Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O-].[Na+].[Na].[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].Br[CH2:18][CH2:19][CH:20]=[CH2:21]>CCO>[CH2:21]([CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13])[CH2:20][CH:19]=[CH2:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: C=CCCC(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of NaOEt, prepared from the treatment of 1 L EtOH with sodium metal (19.5 g, 0.813 mol), was cooled to 0° C. and diethyl malonate (3-1, 100 g, 0.625 mol) was added dropwise over 0.5 h. After the addition was complete, the reaction was stirred for an additional 0.5 h, then a solution of 1-bromo-3-butene (76.1 mL, 0.75 mol) in 100 mL EtOH was added dropwise over forty-five minutes. The reaction was heated to reflux for 18 h, cooled and the solvent was removed in vacuo. The residue was dissolved in H2O and washed with EtOAc. The organic layer was dried with brine and MgSO4, filtered and evaporated. Fractional distillation of the residue (0.25-0.4 mm Hg, 70°-80° C.) gave 3-2 as a clear liquid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:17])[N:6]=[C:7]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]3=2)[N:3]=1.[F-:18].[K+].C1OCCOCCOCCOCCOCCOC1>CN1C(=O)CCC1>[F:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:17])[N:6]=[C:7]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]3=2)[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1nc(Cl)ccc12
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)nc(N)c1nc(F)ccc12
Temperature: 210 °C

Procedure:
A mixture of 3-chloro-8-methylbenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq.) potassium fluoride (4.0 eq.), and 18-crown-6 (0.4 eq.) in NMP (0.1M) was heated in microwave reactor at 210° C. for 2 hours. After cooling to ambient temperature, the reaction residue was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-30% EtOAc/Hexanes to give 3-fluoro-8-methylbenzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (acetone-d6): δ 9.20 (dd, 1H), 8.32 (d, 1H), 7.58 (dd, 1H), 7.46 (d, 1H), 7.21 (dd, 1H), 6.51 (br s, 2H), 2.47 (s, 3H). LRMS [M+H]=228.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([CH:21]([NH2:23])[CH3:22])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1)(=[O:4])=[O:3].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C.O>C(O)CCC>[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([NH:23][CH:21]([C:20]2[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:2]([CH3:1])(=[O:3])=[O:4])=[N:12][C:13]3[C:18]([CH:19]=2)=[N:17][CH:16]=[CH:15][CH:14]=3)[CH3:22])[N:28]=[CH:27][N:26]=1
Reactant: CC(N)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCCCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc(N)c1C#N)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of crude 1-(2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethanamine (600 mg, 1.83 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (283 mg, 1.83 mmol) in n-butanol (11 mL) was added Hunig base (709 mg, 5.49 mmol) at 25° C. The reaction mixture was stirred for overnight at 110° C. Water was added to reaction mixture and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on neutral alumina using 0-5% MeOH in DCM. It was further purified by reversed-phase HPLC to give 4-amino-6-((1-(2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethyl)amino)-5-pyrimidine-carbonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 1.387 (d, J=6.8 Hz, 3H), 5.250-5.322 (m, 1H), 7.246 (br s, 2H), 7.735-7.843 (m, 3H), 7.911-7.940 (m, 3H), 8.110-8.129 (m, 1H), 8.395 (d, J=4.4 Hz, 1H), 8.622 (s, 1H), 9.028-9.074 (m, 1H); LC-MS (ESI) m/z 446.0 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[OH:21])[O:17][C:16](=[O:22])[C:15]([C:23]([OH:25])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12>CN(C=O)C>[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:23]([C:15]3[C:16](=[O:22])[O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([OH:10])=[C:20]([OH:21])[CH:19]=4)=[O:25])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12
Reactant: O=C(O)c1cc2cc(O)c(O)cc2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(O)c(O)cc2oc1=O
Temperature: 25 °C

Procedure:
DIEA (43.1 μL, 0.25 mmol) was added to 6,7-dihydroxy-3-carboxy-coumarin (50.0 mg, 0.23 mmol) and HATU (94.1 mg, 0.25 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (47.1 mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give the final product: LCMS (ESI) m/z 413 (MH+).
Reaction SMILES: C([Li])CCC.[S:6]1[CH2:10][CH2:9][S:8][CH:7]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Br[CH2:17][CH2:18][CH2:19][C:20]#[N:21]>C1COCC1.C(OCC)C>[C:20]([CH2:19][CH2:18][CH2:17][C:7]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:8][CH2:9][CH2:10][S:6]1)#[N:21]
Reactant: CCOC(=O)C1SCCS1
Reactant: N#CCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C1(CCCC#N)SCCS1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (6.5 mL, 1.6 M in hexane) was added to a solution of ethyl 1,3-dithiolane-2-carboxylate (1925 mg, 10 mmol) in THF (10 mL) at −78° C. under N2. The reaction mixture was stirred for 30 min at −78° C. and then 4-bromobutanenitrile (1469 mg, 10 mmol) in THE (10 mL) was added. The mixture was warmed to room temperature and stirred for 30 min. It was diluted with diethyl ether and washed with 1 N HCl and H2O, and dried. Evaporation and purification by column chromatography afforded ethyl 2-(3-cyanopropyl)-1,3-dithiolane-2-carboxylate: LCMS tR=1.86 Min (5 min run, UV254nm), Mass calculated for, M+259.0, observed LC/MS m/z 260.0 (M+H).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[C:14]([NH2:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>C(O)C>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:23][C:14]([CH3:16])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:15])[NH:7][C:6]=2[CH:8]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Solvent: CCO
Product: CC(C)(NC1=NS(=O)(=O)c2sc(Cl)cc2N1)c1ccccc1
Yield: 20 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.0 g, 3.9 mmol) and cumylamine (1.06 g, 7.8 mmol) in ethanol (6 ml) was stirred for 31 h at 120° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue dissolved in 1N sodium hydroxide (50 ml) followed by treatment with decolourising charcoal. After filtration, the clear solution was acidified to pH <2 with 4M hydrochloric acid and the precipitate was filtered off and recrystallised from ethanol to give 278 mg (20%) of the title compound; mp ca. 360° C. (decomposes gradually above 200° C.); 1H-NMR (DMSO-d6): δ1.68 (s, 6H), 7.12 (s, 1H), 7.17-7.41 (m, 6H), 10.72 (br s, 1H); MS: m/e 355/357 (M+); (C14H14ClN3O2S2) calc C, 47,25; H, 3.97; N, 11.81; found C, 46.82; H, 3.96; N, 11.62.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O=P(Cl)(Cl)Cl.[CH2:15]([O:17]C(=O)C)C>CN(C=O)C.CCCCCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:15]=[O:17])=[CH:2]1
Reactant: CCOC(C)=O
Reactant: c1ccc2[nH]ccc2c1
Solvent: CCCCCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
1H-Indole (10 g, 85.360 mmol) in DMF (10 mL) was added dropwise to a stirred solution of POCl3 (8.67 mL, 93.896 mmol) in DMF over a period of 10 minutes at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (40% ethylacetate in hexane). The reaction mixture was quenched with chilled water, followed by the addition of aqueous NaOH solution and refluxed at 100° C. for 15 minutes. The reaction mixture was cooled to room temperature and maintained at 0° C. overnight. The precipitate formed was collected, washed with water and dried to afford 11.6 g of the product (94% yield).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([CH3:32])([CH2:11][C:12](=[O:31])[NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:19]=1)[CH2:7][C:8]([OH:10])=O.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>ClCCl.CN(C)C=O>[CH3:5][C:6]([CH3:32])([CH2:7][C:8]([N:37]1[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]1)=[O:10])[CH2:11][C:12]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:16][CH:15]=1)=[O:31]
Reactant: CN1CCNCC1
Reactant: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)CC(=O)O)cn1)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN1CCN(C(=O)CC(C)(C)CC(=O)Nc2ccc(OC(=O)N(C)c3ccccc3)nc2)CC1
Reaction time: 2 h
Yield: 51 %

Procedure:
Thionyl chloride (56 microL, 0.78 mmol) was added to a stirred solution of 3,3-dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid (0.15 g, 0.39 mmol) in dichloromethane (5 mL) and 2 drops of dimethylformamide. After stirring for 10 minutes N-methylpiperazine (1 mL) was added and stirring was continued for 2 hours. The solvent was evaporated in vacuo. The residue was redissolved in dichloromethane and extracted with water, dried over sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by filtration over a short column (SiO2, ethyl acetate followed by acetone) yielding the title compound (93 mg, 51% yield) as a thick oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]=[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:9]=[C:8]([CH3:21])[S:7]1)=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1>C1COCC1>[F:1][C:2]([F:23])([F:22])[C:3]([N:5]=[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:9]=[C:8]([CH3:21])[S:7]1)=[S:33]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)(F)F)s1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=S)C(F)(F)F)s1
Yield: 47.8 %

Procedure:
A solution of 2-(trifluoroacetyl)imino-3-[3-(trifluoromethyl)phenyl]-5-methylthiazoline (1 g) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (2 g) in THF (10 ml) was refluxed for 2 days. After cooling and removal of the solvent under reduced pressure, the concentrated residue was added pottasium hydrogencarbonate, The obtained crystallines were recrystallized to give 0.5 g of 2-[trifluoromethyl(thiocarbonyl)imino]-3-[3-(trifluoromethyl)phenyl]-5-methylthiazoline (Compound No. 2)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25]>>[C:1]([NH:4][C:5]1[C:6]([C:15]([F:18])([F:17])[F:16])=[CH:7][C:8]([S:11]([Cl:14])(=[O:12])=[O:13])=[CH:9][C:10]=1[N+:24]([O-:26])=[O:25])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(S(=O)(=O)Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.0 G. of 4-acetylamino-3-trifluoromethylbenzenesulfonylchloride is dissolved in 15 ml. of concentrated sulfuric acid. 0.9 Moles of nitric acid is added dropwise over a period of 15 minutes, while the temperature is kept below 35° C. When the addition is complete the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is poured onto 150 ml. of ice water and the precipitate is filtered, washed with water and dried affording 4-acetylamino-3-nitro-5-trifluoromethylbenzenesulfonylchloride, used directly in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]([O:22]C)=O.[H-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]([CH2:2][C:1](=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:22]
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc2ccccc2c1)c1ccccc1
Reaction time: 0.17 h

Procedure:
Acetophenone (500 mg, 4.12 mmol), methyl 2-naphthoate (1.03 g, 5.36 mmol) and THF (20 mL) were added sequentially to a 50 mL round bottom flask. After stirring the mixture for 10 min, a suspension containing NaH (167 mg, 6.61 mmol) in THF (10 mL) was added dropwise at room temperature under N2. The mixture was stirred for 20 h before saturated aqueous NaHCO3 (1 mL) was added to quench the reaction. THF was removed in vacuo before 1 M HCl (20 mL) was added. The aqueous phase was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with distilled water (2×10 mL) and brine (10 mL), and dried over Na2SO4 before concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (6:1) to give 2-naphthoyl benzoylmethane, thin, as a yellow solid: 700 mg (62%). 1H NMR (300 MHz, CDCl3) δ 16.98 (s, 1H, ArCOH), 8.62 (s, 1H, 1′-ArH), 8.08-7.87 (m, 6H, 3′, 4′, 5′, 2″, 6″-ArH), 7.62-7.49 (m, 5H, 6′,7′-ArH. 3″, 4″, 5″-ArH), 7.01 (s, 1H, COCHCO); MS (MALDI) m/z 275.13 (M+H+), calcd m/z 275.11.
Reaction SMILES: [CH2:1]([N:3]([C:19]1[CH:24]=[C:23]([O:25]C)[CH:22]=[CH:21][C:20]=1[CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:37]C)[CH:33]=2)[CH2:28]1)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13](=O)[NH:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[CH3:2].C(N(CC1C=CC(OCCNCC)=CC=1)C1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C>>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][NH:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=1[CH:27]1[CH2:36][CH2:35][C:34]2[CH:33]=[C:32]([OH:37])[CH:31]=[CH:30][C:29]=2[CH2:28]1)[CH3:2]
Reactant: CCNC(=O)COc1ccc(C(=O)N(CC)c2cc(OC)ccc2C2CCc3cc(OC)ccc3C2)cc1
Agent: CCNCCOc1ccc(CN(CC)c2cc(OC)ccc2C2CCc3cc(OC)ccc3C2)cc1
Product: CCNCCOc1ccc(CN(CC)c2cc(O)ccc2C2CCc3cc(O)ccc3C2)cc1

Procedure:
Synthesized from N-ethyl-4-ethylcarbamoylmethoxy-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide according to an analogous synthetic method to Example 337, ethyl[4-(2-ethylaminoethoxy)benzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (143 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (138 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[Br:12]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:9][C:8]1[C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[S:6][CH:7]=1
Reactant: Cc1csc2ccc(F)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Fc1ccc2scc(CBr)c2c1
Yield: 51.8 %

Procedure:
5-Fluoro-3-methyl-benzo[b]thiophene (1.7 g, 10.24 mmol) was reacted with N-bromo succinimide (2 g, 1126 mmol) and benzoyl peroxide (2 mg) in CCl4 (15 mL). The resulting reaction mass was refluxed using photoelectric radiation. The reaction was monitored by TLC (100% hexane). The reaction mass was quenched with water and separated the CCl4 layer. The aqueous layer was extracted with chloroform and the organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated. Purification by column chromatography on silica gel (100% hexane) afforded 1.3 g of the product (52% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[CH2:15]([S:22][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(Cl)n1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc(SCc2ccccc2)n1
Yield: 46.4 %

Procedure:
In a similar fashion using route 38 general procedure 92, 2-chloro-6-methylpyridine (1 g, 7.8 mmol), K2CO3 (1.62 g 11.75 mmol), benzylmercaptan (1.46 g 11.8 mmol) and DMSO (7.5 ml) at 150° C. for 4 h in sealed tube gave the title compound (780 mg, 47%) which was used in the next step without further purification.
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[CH:16]1([NH2:19])[CH2:18][CH2:17]1.S(=O)(=O)(O)O>>[CH:16]1([NH:19][C:2]2[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=2[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6])[CH2:18][CH2:17]1
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1F
Reactant: NC1CC1
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1NC1CC1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
5.0 g (22 mmol) of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid were dissolved in 25.0 ml (356 mmol) of cyclopropylamine. The mixture was heated at 120° C. with stirring in an autoclave for 1 day, cooled to room temperature (RT), added to ice and conc. sulfuric acid and extracted with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC. This gave 1.8 g of a beige solid in a purity of 95%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:20][O:21][N:22]=[C:23]1[C:27]2([CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[CH2:26][NH:25][CH2:24]1>C(#N)C>[C:34]([O:33][C:31]([N:29]1[CH2:30][C:27]2([C:23](=[N:22][O:21][CH3:20])[CH2:24][N:25]([C:11]3[CH:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:26]2)[CH2:28]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Solvent: CC#N
Product: CON=C1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CN(C(=O)OC(C)(C)C)C2
Yield: 46.4 %

Procedure:
1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid and 840 mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate were added to 10 ml of acetonitrile and the resulting mixture was refluxed for 3 hours. Then the precipitated solid was filtered and dried to give 340 mg of the titled compound(yield: 46.4%).
Reaction SMILES: [F:1][CH2:2][C:3]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:7][CH2:6][N:5]([C@H:8]([C:13]2[CH:14]=[N:15][C:16]([NH:19][NH2:20])=[CH:17][CH:18]=2)[C:9]([F:12])([F:11])[F:10])[CH2:4]1.[CH3:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[C:38]([CH:41]=O)[CH:37]=[CH:36]2>>[F:1][CH2:2][C:3]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:7][CH2:6][N:5]([C@H:8]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:41]([C:38]4[CH:37]=[CH:36][C:35]5[C:40](=[C:31]([O:30][CH3:29])[CH:32]=[CH:33][CH:34]=5)[N:39]=4)=[N:20][N:19]=3)[CH:14]=2)[C:9]([F:12])([F:10])[F:11])[CH2:4]1
Reactant: COc1cccc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)NC1(CF)CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Product: COc1cccc2ccc(-c3nnc4ccc([C@@H](N5CCC(CF)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12

Procedure:
Prepared as described in Example 9B using tert-butyl 3-(fluoromethyl)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (Example 154; 0.20 g, 0.491 mmol) in place of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidine-3-ylcarbamate and 8-methoxyquinoline-2-carbaldehyde (0.092 g, 0.491 mmol) in Step E (0.229 g, 81%). LCMS APCI (+) m/z 575 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.NC(C1C=CC(F)=C([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])C=1)C.CCN(C(C)C)C(C)C>C(O)CCC>[C:14]([C:13]1[C:12]([NH:19][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:23]=2)[CH3:21])=[N:11][C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[C:17]([F:18])[CH:16]=1)#[N:15]
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Reactant: CC(N)c1ccc(F)c(NS(C)(=O)=O)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)c(NS(C)(=O)=O)c1
Temperature: 150 °C
Yield: 20.2 %

Procedure:
To a 10-ml microwave vessel was added, 2-chloro-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoronicotinonitrile (Method 1, 600 mg, 2.3 mmol), N-[5-(1-aminoethyl)-2-fluorophenyl]methanesulfonamide (Method 61, 500 mg, 2.3 mmol), DIEA (0.5 ml, 2.76 mmol), and n-butanol (5 ml). The vessel was sealed and subjected to microwave heating at 150° C. for 5 hours (CEM Discover System). The resulting mixture was then purified by silica gel chromatography using 5% MeOH/DCM. The racemic product obtained was then chirally purified by HPLC on Chiralcel OJ column (500×50 mm, 20 microns) using 50:25:25:0.1% of hexane/MeOH/EtOH/diethylamine at 118 ml/min. The chiral purification gave 220 mg of N-{5-[(1R)-1-({3-cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamide 1H NMR: δ 11.77-12.26 (br s, 1H), 9.51 (s, 1H), 9.34-9.48 (br s, 1H), 7.62 (d, J=10.55 Hz, 1H), 7.39 (d, J=8.29 Hz, 1H), 7.02-7.23 (m, 3H), 6.00 (s, 1H), 5.07-5.24 (m, 1H), 2.95 (s, 3H), 1.81-1.95 (m, 1H), 1.49 (d, J=7.54 Hz, 3H), 0.88-0.97 (m, 2H), 0.57-0.68 (m, 2H). MS: Calcd.: 473. Found: [M+H]+ 474 and 223 mg of N-{5-[(1S)-1-({3-cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamidel; 1H NMR: 11.73-12.38 (br s, 1H), 9.42 (s, 1H), 8.41-9.12 (br s, 1H), 7.61 (d, J=11.30 Hz, 1H), 7.37 (d, J=7.54 Hz, 1H), 6.96-7.24 (m, 3H), 6.02 (s, 1H), 5.05-5.26 (m, 1H), 2.90 (s, 3H), 1.79-1.96 (m, 1H), 1.49 (d, J=6.78 Hz, 3H), 0.89-0.98 (m, 2H), 0.59-0.67 (m, 2H). MS: Calcd.: 473. Found: [M+H]+ 474.
Reaction SMILES: Cl[CH2:2][CH:3]=O.[NH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1.Cl.N>CCOCC.O>[C:17]1([N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]3[CH2:7][CH2:6][NH:5][CH2:2][CH2:3][C:9]2=3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CCCl
Reactant: NCCc1cn(-c2ccccc2)c2ccccc12
Agent: Cl
Agent: N
Solvent: O
Solvent: CCOCC
Product: c1ccc(-n2c3c(c4ccccc42)CCNCC3)cc1

Procedure:
55.6 ml chloroacetaldehyde (45% in water) are added dropwise to 87.2 g 3-(2-aminoethyl)-1-phenylindole, 400 ml 2N hydrochloric acid and 2.5 liters water at 50°. The mixture is heated for 1 hour at 95°, treated once more with 55.6 ml chloroacetaldehyde and heated for a further 45 minutes. The mixture is then cooled to 0°, made alkaline with conc. ammonia and shaken with ether. The organic phase is dried over sodium sulphate, and purified with animal charcoal, and concentrated. The residue 1-chloromethyl-1,2,3,4-tetrahydro-9-phenylpyrido[3,4-b]indole is converted into the hydrochloride, m.p. 174°-180° (from ethanol/ether).