Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3=[N:20][C:21]([NH2:24])=[N:22][CH:23]=[C:18]3[CH2:17][N:16]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])[C:15]2=[O:37])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:24][C:21]1[N:20]=[C:19]2[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15](=[O:37])[N:16]([C:25]3[C:26]([F:36])=[C:27]([O:34][CH3:35])[CH:28]=[C:29]([O:32][CH3:33])[C:30]=3[F:31])[CH2:17][C:18]2=[CH:23][N:22]=1
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(N)nc3N(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(N2Cc3cnc(N)nc3N(C3CCNCC3)C2=O)c1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-[7-Amino-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (295 mg, 0.567 mmol) in dichloromethane (5 mL) at 0° C. trifluoroacetic acid (647 μL) was added. The resulting solution was stirred at room temperature for 5 hours. The solution was then concentrated under reduced pressure. The resulting residue was concentrated with toluene (2×50 mL) to give a thick oil. Dichloromethane (2 mL) was added to the oil to produce a white precipitate. To accelerate precipitation diethyl ether (10 mL) was added. The mixture was then filtered to deliver 338 mg (92%) of the title compound as a white powder: mp 200° C.–220° C. (decomposition); MS (APCI) 421.1, 422.2.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][CH:5](OC)[O:4]1.[C:10]1([S:16]([OH:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[Ca+2].[Cl-]>C(Cl)Cl>[C:10]1([S:16]([CH:5]2[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[O:4]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(O)c1ccccc1
Reactant: COC1CCC(OC)O1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: COC1CCC(S(=O)(=O)c2ccccc2)O1
Reaction time: 4 h
Yield: 55 %

Procedure:
2,5-Dimethoxytetrahydrofuran (17.1 ml, 0.13M) was added dropwise to a stirred solution of benzenesulphinic acid (17.0 g, 0.12M) in dry DCM (100 ml) containing a suspension of powdered calcium chloride (1.0 g) at room temperature under argon. After 4 h, the solution was washed with water (2×50 ml), dried over anhydrous sodium sulphate, filtered and evaporated. The product was crystalised (diethyl ether/hexane) to give 2-benzenesulphonyl-5-methoxytetrahydro-furan as a white crystalline solid (15.9 g, 55%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C@:9]3([CH3:14])[C:11]([CH3:12])([CH3:13])[C@@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[N:3]1[CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[C:17]([F:16])([F:26])[F:27]
Reactant: Cn1[nH]c(=O)c2c1[C@@]1(C)CC[C@@H]2C1(C)C
Reactant: FC(F)(F)c1ccccc1CBr
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccccc1C(F)(F)F)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 16 %

Procedure:
A solution of (4R,7S)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 48; 115 mg, 0.55 mmol) and 2-(trifluoromethyl)benzyl bromide (133 mg, 0.55 mmol) in dimethylformamide (5.6 mL) was heated at 100° C. overnight. The solvent was evaporated and the residue was purified on a Biotage chromatography system, eluting with 0-5% methanol/dichloromethane. The resulting clear oil was taken up in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and water, dried (sodium sulfate), filtered, evaporated, and triturated with ether to give (4R,7S)-1,7,8,8-tetramethyl-2-(2-trifluoromethyl-benzyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (32 mg, 16%) as a white solid. APCI(+)-MS (M+H) 365.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][C:28]#[CH:29].C(O)(=O)C(O)=O.CC(C)=O>CC#N>[CH2:29]([N:4]1[CH2:5][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[CH2:1][CH2:2][CH2:3]1)[CH2:28][C:27]#[CH:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Reactant: C#CCCBr
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Product: C#CCCN1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 67.5 °C
Reaction time: 15 h

Procedure:
Charge in order, 23.7 g of CH3CN, 10 g of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate, 9.2 g of K2CO3 then 8.4 g of 4-bromobut-1-yne to R1. Heat the mixture to 65-70° C. and stir the mixture at 65-70° C. for 12-18 hours. Concentrate the mixture to a total weight of 30-40 g below 50° C., then add 76 g of MTBE and 50 g of water. Stir the mixture at 20-25° C. for 30 mins then allow to stand to 30 mins Separate the aqueous. Preopare a solution of 1 g of KOH in 49 g of water and add this to the organic layer at 20-25° C. Stir the mixture at 20-25° C. for 30 mins then allow to stand for 20-30 mins at 20-25° C. Separate the aqueous layer out and wash the organics with 50 g of water. Concentrate the organic phase to 40-50 g total weight below 50° C. in R1. Prepare a solution of 7.4 g of oxalic acid dihydrate in 39.5 g of acetone, then add drop wise the oxalic acid/acetone solution into R1 at 20-25° C. Stir the suspension at 20-25° C. for 2-3 hours then filter. Wash the cake with 15.2 g of MTBE. Slurry the cake in 89 g of THF and stir the mixture at 50° C. for 6-8 hours. Cool the mixture to 20-25° C. and filter. Wash the cake with 17.8 g of THF. Again, slurry the cake in 89 g of THF and stir the mixture at 50° C. for 6-8 hours. Cool the mixture to 20-25° C. and filter. Wash the cake with 17.8 g of THF. Dry the cake under vacuum at 50-60° C. for 16-18 hours to provide the title compound, tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate; oxalic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:22][PH:23]([O-])([O-:27])[O:24][CH2:25][CH3:26].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]([CH3:15])([S@:10]([NH:9][C@H:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[CH:3]=[C:2]([P:23]([CH3:22])(=[O:27])[O:24][CH2:25][CH3:26])[CH:7]=[CH:6][CH:5]=1)=[O:11])[CH3:14]
Reactant: CCO[PH](C)([O-])[O-]
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1ccccc1)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1cccc([C@H](N[S@](=O)C(C)(C)C)c2ccccc2)c1
Reaction time: 8 h

Procedure:
To (R)—N—((R)-(3-bromophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, 24-c, (11.8 g, 32.3 mmol), ethyl methylphosphite (6.5 g, 64.6 mmol) and Et3N (9.09 g, 96.9 mmol) in THF (100 ml) was added PdCl2(dppf) (2.1 g, 3.23 mmol). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum to provide the crude product, 24-d, (15 g). The crude product was used to the next step directly.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:18]([CH3:30])=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:31]O>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:18]([CH3:30])=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:27])([CH3:28])[C:21]=3[CH:29]=2)=[O:31])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SCCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1
Reactant: OO
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-acetamido-phenylmercapto)-butoxy]-4,4,7-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: CC1[CH:15]=[C:14]2[C:5]([S:6](=[O:23])(=[O:22])[C:7]3[CH:8]=[C:9]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:29]([OH:32])(=[O:31])[CH3:30]>O.[O-2].[O-2].[O-2].[Cr+6]>[C:29]([C:30]1[CH:3]=[CH:4][C:5]2[S:6](=[O:23])(=[O:22])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:8]=3)[C:13](=[O:16])[C:14]=2[CH:15]=1)([OH:32])=[O:31]
Reactant: CC(=O)O
Reactant: Cc1ccc2c(c1)C(=O)c1ccc(-c3nnn[nH]3)cc1S2(=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(=O)c1ccc(-c3nnn[nH]3)cc1S2(=O)=O
Reaction time: 16 h

Procedure:
7-Methyl-3-(5-tetrazolyl)thioxanthone-10,10-dioxide (0.78g) was suspended in acetic acid (50 ml) and chromium trioxide (0.98g) in water (2.0 ml) added dropwise, followed by concentrated sulphuric acid (0.5 ml) added dropwise. The mixture was heated on the steam bath for 1 hr., then boiled under reflux for 4 hr. Further chromium trioxide (0.98 g) was added and the mixture boiled for a further 16 hr. The green solution was diluted with water, and the precipitated solid filtered off and washed with water. The solid was boiled with acetic acid (200 ml), filtering at the boil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@@H:12]1[O:16][C:15](=[O:17])[NH:14][C@H:13]1[CH3:18].[H-].[Na+].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br>>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH2:26][N:14]1[C@@H:13]([CH3:18])[C@H:12]([C:3]2[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=2[I:1])[O:16][C:15]1=[O:17]
Reactant: C[C@@H]1NC(=O)O[C@H]1c1cc(C(F)(F)F)ccc1I
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1[C@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Following the procedure described in EXAMPLE 96, 0.108 g of (4S,5S)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one, 23 mg of sodium hydride, and 107 mg of 3,5-bis(trifluoromethyl)benzyl bromide provided the title compound. Mass spectrum (ESI) 598.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.00 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.58 (br s, 3H), 7.34 (dd, J=1.5 Hz, 8 Hz, 1H), 5.36 (d, J=4 Hz, 1H), 4.89 (d, J=16 Hz, 1H), 4.31 (d, J=16 Hz, 1H), 4.48 (dq, J=6 Hz, 4 Hz, 1H), 1.55 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:20])[CH2:9][CH2:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[OH:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:20][CH:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH:11]([O:12][S:29]([CH3:28])(=[O:31])=[O:30])[C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: OC(CCC(O)c1ccc(Cl)nc1)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Cl)nc1)c1ccc(Cl)nc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
The product from Example 207B (2.23 g, 7.12 mmol) and triethylamine (2.98 mL, 21.36 mmol) were combined in dichloromethane (50 mL). The mixture was cooled to −20° C. and methanesulfonyl chloride (1.383 mL, 17.80 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated to give the title product (approx 3.34 g) which was directly used for the next reaction.
Reaction SMILES: [S:1]=[C:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:8]3[C:9]=2[C:4](=[CH:5][CH:6]=[CH:7]3)[N:3]1[CH2:14][C:15]([OH:17])=[O:16].[Br:18]Br>C(O)(=O)C>[Br:18][C:7]1[C:8]2[C:9]3[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:14][C:15]([OH:17])=[O:16])[C:2](=[S:1])[C:10]=3[CH:11]=[CH:12][CH:13]=2
Reactant: BrBr
Reactant: O=C(O)CN1C(=S)c2cccc3cccc1c23
Solvent: CC(=O)O
Product: O=C(O)CN1C(=S)c2cccc3c(Br)ccc1c23
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a suspension of 2-thioxo-benz[cd]indole-1(2H)-acetic acid (4.2 g, 17.26 mmol, described in Example 6), in glacial acetic acid (80 mL) was added a solution of bromine (3.59 g, 22.44 mmol) in glacial acetic acid (20 mL) in two portions with mechanical stirring within one hour. After initial clearing of the suspension, a heavy precipitate was formed. More acetic acid (60 mL) was added in order to make stirring more efficient. The mixture was filtered and the precipitate was washed twice with water (150 mL), dried, crystallized from ethanol-water giving 4.7 g in two crops and recrystallized from methanol to give 3.0 g of the title compound, identical in all respects to that prepared in Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][C@@H:8]2[C@@H:12]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:11][C@@H:10]([N:18]3[CH:25]=[C:24]([F:26])[C:22](=[O:23])[NH:21][C:19]3=[O:20])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:29]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)[CH2:30][CH3:31].C(N(CC)CC)C>O1CCOCC1>[C:15]([O:14][CH2:13][C@H:12]1[O:11][C@@H:10]([N:18]2[CH:25]=[C:24]([F:26])[C:22](=[O:23])[N:21]([C:37](=[O:38])[C:36]3[CH:35]=[CH:34][C:33]([O:32][CH2:29][CH2:30][CH3:31])=[CH:41][CH:40]=3)[C:19]2=[O:20])[CH2:9][C@@H:8]1[O:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=1)(=[O:17])[CH3:16]
Reactant: CCCOc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCOc1ccc(C(=O)n2c(=O)c(F)cn([C@H]3C[C@H](OCc4ccc(Cl)cc4)[C@@H](COC(C)=O)O3)c2=O)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 35.9 %

Procedure:
To a solution of 0.30 g of 3'-O-(4-chlorobenzyl)-5'-O-acetyl-2'-deoxy-5-fluorouridine in 30 ml of dioxane were added 0.44 g of 4-n-propoxybenzoyl chloride and 0.61 ml of triethylamine, and the mixture was stirred at 70° C. for 3 hours. The insolubles were removed by filtration, and the residue was dissolved in ethyl acetate. The solution was washed with water and dried. The ethyl acetate was distilled off, and the residue was placed on a silica gel column and eluted with chloroform-petroleum ether (1:1), thereby producing 0.15 g of the title compound in a yield of 36%.
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[CH:8]=[O:9]>C1COCC1>[F:4][C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[CH3:1])[CH:10]=[C:11]([F:14])[C:12]=1[F:13]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ethereal solution (17.41 ml, 52.24 mmol, 3M) of MeMgBr was slowly added at −78° C. to a solution of 3,4,5-trifluorobenzaldehyde (6.96 g, 43.53 mmol) in THF (125 ml). The reaction mixture was stirred at room temperature for 16 h and was cooled (0° C.) and was quenched, sequentially, with excess ethyl acetate (10 ml) and water (5 ml). Excess anhydrous MgSO4 (5 g) was added and stirred for 30 minutes at room temperature. The suspension was filtered over celite and the solids were washed with ethyl acetate (2×25 ml). The combined filtrate was evaporated to obtain the product in quantitative yield (7.65 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([CH3:13])[C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Br:26][CH:27]([CH3:31])[C:28](Cl)=[O:29]>O>[Br:26][CH:27]([CH3:31])[C:28]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[C:8]([CH3:13])=[CH:9][CH:10]=[C:11]([CH3:12])[C:2]=1[CH3:1])=[O:29]
Reactant: Cc1ccc(C)c(NCC=O)c1C
Reactant: CC(Br)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(C)c(N(CC=O)C(=O)C(C)Br)c1C
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2,3,6-trimethylanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0°C and α-bromopropionyl cloride (0.11 mole) is incrementally added with stirring. After addition is is competed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-bromopropionyl-2,3,6-trimethylanilino)acetaldehyde.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][SH:11].[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:9])([S:11][CH3:10])[CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CS
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC

Procedure:
Ethyl 2-bromoisobutyrate (40.0 g, 0.205 mole), methanethiol (1.09 g, 0.0226 mole), potassium hydroxide (14.4 g, 0.226 mole,), ethyl alcohol (100 g), refluxed reaction mixture until peak for ethyl 2-bromoisobutyrate is no longer detectable by gas chromatography. Distill to purify.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.Cl[C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][N:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][N:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: OB(O)c1ccc2ccccc2c1
Product: CCOC(=O)c1ccnc(-c2ccc3ccccc3c2)c1

Procedure:
2-Naphthylboronic acid (3.50 g) and ethyl 2-chloroisonicotinate (3.77 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.[CH:23]1(O)[CH2:28][CH2:27]C[CH2:25][CH2:24]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C1C=CN=CC=1)C>[CH:1]1([O:2][C:3](=[O:22])[CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:8][N:7]=2)[CH2:27][CH2:28][CH2:23][CH2:24][CH2:25]1
Reactant: OC1CCCCC1
Reactant: COC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OC1CCCCC1
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A mixture of [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid methyl ester (prepared above, 50 mg, 0.17 mmol) and cyclohexanol (51 mg, 0.51 mmol) were slurried in dichloromethane. DMAP (17 mg, 0.14 mmol) was added, and the slurry became homogeneous and colorless. The solution was then treated with 1 M dicyclohexylcarbodiimide (190 μL, 0.19 mmol), which initiated formation of a white slurry within 5 min. After 1 h, thin layer chromatography indicated complete conversion. The reaction was quenched with 10 mL 1 M HCl(aq) and 25 mL dichloromethane. The phases were partitioned, and the aqueous phase extracted with 5 mL dichloromethane. The organic phases were combined and sequentially washed with 10 mL portions of 0.1 M HCl(aq), saturated. NaHCO3(aq) and brine. The organic layer was dried using Na2SO4, filtered and concentrated. The 101 mg of crude product was chromatographed over SiO2 (1:1 ethyl acetate:hexane) to yield 50 mg (79%) of the titled compound. ESI-MS m/z 374 (MH+), 372 (M−H−).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)#[N:9]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][CH:12]=1
Reactant: Brc1ccccn1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2ccccn2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 11 using 2-bromopyridine instead of 1-bromo-3-pentyloxybenzene and 4-cyanophenylboronic acid instead of tert-butyl N-[ 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-benzyl]carbamate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:11]1[NH:12][C:13]([CH:17]=[O:18])=[C:14]([I:16])[N:15]=1)[CH2:8][CH2:9][CH3:10].Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:34][O:33][C:31]([C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([CH2:20][N:12]2[C:13]([CH:17]=[O:18])=[C:14]([I:16])[N:15]=[C:11]2[CH2:7][CH2:8][CH2:9][CH3:10])=[CH:22][CH:23]=1)=[O:32]
Reactant: COC(=O)c1ccc(CBr)c2ccccc12
Reactant: CCCCc1nc(I)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(I)c(C=O)n1Cc1ccc(C(=O)OC)c2ccccc12
Temperature: 70 °C
Reaction time: 15 h
Yield: 85.2 %

Procedure:
A suspension of 29.53 g (0.214 mol) of powdered potassium carbonate, 60.00 g (0.214 mol) of 2-butyl-4-iodoimidazole-5-carboxaldehyde and 65.68 g (0.235 mol) of methyl 4-bromomethylnaphthalene-1-carboxylate (E. A. Dixon, A. Fischer, and F. P. Robinson, Can. J. Chem. 59, 2629 (1981)) in 600 mL of dimethylformamide was stirred for 5 hours under argon at 70° C. An additional 6.56 g (0.0235 mol) of the bromomethyl ester was added and the suspension was stirred an additional 15 hours at 70° C. The reaction mixture was poured into water and the resulting solid was collected by filtration, washed with water, and triturated several times with 250 mL of boiling methanol to give 86.8 g (85%) of a solid; mp 177.5°-179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[N:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:19][CH2:20][CH2:21]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:30][CH2:29][C:27]2[O:26][N:25]=[C:24]([C:23]([F:32])([F:31])[F:22])[N:28]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-cyclobutoxy-nicotinic acid (example CA) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 92.8%, 451.1 (M−H)−.
Reaction SMILES: ClC1C=C(C(CCO)C[NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=1Cl.CC[O:25]CC.[OH-].[Na+]>O1CCCC1.Cl.O>[OH:25][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]([NH2:11])=[O:19]
Reactant: CCOCC
Reactant: O=C(NCC(CCO)c1ccc(Cl)c(Cl)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1ccccc1O

Procedure:
N-[2-(3,4-Dichlorophenyl)-4-hydroxybutyl]benzamide. A solution of the above ether (4.0 g) in tetrahydrofuran (20 mL) and 3 N hydrochloric acid (20 mL) was stirred for 2 hours. The reaction mixture was diluted with water, neutralized with 1 N sodium hydroxide, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (95:5) as eluent, to give the hydroxy benzamide compound as a viscous oil (2.9 g); NMR: 7.63 (m,2), 7.47 (m,1), 7.37 (m,3), 7.32 (d,1, J=2.1), 7.06 (dd,1, J=2.1, 8.3), 6.46 (m,1), 3.82 (m,1), 3.69 (m,1), 3.57-3.39 (m,2), 3.12 (m,1), 2.60 (m,1), 1.97 (m,1), 1.82 (m,1); MS: m/z=338(M+1).