Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH:13]([CH2:17][CH2:18][CH2:19]C)[C:14](Cl)=[O:15].[C:21](=S)=S>>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[CH2:12][CH:13]([CH2:17][CH:18]([CH3:19])[CH3:21])[C:14]2=[O:15]
Reactant: S=C=S
Reactant: CCCCC(Cc1ccccc1Br)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)CC1Cc2c(Br)cccc2C1=O
Reaction time: 1 h

Procedure:
A 500-ml four-necked round flask equipped with a stirrer, a Dimroth condenser, a dropping funnel, a thermometer and a NaOH trap was charged with 20.33 g (152.5 mmol) of anhydrous aluminum chloride and 70 ml of carbon disulfide. To the mixture was added dropwise a solution containing 40.2 g (132.6 mmol) of the above-obtained 3-(2-bromophenyl)-2-1-butylpropionic acid chloride dissolved in 50 ml of carbon disulfide under a nitrogen atmosphere while cooling with ice bath. After the addition was completed, the temperature in the flask was elevated to room temperature, and the mixture was stirred for 1 hour. Then, the reaction mixture was quenched by pouring onto 200 ml of ice water, which was then extracted with 100 ml of ether three times. The combined organic phase was washed with 100 ml of a saturated aqueous solution of sodium bicarbonate, and then 100 ml of a saturated NaCl aq., followed by dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give 37.4 g of the desired produce as an orange liquid. This ketone was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:3]([C:5]1[CH:6]=[C:7]([OH:13])[C:8](=[CH:11][CH:12]=1)[CH:9]=O)[CH3:4])[CH3:2].[C@@H:14]1([NH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH2:20]>>[CH2:1]([N:3]([C:5]1[CH:6]=[C:7]([OH:13])[C:8](=[CH:11][CH:12]=1)[CH:9]=[N:20][C@@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[N:21]=[CH:9][C:8]1[C:7](=[CH:6][C:5]([N:3]([CH3:4])[CH2:1][CH3:2])=[CH:12][CH:11]=1)[OH:13])[CH3:4])[CH3:2]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CCN(C)c1ccc(C=O)c(O)c1
Product: CCN(C)c1ccc(C=N[C@@H]2CCCC[C@H]2N=Cc2ccc(N(C)CC)cc2O)c(O)c1

Procedure:
Synthesis and working up are carried out as in Example 9, starting from 500 mg (2.79 mmol) of 4-(N-ethyl-N-methylamino)salicylaldehyde and 152 mg (1.33 mmol) of trans-1,2-cyclohexanediamine. Yield: 569 mg (98%), yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][OH:28]>CN(C)C=O>[OH:28][CH2:27][CH2:26][CH2:25][N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: OCCCCl
Reactant: O=c1[nH]cc(-c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2c(-c2ccccc2)cn1CCCO
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A mixture of 22.1 g of 4-phenyl-1(2H)-isoquinolone, 20 g of anhydrous potassium carbonate and 100 ml of dimethylformamide was stirred for 2 hours at 100° C. Then, 11 g of 3-chloropropanol was added to the resulting solution and the mixture was stirred at 110° C. for 5 hours. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in dichloromethane. Water was added to the resulting solution and, after thoroughly stirring, the dichloromethane layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 23 g of 2-(3-hydroxypropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 84° C. as colorless prisms.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3([C:32]4[CH:31]=[N:30][N:29]([CH3:33])[C:28]=4[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:21]3)[CH2:17][CH2:16]2)=[O:14])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:3])[CH3:2].[Li+].[BH4-]>C1COCC1>[OH:8][CH2:7][C:6]1[CH:9]=[C:10]([C:13]([N:15]2[CH2:16][CH2:17][C:18]3([C:32]4[CH:31]=[N:30][N:29]([CH3:33])[C:28]=4[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:21]3)[CH2:19][CH2:20]2)=[O:14])[CH:11]=[CH:12][C:5]=1[O:4][CH:1]([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)cc1C=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)cc1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.1 %

Procedure:
2-Isopropoxy-5-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzaldehyde (110 mg, 0.25 mmol) was dissolved in THF (3 mL) and LiBH4 (11 mg, 0.50 mmol) was added. The reaction was stirred at room temperature for 1.5 h before being quenched with methanol (3 mL). The reaction was neutralized by the addition of a saturated sodium bicarbonate solution and was extracted with ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-100% ethyl acetate in hexane) to yield [3-(hydroxymethyl)-4-isopropoxy-phenyl]-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (74 mg, 65%) as a white solid. ESI-MS m/z calc. 447.5. found 448.3 (M+1)+. Retention time: 1.59 minutes (3 min run).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([F:31])=[C:28]([CH:30]=1)[NH2:29])#[CH:23]>C(O)(C)C>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([F:31])=[C:28]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:30]=1)#[CH:23]
Reactant: C#Cc1ccc(F)c(N)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Solvent: CC(C)O
Product: C#Cc1ccc(F)c(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Yield: 63.1 %

Procedure:
4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline (140 mg, 0.447 mmol) and 5-ethynyl-2-fluoroaniline (66 mg, 0.489 mmol) were reacted in refluxing isopropanol (3 mL) overnight under an atmosphere of N2. The solvent was removed by rotary evaporation and the residue was dissolved in CHCl3 and then treated with saturated aqueous NaHCO3. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was chromatographed on silica using 40% acetone/CH2Cl2 to provide 116 mg of the pure title product as its free base. This oil was dissolved in a minimum volume of CHCl3, diluted with several volumes of ether and titrated with 1M HCl in ether to precipitate the title product as a white solid (99 mg; 54%; LC-MS: m/z=412.1664, m/z(calc)=412.1667).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:11]1[NH:12][CH:13]=[CH:14][N:15]=1>>[C:1]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ncc[nH]1
Product: O=C(c1ccccc1)c1ncc[nH]1
Yield: 60 %

Procedure:
Benzoyl imidazole was prepared by the above procedure using benzoyl chloride (28.1 grams, 200 mmole) and 2-methylimidazole (16.4 grams, 210 mmole), in an amount of 22.4 grams (60% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].N1C=CC=CC=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([NH:20][C:29](=[O:30])[O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C#Cc1cccc(Nc2ncnc3cc(F)c(N)cc23)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C#Cc1cccc(Nc2ncnc3cc(F)c(NC(=O)Oc4ccccc4)cc23)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
N4-(3-ethynylphenyl)-7-fluoroquinazoline-4,6-diamine (50 mg, 0.18 mmol) was dissolved into DMF (2 mL) containing pyridine (17.5 μL, 0.21 mmol). Phenyl chloroformate (23 μL, 0.18 mmol) was added to the mixture at room temperature and stirred at 70° C. for 1 h to give phenyl 4-(3-ethynylphenylamino)-7-fluoroquinazolin-6-ylcarbamate. N1-(2,2-diethoxyethyl)-N2,N2-diethylethane-1,2-diamine (42 mg, 0.18 mmol) was added and stirred at 70° C. for 2.5 h. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was concentrated and purified with a silica column to give 45 mg (70%) of 1-(2,2-diethoxyethyl)-1-(2-(diethylamino)ethyl)-3-(4-(3-ethynylphenylamino)-7-fluoroquinazolin-6-yl)urea.
Reaction SMILES: [CH2:1]([O:28][CH2:29]Cl)[CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[N:31]1([CH2:36][CH2:37][OH:38])[CH:35]=[CH:34][N:33]=[CH:32]1.C(O[K])(C)(C)C>O1CCCC1>[CH2:1]([O:28][CH2:29][O:38][CH2:37][CH2:36][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3]
Reactant: OCCn1ccnc1
Reactant: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C)COCCl
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C)COCOCCn1ccnc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.2 %

Procedure:
Under ice cooling, 43.7 g of chloromethyl cholestanyl ether (24) was added to a mixture of 11.2 g of 2-(1H-imidazol-1-yl)ethanol (23), 11.2 g of t-butoxypotassium, and 100 g of tetrahydrofuran. Then the mixture was stirred at room temperature for 10 hours. Subsequent standard aqueous work-up and purification by silica gel column chromatography gave 38.5 g of 1-[2-(cholestanyloxymethoxy)ethyl]imidazole (Quencher 5). Yield 75%.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)=[C:25](O)[CH:26]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH:1]([N:14]1[CH2:17][C:16]([O:18][C:23]2[CH:22]=[C:21]([Br:20])[CH:26]=[CH:25][C:24]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)([CH3:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cc(Br)ccc1OCc1cccc(Cl)c1
Reactant: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC1(Oc2cc(Br)ccc2OCc2cccc(Cl)c2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 150 °C
Yield: 43.7 %

Procedure:
The mixture of the title compound from Step A (0.5 mmol), 5-bromo-2-(3-chloro-benzyloxy)-phenol (0.5 mmol), and cyanomethylenetri-n-butylphosphorane (0.5 mmol) in toluene (3 mL) was heated at 150° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (120 mg). MS (ESI): mass calcd. for C30H27BrClNO2, 547.1; m/z found, 548.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Br:11])[C:5]=1[OH:12])([O-:3])=[O:2].CI.[C:15](=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Br:11])[C:5]=1[O:12][CH3:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1c(Br)cc(Cl)cc1[N+](=O)[O-]
Yield: 96.5 %

Procedure:
2-Nitro-4-chloro-6-bromoanisole was prepared by the same procedure as described for Step 2 of Preparation 2a using 2-nitro-4-chloro-6-bromophenol (16 g), methyl iodide (10.8 g), and potassium carbonate (26.3 g). Workup gave crude 2-nitro-4-chloro-6-bromoanisole (16.3 g, 96%) which was used in the next step without purification. 1H NMR (300 MHz, CDCl3) δ7.80 (d, J=2.5 Hz, 1 H), 7.77 (d, J=2.5 Hz, 1H), 4.01 (s, 3H). 13C NMR (75 MHz, CDCl3) δ149.7, 137.2 (2C), 130.0, 124.4, 120.5, 62.8.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5](=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5](=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)O)cc2)CC1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a stirred solution of 1,1-dimethylethyl(2E)-3-{4-[(4,4-dimethylcyclohexylidene)(4-hydroxyphenyl)methyl]phenyl}-2-propenoate (21) (0.24 g, 0.57 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 1 h and concentrated in vacuo to give an oil. The oil was dissolved in CH2Cl2 and the solvent was removed in vacuo to give a solid which was dried under vacuum at 90° C. to give 0.170 g (82%) of compound 22 as a pale tan solid. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (s, 6 H), 1.31 (m, 4 H), 2.16 (m, 4 H), 6.44 (d, J=15.9 Hz, 1 H), 6.65 (d, J=8.4 Hz, 2 H), 6.84 (d, J=8.3 Hz, 2 H), 7.05 (d, J=7.9 Hz, 2 H), 7.52 (d, J=15.9 Hz, 1 H), 7.57 (d, J=8.1 Hz, 2 H), 9.32 (s, 1 H), 12.33 (br s, 1 H). The compound was silated prior to EI analysis. HRMS (EI) Calcd for C30H42O3Si2: 506.2673 (M+). Found: 506.2669.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[F:37][C:38]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41].C(N(CC)CC)C>CN(C)C=O>[F:37][C:38]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:39]=1[C:40]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)=[O:41]
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4ccc(F)cc4F)cc3)cc21
Yield: 55.9 %

Procedure:
In a similar manner to that described in Example 47, a reaction was carried out using 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), 2,4-difluorobenzoylchloride (141 mg), triethylamine (232 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified to give the title compound (251 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].Cl[C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=1[C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[O:12][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=1[C:24]#[N:25])([CH3:3])[CH3:2]
Reactant: COc1ccc(O)cc1C(C)C
Reactant: Cc1cc([N+](=O)[O-])cc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C#N)cc1C(C)C
Yield: 90.4 %

Procedure:
A mixture of 3-isopropyl-4-methoxyphenol (200 mg), 4-chloro-3-cyano-5-methylnitrobenzene (200 mg) and potassium carbonate (211 mg) in methylethylketone (8 mL) was refluxed for 18 h. The dark mixture was concentrated in vacuo, partitioned between ethyl acetate/water, the organic layer washed with about 2N sodium hydroxide, brine, dried over sodium sulfate and concentrated to a dark oil. Flash chromatography (10% ethyl acetate/hexanes) afforded 2-(3-isopropyl-4-methoxy-phenoxy)-3-methyl-5-nitrobenzonitrile as a yellow oil (300 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]([F:26])([F:25])[CH2:12]OC1C=C(S([O-])(=O)=O)C=CC=1C.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:12][C:11]([F:26])([F:25])[F:10]
Reactant: Oc1ccc(F)cc1Br
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(OCC(F)(F)F)c(Br)c1
Temperature: 110 °C

Procedure:
To a solution of 2-bromo-4-fluorophenol (4 g) and 2,2,2-trifluoroethoxy-p-toluene sulphonate (5 g) in dimethylformamide (40 ml) was slowly added sodium hydride (1 g, 60% in oil) and the mixture then heated at 110° C. for 12 h. The solution was cooled, diluted with water (500 ml) and the product extracted into ethyl acetate (2×150 ml). The organic phase was washed with saturated NaHCO3 solution, water, saturated brine and dried (MgSO4). The solvent was removed in vacuo and the residue was chromatographed on silica gel (eluting with diethyl ether/hexane (1:5)) to give the title compound as a colourless oil. 1H NMR (250 MHz, CDCl3) δ4.36 (2H, q, J 8 Hz), 6.91-7.05 (2H, m), and 7.33 (1H, dd, J 8, 3 Hz).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].O>O1CCCC1>[CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][C:12]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)Oc1ccc(Oc2nccs2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(Oc2ccc(OC(C)C)cc2)s1
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of Example 1B (2.4 g, 0.01 mol) in dry tetrahydrofuran was added n-butyl lithium (4.4 mL, 2.5 M in hexane) at −78° C. drop wise. After stirring at this temperature for 1 h, tributyltin chloride (3.0 mL, 0.011 mol) was added slowly to the mixture. The brown solution was then stirred for 3 hours while warning up to room temperature. Water was added and the solution was extracted with ethyl acetate. The organic layer washed with saturated NH4Cl, brine, and then dried over magnesium sulfate. The solution was concentrated and the crude was purified on a silica gel flash column, eluting with 5-30% EtOAc in hexane, to give 4.85 g of the title compound (93% yield), 1H NMR (300 MHz, CDCl3) δ ppm 0.77-1.74 (m, 33 H) 4.40-4.63 (m, 1 H) 6.84-6.95 (m, 2 H) 7.12 (s, 1 H) 7.14-7.23 (m, 2 H). MS (ESI), m/z 526.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8](=[O:11])(=[O:10])[NH2:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:14].[CH:22]1([NH:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[NH2:9][S:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([N:27]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:28][CH:29]([CH3:31])[CH3:30])[N:18]=[CH:17][N:16]=2)=[O:14])=[C:2]([CH3:1])[CH:7]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CC(C)CNC1CCCC1
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(N(CC(C)C)C2CCCC2)ncn1
Yield: 80 %

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (2-methyl-4-sulfamoyl-phenyl)-amide (Intermediate 17) and cyclopentyl-isobutyl-amine (Intermediate 27), the title compound was obtained as a white solid in 80% yield.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[CH:8]=1)C.C(O)C.O>[OH-].[Na+]>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)=[CH:15][CH2:14][O:13][C:9]2[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH:12]=[CH:11][CH:10]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCc1cccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1cccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)c1
Yield: 59.5 %

Procedure:
3-{3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-propionic acid ethyl ester (example 1) (755 mg, 1.4 mmol) was hydrolysed in 1N NaOH (5.6 ml) and ethanol (15 ml) for 16 h at room temperature. Water (5 ml) was added and ethanol removed by concentration in vacuo. The mixture was neutralised with 6N HCl. The crude product was extracted with ethyl acetate (×3). The organic layers were combined, dried (MgSO4) and evaporated. The residue was dissolved in toluene and the title compound precipitated with petroleum ether, to give 430 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>ClCCl>[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]4)=[CH:4][CH:3]=2)=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Solvent: ClCCl
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
The compound of example 223 (0.230 g, 0.00153 mol) was dissolved in 5 mL dichloromethane and to this reaction mixture, 4-fluorophenyl isocyanate (0.102 g, 0.000744 mol) was added and stirred at room temperature for 8-10 h. The reaction mixture was concentrated and purified by column chromatography (silicagel, 30-40% ethyl acetate in petroleum ether to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: Nc1cccc(F)c1F
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Fc1cccc(N=C=S)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
Into a solution of 2,3-difluoroaniline (1.0 g, 7.74 mmol) in 30 mL of toluene at room temperature, thiophosgene (0.91 mL, 11.6 mmol) and triethylamine (1.3 mL, 11.6 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The combined organic layer was then concentrated to give the desired product (910 mg, 68%). 1H NMR (CDCl3) δ 6.98 (m, 2H), 7.11 (m, 1H).