Water was added to the reaction solution, extracted with chloroform, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The precipitated solid was washed with ethyl acetate and ethanol to give the titled compound (122 mg) as a white solid.
Reaction SMILES: [BH4-].[Na+].C(O)(C(F)(F)F)=O.[Cl:10][C:11]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>C1COCC1>[ClH:10].[Cl:10][C:11]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14]
Reactant: N#Cc1cccc(F)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cl
Product: NCc1cccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 167.4 %

Procedure:
To a solution of NaBH4 (24.3 g, 0.643 mol) in THF (400 mL) was added TFA (48 mL, 0.643 mol) slowly at 0° C. After the addition was completed, the mixture was stirred at 0° C. for about 20 min. 2-Chloro-3-fluorobenzonitrile (20 g, 0.128 mol) in THF (100 mL) was then added slowly into the mixture at 0° C. The mixture was stirred from 0° C. to RT until no starting material was observed by LCMS. Half of the solvent was removed, then 10% HCl (250 mL) was added slowly into the residue at 0° C. The mixture was warmed up and heated to reflux until no boron complex was observed by LCMS. The mixture was extracted by diethyl ether. The aqueous solution was basified to pH 8-10 using NaOH (3 N), extracted with EtOAc. The organic layers were combined and concentrated to about 300 mL. HCl (4 N, 50 mL) was added slowly into the resulting solution. The white solid was precipitated and collected by filtration to give (2-chloro-3-fluorophenyl)methanamine hydrochloride (21 g, 84%). LRMS (M+H+) m/z 160.1.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:12]=C[C:14]=1[OH:15])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])#N.Cl.O.[C:18]([OH:24])([C:20](F)(F)F)=[O:19]>CC#N>[C:18]([C:20]1[CH:12]=[C:5]([CH:4]=[CH:3][C:14]=1[OH:15])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])([OH:24])=[O:19]
Reactant: N#Cc1cc(C[C@H](N)C(=O)O)ccc1O
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CC#N
Product: N[C@@H](Cc1ccc(O)c(C(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 250 mL 3-necked flask equipped with a reflux condenser and a magnetic stirrer was charged with 1.45 g of 3-cyano-L-tyrosine, 50 mL of concentrated HCl, and 50 mL of water. The solution was heated to reflux with stirring. After 2 days, analysis of the reaction mixture by HPLC (C18, 90:10:0.1 H2O:MeCN:TFA) indicated a major component at k1 =2.23 (75%) and a minor component at k1 =1.59 (25%). After 4 days HPLC indicated only the k1 =2.23 material. The reaction mixture was cooled to RT, filtered, and the filtrate was concentrated in vacuo to dryness to give 1.2 g of 3-carboxy-L-tyrosine as a dark brown solid. IR analysis (nujol) indicated loss of the nitrile stretch of 3-cyano-L-tyrosine, at 2223 cm-1. The crude solid was added to 60 mL of anhydrous MeOH in a 250 mL 3-necked flask equipped with a condenser and a magnetic stirrer. The mixture was acidified by bubbling HCl gas through for 5 min and heated to reflux with stirring. After 6 h, the reaction mixture was cooled to RT and neutralized with solid NaHCO3. The mixture was concentrated in vacuo to dryness, mixed with 100 mL of water, and extracted with CH2Cl2 (4×50 mL). The combined extracts were washed with 5% aqueoous NaHCO3 (2×50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to 10 mL. The solution was diluted with 35 mL of ether and treated with 5.5 mL of 1 M etheral HCl. A solid precipitated which was collected by filtration, washed with ether, and dried in vacuo to afford 0.90 (50%) of methyl 3-(methoxycarbonyl)-L-tyrosinate.HCl as an off-white powder, m.p. 211-213° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C[S-:13].[Na+].Cl>CN(C)C(=O)C.C(OCC)(=O)C>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([SH:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[S-]
Reactant: Brc1ccc2ncccc2c1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Sc1ccc2ncccc2c1
Temperature: 150 °C

Procedure:
To a solution of 6-bromoquinoline (0.81 g, 3.89 mmol) in N,N-dimethylacetamide (4 mL) was added sodium methyl mercaptide (2.0 g, 28.5 mmol). The mixture was heated at 150° C. for 2 h. After cooling, the mixture was diluted with ethyl acetate, and neutralized with aqueous 1N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was directly used in the next step without further purification. (0.50 g, 79%) LCMS: (M+H)+=161.9.