Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:20][C:18]1[CH:17]=[CH:16][C:15]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14]([CH2:13][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH3:12])[CH:19]=1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(N)cc1CN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a solution of 15B (2.062 g, 5.34 mmol) in methanol (30 mL) and THF (5 mL) was added zinc (dust) (3.49 g, 53.4 mmol) and ammonium chloride (5.71 g, 107 mmol). The resulting solution was stirred at rt for 18 h. MeOH was removed under reduced pressure, to the residue Na2CO3 (aq, 100 mL) and EtOAc (250 mL) were added, and the suspension was stirred vigorously for 10 min, filtered though glass frit, solid residue was washed with EtOAc (3×150 mL). Combined EtOAc fractions were washed with std. Na2CO3 (aq, 2×100 mL), water (2×100 mL), brine (1×100 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-100% EtOAc/hexanes). Fractions were combined and concentrated under reduced pressure to give 15C (1.546 g, 4.34 mmol, 81% yield) as an amber oil. MS (ESI) m/z: 357.2 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 7.28-7.47 (5H, m), 7.00 (1H, d, J=7.28 Hz), 6.56 (1H, d, J=8.03 Hz), 6.38-6.52 (1H, m), 5.13-5.22 (2H, m), 4.48 (2H, br. s.), 4.08 (2H, br. s.), 3.44-3.58 (2H, m), 2.85 (3H, d, J=17.82 Hz), 1.21 (3H, d, J=7.03 Hz).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH:35]=O.[OH-].[Na+]>C(Cl)Cl.O>[CH3:43][O:42][C:38]1[CH:37]=[C:34](/[CH:35]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:29][CH:28]=2)[CH:33]=[C:32]([O:31][CH3:30])[C:39]=1[O:40][CH3:41]
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C/c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of 4-methoxybenzyltriphenylphosphonium chloride (6.4 g, 15.3 mmol) and 3,4,5-trimethoxybenzaldehyde (3 g, 15.3 mmol) in CH2Cl2 was added a cooled aqueous solution of NaOH (62.5 eq) in H2O. The mixture was stirred at room temperature for 48 hours. The organic phase was separated and the aqueous phase was washed with CH2Cl2. The organic phase was concentrated and the residue was recrystallised from ethanol to yield the title E-trans isomer. 1H NMR (CDCl3) δ 8.7 (1H, d:), 8.2 (4H, m), 8.0 (2H, s), 5.2 (6H, s), 5.0 (6H, s). Mass Spectrum (FAB) 301 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][O:12][C:11]2=[O:16])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][O:12][C:11]2=[O:16])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C1OCCCN1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCCOC2=O)cc1

Procedure:
A mixture of 3-(4-nitrophenyl)-1,3-oxazinan-2-one (0.10 g, 0.00045 mol) in 5 mL of methanol was hydrogenated, in the presence of 10% Pd/C, under balloon pressure of hydrogen, overnight. After filtering off the catalyst, the filtrate was evaporated to dryness and used directly in next step. LCMS (M+H) 193.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:62]3[CH2:63][CH2:64][N:59]([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[CH3:52])[CH2:60][CH2:61]3)[N:9]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC2CO2)C1
Reactant: Cc1ccccc1N1CCNCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC(O)CN2CCN(c3ccccc3C)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
A solution of 1-[3-(4-chloro-3-nitro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.754 g, 2.0 mmol) in dichloromethane (10 mL) was treated with ytterbium(III) triflate (0.25 g, 0.40 mmol) and 1-(2-methylphenyl)-piperazine (0.705 g, 4.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and diluted with dichloromethane (100 mL) and water (50 mL). The organic layer was separated, washed with water (2×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 5% MeOH/CH2Cl2) to afford 0.98 g (90%) of the desired product as a light yellow solid. MS (electrospray): m/z 553.2 (553.2, calculated for C28H33ClN6O4, [M+H]+). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 8.25-8.15 (m, 1H), 7.75-7.70 (m, 1H), 7.63-7.55 (m, 1H) 7.20-7.10(m, 2H), 7.05-6.95 (m, 2H), 4.90-4.70 (m, 1H), 4.65 (s, 1H), 4.30-4.15 (m, 2H), 4.10-3.70 (m, 4H), 3.00-2.40 (m, 12H), 2.20(s, 3H), 2.15 (s, 1.5H), 2.10 (s, 1.5H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=O>C(O)CC>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[N:1]=[C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]3[CH:13]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: CCCO
Product: Cc1ccc(-c2cn3cc(C(F)(F)F)ccc3n2)cc1
Yield: 70.2 %

Procedure:
10 g (0.0616 mole) of 2-amino-5-trifluoromethylpyridine and 17.5 g (0.0616 mole) of 1-bromo-2-(4-methylphenyl)-2-ethanone are mixed in 200 ml of n-propanol and the solution is heated to reflux. At the end of the reaction, the reaction mixture is concentrated under reduced pressure and the evaporation residue taken up with water and treated with an excess of ammonia solution until the pH is basic. The imidazopyridine is extracted with dichloromethane and purified by chromatography. 11.95 g (56%) of white solid are obtained. M.p. 187°-188° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[S:5][C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:1][C:2]1[N:3]=[C:4]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)[S:5][C:6]=1[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(N)c(C(=O)c4cccc(F)c4)s3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(Nc2ccc(N3CCNCC3)cc2)sc1C(=O)c1cccc(F)c1
Reaction time: 8 h
Yield: 1 %

Procedure:
A mixture of 4-[4-[[4-amino-5-(3-fluorobenzoyl)-2-thiazolyl]amino]phenyl]-1-piperazinecarboxylic acid, 1, 1-dimethylethyl ester (75 mg, 0. 15 mmol) (from Step A above) and a solution of TFA/CH2Cl2 (1:1; 1.5 mL) was gently shaken for 1.5 h. The solution was evaporated in vacuo. To the residue was added resin-bound N,N-diisopropylethylamine (2.5 g, loading capacity: 3.8 mmol/g from Argonaut, Inc.) and CH2Cl2 (15 mL). After shaking overnight, the mixture was filtered and washed successively with CH3OH and CH2Cl2. The solvent was evaporated in vacuo and the residue was triturated by diethyl ether/hexanes (1/9) to afford [4-amino-2-[[4-(1-piperazinyl)phenyl]amino]-5-thiazolyl](3-fluorophenyl)methanone (60 mg, 100%).
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1>ClCCCl>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[NH:1][NH2:2])=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCCl
Product: NNC(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrazine (0.83 mL, 26.4 mmol) is added dropwise to a solution of 4-chlorophenyl isocyanate (3.85 g, 25.1 mmol) in 1,2-dichloroethane. The reaction mixture is stirred overnight at room temperature and filtered. The filter cake is washed with ether and dried to give the title product as a white solid, 4.28 g, which is identified by 1HNMR spectral analysis.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:29]([NH:31][CH2:32][CH2:33][OH:34])[CH3:30]>>[CH2:29]([N:31]([CH2:21][CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:1])[F:27])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:32][CH2:33][OH:34])[CH3:30]
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CCNCCO
Product: CCN(CCO)CCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1; Methanesulfonic acid 4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and 2-Ethylaminoethanol were converted to yield 2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-amino)-ethanol as light yellow oil, MS: 423 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][CH:10]=[CH:9][CH2:8]1)([O-])=[O:2].C(N)CCC>C1(C)C=CC=CC=1>[OH:2][NH:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Solvent: CCCCN
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 5.0 parts of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone with 80 parts of toluene and 1.0 part of n-butylamine was stirred at 70°C for 2 hours. The mixture was then distilled under a reduced pressure of 100 mm Hg to remove toluene, washed with 50 parts of methanol and dried under reduced pressure to obtain 4.4 parts of 1-hydroxylaminoanthraquinone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20]#[N:21])=[CH:13][CH:14]=2)[C:9]1([CH2:24][CH3:25])[CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].C([OH:29])C.CN(C=O)C>O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:29])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH2:22][CH3:23])[CH2:24][CH3:25])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC1(CC)c2cc(C#N)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Reactant: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a mixture of trans-(7-cyano-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (33.0 g, 92 mmol), ethanol (45 mL), DMF (25 mL) and water (7.5 mL) was added hydrido(dimethylphosphoniousacid-kP) [hydrogen bis(dimethylphosphinito-kP)]platinum(II) (0.25 g, 0.58 mmol) and the reaction mixture was heated at 80° C. for 24 h. The reaction was cooled to room temperature and concentrated to dryness under vacuum to give the title compound (36.3 g) which was used without further purification. (m/z): [M+H]+ calcd for C21H32N2O4 377.24; found 377.8. 1H NMR (d6-DMSO, 400 mHz) δ (ppm): 7.92 (s, 1H), 7.64 (m, 2H), 7.26 (s, 1H), 7.14 (d, J=7.9 Hz, 1H), 6.64 (d, J=9.4 Hz) 3.81 (t, J=10.0 Hz), 3.58 (m, 1H), 3.30 (s, 3H), 2.58 (dd, J=16.9 Hz, 9.4 Hz, 1H), 1.82 (m, 1H), 1.56-1.45 (m, 4H), 1.41 (s, 9H), 0.58 (m, 6H).
Reaction SMILES: CS(O[C@H:6]1[CH2:10][C@@H:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:8]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:7]1)(=O)=O.CN(C)C=O.[N-:33]=[N+:34]=[N-:35].[Na+]>>[N:33]([C@@H:6]1[CH2:10][C@@H:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:8]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:7]1)=[N+:34]=[N-:35]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](OS(C)(=O)=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N=[N+]=[N-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 55 °C

Procedure:
To a solution of (1S,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl methanesulfonate (2.66 g, 0.00606 mol) in N,N-Dimethylformamide (20 mL, 0.2 mol) was added sodium azide (1.21 g, 0.0186 mol), and the mixture was heated at 55° C. for 3 hours. The reaction was cooled to 23° C., quenched by addition of water and extracted with Et2O (3×), washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 15% ethyl acetate/hexane) to obtain 2.13 g (91.1%).
Reaction SMILES: O=[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=O.[F:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][C:17]2[N:18]([NH2:23])[C:19]([NH2:22])=[N:20][N:21]=2)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][C:17]2[N:18]3[N:23]=[CH:3][C:2]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[N:22][C:19]3=[N:20][N:21]=2)=[CH:14][CH:13]=1
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Reactant: O=CC(=O)c1ccccc1
Product: Fc1ccc(Cc2nnc3nc(-c4ccccc4)cnn23)cc1

Procedure:
General procedure A was followed with the reaction of oxo-phenyl-acetaldehyde and 5-(4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine to provide 3-(4-fluoro-benzyl)-7-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazine and the desired product 3-(4-fluoro-benzyl)-6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazine (example 4).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:8]=[CH:7]2.C([Li])CCC.CN(C)[CH:32]=[O:33].O>O1CCCC1>[CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:8]([CH:32]=[O:33])=[CH:7]2
Reactant: COC(OC)c1ccc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(OC)c1ccc2c(c1)cc(C=O)n2S(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a solution of 5-dimethoxymethyl-1-(4-methylphenyl)sulfonylindole (2.37 g, 6.87 mmol) in tetrahydrofuran (35 mL) was added n-butyllithium (1.6 mol/L in hexanes; 6.2 mL, 9.9 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 2 h. Then dimethylformamide (1.1 mL, 14 mmol) was added, and the mixture was stirred for 20 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (4:1 hexane/ethyl acetate) followed by trituration with hexane to afford 5-dimethoxymethyl-1-(4-methylphenyl)sulfonylindole-2-carboxaldehyde (1.89 g, 74%).
Reaction SMILES: C[CH:2](NC=O)[CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+].[C:20](#[N:22])[CH3:21]>>[CH3:2][CH:3]1[N:22]=[CH:20][C:21]2[S:5][CH:6]=[CH:7][C:8]=2[CH2:4]1
Reactant: CC#N
Reactant: CC(Cc1cccs1)NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC1Cc2ccsc2C=N1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 6.6 g (33.1 mmol) N-(1-methyl-2-thiphen-2-yl-ethyl)-formamide in 200 ml acetonitrile is cooled in the ice bath and slowly combined with a solution of 6.1 ml (66.3 mmol) phosphorus oxychloride in 50 ml acetonitrile. The mixture is first of all stirred for a further three hours in the ice bath and then for 16 hours at RT. Then it is poured onto 200 ml of water, made alkaline with 9 g of solid sodium hydroxide and extracted three times with ethyl acetate. The combined organic phases are combined with activated charcoal and sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][C:37]([F:40])([F:39])[F:38])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:22][N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][C:37]([F:38])([F:39])[F:40])[N:27]=2)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1[N+](=O)[O-]

Procedure:
Oxalyl chloride (118 μL; 1.40 mmol; 3 eq.), Intermediate 22 (120 mg; 0.47 mmol; 1 eq.), Intermediate 2 (103 mg; 0.47 mmol, 1 eq.) and DIEA (103 μL; 1.40 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 90/10) afforded the title compound as a yellow oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[CH3:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(Cl)ccc4C)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cccc(-c3cc(Cl)ccc3C)c2O1

Procedure:
The title compound was prepared (0.051 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.103 g, 0.24 mmol) and methylamine (0.074 g, 2.4 mmol). mp 178-182° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1.[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Br:26])[CH:20]=1)=O.O>O1CCCC1>[Br:26][C:21]1[C:22]([F:25])=[CH:23][CH:24]=[C:19]([C:17]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=2)=[CH2:16])[CH:20]=1
Reactant: COc1ccc(Br)cc1Cl
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1ccc(OC)c(Cl)c1)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
A solution of n-butyllithium (1.6 M solution in hexane, 20 mL, 1.1 eq) was added dropwise to a solution of 4-bromo-2-chloro-1-methoxy-benzene (6 g, 27 mmol, 1 eq) in tetrahydrofuran (25 mL) at −78° C. After stirring 30 min 3-bromo-4-fluoroacetophenone (5.8 g, 27 mmol, 1 eq) in tetrahydrofuran (25 mL) was added dropwise. The mixture was allowed to warm up to room temperature and stirred for 2 h, then treated with water (10 mL), extracted with ethyl acetate, dried (sodium sulfate) and concentrated in vacuo. The crude was dissolved in acetic acid (80 mL) and concentrated sulfuric acid (17 mL) was added. The mixture was warmed to 75° C. for 30 min, cooled at room temperature and neutralized with 1 N NaOH. The aqueous phase was extracted with dichloromethane (3×100 mL), dried (sodium sulfate) the solvent was removed under reduced pressure. The residue was purified by column chromatography (cyclohexane) to afford the title compound as a colourless oil (3.2 g, 36%);
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[C:8]([O:10]CC)=O.[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=1.OS([O-])(=O)=O.[K+]>C(O)C>[Cl:17][C:18]1[CH:27]=[C:26]2[C:21](=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=1)[CH:22]([C:8]([C:7]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])[CH2:23][CH2:24][CH2:25]2
Reactant: O=[N+]([O-])c1cc(Cl)cc2c1CCCC2
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(=O)C1CCCc2cc(Cl)cc([N+](=O)[O-])c21
Reaction time: 2 h
Yield: 37.9 %

Procedure:
To a mixture of potassium t-butoxide (79.49 g, 0.708 mol) and diethyl oxalate (105.8 mL, 0.779 mol) in ethanol (140 mL) was added 7-chloro-5-nitrotetralin (14 g, 0.071 mol) at room temperature. The mixture was stirred for 2 h, poured into 10% aqueous KHSO4, and extracted with ethyl acetate (400 mL×2). The combined organic layers were washed successively with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 15:1~6:1 hexane/-ethyl acetate to give 8.39 g of the title compound: 1H NMR (CDCl3) δ7.91 (d, 1H, J=2.1 Hz), 7.45 (d, 1H, J=6.3, 4.0 Hz), 4.41 (m, 2H), 2.82~3.09 (m, 2H), 2.02 (m, 2H), 1.85 (m, 2H), 1.42 (t, 3H, J=7.3 Hz).
Reaction SMILES: [H-].[Na+].[C:3]([NH:7][C:8]1[C:13]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=2)=[CH:12][N:11]=[C:10]([Cl:26])[CH:9]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[C:3]([N:7]1[C:8]2[CH:9]=[C:10]([Cl:26])[N:11]=[CH:12][C:13]=2[CH2:14][N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=2)[C:28]1=[O:30])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)Nc1cc(Cl)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)N1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
NaH (1.5 g, 36.6 mmol) was added portion wise to a solution of N-tert-butyl-2-chloro-5-((4-fluoro-3-nitrophenylamino)methyl)pyridin-4-amine (4.3 g, 12.2 mmol) in anhydrous dioxane (400 mL) at 0° C. and the resulting mixture was stirred at RT for 10 min. A solution of triphosgene (3.6 g, 12.2 mmol) in dioxane (30 mL) was added to the above mixture at 0° C. After the addition, the mixture was heated at 100° C. for 10 h. The cooled reaction was quenched with water and the pH was adjusted to pH>7 with saturated NaHCO3 solution. The dioxane was removed under reduced pressure and the residue was partitioned between water and EtOAc (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography provided 1-tert-butyl-7-chloro-3-(4-fluoro-3-nitrophenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (3.5 g, 76% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1 H), 8.07 (m, 1 H), 7.71 (m, 1 H), 7.57 (m, 1 H), 7.32 (s, 1 H), 4.70 (s, 2 H) 1.57 (s, 9 H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>CN(C=O)C>[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(N[C@H]1CC[C@H](O)CC1)c1ccccc1Br
Reaction time: 2 h

Procedure:
To a 20 mL vial were added a stir-bar, trans-4-aminocyclohexanol (683 mg, 4.50 mmol), DMF (5 mL), and DIPEA (2.0 mL, 12 mmol). The mixture was then treated with 2-bromobenzene-1-sulfonyl chloride (1.00 g, 3.93 mmol) and the mixture stirred for 2 hours before subjecting the vial's content to FCC to give the title compound. (978 mg, 74%). MS (ESI): mass calcd. for C12H16BrNO3S 333.00, m/z found 334.0 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.12 (dd, J=7.8, 1.7, 1H), 7.70 (dd, J=7.8, 1.2, 1H), 7.49-7.43 (m, 1H), 7.43-7.37 (m, 1H), 5.10 (d, J=7.5, 1H), 3.62-3.47 (m, 1H), 3.11-3.01 (m, 1H), 2.12 (s, 1H), 1.91-1.75 (m, 4H), 1.31-1.15 (m, 4H).