Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].[C-]#N.[K+].[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1/[CH:14]=[CH:15]/[C:16](=[O:18])[CH3:17].[CH3:19][N:20](C)C=O>O>[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[CH:14]([C:19]#[N:20])[CH2:15][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)/C=C/c1ccc(C)cc1C
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CC(=O)CC(C#N)c1ccc(C)cc1C
Yield: 48 %

Procedure:
Ammonium chloride (6.84 g, 0.126 mol) and potassium cyanide (13.68 g, 0.210 mol) were added to a mixed solution (100 mL) of a 15% aqueous solution of (E)-4-(2,4-dimethylphenyl)-3-butene-2-one (18.32 g, 0.105 mol) and N,N-dimethylformamide, and the mixture was heated under reflux for 6 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (10.13 g, 48%).
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][NH:14][C:15]([C@@H:17]1[CH2:21][C@@H:20]([F:22])[CH2:19][N:18]1[C:23](=[O:37])[NH:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([C:34](=[O:36])[NH2:35])[CH:26]=1)=[O:16])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOCC>[C:34]([N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([NH:24][C:23]([N:18]2[CH2:19][C@H:20]([F:22])[CH2:21][C@H:17]2[C:15]([NH:14][CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([OH:38])=[O:5])=[O:16])=[O:37])=[CH:26]1)(=[O:36])[NH2:35]
Reactant: CC(C)(C)OC(=O)c1ccccc1CNC(=O)[C@@H]1C[C@@H](F)CN1C(=O)Nc1cn(C(N)=O)c2ccccc12
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)n1cc(NC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2ccccc2C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-({[(2S,4R)-1-(1-carbamoyl-1H-indol-3-ylcarbamoyl)-4-fluoro-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid tert-butyl ester (prepared according to Scheme D1 using 2-aminomethyl-benzoic acid tert-butyl ester) (76 mg, 0.145 mm) in CH2Cl2 (1 mL) was added TFA (168 μl, 2.18 mmol) and the resulting solution was stirred at RT overnight. The crude mixture was concentrated to give a solid which was suspended in Et2O and filtered to give the desired material. MS (LC-MS): 468.1 [M+H]+, 490.1 [M+Na]+, 957.2 [2M+Na]+, 466.1 [M−H]−, 423.1 [M−CONH2]−, tR (HPLC conditions a): 2.64 min.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[NH2:32][S:33]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39]([NH2:41])=[O:40])(=[O:35])=[O:34]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:32][S:33]([C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=3)[C:39]([NH2:41])=[O:40])(=[O:34])=[O:35])=[O:31])=[CH:18][CH:19]=2)[N:3]=1
Reactant: NC(=O)c1cccc(S(N)(=O)=O)c1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccc(C(N)=O)c3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-(aminosulfonyl)benzamide: 1H-NMR (CDCl3) δ 8.47 (1H, s), 8.01 (2H, d, J=8.9 Hz), 7.60-7.11 (10H, m), 6.70 (1H, br.s), 6.30 (1H, br.s), 3.38-3.35 (2H, m), 2.77-2.71 (2H, m), 2.29 (3H, s), 2.17 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:12]2[C@H:17]([NH:18][C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O:26][CH3:27])=[O:25])=O)[CH2:16][CH2:15][S:14][CH2:13]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].ClC1C=CC=CN=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]2[C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O:26][CH3:27])=[O:25])=[N:18][C@@H:17]3[CH2:16][CH2:15][S:14][CH2:13][C@@H:12]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc([C@H]2CSCC[C@H]2NC(=O)c2cccc(C(=O)OC)c2)ccc1OC
Agent: Clc1ccccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)OC)c1)=N[C@@H]1CCSC[C@H]21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 3-{[(3R,4R)-3-(3-ethoxy-4-methoxyphenyl)tetrahydro-2H-thiopyran-4-yl]carbamoyl}benzoate (2.58 g; compound C11) and 2-chloropyridin (0.68 ml) in toluene (60 ml) is slowly added a solution of POCl3 (1.65 ml) in toluene (6 ml). The reaction mixture is stirred for 12 h at 100° C. The reaction mixture is allowed to come to RT and then quenched by slow addition of water (15 ml). Additional water (30 ml) is added and the pH is adjusted to about 9 by addition of 5 M aqueous solution of sodium hydroxide. The organic phase is separated and the aqueous phase is extracted with toluene (30 ml). The combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. The resulting residue is purified flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 3/1 to 1/1 (v/v)] to yield the title compound as a solid.
Reaction SMILES: CC1C=C[C:19]([C@H:22]2[C@H:27](O)[C@@H:26]([OH:29])[C@H](O)[C@@H](SC)[O:23]2)=CC=1CC1C=CC(OCCCC(O)=O)=CC=1.NC(C)(C)C(N1CCN(C)CC1)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O:82][C:83](=[O:85])[CH3:84])(=O)C>CC#N.CN(C1C=CN=CC=1)C>[CH3:19][C:22]([CH2:27][C:26]([CH2:84][C:83]([OH:82])=[O:85])=[O:29])=[O:23]
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCCC(=O)O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: CN1CCN(C(=O)C(C)(C)N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 492.2 %

Procedure:
4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)butanoic acid (39, 1.47 g, 3.2 mmol), 2-amino-2-methyl-1-(4-methylpiperazin-1-yl)propan-1-one (1.07 g, 2 HCl salt, 4.1 mmol), HATU (1.45 g, 3.8 mmol), and DIPEA (2.2 mL, 13 mmol) were combined in CH3CN (32 mL) and stirred overnight at room temperature. To the reaction were added DMAP (39 mg, 0.32 mmol), DIPEA (3.3 mL, 19 mmol), and acetic anhydride (1.5 mL, 16 mmol). The reaction was stirred for 1 hour, then quenched with saturated aqueous NaHCO3, stirred for 1 hour, and extracted twice with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (gradient 2-10% MeOH/CH2Cl2) to yield 2.27 g (94% yield) of triacetate as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=3)=[C:11]3[O:12][CH2:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])[CH:18]=3)=[C:11]3[O:12][CH2:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2OCCC3)ccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2OCCC3)ccn1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
93 mg (0.3 mmol) of 4-[2-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl]pyridin-2-amine and 46 mg (0.36 mmol, 1.2 eq) of Huenigs base are dissolved in 2 mL tetrahydrofuran. To this are added 63 mg of cyclopropanecarbonyl chloride (0.6 mmol, 2 eq) and the reaction mixture is stirred for 16 hrs at room temperature. Next, the volatile components are removed under vacuum and the crude material treated with 3 mL NH3 in methanol (7 molar). The mixture is stirred for 16 hrs at room temperature and then evaporated. The crude product is purified by preparative HPLC (Phenomenex AMA Gemini C18; 110 A; 10 μm 100×30 mm, gradient: 0-2.0 mins 80% water, 20% acetonitrile, 2.0-12.0 mins linear gradient up to 25% water, 75% acetonitrile, 12.0-16.0 mins 5% water, 95% acetonitrile, modifier 15% NH4OH in H2O, addition of the modifier at 1.0 mL/min throughout the separation). 38.2 mg (33%) of N-{4-[2-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl]pyridin-2-yl}cyclo-propanecarboxamide are obtained as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19]>>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[C:17]3[S:13][C:14](=[O:19])[NH:15][C:16]3=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc2occ(Br)c2c1
Product: O=C1NC(=O)C(=Cc2ccc3occ(Br)c3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from 3-Bromo-benzofuran-5-carbaldehyde (intermediate 58) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:31][CH:30]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Product: CS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexyl-cyclopropylmethyl-amino)-pyrimidine-4-carboxylic acid (Intermediate 13) and 4-(methylsulfonyl)aniline (Enamine), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([CH3:36])=[CH:14][C:15]=3[N:17](COCC[Si](C)(C)C)[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)(=[O:20])=[O:19])[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.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.CC(C)([O-])C.[Na+].[NH:89]1[CH2:93][CH2:92][CH2:91][CH2:90]1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl.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]>[Cl:27][C:23]1[CH:22]=[C:21]([S:18]([NH:17][C:15]2[CH:14]=[C:13]([CH3:36])[N:12]=[C:11]3[S:10][CH:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:89]5[CH2:93][CH2:92][CH2:91][CH2:90]5)[CH:3]=4)[C:16]=23)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: C1CCNC1
Reactant: Cc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(Br)c3)csc2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(N4CCCC4)c3)csc2n1
Temperature: 120 °C
Reaction time: 16 h
Yield: 26.5 %

Procedure:
To a mixture of N-[3-(3-bromophenyl)-6-methylthieno[2,3-b]pyridin-4-yl]-3-chloro-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)benzenesulfonamide (Description 54) (960 mg, 1.538 mmol), BINAP (57.5 mg, 0.092 mmol), Pd2(dba)3 (28.2 mg, 0.031 mmol) and sodium tert-butoxide (443 mg, 4.61 mmol) in toluene (10 mL) was added pyrrolidine (0.254 mL, 3.08 mmol) and the mixture heated at 120° C. for ca. 2 h. After cooling to RT, the mixture was passed through celite, washed with DCM (ca. 20 mL×5) and the filtrate concentrated. The residue was purified by normal phase chromatography, eluting with 0-50% ethyl acetate in cyclohexane to give a residue which was subsequently taken-up in DCM (5 mL) and TFA (2.37 mL, 30.8 mmol) added. The mixture was stirred at RT overnight (ca. 16 h) and was then quenched with NaHCO3 solution (ca. 50 mL) and extracted with DCM (30 mL×3). The combined organics were dried and concentrated and the residue purified by normal phase chromatography, eluting with a gradient of 0-100% ethyl acetate in cyclohexane and then further purified by MDAP (basic conditions). Final purification by normal phase chromatography, eluting with 0-100% ethyl acetate in DCM, afforded the title compound (197 mg). LCMS (A) m/z: 484 [M+1]+, Rt 1.53 min (acidic).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]#[N:21])=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>ClCCl>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]#[N:21])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCC#N)c2ccccc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCOc1ccc(N)c2ccccc12

Procedure:
To a stirred solution of (4-cyanomethoxynaphthalen-1-yl)-carbamic acid tert-butyl ester (1.13 g, 3.8 mmol) in anhydrous dichloromethane (15 ml) at room temperature is added trifluoroacetic acid (5 ml). After 4 hours the mixture is poured into ethyl acetate (100 ml) and washed with saturated sodium bicarbonate solution (150 ml). The organic layer is then dried over anhydrous sodium sulfate and evaporated to dryness to give (4-aminonaphthalen-1-yloxy)-acetonitrile as a red brown solid.
Reaction SMILES: C(OC(CCC(OC1C2C(=CC=CC=2)C=CC=1)C(O)=O)=O)(C)(C)C.[C:25]1([OH:35])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.[H-].[Na+].[CH2:38]([O:40][C:41](=[O:49])[CH:42](Br)[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41](=[O:49])[CH:42]([O:35][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:39]
Reactant: Oc1cccc2ccccc12
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: CC(C)(C)OC(=O)CCC(Oc1cccc2ccccc12)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cccc2ccccc12)C(=O)OCC
Reaction time: 0.5 h

Procedure:
4-tert.-butoxycarbonyl-2(R,S)-α-naphthoxybutyric acid: A solution of 25 g of 1-naphthol in 50 ml of DMF is slowly added dropwise to a solution of 7.6 g of sodium hydride dispersion in 300 ml of DMF. The suspension is stirred for 30 minutes and subsequently 41.5 g of bromomalonic acid diethyl ester in 50 ml of DMF are added dropwise. The reaction mixture is further stirred for 16 hours at room temperature and then concentrated by evaporation in a high vacuum. The residue is dissolved in ethyl acetate and washed with 2N sodium hydroxide solution, water and brine, dried over sodium sulphate and concentrated by evaporation. The residue is distilled at 145°-170°/2.6 Pa and yields α-naphthoxymalonic acid diethyl ester in the form of an orange-coloured oil.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl.O>CN(C)C=O>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][O:1][CH:2]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:8]=1
Reactant: CN(C)CCCl
Reactant: COC(=O)c1ccc(C(O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
4.66 g (19.23 mmol) of methyl α-hydroxy-α-phenyl-p-toluate was dissolved in 50 ml of N,N-dimethylformamide. 0.77 g (19.23 mmol) of 60% sodium hydride was added thereto and the mixture was stirred at room temperature for 1 hour. 3.10 g (28.85 mmol) of 2-dimethylaminoethyl chloride was added thereto and the mixture was heated at 80° C. for 2.5 hours. After the reaction mixture was cooled and poured into water, the obtained mixture was extracted twice with ethyl acetate and the extract was washed with brine, and dried (MgSO4). The solvent was distilled off and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=40:1 (v/v)) to obtain 0.53 g (1.69 mmol) of methyl α-(2-dimethylaminoethoxy)-α-phenyl-p-toluate as a brown oily substance. Its spectroscopic data are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl:9][CH2:10][C:11](=[O:14])[CH2:12]I>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:9][CH2:10][C:11](=[O:14])[CH2:12][O:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: O=c1ccc(Cl)c[nH]1
Reactant: O=C(CCl)CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(CCl)COc1ccc(Cl)cn1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
5-Chloro-2-pyridone (2.58 g.), silver carbonate (3.44 g.) and dry toluene (14 ml.) were stirred together under argon and heated to 65° C. for 20 minutes. A solution of 1-chloro-3-iodopropan-2-one (4 g.) in dry toluene (10 ml.) was added, and the mixture was stirred at 60°-65° C. for 3 hours, cooled, and filtered through "Hyflo" (trade mark) kieselguhr, washing the filter cake with toluene (15 ml.). The filtrate was evaporated to dryness, and the residue was purified by column chromatography on silica gel (100 g.), eluting with 10% v/v ethyl acetate in toluene. The first 130 ml. of eluate was discarded, and the next 60 ml. was collected, and evaporated to dryness to give 1-chloro-3-(5-chloropyrid-2-yloxy)propan-2-one, RF = 0.80 (50% v/v toluene in ethyl acetate).
Reaction SMILES: C[O:2][C:3]1[C:12]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br.C1(O)C=CC=CC=1>C(O)(=O)C>[OH:2][C:3]1[C:12]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OCCC2
Agent: Br
Solvent: Oc1ccccc1
Solvent: CC(=O)O
Product: Oc1cccc2c1OCCC2

Procedure:
The compound obtained in Step C (1 g; 6.09 mmol) is dissolved in glacial acetic acid (10.2 ml) and then hydrobromic acid (48% solution in water) (3.7 eq.; 47 mmol; 2.54 ml) is added dropwise. The phenol is fully deprotected after 5 hours' reflux. After removal of the solvent under reduced pressure, the dry residue is taken up in aqueous medium and then neutralised with a saturated sodium hydrogen carbonate solution to a pH of 8. Extraction with ethyl acetate yields an orange oil after drying and concentration. After purification of the latter over a silica column. AcOEt/PE (3:7), the oil is yellow in colour.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:21][C:22]1[C:27](Cl)=[N:26][C:25]([Cl:29])=[CH:24][N:23]=1)(=[O:20])=[O:19]>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:21][C:22]1[C:27]([O:9][CH2:8][C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:26][C:25]([Cl:29])=[CH:24][N:23]=1)(=[O:20])=[O:19]
Reactant: Cc1ncccc1CO
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: Cc1ncccc1COc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using (2-methyl-3-pyridinyl)methanol (0.15 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.15 g).
Reaction SMILES: [C:1](=[O:14])([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:2][CH2:3]Cl.[I-:15].[Na+]>CC(C)=O>[C:1](=[O:14])([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:2][CH2:3][I:15]
Reactant: CCCCCCCCOC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCOC(=O)OCI
Reaction time: 3 h
Yield: 72.6 %

Procedure:
To a solution of chloromethyl octyl carbonate (1.14 g, 0.005 mol) in acetone (10 ml) was added sodium iodide (2.3 g, 0.015 mol). The mixture was stirred for 3 hours, concentrated invacuo, and dissolved in dichloromethane (50 ml). This solution was washed with saturated aqueous sodium chloride, aqueous sodium thiosulfate, and saturated aqueous sodium chloride, dried (sodium sulfate) and concentrated invacuo to yield iodomethyl octyl carbonate (1.14 g).
Reaction SMILES: [Br:1][C:2]1[C:6](Br)=[CH:5][S:4][CH:3]=1.C([Li])CCC.[CH2:13]([S:15]SCC)[CH3:14].[OH-].[Na+]>O.C(OCC)C>[Br:1][C:2]1[C:6]([S:15][CH2:13][CH3:14])=[CH:5][S:4][CH:3]=1
Reactant: Brc1cscc1Br
Reactant: CCSSCC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCSc1cscc1Br
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A mixture of 9.68 g of 3,4-dibromothiophene and 80 mL of diethylether was cooled to −70° C., 27 mL of n-butyl lithium (1.63 M hexane solvent) was added over 30 minutes, and the mixture was stirred at −70° C. for 30 minutes. To the mixture was added 5.86 g of diethyl disulfide at such a rate that the internal temperature is maintained at −60° C. or less, and the mixture was stirred at −70° C. for 2 hours. The reaction mixture was heated to −35° C. and then 100 mL of water was added. After heating to room temperature, a 2 N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 3.27 g of 3-bromo-4-ethylthiothiophene.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[CH:8][NH:7][C:6]1=[O:13].[N:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[CH:8][N:7]([CH2:20][C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[C:6]1=[O:13]
Reactant: ClCc1ccncc1
Reactant: Cc1c[nH]c(=O)n(CCCCl)c1=O
Product: Cc1cn(Cc2ccncc2)c(=O)n(CCCCl)c1=O

Procedure:
substituting 3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione and pyrid-4-ylmethyl chloride gave 3-(3-chloropropyl)-5-methyl-1-pyrid-4-ylmethyl-2,4(1H,3H)-pyrimidinedione;
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:36])[C:18]([C:24]3[CH:35]=[CH:34][C:27]4[N:28]([CH3:33])[C:29](=[O:32])[N:30]([CH3:31])[C:26]=4[CH:25]=3)([OH:23])[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:37])[CH:12]=2)=[CH:6][C:5]=1[F:38].[Li+].[OH-].CO>C1COCC1>[Cl:37][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[CH:17]([CH3:36])[C:18]([C:24]1[CH:35]=[CH:34][C:27]2[N:28]([CH3:33])[C:29](=[O:32])[N:30]([CH3:31])[C:26]=2[CH:25]=1)([OH:23])[C:19]([F:21])([F:22])[F:20])[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[C:5]([F:38])[CH:6]=1
Reactant: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)n(C)c(=O)n4C)C(F)(F)F)c(Cl)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(c1ccc(Oc2ccc(C(=O)O)c(F)c2)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To 4-{3-chloro-4-[2-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-2-fluoro-benzoic acid methyl ester (400 mg) aqueous 1N LiOH (1.5 ml), MeOH (5 ml) and THF (10 ml) were added. The resulting solution was stirred for 1 h at room temperature. Volatile solvents were removed in vacuo. The residual aqueous solution was diluted with water (10 ml) and then acidified to pH 6 with 1 N aqueous HCl and extracted with EtOAc. The combined EtOAc layers were dried over Na2SO4 and concentrated to give the title compound (300 mg) as a white foam. MS (m/e)=551.2 [M+H+].