Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([S:8]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][NH:16][CH2:17]3)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[C:2]1([S:8]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:17]3)(=[O:10])=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Nc1cccc2c1CCNC2)c1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Product: CCOC(=O)CCCN1CCc2c(cccc2NS(=O)(=O)c2ccccc2)C1

Procedure:
5-Phenylsulphonamido-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.7 g) was reacted with ethyl 4-bromobutyrate in the manner described in Example 2(a). After elution from a silica column with ethyl acetate:methanol mixtures, the product was recrystallised from ethanol to give ethyl 4-[5-phenylsulphonamido-1,2,3,4-tetrahydroisoquinolin-2-yl]butyrate as a white solid (2.0 g).
Reaction SMILES: ClC1C=CC(C(NC2C=CC(C)=C(I)C=2)=O)=CN=1.C(N[C@H]1CCNC1)(OC(C)(C)C)=O.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48]([C:51](=[O:61])[NH:52][C:53]3[CH:58]=[CH:57][C:56]([CH3:59])=[C:55]([I:60])[CH:54]=3)=[CH:47][N:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:38])[NH:39][C@H:40]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48]([C:51](=[O:61])[NH:52][C:53]3[CH:58]=[CH:57][C:56]([CH3:59])=[C:55]([I:60])[CH:54]=3)=[CH:47][N:46]=2)[CH2:41]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1I
Agent: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Product: Cc1ccc(NC(=O)c2ccc(N3CC[C@H](NC(=O)OC(C)(C)C)C3)nc2)cc1I

Procedure:
{(S)-1-[5-(3-Iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester was prepared from 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide and (−)-(S)-3-(Boc-amino)pyrrolidine following a method similar to the one described in the synthesis of 4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester above. The product was isolated after a silica gel column purification and a precipitation out of THF with excess of hexanes. HRMS m/z calcd for C22H27N4O3I [M+H]+: 523.1201. Found: 523.1201.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)=[C:17]([F:32])[CH:16]=2)[CH2:11][CH2:10]1>C1COCC1>[CH2:1]([Si@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=3)=[C:17]([F:32])[CH:16]=2)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Fc1cc(C2CC[SiH](Cl)CC2)ccc1-c1ccc(OC(F)(F)F)cc1
Reactant: CCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(OC(F)(F)F)cc3)c(F)c2)CC1

Procedure:
3.0 g (20 mmol) of n-pentyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.8 g (21 mmol) of 4'-(4-chloro-4-silacyclohexyl)-2'-fluoro-4-trifluoromethoxybiphenyl to obtain 4'-(trans-4-n-pentyl-4-silacyclohexyl)-2'-fluoro-4-trifluoromethoxybiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 6.8 g of the trans isomer (yield 80%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[CH:23]([CH2:31][CH2:32]OS(C)(=O)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:16][CH:15]=1>CN(C)C=O>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[CH2:32][CH2:31][CH:23]([CH:22]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)[CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([I:13])=[CH:15][CH:16]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: COc1ccc(COC(CCc2ccc(I)cc2)C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(COC(CCc2ccc(I)cc2)C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 20.9 %

Procedure:
Potassium phthalimide (0.33 g, 2.2 mmol) was added in one portion to a stirred solution of 1,1-dimethylethyl 5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl)oxy]ethyl}pentanoate (1.15 g, 1.86 mmol) in dimethylformamide (6 mL) at room temperature under nitrogen. The resulting solution was heated at 80° C. for 1 h 45 min then cooled to room temperature. The volatiles were evaporated and the residue partitioned between dichloromethane (50 mL) and water (50 mL). The layers were separated and the organic phase evaporated to dryness. The residue was chromatographed on silica gel (50% ethyl acetate: cyclohexane) to give the title compound (0.26 g, 21%) as a yellow oil which was a mixture of diastereoisomers. LC/MS: 4.29 min; z/e 687, calcd (M+18) 687. 1H NMR (400 MHz: CDCl3): 7.85 (2H), 7.70 (2H), 7.55-7.20 (4H), 6.90-6.75 (4H), 4.55-4.30 (2H), 3.80 (3H), 3.75 (1H), 3.65 (2H), 2.80-2.45 (3H), 2.10-1.50 (4H), 1.40 (9H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[N:13]2[N:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1>N1C=CC=CC=1>[Cl:8][C:9]1[N:13]2[N:14]=[C:15]([NH:18][C:5](=[O:7])[CH3:6])[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2nnc(Cl)n2n1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2nnc(Cl)n2n1
Reaction time: 6 h

Procedure:
0.11 cm3 of acetic anhydride is added to a mixture of 202 mg of 3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-amine in 5 cm3 of pyridine at 0° C. The temperature is allowed to rise to 20° C. over 6 h, then 0.05 cm3 of acetic anhydride is again added and stirring is maintained for 24 h. The precipitate formed is spin-filter-dried and then washed with ethyl ether and pentane. This solid is purified by chromatography on Biotage Quad 12/25 (KP-SIL, 60 A; 32-63 μM), elution being carried out with a gradient of dichloromethane/methanol of 100/0 to 90/10. 41 mg of N-(3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-yl)acetamide are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C]=O.C(=O)=O.[CH2:16]([O:18][C:19]1([CH2:34][CH2:35][OH:36])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][O:22][C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]1=2)[CH3:17].C(N(CC)CC)C>ClCCl.O>[CH2:16]([O:18][C:19]1([CH2:34][CH:35]=[O:36])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][O:22][C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]1=2)[CH3:17]
Reactant: CCOC1(CCO)c2ccccc2COc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Agent: [C]=O
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CCOC1(CC=O)c2ccccc2COc2ccccc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
Dissolved oxalyl chloride (3.62 g, 2.5 mL, 0.0285 mol) in 30 mL of dry dichloromethane, and cooled to -78° C. under a nitrogen atmosphere. Added dimethylsulfoxide (4.45 g, 4.0 mL, 0.0570 mol) in 10 mL of dry dichloromethane dropwise via addition funnel. Carbon monoxide and carbon dioxide evolution observed. Stirred at -78° C. for 15 mins. Added 2-[6,11-dihydro-11-ethoxydibenz[b,e]oxepin-11-yl]-ethanol (6.75 g, 0.0237 mol) dissolved in 30 mL of dry dichloromethane dropwise via addition funnel. Stirred at -78° C. for 15 mins. then added triethylamine (7.21 g, 9.9 mL, 0.0712 mol). Warmed slowly to room temperature. Added 150 mL of water, and separated layers. Extracted aqueous solution with dichloromethane. Washed combined organic extracts with 0.5N HCl and then saturated NaCl, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 5% ethyl acetatehexane then 10% ethyl acetate-hexane. Combined appropriate fractions, and evaporated to give 3.47 g (52% yield) of 2-[6,11-dihydro-11-ethoxydibenz[b,e]oxepin-11-yl]-ethanal as a colorless oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=O.O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[O:9][C:1](=[O:10])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[N:4]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: O=c1oc(-c2cccc(Cl)c2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a stirred solution of 76.5 g (0.56 mole) of anthranilic acid in 1000 ml of pyridine at room temperature was added 197 g (1.12 mole) of m-chlorobenzoyl chloride at a rapid dropwise rate. The temperature rose to 45°-50° and, midway through the addition, a precipitate began forming. After stirring one hour at room temperature the slurry was poured into 1500 ml of water and the precipitate was filtered, washed well with water and air dried to give 139 g (96.5%) of 2-(m-chlorophenyl)-4H-3,1-benzoxazin-4-one, m.p. 158°-60°. Crystallization from ethanol gave an analytical sample, m.p. 159°-60°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Br)cc2)C1
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3CCCC3)cc2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 1-(4-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate I, 200 mg, 0.592 mmol) in anhydrous toluene (15 mL) were added Pd2(dba)3 (1.35 mg, 0.002 mmol), BINAP (2.76 mg, 0.004 mmol), sodium tert-butoxide (68.20 mg, 0.710 mmol) and pyrrolidine (0.05 mL, 0.651 mmol) at r.t. and reaction mixture was stirred for 8 h at 80° C. Reaction mixture was then concentrated and the crude product was purified by column chromatography (silica gel, 0.4:9.6 EtOAc:Pet. ether) to afford the title compound as viscous liquid (140 mg, 72%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:4]=1[Cl:13].[C:14]([O-:17])(=[O:16])[CH3:15].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:14]([O:17][CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:4]=1[Cl:13])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCc1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 50 %

Procedure:
A rapidly stirred solution of the mixture from Step A, 20.6 grams (0.21 mole) of potassium acetate and 3.0 grams of tetrabutylammonium bromide in 250 ml of acetonitrile was heated under reflux for 24 hours. The reaction mixture was cooled and filtered. The filtrate was washed with two portions of an aqueous solution saturated with sodium chloride. The organic layer was slurried with magnesium sulfate, decolorizing carbon, and 500 grams of silica gel. The mixture was filtered and the filtrate concentrated under reduced pressure to give 28.7 grams of 50% 2,6-dichloro-3-nitrophenylmethyl acetate and 50% 2,6-dichloro-3-nitrotoluene. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH:4](Br)Br.C(O)=[O:13].Cl>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH:4]=[O:13]
Reactant: O=CO
Reactant: Fc1ccc(C(Br)Br)c(Cl)c1
Agent: Cl
Product: O=Cc1ccc(F)cc1Cl
Temperature: 25 °C
Yield: 107.2 %

Procedure:
In a flask were placed 30.25 g (0.100 mole) of 2-chloro-4-fluorobenzal bromide, 45 ml (1.2 mole) of formic acid, and 15 ml of concentrated hydrochloric acid. This mixture was heated at 100°-105° C. overnight. After cooling to room temperature, the reaction mixture was poured into 200 ml of an ice/water mixture which was then extracted twice with diethyl ether. The combined extracts were washed successively with a saturated, aqueous, sodium bicarbonate solution and water. After being dried over anhydrous magnesium sulfate, the extract was filtered, and the solvent was evaporated under reduced pressure, leaving 17 g of 2-chloro-4-fluorobenzaldehyde as a residue.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C@@H:27]1[CH2:38][CH2:37][C@@H:36]([O:39][Si](C(C)C)(C(C)C)C(C)C)[C:30]2=[N+:31]([O-:35])[CH:32]=[CH:33][CH:34]=[C:29]2[CH2:28]1>C1COCC1>[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C@@H:27]1[CH2:38][CH2:37][C@@H:36]([OH:39])[C:30]2=[N+:31]([O-:35])[CH:32]=[CH:33][CH:34]=[C:29]2[CH2:28]1
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2ccc[n+]([O-])c21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: [O-][n+]1cccc2c1[C@H](O)CC[C@@H](c1cccc(F)c1F)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
TBAF (4.18 mL, 4.18 mmol) was added to the THF (10 mL) solution of (6R,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 1-oxide (1.56 g, 3.48 mmol) at rt. The reaction was stirred at room temperature for 2 hours and LCMS showed that the reaction was completed. The solvent was removed via vacuum and the crude was load to flash column and eluted with methanol in CH2Cl2 from 0 to 10% to afford the desired product (0.7662 g, 75%) as a yellow solid. MS(ESI)[M+H+]=292. 10; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.16-8.26 (m, 1H) 7.14-7.20 (m, 1H) 6.98-7.12 (m, 3H) 6.90 (td, J=7.55, 1.76 Hz, 1H) 5.38-5.48 (m, 1H) 3.24-3.47 (m, 2H) 3.02 (dd, J=14.60, 1.76 Hz, 1H) 2.27-2.44 (m, 3H) 1.79-1.94 (m, 1H).
Reaction SMILES: C([C:3]1([C:19]([O-:21])=[O:20])[O:7][C:6]2=[C:8]([O:16]C)[CH:9]=[CH:10][C:11](C)([C:12]([O-:14])=[O:13])[C:5]2=[C:4]1[CH3:18])C.CN(C)P(=O)(N(C)C)N(C)C.O.[C:34]1(C)C=CC=C[CH:35]=1>>[CH2:34]([O:21][C:19]([C:3]1[O:7][C:6]2[C:8]([OH:16])=[CH:9][CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:5]=2[C:4]=1[CH3:18])=[O:20])[CH3:35]
Reactant: Cc1ccccc1
Reactant: CCC1(C(=O)[O-])OC2=C(OC)C=CC(C)(C(=O)[O-])C2=C1C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1oc2c(O)ccc(C(=O)O)c2c1C
Temperature: 25 °C

Procedure:
The solution of 2-ethyl-4-methyl-7-methoxy-3-methylbenzo[b]furan-2,4-dicarboxylate (from step 5 of example 1) (13.0 g), sodium p-thiocresolate (20.26 g, 1.5 equiv.) and hexamethylphosphoric acid triamide (24.80 g, 1.5 equiv.) was heated in dry toluene at reflux temperature under nitrogen for 2-6 h. The reaction mixture was cooled to room temperature, water was added and aqueous layer was washed with dichloromethane. Aqueous layer was acidified at 10-15° C. with concentrated hydrochloric acid. The precipitated product was filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[Cl:10])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH:55]1[C:63]2[C:58](=[C:59]([CH2:64][NH2:65])[CH:60]=[CH:61][CH:62]=2)[CH:57]=[N:56]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:65][CH2:64][C:59]2[CH:60]=[CH:61][CH:62]=[C:63]3[C:58]=2[CH:57]=[N:56][NH:55]3)=[CH:8][C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1Cl
Reactant: NCc1cccc2[nH]ncc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 22.9 %

Procedure:
To a solution of 3-Chloro-thiophene-2,5-dicarboxylic acid 2-methyl ester (200 mg, 0.91 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.38 mL, 2.73 mmol), HBTU (0.52 g, 1.37 mmol), HOBT (0.147 mg, 1.09 mmol), and C-(1H-Indazol-4-yl)-methylamine (146 mg, 1.0 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-70% EtOAc in hexane to afford the desired product (0.073 g, 23% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[S:6][N:5]=1)[CH3:2].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CN(C)C=O>[CH2:24]([N:26]([CH2:27][CH3:28])[C:15]([NH:14][C:7]1[S:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:23])[CH3:25]
Reactant: CCNCC
Reactant: CCOC(=O)c1c(OCC)nsc1NC(=O)Oc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCC)nsc1NC(=O)N(CC)CC
Yield: 40.6 %

Procedure:
In the manner of Example II B, 8.4 g of phenyl (3-ethoxy-4-ethoxycarbonyl-5-isothiazolyl)carbamate in 20 ml of dimethylformamide were allowed to react with 3.7 g of diethylamine. The solid from the reaction mixture was recrystallized from ethanol:water (70:30) to give 3.2 g of 1,1-diethyl-3-(3-ethoxy-4-ethoxycarbonyl-5-isothiazolyl)urea, m.p. 77°-80°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+].[Ni]>[CH2:1]([CH:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2ccccc2)N1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: O=C1NC(=O)C(Cc2ccccc2)N1
Yield: 79.9 %

Procedure:
190 g (1 mole) of 5-benzylidene-hydantoin are dissolved in 2 l of a N sodium hydroxide solution and 95 g of wet Raney-nickel are added. The hydrogen uptake is terminated after about 6-8 hours (the reaction mixture is shaken at atmospheric pressure). The catalyst is filtered off and washed with N sodium hydroxide. The filtrate is acidified to pH 3 with concentrated hydrochloric acid. The precipitated white crystals are filtered off, dried and washed with cold water. Thus 152 g of the desired compound are obtained, yield 80%. Mp.: 187°-189° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.O>CN(C=O)C>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:13]1[N:14]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:26]=[CH:27][C:3]([CH2:2][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[CH:4][CH:5]=2)[S:11][C:12]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: c1c[nH]cn1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(Cn2ccnc2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
Compound 59 (448 mg, 1.00 mmol) was dissolved in DMF (4 mL), imidazole (204 mg, 3.00 mmol) was added thereto, followed by stirring at 65° C. for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=20:1) to afford the entitled Compound 60 (348 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:11]([O:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([OH:10])=[C:4]([CH3:9])[CH:5]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(O)cc(C)c1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(OC(=O)c2ccccc2)cc(C)c1O

Procedure:
Using 4.70 g of 2,6-dimethyl-1,4-dihydroxybenzene, 4.0 ml of benzoyl chloride and 100 ml of pyridine, reaction and workup carried out as in Reference Example gave 6.35 g of 4-benzoyloxy-2,6-dimethylphenol as white crystals, m.p. 139.5-141.0° C. Using 6.35 g of the white crystals, 1.26 g of sodium hydride, 4.2 ml of benzyl bromide and 50 ml of DMF, reaction and workup carried out as in Example 12 gave 4.22 g of yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.Cl[C:17]1[CH:18]=[C:19]([C:24]2[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[N:25]=2)[C:20]([F:23])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CC(N)CC1C=CC=CC=1.OP(O)(O)=O.Cl[Pd]Cl>[O:1]1[CH2:6][CH:5]=[C:4]([C:17]2[CH:18]=[C:19]([C:24]3[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)[CH2:41][C:42]4[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=4)[N:25]=3)[C:20]([F:23])=[N:21][CH:22]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Agent: Cl[Pd]Cl
Agent: CC(N)Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4=CCOCC4)cnc3F)n2)cc1
Temperature: 110 °C
Reaction time: 14 h

Procedure:
A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (320 mg, 1.523 mmol) (Frontier Scientific), 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (600 mg, 1.250 mmol), potassium carbonate (400 mg, 2.89 mmol), and Amphos-PdCl2 (50 mg, 0.071 mmol) in dioxane (8 mL) was sparged with argon for 5 min. The mixture was heated at 110° C. under nitrogen. After 14 h, x-phos and Pd2dba3 (40 mg each) were added. After 3 h, more x-phos, Pd2dba3 and boronic ester were added. After 16 h, the mixture was cooled to room temperature, and partitioned between EtOAc (40 mL) and water (20 mL). The aqueous phase was extracted with EtOAc once. The combined organic phase was washed with water (3×), dried over Na2SO4 and concentrated. The residue was purified on silica gel (5 to 30% EtOAc). The dechlorinated fraction came out as the first major peak, followed by the product as the next major peak. The product was collected as a pink solid (130 mg). m/z (ESI, positive ion): 528.2 (M+H)+. 1H NMR (400 MHz, CDCl3-d) δ ppm 2.49-2.58 (m, 5H) 3.79 (s, 3H) 3.91 (s, 3H) 3.95 (t, J=5.38Hz, 2H) 4.31-4.36 (m, 2H) 4.82 (d, J=8.61 Hz, 4H) 6.20 (br. s., 1H) 6.86 (dd, J=11.15, 8.61Hz, 4H) 7.22 (d, J=6.85 Hz, 4H) 8.31 (d, J=1.96 Hz, 1H) 8.50 (dd, J=9.00, 2.54 Hz, 1H).
Reaction SMILES: NC1C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+].Cl[CH2:31][C:32]([O:34][CH3:35])=[O:33]>C(#N)C.O>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([NH:24][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(COc2cccc(N)c2)cc1
Reactant: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: O
Solvent: CC#N
Product: COC(=O)CNc1cccc(OCc2ccc(OC)cc2)c1

Procedure:
A mixture of the aniline (Intermediate 87, 24.6 g, 107.3 mmol), sodium bicarbonate (13.5 g, 161 mmol) and methyl chloracetate (10.1 ml, 118 mmol) in acetonitrile (30 ml) was heated at 90°-100° for 48 h. Water (200 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water (2×100 ml) and brine (100 ml) before drying (Na2SO4) and evaporating in vacuo to leave the crude product as a peach solid. Trituration with ether-hexane (1:1) gave the title compound (Intermediate 88) as a flesh coloured solid (30.3 g; 94%), m.p. 79°-81°.