Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][C:13]([NH:15][CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:14])[CH:8]=[CH:7][CH:6]=2.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[N-]=C=O>ClCCl>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][C:13]([NH:15][CH:16]1[CH2:20][CH2:19][N:18]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[C:22]([F:21])([F:31])[F:32])[CH2:17]1)=[O:14])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2c(NC(=O)NC3CCNC3)cccc2cn1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [N-]=C=O
Solvent: ClCCl
Product: Cc1cc2c(NC(=O)NC3CCN(Cc4ccccc4C(F)(F)F)C3)cccc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A mixture of (D4) (40 mg, 0.15 mmol) and 2-trifluoromethyl benzaldehyde (23 mg, 0.13 mmol) in dichloromethane (5 ml) was stirred at 25° C. for 1 h. Sodium triacetoxyborohydride (32 mg, 0.15 mmol) was added and the reaction stirred for 48 h. A saturated solution of sodium hydrogen carbonate (5 mL) was added and the mixture stirred for 15min. The organic layer was removed, stirred with polymer supported isocyanate resin (2.1 eq.) for 3 h and then filtered. The filtrate was applied to an SCX column and eluted with methanol followed by 2% ammonia in methanol. Evaporation of the solvent in vacuo gave the title compound as a pale yellow solid (32 mg, 56%). 1H NMR (CDCl3) δ: 2.25-2.35 (2H, m), 2.50-2.70 (3H, m), 2.62 (3H, s), 2.80-2.90 (1H, m), 3.67-3.75 (2H, m), 4.30-4.40 (1H, m), 5.35 (1H, d, J=8.1 Hz), 7.25-7.40 (3H, m), 7.45-7.55 (4H, m), 7.70-7.80 (2H, m), 9.16 (1H, s); MS: C23H23N4OF3 requires 428, found 429 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=1)[CH2:3][OH:4].[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=[O:24].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23]([NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=1)[CH2:3][OH:4])=[O:24]
Reactant: O=C(O)C=Cc1ccccc1Cl
Reactant: N[C@@H](CO)c1ccc(F)c(N2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1Cl)N[C@@H](CO)c1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.6 %

Procedure:
A mixture of (R)-2-amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol (0.1 mmol), 2-chloro-cinnamic acid (0.1 mmol), EDC·HCl (0.2 mmol), DMAP (0.1 mmol), triethyl amine (0.3 mmol) in dichloromethane (2 mL) was stirred at room temperature for 14 h. The reaction mixture was purified by flash chromatography with 5% methnol in ethyl acetate to provide the title compound as a solid (29 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([F:25])[C:20]=1[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:33]1[N:38]=[CH:37][C:36]([CH2:39][O:40][CH3:41])=[CH:35][N:34]=1>CS(C)=O.CCOC(C)=O>[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([F:25])[C:20]=1[S:21]([CH3:24])(=[O:22])=[O:23])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:13][CH2:14][N:15]([C:33]2[N:38]=[CH:37][C:36]([CH2:39][O:40][CH3:41])=[CH:35][N:34]=2)[CH2:16][CH2:17]1
Reactant: CS(=O)(=O)c1c(F)cc(COC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Reactant: COCc1cnc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3cc(F)c(S(C)(=O)=O)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
4-((1R,2R)-2-(((3,5-difluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine hydrochloride (Step C product, 100 mg, 0.25 mmol) was dissolved in DMSO (3 ml) at RT under N2 and Cs2CO3 (288 mg, 0.884 mmol) was added. The mixture was stirred at RT for 5 min and 2-chloro-5-methoxymethylpyrimidine (Intermediate 18, 48 mg, 0.3 mmol) in DMSO (0.5 mL) was added. The mixture was stirred at 60° C. overnight. The mixture was diluted with EtOAc, washed with sat. NH4Cl, dried over MgSO4, and evaporated to dryness. The crude material was purified by preparative TLC (60% EtOAc in hexane) to afford 50.5 mg (41.5%) of the desired product. LC/MS (m/z): 482 (M+H)±1H NMR (500 MHz, CDCl3) δ 8.30 (s, 2H), 7.15 (dd, 2H), 4.80-4.64 (m, 4H), 4.25 (s, 2H), 3.60 (m, 2H), 3.37 (s, 3H), 3.35 (s, 3H), 2.93-2.80 (m, 2H), 1.96-1.80 (m, 2H), 1.40-1.10 (m, 4H), 0.94-0.71 (m, 2H), 0.12-0.08 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[O:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.O>O1CCCC1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([N:19]3[CH2:20][CH2:21][O:16][CH2:17][CH2:18]3)=[CH:28][CH:27]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Clc1ncc(Cl)c(Nc2ccc(N3CCOCC3)cc2)n1
Reaction time: 8 h

Procedure:
2,4,5-Trichloropyrimidine (1.05 g, 5.73 mmol) was dissolved in tetrahydrofuran (30 mL). Potassium carbonate (1.18 g, 8.55 mmol) was added, followed by 4-morpholinoaniline (1.017 g, 5.71 mmol). After stirring overnight, water (30 mL) and dichloromethane (30 mL) were added, the phases separated and the aqueous layer extracted once with dichloromethane (30 mL). The combined organic fractions were dried over sodium sulfate, concentrated onto silica gel and chromatographed (120 g SiO2, 0-60% EA:Hex). (2,5-Dichloro-pyrimidin-4-yl)-(4-morpholin-4-yl-phenyl)-amine was isolated as a yellow solid (1.29 g, 70%). m.p.=168-172° C.; LCMS (m/e) 325 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 9.38 (s, 1H), 8.30 (s, 1H), 7.37 (d, 2H, J=9.0 Hz), 6.96 (d, 2H, J=9.0 Hz), 3.74 (t, 4H, J=4.9 Hz), 3.11 (t, 4H, J=4.9 Hz).
Reaction SMILES: [H-].[Na+].[OH:3][C@:4]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:24]([CH:34]=[CH2:35])[CH:23]=2)[CH2:8][N:7]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[C@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5]1.[CH3:36]I>CN(C=O)C>[CH3:36][O:3][C@:4]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:24]([CH:34]=[CH2:35])[CH:23]=2)[CH2:8][N:7]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[C@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5]1
Reactant: CI
Reactant: C=Cc1cc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)ccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1cc([C@]2(OC)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)ccc1-c1ccccc1
Reaction time: 3 h
Yield: 31.4 %

Procedure:
NaH (60% in oil) (0.239 g, 5.97 mmol) was added to a solution of (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(2-vinylbiphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (1.55 g, 3.31 mmol) and methyl iodide (0.373 mL, 5.97 mmol) at 0° C. in DMF and stirred at this temperature for 3 hrs. The reaction was then quenched with sat. NH4Cl solution and ether. The ether layer was washed with brine, dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (20-40% EtOAc in hexanes) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-methoxy-4-(2-vinylbiphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (0.5 g, 1.038 mmol, 31% yield) as a clear oil. LCMS: rt=2.11 min. [M+Na]+=504; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH2:36](I)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:36][CH3:37])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: CCI
Product: CCOc1ccc(OC)c2c1CCN(CC(=O)NCc1ccccn1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with ethyl iodide
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].O>CN(C)C=O>[N:15]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[N+:16]=[N-:17]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Temperature: 60 °C
Yield: 79.2 %

Procedure:
To a solution of N-t butyloxycarbonyl-4-bromopiperidine (8.8 g, 33.5 mmol) in N,N-dimethylformamide (50 ml) was added sodium azide (6.5 g, 100.4 mmol) and the reaction mixture was heated at 60° C. for 18 hrs., cooled to room temperature, poured into water (200 ml) and extracted with dichloromethane (2×200 ml). The combined organic layers were washed with brine (2×50 ml), dried (MgSO4), filtered and concentrated under vacuum, to give the required product (6.0 g). 1H NMR (CDCl3) δ 1.28 (9H, s), 1.56 (2H,m), 1.88 (2H,m), 3.10 (2H,m), 3.58 (1H,m), 3.82 (2H,m).
Reaction SMILES: [CH3:1][Mg]I.[C:4]1([C:10]([CH:12]=[CH:13][CH2:14]N(C)C)=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OCC)C>[CH3:1][C:12]([C:10]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:11])=[CH:13][CH3:14]
Reactant: CN(C)CC=CC(=O)c1ccccc1
Reactant: C[Mg]I
Solvent: CCOCC
Product: CC=C(C)C(=O)c1ccccc1

Procedure:
Amer. Chem. Soc. 71 (1949), 2671-2676 discloses that methylmagnesium iodide reacts with dimethylaminomethylvinyl phenyl ketone in diethyl ether to give phenyl 1,2-dimethylvinyl ketone.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([OH:17])[C@@H:12]1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][C:21](OC=C)=[O:22]>C(COC)OC>[C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([O:17][C:21](=[O:22])[CH2:20][Cl:19])[C@@H:12]1[OH:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@H]1OC=C[C@@H](O)[C@@H]1O)c1ccccc1
Reactant: C=COC(=O)CCl
Solvent: COCCOC
Product: O=C(CCl)O[C@@H]1C=CO[C@H](COC(=O)c2ccccc2)[C@H]1O
Yield: 82 %

Procedure:
1.0 g (4 mmol) of 6-O-benzoylglucal is dissolved in 2-5 ml of dimethoxyethane and 10-15 ml of vinyl chloroacetate and stirred with 1 g of lipase P (Amano) for 1-2 h. Filtering off the enzyme and chromatography on silica gel (ether/hexane 1:1) yield 6-O-benzoyl-3-O-chloroacetylglucal in 82-87% yield.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:36])[C:4]([CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)=[CH:5][C@@H:6]1[O:10]C(C)(C)[N:8](C(OCC2C=CC=CC=2)=O)[C@H:7]1[CH2:23][CH:24]([CH3:26])[CH3:25]>C(O)C.[Pd]>[CH3:1][NH:2][C:3](=[O:36])[CH:4]([CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[CH2:5][C@H:6]([OH:10])[C@@H:7]([NH2:8])[CH2:23][CH:24]([CH3:25])[CH3:26]
Reactant: CNC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CCOC1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)C(CCOC1CCCCO1)C[C@H](O)[C@@H](N)CC(C)C
Yield: 100 %

Procedure:
29.2 mg of 3-[(4S,5S)-3-benzyloxycarbonyl-4-isobutyl-2,2-dimethyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)ethyl]-2-propenoic acid methylamide was dissolved in ethanol and then hydrogenated by using palladium black as a catalyst under atmospheric pressure. The reaction mixture was subjected to filtration, and the solvent of the filtrate was distilled off under reduced pressure to obtain 19.2 mg of (2RS,4S,5S)-5-amino-4-hydroxy-2-[2-(2-tetrahydropyranyloxy)ethyl]-7-methyl-octanoic acid methylamide.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:11]1[CH:16]2[CH2:17][CH2:18][CH:12]1[CH2:13][CH:14]([N:19]([C:23]1[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=1)[N:28](C1CCCCO1)[N:27]=[CH:26]3)[C:20](=[O:22])[CH3:21])[CH2:15]2)[CH2:9][CH3:10].C(=O)([O-])O.[Na+]>ClCCl>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([N:19]([CH:14]3[CH2:15][CH:16]4[N:11]([CH2:8][CH2:9][CH3:10])[CH:12]([CH2:18][CH2:17]4)[CH2:13]3)[C:20](=[O:22])[CH3:21])=[CH:31][CH:30]=2)[CH:26]=[N:27]1
Reactant: CCCN1C2CCC1CC(N(C(C)=O)c1ccc3c(cnn3C3CCCCO3)c1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN1C2CCC1CC(N(C(C)=O)c1ccc3[nH]ncc3c1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64643.6 %

Procedure:
Trifluoroacetic acid (0.2 ml) was added to a solution of N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-N-(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-acetamide (35 mg, 0.0853 mmol) in dichloromethane (0.8 ml), and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby N-(1H-indazol-5-yl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)acetamide (18 g, 64%) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1>>[S:6]1[CH:7]=[C:3]([CH2:2][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=2)[N:4]=[CH:5]1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: ClCc1cscn1
Product: CC(=O)Cc1ccc(OCc2cscn2)cc1

Procedure:
Prepared from 4-chloromethylthiazole and 4-hydroxyphenylacetone by the method of Example 1.
Reaction SMILES: [CH2:1]([CH:3]1[C:7]2=[N:8][C:9]3[C:10]([C:17]([F:20])([F:19])[F:18])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]([OH:16])=[C:6]2[C:5](=[N:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[O:4]1)[CH3:2].[OH2:27]>C(O)(=O)CC>[OH:16][C:15]1[C:14]2[C:9](=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH:3]([O:27][C:3](=[O:4])[CH2:1][CH3:2])[CH2:1][CH3:2])[C:6]=1[C:5]([NH:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=[O:4]
Reactant: CCC1OC(=Nc2nccs2)c2c1nc1c(C(F)(F)F)cccc1c2O
Reactant: O
Solvent: CCC(=O)O
Product: CCC(=O)OC(CC)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Reaction time: 0.83 h

Procedure:
A suspension of 3 g of 1,3-dihydro-3-ethyl-1-[(2thiazolyl)-imino]-5-(trifluoromethyl)-furo-[3,4-b]-quinolin-9-ol in 60 ml of propionic acid was held in a bath at 100°-110° C. for 2 hours and 50 minutes and the solution obtained was cooled and poured into 600 ml of water. After separating and washing with water, 2.5 g of product were obtained which was purified by crystallization from 40 ml of ethyl acetate. The crystals were cooled and recovered by filtration to obtain 1 7 g of 4-hydroxy-2-[1-(1-oxopropoxy)-propyl] -N-(2-thiazolyl)-8-(trifluoromethyl)-3-quinoline carboxamide melting at 216° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17]/[C:18](/[C:26]([F:29])([F:28])[F:27])=[CH:19]/[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:19]([CH:18]([NH:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:26]([F:29])([F:27])[F:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Fc1ccc(-n2ncc3cc(N/C(=C/c4ccccc4)C(F)(F)F)ccc32)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(-n2ncc3cc(NC(Cc4ccccc4)C(F)(F)F)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
To a solution of 66 mg (0.17 mmol) of [1-(4-fluorophenyl)-1H-indazol-5-yl]-((E)-2-phenyl-1-trifluoromethylvinyl)amine in THF was added 10 mg (0.26 mmol) of lithium aluminum hydride. The mixture stirred for 2 hours at room temperature and was then quenched with saturated aqueous sodium sulfate and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude was purified by prep. TLC using 100% dichloromethane to provide 10 mg (7%) of the title compound as a yellow solid. MS m/z 400 (MH+).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:17][CH:18]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH3:19])(=[O:16])[CH2:13][CH2:14][CH3:15]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:17][CH:18]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH3:19])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCC(=O)OC(C)OC(=O)ON1C(=O)CCC1=O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: O
Product: CCCC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (800 mg, 5 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl butanoate (700 mg, 2.6 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 10 (200 mg, 28% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.89-0.97 (m, 5H), 1.22-1.36 (br. m, 3H), 1.42 (d, J=5.6 Hz, 3H), 1.51-1.60 (m, 2H), 1.72-1.73 (br. m, 2H), 1.90-1.93 (m, 2H), 2.13 (tt, J=12, 3.6 Hz, 1H), 2.29 (t, J=6.8 Hz, 2H), 2.85 (t, J=6.4 Hz, 2H), 6.69 (q, J=5.6 Hz, 1H), 7.48 (t, J=6.0 Hz, 1H), 12.03 (br. s, 1H). MS (ESI) m/z 338.15 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:12][C:4]1[S:3][C:2]2[N:1]=[C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][N:19]3[C:7](=[O:9])[C:6]=2[CH:5]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1cc(C)sc1N
Product: Cc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1

Procedure:
A mixture of 2-amino-5-methyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, page 94-100, 1966), 18.5 g (0.1 mol) and 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company), 15.7 g (0.1 mol) is heated in an oil bath at 170°-190° C. for 20 hours. The mixture is cooled, extracted with hot chloroform and the residue is dissolved in hot pyridine, cooled and 0.4 g of 2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid is collected; mp 312°-315° C. after recrystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[B-](F)(F)(F)[F:13].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N.CC(O)=O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[C:10]([F:13])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CC(=O)O
Product: Fc1c[nH]c2nc(Cl)nc(Cl)c12
Temperature: 70 °C
Reaction time: 18 h
Yield: 22.9 %

Procedure:
A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 1.06 mmol) and SelectFluor (560 mg, 1.58 mmol) in CH3CN (5 mL) and HOAc (1 mL) was stirred at 70° C. for 18 h. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give 2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (50 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=3)[CH:11]=[N:10]2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>>[NH2:8][C:5]1[N:4]=[C:3]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:23]#[C:22][C:20]([CH3:21])([OH:24])[CH3:19])[CH:16]=3)[CH:11]=[N:10]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: C#CC(C)(C)O
Reactant: Nc1ncc(Br)c(-n2ncc3ccc(Br)cc32)n1
Product: CC(C)(O)C#Cc1ccc2cnn(-c3nc(N)ncc3Br)c2c1

Procedure:
5-bromo-4-(6-bromoindazol-1-yl)pyrimidin-2-amine (3 g) was reacted with 2-methyl-3-butyn-2-ol (1 eq) via General Procedure Sonagashira Coupling (See, Chinchilla, R.; Najera, C. (2007), “The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry”, Chem. Rev. 107: 874-922) to afford 0.7 g of 4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol following flash column chromatography. 4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol (0.1 g) was reacted with 1-methyl-4-pyrazoleboronic acid pinacol ester via General Procedure Suzuki Coupling to afford 12.2 mg of 4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-ol following reverse phase hplc purification. MS (Q1) 374. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.30 (s, 1H), 7.88-7.81 (m, 2H), 7.48 (s, 1H), 7.24 (dd, J=8.3, 1.1 Hz, 1H), 7.05 (s, 2H), 6.98 (s, 1H), 5.47 (s, 1H), 3.73 (s, 3H), 1.48 (s, 6H).
Reaction SMILES: I[C:2]1C(C2SC=CC=2)=NN[CH:6]=1.[H-].[Na+].C(I)C.[Cl:17][C:18]1[CH:19]=[C:20]([C:23]2[C:27]([I:28])=[CH:26][N:25](CC)[N:24]=2)[S:21][CH:22]=1>CN(C)C=O.CC(OC)(C)C.O>[Cl:17][C:18]1[CH:19]=[C:20]([C:23]2[N:24]([CH2:2][CH3:6])[N:25]=[CH:26][C:27]=2[I:28])[S:21][CH:22]=1
Reactant: CCn1cc(I)c(-c2cc(Cl)cs2)n1
Reactant: Ic1c[nH]nc1-c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: CCn1ncc(I)c1-c1cc(Cl)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a solution of 4-iodo-3-(2-thienyl)-1H-pyrazole (4.8 mmol) in 15 mL dry N,N-dimethylformamide under argon atmosphere was added sodium hydride (5.8 mmol, 60% dispersion in mineral oil) in portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 15 min. After cooling to 0° C., ethyliodide (7.2 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. Sodium hydride (1.2 mmol) and ethyliodide (2.5 mmol) were added and stirring was continued for 24 h. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated to afford 1.71 g of a mixture of 3-(4-chloro-2-thienyl)-1-ethyl-4-iodo-1H-pyrazole and 5-(4-chloro-2-thienyl)-1-ethyl-4-iodo-1H-pyrazole (80:20; 84% yield). The mixture was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 1.27 g 3-(4-chloro-2-thienyl)-1-ethyl-4-iodo-1H-pyrazole (78% yield) and 92 mg of 5-(4-chloro-2-thienyl)-1-ethyl-4-iodo-1H-pyrazole (6% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[Br:8].O.O.Cl[Sn]Cl>>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([Br:8])=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Br)c(Br)c1
Agent: Cl[Sn]Cl
Solvent: O
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)c(Br)c1
Yield: 27.3 %

Procedure:
Prepared from 4.90 g of 4-(3,4-dibromophenylamino)-6-nitroquinoline-3-carbonitrile and 12.4 g of SnCl2.2H2O in the same manner as Example 378. There was obtained 1.25 g of 6-amino-4-(3,4-dibromophenylamino)quinoline-3-carbonitrile as a brown solid: mass spectrum (electrospray, m/e): M+H 416.9, 418.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2/[CH:12]=[C:13](\[F:16])/[CH2:14][OH:15])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2/[CH:12]=[C:13](\[F:16])/[CH:14]=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC/C(F)=C/[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C/C(F)=C/[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 99.3 %

Procedure:
The above alcohol (3.3 g) was oxidised using the conditions of Swern oxalyl chloride, 1.2 ml; dimethyl sulphoxide, 2.0 ml; triethylamine, 8.8 ml] in dichloromethane to give (±)-(2Z)-3-[trans-2-(3,4-dichlorophenyl)cyclopropyl]-2-fluoroprop-2-enal (3.25 g). NMR 1H: 9.20(1H,d), 7.39(1H,d), 7.22(1H,d), 6.95(1H,dd), 5.60(1H,dd), 2.20(2H,m), 1.50(2H,m).