Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[C:25]#[C:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[C:25]#[C:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: Nc1ccc2[nH]nc(C#Cc3ccccc3)c2c1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(C#Cc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
2-Methylsulfonyl-N-(3-phenylethynyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 0.23 g of 2-methylsulfonylbenzenesulfonyl chloride is added to a solution, at a temperature in the region of 0° C. and under argon, of 0.2 g of 5-amino-3-phenylethynyl-1H-indazole in 3.5 ml of pyridine. The reaction mixture is then stirred for 1.5 hours at 0° C. and then 2 hours at a temperature in the region of 20° C., and is then diluted with 10 ml of water. After settling out, the aqueous phase is washed with 3 times 15 ml of ethyl acetate. The organic extracts are pooled, washed with 3 times 5 ml of water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 25 g of silica (particle size 20-40 μm), eluting with pure dichloromethane then successively with dichloromethane/methanol (99.5/0.5; 99/1 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. The residue is recrystallized from 5 ml of isopropanol in the presence of 3S black. The crystals are filtered through sintered glass, washed with diisopropyl ether, partially dried, and then dried under reduced pressure (3 kPa) at a temperature in the region of 50° C. for 2 hours. 66 mg of 2-methylsulfonyl-N-(3-phenylethynyl-1H-indazol-5-yl)benzenesulfonamide are obtained in the form of an off-white powder melting at 198° C. (analysis C22H17N3O4S2 % calculated C, 58.52; H, 3.79; N, 9.31; O, 14.17; S, 14.20. % found C, 58.37; H, 3.88; N, 9.11; S, 13.73).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[CH:19]4[O:23][C:22](C)([C:11]=3[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)[CH:21]=C4)[CH2:4][CH2:3]1.C1(C2C(=O)C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C=2C2C=CC=CC=2)C=CC=CC=1.Cl>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[CH:19][O:23][C:22]([CH3:21])=[C:11]3[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3ccccc3C3=C(c4ccccc42)C2(C)C=CC3O2)CC1
Agent: Cl
Agent: O=C1C(c2ccccc2)=C(c2ccccc2)C(c2ccccc2)=C1c1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1occ2c1-c1ccccc1C(=C1CCN(C)CC1)c1ccccc1-2

Procedure:
To a solution of 2.00 g. (0.00545 mole) of 1-methyl-4-(1-methyl-1,4-dihydro-1,4-epoxy-9H-tribenzo[a,c,e]cyclohepten-9-ylidene)piperidine and 2.16 g. (0.0056 mole) of tetraphenylcyclopentadienone in 60 ml. of xylene (b.p. 139°-140°) is stirred and refluxed for 20 hours. After cooling, 30 ml. of 6N hydrochloric acid is added. The precipitate that forms is removed by filtration and the solid precipitate is washed with ether and benzene. The solid is collected and made basic with 40% sodium hydroxide solution. The mixture is extracted with ether, and the ether extract is washed with water and dried over magnesium sulfate. After filtration, the ether is removed to give a crystalline residue which is recrystallized from methanol to give 1-methyl-4-(1-methyl-8H-dibenzo[a,e]furo[3,4-c]cyclohepten-8-ylidene)piperidine, m.p. 80°-86°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][CH2:10][CH2:11][CH2:12]O)=[O:8])[CH:2]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[C:28]([OH:31])(=[S:30])[CH3:29]>O1CCCC1.O>[C:28]([S:30][CH2:12][CH2:11][CH2:10][CH2:9][C:7](=[O:8])[C:3]1[CH:4]=[CH:5][CH:6]=[N:1][CH:2]=1)(=[O:31])[CH3:29]
Reactant: O=C(CCCCO)c1cccnc1
Reactant: CC(O)=S
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)SCCCCC(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
A solution of 4-hydroxybutyl 3-pyridyl ketone (89.6 g) in tetrahydrofuran (750 ml) under nitrogen at room temperature is treated with N,N-diisopropylethylamine (155.1 g). The mixture is then cooled to 0° C. and treated with methanesulphonyl chloride (63.0 g) continually during 10 minutes, maintaining the temperature at between 5° C. and 10° C., and then the mixture is stirred for 10 minutes. It is then treated with thioacetic acid (45.7 g) during 10 minutes and allowed to warm to 35° C. It is stirred for 1 hour at 35° C. and then cooled to 20° C. It is then treated with water (750 ml) during 5 minutes and the mixture is extracted twice with toluene (750 ml and 350 ml). The combined extracts are washed with water and evaporated, to give S-(4-nicotinoylbutyl) thioacetate (113.4 g), in the form of an oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:21][CH:18]1[CH2:19][CH2:20][N:15]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
A mixture of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (3.15 g, 15.8 mmol), 4-piperidinol (1.0 g, 9.88 mmol), and acetic acid (0.8 mL) in methylene chloride (30 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (3.35 g, 15.8 mmol) was added and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the residue was dissolved in methylene chloride and washed with 1N HCl. The aqueous phase was extracted with ether (3×10 mL) and adjusted to pH 9-10 with 1N NaOH. The basic aqueous mixture was extracted with methylene chloride (3×10 mL). The combined organic extracts were concentrated in vacuo to afford 1,1-dimethylethyl 4-hydroxy-1,4′-bipiperidine-1′-carboxylate (1.1 g, 39% yield). This material was used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:24][Si:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][O:28][CH2:29]Cl>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[N:7]([CH2:29][O:28][CH2:27][CH2:26][Si:25]([CH3:32])([CH3:31])[CH3:24])[C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])cc(I)c2o1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)oc2c(I)cc([N+](=O)[O-])cc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A solution of 7-iodo-5-nitro-1,3-benzoxazol-2(3H)-one (0.76 g, 2.5 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was treated with N,N-diisopropylethylamine (0.65 mL, 3.7 mmol) followed by [β-(trimethylsilyl)ethoxy]methyl chloride (0.61 mL, 3.5 mmol) dropwise and stirred at 20° C. for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 0.5 M HCl (50 mL), brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil. This material was purified by flash column chromatography to give the desired product (0.93 g, 86%) as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH2:6][N:7]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:8]1([C:16](=[O:19])[NH:17][OH:18])[CH2:14][CH:13]2[CH2:15][CH:10]([CH2:11][CH2:12]2)[O:9]1)C.C1(C)C=CC=CC=1.O.[OH-].[Na+]>ClCCl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([S:20]([N:7]([C:8]3([C:16](=[O:19])[NH:17][OH:18])[CH2:15][CH:10]4[O:9][CH:13]([CH2:12][CH2:11]4)[CH2:14]3)[CH2:6][CH2:5][C:4]([OH:3])=[O:37])(=[O:22])=[O:21])=[CH:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)CCN(C1(C(=O)NO)CC2CCC(C2)O1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(O)CCN(C1(C(=O)NO)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of (15.1 mmol) of the product from Step G in dichloromethane is concentrated by rotary evaporation with the addition of 75 mL of toluene. This solution is treated with 75 mL of water, cooled to 0° C., and treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide pellets over 10 minutes with vigorous stirring. This mixture is stirred for 15 minutes at 0° C. and warmed to ambient temperature over one hour. The aqueous phase is separated, diluted with 7.5 mL of tetrahydrofuran, cooled to 0° C., and treated with 33 mL of 6N aqueous hydrochloric acid over 20 minutes. This mixture is stirred with 75 mL of ethyl acetate at 0° C. to ambient temperature, and the ethyl acetate phase is separated and washed with water. The ethyl acetate solution was concentrated to yield the title compound.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6](N)=[CH:5][CH:4]=1.C([N:12]([CH2:15]C)CC)C.CC(C)=[O:19]>>[C:15]([NH2:12])(=[O:19])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCN(CC)CC
Reactant: CC(C)=O
Reactant: COc1ccc(N)cc1
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (3.0 g, 10.8 mmol) was dissolved in 200 mL dichloromethane and added dropwise to a solution of CSI (1.15 mL, 12.9 mmol) in 50 mL of dichloromethane at 0° C. The resulting white suspension was stirred for 1 hour and then filtered to give 2.94 g of a chlorosulfonyl urea intermediate. This intermediate (1.4 g, 3.5 mmol) was added in portions to a solution of p-anisidine (0.43 g, 3.5 mmol) in 50 mL acetone with triethylamine (1.94 mL, 13.9 mmol). The resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and 1 M HCl. The ethyl acetate layer was dried over magnesium sulfate, filtered, and concentrated to give a pale pink oily solid. Recrystallization from dichloromethane gave 0.55 g of pure benzamide, N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[(4-methoxyphenyl)amino]-sulfonyl]amino]carbonyl]amino]-. Microanalysis: C22H20F2N4O6S; calculated: C=52.17; H=3.98; N=11.06. found: C=52.20; H=4.06; N=10.98. MS: M++1=507 Da.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[F:23][C:24]([F:51])([F:50])[C:25]1[CH:26]=[C:27]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:28][N:29]1[CH2:36][CH2:35][CH2:34][O:33][C:32]2[N:37]=[CH:38][CH:39]=[C:40](I)[C:31]=2[C:30]1=[O:42]>C(OCC)(=O)C.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.O1CCOCC1>[F:23][C:24]([F:51])([F:50])[C:25]1[CH:26]=[C:27]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:28][N:29]1[CH2:36][CH2:35][CH2:34][O:33][C:32]2[N:37]=[CH:38][CH:39]=[C:40]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:31]=2[C:30]1=[O:42]
Reactant: OB(O)c1ccccc1
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C1c2c(-c3ccccc3)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 7 h
Yield: 80.5 %

Procedure:
Phenylboronic acid (417 mg), tetrakis(triphenylphosphine)palladium (132 mg), toluene (10 mL), 1,4-dioxane (5 mL), and a 2 mol/L aqueous solution of sodium carbonate (10 mL) were added to 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (1.00 g). While heated, the mixture was stirred for 7 hours under a stream of argon gas. The mixture was then diluted with ethyl acetate, was washed with a 2 mol/L aqueous solution of sodium carbonate, and was dried on anhydrous sodium sulfate. The solvent was removed and the resulting residue was recrystallized from isopropanol to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (729 mg, 80%).
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([C:24](=O)/[CH:25]=[CH:26]/[N:27]([CH3:29])C)=[CH:19][C:18]=1[CH3:31])/[C:5]([O:7][CH3:8])=[O:6].C[NH:33]O>CO>[CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([C:24]2[CH:25]=[CH:26][N:27]([CH3:29])[N:33]=2)=[CH:19][C:18]=1[CH3:31])/[C:5]([O:7][CH3:8])=[O:6]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C(=O)/C=C/N(C)C)cc1C
Reactant: CNO
Solvent: CO
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(-c2ccn(C)n2)cc1C
Yield: 73.8 %

Procedure:
(E)-methyl 3-methoxy-2-(2-((4-((E)-3-(dimethylamino)acryloyl)-2,5-dimethylphenoxy)-methyl)phenyl)acrylate (0.11 g, 0.25 mmol) obtained in Step 1 was reacted with 17 mg (1.5 eq) of methylhydroxyamine in 10 mL of methanol at room temperature for 3 hours with stirring, and then the reaction solvent was removed at a reduced pressure. The residue was stirred in water (20 mL), and the aqueous layer was extracted twice with 30 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum. Purification by chromatography afforded (E)-methyl 3-methoxy-2-(2-((2,5-dimethyl-4-(1-methyl-1H-pyrazol-3-yl)phenoxy)methyl)phenyl)acrylate as a white solid (75 mg, yield: 74%).
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[C:15]([C:10]1[CH:9]=[CH:8][C:7]2[O:6][C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[S:13][C:12]=2[CH:11]=1)(=[O:17])[CH3:16]
Reactant: c1ccc2c(c1)Oc1ccccc1S2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)Sc1ccccc1O2
Reaction time: 2 h

Procedure:
Phenoxathiin (22.9 g.) and acetyl chloride (8.8 ml) were dissolved in carbon disulphide (120 ml) and mechanically stirred while aluminium chloride (15.5 g) was added in small portions. The red mixture was stirred for 2 hr. at room temperature, then boiled under reflux on the water bath for a further 21/4 hr. The mixture was cooled and poured on to ice and hydrochloric acid, and the precipitated product filtered off, washed with water, and recrystallised once from ethanol and twice from petroleum ether (b.p. 80°-100° C.) to give the product m.p. 112° C.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:21]1([C:27]#[CH:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C1(CC#C)CCCC1>>[CH:25]1([CH2:24][C:23]#[C:22][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:26][CH2:21][CH2:27][CH2:28]1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CC1CCCCC1
Agent: C#CCC1CCCC1
Product: Nc1nc(C#CCC2CCCC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 70.3 %

Procedure:
The procedure of Example 1 was repeated except that 1.56 g (3.98 mmol) of 2-iodoadenosine was used as the starting compound and that the cyclohexylacetylene was replaced by 3-cyclopentylpropyne, whereby 1.05 g (2.8 mmol) of crystalline 2-(3-cyclopentyl-1-propynyl)adenosine was obtained (yield: 70.3%).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@H:11]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:12]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:34])[NH:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:20][CH:19]=2)[N:13]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].I[CH3:49].O>O1CCCC1>[Si:3]([O:10][C@H:11]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C@H:12]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:34])[N:25]([CH3:49])[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:20][CH:19]=2)[N:13]1[C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)NCCc3ccccn3)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCc1ccccn1)C(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
NaH (8.38 mg of a 60 wt % dispersion in mineral oil, 0.210 mmol) was added to a stirred, room temperature mixture of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-{[2-(pyridine-2-yl)ethyl]carbamoyl}benzyl)pyrrolidine-1-carboxylate (120 mg, 0.191 mmol) in tetrahydrofuran (1.9 mL), and the mixture was stirred for 30 minutes. After 30 minutes, iodomethane (0.014 mL, 0.23 mmol) was added and the mixture was stirred for 12 hours. Water was then added and the mixture was partitioned with EtOAc. The aqueous extracts were extracted with EtOAc (3×), and the combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to give the product as an orange oil that was used directly in the next step. LC-MS=644.3 (M+1)+.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[C:35]([OH:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][CH2:47][O:48][CH3:49].[I-].[K+]>CN(C)C=O.O>[F:38][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[C:35]([O:36][CH2:46][CH2:47][O:48][CH3:49])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: COCCBr
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4c(O)cccc4Cl)C3)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cccc(Cl)c1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 80 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (39 mg) and potassium carbonate (47 mg) in N,N-dimethylformamide (5 ml) are added, at room temperature, 1-bromo-2-methoxyethane (38 mg) and potassium iodide (1.1 mg). The reaction mixture is stirred at 80° C. for 3 h. Then the mixture is admixed with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-chloro-6-(2-methoxyethoxy)-phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (17 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH2:19].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:15]([Cl:14])[CH:16]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Cl)c2cccc(Br)c2n1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(Br)c2n1
Yield: 20.2 %

Procedure:
8-Bromo-4-chloro-2-methylquinoline (4.50 g, 17.5 mmole) and 3,4-dichlorobenzylamine (6.30 g, 35.8 mmole) in dimethylsulfoxide (6 mL) were stirred at 140° C. for 2 h in a microwave oven. Water was added and the mixture was decanted to obtain an oily residue. The residue was washed with ethyl acetate to give a white solid (1.40 g, 20%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:11])=[O:10])[CH2:2]1.[CH3:15][N:16]=[C:17]=[O:18]>>[CH3:15][NH:16][C:17]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[CH:7]=2)[CH2:2]1)=[O:18]
Reactant: NC(=O)c1cccc(OC2CNC2)c1
Reactant: CN=C=O
Product: CNC(=O)N1CC(Oc2cccc(C(N)=O)c2)C1

Procedure:
The compound was prepared from 3-(3-azetidinyloxy) benzamide and methylisocyanate as described in Example 6 of U.S. Pat. No. 4,226,861, m.p. 238°-240° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=2)=[CH:22][C:21]=1[Cl:33].NCCC(O)=O.CO.C(Cl)Cl>C(O)(=O)C>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29](/[CH:31]=[C:3]3/[NH:4][C:5](=[S:18])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:2]/3=[O:1])=[CH:28][CH:27]=2)=[CH:22][C:21]=1[Cl:33]
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Reactant: O=Cc1ccc(-c2ccc(Br)c(Cl)c2)s1
Agent: NCCC(=O)O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)N1C(=O)/C(=C\c2ccc(-c3ccc(Br)c(Cl)c3)s2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.044 g, 0.175 mmol) and 5-(4-bromo-3-chloro-phenyl)thiophene-2-carbaldehyde (0.050 g, 0.166 mmol) in acetic acid 5 mL is added β-alanine (1.6 mg, 0.01 r8 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.075 g, 0.141 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CDCl3/300 MHz): 9.88 (br, 1H), 8.92 (br, 1H), 7.65 (m, 2H), 7.31 (m, 8H), 6.85 (s, 1H), 5.76 (dd, J=11.1, 5.4 Hz, 1H), 3.70 (m, 2H). MS (ES−, m/z): 545.2 (M−, 100.0).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([CH2:20][NH:21][CH2:22][CH2:23][C:24]#[N:25])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C1COCC1.O>[C:24]([CH2:23][CH2:22][N:21]([CH2:20][C:18]1[S:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]3[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3][C:2]([CH3:28])([CH3:1])[CH2:7]3)[N:14]=2)=[CH:16][CH:17]=1)[C:36](=[O:38])[CH3:37])#[N:25]
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(CNCCC#N)s3)n2)CC(C)(C)N1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(CCC#N)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound of Example 86 (119 mg, 0.3 mmol) was dissolved in 5 ml THF and 0.5 ml triethylamine and 36 μl (0.33 mmol) acetic anhydride were added. This mixture was stirred at room temperature for 16 hours. Afterwards the solution was diluted with 100 ml water and extracted with EtOAc. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 103 mg (78%).