Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1.Cl>ClC1C=CC=CC=1>[Cl:1][C:6]1[CH:11]=[CH:10][C:9]([C:13](=[O:14])[CH2:12][C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)=[CH:8][CH:7]=1
Reactant: [Cl-]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
Aluminum trichloride (11.75 g.; 0.088 mole) was added portionwise to a stirred mixture of the p-chlorophenylacetyl chloride and chlorobenzene (30 ml.). Following addition, the mixture was allowed to stand for 24 hours. The resulting dark brown paste was scooped out and stirred into a slurry of ice and conc. hydrochloric acid which was then extracted with methylene chloride. The organic extracts were washed with 1 N hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride; dried over sodium sulfate and concentrated in vacuo. Recrystallization from methanol afforded 16.47 g. (71% yield), m.p. 111.5°-114° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C@H:18]([C:49](=[O:89])[NH:50][C@@H:51]([C:73](=[O:88])[NH:74][C@H:75]([CH:85]([CH3:87])[CH3:86])[C@@H:76]([OH:84])[CH2:77][C:78]([O:80]CC=C)=[O:79])[CH2:52][S:53][C:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[NH:19][C:20](=[O:48])[CH2:21][C@H:22]([OH:47])/[CH:23]=[CH:24]/[CH2:25][CH2:26][S:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCOCC1.CC(O)=O>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C@H:18]([C:49](=[O:89])[NH:50][C@@H:51]([C:73](=[O:88])[NH:74][C@H:75]([CH:85]([CH3:86])[CH3:87])[C@@H:76]([OH:84])[CH2:77][C:78]([OH:80])=[O:79])[CH2:52][S:53][C:54]([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[NH:19][C:20](=[O:48])[CH2:21][C@H:22]([OH:47])/[CH:23]=[CH:24]/[CH2:25][CH2:26][S:27][C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCOC(=O)C[C@H](O)[C@H](NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](Cc1cn(C(=O)OC(C)(C)C)c2ccccc12)NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@@H](NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](Cc1cn(C(=O)OC(C)(C)C)c2ccccc12)NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](O)CC(=O)O
Reaction time: 0.33 h
Yield: 72.3 %

Procedure:
To a solution of 4B (166 mg, 0.13 mmol), Pd(PPh3)4 (15.7 mg, 0.014 mmol) in dry methanol (4 mL) under argon was added morpholine (24 μL, 0.27 mmol) which was allowed to stir for 1 h 20 min. The reaction mixture was concentrated in vacuo, CH2Cl2 (15 mL) was then added before washing with 1M HCl (10 mL), sat. sodium hydrogen carbonate (10 mL) and sat. brine (10 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography on silica gel (eluent 5:95 MeOH/CH2Cl2 then +AcOH 1%) to give a white solid 5B (113 mg, 0.094 mmol, 70%): Rf 0.19 MeOH/CH2Cl2 (5:95); IR (thin film) 3305 (br), 3292 (br), 1731 (s), 1649 (s), 1538 (s).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.Cl[CH2:18]Cl.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[OH:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][CH3:18])=[O:6])=[CH:3][C:2]=1[I:1]
Reactant: ClCCl
Reactant: O=C(O)c1ccc(O)c(I)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
A solution of 3-iodo-4-Hydroxybenzoic acid (7.25 g, 27.4 mmol) and sulfuric acid (1.9 ml, 36 mmol) in methanol is stirred at 55° C. for 6 hours. TLC (dichloromethane): 30% of starting material. The solution is stirred 12 h at room temperature. TLC (dichloromethane): 10% of starting material and stirred at 55° C. for 2 h. After cooling, ethyl acetate (200 mL) was added and the mixture was adjusted to pH 3 using sodium bicarbonate. The organic layer was washed two times with water and then dried over MgSO4. Filtration and rotary evaporation at 40° C. afforded a white solid. The solid was triturated with hexane, filtered off and dried under reduced pressure. M=4.47 g. Yield: 59%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[CH2:7][N:8]1[C:12]2[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]1=[O:21])([O-])=O>C1COCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[NH2:25])[CH2:7][N:8]1[C:12]2[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]1=[O:21]
Reactant: COC(=O)c1ccc2oc(=O)n(Cc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)c2c1
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2oc(=O)n(Cc3ccc(N)c(N)c3)c2c1
Reaction time: 24 h

Procedure:
1.45 g (3.8 mmol) of methyl 3-(3,4-dinitrobenzyl)-2-oxo-2,3-dihydrobenzoxazole-5-carboxylate are dissolved in 20 ml of THF and hydrogenated under a hydrogen atmosphere using 1 g of Raney nickel (water-wet). After 24 h, the reaction solution is filtered, and the filtrate is evaporated to dryness; product: 1.1 g, ESI: 314 (M+H).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:22][N:23]=[C:24]=[O:25]>C1COCC1>[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:22][NH:23][C:24]([NH:16][C:13]1[S:14][CH:15]=[C:11]([CH2:10][S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[N:12]=1)=[O:25]
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cc2csc(N)n2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Cc2csc(NC(=O)NCc3ccc(Cl)c(Cl)c3)n2)cc1
Temperature: 150 °C
Yield: 66 %

Procedure:
4-(Toluene-4-sulfonylmethyl)-thiazol-2-ylamine (0.5 mmol) was dissolved in THF (3 ml) and 3,4-dichlorobenzylisocyanate (1.2 eq., 0.6 mmol) was added. The reaction was heated by microwave for 30 min. at 150° C. Solvent was removed in vacuo. The crude product was purified by column chromatography eluting with a gradient of 0-20% EtOAc (with 10% MeOH) in hexanes to give the title compound as a white solid in 66% yield.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(Cl)Cl.C(Cl)Cl.[OH2:23]>>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([CH:9]3[CH2:10][CH2:11][N:12]([C:7]([O:8][CH:4]([CH3:5])[CH3:3])=[O:23])[CH2:13][CH2:14]3)[O:8][C:4]=2[CH:3]=1
Reactant: O
Reactant: Brc1ccc2nc(C3CCNCC3)oc2c1
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(c2nc3ccc(Br)cc3o2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Intermediate 9 (1.3 g, 4.4 mmol) was dissolved in DCM (50 mol) and added TEA (1.22 ml, 8.8 mmol). Reaction mixture cooled to 0° C., isopropylchloro formate (2.6 ml, 6.6 mmol) was added and stirred the reaction mixture for 3 h at rt. Work up (DCM/H2O) followed by purification on combiflash using gradient mixture of EtOAc and Petether (15:85) as eluent afforded the titled compound (510 mg) as a brown viscous liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:22])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(OCC[O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][F:48])(=O)=O)=CC=1>CN(C=O)C.O.C(O)(=O)C.[Pd]>[F:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:2][CH2:1][O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:22])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1
Reactant: Oc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)[nH]c1cc(OCCOCCOCCF)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 27 %

Procedure:
To a round bottom flask containing Compound 8 (50 mg, 0.17 mmol) in DMF (1 ml), was added cesium carbonate (56 mg, 0.17 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (53 mg, 0.17 mmol). The reaction was stirred at rt for 15 h and then diluted with water (15 mL). White precipitate (72 mg) was collected via filtration and dried in vacou. The solid was dissolved in MeOH (10 mL). To the reaction, was added Pd/C (20 mg) and acetic acid (5 drops). The mixture was stirred under hydrogen (1 atm) atmosphere for 20 h and then filtered through a celite plug and concentrated in vacuo. The residue was purified on HPLC to afford CB-26 (20 mg, 0.046 mmol, 27% yield). 1H NMR (400 MHz, CD3CN) δ: 9.03 (br, 1H), 7.81-7.75 (m, 2H), 6.96 (d, J=2.4 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.76 (dd, J=7.6 Hz, 2.0 Hz, 1H), 6.67 (dd, J=7.6 Hz, 2.0 Hz, 1H), 4.59-4.57 (m, 1H), 4.47-4.45 (m, 1H), 4.17-4.15 (m, 2H), 3.83-3.63 (m, 8H); LRMS for C20H20NO5+H+, calc'd: 431.1. found: 334.1 (M+H+-TFA).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[C:16]1(C)C=CC=CC=1.C1CCCCC1.C(OCC)(=O)C>O1CCCC1.[CH3-].C[Al]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+4]>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH2:16])[CH:3]=1
Reactant: Cc1ccccc1
Reactant: O=C(c1ccccc1)c1cccc(Br)c1
Agent: [Ti+4]
Agent: C[Al]C
Agent: [CH3-]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(c1ccccc1)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromobenzophenone (2.2 g, 8.5 mmol, 1 eq) in 20 mL of dry tetrahydrofuran at 0° C. under N2 atmosphere, was added a toluene solution of the Tebbe's reagent (17 mL of 0.5 M solution, 8.5 mmol, 1 eq.) and the mixture was allowed to warm to room temperature. The reaction mixture was examined after 20 min by TLC (cyclohexane/ethyl acetate 2%) which showed complete conversion to the desired product. Diethyl ether (50 mL) was added and some drops of NaOH 0.1 M aqueous solution was slowly added to quench the reaction. The mixture was dried over magnesium sulfate, passed through a pad of Celite and evaporated. The solid formed was triturated with cyclohexane and filtered; the solution was collected and concentrated under reduced pressure. The crude was purified by flash chromatography eluting with cyclohexane. 2.02 g of clean product was obtained as colorless liquid (yield: 91%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:9][CH2:10][CH2:11]Br.[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][C:22]=1[OH:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CS(C)=O>[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][C:22]=1[O:29][CH2:9][CH2:10][CH3:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCBr
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCOc1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
2.15 g (15.6 mmol) of potassium carbonate, 0.20 g (1.22 mmol) of potassium iodide and 1.20 ml (13.2 mmol) of n-propyl bromide were added to a solution of 2.73 g (12.0 mmol) of 4-benzyloxy-3-hydroxybenzaldehyde in 18 ml of dimethyl sulfoxide (DMSO) and were allowed to react for 24 hours at 60° C. Thereafter, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water and the organic phase was washed several times with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated down. Chromatography of the residue over 50 g of silica gel using toluene gave 2.90 g of 4-benzyloxy-3-propoxybenzaldehyde.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:47])=[C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:36][C:37]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:38]=4[C:39]([NH2:41])=[O:40])[C:20]4[CH:25]=[CH:24][N:23](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].[OH-].[K+].CCOC(C)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:47])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[CH:25][C:20]4=[C:19]([NH:36][C:37]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:38]=4[C:39]([NH2:41])=[O:40])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Nc4cc5c(cc4C)CCCN5C(=O)CN(C)C)nc32)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CCC2
Yield: 74.4 %

Procedure:
A mixture of 2-({2-{[1-(N,N-dimethylglycyl)-6-methyl-1,2,3,4-tetrahydro-7-quinolinyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (414 mg, 0.617 mmol) and a 1N aqueous KOH solution (6.17 mL, 6.17 mmol) in dioxane (20 mL) was heated at 80° C. for 17 h. EtOAc (50 mL) and a saturated NaHCO3 solution (50 mL) were added. The organic layer was washed with a saturated NaCl solution (50 mL), concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-6-methyl-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide as a white solid (237 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.96 (m, 2H), 2.12 (s, 6H), 2.17 (s, 3H), 2.70 (t, J=6.50 Hz, 2H), 3.17 (s, 2H), 3.72 (t, J=6.04 Hz, 2H), 6.19 (dd, H=3.39, 1.92 Hz, 1H), 6.82-6.91 (m, 1H), 6.93 (dd, J=3.39, 2.29 Hz, 1H), 7.00 (s, 1H), 7.19-7.30 (m, 1H), 7.78 (br s, 1H), 8.00 (s, 1H), 8.09 (s, 1H), 8.11 (s, 1H), 8.47 (d, J=8.61 Hz, 1H), 10.54 (s, 1H), 11.24 (s, 1H); ESIMS (M+H)+=517.26.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:3]=1[O:4][CH2:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.Cl.[CH2:27]([O:30][NH2:31])[CH2:28][CH3:29].Cl>N1C=CC=CC=1>[CH2:27]([O:30][N:31]=[CH:11][C:10]1[CH:13]=[CH:14][C:7]([CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:18][C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])=[CH:16][C:15]=2[Cl:25])=[CH:8][CH:9]=1)[CH2:28][CH3:29]
Reactant: O=Cc1ccc(CCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: CCCON
Agent: Cl
Solvent: c1ccncc1
Product: CCCON=Cc1ccc(CCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
To a mixture of 0.55 g of 4-(2-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)ethyl)benzaldehyde (which had been produced in Intermediate Production Example 3 as described below) and 5 ml of pyridine was added 0.18 g of O-propylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.45 g (yield, 72%) of 4-(2-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)ethyl)benzaldehyde O-propyloxime, m.p., nD24.5 1.5773.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1.CO>[Pd].C(O)C.Cl>[ClH:1].[NH2:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][C:4]3[CH:19]=[C:20]([O:24][C:25]([O:27][CH3:28])=[O:26])[C:21]([CH3:23])=[CH:22][C:3]=3[F:2])=[N:7][CH:8]=[N:9]2)=[CH:14][CH:13]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c(F)cc1C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COC(=O)Oc1cc(Nc2ncnc3cc(N)ccc23)c(F)cc1C
Reaction time: 1.25 h
Yield: 97.5 %

Procedure:
A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-nitroquinazoline hydrochloride (5.3 g, 13 mmol) and 10% palladium-on-charcoal catalyst (1 g) in ethanol (100 ml), ethanolic hydrogen chloride (1.8 ml of a 7M solution) and methanol (20 ml) was stirred under hydrogen at 1.7 atmospheres pressure for 75 minutes. The catalyst was removed by filtration through diatomaceous earth and the filter pad thoroughly washed with methylene chloride, methanol and ether and the solvent was removed from the filtrate by evaporation to give 7-amino4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (4.8 g, 97%) as a yellow solid.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[S:15][CH3:16])(=[O:8])=[O:7])(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:14][N:11]1[CH:12]=[CH:13][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[C:10]1[S:15][CH3:16]
Reactant: CSc1c(S(=O)(=O)NC(C)(C)C)ccn1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a solution of 4.63 g (17.66 mmol) N-(1,1-dimethylethyl)-1-methyl-2-(methylthio)-1H-pyrrole-3-sulfonamide in 50 mL of methylene chloride was added 50 mL of trifluoroacetic acid (TFA) under a nitrogen atmosphere. The orange reaction mixture was stirred at room temperature overnight ca. 16 hours. The reaction mixture was concentrated to a tan solid. Diethyl ether was added to the tan solid and was removed by evaporation to remove residual TFA. The solid was suspended in diethyl ether and filtered giving 2.9 g of the title compound as a solid, m.p. 135°-137° C. 1H NMR (Acetone-d6, 200 MHz.) δ: 6.93(d,1H), 6.45(d,1H), 6.19(bs,2H), 3.78(s,3H), 2.33(s,3H).
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:23][C:24]1[N:28]=[C:27](Cl)[S:26][N:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1.O>[CH2:2]([C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:27]3[S:26][N:25]=[C:24]([Br:23])[N:28]=3)[CH2:19][CH2:18]2)[N:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(Cc2ccccc2)nc(NC2CCNCC2)n1
Reactant: Clc1nc(Br)ns1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cc2ccccc2)nc(NC2CCN(c3nc(Br)ns3)CC2)n1

Procedure:
A solution of (4-benzyl-6-methyl-pyrimidin-2-yl)-piperidin-4-yl-amine hydrochloride (125 mg, 0.39 mmol), 3-bromo-5-chloro-[1,2,4]thiadiazol (39 mg, 0.19 mmol) and N,N-diisopropylethyl amine (66 L, 0.39 mmol) in tetrahydrofurane (3 mL) was heated to 95° C. 4.5 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient from CH2Cl2 to CH2Cl2/MeOH 19:1 (v/v) as eluent. The title compound was obtained as a colorless oil (84 mg, 96%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]([O:13][CH2:14][CH3:15])=[CH:7][C:6]=1[CH3:16])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:16][C:6]1[CH:7]=[C:8]([O:13][CH2:14][CH3:15])[CH2:9][C:10]([CH3:12])([CH3:11])[C:5]=1[CH2:3][OH:2]
Reactant: CCOC1=CC(C)=C(C(=O)OC)C(C)(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCOC1=CC(C)=C(CO)C(C)(C)C1
Reaction time: 4 h

Procedure:
250 g. of crude 2,6,6-trimethyl-4-ethoxy-1,3-cyclohexadien-1-carboxylic acid methyl ester, prepared in Example 3, was added over a 1-hour period to a suspension of 50 g. of lithium aluminum hydride in 1 l. of diethyl ether at a temperature of 10°-15°. Stirring of the reaction mixture at this temperature was continued for an additional 4 hours. The reaction mixture after this period was quenched by slow addition of 250 ml. of water while the temperature was kept below 15°. The inorganic material was filtered by suction and the filtrate was washed well with diethyl ether. The filtrate was dried over sodium sulfate and concentrated under vacuum at 20°-30° to yield crude 2,6,6-trimethyl-4-ethoxy-1,3-cyclohexadien-1-methanol as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:24])[CH:7]2[C:14]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15]1.[BrH:25]>C(O)(=O)C>[BrH:25].[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:24])[CH:7]2[C:14]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: COc1ccc(Cl)c2c1C(C1(c3ccccc3)CCC1)N(C)CC2
Agent: Br
Solvent: CC(=O)O
Product: CN1CCc2c(Cl)ccc(O)c2C1C1(c2ccccc2)CCC1

Procedure:
A mixture of 5-chloro-8-methoxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline (5.5 g) prepared as described in Example MI5), 48% aqueous hydrobromic acid (50 ml) and glacial acetic acid (50 ml) was heated under reflux in a nitrogen atmosphere for 24 hours. The solvents were removed by evaporation The residue was decolourised with charcoal in methanol. The mixture was filtered and the solvent removed from the filtrate. The residue was dried by azeotropic distillation with propan-2-ol, and decolourised with charcoal in methanol. The mixture was filtered and the solvent removed from the filtrate. The residue was dried by azeotropic distillation with propan-2-ol and treated with ether to give 5-chloro-8-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 197°-200° C. (dec).
Reaction SMILES: [CH3:1][C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH2:3][CH2:4]/[CH:5]=[N:6]/[S@:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].[C-:23]#[N:24].C([Al+]CC)C.C(O)(C)C.[Cl-].[NH4+]>O1CCCC1>[C:23]([C@@H:5]([NH:6][S@:7]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:8])[CH2:4][CH2:3][C:2]([CH3:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])#[N:24]
Reactant: Cc1ccc([S@](=O)/N=C/CCC(C)(C)c2ccccc2)cc1
Reactant: [C-]#N
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1ccc([S@](=O)N[C@H](C#N)CCC(C)(C)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
(S)-4-methyl-benzenesulfinic acid [4-methyl-4-phenyl-pent-(E)-ylidene]-amide (1.29 g) was dissolved in tetrahydrofuran (35 ml) and cooled to −78° C. In a second flask diethylaluminium cyanide solution (1N in toluene, 9.5 ml) was diluted with tetrahydrofuran (35 ml). After cooling down to −78° C. isopropanol (0.31 ml) was added and the mixture was stirred additional 30 min at room temperature. This mixture was added slowly to the imine solution in the first flask at −78° C. and stirred overnight while warming up to room temperature. After cooling down to −78° C. saturated ammonium chloride solution (18 ml) was added. The suspension was filtered through Celite. Ethyl acetate was added and the solution was washed with sodium chloride solution, dried (MgSO4) and concentrated. The crude product was purified by column chromatography (SiO2; heptane/EtOAc 4:1) to give (S)-4-methyl-benzenesulfinic acid ((S)-1-cyano-4-methyl-4-phenyl-pentyl)-amide (0.6 g, 43%) as a light yellow oil.