Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:38][C:39]3[CH:44]=[C:43]([CH3:45])[C:42]([OH:46])=[C:41]([CH3:47])[CH:40]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1.O[CH2:53][C:54]([N:56]([CH3:58])[CH3:57])=[O:55]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:38][C:39]3[CH:44]=[C:43]([CH3:45])[C:42]([OH:46])=[C:41]([CH3:47])[CH:40]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]([O:37][CH2:53][C:54](=[O:55])[N:56]([CH3:58])[CH3:57])=[O:36])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1
Reactant: CN(C)C(=O)CO
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CCC(=O)O)CC3)CC2)cc(C)c1O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CCC(=O)OCC(=O)N(C)C)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 1i from 100 mg (0.14 mmol) (R)-2-[1′-(2-carboxy-ethyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 16 mg (0.16 mmol) 2-hydroxy-N,N-dimethyl-acetamide.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:4]([NH2:18])[S:3]1.[CH3:19]N>CO.O>[CH3:1][CH:2]1[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)=[C:4]([NH:18][CH3:19])[S:3]1
Reactant: CC1SC(N)=C(c2cccc(C(F)(F)F)c2)C1=O
Reactant: CN
Solvent: CO
Solvent: O
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(C)S1

Procedure:
In this example a mixture containing 5.46 g of 2-methyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrothiophene; 6.2 g of methyl amine; 9.30 g of water in 20 ml of methanol was placed in a sealed pressure vessel (steel bomb) and heated for 18 hours at 105° C.; then 18 hours at 120° C.; and then 18 hours at 115° C. The mixture was diluted with water and extracted three times with dichloroethane. The extracts were combined and then washed with water, dried over magnesium sulfate and then evaporated affording the title compound as an impure oil residue which was then purified by chromatography over silica gel eluting with methanol:chloroform.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[Br:14]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O.OS(O)(=O)=O>[Br:14][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][C:2]([F:12])([F:13])[F:1])[CH:8]=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of 4-trifluoromethoxybenzaldehyde (150 g, 0.79 mol) in a mixture of TFA (400 mL) and H2SO4 (80 mL) was added at 40–45° C. N-bromosuccinimide (281 g, 1.579 mol) in equal portion over 2 hours. The reaction mixture was stirred at 40–45° C. overnight, poured into ice-water and extracted with CH2Cl2. The organic layer was washed with water then treated with saturated NaHCO3 (800 mL) for 30 minutes. The layers were separated and the organic layer further washed with water and brine, dried over MgSO4, filtered-and evaporated. The residue was triturated with hexane and filtered. After evaporation of the solvent, the residue was distilled to give 3-bromo-4-trifluoromethoxybenzaldehyde (150.2 g, 60° C., 0.3 mm/Hg, 70%). 1H NMR (300 MHz; CDCl3): δ 7.49 (dd, J1=1.8 Hz and J2=8.7 Hz, 1H), 7.88 (dd, J1=2.1 Hz and j2=8.4 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 9.97 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br.[OH2:18]>CS(C)=O>[C:3]1([C:2]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[O:18])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cc1ccccc1)c1cccnc1
Reactant: O
Agent: Br
Agent: Cl
Solvent: CS(C)=O
Product: O=C(C(=O)c1cccnc1)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
23.4 g (0.1 mol) of benzyl-(3-pyridyl)-ketone-hydrochloride are taken up in 180 ml of dimethyl sulphoxide and the solution is treated with 20 ml of 48% hydrobromic acid. The reaction mixture is stirred for 18 hours at 80° - 85°C and subsequently poured on a mixture of 800 g of ice and 1000 ml of water. The yellow emulsion is extracted with 2 × 200 ml of ethyl acetate. The two organic phases are combined, washed with water and dried over sodium sulphate. The red solution is concentrated in a rotary evaporator until a residual oil is left which is distilled in a bulb tube at 140° - 150°C/0.1 Torr (m.p. 56° - 57°C).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[S:13]([OH:23])(=[O:22])([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14]>C(O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:21][C:18]1[CH:19]=[CH:20][C:15]([S:13]([OH:23])(=[O:14])=[O:22])=[CH:16][CH:17]=1
Reactant: Clc1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=S(=O)(O)c1ccc(Nc2ncnc3ccc(Cl)cc23)cc1
Yield: 91.3 %

Procedure:
4,6-Dichloroquinazoline (5.9 g, 0.03 mole) was added portionwise to sulphanilic acid (5.2 g, 0.03 mole) in 50% aqueous ethanol (200 ml) at 90° C. with stirring. The mixture was refluxed for 2 hours, cooled and filtered. The solid was washed with 50% aqueous ethanol and dried in an oven to give the title compound (9.2 g) as the hemihydrate m.p. greater than 300° C.
Reaction SMILES: O([C@:9]([C@@H:21]([CH:23]([O:25][Si](C(C)(C)C)(C)C)O)[OH:22])([OH:20])[C:10]([F:19])([F:18])[C:11]([O:13]S(C)(=O)=O)=O)[Si](C(C)(C)C)(C)C.C[Si]([N:37]([Si](C)(C)C)[C:38]1[C:43]([I:44])=[CH:42][N:41]([Si](C)(C)C)[C:40](=[O:49])[N:39]=1)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.CO>ClCCCl>[NH2:37][C:38]1[C:43]([I:44])=[CH:42][N:41]([C:11]([C:10]([F:18])([F:19])[C@@H:9]([C@@H:21]([CH2:23][OH:25])[OH:22])[OH:20])=[O:13])[C:40](=[O:49])[N:39]=1
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)OS(C)(=O)=O
Reactant: C[Si](C)(C)N(c1nc(=O)n([Si](C)(C)C)cc1I)[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CO
Solvent: ClCCCl
Product: Nc1nc(=O)n(C(=O)C(F)(F)[C@H](O)[C@H](O)CO)cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.8 %

Procedure:
To 1.99 g (0.0042 mol) of 3,5-bis(t-butyldimethylsiloxy)-1-methanesulfonyloxy-2-desoxy-2,2-difluororibose in 35 ml of dry 1,2-dichloroethane was added 2.08 g (0.0046 mol) of tris-trimethylsilyl-5-iodocytosine followed by 1.11 g (0.005 mol) of trifluoromethanesulfonyloxytrimethylsilane. The reaction mixture was refluxed for about 16 hours under a nitrogen atmosphere and cooled to room temperature. Five milliliters of methanol were added to the reaction mixture and the mixture was stirred for an additional 30 minutes. The mixture was filtered and the precipitated solid was collected by filtration. The filtrate was evaporated to dryness under reduced pressure, and the resulting residue was dissolved in 20 ml of dichloromethane saturated with anhydrous hydrogen bromide. This mixture was stirred for about 3 hours. The volatiles were removed in vacuo at 45° C. The residue was dissolved in 15 ml of water, neutralized to pH 7-8 with 10% sodium bicarbonate, and the resulting solution was washed once with 10 ml of ethyl acetate. The aqueous layer was chromatographed on a Whatman Prep ODS-3 reverse phase column in 2.0 ml portions using water/methanol (9:1, v:v) to afford 30 mg of 1-(4-amino-5-iodo-2-oxo-1H-pyrimidin-1-yl)-2-desoxy-2,2-difluororibose.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5]Cl.[C:11]([NH:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:12].[O-]CC.[Na+]>C(O)C>[C:11]([NH:14][C:15]([CH2:5][C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([CH3:1])[CH:3]=1)([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:12]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Cc1ccc(CCl)cc1C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(C)c(C)c1)(NC(C)=O)C(=O)OCC
Yield: 53.4 %

Procedure:
3,4-Dimethylbenzyl chloride (10.2 g) and diethyl acetamidomalonate (14.3 g) were added successively into a solution of sodium ethoxide (4.94 g) in ethanol. The mixture was stirred under reflux for 2 hours and filtered through Celite®. The filtrate was concentrated under reduced pressure to give crystals which were collected by filtration and washed with isopropyl ether to give colorless crystals of diethyl 2-acetylamino-2-(3,4-dimethylbenzyl)malonate (11.8 g).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](I)=[N:12][CH:13]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>O1CCOCC1.CO>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[N:12][CH:13]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Brc1ccc(I)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Clc1ccc(-c2ccc(Br)cn2)cc1
Temperature: 110 °C

Procedure:
Under an N2 atmosphere 11 mL 2 M Na2CO3 solution and 240 mg (0.21 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 3.00 g (10.6 mmol) 5-bromo-2-iodo-pyridine and 3.37 g (21.1 mmol) 4-chlorophenyl-boric acid in 60 mL 1,4-dioxane and 15 mL MeOH and the reaction mixture is heated to 110° C. for 3 h. The mixture is evaporated down i. vac., the residue is combined with 50 mL water, 10 mL 3% NH3 solution and 150 mL EtOAc, the organic phase is separated off and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:5]2.[CH3:19][N:20](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[O:12]=[C:7]1[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]#[N:20])[CH:3]=2)[NH:8]1
Reactant: O=C1Nc2ccc(Br)cc2CN1C1CCNCC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)CN(C1CCNCC1)C(=O)N2
Temperature: 90 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
6-Bromo-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (0.16 g, 0.52 mmol), zinc cyanide (37 mg, 0.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) were combined in dimethylformamide (4 mL). The reaction flask was connected to high vacuum and degassed (3×) by a freeze-thawing method, before being heated at 90° C. with stirring under nitrogen for 1 h. After cooling to room temperature, the solution was evaporated in vacuo and the crude mixture purified by preparative HPLC to afford 50 mg (38%) of the desired nitrile. 1H-NMR (CD3OD) δ 1.99 (m, 2H), 2.08-2.23 (m, 2H), 3.15 (m, 2H), 3.50 (bs, 1H), 3.55 (bs, 1H), 4.40 (m, 1H), 4.47 (s, 2H), 6.93 (d, J=8.1, 1H), 4.10 (m, 2H). Mass spec.: 257.13 (MH)+.
Reaction SMILES: Cl.N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27].C(O)C.C>CO>[ClH:23].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:27][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: Cc1ccc(N)cc1Cl
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1cc(Nc2ccc(C)c(Cl)c2)c2c(ccc3nc[nH]c32)n1
Reaction time: 8 h

Procedure:
A 500 ml., 3-neck, r.b. flask fitted with stirrer, condenser, and thermometer was charged with a mixture of the compound of Example I, C. (21.7 g., 0.1 mole), 3-chloro-4-methylaniline (14.2 g., 0.1 mole) and ethanol (300 ml.). The mixture was heated at reflux, while stirring, overnight. The near solution was concentrated to dryness by rotary evaporator and the residue was collected and dried to yield 35 g. (97.5%), m.p. 352°-364°C (dec). A 10 g. sample was dissolved in methanol (200 ml.), treated with charcoal and filtered while hot. Ether (ca 750 ml.) was added until the filtrate remained turbid and was then chilled. The crystals were collected by filtration and dried to yield 3.4 g. yellow crystals, m.p. 362°-370°C (dec). After two recrystallizations a m.p. 368°-372°C (dec) was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)=[O:6].[NH2:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CS(C)=O>[CH3:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:22]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:17])[CH:23]=3)=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: CNC(=O)N1CCc2cc(O)ccc21
Reactant: Nc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNC(=O)N1CCc2cc(Oc3ccnc(N)c3)ccc21
Temperature: 160 °C
Reaction time: 12 h
Yield: 4.6 %

Procedure:
Sodium hydride (202 mg, 3.89 mmol, 60% in oil) was suspended in dimethyl sulfoxide (5.0 ml), then 5-hydroxy-2,3-dihydro-1H-indole-1-carboxylic acid methylamide (971 mg, 5.06 mmol) and 2-amino-4-chloropyridine (500 mg, 3.89 mmol) were added at room temperature under nitrogen atmosphere, and the reaction mixture was heated and stirred at 160° C. for 12 hours under nitrogen atmosphere. After naturally cooled down to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, was dried over anhydrous magnesium sulfate, and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300; eluent: ethyl acetate, ethyl acetate:methanol=85:10 in this order). The fractions containing the desired compound were concentrated, and the residue was further purified by silica gel column chromatography (Fuji Silysia NH, eluent; from ethyl acetate to ethyl acetate:methanol=90:10). The obtained crystals were suspended in diethyl ether:acetone=3:1, filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (51 mg, 0.18 mmol, 4.6%) as pale green crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[N:4][CH:3]=1.[C:16]([O:20][C:21](=[O:29])[NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:26]2[CH2:25][CH2:24][CH:23]([NH:22][C:21](=[O:29])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:28][CH2:27]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2ncc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 18.8 %

Procedure:
To a solution of 1.66 g of (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde in 42 mL of chloroform, 1.61 g of tert-butyl(piperidin-4-yl)carbamate and 0.48 g of acetic acid were added, and the mixture was stirred at room temperature for 7.5 hours. To the reaction mixture, 2.56 g of sodium triacetoxyborohydride was added, and the mixture was stirred for 10 hours. Thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol was added to the resultant residue, and the solid was filtered off to obtain 0.59 g of tert-butyl (1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [Br:1]Br.[Cl:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6]>C(O)(=O)C>[Br:1][C:12]1[CH:13]=[C:8]([S:5]([CH2:4][Cl:3])(=[O:6])=[O:7])[CH:9]=[CH:10][C:11]=1[OH:14]
Reactant: BrBr
Reactant: O=S(=O)(CCl)c1ccc(O)cc1
Solvent: CC(=O)O
Product: O=S(=O)(CCl)c1ccc(O)c(Br)c1
Temperature: 45 °C
Yield: 64.8 %

Procedure:
160 g (1 mole) of bromine were added dropwise at room temperature to a solution of 206.5 g (1 mole) of 4-chloromethylsulfonylphenol in 500 ml of glacial acetic acid; the mixture was stirred for a further hour at 45° C and, when it has cooled, was poured onto 1.5 l of ice-water. The product which had precipitated was filtered off and recrystallized from toluene. 185 g (65% of theory) of 2-bromo-4-chloromethylsulfonylphenol were thus obtained as a colorless powder of melting point 158°-160° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH2:5][NH:6][C:7]([C:9]1[C:14]([O:15]CC2C=CC=CC=2)=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([C:43](=[O:45])[CH3:44])=[CH:39][CH:38]=4)=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[N:10]=1)=[O:8])[CH3:2]>C(OCC)(=O)C.ClCCl.[Pd]>[CH2:1]([O:3][C:4](=[O:46])[CH2:5][NH:6][C:7]([C:9]1[C:14]([OH:15])=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:38]=[CH:39][C:40]([CH:43]([OH:45])[CH3:44])=[CH:41][CH:42]=4)=[CH:35][CH:36]=3)[CH2:29][CH2:30]2)[N:10]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(C(C)=O)cc4)cc3)CC2)nc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(C(C)O)cc4)cc3)CC2)nc(C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Ethyl({[2-{[1-(4′-acetylbiphenyl-4-yl)piperidin-4-yl]methyl}-5-(benzyloxy)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.67 g, 1.1 mmol) was dissolved in a mixed solvent of ethyl acetate (35 mL) and dichloromethane (35 mL), and 10% palladium-activated carbon (0.65 g) was added, followed by stirring at room temperature for 8 hours under a hydrogen atmosphere. After the reaction solution was filtered with celite, the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: dichloromethane/ethyl acetate), and a fraction corresponding to the Rf value=0.27 (dichloromethane/ethyl acetate=1/3) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.44 g, 0.82 mmol) as a white solid (yield 77%).
Reaction SMILES: [Cl:1][C:2]([Cl:25])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)O)[C:3]([O:5][CH3:6])=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:25][C:2]([Cl:1])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)(Cl)CCCCCCCCCC(O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(Cl)(Cl)CCCCCCCCC=Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
Methyl 2,2-dichloro-12-(4-chlorophenyl)-12-hydroxydodecanoate (8.89 g, 21.91 mmol) was dissolved in 300 ml of toluene. The solution was added with p-toluenesulfonic acid monohydrate (1.67 g, 8.78 mmol), and stirred at 80° C. for 4 hours. The reaction mixture was washed with 200 mL of water and 10 ml of aqueous saturated sodium hydrogencarbonate. The aqueous layer was further extracted with 100 mL of ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The extracts were purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). The solvent was evaporated under reduced pressure to obtain the desired compound (8.38 g, yield 97.6%) as yellow oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[C:29]([OH:28])([CH3:34])[CH3:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CC(C)(O)C(=O)O
Agent: Cl
Product: CC(C)(O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (11.2 mg, 38.3%), MS (ISP) m/z=418.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2-hydroxy-2-methylpropanoic acid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1>>[Cl:9][C:10]1[N:15]=[C:14]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][N:11]=1
Reactant: BrCc1ccccc1
Reactant: Clc1ccnc(Cl)n1
Product: Clc1nccc(Cc2ccccc2)n1

Procedure:
The title compound (quantitiative yield) was prepared from benzyl bromide (1.71 g, 1.19 ml, 10 mmol) and 2,4-dichloropyrimidine (1.49 g, 10 mmol) in a similar manner to Intermediate 2, and was used without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>>[OH:10][CH2:9][CH2:8][N:6]1[CH:7]=[C:2]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)[CH:3]=[CH:4][C:5]1=[O:11]
Reactant: O=c1ccc(Br)cn1CCO
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1ccc(-c2cccs2)cn1CCO
Reaction time: 0.33 h

Procedure:
To a microwave vial with 5-bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one (0.400 g, 2 mmol), 2-thiopheneboronic acid (0.800 g, 6 mmol), Potassium Carbonate (2 mL, 4 mmol) and 1,4-Dioxane (2.5 mL, 29 mmol) was added Palladium-Fibrecat. The vial was equipped with a stir bar and capped. The vial was placed into the CEM microwave for 20 minutes at 140° C., while 50 Watts of energy was supplied via Powermax. The progress of the reaction was monitored by LC/MS, which showed mostly desired product in the mixture. The mixture was diluted with CH2Cl2 (3 mL) and Water (2 mL). The organic layer was extracted with 3:1 CH2Cl2/MeOH (3×16 mL). Combined organics, dried over Sodium sulfate, filtered and concentrated in-vacuo. The crude was recrystallized from 5:1 CH2Cl2/MeOH and Hexanes to give the desired product as a light-yellow crystalline solid (0.280 g, 69% yield). MS (ESI pos. ion) m/z (MH+): 222. Calc'd exact mass for C11H11NO2S: 221. 1H NMR (300 MHz, CDCl3): 7.60 (s, 3H), 7.06 (s, 3H), 4.16 (s, 2H), 3.98 (s, 2H).