Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[C:12]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)(=[O:14])[CH3:13].C(=O)([O-])O.[Na+]>C(OCC)C>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:12]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)([OH:14])[CH3:13]
Reactant: Brc1nccs1
Reactant: CC(=O)c1nccs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CC(O)(c1nccs1)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 17.3 ml) was added dropwise to a stirred solution of 2-bromothiazole (6.5 g) in anhydrous diethyl ether (40 ml) at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, 2-acetylthiazole (5 g) in diethyl ether (10 ml) was added dropwise. After a further 1 hour, the mixture was allowed to warm to room temperature. After 1 hour, saturated aqueous sodium hydrogen carbonate solution was added and the organic phase was separated. Further processing in the usual fashion then gave the title compound.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][C:16](Cl)=[O:17].C(Cl)Cl.CCCCCC.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.OS(O)(=O)=O>[Cl:14][CH2:15][C:16]([O:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CCl)O[C@@H]1CCCC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.17 k9 (12.3 mole) of (±)-trans-2-phenylcyclohexanol, 1475 mL (18.43 mole) of chloroacetyl chloride, 6 g (0.049 mole) of 4-dimethylaminopyridine, and 5.5 L of methylene chloride was heated at reflux. After 8 hours, thin layer chromatography analysis (4:1 hexane-ethyl acetate: Spray 5% NH4MoO4 in 10% aqueous H2SO4) indicated complete reaction. The reaction mixture was allowed to cool to room temperature and was stirred with 2×4 L=8 L of saturated NaHC03. The organic layer was dried (Na2SO4) evaporated in vacuo on a rotary evaporator, and finally at 0.5 mmHg to afford 3.21 kg of crude (±)-trans-2-phenylcyclohexyl chloroacetate. Distillation of the tan liquid afforded 2.76 kg (88%) of the desired product as a colorless liquid, (b.p. 125-133°/0.3-0.5 mmHg). The chloroacetylation of other lots of (±)-trans-2-phenylcyclohexanol was accomplished in ← 95%. The particular lot of (±) alcohol used in this example was only about 91% pure.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(#N)C.[CH:18]1(/[CH:21]=[CH:22]/[C:23]#[N:24])[CH2:20][CH2:19]1.N12CCCN=C1CCCCC2>>[CH:18]1([CH:21]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:22][C:23]#[N:24])[CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#C/C=C/C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C(CC#N)C3CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.0 g, 0.0515 mol) in acetonitrile (129 mL, 2.46 mol) was added (E)-3-cyclopropylacrylonitrile (5.75 g, 0.0617 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (3.85 mL, 0.0258 mol). The resulting mixture was stirred at room temperature overnight, and evaporated to dryness. The mixture was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product as racemic mixture (10.8 g, 73.0%). LCMS (M+H) 288.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]1[OH:21].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C1(=O)CCCCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]1=[O:21]
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 88.1 %

Procedure:
Dissolve dl-3-methoxyestra-2,5(10)-dien-17β-ol (4 g) in cyclohexanone (40 ml) and toluene (140 ml) and add a solution of aluminum isopropoxide (4 g) in toluene (56 ml). Reflux in an atmosphere of nitrogen for two hours and cool. Add water (7.5 ml), shake, and then dry by adding sodium sulfate (10 g). Filter and evaporate under vacuum and recrystallize the residue from methanol to obtain dl-3-methoxyestra-2,5(10)-dien-17-one (3.5 g); m.p. 116°-118°; infrared absorption maxima at 5.76 μ, 5.9 μ, 6.01 μ.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][CH:9]=1>O1CCCC1>[CH3:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(COS(C)(=O)=O)cn1
Solvent: C1CCOC1
Product: Cc1ccc(CN2CCOCC2)cn1
Temperature: 20 °C
Reaction time: 19 h
Yield: 66.8 %

Procedure:
Morpholine (43.2 kg, 495.9 mol) was then added over 2 hrs to the solution of methanesulfonic acid 6-methyl-pyridin-3-ylmethyl ester (198 mol; Example 1) in tetrahydrofuran (161 kg) under nitrogen at 15-20° C. and the resulting slurry stirred for 19 hrs. The suspension was filtered through a Silica (15.5 kg) column and the cake washed five times with tetrahydrofuran (43.5 kg). 440 L of the solution was then removed under vacuum distillation and heptane (41.52 kg) added. This was repeated two more times followed by the addition of heptane (48.6 kg) and the solution filtered through a Celite® (4.08 kg) bed at 40° C. and the cake washed twice with heptane (7.2 kg). Then the filtrate cooled to 20° C. over 3 hrs then to −12° C. over 5 hrs and held for 12 hrs at −12° C. The suspension was filtered and the cake washed with cold (0° C.) heptane (8.5 kg) and then dryed at 25° C. under vacuum, which gave 25.44 kg, 67% yield of 4-(6-Methyl-pyridin-3-ylmethyl)-morpholine as a beige solid. 1H NMR (400 MHz; CDCl3): δ 8.4 (d, J=1.72 Hz, 1H), 7.54 (dd, J=2.1, 7.91 Hz, 1H), 7.1 (d, J=7.92 Hz, 1H), 3.68 (apparent t, J=4.6, 9.28 Hz, 4H), 3.4 (s, 2H), 2.5 (s, 3H), 2.4 (apparent t, J=4.5, 8.93 Hz, 4H); 13C NMR (100 MHz, CDCl3): δ 157.3, 149.8, 137.2, 129.9, 122.9, 66.9, 60.3, 53.5, 24.1 ppm; MS (ESI) m/z 193 [M+1]+; Melting point: 51-52° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
A mixture of 1-chloro-4-nitro benzene (3 g, 19 mmol), 1-methyl piperazine (2.28 g, 22.8 mmol) and ethyl-diisopropylamine (2 ml) in THF (20 ml) was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue, which was then partitioned between dichloromethane and water. The organic layer was separated and evaporated under reduced pressure to give crude compound, which was purified by column chromatography over silica gel, using ethyl acetate as eluent, to yield 1-methyl-4-(4-nitro-phenyl)-piperazine (1.8 g, 44%) as solid.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[C:37](=[O:38])[NH:36][N:35]=[CH:34]2)[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:36]2[C:37](=[O:38])[N:33]([C:25]3[S:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:22])[N:24]=3)[CH:34]=[N:35]2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)nc1C
Yield: 84 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 1-(bromomethyl)-4-fluorobenzene to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 84% yield: 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.47-7.30 (m, 2H), 7.11-6.97 (m, 2H), 4.98 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.65 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 363.1 (M+
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8](I)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: C1COCCN1
Reactant: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Solvent: c1ccncc1
Product: CNC(=O)c1c(N2CCOCC2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To a suspension of compound 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.1 mmol) in pyridine (3 mL) was added morpholine (18 mg, 0.2 mol) under N2, and then the mixture was stirred at 60° C. for 3 hours. After concentration in vacuo, DCM was added and the resulting residue was washed with 10% HCl (a.q., 3 mL) and dried over Na2SO4. After concentration, the residue was purified by prep-TLC (DCM:MeOH=20:1) to give the product of 5-bromo-N-methyl-6-(N-methylmethylsulfonamido)-2-morpholinobenzofuran-3-carboxamide (20 mg, yield: 44%). 1H-NMR (CDCl3, 400 MHz) δ 8.05 (s, 1H), 7.47 (s, 1H), 6.48 (s, 1H), 3.86 (t, J=4.4 Hz, 4H), 3.46 (t, J=6.4 Hz, 4H), 3.28 (s, 3H), 3.04 (s, 3H), 2.99 (d, J=4.8 Hz, 3H). MS (M+H)+: 446/448.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([O:11][CH3:12])=[O:10].[CH3:14][O:15][NH3+:16].[Cl-].O>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:16][O:15][CH3:14])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CO[NH3+]
Reactant: COC(=O)C(=O)c1ccccc1O
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CON=C(C(=O)OC)c1ccccc1O

Procedure:
10.4 g (0.0533 mol) of methyl 2-hydroxyphenylglyoxylate (HPLC: 92.4%, log p=1.87) from process step 2 and 7.4 g (0.089 mol) of 0-methylhydroxylamine hydrochloride in 150 ml of methanol are boiled under reflux for three hours. The reaction mixture is poured into water, the product is extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. This gives 8.2 g of crude product which, according to HPLC, contains 17.2% methyl E-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=1.48 and 65.4% methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.38.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7]2.[H-].[Na+].Cl[CH2:19][C:20]([NH2:22])=[O:21]>CN(C)C=O>[C:20]([CH2:19][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7]2)(=[O:21])[NH2:22]
Reactant: NC(=O)CCl
Reactant: COC(=O)c1cc2cccc(O)c2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cccc(OCC(N)=O)c2n1C
Temperature: 25 °C
Yield: 84.4 %

Procedure:
After 0.50 g (2.44 mmol) of methyl 7-hydroxy-1-methyl-2-indolecarboxylate was added to a suspension of 0.01 g (2.44 mmol) of 60% sodium hydride in 25 ml of dimethyl-formamide, the mixture was stirred at room temperature until the mixture became a transparent solution. Then 0.25 g (2.68 mmols) of 2-chloroacetamide as added dropwise to the transparent solution at room temperature followed by stirring at 50° C. for an hour. The reaction mixture was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate. The combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 0.54 g (84.4%) of methyl 7-carbamoylmethoxy-1-methyl-2-indolecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].Cl[C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=[CH:15][N:14]=1>>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Clc1ncccc1OCc1ccccc1
Reactant: Cc1[nH]cnc1CSCCN
Product: Cc1[nH]cnc1CSCCNc1ncccc1OCc1ccccc1
Yield: 9.8 %

Procedure:
2-(5-Methyl-4-imidazolylmethylthio)ethylamine (18.13 g; 0.105 moles) and 2-chloro-3-benzyloxypyridine (11.63 g; 0.053 moles) were mixed and heated to 120° for 9 days. The resulting reaction mixture was purified by chromatography using silica-gel, and chloroform as eluant. The red oil obtained, corresponding to 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-benzyloxypyridine (1.85 g), was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:59](Br)[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]>CN(C=O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: CCCCCCCCCBr
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
5,10,15,20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (200 mg, 0.294 mmol) is dissolved and potassium carbonate (487 mg, 3.53 mmol, 12 eqv.) is suspended under argon in absolute DMF (50 mL) and the mixture heated to 55° C. A solution of nonyl bromide (49.4 μl, 0.206 mmol, 0.7 eqv.) in absolute DMF (10 mL) is added dropwise during 30 min. The mixture is stirred at 55° C. for 2 h. The solvent is removed in vacuo at 50° C., water (80 mL) is added and the mixture extracted with ethyl acetate (3×40 mL). The combined organic extracts are dried (Na2SO4) and solvent removed under reduced pressure. The product is isolated by chromatography on a column (300 g) of silica. Tetra-alkylated and tri-alkylated compounds are eluted with toluene:ethyl acetate (30:1 by vol.), di-substituted compound (trans-isomer) with toluene:ethyl acetate (15:1 by vol.). di-substituted compound (cis-isomer) with toluene:ethyl acetate (10:1 by vol.) and the desired product (mono-alkylated compound) is eluted with toluene:ethyl acetate (5:1 by vol.). The solvent is removed under reduced pressure and the residue dried at high vacuum to afford the product as a violet solid.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.[CH:16]([O:21][CH3:22])([O:19][CH3:20])OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:22][O:21][CH:16]([O:19][CH3:20])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COC(OC)OC
Reactant: CCOC(=O)c1ccc(OC)c(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1ccc(OC)c(C(OC)OC)c1
Yield: 97 %

Procedure:
Ethyl 3-formyl-4-methoxybenzoate (500 mg) obtained in step C of Example 1-2-1 was dissolved in 10 mL of methanol. Trimethyl orthoformate (263 μL) and 41 mg of p-toluenesulfonic acid monohydrate were added to the solution, and then the mixture was heated for 2 hours under reflux. After the reaction solution was cooled, 5 mL of a saturated aqueous solution of sodium bicarbonate was added, and the resulting mixture was concentrated under reduced *pressure. The residue was diluted with ethyl acetate, washed with purified water and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, whereafter the filtrate was concentrated under reduced pressure. The residue was dried under reduced pressure to obtain 596 mg (97%) of ethyl 3-dimethoxymethyl-4-methoxybenzoate.
Reaction SMILES: [N:1]1([C:7]2[CH:25]=[CH:24][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([Cl:26])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.N1C2C=CC=CC=2CCC[CH2:30]1.[Na].[Na]>C(OCC)(=O)C>[CH3:30][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:25]=[CH:24][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([Cl:26])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=C(c1ccc(N2CCNCC2)cc1Cl)N1CCCCc2ccccc21
Agent: C=O
Agent: [Na]
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(C(=O)N3CCCCc4ccccc43)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a mixture of 1-[4-(1-piperazinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g), 37% formaldehyde (0.45 g) and sodium tetrahydro-1H-benzazepine (0.25 g), 37% formaldehyde (0.45 g) and sodium (0.12 g) under ice-cooling, and the mixture is stirred at room temperature for one hour. To the reaction solution is added ethyl acetate, and the mixture is washed with a 2N aqueous sodium hydroxide solution and distilled water. The organic layer is dried over magnesium sulfate, filtered, and concentrated, and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=10:1) to give 1-[4-(4-methyl-1-piperazinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.10 g) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][C:21](OC)=[CH:20][C:19](=[O:25])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CCOCC.C1COCC1>[CH2:10]([N:17]1[CH2:22][C:21]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:20][C:19](=[O:25])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COC1=CC(=O)CN(Cc2ccccc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1C=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
A solution of p-chlorophenyl magnesium bromide (0.17 M) in ether (100 ml) was treated with a solution of 1-benzyl-1,6-dihydro-5-methoxy-3-[2H]pyridone (32.5 g, 0.25 M) in THF (150 ml). The reaction was stirred 1 hour, poured onto cold 2 N hydrochloric acid (250 ml) and stirred 30 min. Removal of the resulting precipitate by filtration, followed by air-drying and recrystallisation from methanol gave the title compound as the hydrochloride hydrate (24.1 g) m.p. 166°-8°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[C:7]3[CH2:8][CH2:9][CH2:10][NH:11][C:12]=3[CH2:13][CH2:14][C:5]=2[CH:4]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([N:11]1[C:12]2[CH2:13][CH2:14][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:16]=[CH:15][C:6]=3[C:7]=2[CH2:8][CH2:9][CH2:10]1)(=[O:19])[CH3:18]
Reactant: COc1ccc2c(c1)CCC1=C2CCCN1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CCC1=C2CCCN1C(C)=O
Reaction time: 20 h

Procedure:
A mixture of 4.70 g of 8-methoxy-1,2,3,4,5,6-hexahydrobenzo[f]quinoline in 15 ml of pyridine and 11 ml of acetic anhydride is left to stand at room temperature for 20 hours and evaporated. The residue remaining behind is taken up twice in 50 ml of dry toluene each time and the solutions obtained are evaporated to dryness. The residue is chromatographed on 50 g of silica gel with methylene chloride and gives 4-acetyl-8-methoxy-1,2,3,4,5,6-hexa -hydrobenzo[f]quinoline with a melting point of 119-120° after recrystallization from ispropyl ether.
Reaction SMILES: Cl.[CH2:2]([CH:4]1[C:24]2[C:7](=[CH:8][C:9]3[NH:13][C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=4[O:21][CH3:22])=[N:11][C:10]=3[CH:23]=2)[NH:6][C:5]1=[O:25])[CH3:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].C([O-])(=O)C.[Na+]>>[CH2:2]([CH:4]1[C:24]2[C:7](=[CH:8][C:9]3[NH:13][C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:26](=[O:28])[CH3:27])=[CH:16][C:15]=4[O:21][CH3:22])=[N:11][C:10]=3[CH:23]=2)[NH:6][C:5]1=[O:25])[CH3:3]
Reactant: CCC1C(=O)Nc2cc3[nH]c(-c4ccc(N)cc4OC)nc3cc21
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CCC1C(=O)Nc2cc3[nH]c(-c4ccc(NC(C)=O)cc4OC)nc3cc21

Procedure:
0.7 g. (1.8 mmol) 7-ethyl-2-(2-methoxy-4-aminophenyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one hydrochloride, 15 ml. acetic anhydride and 0.3 g. sodium acetate were stirred for 3 hours at 40° C. After cooling, the product was filtered off with suction and, after treatment with charcoal, crystallised from methanol. There was obtained 0.44 g. (69% of theory) of the title compound; m.p. 245°-249° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:24]=[C:23]([NH:25][CH3:26])[C:22]([N+:27]([O-])=O)=[CH:21][C:7]=1[C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]1)=[O:9].CO>[Ni].C1COCC1>[NH2:27][C:22]1[C:23]([NH:25][CH3:26])=[N:24][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:7]([CH:21]=1)[C:8]([NH:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]([F:19])([F:18])[F:20])[CH2:15][CH2:16]1)=[O:9]
Reactant: CNc1nc(OCCOC)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1nc(OCCOC)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-methoxy-ethoxy)-6-methylamino-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (170 mg, 0.40 mmol), Ra—Ni (50 mg), MeOH (5 mL) and THF (15 mL) is stirred at rt for 2 h under a hydrogen atmosphere (3.0 bar). The catalyst is removed by filtration and the filtrate is concentrated.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:22][CH2:23][CH3:24])([CH2:6][CH:7]=[CH:8][C:9]1[CH:10]=[C:11]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:23]([O:22][P:4]([O:3][CH2:1][CH3:2])([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:24]
Reactant: CCOC(=O)CNc1cccc(C=CCP(=O)(OCC)OCC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CNc1cccc(CCCP(=O)(OCC)OCC)c1

Procedure:
A solution of ethyl N-[3-[3-(diethoxyphosphinyl)1-propenyl]phenyl]glycinate (Example 2a) in ethanol (75 ml) is treated with 10% palladium on carbon (0.25 g) and shaken on a Parr apparatus under a hydrogen atmosphere (50 pounds per square inch (psi)). After filtration, the filtrate is evaporated and the residue purified over silica gel (ethyl acetate as eluant) to give 1.24 g of a clear oil.