Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH2:3][OH:4].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:15]([NH:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH2:3][OH:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H](CO)Cc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C[C@@H](CO)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.3 %

Procedure:
A suspension of (2S)-2-amino-3-(4-nitrophenyl)-1-propanol (5.89 g) and benzaldehyde (3.39 g) in dichloromethane (59 ml) was stirred at room temperature for 2.5 hours. The mixture was evaporated, and the residual solid was suspended in ethanol (47 ml)-dichloromethane (11.8 ml). Sodium borohydride (1.25 g) was slowly added to the suspension, and the mixture was stirred at room temperature for 5 hours. The mixture was poured onto water (47 ml) and stirred at room temperature for 15 minutes. The precipitate formed was collected by filtration, washed with water, and dried in vacuo. The crude product was recrystallized from ethanol to give (2S)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (5.18 g) as a pale yellow powder. The filtrates obtained above were combined, concentrated, and partitioned between chloroform and water. The organic layer was separated, washed successively with water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, chloroform/methanol) to give the additional amount of product (2.78 g) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:16]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[O:31][CH2:32][C:33]([O:35]CC)=[O:34].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)[N:16]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[O:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: CCCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCC(Oc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reaction time: 2.5 h
Yield: 73.1 %

Procedure:
To a solution of ethyl ({2-methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}hexyl)oxy]phenyl}oxy)acetate (80 mg, 0.16 mmol) in MeOH (2 mL) and THF (2 mL) at rt was added aqueous NaOH (2M, 1 mL, 2.0 mmol) and the resulting mixture stirred for 2.5 hours. The solvents were then removed under vacuum and the residue partitioned between DCM (20 mL) and aqueous HCl (2M, 20 mL), the layers separated and the aqueous re-extracted with DCM (20 mL). The combined organic solution was passed through a hydrophobic frit and then reduced affording the title compound as colourless oil (57 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH:15][C:16]2[C:17]3[S:24][CH:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][N:12]=1)([CH3:4])([CH3:3])C.Cl.C(N(CC)CC)C.ClC(O[C:38]1[CH:43]=CC=C[CH:39]=1)=O>O1CCOCC1.C1COCC1>[C:1]1([O:5][C:6](=[O:25])[NH:7][C:8]2[S:9][C:10]([CH2:13][CH2:14][NH:15][C:16]3[C:17]4[S:24][CH:23]=[CH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:11][N:12]=2)[CH:3]=[CH:43][CH:38]=[CH:39][CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ncc(CCNc2ncnc3ccsc23)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1ncc(CCNc2ncnc3ccsc23)s1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of compound 14.2 (23.7 mmol) in 1,4-dioxane (100 mL) was added HCl (70 mL of a 4.0 M in 1,4-dioxane) at 0° C. The reaction was allowed to warm to room temperature, stirred for 2 hours and concentrated to dryness to give a tan solid. The crude solid was suspended in THF (200 mL) and cooled to 0° C. Triethylamine (33 mL) was added followed by phenyl chloroformate (26.1 mmol). The reaction mixture was allowed to slowly warm to room temperature and stirred for 2 hours. Volatiles were removed under reduced pressure at room temperature, water was added and the solid collected by vacuum filtration. The solid was washed with ethyl ether and dried under vacuum to give {5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-carbamic acid phenyl ester (compound 16.1) in 80% yield as a tan solid.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@:19]2([CH2:20][OH:21])[C:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[OH:22])=[CH:5][CH2:4][CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH3:1][C@@H:2]1[C@@:19]2([CH:20]=[O:21])[C:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:22])=[CH:5][CH2:4][CH2:3]1
Reactant: C[C@H]1CCC=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: C[C@H]1CCC=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C=O
Temperature: 40 °C
Reaction time: 5 h

Procedure:
1α-Methyl-4-androstene-17β,19-diol is dissolved in dimethylformamide at 40° C. and two equivalents of Jones Reagent are added all at once. The mixture is stirred for about 5 hours at 40° C., cooled and a 1% aqueous sodium sulfite solution is added. After several hours the crystals which form are collected by filtration, thoroughly washed with water and air dried. Crystallization from hexane yields the desired 1α-methyl-4-androstene-17,19-dione.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O=[C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:34])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19])[C@H:12]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl.[SH:65][C:66]1[CH:67]=[N:68][CH:69]=[CH:70][CH:71]=1>ClCCl.CN(C1C=CN=CC=1)C.CN(C)C=O>[CH3:19][C:18]([C@@H:15]1[C:14](=[O:35])[N:13]2[C@@H:16]1[CH2:17][C:11]([S:65][C:66]1[CH:67]=[N:68][CH:69]=[CH:70][CH:71]=1)=[C:12]2[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=1)=[O:37])([O:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:34]
Reactant: Sc1cccnc1
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3cccnc3)C[C@H]12
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
A solution of N,N-diisopropyl-N-ethylamine (0.579 ml) in dichloromethane (5.21 ml) was added to a solution of 4-nitrobenzyl (2R, 5R, 6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (1.50 g) and 4-(N,N-dimethylamino)pyridine (33.8 mg) in dichloromethane (75.0 ml) at -30° C. To this solution was added a solution of trifluoromethanesulfonic anhydride (0.489 ml) in dichloromethane (9.29 ml) and the mixture was stirred at -30° C. for 20 minutes. N,N-Diisopropyl-N-ethylamine (5.31 ml) and a solution of stannic chloride and hydrochloric acid salts of 3-mercaptopyridine (1.70 g) in N,N-dimethylformamide (15.3 ml) were then added to the mixture and the resultant mixture was allowed to warm to 20° C. over a period of 3 hours. After cooling to 0° C., additional N,N-diisopropyl-N-ethylamine (2.89 ml) and a solution of stannic chloride and hydrochloric acid salts of 3-mercaptopyridine (0.570 g) in N,N-dimethylformamide (5.13 ml) were added to the mixture. The resultant mixture was allowed to warm to 20° C. over a period of an hour and evaporated in vacuo. The residue was dissolved in dichloromethane (250 ml), washed in turn with cold water (x6) and an aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on deactivated silica gel with 15% water (150 g), eluting with a mixture of benzene and acetone (50:1 to 8:1). Crystallization from a mixture of dichloromethane and diethyl ether gave 4 -nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-3-(3-pyridylthio)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.9747 g). The mother liquor was purified by column chromatography on silica gel, followed by crystallization to give the same product (0.2680 g) as a pale yellow powder. Total yield is 1.2427 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:23]=[C:22]3[C:17]([C:18]([CH3:28])([CH3:27])[CH2:19][N:20](C(=O)C)[CH2:21]3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:23]=[C:22]3[C:17]([C:18]([CH3:28])([CH3:27])[CH2:19][NH:20][CH2:21]3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(=O)N1Cc2cc(S(=O)(=O)n3ccc4ccc(Cl)cc43)ccc2C(C)(C)C1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(C)CNCc2cc(S(=O)(=O)n3ccc4ccc(Cl)cc43)ccc21

Procedure:
1-[7-(6-Chloro-indole-1-sulfonyl)-4,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone (D4) was N-deacetylated as described in Example 1 to afford, after treatment with sodium hydrogen carbonate solution, the title compound (E28). Treatment of a solution of this material in dichloromethane/diethyl ether with oxalic acid (1.5 equivalents) afforded the corresponding crystalline oxalate salt (65 mg, 42%), δH (CD3OD)/ppm 1.13 (6H, s), 2.71 (2H, br,s), 3.86 (2H, br,s), 6.61 (1H, d, J=3.7 Hz), 7.12 (1H, dd, J=8.4, 1.8 Hz), 7.40-7.86 (4H, m), 7.86 (1H, d, J=1.7 Hz). MS: m/z (MH30) 375/377.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][C:5](=[O:8])[C:4]2=[C:9](S(C)(=O)=O)[S:10][C:11]([C:12]3[CH:16]=[CH:15][NH:14][N:13]=3)=[C:3]12.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>CC(N(C)C)=O>[CH:21]1([NH:26][C:9]2[S:10][C:11]([C:12]3[CH:16]=[CH:15][NH:14][N:13]=3)=[C:3]3[CH:2]([CH3:1])[CH2:7][NH:6][C:5](=[O:8])[C:4]=23)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1CNC(=O)c2c(S(C)(=O)=O)sc(-c3cc[nH]n3)c21
Reactant: NC1CCCC1
Solvent: CC(=O)N(C)C
Product: CC1CNC(=O)c2c(NC3CCCC3)sc(-c3cc[nH]n3)c21

Procedure:
To a sealed tube, the 7-methyl-3-(methylsulfonyl)-1-(1H-pyrazol-3-yl)-6,7-dihydrothieno[3,4-c]pyridin-4(5H)-one from Step 6 (30 mg, 0.096 mmol) was added and dissolved in DMA (193 μl), treated with cyclopentylamine (189 μl, 1.927 mmol) and subjected to microwave conditions: 160° C., 8 hrs, normal absorption. The reaction mixture was diluted with CH2Cl2 and washed with water, dried by filtering through a hydrophobic frit and evaporated to give solid residue. This was purified via reverse phase HPLC (5-95% CH3CN/H2O/0.025% TFA) to give afford the title compound: 1H NMR (400 MHz, CDCl3) δ 8.16 (m, 2H), 7.66 (d, J=2.4 Hz, 1H), 6.43 (d/=2.3 Hz, 1H), 3.75 (m, 1H), 3.63 (dd, J=12.5, 4.4 Hz, 1H), 3.35 (m, 1H), 3.27 (d, J=12.4 Hz, 1H), 2.18 (s, 1H), 2.10 (m, 2H), 1.78 (m, 2H), 1.65 (m, 3H), 1.31 (d, J=7.1 Hz, 3H). LRMS (M+H)+=317.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(NCC)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:28]#[C:27][CH2:26][CH2:25][OH:29])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCCO)cc2c1O
Reaction time: 8 h

Procedure:
To a mixture of the title compound of Example 5 (0.457 g), copper iodide (0.010 g) and dichlorobis(triphenylphosphine)palladium (II) (0.035 g) in 15 mL diethylamine is added 3-butyne-1-ol (0.076 mL). The reaction is allowed to stir overnight. The solvents are evaporated and the residue is chromatographed on silica, eluting with 3% MeOH/CH2Cl2 to yield 0.279 g of the desired product as a tan solid.
Reaction SMILES: C([O:7][C:8]1[C:9]([CH3:28])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27])(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:17][C:11]1[C:10]2=[C:9]([CH3:28])[C:8]([OH:7])=[CH:16][N:15]2[N:14]=[CH:13][N:12]=1
Reactant: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(O)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Reaction time: 0.08 h
Yield: 85.5 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (80 mg, 0.2 mmol) in THF (1 mL) was added a solution of NaOH in MeOH/H2O (0.2 mL, 1 M). The solution turned red instantly. After 5 minutes, the reaction was quenched with EtOAc (5 mL) and H2O (5 mL). The organic layer was separated, dried with sodium sulfate and concentrated in vacuo to give the title compound (52 mg, 85%) as a yellow solid.
Reaction SMILES: C1(S([N:10]2[C:18]3[CH:17]=[C:16]([Cl:19])[CH:15]=[C:14]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24](=[O:50])[NH:25][C:26]5[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:28][C:27]=5[O:41][CH2:42][C:43]([O:45]C(C)(C)C)=[O:44])[C:12]([C:13]=34)=[C:11]2[C:51]([O:53]C)=[O:52])(=O)=O)C=CC=CC=1.CO.[Li+].[OH-].OS([O-])(=O)=O.[K+]>C1COCC1>[Cl:19][C:16]1[CH:15]=[C:14]2[CH2:20][CH2:21][CH:22]([CH2:23][C:24](=[O:50])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:28][C:27]=3[O:41][CH2:42][C:43]([OH:45])=[O:44])[C:12]3=[C:11]([C:51]([OH:53])=[O:52])[NH:10][C:18]([CH:17]=1)=[C:13]23
Reactant: COC(=O)c1c2c3c(cc(Cl)cc3n1S(=O)(=O)c1ccccc1)CCC2CC(=O)Nc1ccc(CNC(=O)OC(C)(C)C)cc1OCC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CC2CCc3cc(Cl)cc4[nH]c(C(=O)O)c2c34)c(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 64.1 %

Procedure:
A solution of methyl 1-benzenesulfonyl-7-chloro-3-[p-tert-butoxycarbonylaminomethyl-o-(tert-butoxycarbonylmethoxy)phenylcarbamoylmethyl]-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylate (410 mg, 0.532 mmol) in a mixture of THF (6 mL ), MeOH (6 mL), and 1N LiOH (6 mL) was stirred for 17 h at room temperature, acidified to pH 2 with 5% KHSO4, and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulfate, and concentrated. The residue was rinsed with diethyl ether and dried in vacuo to give 195 mg of the title compound (quant): 1H NMR (DMSO-d6) δ13.01 (br, 2H), 11.43 (s, 1H), 9.13 (s, 1H), 7.90 (d, 1H, J=8.3 Hz), 7.33 (d, 1H, J=6.3 Hz), 7.15 (s, 1H), 6.84 (s, 2H), 6.82 (d,1H, J=8.3 Hz), 4.05 (d, 2H, J=6.3 Hz), 3.88 (m, 1H), 3.32 (bs, 2H), 3.09 (mt, 1H, J=12.2 Hz), 2.79 (md, 1H, J=17.8 Hz), 2.68 (bd, 1H, J=13.9 Hz), 2.61 (bd, 1H, J=13.9 Hz), 2.09 (md 1H, J=14.2 Hz), 1.84 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:14]O)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].S(Cl)([Cl:18])=O>C(Cl)Cl>[Cl:18][CH2:14][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=1
Reactant: Cc1cc(CO)cnc1OCC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(CCl)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A mixture of (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (0.70 g, 3.18 mmol, Step-2), and thionyl chloride (0.46 mL, 6.36 mmol) in DCM (10 mL) is stirred at rt for 1 hour. The organic solvent is concentrated under reduced pressure and the residue is dried to give 0.75 g (>99% yield) of the title compound as white solid. This material is used for the next reaction (Step-4) without further purification.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:17])=[C:12](F)[C:13]=3[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]2)[CH2:3][CH2:2]1.[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23]>C(#N)C>[CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:17])=[C:12]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:22][CH3:23])[CH2:27]4)[C:13]=3[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]2)[CH2:3][CH2:2]1
Reactant: CCNCC1CCNC1
Reactant: O=C(O)c1cn(CC2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.0 g (3.36 mmol) of 1-(cyclopropylmethyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 8 ml of acetonitrile was added 0.51 g (3.36 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.43 g (3.36 mmol) of 3-[(ethylamino)methyl]pyrrolidine each in 1 ml of acetonitrile. The mixture was refluxed for two hours and stirred overnight at room temperature. The mixture was filtered, and washed with ether to give 0.935 g of 1-(cyclopropylmethyl)-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecrboxylic acid, mp 185°-188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[O:15]=[C:12]1[NH:11][C:10]2[C:16]3[C:21]([CH:22]=[CH:23][C:9]=2[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:32])=[O:31])[CH:7]=[CH:6][CH:5]=2)=[N:14][CH2:13]1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc(C2=NCC(=O)Nc3c2ccc2ccccc32)c1
Solvent: c1ccncc1
Product: O=C1CN=C(c2cccc(NS(=O)(=O)c3ccccc3)c2)c2ccc3ccccc3c2N1
Yield: 96.1 %

Procedure:
5-(3-Aminophenyl)-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one (10 mg, 0.033 mmol), and benzenesulfonyl chloride (13 μL, 0.1 mmol) were treated by heating in pyridine (1.0 mL). A post-treatment was performed in a conventional manner to give the title compound (14 mg, yield 95%) as white amorphous.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[K].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=1[OH:21].Cl[CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C>[NH2:18][C:16]1[CH:15]=[CH:14][C:13]([O:21][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:12]([O:11][CH3:10])[CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCCl
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N)ccc1OCCNC(=O)OC(C)(C)C

Procedure:
A suspension of K2CO3 (280 mg, 2 mmol), NaI (700 mg, 5 mmol), the potassium salt of 2-methoxy-4-nitrophenol (1.37 g, 6.6 mmol), and t-butyl 2-chloroethylcarbamate (1.4 g, 8 mmol) in DMF (8 mL) was heated at 90° C. for 6 hr. After dilution with H2O, the mixture was extracted 4× with CH2Cl2. The combined organic layers were washed 2× with aq. K2CO3, then with brine prior to drying over Na2SO4. After removal of the solvent under vacuum, the residue was chromatographed on silica gel using 5% EtOAc/CH2Cl2 to elute 870 mg of nitrophenyl ether. Pd catalyzed reduction in ethanol as described in step C of Example 6 yielded tert-butyl 2-(4-amino-2-methoxyphenoxy)ethylcarbamate (700 mg) as an off white solid which was carried forward without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH:22]4[CH2:27][CH2:26][N:25]([C:28](=[O:33])[C@H:29]([NH:31][CH3:32])[CH3:30])[CH2:24][CH2:23]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C=O.S([O-])([O-])(=O)=O.[Mg+2].Cl.O1CCOC[CH2:45]1.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH:22]4[CH2:27][CH2:26][N:25]([C:28](=[O:33])[C@H:29]([N:31]([CH3:45])[CH3:32])[CH3:30])[CH2:24][CH2:23]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCO1
Reactant: CN[C@H](C)C(=O)N1CCC(Oc2cc3ncnc(Nc4cccc(Cl)c4F)c3cc2OC)CC1
Agent: C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)[C@@H](C)N(C)C)CC1
Temperature: 40 °C
Yield: 80.7 %

Procedure:
A mixture of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2-(methylamino)propanoyl]piperidin-4-yl}oxy)quinazolin-4-amine (0.5 g, 1.03 mmol (Example 10), paraformaldehyde (0.3 g, 10.0 mmol) and anhydrous magnesium sulfate (0.25 g, 2.08 mmol) in methanol (5 ml) was treated with 4M hydrogen chloride in dioxane (257 μl, 1.03 mmol). Sodium cyanoborohydride (0.26 g, 4.12 mmol) was added and the mixture heated to 40° C. for 3 hours. The reaction mixture was then partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with dichloromethane/7N ammonia in methanol (96/4). Fractions containing the desired product were evaporated to give a gum which was triturated with diethyl ether/isohexane (1:1) to give the title product as a white powder (0.415 g, 80.7%); 1H NMR Spectrum: (DMSO d6 +CD3CO2D) 1.18-1.25 (m, 3H), 1.52-1.80 (m, 2H), 1.95-2.15 (m, 2H), 2.48 (s, 6H), 3.18-3.54 (m, 2H), 3.73-3.91 (m, 1.5H), 3.92 (s, 3H), 4.00-4.14 (m, 1.5H), 4.83-4.95 (m, 1H), 7.21-7.29 (m, 1H), 7.35 (s, 1H), 7.41-7.55 (m, 2H), 7.80 (s, 1H), 8.35 (s, 1H); Mass Spectrum: (M+H)+ 502.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C(=O)N2CC(Oc3ccc(Br)cc3)C2)CC1
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A solution of 2.9 g (0.01 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated while stirring with 1 g (0.01 mole) of 1-methylpiperazine and stirred for 2 hr. The paste-like slurry was diluted with water and the solid was collected by filtration (4 g, wet). Recrystallization from benzene/ligroin yielded 3.0 g of white crystalline product, m.p. 91°-95° C. The solid and 1.16 g of fumaric were dissolved in isopropanol by boiling until a clear solution was obtained. Upon cooling, the precipitated salt was collected by filtration to yield 3 g (63.8%) of fine white crystals, m.p. 197°-198° C.