Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[N:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[CH:29]([NH2:31])[CH3:30].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:31][CH:29]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][N:23]=2)[CH3:30])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: CC(N)c1cnccn1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)c1cnccn1
Temperature: 165 °C
Yield: 55.6 %

Procedure:
This compound (40 mg, 55% yield) as a yellow crystalline solid was prepared according the procedures described for Example 318, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (54 mg, 0.18 mmol), 1-(pyrazin-2-yl)ethanamine (45 mg, 0.36 mmol) (Essen Scientific LLC, cat # ES10-0543) and DIEA (64 μL, 0.36 mmol) in 2 mL of DMSO (heated in a microwave at 165° C. for 45 min). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, br.), 8.87 (1H, m), 8.59 (1H, m), 8.50 (1H, d, J=2.5 Hz), 7.87 (1H, d, J=7.2 Hz), 7.67 (1H, d, J=7.0 Hz), 7.57 (1H, d, J=7.4 Hz), 7.32 (1H, t, J=7.8 Hz), 6.99 (1H, br.), 6.90 (1H, d, J=2.2 Hz), 5.41 (1H, m), 3.48 (2H, m), 3.03 (2H, m), 2.68 (3H, s), 1.74 (3H, d, J=7.0 Hz). m/z (ESI, +ve) 400.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[C:15]([O:20]C)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:35]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[C:15]([OH:20])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:36]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CCN(Cc2ccccc2)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(O)cccc1N2C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
To a solution of 10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic acid diethylamide, 4d (50 mg, 0.1 mmol) in methylene chloride (2 mL) at 0° C. was added a 1M solution of boron tribromide in methylene chloride (0.8 mL, 0.8 mmol). The mixture was allowed to stir for 15 min at rt, followed by stirring at rt for 4 h. A saturated NaHCO3 solution and methylene chloride were added, and the organic phase was separated. The organic phase was dried, filtered, and evaporated. The residue was purified via reverse phase HPLC (eluent: CH3CN in water containing 0.1% TFA) to yield 17 mg (29%) of title compound 10-(1-benzyl-piperidin-4-yl)-6-hydroxy-10H-phenoxazine-3-carboxylic acid diethylamide, 6d as a TFA salt. MS m/z (MH+) 471.0.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
A mixture of 4-nitrobenylchloride (4.1 g, 23.90 mmol), N-isopropylpiperazine (3.6 g, 28.67 mmol, 1.2 eq.), potassium carbonate (6.5 g, 47.79, 2 equiv), and acetone (82 mL) is stirred for 16 h at reflux. The reaction mixture is allowed to cool to rt, filtered and concentrated. Purification of the residue by silica gel column chromatography (CH2Cl2/MeOH+1% NH3aq, 9:1) affords 6.2 g of the title compound as a yellow solid: to afford the title compound as a yellow solid: ESI-MS: 264.1 [M+H]+; tR=1.73 min (System 1); TLC: Rf=0.34 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [F:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:18][Si](C)(C)Cl>CO>[CH3:18][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[C:3]([C:14]([F:15])([F:16])[F:17])=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
A solution of 6.2 g (24.5 mmole) of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid in 250 ml of methanol is treated with 9.28 ml (73.5 mmole) of trimethylchlorosilane and heated to reflux for six days during which every evening additional 9.28 ml of trimethylchlorosilane are added. The cooled solution is evaporated in vacuo and distributed between dichloro-methane and water. The combined organic phases are extracted twice with 50 ml of a 0.5 M sodium hydroxide solution and with 50 ml brine. After drying over sodium sulfate, filtering and evaporation the crystalline residue is recrystallized from acetone/petrolether to give 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester of m.p. 66-68° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:10](=[O:27])[N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:14]=2)[N:4]=1.Cl>>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:10](=[O:27])[N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:14]=2)[N:4]=1
Reactant: COc1cccc(-c2cc(-c3ccccn3)cn(-c3ccccc3)c2=O)n1
Agent: Cl
Product: O=c1c(-c2cccc(O)n2)cc(-c2ccccn2)cn1-c1ccccc1
Reaction time: 1 h

Procedure:
20 mg of 3-(2-methoxypyridin-6-yl)-1-phenyl-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one is added to 3 ml of 5N hydrochloric acid. The mixture was heated under reflux for 3 hours, to which 0.5 ml of concentrated hydrochloric acid was added, and further stirred for 1 hour. The reaction mixture was concentrated under a vacuum and washed with ether, to quantitatively obtain the subject compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[F:14][C:15]([F:34])([F:33])[C:16]1[O:20][C:19]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[C:23]2=[O:32])=[CH:18][CH:17]=1>O1CCCC1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:24]2([OH:31])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:22]([CH2:21][C:19]3[O:20][C:16]([C:15]([F:34])([F:33])[F:14])=[CH:17][CH:18]=3)[C:23]2=[O:32])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1ccc(Br)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a stirred solution of 3-bromophenol (4.4 g, 25.4 mmol) in tetrahydrofuran (100 mL) was added iso-propylmagnesium chloride (12.7 mL, 2 M tetrahydrofuran solution, 25.4 mol) slowly at 0° C. The mixture was allowed to stir for 30 min at 0° C., then the solvent was removed in vacuo. Dichloromethane (100 mL) was added, followed by the addition of a solution of 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione (5.0 g, 16.9 mol) in dichloromethane (100 mL) at 0° C. The mixture was stirred at ambient temperature for 16 h, quenched by the addition of saturated ammonium chloride solution. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The obtained solid was recrystallized from ethyl acetate/hexanes to afford 3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (6.4 g, 81%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.49-5.83 (m, 9H), 5.13-4.71 (m, 2H); MS (ES+) m/z 449.9 (M−17), 451.9 (M−17).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][C:12](=[O:15])[CH:13]=[CH2:14])[CH:5]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:38])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:19][CH2:18]1>CCO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][C:12](=[O:15])[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:24](=[O:38])[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:21][CH2:22]2)[CH:5]=1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reactant: C=CC(=O)CNc1cccc(C(=O)OC)c1
Solvent: CCO
Product: COC(=O)c1cccc(NCC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1
Yield: 45 %

Procedure:
A stirred solution of 3-(acryloylmethylamino)benzoic acid methyl ester (estimated ˜56 mmol) and biphenyl-2-ylcarbamic acid piperidin-4-yl ester (16.6 g, 56.0 mmol) in EtOH (20.0 mL) was heated at 90° C. overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel flash chromatography (0-10% MeOH in DCM) to give the title compound (13.0 g, 45% yield) as an off-white solid.
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[C:13](=O)[NH:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[O:9][C:8]=3[S:19][C:5]=2[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[CH3:42][N:43]1[CH2:48][CH2:47][N:46]([C:13]2[C:7]3[C:6]4[CH2:1][CH2:2][CH2:3][CH2:4][C:5]=4[S:19][C:8]=3[O:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[N:12]=2)[CH2:45][CH2:44]1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccccc2Oc2sc3c(c21)CCCC3
Agent: O=C(O)/C=C/C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CN1CCN(C2=Nc3ccccc3Oc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one (0.6 g), phosphorus oxychloride (5 ml), N,N-dimethylaniline (0.14 ml), 1-methylpiperazine (10 ml) and fumaric acid (260 mg), 1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzoxazepine fumarate (575 mg) was obtained.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:28]=4[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])[CH:19]=3)[C:14](O)=[O:15])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:49][NH:50][CH3:51]>>[C:44]([CH2:43][CH2:42][C:28]1[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]2[CH:17]=[C:13]([C:14](=[O:15])[N:50]([CH3:51])[CH3:49])[CH:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:19]=2)=[CH:32][CH:31]=[CH:30][C:29]=1[O:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])([OH:46])=[O:45]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Reactant: CNC
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCCO3)c1

Procedure:
The title compound was prepared according to the general procedure described in Example 74 starting from 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid and dimethylamine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:18]=[C:19]([NH2:22])[S:20][CH:21]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.[O:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH:24]1[C:33](O)=[O:34].N1(O)C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:18]=[C:19]([NH:22][C:33]([CH:24]3[CH2:25][CH2:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:23]3)=[O:34])[S:20][CH:21]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=NOCc1csc(N)n1)c1ccccc1
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cn1nnnc1C(=NOCc1csc(NC(=O)C2CCc3ccccc3O2)n1)c1ccccc1
Yield: 44 %

Procedure:
To a stirred solution of 4-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-amine (200 mg, 0.63 mmol) in dimethylformamide (1.5 mL) were added chromane-2-carboxylic acid (124 mg, 0.70 mmol) and 1H-benzotriazol-1-ol (94 mg, 0.70 mmol). The reaction mixture was poured at room temperature on a cartridge filled with 1.44 g of silica linked with N,N′-dicyclohexylcarbodiimide (loading: 1.05 mmol/g). After one night at room temperature, the cartridge was eluted with 1 mL of dimethylformamide. The filtrated solution was then poured on a cartridge filled with 1.5 g of basic alumina. After 2 hours of reaction a room temperature, the cartridge was rinsed twice with 10 mL of ethyl acetate. The combined filtrated solutions were evaporated in vacuo to yield a yellow oil. Purification on silica gel afforded of N-{4-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}chromane-2-carboxamide as a colorless oil [150 mg, yield 44%; HPLC/MS: nm/z=476 (M+H); log P(HCOOH)=3.78].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([OH:17])[CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([O:17][C:18](=[O:20])[CH3:19])[CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@H](O)C[C@H]2CCCN2C)c1
Reactant: CC(=O)OC(C)=O
Product: COc1cccc([C@@H](C[C@H]2CCCN2C)OC(C)=O)c1

Procedure:
According to the method of working described in Example 28, from 3.0 g of (R*,R*)-1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)-ethanol and 30 ml of acetic acid anhydride there are obtained 1.56 g of the title compound as tough, colourless oil of b.p. 130° at 0.008 mm Hg.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([O:22][C@H:23]3[CH2:27][CH2:26][NH:25][C:24]3=[O:28])=[C:16]2[CH:15]=[N:14]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([O:22][C@H:23]3[CH2:27][CH2:26][N:25]([S:30]([CH3:29])(=[O:32])=[O:31])[C:24]3=[O:28])=[C:16]2[CH:15]=[N:14]1
Reactant: O=C1NCC[C@@H]1Oc1ncnc2c1cnn2-c1ccccc1Cl
Reactant: CS(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CC[C@H](Oc2ncnc3c2cnn3-c2ccccc2Cl)C1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
Butyllithium (1.6M in hexane, 1.668 mL, 2.67 mmol) was added dropwise to (3S)-3-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)pyrrolidin-2-one (Intermediate AC2) (800 mg, 2.43 mmol) in THF (15 mL) cooled to −78° C. under nitrogen. The resulting solution was allowed to warm to r.t., then recooled to −78° C. methanesulfonyl chloride (0.207 mL, 2.67 mmol) was added dropwise and the resulting solution was stirred at r.t. for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4) and evaporated (995 mg). The crude product was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to afford the product (368 mg, 37.2%). 1H NMR (400 MHz, CDCl3) δ 2.35-2.47 (1H, m), 2.83-2.92 (1H, m), 3.37 (3H, s), 3.85-3.94 (1H, m), 4.06-4.16 (1H, m), 6.13 (1H, t), 7.44-7.56 (3H, m), 7.59-7.66 (1H, m), 8.32 (1H, s), 8.57 (1H, s); m/z (ES+) (M+H)+=408.29; HPLC tR=2.10 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[N:15]12[CH2:23][CH2:22][CH2:21][C@@H:20]1[CH2:19][NH:18][CH2:17][CH2:16]2.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH2:17][CH2:16][N:15]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[CH2:19]2)=[CH:3][C:4]=1[O:11][CH:12]([CH3:14])[CH3:13])([O-:10])=[O:9]
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1C[C@@H]2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1cc(N2CCN3CCC[C@@H]3C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.9 %

Procedure:
A mixture of 1.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 634 mg of (R)-1,4-diazabicyclo[4,3,0]nonane and 1.04 g of potassium carbonate in 7 ml of DMSO is stirred at ambient temperature for 21 hours. The reaction medium is run into 15 ml of water and the mixture is then extracted three times with 30 ml of ethyl acetate. The organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum, so as to obtain 1.44 g of (8aR)-2-[4-nitro-3-(propan-2-yloxy)phenyl]octahydropyrrolo[1,2-a]pyrazine in the form of an orangey-coloured oily residue.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:19])[CH2:17][OH:18])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[K+].[NH3:22]>>[NH2:22][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:19])[CH2:17][OH:18])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(CO)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: N
Agent: [K+]
Agent: [OH-]
Product: CC(CO)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 25 °C

Procedure:
R 3-(4-Chloro-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-1-ol (1.0 g, 3.6 mmol) and methanolic ammonia (30 mL of 15%) were combined and then heated in a steel bomb at 150° C. The container was allowed to cool to ambient temperature. Excess methanolic potassium hydroxide was added to the reaction mixture which was then concentrated under reduced pressure to decrease the volume. Water was added and then concentration was continued until a solid formed. The solid was isolated by filtration, washed with water and then dried to provide a near white solid. This material was recrystallized from methanol/dichloromethane to provide R 3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-1-ol as colorless solid, m.p. 258-261° C. Analysis: Calculated for C14H16N4O: %C, 65.61, %H, 6.29; %N, 21.86; Found: %C, 65.50, %H, 6.3, %N, 21.7.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH3:26][N:27]([CH3:29])[NH2:28]>>[CH3:26][N:27]([CH3:29])[NH:28][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: CN(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)nn1C
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NN(C)C)n(C)n1
Yield: 94 %

Procedure:
As described for example 81c, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (73 mg, 0.21 mmol) was converted, using N,N-dimethylhydrazine instead of morpholine, to the title compound (74 mg, 94%) which was obtained as a colorless oil. MS: m/e=375.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:14][O:15][C:16]1[S:20][C:19]([C:21](Cl)=[O:22])=[CH:18][CH:17]=1.Cl[Sn](Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:21]([C:19]1[S:20][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2o1
Reactant: COc1ccc(C(=O)Cl)s1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(OC)s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.0 g (17.2 mmol) 2-butylbenzo[b]furan were dissolved in 30 ml abs. chloroform, the solution was cooled to 0° C., and reacted with 3.6 g (20.4 mmol) 5-methoxy-2-thiophenecarbonyl chloride, dissolved in 5 ml abs. chloroform, and then, at a temperature between 0° and 3° C., 2.8 ml SnCl4 were added dropwise. Stirring for 2 hours at 0° C. followed. The reaction mixture was evacuated under ice-cooling over 50 ml 2N HCl, the phases were separated and the aqueous phase thoroughly extracted with ether. The chloroform and ether phases were each washed with 50 ml 2N NaOH, combined, dried over sodium sulphate and evaporated. The crude product was quickly distilled.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:44])[CH2:21][NH:22][C:23]([CH3:43])([CH3:42])[CH2:24][CH2:25][N:26]2[C:31]3[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=3[C:29]([CH2:39][CH3:40])([CH2:37][CH3:38])[O:28][C:27]2=[O:41])[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.Cl>>[CH2:39]([C:29]1([CH2:37][CH3:38])[O:28][C:27](=[O:41])[N:26]([CH2:25][CH2:24][C:23]([NH:22][CH2:21][CH:20]([OH:44])[C:11]2[C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=[C:9]([OH:8])[CH:10]=2)([CH3:42])[CH3:43])[C:31]2[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]1=2)[CH3:40]
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)c2cc(F)ccc21
Agent: Cl
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(O)cc3c2OCC(=O)N3)c2cc(F)ccc21

Procedure:
The product is prepared analogously to Example 12b starting from 1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-7-fluoro-1,4-dihydrobenzo[d][1,3]oxazin-2-one. Yield: 170 mg (78%; hydrochloride); HPLC-MS: Rt=10.6 min. (method A); ESI-MS: [M+H]+=516.
Reaction SMILES: C[Si](Cl)(C)C.BrCCBr.[CH:10]1(I)[CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1>CN(C)C(=O)C.[Zn].[Cu]I>[Cl:16][C:17]1[C:22]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: Clc1nccnc1Cl
Reactant: IC1CCCC1
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Product: Clc1nccnc1C1CCCC1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a suspension of zinc dust (2.00 g, 30.6 mmol) in N,N-dimethylacetamide (20 mL) was added a mixture of trimethylsilyl chloride and 1,2-dibromoethane (7:5, v/v, 0.95 mL total volume) dropwise over 5 minutes. The mixture was stirred for 15 min before cyclopentyl iodide (5.00 g, 25.5 mmol) was added dropwise over 15 min. This mixture was stirred for an additional 15 min and then was added via syringe over 5 min to a mixture of copper(I) iodide (0.30 g, 1.60 mmol), dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (0.65 g, 0.80 mmol), and 2,3-dichloropyrazine (1.66 mL, 16.0 mmol) in N,N-dimethylacetamide (30 mL) under argon atmosphere. The mixture was heated to 80° C. for 7 h, cooled to room temperature and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The resulting layers were separated and the aqueous layer was extracted with ethyl acetate (1×). The combined extracts were washed with water (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give 2-chloro-3-cyclopentylpyrazine.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=[CH:3]1.[B-](F)(F)(F)[F:13].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>CC#N>[F:13][C:3]1[C:2](=[O:1])[NH:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1
Reactant: COC(=O)c1ccc(=O)[nH]c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: COC(=O)c1c[nH]c(=O)c(F)c1
Temperature: 65 °C

Procedure:
To a solution of methyl 6-oxo-1,6-dihydro-3-pyridinecarboxylate (2.00 g, 13.06 mmol, Bionet Research) in MeCN (40 mL) was added SelectFluor® (4.63 g, 13.06 mmol, Aldrich). The resulting mixture was then heated at 65° C. for 18 h. Then, the mixture was cooled to rt and water (20 mL) was added. The solvent, (MeCN) was removed and the remaining aqueous solution was extracted with EtOAc (2×20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in MeOH (100 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. Purification by silica gel flash column chromatography (0%-100% EtOAc/hexane) gave the title compound as a white solid. MS (ESI, positive ion) m/z: 172 (M+H).