Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Cl[CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14].[OH-].[Na+]>CC(C)=O.ClC(Cl)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:13]([CH:12]=[CH2:11])(=[O:15])=[O:14])=[C:4]([CH3:9])[CH:3]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC(Cl)Cl
Solvent: O
Product: C=CS(=O)(=O)Oc1ccc(Cl)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a stirred mixture of 4-chloro-2-methylphenol (24.7 g, 173 mmol) in acetone (10 ml), dichloroethane (25 ml) and water (45 ml) at 0-5° C. was added drop wise simultaneously 2-chloro-1-ethane sulfonyl chloride (28.2 g, 173 mmol) and a solution of 25% sodium hydroxide (60 g) during approximately one hour. The mixture was stirred for one hour at Sand for one hour at room temperature. Water was added and the mixture was extracted twice with DCM. The organic phase was dried with sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with hexane-ethyl acetate which gave the title compound (33.4 g, 83%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=O>>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(Cl)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chlorobenzoic acid: MS (ESI): m/z 403 (M+1).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].C(N([CH2:29][CH3:30])CC)C.[C:31](Cl)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)Cl>CN(C)C=O>[CH:35]1[CH:36]=[CH:37][C:32]([C:31]([O:23][CH2:1][C@H:2]2[O:7][CH:6]([O:8][C@:9]3([CH2:18][O:19][C:31]([C:30]4[CH:29]=[CH:49][CH:44]=[CH:45][CH:46]=4)([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[O:13][C@H:12]([CH2:14][O:15][C:31]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C@@H:11]([OH:16])[C@@H:10]3[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@H:3]2[OH:22])([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][CH:34]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O[C@@H]1[C@H](O)[C@@H](O)C(O[C@]2(COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](O)[C@@H]2O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
In a dry 5-L four-neck flask is dissolved 70 grams of sucrose (204.5 mmol) in 1 liter dry dimethylformamide (DMF) and dry triethylamine (200 ml, 145 grams, 1,423 mmol). The solution is allowed to attain a temperature of 25° to 30° C. and treated with a solution of trityl chloride (260 grams, 935.2 mmol, 4.5 equiv.) in dimethylformamide (600 ml), added dropwise over 1 hour. After the addition is complete, the reaction mixture is heated to a temperature of 50° C. and allowed to stir for 48 hours at that temperature. After 2 days, the reaction mixture is filtered through a short pad of silica gel to remove the precipitated triethylammonium hydrochloride and the residue is washed with methylene chloride:acetone (4:1). The effluent is then concentrated to a residue, which is reconstituted in methylene chloride and washed successively with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water, and brine and then dried over anhydrous sodium sulfate. The dry organic extract is then filtered and concentrated in vacuo to provide a yellow foamy solid. This material is then applied on a silica gel column (230 to 400 mesh, 10 cm×50 cm) packed with methylene chloride and successively eluted with methylene chloride, then 10% acetone in methylene chloride, followed by elution with 20% acetone in methylene chloride. The desired tri-O-tritylsucrose elutes with 20% acetone in methylene chloride and has an Rf of 0.21 in the same solvent. The amount of 1',6,6'-tri-O-tritylsucrose obtained by this method of synthesis and isolation is typically between 146 to 150 grams or 67% to 68.8%. On scales between 1 mmol and 50 mmol (314 mg to 15.7 grams) yields average about 76%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:32]=[CH:31][C:17]2/[C:18](=[C:27](/[CH3:30])\[C:28]#[N:29])/[C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[O:21][CH2:22][C:16]=2[CH:15]=1.C(OCC)(=O)C>CN(C=O)C>[N:1]1([CH2:13][C:14]2[CH:32]=[CH:31][C:17]3/[C:18](=[C:27](/[CH3:30])\[C:28]#[N:29])/[C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[O:21][CH2:22][C:16]=3[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N:1]1[N:2]([CH2:13][C:14]2[CH:32]=[CH:31][C:17]3/[C:18](=[C:27](/[CH3:30])\[C:28]#[N:29])/[C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[O:21][CH2:22][C:16]=3[CH:15]=2)[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: C/C(C#N)=C1/c2ccc(CCl)cc2COc2ccccc21
Reactant: c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C/C(C#N)=C1/c2ccc(Cn3cc4ccccc4n3)cc2COc2ccccc21
Product: C/C(C#N)=C1/c2ccc(Cn3ncc4ccccc43)cc2COc2ccccc21
Reaction time: 0.25 h
Yield: 64 %
Yield: 36 %

Procedure:
[step 1] Indazole (240 mg, 2.03 mmol) was dissolved in DMF (5.0 mL), sodium hydride (60%, 81 mg, 2.03 mmol) was added, and the mixture was stirred for 15 min. To this mixture was added (E)-2-(8-chloromethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiononitrile (300 mg, 1.01 mmol) obtained in Reference Example B5, and the mixture was stirred at room temperature for 3 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 75/25) to give (E)-2-[8-(indazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (245 mg, 64%) and (E)-2-[8-(indazol-2-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (138 mg, 36%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=O)[NH:7][C:8]2[CH:9]=[C:10]3[O:20][CH2:19][CH2:18][O:17][C:11]3=[CH:12][C:13]=2[C:14]=1CCl)=[O:4].P(Br)(Br)([Br:24])=O.C(O)C>ClCCCl>[BrH:24].[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[CH:9]=[C:10]3[O:20][CH:19]=[CH:18][O:17][C:11]3=[CH:12][C:13]=2[CH:14]=1)=[O:4]
Reactant: O=P(Br)(Br)Br
Reactant: COC(=O)c1c(CCl)c2cc3c(cc2[nH]c1=O)OCCO3
Solvent: CCO
Solvent: ClCCCl
Product: Br
Product: COC(=O)c1cnc2cc3c(cc2c1)OC=CO3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 9-chloromethyl-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester (Intermediate 5, 25 g), in 1,2-dichloroethane (DCE, 90 mL) is added a solution of phosphorus oxybromide (44 g, 2 eq) in DCE (90 mL). The resultant mixture is heated at reflux for 4.0 h, and then cooled to <15° C. Ethanol (91 mL, 20.0 eq) is added while keeping the temp <20° C. The mixture is then allowed to warm to room temperature and stirred overnight. The mixture is filtered and the solid is washed with DCE (30 mL). The solid is dried under high vacuum (about 1 mm Hg) at room temperature overnight to yield 7-bromo-9-bromomethyl-2,3-dihydro[1,4)]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester hydrobromic acid salt as a yellow solid. HRMS (EI+): calc for C15H13Br2NO4: 428.9211, Found: 428.9238.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[NH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[NH2:16][C:17]1[CH:22]=[C:21]([C:2]2[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[O:11])[CH:5]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Reactant: Nc1cccc(B(O)O)c1
Product: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(N)c1

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-aminobenzene boronic acid, gave 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:25]=4)=[CH:17][CH:16]=3)=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[Cl-].C[Zn+].[CH3:34]N1CCCC1>[Pd].ClCCl>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12]([CH:10]3[CH2:11][N:8]([C:5]4[N:6]=[N:7][C:2]([CH3:34])=[CH:3][CH:4]=4)[CH2:9]3)=[O:13])=[CH:16][CH:17]=2)[CH:22]=[N:23]1
Reactant: CC(C)(C)Cn1cc(-c2ccc(NC(=O)C3CN(c4ccc(Cl)nn4)C3)cc2)cn1
Reactant: CN1CCCC1
Agent: [Pd]
Agent: C[Zn+]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(N2CC(C(=O)Nc3ccc(-c4cnn(CC(C)(C)C)c4)cc3)C2)nn1
Temperature: 60 °C

Procedure:
To 1-(6-chloropyridazin-3-yl)-N-(4-(1-neopentyl-1H-pyrazol-4-yl)phenyl)azetidine-3-carboxamide (0.076 g, 0.179 mmol) was added methylzinc(II) chloride (2.0M in THF) (0.179 ml, 0.358 mmol) and 5 mg of palladium catalyst. The reaction mixture was heated to 60° C. and a thick precipitate developed. N-methylpyrrolidine (0.2 ml) was added and the mixture was heated to 85° C. for 2 hours. The mixture was diluted with dichloromethane and purified by normal phase chromatography to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.11 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H), 7.43 (d, J=9.2 Hz, 1H), 6.99 (d, J=9.1 Hz, 1H), 4.27 (t, J=8.5 Hz, 2H), 4.19 (dd, J=8.2, 6.1 Hz, 2H), 3.90 (s, 2H), 3.75 (ddd, J=17.0, 8.5, 6.0 Hz, 1H), 2.45 (s, 3 H), 0.92 (s, 9 H); MS (ESI(+)) m/e 405 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][N:6]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:19]=1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:3].Cl.[C:21]([O-:33])(=[O:32])[CH2:22][C:23](CC([O-])=O)([C:25]([O-:27])=[O:26])[OH:24]>>[CH3:3][N:2]([CH2:4][CH2:5][N:6]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:19]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:24][CH3:23])=[CH:12][CH:13]=1)[CH3:1].[CH:22](/[C:21]([OH:33])=[O:32])=[CH:23]/[C:25]([OH:27])=[O:26]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Reactant: CN(C)CCN(Cc1ccccc1)c1ccccn1
Agent: Cl
Product: COc1ccc(CN(CCN(C)C)c2ccccn2)cc1
Product: O=C(O)/C=C\C(=O)O

Procedure:
Tripelennamine hydrochloride (or citrate)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[CH:13][C:8]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])=[N:9][C:10]1=[O:14]
Reactant: ClCCCCBr
Reactant: Cc1nc(C)c(-c2cc[nH]c(=O)n2)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C)c(-c2ccn(CCCCCl)c(=O)n2)s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a solution of 4-(2,4-Dimethyl-thiazol-5-yl)-1H-pyrimidin-2-one (120 mg, 0.58 mmol) in dry DMF (21 ml), 60% NaH (24 mg, 0.75 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (86 μl, 0.75 mmol) was added at room temperature and the mixture was stirred overnight then was heated at 69° C. for 2 hours. Water was added and the mixture extracted with diethyl ether to remove the dialkylated product and finally with ethyl acetate. Ethyl acetate was washed with brine, dried (Na2SO4) and evaporated to give 80 mg of the title compound as a solid (48% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([Br:16])[CH:8]=[C:9]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:10]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[CH3:18].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH2:21]([O:1][C:2]1[C:11]2[C:6](=[C:7]([Br:16])[CH:8]=[C:9]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:10]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[CH3:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCC(C)c1cc(Br)c2nc(C)c(C)c(O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)c1cc(Br)c2nc(C)c(C)c(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5 Grams of 4-hydroxy-6-s-butyl-8-bromo-2,3-dimethylquinoline synthesized in the same way as that described in Example 1 was suspended in 20 ml of dimethylformamide, to which 700 mg of 60% sodium hydride was added under cooling with ice and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added dropwise 3 g of benzyl bromide under cooling with ice and the mixture was allowed to react at room temperature overnight. After the addition of 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate overnight. After the solvent was evaporated under reduced pressure, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane to obtain 2.5 g of 4-benzyloxy-6-s-butyl-8-bromo-2,3-dimethylquinoline. 2.5 Grams of the thus-obtained 4-benzyloxy-6-s-butyl-8-bromo-2,3-dimethylquinoline was dissolved in 25 ml of anhydrous tetrahydrofuran and cooled to −78° C., to which 2.8 ml of a 2.5 M solution of n-butyl lithium in n-hexane was added dropwise and the mixture was stirred for 10 minutes. One ml of methyl formate dissolved in 2 ml of anhydrous tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at 0° C. for 30 minutes. After the addition of 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated ammonium chloride solution and a saturated brine and then dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (20:1) to obtain 800 mg of 4-benzyloxy-6-s-butyl-8-formyl-2,3-dimethylquinoline.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:41]1[S:45][C:44]([C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=[O:51])=[CH:48][C:47]=2[CH3:55])=[N:43][C:42]=1[C:56]([CH3:59])([CH3:58])[CH3:57].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.O.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>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:41]4[S:45][C:44]([C:46]5[CH:54]=[CH:53][C:49]([C:50]([OH:52])=[O:51])=[CH:48][C:47]=5[CH3:55])=[N:43][C:42]=4[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CSc1ncc(B2OC(C)(C)C(C)(C)O2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc(-c2sc(-c3ccc(C(=O)O)cc3C)nc2C(C)(C)C)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Yield: 9 %

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-{[2-(methylsulfanyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-1,3-oxazolidin-2-one (INTERMEDIATE 21, 2.0 g, 3.46 m mol), 4-(5-bromo-4-tert-butylthiazol-2-yl)-3-methylbenzoic acid (INTERMEDIATE 41, 1.350 g, 3.81 mmol), potassium phosphate (8.18 mL, 1.27 M, 10.39 m mol) in THF (5 mL) and water (5.00 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.400 g, 0.346 mmol). It was degassed, and refilled with nitrogen. The reaction mixture was heated to reflux for 2 hours to see complete conversion by LCMS. It was distributed between 100 mL of water and 300 mL of ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and the filtrate concentrated. The crude isolate was purified by silica gel chromatography, eluting with 30% ethyl acetate in hexanes to give the title compound as white solid (225 mg, 9.0% yield). LCMS (M+H)+: 725.0
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[CH3:31][O:32][CH2:33][C:34]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:35]
Reactant: COCC(=O)Cl
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)COC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A178) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C1(C)C(C#N)=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C#N
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 55 %

Procedure:
To a mixture of 301 mg (purity: 100%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 842 mg (5.59 mmol) of 2-cyclopropyl-6-methylphenol were added orthotolunitrile (2.76 g) and 325 mg (5.51 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 277 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 55%) and 3.2 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.6%) were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].Cl>N1C=CC=CC=1.ClCCl.C(OCC)(=O)C>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:16]=[CH:15][C:5]([CH2:6][CH:7]3[CH2:11][CH2:10][CH2:9][N:8]3[CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CCCN1CCCC1Cc1ccc(N)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCN1CCCC1Cc1ccc(NS(=O)(=O)c2ccc(C(C)C)cc2)cc1
Temperature: 5 °C
Reaction time: 18 h
Yield: 187.2 %

Procedure:
2-(4-Aminobenzyl)-1-propylpyrrolidine (300 mg, 1.37 mmol) was dissolved in pyridine-dichloromethane (1:2, 9 mL) and cooled to 5° C. 4-Isopropylbenzenesulfonyl chloride (300 mg, 0.24 mmol) was added and the solution stirred at 5° C. for 18 h. The solution was evaporated, partitioned between ethyl acetate and water, and the organic phase separated and dried over MgSO4. The filtered solution was concentrated and separated by column chromatography (dichloromethane-2% methanol) to give an oil. The oil was dissolved in ethyl acetate and HCl (4M, dioxane) was added to give the product as a white solid (180 mg, 30%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=1.IC.O>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]([CH3:1])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:13]=1
Reactant: Brc1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1c(-c2ccc(Br)cc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
Potassium tert-butoxide (1.23 g) was added to a solution of 2-(4-bromophenyl)indole (2.72 g) in dimethylformamide (40 ml). Iodomethane (1.25 ml) was added and the reaction mixture stirred at ambient temperature for 18 hours. The reaction mixture was added to water. This solid was collected by filtration and purified by vacuum chromatography on silica gel (Merck Art. 7736) using 5% ethyl acetate/hexane as eluent to give 2-(4-bromophenyl)-1-methylindole (1.625 g) as a solid, m.p. 114°-115° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12](=[O:15])[CH:13]=[CH2:14])[CH3:2].[CH3:16][C:17]([C:20]1[CH:25]=[C:24]([SH:26])[CH:23]=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]=1[OH:31])([CH3:19])[CH3:18].C(N(CC)CC)C>CO>[CH3:30][C:27]([C:22]1[CH:23]=[C:24]([S:26][CH2:14][CH2:13][C:12]([NH:11][C:4]2[C:5]([CH2:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])=[O:15])[CH:25]=[C:20]([C:17]([CH3:19])([CH3:18])[CH3:16])[C:21]=1[OH:31])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)Nc1c(CC)cccc1CC
Solvent: CO
Solvent: CCN(CC)CC
Product: CCc1cccc(CC)c1NC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared by the method of Example 4 from N-(2,6-diethylphenyl)-2-propenamide (1.01 g, 0.005 mole), 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 0.005 mole) and triethylamine (0.5 ml) in methanol, m.p. ca. 150.5°-151.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[Se:10][C:9]([CH3:11])=[N:8][C:7]=2[CH:12]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([O-:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1.[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[Se:10][C:9]([CH3:11])=[N+:8]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])[C:7]=2[CH:12]=1
Reactant: COc1ccc2[se]c(C)nc2c1
Reactant: CCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(Cl)cc1
Product: CCCCCCCCCCCCCCCCCC[n+]1c(C)[se]c2ccc(OC)cc21
Product: O=S(=O)([O-])c1ccc(Cl)cc1
Temperature: 130 °C
Yield: 49.4 %

Procedure:
Into a sealed tube in which air was replaced by nitrogen were placed 0.50 g (2.17 mmoles) of 5-methoxy-2-methylbenzoselenazole and 1.06 g (2.39 mmoles) of octadecyl parachlorobenzenesulfonate. The mixture obtained was heated at 130° C. for 4 hours. The resulting reddish purple solid was washed with ether and dried under reduced pressure, giving 0.72 g (yield: 49.3%) of 5-methoxy-2-methyl-3-octadecylbenzoselenazolium parachlorobenzenesulfonate as a reddish purple powder.