Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]([CH3:23])=[CH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)=[O:5])C.[OH-].[Na+]>CO.O>[C:4]([C:6]([CH3:23])=[CH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)=Cc1cn(-c2cccnc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=Cc1cn(-c2cccnc2)c2ccccc12)C(=O)O

Procedure:
A solution of 1.1 g of 3-[2-(ethoxycarbonyl)-prop-1-enyl)-N-(3-pyridyl)indole, and 0.288 g of sodium hydroxide in 10 ml of methanol and 10 ml of water is heated under reflux for 2 hours, cooled and evaporated. The resulting oil is redissolved in 10 ml of ice water and is neutralized with 0.59 ml of concentrated hydrochloric acid. The resulting solid is filtered and dried to yield 3-(2carboxyprop-1-enyl)-N-(3-pyridyl)indole, m.p. 213°-215°.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].CS[C:10]1[S:11][CH2:12][CH2:13][N:14]=1>C(O)C>[CH2:6]([O:5][C:1]([NH:2][N:3]=[C:10]1[NH:14][CH2:13][CH2:12][S:11]1)=[O:4])[CH3:7]
Reactant: CSC1=NCCS1
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)NN=C1NCCS1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.5 %

Procedure:
A mixture of ethyl carbazate (23.4 g), 2-(methylthio)-2-thiazoline (25 g) and ethanol (250 ml) was heated to reflux for 3 days. It was then stirred at room temperature for 2 days. The precipitate was collected by filtration and washed with ethanol to obtain the title compound (9.05 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[CH:7]2)([O-:3])=[O:2].Cl.Cl[CH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH3:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[CH3:34][N:30]1[CH2:31][CH2:32][CH2:33][CH:29]1[CH2:28][CH2:27][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[C:8]1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc2[nH]c(Cc3ccc(OC(F)(F)F)cc3)cc2c1
Reactant: CN1CCCC1CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCC1CCn1c(Cc2ccc(OC(F)(F)F)cc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 65 °C

Procedure:
compound 8 (75 mg, 0.223 mmol), 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (45.2 mg, 0.245 mmol), potassium carbonate (92.4 mg, 0.669 mmol) and anhydrous dimethylformamide (5 mL) were charged to a small, argon purged flask fitted with a magnetic stirbar and resulting solution heated in an oil bath at 65° C. for 20 hours. After cooling to room temperature the mixture was diluted with H2O and ethyl acetate, transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford crude solid. The crude product was purified using dry silica gel column chromatography eluting with 25 mL portions of solvent system (2M NH3 in MeOH:CH2Cl2, 2.5:97.5) to yield a yellow residue, 12 (100 mg, quantitative). 1H NMR (DMSO-d6) δ 1.35-1.45 (m, 2H), 1.58-1.64 (m, 3H), 1.72-1.88 (m, 1H), 1.97-2.05 (m, 2H), 2.08 (s, 3H), 2.86-2.95 (m, 1H), 4.15 (t, 2H, J=7.7 Hz), 4.29 (s, 2H), 6.49 (s, 1H), 7.33-7.43 (m, 4H), 7.57 (d, 1H, J=9.1 Hz), 8.00 (dd, 1H, J=9.1, 2.2 Hz), 8.50 (d, 1H, J=2.2 Hz); ESI-MS (m/z, %): 448 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:7]([OH:9])=O)[CH3:2].[C:18]([Cl:23])(=O)[C:19](Cl)=O.[CH3:24][N:25]([CH3:28])C=O>ClCCl>[Cl:23][C:18]1[CH:19]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:28][N:25]([C:7](=[O:9])[CH:6]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH2:24]2
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC(C(=O)O)c1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)CC(C(=O)N1Cc2ccc(Cl)cc2C1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-(4-Chlorophenyl)succinic acid 4-monoethylester (1.11 g) was converted to the corresponding acid chloride by treatment with oxalyl chloride (0.7 ml) in dichloromethane (3 ml) and catalytic amounts of N,N-dimethylformamide (0.5 h at rt, then 0.5 h reflux). All volatiles were removed in vacuo and the crude acid chloride dissolved in dichloromethane (4 ml). This solution was added dropwise to a stirred, ice-cold solution of 5-chloroisoindoline (0.86 g) and triethyl amine (1.7 ml) in dichloromethane (6 ml). After the addition the cooling bath was removed and the solution stirred at rt for 1.5 h. Then the organic layer was diluted with dichloromethane (50 ml), extracted two times with 1M HCl (50 ml), and dried (sodium sulfate). After removal of the solvent the crude was purified by flash chromatography on silica gel (petrol ether/ethyl acetate 2:1) to afford ethyl 4-(5-chloro-2-isoindolinyl)-3-(4-chlorophenyl)-4-oxobutanoate (1.13 g) as amorphous, colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C[C:16]([N:18]([CH3:20])[CH3:19])=O.CN(C=O)C>O>[F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6](/[CH:8]=[CH:16]/[N:18]([CH3:20])[CH3:19])[CH:7]=1
Reactant: CC(=O)N(C)C
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)/C=C/c1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 62.7 %

Procedure:
A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol), DMA (12 g, 100 mmol) and DMF (50 mL) was heated at 100° C. for 4 h. The solution was cooled and poured into water. The precipitated red solid was collected, washed with water, and dried to give (E)-2-(5-fluoro-2,4-dinitrophenyl)-N,N-dimethylethenamine (8.0 g, 63%).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[N+:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([O-:30])=[O:29]>C1(C)C=CC=CC=1>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:36])=[CH:38][CH:39]=1)([O-:30])=[O:29]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (0.5 g) and triethylamine (1.0 ml), and 4-nitrobenzoyl chloride (0.5 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=[O:2].[NH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20].CCN(CC)CC>C1COCC1>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][NH:17][C:16]2=[O:20])=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: NCCN1CCNC1=O
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1ccc(C(=O)NCCN2CCNC2=O)cc1
Reaction time: 4 h

Procedure:
A solution of the 4-formylbenzoyl chloride (16.5 g, 0.098 mol) in dry THF (100 ml) was added, over a period of minutes, to a suspension of 1-(2-amino-ethyl)imidazolidin-2-one (12.6 g, 0.098 mol) and Et3N (19.8 g, 0.195 mol) in dry THF (300 ml) at −35° C. During the addition, the temperature of the reaction medium was maintained between −35 and −38° C. The temperature of the reaction medium was then slowly brought back to ambient temperature over a period of 4 hours. The precipitate obtained (mainly the expected product as a mixture with triethylamine hydrochloride Et3N.HCl) was filtered off and washed with THF (twice with 20 ml). The reaction crude was solubilized in an aqueous solution of Na2CO3 (3.4 g, 0.032 mol in 40 ml of water). The expected compound was extracted several times with EtOAc (total volume: 3.5 l).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[N:33][C:34]=3[NH2:36])[N:29]([C@H:37]3[CH2:42][CH2:41][C@H:40]([N:43]4[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]4)[CH2:39][CH2:38]3)[N:28]=2)=[CH:23][C:22]=1[O:50][CH3:51]>ClCCl.CN(C=O)C.N1C=CC=CC=1>[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([C@H:37]3[CH2:42][CH2:41][C@H:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)[CH2:39][CH2:38]3)[N:28]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([NH:20][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:13])=[C:22]([O:50][CH3:51])[CH:23]=3)[C:35]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 8 h

Procedure:
To 1-methyl-1H-2-indolecarboxylic acid (0.802 g, 4.58 mmol) in dichloromethane (14 mL) was added oxalyl chloride (4 mL, 45.8 mmol) and DMF (1 drop). The reaction mixture was stirred overnight. Solvent was evaporated and the residue was dissolved in Dichloromethane (5 mL). Half of the dichloromethane solution (2.5 mL) was added to a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.50 g, 1.145 mmol) in pyridine (6 mL) at 0° C. After 30 minutes, the solid was collected by filtration. Water was then added to the solid and the pH of the solution was adjusted to 10 with sodium hydroxide (1.0N). The aqueous was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide (0.545 g, 80%). 1H NMR (DMSO-d6) δ 1.49 (m, 2H), 2.02 (m, 6H), 2.17 (s, 3H), 2.36 (m, 5H), 2.55 (m, 4H), 3.96 (s, 3H), 4.04 (s, 3H), 4.66 (m, 1H), 7.15 (m, 1H), 7.28-7.35 (m, 4H), 7.58 (d, J=8.42 Hz, 1H), 7.70 (d, J=7.96 Hz, 1H), 8.11 (d, J=8.14, 1H), 8.24 (s, 1H), 9.43 (s, 1H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1CCC(Cc2ccccc2)CC1
Temperature: 110 °C
Yield: 40.7 %

Procedure:
To a solution of 4-benzylpiperidine (0.50 mL, 2.8 mmol) in DMF (15 mL) were added 2-chloroethanol (0.25 mL, 3.70 mmol) and K2CO3 (0.79 g, 5.70 mmol). The heterogeneous mixture was heated at 110° C. for 2 h. It was then cooled to 25° C. and was diluted with water (100 mL) and extracted with ether (2×70 mL). The collected organic phase was washed with water (2×100 mL), dried and concentrated in vacuo. The crude compound was purified by filtration on silica gel using CH2Cl2/MeOH as eluant to afford the title compound as a colorless solid (0.25 g, 40%): mp 62-64° C.; 1H NMR (CDCl3) δ 1.15-1.35 (m, 2H), 1.45-1.60 (m, 1H), 1.63 (bd, J=13.8 Hz, 2H), 1.99 (t, J=11.7 Hz, 2H), 2.48 (t, J=5.7 Hz, 2H), 2.53 (d, J=6.9 Hz, 2H), 2.87 (bd, J=11.7 Hz, 2H), 2.9 (bs, 1H), 3.574 (t, J=5.4 Hz, 2H), 7.14 (d, J=7.2 Hz, 2H), 7.20 (d, J=6.9 Hz, 1H), 7.28 (t, J=6.2 Hz, 2H); MS (m/z) 219, 188, 91. Anal. Calcd for C1-4H21NO: C, 76.71; H, 9.65; N, 6.40. Found: C, 74.49; H, 9.29; N, 6.08.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Cl:27]N1C(C)(C)C(=O)N(Cl)C1=O.[OH-].[Na+]>O1CCCC1.CCCCC>[Cl:27][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)nc2)CC1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)nc2)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 1-(6-Bromo-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (3.6 g, 10 mmol) in tetrahydrofuran (200 ml) was cooled to −78° C. Tert-butyllithium (14.7 ml, 1.5 M) in pentane was added during 10 min, followed by stirring for 5 min at −78° C. 1,3-Dichloro-5,5-dimethylhydantoin (1.97 g, 10 mmol) was added in small portions. The mixture was stirred for 0.5 min. Aqueous sodium hydroxide was added (100 ml, 4 M), and the reaction was allowed reach room temperature. The mixture was extracted twice with diethyl ether (100 ml) Chromatography on silica gel with a mixture of petroleum:ethyl acetate (1:1) gave the title compound as free base. Yield 1.7 g, 55%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:5]=[CH:6][CH:7]=1.N#N.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[S:24]([O-:26])(=[O:20])(=[O:25])[CH3:23].[CH3:23][S:24]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)(=[O:26])=[O:25]
Reactant: OCCCCCCCCCCCCc1cccc(I)c1
Reactant: CS(=O)(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCCCCCCCCCCc1cccc(I)c1
Product: CS(=O)(=O)[O-]
Temperature: 25 °C
Yield: 139.9 %

Procedure:
12-m-Iodophenyldodecanol (5.88 g, 15.17 mmol) was placed into a flame-dried three-neck 100 ml round-bottomed flask equipped with a reflux condenser and charged with N2. Anhydrous pyridine (30 ml) was added. The mixture was cooled to 0° C. before freshly distilled methanesulfonyl chloride (2.0 ml, 25.96 mmol) was added drop-wise. The reaction mixture was allowed to warm to room temperature. After the reaction mixture had been stirred for several hours, it was poured into ice cold H2O and the resulting precipitate was filtered. The solid was dissolved in ether and extracted with H2O, 1N HCl, and H2O. The ether layer was dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was recyrstallized with a hexanes and ethyl acetate mixture to yield the pure mesylate, compound 9, 12-(m-iodophenyl)dodecyl methane sulfonate (4.95 g, 70.7%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:22]([CH2:45][C:46]#[C:47][CH3:48])[C:23]3[C:28](=[O:29])[N:27]([CH2:30][C:31]4[CH:32]=[C:33]5[C:38](=[C:39]([CH3:41])[CH:40]=4)[N:37]=[C:36]([CH3:42])[C:35]([CH3:43])=[N:34]5)[N:26]=[CH:25][C:24]=3[N:44]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:18]1([C:21]2[N:22]([CH2:45][C:46]#[C:47][CH3:48])[C:23]3[C:28](=[O:29])[N:27]([CH2:30][C:31]4[CH:32]=[C:33]5[C:38](=[C:39]([CH3:41])[CH:40]=4)[N:37]=[C:36]([CH3:42])[C:35]([CH3:43])=[N:34]5)[N:26]=[CH:25][C:24]=3[N:44]=2)[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(Cc3cc(C)c4nc(C)c(C)nc4c3)c(=O)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCn1c(N2CCNCC2)nc2cnn(Cc3cc(C)c4nc(C)c(C)nc4c3)c(=O)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 ml of trifluoroacetic acid are added to 220 mg of 2-(4-tert.-butyloxycarbonyl-piperazin-1-yl)-3-(2-butyn-1-yl)-5-[(2,3,8-trimethyl-quinoxalin-6-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 4 ml methylene chloride. The reaction mixture is stirred for one hour at ambient temperature. Then it is diluted with methylene chloride and washed with saturated sodium hydrogen carbonate solution. The organic phase is dried and evaporated down. The glassy residue is dissolved in dioxane, frozen with liquid nitrogen and dried at 6×10−3 mbar. A white solid remains.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][N:11]([CH2:34][CH2:35]Cl)[C:12]1[CH:32]=[C:31]([Cl:33])[C:15]2[O:16][C:17]3[C:26]([CH3:27])=[CH:25][C:24]([C:28]([OH:30])=[O:29])=[CH:23][C:18]=3[S:19](=[O:22])(=[O:21])[CH2:20][C:14]=2[CH:13]=1.[CH3:37]O>>[CH3:37][O:30][C:28]([C:24]1[CH:25]=[C:26]([CH3:27])[C:17]2[O:16][C:15]3[C:31]([Cl:33])=[CH:32][C:12]([N:11]4[CH2:10][CH2:9][N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:35][CH2:34]4)=[CH:13][C:14]=3[CH2:20][S:19](=[O:21])(=[O:22])[C:18]=2[CH:23]=1)=[O:29]
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Reactant: CO
Reactant: NC1CCCCC1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C4CCCCC4)CC3)cc(Cl)c1O2

Procedure:
Cyclohexylamine (0.7 mL 6.25 mmol) was added to a solution of Example 102j (0.6 g, 1.25 mmol) in methanol (10 mL), followed by the addition of n-tetrabutylammonium iodide (0.010 g, 0.027 mmol) in an atmosphere of nitrogen and sealed in a pressure reactor vessel at 110° C. for 6 h. It was processed as described in the synthesis of Example 129k to obtain the title compound as a white solid. Yield: 0.290 g, (45.95%); 1H NMR (DMSO-d6): δ 1.10-2.00 (m, 11H, cyclohexyl), 2.70 (s, 3H, CH3), 3.20-3.30 (m, 4H, 2CH2), 3.75-3.8 (m, 4H, 2CH2), 3.95 (s, 3H, OCH3), 4.75 (s, 2H, CH2), 6.70 (s, 1H, Ar), 6.90 (s, 1H, Ar), 8.05 (s, 1H, Ar), 8.45 (s, 1H, Ar); MS: m/e (CI+) 519 (M+1).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[O:11]=[P:12](Cl)(Cl)Cl>BrCCBr.C1COCC1>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([P:12](=[O:11])([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(P(=O)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A reaction flask under nitrogen containing magnesium turnings (223.9 g, 9.21 mol) and 1950 mL THF was charged with 1 drop of 1,2-dibromoethane and heated to reflux for 1 h. Heating was removed and p-bromoanisole (1683 g, 9.00 mol) was added dropwise at a rate to maintain reflux. After holding the reaction mixture overnight, POCl3 (460.0 g, 3.00 mol) was added slowly over 2 h at 50–79° C. and the resulting mixture was held overnight at 50° C. The product was isolated by aqueous workup to give 984.5 g of tris(4-methoxyphenyl)phosphine oxide (89.0% yield). Recrystallized analytical specimen (from ethyl acetate): mp 145.2° C. (DSC), lit. 143–144° C. (J. Org. Chem. 1960, 25, 2001).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CN(C1C=CC=CN=1)C>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCBr
Reactant: C1CCNC1
Agent: CN(C)c1ccccn1
Solvent: c1ccccc1
Product: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCN1CCCC1

Procedure:
0.10 g (0.23 mmol) of N-{3-(3,4-dimethylphenyl)propyl}-4-(2-bromoethoxy)-3-methoxyphenylacetamide obtained in Step 5 of Example 3, 0.16 g (2.3 mmol) of pyrrolidine and a catalytic amount of dimethylaminopyridine were dissolved in 10 ml of benzene, and the mixture was refluxed for 5 hours. After removing the solvent under a reduced pressure, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate:hexane=1:1) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6]Cl)[CH3:3].[Mg].[CH2:9]1[CH2:19][C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1>O1CCCC1>[CH3:1][N:2]([CH3:3])[CH:4]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:19][CH:9]=1)[CH2:5][CH3:6]
Reactant: O=C1CCCc2ccccc21
Reactant: CN(C)CCCCl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(C1=CCCc2ccccc21)N(C)C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
The Grignard reagent from 300 g (2.5 moles) of dimethylaminopropyl chloride and 60 g (2.5 moles) of magnesium turnings is prepared in 2 l. of tetrahydrofuran. To this is added 300 g (2.0 moles) of α-tetralone in 1 l. of tetrahydrofuran, at a rate to maintain reflux. After the addition the reflux is continued for 1.5 hours, then the mixture is cooled in ice and quenched with 500 ml of saturated ammonium chloride. The layers are separated, and the aqueous diluted with water and reextracted with ether. The organics are evaporated, then treated with a mixture of 350 ml of concentrated HCl and 1400 ml of glacial acetic acid at reflux for 1/2 hour. The solvents are removed in vacuo, and the residue taken up in water, and the aqueous extracted with benzene. Basification liberates the product which is extracted with benzene, dried over carbonate, the solvent evaporated, and the product distilled at 129° C., 0.3 mmHg to give 250 g (58%) of a light yellow liquid, 1-dimethylaminopropyl-3,4-dihydronaphthalene.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14]1([CH2:20][CH2:21][CH2:22][Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[CH:12]([OH:13])[CH2:22][CH2:21][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Br[Mg]CCCc1ccccc1
Reactant: O=Cc1c(Cl)ncc2ccccc12
Product: OC(CCCc1ccccc1)c1c(Cl)ncc2ccccc12

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 3-chloro-isoquinoline-4-carbaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:12][CH:13]=[O:14])[CH:5](O)[C:6](=[CH2:10])[CH2:7][CH:8]=[CH2:9].C=CCCC=C.S(Br)([Br:24])=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:12][CH:13]=[O:14])/[CH:5]=[C:6](/[CH2:10][Br:24])\[CH2:7][CH:8]=[CH2:9]
Reactant: C=CCC(=C)C(O)C(NC=O)C(=O)OC
Reactant: O=S(Br)Br
Agent: C=CCCC=C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC/C(=C\C(NC=O)C(=O)OC)CBr
Reaction time: 3 h

Procedure:
5.0 g of 2-formylamino-3-hydroxy-4-methylene-6-heptenoic acid methyl ester in 200 ml of dry tetrahydrofuran are cooled to -78°, and 20 ml of 1,5-hexadiene are added thereto. 9 ml of thionyl bromide are added slowly dropwise in such a manner that the reaction temperature does not exceed -50°. When the addition is complete, the reaction solution is heated to 0° within a period of approximately 3 hours and is stirred at that temperature for 3 hours. The solution is then poured onto 300 ml of a cold (5°-10°) saturated sodium bicarbonate solution and extracted with diethyl ether. The organic extracts are washedwith saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation in vacuo. Purification by column chromatography (silica gel, ethyl acetate/hexane 1:1) yields E-2-formylamino-4-bromomethyl-3,6-heptadienoic acid methyl ester in the form of a colourless oil, 1H-NMR (CDCl3): 3.20 (d, 2H, C(5 )--H); 4.00 (s, 2H, CH2Br).