Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[O:14]1CCOCC1.Cl>O>[N:9]1[CH:10]=[CH:11][CH:12]=[N:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2](=[O:14])[NH:7][CH:6]=1
Reactant: Fc1ccc(-c2ncccn2)cn1
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: O=c1ccc(-c2ncccn2)c[nH]1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
A resealable tube was charged with 2-(6-fluoropyridin-3-yl)pyrimidine (0.150 g, 0.856 mmol), dioxane (3.0 mL), and water (1.00 mL). Concentrated hydrochloric acid (37%)(0.25 mL) was added, the system was flushed with argon, the tube was sealed, and the reaction mixture stirred at 100° C. for 1.5 hours. The reaction mixture was then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 5-(pyrimidin-2-yl)pyridin-2(1H)-one (0.079 g, 0.456 mmol, 53% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.45 (dd, J=9.59, 0.78 Hz, 1H), 7.33 (t, J=4.89 Hz, 1H), 8.32 (td, J=10.07, 2.35 Hz, 2H), 8.79 (d, J=4.89 Hz, 2H), 11.96 (br. s., 1H). m/z (ESI) 174 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1)#[CH:26].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:24])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:26]#[C:25][C:27]3[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(C=O)cc1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(C#Cc4ccc(C=O)cc4)n[nH]c3c1)C(=O)N2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 12.2 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro [cyclopropane-1,3′-indolin]-2′-one (862 mg, 2 mmol), 4-ethynylbenzaldehyde (286 mg, 2.2 mmol), Pd(PPh3)2Cl2 (28 mg, 0.04 mmol, 2 mmol %) and CuI (15.3 mg, 0.08 mmol, 4 mmol %) in a 50 mL of flask was added DMF (6 mL) and Et3N (10 mL). The resulting mixture was stirred at 100° C. (oil temp.) for 90 min. After removal of Et3N, H2O (20 mL) was added and the precipates were collected by suction filtration. Crystals formed in the mother liquor were collected and dried to give the title compound (106 mg) as a yellow solid. The remaining residue was combined and purified by flash chromatography (gradient: EtOAc.hex 0 to 50% to 100%), followed by trituration with H2O to give the title compound (440 mg) as a yellow solid. Total 546 mg (yield 63%). 1H NMR (400 MHz, DMSO-d6) δ 13.63 (s, 1H), 10.44 (s, 1H), 10.05 (s, 1H), 7.98 (d, J=7.6 Hz, 2H), 7.87 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.58 (d, J=8.0 Hz, 1H), 5.63 (s, 1H), 3.29 (s, 3H), 3.22 (t, J=8.4 Hz, 1H), 2.40-2.33 (m, 1H), 1.99 (dd, J=8.8 Hz, 4.8 Hz, 1H); MS ESI 434.2 [M+H]+, calcd for [C27H19N3O3+H]+ 434.1.
Reaction SMILES: [CH3:1][C:2]1([C:5]([NH:7][NH2:8])=[O:6])[CH2:4][CH2:3]1.[C:9](Cl)(Cl)=[O:10]>C(OCC)(=O)C>[CH3:1][C:2]1([C:5]2[O:6][C:9](=[O:10])[NH:8][N:7]=2)[CH2:4][CH2:3]1
Reactant: CC1(C(=O)NN)CC1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CC1(c2n[nH]c(=O)o2)CC1
Yield: 103.8 %

Procedure:
A solution containing 54.0 g (0.385 mol) of 1-methylcyclopropanecarboxylic acid hydrazide (m.p. 72°-74°) and 90 g (0.9 mol) of phosgene in 1000 ml of ethyl acetate was refluxed for 2 hours. The reaction mixture was concentrated on a rotary evaporator. The residual solid crystallized from ether-hexane (1:5) to give 56.0 g (85%) of product as a white crystalline solid; m.p. 77°-78°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:7][C:6]=12.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].CCN(CC)CC>C1COCC1>[F:12][C:11]([F:14])([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[C:6]2[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(Br)c3n2)cc1
Reactant: C#C[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-bromo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (Example C.1 step 2a) (12.30 g, 30 mmol), trimethylsilylacetylene (8.3 mL, 60 mmol) and Et3N (6.3 mL, 45 mmol) in THF (30 mL) was stirred for 10 min at 23° C. while being purged with Argon, then PdCl2(PPh3)2 (105 mg, 0.5 mol %), PPh3 (20 mg, 0.25 mol %) and CuI (17 mg, 0.3 mol %) were added. Stirring was continued at 75° C. for 38 h. After 22 h, trimethylsilylacetylene (2.1 mL) and Et3N (2.1 mL) was added. Cooled to 23° C., diluted with ethyl acetate (100 mL), filtered through celite, washed with ethyl acetate. Removal of the solvent in vacuum left the 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (13.65 g, 106%) as an orange solid, which can directly be used in the subsequent step. An analytical sample was obtained by silica gel column chromatography with heptane/EtOAc. MS (ISP) 427.0 [(M)+]; mp 136° C.
Reaction SMILES: [CH3:1][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[N:17]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:16]1=[O:37])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:45][CH2:46][CH2:47][F:48]>CN(C=O)C.CCOC(C)=O>[CH3:3][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:45][CH2:46][CH2:47][F:48])[CH:21]=2)[N:17]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:32]=2)[C:16]1=[O:37])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:1]
Reactant: FCCCBr
Reactant: CC(C)(N[C@@H]1C[C@H](c2cccc(O)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(N[C@@H]1C[C@H](c2cccc(OCCCF)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 77.4 %

Procedure:
Dissolve (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-(3-hydroxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (520 mg, 0.99 mmol) in DMF (9 mL) and add cesium carbonate (1.9 g, 5.9 mmol) and 1-bromo-3-fluoro-propane (170 mg, 1.19 mmol). Stir the mixture at ambient temperature for 19.5 hours and dilute with EtOAc. Wash with brine, dry over sodium sulfate, filter, and concentrate the organic to residue. Purify the residue by silica gel chromatography (30% EtOAc-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-[3-(3-fluoro-propoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (447 mg, 77%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (d, J=7.9 Hz, 1H), 8.01 (dd, J=7.7, 7.7 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.13 (dd, J=7.9, 7.9 Hz, 1H), 6.82-6.70 (m, 3H), 5.18 (dd, J=9.7, 6.6 Hz, 1H), 4.58 (t, J=5.9 Hz, 1H), 4.46 (t, J=5.9 Hz, 1H), 4.02-3.88 (m, 2H), 3.47-3.39 (m, 1H), 2.96 (d, J=3.5 Hz, 1H), 2.73-2.63 (m, 1H), 2.06-1.92 (m, 2H), 1.63 (dd, J=22.0, 10.5 Hz, 1H), 1.47 (s, 3H), 1.42 (s, 3H). LC-MS ESI m/z: 584.0 (M+H)+, Tr=3.61 min., method 1.
Reaction SMILES: [CH2:1]([N:3]1[CH:15]=[C:14]2[C:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)=[N:4]1)[CH3:2].CN(CCN(C)C)C.C([Li])CCC.Cl.CN([CH:34]=[O:35])C>C(#N)C.C1COCC1>[CH2:1]([N:3]1[C:15]([CH:34]=[O:35])=[C:14]2[C:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)=[N:4]1)[CH3:2]
Reactant: CCn1cc2c(n1)c(=O)[nH]c1ccccc12
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCn1nc2c(=O)[nH]c3ccccc3c2c1C=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, a mixture of 2-ethyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (10 g, 46.8 mmol), N,N,N,N-tetramethylethylenediamine (31 mL), and THF (520 mL) was chilled to 0° C. A solution of n-butyllithium in hexanes (56 mL of 2.5 M) was added dropwise. After the addition was complete the reaction mixture was stirred for 5 minutes and then DMF (72 mL) was added dropwise. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. 1 N hydrochloric acid was added and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to about half the original volume and then diluted with water and extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide a dark yellow oil. The oil was combined with acetonitrile and stirred for 20 minutes. A bright yellow solid was isolated by filtration to provide 4 g of 2-ethyl-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinoline-1-carbaldehyde as a yellow powder. An additional 3 g of material was isolated from the mother liquor.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:25]=[C:26]([CH2:30]OS(C)(=O)=O)[CH:27]=[N:28][CH:29]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[CH3:36][NH:37][CH3:38]>C1COCC1.O>[CH3:36][N:37]([CH2:30][C:26]1[CH:25]=[C:24]([C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([CH3:1])[CH:3]=2)[C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=2)[CH2:7]3)[CH:29]=[N:28][CH:27]=1)[CH3:38]
Reactant: CNC
Reactant: Cc1cc(-c2cncc(COS(C)(=O)=O)c2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2cncc(CN(C)C)c2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 50 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
Methanesulfonic acid 5-[7-methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-yl]-pyridin-3-ylmethyl ester (70 mg, 0.138 mmol) was dissolved in 2M dimethylamine in THF (5 mL) and stirred at 50° C. for 18 hrs. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (5% 2M N13 in MeOH/CH2Cl2) provided the title compound (37 mg, 59%) as a brown oil. 1H NMR (300 MHz, CDCl3): δ 8.75 (s, 1H), 8.53 (s, 1H), 7.89 (s, 1H), 7.44 (d, 2H), 7.37 (d, 2H), 7.20 (d, 2H), 4.81 (s, 2H), 4.31 (s, 2H), 3.52 (s, 2H), 2.84 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]#[N:8])[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[N+:17]([O-])=O)=[N:3]1>C(O)C.Cl>[NH2:8][C:7]1[C:5]2[C:4](=[N:3][N:2]([CH3:1])[CH:6]=2)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[N:17]=1
Reactant: Cn1cc(C#N)c(Nc2ccc(Cl)cc2[N+](=O)[O-])n1
Agent: Cl
Solvent: CCO
Product: Cn1cc2c(n1)Nc1ccc(Cl)cc1N=C2N

Procedure:
To 1-methyl-3-(4-chloro-2-nitroanilino)pyrazole-4-carbonitrile (16 g) stirred in ethanol (500 ml) was added a solution of anhydrous stannous chloride (33.1 g) in concentrated hydrochloric acid (176 ml). The mixture was heated under reflux for 2 hours, cooled, filtered and crystallised from methylated spirits (1 liter) to give the title compound as its hydrochloride salt m.p. >260° C. 2.0 g of the hydrochloride salt was partitioned between dilute ammonia solution and chloroform. The organic phase was washed with water, dried with magnesium sulphate, evaporated and the residue crystallised from chloroform-n-hexane to give the title compound as the free base m.p. 240° C.
Reaction SMILES: [CH3:1][N:2]([C:14]1[C:23]([CH3:24])=[CH:22][C:21]2[C:20]([CH3:25])=[CH:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)[C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][CH:4]=1.C(O)C.[OH-].[K+]>O>[CH3:1][N:2]([C:14]1[C:23]([CH3:24])=[CH:22][C:21]2[C:20]([CH3:25])=[CH:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1ccc(N(C)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1=CCC(C)(C)c2cc(N(C)c3ccc(C(=O)O)cc3)c(C)cc21
Temperature: 60 °C
Yield: 89.4 %

Procedure:
Following previously described General Procedure E, to a solution of ethyl 4-[methyl-(3,5,8,8-tetramethyl-7,8-dihydronaphthalen-2-yl)amino]benzoate (Compound 40, 0.05 g, 0.14 mmol) and 2 mL of absolute ethyl alcohol was added aqueous 5M KOH (0.3 mL). The resulting solution was heated in an 60° C. bath for 24 h. The solution was cooled to room temperature, diluted with water and washed once with 2:1 hexane:ethyl acetate solution, and the layers were separated. The aqueous layer was acidified with HCl 2N to pH=0-1 and the product extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, and filtered. The solvent was removed to give 0.042 g (92%) of the title compound as a dark green solid. PNMR (300 MHz, CDCl3) δ—1.24 (s, 6H), 2.12 (s, 3H), 2.14 (s, 3H), 2.22 (d, 2H, J=2.4 Hz), 3.32 (s, 3H), 5.81 (s, 1H), 6.52 (d, 2H, J=7.5 Hz), 7.08 (s, 1H), 7.19 (s, 1H), 7.92 (d, 2H, J=7.5 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCN(c2ccc(N)cc2)CC1

Procedure:
A mixture of intermediate (3) (0.0055 mol) in THF (50 ml) was hydrogenated with palladium on carbon (10%; 0.16 g) as a catalyst for 30 minutes at a temperature of 50° C. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated, yielding [1-(4-amino-phenyl)-piperidin-4-yl]-acetic acid ethyl ester (intermediate 4).
Reaction SMILES: CN(C)C=[O:4].Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:34][O:33][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][OH:4])[N:18]=[CH:17][CH:16]=[C:15]2[O:21][C:22]1[C:23]([CH3:32])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCCl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCO
Temperature: 80 °C
Reaction time: 72 h
Yield: 61 %

Procedure:
N,N-Dimethylformamide (2 ml) was added to 7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 375) (69 mg), potassium carbonate (70 mg), and water (10 mg), and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (40 mg, yield 61%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]1[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=1>C(Cl)Cl.CO.O=[Mn]=O>[CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]1[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=1
Reactant: Cc1nnsc1-c1nc(CO)cs1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: Cc1nnsc1-c1nc(C=O)cs1

Procedure:
A mixture of [2-(4-methyl[1,2,3]thiadiazol-5-yl)thiazol-4-yl]methanol (1.06 g; 4.97 mmol) and MnO2 (8.64 g; 99.39 mmol) in CH2Cl2 (100 ml) and methanol (10 ml) was refluxed for 6 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]2[NH:7][C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.[CH:18](=O)[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:18]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]=2[NH:7][C:8](=[O:12])[CH2:9]1)[CH3:19]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CNC2
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN1CC(=O)Nc2cc([N+](=O)[O-])c(OC)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of 7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (400 mg, 1.69 mmol) in methanol (100 mL) was added acetaldehyde (2.0 mL, 30 mmol) followed by acetic acid (0.29 mL, 5.0 mmol). The mixture was stirred for 20 minutes at room temperature whereupon sodium triacetoxyborohydride (1.10 g, 5.0 mmol) was added. The mixture was stirred at room temperature overnight and then concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated. Flash chromatography over silica gel (0-5% MeOH-EtOAc) gave 4-ethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (330 mg, 72%) as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 7.60 (s, 1H), 7.35 (s, 1H), 3.91 (s, 3H), 3.86 (s, 2H), 3.35 (s, 2H), 2.55 (q, J=6 Hz, 2H), 1.06 (t, J=6 Hz, 3H); MS (m/e) 266 (M+1); mp 168° C. (dec.).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][CH2:15][NH:16]C(=O)C(F)(F)F)#[N:2].C(O)C.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:2][CH2:1][CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][C:15]#[N:16]
Reactant: COc1cc(CC#N)c(CCNC(=O)C(F)(F)F)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(CC#N)c(CCN)cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
Heat, at 50° C., a mixture of N-{2-[2-(cyanomethyl)-4,5-dimethoxyphenyl]ethyl}-2,2,2-trifluoroacetamide (20.5 g, 64.8 mmoles), ethanol (160 mL), potassium carbonate (13.2 g, 97.2 mmoles) and water (40 mL). After being in contact for 1 hour 30 minutes, extract the mixture by adding 200 mL of dichloromethane and 100 mL of saturated aqueous NaCl solution. Extract the aqueous phase with 100 mL of dichloromethane. Combine the organic phases, wash them with saturated aqueous NaCl solution (100 mL), dry them over MgSO4 and carry out drying in vacuo to obtain 10 g of a yellow oil corresponding to the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:15]=[C:5]2[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]([C:10]([NH:12][NH2:13])=[O:11])[N:4]2[N:3]=1.[CH2:16]=[C:17]1[O:21][C:19](=O)[CH2:18]1.C1COCC1>C(Cl)Cl>[NH2:1][C:2]1[N:15]=[C:5]2[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]([C:10]3[O:11][C:19]([CH2:18][C:17](=[O:21])[CH3:16])=[N:13][N:12]=3)[N:4]2[N:3]=1
Reactant: NNC(=O)c1cc(Br)cc2nc(N)nn12
Reactant: C=C1CC(=O)O1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)Cc1nnc(-c2cc(Br)cc3nc(N)nn23)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product of Step 1, 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid hydrazide (1.0 g, 3.7 mmol), diketene (0.28 mL, 3.7 mmol) and THF (˜25 mL) were placed in a flask. The mixture was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and a solution of 9:1 CH2Cl2/MeOH. The organics were dried with MgSO4 and concentrated to give an oily yellow solid. The solid was dissolved in a small amount of CH2Cl2 and filtered through a plug of silica, eluting with CH2Cl2. The filtrate was concentrated to give 1-[5-(2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-[1,3,4]oxadiazol-2-yl]-propan-2-one, which was used without further purification, in Step 3. MS (APCI+): m/z 337.0, 339.0.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]([CH2:18][CH:19]=[CH2:20])[CH:4]=[C:3]1[C:21](O)=[O:22].O=C1C2C(=CC(C3C=CN=CC=3)=CC=2)[NH:28]C=C1C(OCC)=O.C(Br)C=C>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]([CH2:18][CH:19]=[CH2:20])[CH:4]=[C:3]1[C:21]([NH2:28])=[O:22]
Reactant: C=CCn1cc(C(=O)O)c(=O)c2ccc(-c3ccncc3)cc21
Reactant: CCOC(=O)c1c[nH]c2cc(-c3ccncc3)ccc2c1=O
Solvent: C=CCBr
Product: C=CCn1cc(C(N)=O)c(=O)c2ccc(-c3ccncc3)cc21

Procedure:
The starting acid, 1,4-dihydro-4-oxo-1-(2-propenyl)-7-(4-pyridinyl)-3-quinolinecarboxylic acid (golden crystals, m.p. 259.5°-261° C. from methanol), was prepared by hydrolysis of the corresponding ethyl ester (yellow powder, m.p. 155°-157° C.), in turn prepared by alkylation of ethyl 1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxylate with allyl bromide.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][O:6][CH:7]1[C:12]([O:15][CH3:16])([O:13][CH3:14])[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8]1)[CH3:2].[H][H]>[Pd].CO>[CH2:24]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][CH:7]1[C:12]([O:15][CH3:16])([O:13][CH3:14])[CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:25]
Reactant: [H][H]
Reactant: CCN(CC)CCOC1CN(Cc2ccccc2)CCC1(OC)OC
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCOC1CNCCC1(OC)OC
Yield: 100 %

Procedure:
A mixture of 13.5 parts of N,N-diethyl-2-[[4,4-di-methoxy-1-(phenylmethyl)-3-piperidinyl]oxy]ethanamine and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 10.5 parts (100%) of N,N-diethyl-2-[(4,4-dimethoxy-3-piperidinyl)oxy]ethanamine as a residue (intermediate 109).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:15]3=[O:25])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:26][S:27](O)(=[O:29])=[O:28].C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([S:27]([Cl:26])(=[O:29])=[O:28])=[CH:23][CH:24]=4)[C:15]3=[O:25])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Cl)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Synthesized according to General Procedure 11. To a solution of (3R,3′S)-3-(3,5-dichlorophenyl)-1′-phenyl-1,3′-bipyrrolidin-2′-one (900 mg, 2.40 mmol) in DCE (10 mL) at 0° C. was added chlorosulfonic acid (1.40 g, 800 μL, 12.0 mmol) slowly. The reaction mixture was then stirred at 0° C. for 30 min, at RT for 1 hour and at 50° C. for 1 hour. At this time more chlorosulfonic acid (279 mg, 160 μL, 2.40 mmol) was added and the reaction mixture was stirred at 50° C. for 1 hour, the reaction mixture was then heated to 70° C. for 10 min, cooled to RT and slowly poured onto ice water. The pH was brought to ˜7 with saturated aqueous NaHCO3 and the reaction mixture was extracted with EtOAc (3×). The combined organic phases were washed with water, brine, dried over MgSO4 and evaporated to dryness to afford 4-[(3R,3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]benzene-1-sulfonyl chloride as a tan solid (1.00 g, 88%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=473.3; tR=1.58 min.