Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[Cl:14].[CH3:15][O:16][C:17]([C:19]1(OC)[CH2:23][CH2:22][CH:21](OC)O1)=[O:18]>C(O)(=O)C>[Cl:14][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:1]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]([O:16][CH3:15])=[O:18])[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6]2
Reactant: COC(=O)C1(OC)CCC(OC)O1
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Solvent: CC(=O)O
Product: COC(=O)c1cccn1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Yield: 43.7 %

Procedure:
10 g (47.25 mmol) of 7-amino-6-chloro-2,3(1H,4H)-quinoxalinedione and 8.9 g (47.25 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran in 150 ml of acetic acid were refluxed for 2 h. The precipitate was then filtered off with suction to yield 6.6 g (44%) of the product. Melting point >260° C.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]3[OH:30])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl[CH2:34][C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=2[CH:50]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH:18]3[O:30][CH2:34][C:35]3[CH:36]=[CH:37][C:38]4[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=4[CH:50]=3)=[CH:15][CH:16]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc(F)cc3)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccc(F)cc4)cc3)cc21

Procedure:
Analogously to Method D, 0.600 g of tert-butyl 4-{4-[3-(4-fluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.408 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.17 (1:2 EtOAc-heptane); Rt=5.82.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:30]([CH:31]=O)=[CH:29][C:12]3[C:13]([C:16]4[S:17][CH:18]=[C:19]([C:21]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[O:22])[N:20]=4)=[N:14][O:15][C:11]=3[C:10]=2[F:33])[CH2:3]1.[NH:34]1[C:41](=[O:42])[CH2:40][C:38](=[O:39])[NH:37][C:35]1=[O:36]>CC(O)C>[F:33][C:10]1[C:11]2[O:15][N:14]=[C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[O:22])[N:20]=3)[C:12]=2[CH:29]=[C:30]2[C:9]=1[N:4]1[CH2:3][C@@H:2]([CH3:1])[O:7][C@@H:6]([CH3:8])[C@@H:5]1[C:40]1([C:38](=[O:39])[NH:37][C:35](=[O:36])[NH:34][C:41]1=[O:42])[CH2:31]2
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(-c4nc(C(=O)N5CCOCC5)cs4)noc3c2F)C[C@H](C)O1
Solvent: CC(C)O
Product: C[C@@H]1CN2c3c(cc4c(-c5nc(C(=O)N6CCOCC6)cs5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 85 °C

Procedure:
To a solution of 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-3-[4-(morpholin-4-ylcarbonyl)-1,3-thiazol-2-yl]-1,2-benzoxazole-5-carbaldehyde (Intermediate 389, 90 mg, 0.19 mmol) in IPA was added barbituric acid (24 mg, 0.103 mmol) and the mixture heated at 85° C. for 16 hours. Solvents were evaporated and the residue was purified by reverse phase HPLC to give product as solid (as a TFA salt). Yield: 16 mg (14%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[CH2:4][CH2:3]1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=[O:25]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:16][C:17]2=[O:25])[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccccc2C=O)CC1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Product: CN1CCN(c2ccccc2C=C2C(=O)Nc3ccccc32)CC1
Yield: 116.9 %

Procedure:
Under nitrogen in a dry round bottom flask fitted with a condensor and magnetic stir bar were placed 2-(4methyl-1-piperazinyl)-benzaldehyde (0.152 g, 0.75 g, 0.75 mmol), oxindole (0.104 g, 0.78 mmol) pyrrolidine (62 μL) and ethanol (7.0 mL). The mixture was heated to reflux for 16 hours, cooled and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer was washed with saturated aqueous sodium chloride (NaCl), dried over magnesium sulfate (MgSO4)1, filtered and absorbed onto 437 mg of silica gel. Elution with ethyl acetate (EtOAc) (125 mL), 1% methanol (CH3OH) in EtOAc (100 mL), 2% CH3OH in EtOAc (100 mL) and 4% CH3OH+1% triethylamine (Et3N) In EtOAc (50 mL) gave 280 mg of a yellow solid. Recrystallization from hot CH3OH gave the title product, m.p. 226-2280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[C:4]([CH3:10])[CH:3]=1.[CH2:11]([O:13][C:14]([C:16]1[CH:20]=[CH:19][N:18]([CH:21]([CH3:23])[CH3:22])[C:17]=1[CH:24]=[O:25])=[O:15])[CH3:12]>C1COCC1>[CH2:11]([O:13][C:14]([C:16]1[CH:20]=[CH:19][N:18]([CH:21]([CH3:22])[CH3:23])[C:17]=1[CH:24]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:10])[OH:25])=[O:15])[CH3:12]
Reactant: Cc1cc(Cl)ccc1[Mg]Br
Reactant: CCOC(=O)c1ccn(C(C)C)c1C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1C
Reaction time: 2 h

Procedure:
A solution (0.5 M in THF) of 4-chloro-2-methylphenylmagnesium bromide [480438-47-9] (68.8 mmol) was added to a mixture of 2-formyl-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step A5) (68.8 mmol) in THF (160 mL) at 0° C. After stirring for 2 h, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with MTBE (2×). The combined organic phases were successively washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was suspended in hexanes, stirred for 30 min and then filtered to afford the title compound as a white solid. tR: 7.74 min (HPLC 2); ESI-MS: tR=1.26 min, [M]+318/320 (i.e. fragmented pyrrolium ion) (LC-MS 1); TLC: Rf=0.20 (1:6 EtOAc/hexanes).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][N:20](C(OCC4C=CC=CC=4)=O)[CH2:21][C:5]=3[C:4]=2[CH:3]=1>C(OCC)(=O)C.CO.[Pd]>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:6]3[CH2:18][CH2:19][NH:20][CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Fc1ccc(-n2c3c(c4cc(F)ccc42)CNCC3)cc1
Reaction time: 4 h

Procedure:
In a Parr bottle were combined 5% Pd/C (10 g of 50% water-wet) and 60 g of 8-fluoro-5- (p-fluorophenyl)-2-carbobenzoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-indole (60 g, 0.143 mole) in 400 ml ethyl acetate and 100 ml methanol and the mixture hydrogenated at 44-80 psig for 4 hours. Catalyst was recovered by filtration and the filtrate evaporated to solids in vacuo. The residue taken into CH2Cl2, carbon treated, dried (Na2SO4) and CH2Cl2 displaced with hexane by distillation to a final pot temperature of 70° C. The white, crystalline product was recovered by filtration, 35.6 g, m.p. 126°-129° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26]O)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl>[Br:48][CH2:26][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18]2)[N:11]=3)=[C:2]([F:1])[CH:3]=1
Reactant: OCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Temperature: 25 °C

Procedure:
To a slurry of (3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methanol (2.05 g, 5.45 mmol), triphenylphosphine (1.64 mL, 7.08 mmol) in DCM (25 mL) at 0° C. under N2, carbon tetrabromide (0.634 mL, 6.53 mmol) was added. The reaction mixture was allowed to warm up to ambient temperature. The crude reaction mixture after 1 h, was concentrate in vacuo and purified by silica gel chromatography to afford 2-(4-(bromomethyl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine. MS (ESI) m/z; calculated: 438.0; Observed: 438.9 (M++1).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:26])[C@@H:11]([NH:22][C:23](=[O:25])[CH3:24])[CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35](O)=[O:36])=[CH:29][CH:28]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:2]([O:9][C:10](=[O:26])[C@@H:11]([NH:22][C:23](=[O:25])[CH3:24])[CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:35](=[O:36])[CH:34]=[CH:33][C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)[CH2:17]1)=[O:15])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCNC1)C(=O)OCc1ccccc1
Reactant: O=C(O)C=Cc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)C=Cc2ccncc2)C1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of N-[(R)-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine benzyl ester hydrochloride (231 mg), 3-(4-pyridyl)-2-propenoic acid (82 mg) and 1-hydroxybenzotriazole (81 mg) in dimethylformamide (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.11 ml) at 0° C. The mixture was stirred for 2 hours at room temperature, then poured into ice water-ethyl acetate. The separated organic layer was washed with water, aqueous saturated NaHCO3, brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with CHCl3—MeOH (96:4) to give N-[(R)-1-[3-(4-pyridyl)-2-propenoyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine benzyl ester (263 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=O)[N:10]([CH3:18])[N:9]=2)=[C:4]2[NH:19][CH:20]=[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]3[CH2:29][CH2:28][N:27]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:33]=[N:32][N:31]=4)[CH2:26][CH2:25]3)[C:3]=12.[CH3:43][N:44]([CH3:49])[CH2:45][CH2:46][CH2:47][NH2:48]>CN(C=O)C>[CH3:43][N:44]([CH3:49])[CH2:45][CH2:46][CH2:47][NH:48][C:13]([C:11]1[N:10]([CH3:18])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([F:1])=[C:3]3[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]4[CH2:29][CH2:28][N:27]([C:30]5[N:34]([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[N:33]=[N:32][N:31]=5)[CH2:26][CH2:25]4)=[CH:20][NH:19][C:4]=23)[CH:12]=1)=[O:15]
Reactant: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)nn1C
Reactant: CN(C)CCCN
Solvent: CN(C)C=O
Product: CN(C)CCCNC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)nn1C
Temperature: 50 °C

Procedure:
To a sealable flask containing ethyl 3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxylate (0.058 g, 0.10 mmol) was added N1,N1-dimethylpropane-1,3-diamine (0.7 mL). The mixture was sealed and heated to 50° C. for 20.5 h. The mixture was cooled to rt, and was diluted with DMF and was passed through a plug of celite to remove any solids. The DMF solution was purified by prep HPLC to give N-(3-(dimethylamino)propyl)-3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide.TFA. (0.020 g) as an off-white solid. LCMS: m/e 629.5 (M+H)+, ret time 1.93 min (method 2). 1H NMR (500 MHz, MeOD) δ ppm 8.75 (s, 1H) 8.61 (s, 1H) 7.97-8.11 (m, 5H) 7.79 (s, 1H) 4.69 (s, 3H) 4.21-4.25 (m, 2H) 4.01-4.04 (m, 2H) 3.91 (t, J=6.26 Hz, 2H) 3.76-3.82 (m, J=3.66 Hz, 2H) 3.65-3.75 (m, 10H) 2.45-2.52 (m, 2H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH2:16]([N:23]1[CH2:1][CH:3]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:9]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)/C=C/C1CCCCC1C=O
Solvent: ClCCl
Product: CCOC(=O)CC1C2CCCCC2CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (E)-ethyl 3-(2-formylcyclohexyl)acrylate, benzyl amine and NaBH(Oac)3 in DCM was stirred at rt for 3 h. The reaction mixture was quenched with saturated NaHCO3. The organic layer was separated and the aqueous layer was extracted with DCM (2×). All organic layers were combined, dried with dried with MgSO4 and concentrated in vacuo to give the crude product which was purified by chromatography to afford desired ethyl 2-(2-benzyloctahydro-1H-isoindol-1-yl)acetate. MS (ESI) 302 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[C:7]([CH3:13])[CH:6]=[CH:5]2.C1(C)C=CC(S([Cl:23])(=O)=O)=CC=1>ClC(Cl)C>[Cl:23][CH2:13][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: Cc1ccc2cc(F)ccc2[n+]1[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(Cl)Cl
Product: Fc1ccc2nc(CCl)ccc2c1
Temperature: 100 °C
Yield: 53.4 %

Procedure:
6-Fluoro-2-methylquinoline N-oxide (2.70 g, 15.25 mmol) was added to a stirring solution of p-toluenesulfonyl chloride (2.9 g, 15.21 mmol) in dichloroethane (100 mL). The reaction mixture was heated to 100° C. overnight under N2, cooled and concentrated, partitioned between 10% K2CO3 /ethyl acetate, dried over MgSO4 and evaporated under reduced pressure to afford a solid. The crude solid was purified by flash chromatography (15:1 hexane/ethyl acetate) to afford 1.59 g (63%) of pure product as an off white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O-:17])=[O:16])=[CH:5][C:4]=2[N:3]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>CN1C(=O)CCC1.CO>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][NH:18][C:2]2[C:11]3[CH:12]=[CH:13][S:14][C:10]=3[C:9]3[CH:8]=[CH:7][C:6]([C:15]([OH:17])=[O:16])=[CH:5][C:4]=3[N:3]=2)[CH:21]=1
Reactant: O=C([O-])c1ccc2c(c1)nc(Cl)c1ccsc12
Reactant: NCc1cccnc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)nc(NCc1cccnc1)c1ccsc12
Temperature: 120 °C
Reaction time: 17 h
Yield: 62 %

Procedure:
4-chlorothieno[3,2-c]quinoline-7-carboxylate (10 mg, 0.036 mmol) was suspended in NMP (0.1 ml) and 3-aminomethylpyridine (0.1 ml). The mixture was heated in a microwave oven at 120° C. for 10 nm. The reaction mixture was dissolved in a mixture of NMP and MeOH and the ester intermediate purified by preparative HPLC. After genevac evaporation of the solvents, the resulting solid was dissolved in a 1:1 mixture of THF and MeOH (0.6 ml). 5N aqueous LiOH (0.2 ml) was added and the mixture stirred at room temperature for 17 hrs. Water and aqueous HCl were added and the solution of 4-(pyridin-3-ylmethylamino)thieno[3,2-c]quinoline-7-carboxylic acid was purified by preparative HPLC. Removal of the solvents by genevac evaporation provided compound 4-(pyridin-3-ylmethylamino)thieno[3,2-c]quinoline-7-carboxylic acid as a white solid (10 mg, 62% yield). LCMS (ES): 95% pure, m/z 336 [M+1]+. 1H NMR (CDCl3, 400 MHz) δ 5.23 (s, 2H), 7.71-7.78 (m, 4H), 8.11 (d, J=5.6, 1H), 8.47 (d, J=8.0, 1H), 8.49 (d, J=0.8, 1H), 8.62 (d, J=5.2, 1H), 8.97 (s, 1H) ppm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24].[NH4+].[Cl-]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)NCCCCCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)NCCCCCCOS(C)(=O)=O
Temperature: 0 °C

Procedure:
A solution of N-(6-hydroxyhexyl)prop-2-enyloxycarboxamide (2.55 g, 12.7 mmol; Charreyre, M. T.; Boullanger, P.; Pichot, C.; Delair, T.; Mandrand, B.; Llauro, M. F. Mak. Chem. 1993, 194(1), 117-35.) in dry CH2Cl2 (30.0 mL) was treated with Et3N (4.06 mL, 29.1 mmol) then cooled to 0° C. To this solution was transferred MsCl (15.2 mmol; 20.0 mL of a 0.76 M solution in CH2Cl2) using a cannula; full conversion coincided with completion of the transfer. The resulting solution was warmed to 22° C., then treated with 2 M NH4Cl (50 mL) and transferred to a separatory funnel. The layers separated and the aqueous layer washed with CH2Cl2 (3×50 mL). The combined washes were washed with 20% aqueous NaCl then dried over MgSO4, filtered and concentrated in vacuo to a pale yellow oil (3.2 g) that was used without further purification in the subsequent alkylation step. 1H NMR (CDCl3, 300 MHz): δ 5.90 (1H, ddt, J=17.2, 10.4, 5.6 Hz), 5.29 (1H, dq, J=17.2, 1.6 Hz), 5.19 (1H, dq, J=10.4, 1.3 Hz), 4.71 (1H, brs), 4.54 (2H, brd, J=5.5 Hz), 4.20 (2H, t, J=6.5 Hz), 3.17 (2H, brs), 2.98 (3H, s), 1.79-1.69 (2H, m), 1.55-1.29 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[NH:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCCNC12CCCCC2
Agent: O=S(=O)(O)O
Product: Clc1ccc(C2=CCCNC23CCCCC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(4-Chlorophenyl)-5-hydroxy-1-azaspiro[5.5]undecane (105.1 g) was added in portions to vigorously stirred concentrated sulphuric acid (600 ml) over 20 minutes, then the mixture was stirred at ambient temperature for a further 1 hour and poured carefully onto ice (2 l) causing a white solid to precipitate. The mixture was cooled in ice for 2 hours and the solid was collected by filtration. The solid was basified by addition to an excess of 5M aqueous sodium hydroxide solution and the product was extracted into ether (4×200 ml) followed by dichloromethane (2×250 ml). The extracts were combined, dried over sodium sulphate and the solvents removed in vacuo to give 5-(4-chlorophenyl)-1-azaspiro[5.5]undec-4-ene as a cream solid. Yield 98 g.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1.S([C:27]1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>COC(OC)(C)C.C(OCC)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9](=[CH:10][C@H:11]2[CH3:21])[CH:8]=[C:7]([O:22][CH3:27])[CH2:6][CH2:5]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Product: COC1=CC2=C[C@@H](C)[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1
Yield: 789.2 %

Procedure:
A solution of 2 g of 11β-fluoro-7α-methylestr-4-ene-3,17-dione in 20 ml 2,2-di-methoxypropane was stirred with 200 mg of pyridinium tosylate for 6.5 hours at 80° C. Then, it was diluted with ethyl acetate, washed with sodium bicarbonate solution and sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 2 g of crude 11β-fluoro-3-methoxy-7α-methylestra-3,5-dien-17-one was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:16]([CH:17]=2)[N:15]=[C:14]([C:18]2[C:19]([C:24]([F:27])([F:26])[F:25])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:12]3)=[CH:5][C:3]=1[NH2:4].[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33].N1C=CC=CC=1>CC#N>[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:4][C:3]1[CH:5]=[C:6]([C:9]2[N:10]=[C:11]3[N:16]([CH:17]=2)[N:15]=[C:14]([C:18]2[C:19]([C:24]([F:25])([F:27])[F:26])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:12]3)[CH:7]=[CH:8][C:2]=1[CH3:1])=[O:33]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1N
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1NC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A 20 mL vial is charged with 2-methyl-5-[6-[2-(trifluoromethyl)-3-pyridyl]imidazo[2,1-f]pyridazin-2-yl]aniline (0.444 g, 1.2 mmol), 3-bromobenzoyl chloride (0.378 mL, 1.8 mol), pyridine (0.292 mL, 3.6 mmol), MeCN (4 mL) and the mixture is stirred at room temperature for 18 hr. The reaction mixture is concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in CH2Cl2) to give the title compound (530 mg). LCMS (m/z)=552.3 and 554.3 [M+H]+, tR=3.04 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[Li]C(C)(C)C.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:25]=[CH:26][C:27]([C:30](OC)=[O:31])=[N:28][CH:29]=1>CCOCC>[C:12]([O:11][C:10](=[O:16])[NH:9][C:4]1[C:5]([C:30](=[O:31])[C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:34])([F:22])[F:35])=[CH:29][N:28]=2)=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:13])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(C(F)(F)F)cn1
Reactant: COc1ccccc1NC(=O)OC(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COc1cccc(C(=O)c2ccc(C(F)(F)F)cn2)c1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a cold (−23° C.), stirred solution of tert-butyl 2-methoxyphenylcarbamate (443.3 mg, 1.986 mmol) in ether (5 mL) under N2 was added t-BuLi (2.6 mL, 4.42 mmol). The reaction mixture was stirred for 2 h, and then cooled to −78° C. To the reaction mixture was added a solution of methyl 5-(trifluoromethyl)picolinate (501.3 mg, 2.44 mmol) in ether (10 mL) dropwise via cannula over 5 min. After 2 h, the reaction mixture was warmed to room temperature, stirred for an additional hour, and then the reaction was quenched by the addition of water with vigorous stirring. The reaction mixture was diluted with EtOAc, the organic phase was separated, washed with sat NaCl then dried (Na2SO4), filtered and concentrated to yield a yellow solid. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=hexane/EtOAc, REDISEP® SiO2 40 g) to obtained Intermediate A-28A (546.8 mg, 69.5% yield)) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ ppm 8.83-8.88 (1H, m), 8.24 (1H, d, J=8.4 Hz), 8.07 (1H, dd, J=8.4, 1.8 Hz), 7.25 (1H, d, J=1.5 Hz), 7.18-7.24 (1H, m), 7.09 (1H, dd, J=8.0, 1.7 Hz), 6.95 (1H, s), 3.93 (3H, s), 1.25 (9H, s).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C=Nc1ccsc1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccsc3)c(=O)n(C3CCCC3)c12

Procedure:
1-Cyclopentyl-7-methoxy-3-thiophen-3-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione (21 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1. mmol) and 3-isocyanato-thiophene (0.5 mmol) following general procedure C. LCMS: m/z 394 [M+1]+.