Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>O.CO>[C:1]([CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(CC#N)cccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of KCN (474 mg, 7.2 mmol) in water (1 mL) was slowly added to a solution of methyl 2-(bromomethyl)-6-nitrobenzoate (1 g, 3.6 mmol) in methanol (20 mL). This mixture was allowed to stir for 4 h at 50° C. The reaction mixture was concentrated to remove methanol, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried (Na2SO4), concentrated and purified by flash column chromatography (25% EtOAc in hexanes) to give the title compound as 0.5 g of an oily liquid (62%). 1H NMR (CDCl3, 600 MHz): δ 3.9 (s, 2H), 3.97 (s, 3H), 7.65 (t, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-:33].[Na+]>>[OH:33][C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Reactant: [OH-]
Agent: [Na+]
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1O)CC2

Procedure:
The title compound was prepared in analogy to example 189 from 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188) and 6N NaOH. White solid. MS (ESI): 472.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C@H:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([C@@H:20]([NH:19][C:15]([C@H:14]2[CH2:13][CH2:12][CH:11]3[CH:9]([CH2:10]3)[N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH3:21])=[CH:23][CH:24]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1C2CC2CC[C@@H]1C(=O)O
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCC3CC3N2C(=O)OC(C)(C)C)cc1
Yield: 27.6 %

Procedure:
The title compound (D71) (46 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (3R)-2-(tert-butoxycarbonyl)-2-azabicyclo[4.1.0]heptane-3-carboxylic acid (D22) (100 mg) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (115 mg). Reaction time: 1 h
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([O-:9])=O)[C:2]=1[C:10]([O:12]C)=O.[CH2:14]([CH2:16][NH2:17])[OH:15]>CCO>[OH:15][CH2:14][CH2:16][NH:17][C:7]([C:3]1[C:2]([C:10]([NH:1][CH2:2][CH2:10][OH:12])=[O:12])=[N:1][CH:6]=[CH:5][N:4]=1)=[O:9]
Reactant: NCCO
Reactant: COC(=O)c1nccnc1C(=O)[O-]
Solvent: CCO
Product: O=C(NCCO)c1nccnc1C(=O)NCCO
Yield: 131.1 %

Procedure:
Methyl pyrazine-2,3-dicarboxylate (2 g, 10.2 mmol) was dissolved in EtOH (3 mL). Ethanolamine (1.25 g, 20.4 mmol) was added and the mixture was heated under reflux for 6 h. After cooling the solvent was evaporated and the residue was purified by silica gel chromatography (EtOAc/MeOH, 3:1) to afford the title compound (1.7 g, 65.4%).
Reaction SMILES: [N+:1]([CH:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])([O-:3])=[O:2].O.[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][C:12]([CH:4]([N+:1]([O-:3])=[O:2])[C:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:14])=[O:13])[CH3:17]
Reactant: O=C1c2ccccc2C(=O)C1[N+](=O)[O-]
Reactant: CCO
Solvent: O
Product: CCOC(=O)C(C(=O)c1ccccc1)[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-Nitroindane-1,3-dione (20.5g; 0.107 moles) in ethanol (100 ml) was heated under reflux for 4 hours, cooled, poured into water (1 liter), allowed to stand overnight and filtered. The solid was extracted with 5% sodium bicarbonate solution (3 × 100 ml) and filtered. The insoluble solid was predominantly the Ψ-ethyl ester, 3-ethoxy-3-nitromethylphthalide, contaminated with some α-ethyl ester. Acidification of the combined sodium bicarbonate filtrates, filtration and recrystallisation from ethanol gave the α-ethyl ester, 2-ethoxycarbonyl-ω-nitroacetophenone, m.p. 81°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1([CH3:17])[NH:11][C:10]2[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:9]=2[O:8]1)[CH3:2].Cl[CH2:20][C:21]1[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=1)[O:24][CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1([CH3:17])[NH:11][C:10]2[CH:12]=[CH:13][C:14]([O:16][CH2:20][C:21]3[CH:38]=[CH:37][CH:36]=[C:23]([O:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[CH:22]=3)=[CH:15][C:9]=2[O:8]1)[CH3:2]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CCOC(=O)CCC1(C)Nc2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC1(C)Nc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of ethyl-3-(2,3-dihydro-6-hydroxy-2-methyl-benzoxazol-2-yl)propanoate, 3.1 g of 2-(3-chloromethylphenoxy)methylquinoline and 1.2 g potassium carbonate are combined in 25 ml of dimethylformamide and stirred at room temperature overnight, then at 60° C. for 4 hours. The reaction mixture is diluted with ethyl acetate and this solution washed with water, dried and concentrated. The residue is chromatographed on silica gel to give ethyl-3-(6-(3-(quinolin-2-ylmethyloxy)benzyloxy)-2,3-dihydro -2-methylbenzoxazol-2-yl)propanoate which is used, without further purification, for the next step.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[F:17]>>[F:10][C:11]1[CH:12]=[C:13]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]#[N:9])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1ccc(F)c(F)c1
Yield: 77 %

Procedure:
Prepared in 77% yield from 2-chloro-3-cyanopyridine and 3,4-difluorophenylboronic acid according to the procedure described for Example 153A. 1H NMR (DMSO-d6) δ 7.62-7.71 (m, 2H), 7.74-7.79 (m, 1H), 7.95 (ddd, J=11.7, 7.8, 2.2 Hz, 1H), 8.46 (dd, J=7.8, 1.7 Hz, 1H) 8.94 (dd, J=5.1, 1.7 Hz, 1H).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([P:16]([O:21][CH2:22][CH3:23])(=[O:20])[O:17][CH2:18][CH3:19])=[CH:12][CH:11]=1)(OCC)=O)C.[H-].[Na+].[CH:26]([C:28]1[CH:37]=[CH:36][C:35]2[C:34]([CH3:39])([CH3:38])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]=2[CH:29]=1)=O.Cl>CS(C)=O>[CH3:38][C:34]1([CH3:39])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]2[CH:29]=[C:28](/[CH:26]=[CH:9]/[C:10]3[CH:11]=[CH:12][C:13]([P:16]([O:17][CH2:18][CH3:19])(=[O:20])[O:21][CH2:22][CH3:23])=[CH:14][CH:15]=3)[CH:37]=[CH:36][C:35]1=2
Reactant: CCOP(=O)(Cc1ccc(P(=O)(OCC)OCC)cc1)OCC
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOP(=O)(OCC)c1ccc(/C=C/c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 1 h
Yield: 32.2 %

Procedure:
A solution of 22 g (53 millimoles) of diethyl 4diethylphosphonomethylbenzenephosphonate in 100 ml of dimethyl sulfoxide was added dropwise to a suspension of 1.8 g (64 millimoles) of sodium hydride in 50 ml of dry dimethyl sulfoxide at room temperature. Stirring was continued for 1 hour, after which a solution of 8.7 g (40 millimoles) of 2-formyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene in 75 ml of dimethyl sulfoxide was added dropwise. Stirring was continued for 16 hours at room temperature and the mixture was poured onto water, acidified with 2N hydrochloric acid and extracted three times with ether. The combined organic phases were washed twice with water and twice with saturated sodium chloride solution, dried over sodium sulfate and evaporated down. The residue was purified by column chromatography (silica gel; heptane/0.55 - 10% ethyl acetate) to give 5.5 g of the title compound of melting point 83°-84° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH2:10][NH:11][C@@H:12]2[C@H:16]([CH2:17][CH3:18])[CH2:15][C@H:14]([NH:19][S:20]([CH:23]3[CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH2:13]2)=[CH:6][N:5]=[C:4]2[N:26]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:27]=[CH:28][C:3]=12.CCN(C(C)C)C(C)C.[I-].[K+]>C(O)CC>[CH2:17]([C@H:16]1[C@@H:12]([N:11]2[C:2]3[C:7](=[CH:6][N:5]=[C:4]4[N:26]([S:29]([C:32]5[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[CH:27]=[CH:28][C:3]4=3)[CH2:8][CH2:9][CH2:10]2)[CH2:13][C@@H:14]([NH:19][S:20]([CH:23]2[CH2:25][CH2:24]2)(=[O:22])=[O:21])[CH2:15]1)[CH3:18]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1NCCCc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1N1CCCc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c21
Temperature: 150 °C
Yield: 26.7 %

Procedure:
A microwave vial was charged with a solution of N-((1S,3S,4R)-3-(3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.200 g, 0.345 mmol) in 1-propanol (1.70 mL). DIEA (0.180 mL, 1.04 mmol) and potassium iodide (0.057 g, 0.345 mmol) were added and the reaction mixture was heated in a Biotage® microwave at about 150° C. for about 30 min. The reaction was resubmitted to microwave heating at about 180° C. for about 1 h. The reaction was resubmitted to microwave heating at about 180° C. for about 10 h. The reaction mixture was transferred to a round bottom flask and silica gel (about 1 g) was added. The solvent was removed under reduced pressure and the resulting silica gel mixture was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to give N-((1S,3R,4S)-3-ethyl-4-(7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.050 g, 27%) as a yellow foam: LC/MS (Table 1, Method b) Rt=2.52 min; MS m/z: 543 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=O)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.C[O-].[Na+].Cl.[CH3:19][N:20]([CH3:33])[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=1>CO.O>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](/[CH:13]=[CH:31]/[C:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][N:20]([CH3:19])[CH3:33])=[CH:25][CH:26]=3)=[O:32])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)c1ccc(OCCN(C)C)cc1
Reactant: CON=C1CCc2cc(C=O)ccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CON=C1CCc2cc(/C=C/C(=O)c3ccc(OCCN(C)C)cc3)ccc21
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A solution of the product of Example 1 Step 2 (1.06 g, 5.6 mmol), sodium methoxide (0.750 g, 13.9 mmol) and 1-[4-(2-dimethylaminoethoxy) phenyl]ethanone hydrochloride (1.36 g, 5.6 mmol) (J. H. Short et al., J. Med. Chem. 1965, 8, 223) in methanol (30 ml) and water (1 ml) was heated under reflux for 5 hours. After cooling to room temperature the solid was collected, washed with cold methanol and diethyl ether and dried to give the title compound (1.74 g, 83%); MS(ES+) m/e 378 [M+H]+.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:33])[CH2:10][C:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH:34]([N:37]=[C:38]=[O:39])([CH3:36])[CH3:35]>C(Cl)(Cl)Cl>[OH:7][NH:8][C:9](=[O:33])[CH2:10][C:11]1([C:20]2[S:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][N:14]([C:38](=[O:39])[NH:37][CH:34]([CH3:36])[CH3:35])[CH2:13][CH2:12]1
Reactant: CC(C)N=C=O
Reactant: CCc1ccc(-c2ccc(C3(CC(=O)NOC4CCCCO4)CCNCCS3(=O)=O)s2)cc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(C3(CC(=O)NO)CCN(C(=O)NC(C)C)CCS3(=O)=O)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
To a mixture of N-(2-tetrahydropyranyloxy)-2-[7-(5-(4-ethylphenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (80 mg) in chloroform (3 ml) was added isopropyl isocyanate (16.6 mg) and the mixture was stirred at ambient temperature for 3 hours. The mixture was partitioned between water and chloroform. The organic layer was separated, washed with 5% citric acid water solution, water, saturated sodium bicarbonate solution and brine. To the reaction mixture were added 4N hydrogen chloride ethyl acetate solution (0.5 ml), chloroform (1 ml) and methanol (1.5 ml) and the reaction mixture was stirred at ambient temperature for 30 minutes. After evaporation of solvent, the residue was purified by HPLC (0.1% trifluoroacetic acid in 20% acetonitrile-water ˜0.1% trifluoroacetic acid in 80% acetonitrile-water) to give N-hydroxy-2-[7-(5-(4-ethylphenyl)-2-thienyl)-4-isopropylcarbamoyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (36 mg) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([S:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:7]1[CH3:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(CC(=O)O)c1
Reactant: BrCc1ccccc1
Product: Cc1c(Sc2cccc(CC(=O)O)c2)c2ccc(Cl)cc2n1Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and benzyl bromide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:24])[CH:3]=1.C(O)(=O)C>C(O)C.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:24])=[C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])[CH:6]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Yield: 93.9 %

Procedure:
Under a nitrogen atmosphere a solution of 3.0 grams (8.2 mmole) of 3-(4-chloro-2-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, and 20 mL of acetic acid in 80 mL of ethanol was stirred, and 1.8 grams (32 mmole) of iron powder was added. The reaction mixture was then heated under reflux for one hour, after which analysis by thin layer chromatography (TLC) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The concentrate was then taken up in 50 mL of aqueous 5% sodium bicarbonate solution and 100 mL of ethyl acetate. The mixture was filtered through diatomaceous earth, and the filter cake was washed with 20 mL of water and three 50 mL portions of ethyl acetate. The filtrate was placed in a separatory funnel and 100 mL of aqueous 5% sodium bicarbonate solution was added. The aqueous phase was separated and the organic phase was washed with 50 mL of aqueous saturated sodium bicarbonate solution, then with 50 mL of aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 2.6 grams of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=2[O:31][CH3:32])[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:36]1C=C(S(Cl)(=O)=O)C=C[C:41]=1Cl>>[CH2:36]([O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:13]([NH:12][S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH:14]=2)=[CH:27][CH:26]=1)[CH3:41]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)c1OC
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c(OC)c(OC)c2)cc1

Procedure:
4-[3-(3,4-Dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid, MS (ISP): m/e=523.1 (M−H), was prepared in analogy to example 31, steps A to D. Step C was performed using 3,4-dichloro-benzenesulfonyl chloride and yielded 4-[3-(3,4-dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: Br[CH:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:7]=1)[CH3:3].[NH2:20][OH:21]>CN1CCCC1=O.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[C:6]([C:5]#[C:4][CH:2]([NH:20][OH:21])[CH3:3])[CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: CC(Br)C#Cc1cccc(Oc2ccc(F)cc2)c1
Reactant: NO
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)NO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The 2-bromo-4-[3-(4-fluorophenoxy)phenyl]-3-butyne prepared in step 2 was taken up in N-methyl-2-pyrollidinone (27 kg) and 50% aqueous hydroxylamine (21 kg) was added. The reaction mixture was agitated for 2.5 hours at ambient temperature and then was diluted with distilled water (18 kg). The layers were separated and the organic phase was concentrated in vacuo to give N-[4-(3-(4-fluorophenoxy)phenyl)-3-butyn-2-yl]hydroxylamine.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[F:17])([CH3:4])([CH3:3])[CH3:2].C[Li].[CH3:22][Si](C)(C)Cl>C1COCC1.C(OCC)C>[C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:16]=[CH:15][C:11]([C:12](=[O:14])[CH3:22])=[CH:10][C:9]=1[F:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(=O)O)cc1F
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(C)(C)O[SiH2]C(C)(C)C)c(F)c1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A solution of 540 mg (1.90 mmol) 4-(tert-butyl-dimethyl-silanyloxymethyl)-3-fluoro-benzoic acid (preparation 16d) in 20 mL THF is degassed and cooled to −30° C. 3.56 mL (5.67 mmol) 1.6 M methyl-lithium solution in diethylether is added, the mixture is stirred 2 h at −30° C. and 3.12 mL (24.7 mmol) trimethyl-chloro-silane are added. The mixture is stirred 2 min and is transferred to a pH 7 buffer solution (0° C.). The aqueous phase is extracted with EtOAc and diethylether. The combined organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is purified by silica gel column chromatography with PE/EtOAc (9:1) as eluent.
Reaction SMILES: [S:1]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O:4][CH2:5][C@@:6]1([CH3:16])[CH2:10][O:9]C2(CCCCC2)[O:7]1)(=[O:3])=[O:2].CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[S:1]([C:17]1[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=1)([O:4][CH2:5][C@@:6]([OH:7])([CH3:16])[CH2:10][OH:9])(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@]2(C)COC3(CCCCC3)O2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@](C)(O)CO)cc1

Procedure:
2.22 g (6.52 mmol) of {(R)-2-methyl-1,4-dioxaspiro[4,5]dec-2-yl}methyl tosylate are repeatedly evaporated from methanol in the presence of a catalytic amount of p-toluenesulfonic acid and the residue is finally purified by chromatography over silica gel 60 (0.040-0.063 mm, 55 g) using diethyl ether/methylene chloride (1:2) as the eluent. There are obtained 829 mg (3.18 mmol, 49% of the theoretical yield) of (R)-2,3-dihydroxy-2-methylpropyl tosylate, 98% pure by gas chromatography, [α]365 =-19.9° (1% in CHCl3).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH:15]=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][Mg]Br>C1COCC1>[OH:16][CH:15]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8])[CH3:17]
Reactant: C[Mg]Br
Reactant: O=Cc1cnccc1C(=O)c1ccccc1
Solvent: C1CCOC1
Product: CC(O)c1cnccc1C(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzoyl-pyridine-3-carbaldehyde (114 mg, 0.54 mmol) in THF (3 mL) at −78° C. was added 3.0 M methylmagnesium bromide in THF (0.27 mL) and the reaction mixture was stirred for 15 min. The- reaction mixture was then quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by chromatography of silica gel with 5% methanol in dichloromethane to yield [3-(1-hydroxy-ethyl)-pyridin-4-yl]-phenyl-methanone as white crystals.
Reaction SMILES: [N:1]1([S:5]([NH:8][C:9](=[O:39])[C:10]2[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH2:18][C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][C:21]([CH2:29][O:30][Si](C(C)(C)C)(C)C)([CH2:22]5)[CH2:20]3)[CH2:26]4)=[CH:12][C:11]=2[F:38])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[N:1]1([S:5]([NH:8][C:9](=[O:39])[C:10]2[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH2:18][C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][C:21]([CH2:29][OH:30])([CH2:22]5)[CH2:20]3)[CH2:26]4)=[CH:12][C:11]=2[F:38])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)OCC12CC3CC(CC(COc4cc(F)c(C(=O)NS(=O)(=O)N5CCC5)cc4Cl)(C3)C1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC23CC4CC(CC(CO)(C4)C2)C3)cc1F

Procedure:
A solution of N-(azetidin-1-ylsulfonyl)-4-((3-(((tert-butyldimethylsilyl)oxy)-methyl)adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzamide (0.82 g, 1.36 mmol) in anhydrous tetrahydrofuran (24 mL) was treated with tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran,
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1>CN1C(=O)CCC1>[C:11]([NH:10][C:4]1[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH2:19]2)[CH:3]=1)(=[O:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CSc1nc(Cl)cc(NC(C)=O)n1
Solvent: CN1CCCC1=O
Product: CSc1nc(NC(C)=O)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Yield: 93.8 %

Procedure:
TEA (0.32 ml, 2.28 mmol) and N-[6-chloro-2-(methylthio)pyrimidin-4-yl]acetamide (Intermediate 44, 0.50 g, 2.28 mmol) were added to a solution of tert-butyl piperidin-4-ylcarbamate (0.46 g, 2.28 mmol) in NMP (2 ml) at room temperature. Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 10 minutes. The mixture was partitioned between water and EtOAc. The layers were separated and the organic layer was washed with water two more times. The organic phase was dried over magnesium sulfate and concentrated to give the title compound (816 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([N:6]2[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2)[CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[O:1]1[CH2:5][CH2:4][CH:3]([N:6]2[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)[CH2:2]1
Reactant: OC1CCN(C2CCOC2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCN(C2CCOC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To R91.1 1-tetrahydrofuran-3-ylpiperidin-4-ol (200 mg, 1.17 mmol) in dichlormethane (5 mL) is added dess-martin periodine (595 mg, 1.40 mmol) and stirred at r.t. for 5 h. The reaction mixture is filtered through ALOX/N and washed with cyclohexane/ethyl acetate 1:3. The filtrate is concentrated.