Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[O:4]/[C:5](=[CH:9]\[C:10]([O-:12])=[O:11])/[C:6]([O-:8])=[O:7].[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[O:4]/[C:5](=[CH:9]\[C:10]([OH:12])=[O:11])/[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(O/C(=C\C(=O)[O-])C(=O)[O-])c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(O/C(=C\C(=O)O)C(=O)O)c(Br)c1
Yield: 88.5 %

Procedure:
Diethyl, (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioate (29.9 g, 86.6 mmol) as prepared in Reference Example 2a was suspended in ethanol (55 ml) and a solution of sodium hydroxide (7.0 g, 0.175 mol) in water (55 ml) was added. The solution was refluxed for 1 h to give a clear orange solution. Most of the ethanol was removed in vacuo then 6 M HCl (50 ml) was added. The solid was filtered, washed with water and dried to give (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioic acid as a light orange solid (24.3 g, 88% yield).
Reaction SMILES: Br[C:2]1[C:3](C)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[O:12]1[CH2:16][CH2:15][O:14][CH:13]1[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>C1(C)C=CC=CC=1.CCO>[O:12]1[CH2:16][CH2:15][O:14][CH:13]1[C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=2)=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: OB(O)c1ccc(C2OCCO2)c(C(F)(F)F)c1
Reactant: Cc1c(Br)cccc1C(N)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: NC(=O)c1cccc(-c2ccc(C3OCCO3)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 3-bromo-2-methylbenzamide (Ex IV-2) and 4-(1,3-dioxolan-2-yl)-3-(trifluoromethyl)phenylboronic acid (I-IX-8) according to the procedure described in Example IX-10, using PhMe/EtOH (4:1) as organic colsovent. LC/MS (method A) 2.36 min; m/z 351 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:39][CH:40]1[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH:40]4[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:41]4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CI)C1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(C(=O)OC(C)(C)C)C4)c4ccc(OC(F)F)cc34)nc12
Yield: 82.1 %

Procedure:
N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 188 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (56.0 mg, 188 μmol) and cesium carbonate (184 mg, 565 μmol) in dimethylformamide (2 mL) were heated in a microwave at 150° C. for 30 min. The mixture was cooled, partitioned between ethyl acetate and water, and the organic phase washed with water 3 times then dried and concentrated. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (108 mg, 82%). MS (M+H)+=700; 1H NMR (CDCl3) δ: 9.18 (s, 1H), 8.34 (s, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.00 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.35 (dd, J=9.0, 2.1 Hz, 1H), 6.24-6.81 (m, 1H), 5.72 (s, 3H), 5.30 (s, 2H), 4.66 (d, J=7.5 Hz, 2H), 3.89 (dd, J=8.9, 5.2 Hz, 2H), 3.58 (dd, J=8.8, 7.6 Hz, 2H), 3.21-3.33 (m, 1H), 1.61 (s, 9H), 1.45 (s, 9H), 0.88-1.00 (m, 2H), −0.08-−0.01 (m, 9H).
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][CH:3]=[C:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])=[CH:13][CH:12]=1
Reactant: O=C1OCCC1=CO
Reactant: NCc1ccc(Cl)cc1
Agent: [Na]
Product: O=C1OCCC1=CNCc1ccc(Cl)cc1
Yield: 63.1 %

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (10 mmol) and 4-chlorobenzylamine (11 mmol) and proceeding according to the abovementioned method A2, 3-(4-chlorobenzylamino)methylenedihydrofuran-2-one (1.5 g, 73%) is produced in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH3:9])=[C:4]([N+:16]([O-])=O)[CH:3]=1>CCO.O.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]([CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: CN(C)CCCN(C)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CN(C)CCCN(C)c1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 4-chloro-N-(3-(dimethylamino)propyl)-N-methyl-2-nitrobenzenamine (4.0 g, 15 mmol) in EtOH (80 ml) and water (10 ml) was added Raney-Ni (10 g). The mixture was stirred for 5 hours at RT, filtered through a pad of Celite and concentrated to yield 4-chloro-N1-(3-(dimethylamino)propyl)-N1-methylbenzene-1,2-diamine as a deep red oil. MS m/z=242 [M+H+. Calc'd for C12H20ClN3: 241.77.
Reaction SMILES: [BrH:1].[Br:2][C:3]([CH3:28])([CH3:27])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:5].BrBr>ClCCl>[Br:2][C:3]([CH3:28])([CH3:27])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:21]3([Br:1])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:5]
Reactant: Br
Reactant: CC(C)(Br)C(=O)c1ccc(Sc2ccc(C(=O)C3CCCCC3)cc2)cc1
Agent: BrBr
Solvent: ClCCl
Product: CC(C)(Br)C(=O)c1ccc(Sc2ccc(C(=O)C3(Br)CCCCC3)cc2)cc1

Procedure:
A drop of 48% HBr was added to a solution of 11.95 g (26.83 mmol) of 2-bromo-1-[4-(4-cyclohexancarbonyl-phenylsulphanyl)-phenyl]-2-methyl-propan-1-one dissolved in 120 ml of dichloromethane; in 15′ 1.37 ml (26.83 mmol) of bromine dissolved in 10 ml of dichloromethane were added drop wise. After 1 h the organic phase was washed with water and with a sodium metabisulphite solution. The organic phase was separated, washed with brine, dried with sodium sulphate, filtered and evaporated under vacuum obtaining 14.07 g of a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]([O-:12])=O)=[CH:7][CH:6]=1)=[O:4].[K+].CN(C)C=O.S(Cl)([Cl:21])=O>ClCCCl>[Cl:21][C:10]([C:8]1[S:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)=[O:12]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(C(=O)[O-])s1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(C(=O)Cl)s1
Temperature: 90 °C
Yield: 371.2 %

Procedure:
150 g (749 mmol) of dimethyl thiophene-2,5-dicarboxylate in 1350 mL of toluene was azeotropically distilled at 130° C. to evaporate 150 mL of it. The reaction solution was cooled to an inner temperature of 70° C., then stirred with 300 mL of 2.5 M potassium hydroxide/methanol for 40 minutes and cooled to room temperature, and the precipitated solid was washed with ethyl acetate by filtration and dried under reduced pressure to obtain 160 g of potassium 5-(methoxycarbonyl)-thiophene-2-carboxylate. 100 g (446 mmol) of potassium 5-(methoxycarbonyl)-thiophene-2-carboxylate in 700 mL of 1,2-dichloroethane was mixed with 1.73 mL of N,N-dimethylformamide and heated to 90° C., and 68.9 g (119 mmol) of thionyl chloride was added dropwise. The reaction solution was refluxed for 1 hour and then cooled to room temperature, and the resulting crystals were filtered off with 300 mL of 1,2-dichloroethane. The filtrate was concentrated to dryness to obtain 90.4 g (yield 99%) of methyl 5-(chlorocarbonyl)thiophene-2-carboxylate (TEC).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:26])[CH:20]=3)[NH:15]2)[CH:9]=1)([CH3:6])[CH3:5].Cl>O1CCCC1.[OH-].[Li+].O>[Cl:26][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]([C:10]1[CH:9]=[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:27])=[O:2])[CH:13]=[CH:12][CH:11]=1)[C:23]([CH3:25])([CH3:24])[CH2:22]2
Reactant: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(Cl)cc3CC2(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Nc1cccc(C2Nc3ccc(Cl)cc3CC2(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.6 %

Procedure:
A mixture of 2-[3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (450 mg, 1.16 mmol) in tetrahydrofuran (30 mL), 2M lithium hydroxide in water (15 mL) was stirred at 25° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (50 mg, 11%) as a white solid: LC/MS m/e calcd for C21H25ClN2O2 (M+H)+: 373.90, observed: 373.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29](F)[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29]([NH:37][CH2:38][C:39]6[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=6)[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cccnc1
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(F)c5)CC4)cccc3[nH]2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(NCc6cccnc6)c5)CC4)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a mixture of 2-(4-tert-Butyl-phenyl)-4-[4-(3-fluoro-4-nitro-benzyl)-piperazin-1-yl]-1H-benzoimidazole (75 mg, 0.15 mMol) in dimethylformamide (2 mL) under nitrogen was added 3-(Aminomethyl) pyridine (0.078 mL, 0.77 mMol) and the resulting solution stirred overnight at room temperature. Upon arrival the reaction mixture was diluted with ethyl acetate (50 mL) and washed three times with water (50 mL) followed by brine (50 mL). The organics were dried with magnesium sulfate, filtered, and evaporated to dryness. Purification by flash column chromatography on silica gel and 5% methanol in dichloromethane as eluant yielded 50 mg of (5-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol -4-yl]-piperazin-1-ylmethyl}-2-nitro-phenyl)-pyridin-3-ylmethyl-amine as a yellow-orange solid (56% yield). 1H NMR (CDCl3): δ=9.24 (s, 1H), 8.66 (s, 1H), 8.55 (m, 1H), 8.43 (m, 1H), 8.16 (d, 1H, J=7.5 Hz), 8.03 (m, 1H), 7.93 (d, 2H, J=7.5 Hz), 7.69 (d, 1H, J=6.0 Hz), 7.49 (d, 2H, J=7.5 Hz), 7.14 (m, 1H), 7.04 (d, 1H, J=6.0 Hz), 6.87 (s, 1H), 6.73 (m, 1H), 6.59 (d, 1H, J=6.0 Hz), 4.60 (m, 2H), 3.55 (m, 6H), 2.68 (m, 4H), 1.34 (s, 9H). LC/MS (Method A), rt=1.05 mins., purity=98.5%, calculated mass=575, [M+H]+=576, [M−H]−=574.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:11]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:12][CH:13]=[C:14]([O:17][CH3:18])[C:15]=2[N:16]=1)=[O:6].Cl.[NH:29]1[CH2:32][CH:31]([OH:33])[CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[OH:33][CH:31]1[CH2:32][N:29]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:11]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:12][CH:13]=[C:14]([O:17][CH3:18])[C:15]=3[N:16]=2)=[O:6])[CH2:30]1
Reactant: OC1CNC1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CC(O)C4)c3)nc12
Temperature: 150 °C
Yield: 14.9 %

Procedure:
A stirred suspension of 200 mg (0.44 mmol) 2-bromo-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-isonicotinamide, 487 mg (4.44 mmol) azetidin-3-ol hydrochloride and 2.17 g (6.66 mmol) cesium carbonate in 6 ml N-methyl-pyrrolidone in a thick-walled glass pressure tube fitted with a teflon cap was heated at 150° C. for 6 h. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (methanol/dichloromethane) followed by trituration in ether afforded 29 mg (15%) 2-(3-hydroxy-azetidin-1-yl)-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-isonicotinamide as a brown crystalline solid. ES-MS m/e (%): 443 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:10]2[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[O:13][C:9]=2[C:8](=[O:18])[N:7]([OH:19])[C:6]1=[O:20].[CH2:25]1[O:33][C:32]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=2[O:26]1>>[O:26]1[C:27]2[CH:28]=[CH:29][C:30]([C:24]3[CH:2]=[C:3]([CH:21]=[CH:22][CH:23]=3)[CH2:4][N:5]3[C:10]4[C:11]5[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=5[O:13][C:9]=4[C:8](=[O:18])[N:7]([OH:19])[C:6]3=[O:20])=[CH:31][C:32]=2[O:33][CH2:25]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: O=c1c2oc3ccccc3c2n(Cc2ccccc2Br)c(=O)n1O
Product: O=c1c2oc3ccccc3c2n(Cc2cccc(-c3ccc4c(c3)OCO4)c2)c(=O)n1O

Procedure:
1-(2-Bromo-benzyl)-3-hydroxy-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was treated with 3,4-methylenedioxyphenylboronic acid according to general procedure C to provide the title compound as a yellow solid. 1H NMR (d6-DMSO, 300 MHz) 5.61 (s, 2H); 6.05 (s, 2H); 6.98 (d, J=8 Hz, 1H); 7.10 (dd, J1=8 Hz, J2=2 Hz, 1H); 7.18-7.21 (m, 2H); 7.35 (dd, J=8 Hz, 2H); 7.49 (br d, J=8 Hz, 1H); 7.57-7.62 (m, 2H); 7.80 (d, J=8 Hz, 1H); 7.87 (d, J=8 Hz, 1H); Ret. time=2.95 min., m/z=429.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CS(C)=O.CCOCC>[CH3:9][O:10][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 92.4 %

Procedure:
To a solution of 2,5-dibromopyridine (20 g, 84 mmol) in DMSO (84 mL) is added (25 wt %) sodium methoxide (21.2 mL, 93 mmol). The resulting solution is heated to 80° C. and stirred for 45 min then cooled to 20° C., diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% ether in hexanes) to give 14.6 g of title compound as a colorless oil. 1H NMR (CDCl3) δ 3.90 (s, 3H), 6.66 (d, J=9 Hz, 1H), 7.63 (dd, J=9, 3 Hz, 1H), 8.20 (d, J=3 Hz, 1H). MS (EI) m/z 187/189 (M+, Br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6](F)[C:5]=1[CH3:14].CS(CCO)(=O)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([OH:18])[C:5]=1[CH3:14]
Reactant: CS(=O)(=O)CCO
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(F)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c([N+](=O)[O-])ccc(O)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a stirring solution of 3-Fluoro-2-methyl-6-nitro-benzoic acid methyl ester (6 g, 28.2 mmol) and 2-(methylsulfonyl)ethanol (5.2 g, 42.2 mmol) in 47 mL of DMF is added sodium hydride (3.38 g, 84.6 mmol) at 0° C. and the reaction mixture is allowed to warm to room temperature and then stirred for 1.5 hours. The mixture is quenched with 1N HCl solution and partitioned between ethyl acetate. The organic layer is washed with brine and concentrated to dryness and the crude organics purified by flash column chromatography to give 3-Hydroxy-2-methyl-6-nitro-benzoic acid methyl ester (5.3 g) in 89% yields. 1H-NMR (400 MHz, δ, ppm) CDCl3: 2.22 (s, 3H), 3.99 (s, 3H), 6.38 (s, 1H), 6.87 (d, 1H), 7.99 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[CH2:10][N:11]1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)[C:12]1=[O:30])[C:2]1C=CC=CC=1.[O:32]=[C:33]1[N:39](CC(N[C@H]2CC(=O)OC2OCC2C=CC=CC=2)=O)[C:38]2[CH:58]=[CH:59][CH:60]=[CH:61][C:37]=2[N:36]([C:62](=[O:65])[CH2:63][OH:64])[CH2:35][C@@H:34]1[NH:66][C:67](=[O:77])[C:68]1C=[C:72](C)[C:71](O)=[C:70](C)[CH:69]=1>>[O:32]=[C:33]1[N:39]([C:12]([NH:11][C@H:10]2[CH2:34][C:33](=[O:32])[O:31][CH:9]2[O:8][CH2:1][CH3:2])=[O:30])[C:38]2[CH:58]=[CH:59][CH:60]=[CH:61][C:37]=2[N:36]([C:62](=[O:65])[CH2:63][OH:64])[CH2:35][C@@H:34]1[NH:66][C:67]([C:68]1[C:69]2[C:58](=[CH:59][CH:72]=[CH:71][CH:70]=2)[CH:38]=[CH:37][N:36]=1)=[O:77]
Reactant: Cc1cc(C(=O)N[C@H]2CN(C(=O)CO)c3ccccc3N(CC(=O)N[C@H]3CC(=O)OC3OCc3ccccc3)C2=O)cc(C)c1O
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Product: CCOC1OC(=O)C[C@@H]1NC(=O)N1C(=O)[C@@H](NC(=O)c2nccc3ccccc23)CN(C(=O)CO)c2ccccc21

Procedure:
(3S)-2-oxo-3-(isoquinolin-1-oyl)amino-5-hydroxyacetyl-N-[(2RS,3S)-ethoxy-5-oxo-tetrahydrofuran-3-yl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carboxamide (696b) was synthesized from 600b via methods used to prepare 690a from 600b to afford 696b. 1H NMR (CDCl3) δ 0.9 (m, 3H), 1.15 (q, 3H), 1.15 (m, 1H), 1.65 (m, 1H), 2.5 (m, 1H), 2.8 (m, 1H), 2.95-3.0 (m, 2H), 3.6 (m, 2H), 3.7-3.85 (m, 4H), 4.0 (m, 2H), 4.3 (m, 1H), 4.55 (m, 1H), 4.65 (m, 1H), 4.85-4.95 (m, 1H), 5.05 (m, 1H), 5.35 (s, 1H), 5.45 (d, 1H), 6.85 (d, 1H), 7.25 (d, 1H), 7.35-7.85 (6H), 8.85 (dd, 2H), 9.05 (m, 1H), 9.35 (dd, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:21])([CH3:20])[CH2:11][C:12](O)([C:15]([F:18])([F:17])[F:16])[CH:13]=O.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)(O)[O-]>>[CH3:20][C:10]1([CH3:21])[C:4]2[C:5](=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[O:2][CH3:1])[CH:13]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)[CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:11]1
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Product: COc1cc(C)cc2c1C(C)(C)CC(C(F)(F)F)C2Nc1cccc2[nH]c(=O)ccc12
Yield: 6.1 %

Procedure:
Analogously to Example 2, the corresponding imine is produced starting from 280 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 156 mg of 5-aminoquinolin-2(1H)-one. The latter is stirred at room temperature with 93 mg of aluminum chloride for 2.5 hours. The batch is added to saturated bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation in a vacuum. After chromatography on silica gel (dichloromethane/2-propanol 0->5%), 24 mg of the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:28][NH:29]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:35]4[CH2:36][CH2:37][N:32]([C:27]5[C:26]6[C:30](=[CH:31][C:23]([F:22])=[CH:24][CH:25]=6)[NH:29][N:28]=5)[CH2:33][CH2:34]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2n[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 6-fluoro-3-piperazin-1-yl-1H-indazole (Table No.1, SM 4) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=506.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].S(O)(O)(=O)=O.[CH:16]1([C:19]2[CH:23]=[C:22]([CH:24]3[CH2:28][CH2:27][CH2:26][N:25]3[C:29](=[NH:31])[NH2:30])[O:21][N:20]=2)[CH2:18][CH2:17]1.C[O:33][CH2:34][C:35](=O)[CH2:36][C:37]([O:39][CH3:40])=O>C1COCC1.CO>[CH:16]1([C:19]2[CH:23]=[C:22]([CH:24]3[CH2:28][CH2:27][CH2:26][N:25]3[C:29]3[N:30]=[C:34]([OH:33])[CH:35]=[C:36]([CH2:37][O:39][CH3:40])[N:31]=3)[O:21][N:20]=2)[CH2:17][CH2:18]1
Reactant: COCC(=O)CC(=O)OC
Reactant: N=C(N)N1CCCC1c1cc(C2CC2)no1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cc(O)nc(N2CCCC2c2cc(C3CC3)no2)n1
Yield: 29.3 %

Procedure:
Sodium bis-(trimethylsilyl)amide (3.65 ml of a 2M solution in THF, 7.3 mmol) was added to a solution of 2-(3-cyclopropylisoxazol-5-yl)pyrrolidine-1-carboximidamide mono sulphate (Method 17) (1.83 g, 6.09 mmol) and methyl 4-methoxyacetoacetate (0.867 ml, 6.7 mmol) in methanol (30 ml) and the mixture heated at reflux for 4 hours. The solvent was removed by evaporation and the residue purified by chromatography on silica gel eluting with DCM/Methanol (100:0 increasing in polarity to 95:5). The purified product was triturated with ether and the solid then recrystallised from methanol to give the title compound (565 mg, 29%) as white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[OH-:12].[Na+]>C(O)CCC>[NH:2]1[C:3]2[CH:7]=[CH:6][S:5][C:4]=2[C:8](=[O:9])[O:10][C:11]1=[O:12]
Reactant: COC(=O)c1sccc1N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: O=c1[nH]c2ccsc2c(=O)o1
Reaction time: 2.5 h

Procedure:
A mixture of 175 g (0.93 mol) of methyl 3-amino-2-thiophenecarboxylate hydrochloride, 1.8 liters of n-butanol and 77 g of sodium hydroxide is heated to boiling under reflux for 30 minutes. After concentration of the resulting suspension on a rotary evaporator, the mixture of sodium 3-amino-2-thiophenecarboxylate and sodium chloride is used directly in the next step. For this purpose, the mixture is treated with 800 ml of water, 280 ml of concentrated hydrochloric acid and 230 ml of tetrahydrofuran. Phosgene is conducted through this mixture at 15°-25° C. for 2.5 hours and then air conducted through for 15 minutes. The separated solid material is filtered off under suction, washed with water and dried. There is obtained 2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione of melting point 220°-221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.[OH-].[Na+].[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:26]=[CH2:27])[CH:25]=1>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:24]3[CH:23]=[N:22][CH:21]=[C:20]([Cl:19])[CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cncc(Cl)c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2c(n(CCc3cncc(Cl)c3)c3ccc(Cl)cc23)CC1
Temperature: 60 °C
Yield: 3.2 %

Procedure:
The title compound was prepared by following general procedure 4. To a solution of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.42 mmol) in 50% aq. NaOH solution (5 mL) tetra n-butyl ammonium chloride (9 mg, 0.03 mmol) followed by 3-chloro-5-vinylpyridine (65 mg, 0.47 mmol) was added. The reaction mixture was heated at 60° C. for 8 h. After completion of reaction, the reaction mixture was diluted with water, extracted with ethyl acetate; the organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford 5 mg of 9-chloro-6-(2-(5-chloropyridin-3-yl)ethyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt.