Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:9]([C:20]([OH:22])=[O:21])=[N:10][C:11]([O:18][CH3:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.OS(O)(=O)=O.[CH3:28]O>>[CH3:7][C:4]1[N:3]([C:8]2[C:9]([C:20]([O:22][CH3:28])=[O:21])=[N:10][C:11]([O:18][CH3:19])=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CO
Reactant: COc1nc(C(=O)O)c(-n2c(C)ccc2C)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: COC(=O)c1nc(OC)c(C(F)(F)F)cc1-n1c(C)ccc1C

Procedure:
3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D2)(500 mg, 1.591 mmol) in methanol (15.91 ml) was treated with H2SO4 (0.0424 ml, 0.795 mmol) and the solution was heated at reflux for overnight. The solvent removed was removed in vacuo and the resulting brown oil was neutralised to pH 7 using saturated sodium bicarbonate. The mixture was extracted with EtOAc (20 ml) and the combined organic extracts were washed with water (20 ml), brine (20 ml), passed though a phase separator and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with iso-hexane: EtOAc (gradient of 0 to 10% EtOAc) afforded the title compound as an off-white powder.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:11](=[O:12])[C:10]([CH3:15])([CH3:14])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(Br)n1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 6-bromopyridin-2-amine (10 g, 57.79 mmol, 1 eq.) in 150 ml of DCM were added TEA (17.54 g, 173.3 mmol, 3 eq.) and 2,2-dimethylpropionyl chloride (10.45 g, 86.69 mmol, 1.5 eq.) dropwise. The temperature rose slowly. The reaction was stirred overnight at r.t. The white solid was removed by filtration and the solvent was evaporated. The crude was dissolved in with EtOAc and washed with 0.1N aq. HCl, sat. aqueous NaHCO3. The organics were dried over MgSO4 and concentrated. The resulting solid was recrystallized in EtOAc to give N-(6-bromopyridin-2-yl)-2,2-dimethylpropanamide (13.52 g, 91% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([OH:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22][O:23][CH2:24]Cl>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([O:19][CH2:22][O:23][CH3:24])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(Br)c(O)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A solution of 4-bromo-3-hydroxyphenyl 4-methylbenzenesulfonate in dry DMF (1.0 M) was treated with NaH (1.2 eq of a 60% dispersion in mineral oil) and the mixture was stirred at RT for 30 min. Chloromethyl methyl ether (1.2 eq) was then added dropwise and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc and the organic phase washed with 1 N HCl and brine before drying (Na2SO4), filtering and concentrating in vacuo. The crude was purified by FC (PE/EtOAc 1/9) to afford the title compound (77%). (ES+) m/z 387, 389 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8]2.[ClH:22]>CO>[ClH:22].[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2
Reactant: COc1ccc2c(c1OC)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1OC)CCNC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (800 mg, 2.73 mmol, 1.00 equiv) in methanol (15 mL) and hydrogen chloride (4 mL). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 5 mL of water. The resulting mixture was extracted with 3×30 mL of ethyl acetate and the aqueous layer combined. The mixture was concentrated under vacuum. This resulted in 500 mg (80%) of 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride as a white solid. MS (ESI) m/z 194 ([M+H]+).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C:5]1([CH3:29])[CH:7]([CH:8]=C(C)C)[CH:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13]>C(OCC)(=O)C>[CH3:29][C:5]1([CH3:4])[CH:7]([CH:8]=[O:1])[CH:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13]
Reactant: O=[O+][O-]
Reactant: CC(C)=CC1C(C(=O)OCc2cccc(Oc3ccccc3)c2)C1(C)C
Solvent: CCOC(C)=O
Product: CC1(C)C(C=O)C1C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
Ozone gas was bubbled at -78° C. into a solution of 3.50 g (10.0 mmol) of 3-phenoxyphenylmethyl 2,2-dimethyl- 3-(2-methyl-1-propenyl)cyclopropanecarboxylate obtained in Reference Example 2, in 20 ml of ethyl acetate. The subsequent operation was conducted in the same manner as those in Reference Example 5, whereby 2.66 g of 3-phenoxyphenylmethyl 2,2-dimethyl-3-formylcyclopropanecarboxylate was obtained as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([Br:14])[O:13][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[Br:14][C:12]1[O:13][C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2oc(Br)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2oc(Br)cc2[nH]1
Temperature: 25 °C

Procedure:
2-Bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester (Krutosikova, A.; Kovac, J.; Dandarova, M.; Lesko, J.; Ferik, S., Collect. Czech. Chem. Commun., 46: 2564-2573 (1981)) was hydrolyzed according to Procedure E (4 equiv 2 N NaOH, ethanol; reflux 5 h, room temperature overnight; after concentration to remove ethanol, residue partitioned between ethyl acetate and 2 N HCl; combined organic phases dried over Na2SO4; no purification).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([NH2:13])=O)[CH:8]=[C:7]([CH3:14])[N:6]=1)([CH3:3])[CH3:2].N1C=CC=CC=1>C(Cl)Cl>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]#[N:13])[CH:8]=[C:7]([CH3:14])[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C(N)=O)nc(NC(C)C)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C#N)nc(NC(C)C)n1
Reaction time: 4 h
Yield: 249.2 %

Procedure:
To a suspension of 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid amide (1.24 g, 6.4 mmol) in DCM (20 mL), pyridine (2.53 mL, 25.6 mmol) is added followed by TFFA (2.7 mL, 19.2 mmol). The reaction mixture is stirred for 4 h, and then is quenched with water. The mixture is extracted with DCM. The org. phase is washed with sat. aq. NaHCO3 and dried over MgSO4, filtered and evaporated. Purification by CC on silica gel (eluting with Heptane/EtOAc 4:1) affords the 2-isopropylamino-6-methyl-pyrimidine-4-carbonitrile as a yellow oil (2.81 g); LC-MS: tR=0.89; [M+H]+=177.04.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH3:37][S:38]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)[CH2:10]1)(=[O:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N[C@@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(t-butoxycarbonyl)amino)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 30 in Step A and methylsulfonyl chloride in Step B, the title compound can be prepared.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]=[C:8]=[O:9].[N+:10](=[C:12]1[N:16]=[CH:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])=[N-:11]>CS(C)=O>[O:9]=[C:8]1[N:7]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:11]=[N:10][C:12]2=[C:13]([C:17]([NH2:19])=[O:18])[N:14]=[CH:15][N:16]12
Reactant: O=C=NCc1cccs1
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CS(C)=O
Product: NC(=O)c1ncn2c(=O)n(Cc3cccs3)nnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiophen-2-ylmethyl isocyanate (0.350 g, 2.5 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.314 g, 2.3 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (off-white) was removed by filtration, washed with water and ethyl acetate and air dried to give the title compound. Yield: 0.405 g, 64%. IR vmax/cm−1 3094, 1732, 1690, 1607. 1H NMR δH (DMSO-d6) 5.68 (2H, s, CH2Ar), 7.03 (1H, dd, J=5.1, 3.5, ArH), 7.25 (1H, dd, J=3.5, 1.0, ArH), 7.55 (1H, dd, J=5.1, 1.0, ArH), 7.71 (1H, br s, NH), 7.83 (1H, br s, NH), 8.85 (1H, s, 6-H).
Reaction SMILES: S(Cl)([Cl:3])=O.N1C=CC=CC=1.O[CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1>O>[Cl:3][CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: O=S(Cl)Cl
Reactant: OCC1COc2ccccc2O1
Solvent: c1ccncc1
Solvent: O
Product: ClCC1COc2ccccc2O1

Procedure:
In a three neck flask fitted with a stirring device, 218 g thionyl chloride are mixed with 1000 g pyridine while cooling. They are added further, portionwise 500 g 2(hydroxy methyl) (2,3-dihydro [4H] 1,4-benzodioxin) while keeping the inner temperature below 20°. When the reaction is completed, the mixture is heated at 100° for 3 hours then poured into water and extracted with chloroform. The solvent is distilled off and the raw residue is purified by fractional distillation under reduced pressure. 340 g of the chloromethylated derivative are obtained. It boils at 85°-90°/0.2 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][C:12](=[CH2:17])[C:13]([O:15]C)=[O:14])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[C:18]([OH:21])(=[S:20])[CH3:19]>>[C:18]([S:20][CH2:17][CH:12]([CH2:11][C:3]1[C:2]([Cl:1])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)[C:13]([OH:15])=[O:14])(=[O:21])[CH3:19]
Reactant: C=C(Cc1cc2c(cc1Cl)OCO2)C(=O)OC
Reactant: CC(O)=S
Product: CC(=O)SCC(Cc1cc2c(cc1Cl)OCO2)C(=O)O

Procedure:
The operation is carried out as in Stage 4 of Example 1 starting with 223 mg of product obtained in Stage 4 above and 0.16 ml thioacetic acid. In this way 172 mg of expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38]>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Clc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCN1CCN(c2n[nH]c3cc(Cl)ccc23)CC1
Reaction time: 40 h
Yield: 111.3 %

Procedure:
A mixture of 6-chloro-3-(1-piperazinyl)-1H-indazole (3.4 g, 14 mmol), K2CO3 (2.5 g, 18 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (3.8 g, 16 mmol), KI (200 mg), and acetonitrile (125 ml) was stirred at reflux under N2 for 30 hours. After standing at room temperature for 40 hours, the reaction was filtered and the filter cake was washed well with acetonitrile. The filtrate was concentrated to an oily solid, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4, and concentrated to yield 6.9 g of a dark oil, which solidified after 2 days under vacuum. The product was purified by preparative HPLC (Waters Associates Prep LC/system 500 utilizing 2 silica gel columns and 6% methanol/methylene chloride as eluent) to yield 4.2 g. The material was recrystallized from ethanol to yield 3.4 g of glistening, beige, 1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]ethanone crystals, m.p.=132°-134° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].C([NH2:20])(=O)C1C=CC=CC=1.C(Cl)(C(Cl)=O)=O.[NH4+].[OH-]>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:20])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: NC(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc(C(N)=O)cc1I
Yield: 93 %

Procedure:
3-Iodo-4-methyl benzoic acid was converted to the corresponding benzamide according to the procedure described for compound la above ((COCl)2, NH4OH), to provide 3-iodo-4-methyl benzamide in 93% yield. Further conversion according to Method B described above provided compound 10 in 48% yield. 1H NMR (CDCl3) δ 8.02 (1 H, d, J=1.6 Hz), 7.95 (1 H, d, J=7.9 Hz), 7.29 (1 H, d, J=7.9 Hz), 6.46 (1 H, d, J=15.9 Hz), 6.10 (1 H, br s), 5.75 (1 H, br s), 4.08 (2 H, q, J=7.1 Hz), 2.48 (3 H, s), 1.42 (3 H, t, J=7.1 Hz) Anal. (C13H12N2O3.0.2 H2O) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH2:7].[F:11][C:12]([F:19])([F:18])[C:13](OCC)=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH:7][C:13](=[O:14])[C:12]([F:19])([F:18])[F:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCc1cccc(Br)c1
Product: O=C(NCCc1cccc(Br)c1)C(F)(F)F

Procedure:
Condensation of 3-bromophenethylamine with ethyl trifluoroacetate gave N-(3-bromophenethyl)-2,2,2-trifluoroacetamide as a colorless oil. Yield (3.30 g, quant.). 1H NMR (400 MHz, CDCl3) δ 7.40 (ddd, J=7.8, 1.8, 1.0 Hz, 1H), 7.53 (t, J=1.8 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 7.10-7.13 (m, 1H), 6.32 (br s, 1H), 3.61 (q, J=6.7 Hz, 2H), 2.87 (t, J=7.2 Hz, 2H).
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[OH-].[Na+].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>O>[CH3:8][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[N:1][C:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:22])[F:23])=[CH:18][CH:17]=1)=[O:21]
Reactant: CN1CCCCC1=N
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCCCC1=NC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The hydrochloride salt of 2-imino-1 -methylpiperidine (7.60 g.; 0.068 mole) is converted to free base by adding 7 ml. of NaOH (50%) to an aqueous slurry (using a minimal amount of water) of the salt and then extracting with benzene. After drying over K 2 CO 3, the benzene solution is filtered through diatomaceous earth. A benzene solution of 12.73 g. (0.068 mole) of p-trifluoromethylphenylisocyanate [prepared according to Inukai and Maki, Kogyo Kagaku Zasshi, 67 (5) 807-9 (1964[ is added to the above solution slowly. After 4 hours of stirring at room temperature, the benzene is evaporated in vacuo to give a solid residue. Repeated recrystallizations of the solid from methanol yields the pure product, 1-(1 -methyl-2 -piperidylidene)-3-(4-trifluoromethylphenyl)urea, m.p. = 154 -155° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14]Br)=[N:5]1)(=[O:3])[CH3:2].[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14][N:17]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(=O)n1nc(CBr)c2ccc(F)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)n1nc(CN2CCc3ccccc3C2)c2ccc(F)cc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
1-Acetyl-3-bromomethyl-6-fluoro-1H-indazole (0.53 g, 1.96 mmol) in CH2Cl2 (10 mL) was treated with 1,2,3,4-tetrahydroisoquinoline (0.261 g, 1.96 mmol) and Hunig's base (0.44 mL, 2.5 mmol) and the mixture stirred at 20° C. for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (7%→12% EtOAc in hexane) to give the title compound as a white solid (475 mg, 53%); mp 106°-107° C. (from Et2O/hexane); 1H NMR (360 MHz, d6 -DMSO) δ 8.08 (dd, J=8.8, 5.4 Hz, 1H, indazole), 8.00 (dd, J=9.6, 2.2 Hz, 1H, indazole), 7.29 (dt, J=9.1, 2.5 Hz, 1H, indazole), 7.10 (m, 3H, tetrahydroisoquinoline), 7.02 (m, 1H, tetrahydroisoquinoline), 4.05 (s, 2H, Ar--CH2N), 3.68 (s, 2H, Ar--CH2N)), 2.79 (m, 4H, tetrahydroisoquinoline)2.72 (s, 3H, Ac); MS (CI+) m/e 324 (M+H+); Anal. calcd for C19H18FN3O: C, 70.57; H, 5.61; N, 12.99. Found: C, 70.28; H, 5.32; N, 12.84.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(=O)OC(C)(C)C)=[C:20]([O:32][CH3:33])[CH:19]=3)[CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2[CH:9]=[C:10]([CH2:11][N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[N:6]3[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[CH:19][C:20]=1[O:32][CH3:33]
Reactant: COc1cc(-c2cc(CN3CCOCC3)n3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cc(CN3CCOCC3)n3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
To a solution of t-butyl {4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2methoxyphenyl}carbamate (100 mg, 0.22 mmol) in CH2Cl2 (4 ml) was added trifluoroacetic acid (1.5 ml) and was stirred at rt for 3 h. The reaction mixture was partially evaporated and was added 10 ml ethyl acetate and washed with saturated aq. NaHCO3. The organic was dried over Na2SO4 and concentrated to afford 80 mg of the title compound. 1H-NMR (DMSO-d6) δ 7.84 (s, 1H), 6.84 (d, J=2 Hz, 1H), 6.84 to 6.68 (m, 2H), 6.55 (s, 1H), 4.87 (s, 2H), 4.01 to 3.99(m, 5H), 3.53 (t, J=4 Hz, 4H), 2.42(t, J=4 Hz, 4H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][C:14]#[N:15])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9][C@H:8]1[CH2:13][C:14]#[N:15])=[O:6])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CC#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 109.7 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-2-cyanomethyl-4-hydroxypyrrolidine (2.95 g) in dichloromethane (30 ml) were added triethylamine (1.85 g) and a solution of methanesulfonyl chloride (1.76 g) in dichloromethane (2 ml) at ice-cooling. After stirring at 5°-10° C. for 1 hour, the solution was poured into an ice water. The separated organic layer was washed with water and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated to give (2R,4R)-1-allyloxycarbonyl-2-cyanomethyl-4-methanesulfonyloxypyrrolidine (4.44 g).
Reaction SMILES: N#N.[Br:3][C:4]1[C:11]([F:12])=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[F:13].CCN(CC)CC.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][S:21]([O:9][CH2:8][C:7]1[CH:10]=[C:11]([F:12])[C:4]([Br:3])=[C:5]([F:13])[CH:6]=1)(=[O:23])=[O:22]
Reactant: OCc1cc(F)c(Br)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(F)c(Br)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-3,5-difluorobenzyl alcohol (100 mg, 0.45 mmol) in dry CH2Cl2 (3 mL) was treated at 0° C. with Et3N (0.081 mL, 0.58 mmol) followed by DMAP (5 mg, 0.045 mmol) and Ms-Cl (0.037 mL, 0.47 mmol). After stirring at 0° C. for 0.5 h and at rt for 0.5 h, the reaction was quenched with water (2 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromo-3,5-difluorophenyl)methyl methanesulfonate as a yellow oil. This material was dissolved in dry DMF (3 mL) and treated with NaN3 (29 mg, 0.45 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(azidomethyl)-4-bromo-3,5-difluorobenzene as a yellow oil. LC-MS-conditions 07: tR=0.90 min.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[CH3:5][O:6][C:7](=[O:18])[C:8](=[C:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].[NH4+].[Cl-]>O1CCCC1.[Cu]I>[CH3:12][O:11][C:9](=[O:10])[CH:8]([C:13]([CH2:1][CH3:2])([CH2:16][CH3:17])[CH2:14][CH3:15])[C:7]([O:6][CH3:5])=[O:18]
Reactant: CCC(CC)=C(C(=O)OC)C(=O)OC
Reactant: CC[Mg]Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)(CC)C(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
Step B To a suspension of CuI (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at −50° C. was added ethylmagnesium chloride (2 M, 40 mL, 80 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to −50° C., a tetrahydrofuran solution (50 mL) of 2-(1-ethyl-propylidene)-malonic acid dimethyl ester (3.5 g, 17.5 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4Cl solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:30) to give 2-(1,1-diethyl-propyl)-malonic acid dimethyl ester as a colorless oil (2.6 g, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C@@H:17]1[CH2:29][C:30]([OH:32])=[O:31].S(=O)(=O)(O)O.[CH3:38]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]1[CH2:29][C:30]([O:32][CH3:38])=[O:31]
Reactant: COc1ccc2nccc(CCC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3CC(=O)O)c2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C[C@H]1CNCC[C@H]1CCCc1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 2.8 g of (3R,4R)-4-(3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetic acid in 100 cm3 of anhydrous methanol to which had been added 1 cm3 of 95% sulfuric acid was heated with stirring at a temperature in the region of the boiling point for 2 hours. After cooling to a temperature in the region of 20° C., the reaction mass was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and then 20 cm3 of a saturated aqueous sodium hydrogencarbonate solution were added to the residue obtained. The mixture was extracted with 4 times 20 cm3 of dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.25 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate were obtained in the form of an oil with a brown color.