Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].[CH:24]1([C:27]2[C:28]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=2)[CH2:26][CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:21])=[O:22])[CH:13]=[CH:12][C:8]=1[C:9]([N:37]1[CH2:38][CH2:39][N:34]([C:28]2[C:27]([CH:24]3[CH2:25][CH2:26]3)=[CH:32][C:31]([CH3:33])=[CH:30][N:29]=2)[CH2:35][CH2:36]1)=[O:10]
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCS1(=O)=O
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCCS3(=O)=O)CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Bis(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (200 mg) described in Preparation Example 34, 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine (121 mg) described in Preparation Example 86, and 1-hydroxybenzotriazole 1 hydrate (79 mg) were dissolved in N,N-dimethylformamide (3 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (112 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give [2,4-bis(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone. The obtained [2,4-bis(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone (240 mg) was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.11 mL) was added, and the precipitate was collected by filtration to give the title compound (104 mg).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17](O)[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3]CC(O)=O.[OH-:29].[Na+].[OH2:31]>>[OH:29][C@@H:17]1[CH2:18][C:19]2[C@:20]([CH3:26])([CH:21]=[CH:22][C:23](=[O:25])[CH:24]=2)[C@@H:15]2[C@@H:16]1[C@H:11]1[C@:12]([CH3:28])([CH2:13][CH2:14]2)[C@@H:8]([CH:2]([CH:3]=[O:31])[CH3:1])[CH2:9][CH2:10]1
Reactant: O
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [OH-]
Agent: [Na+]
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 48 h

Procedure:
The cultivation procedure of Example 1 was repeated except that chenodeoxycholic acid was used in an amount of 1.0 g instead of 2.0 g, that sodium hydroxide was used in an amount of 0.1 g instead of 0.2 g and that the cultivation time was 1 day instead of 2 days. The resulting culture broth was adjusted to pH 9.0 with 1N-aqueous sodium hydroxide solution and centrifuged to separate the cells and the precipitate formed in the course of culture from the supernatant. The precipitate and cells were mixed with 50 ml of water and the mixture was centrifuged to separate the aqueous layer from the insoluble fraction. The insoluble fraction was mixed with 200 ml of methanol and the mixture was centrifuged to separate the cells from the methanol layer. The methanol layer was diluted with 10 ml of water and the methanol was distilled off under reduced pressure. The resulting precipitate was recovered by filtration and dried to give 0.77 g of 7α-hydroxypregna-1,4-dien-3-one-20 -carbaldehyde. Determined by high performance liquid chromatography, this product had a purity of 95.1%.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24])([O-:14])=[O:13].N1C=CC=CC=1>CC(C)=O>[C:1]([O:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(C=Cc1ccccc1)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
66.64 g (0.4 mole) of cinnamoyl chloride and 300 g of methyl ketone (hereinafter referred to as MEK) were placed in a reaction vessel to be stirred by heating at 60° C. under a nitrogen current. 73.64 g (0.4 mole) of 2,4-dinitrophenol, 50 g of pyridine, and 500 g of MEK were added dropwise to the above reaction vessel using a dropping funnel. After that, reflux stirring was conducted for approximately 20 hours under a nitrogen current. After the completion of the reaction, the precipitate was separated by filtration. The filtrate was concentrated until crystals separated out and poured into methanol. 90 g of light yellow colored needle-like crystals (2,4-dinitrophenyl cinnamate) were yielded.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10](=[O:27])[C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)[NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH3:8].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1B(O)O>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:7]([O:9][C:10](=[O:27])[C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:30]2[CH:29]=[CH:28][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH:21]=1)[NH:12][C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])[CH3:8]
Reactant: CCOC(=O)[C@H](Cc1cccc(O)c1)NC(=O)C(F)(F)F
Reactant: OB(O)c1ccc2ccccc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cccc(Oc2ccc3ccccc3c2)c1)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Pyridine (0.22 ml, 2.72 mmol) was added to a suspension of N-trifluoroacetyl-3-hydroxy-L-phenylalanine ethyl ester (159 mg, 0.521 mmol), 2-naphthaleneboronic acid (186 mg, 1.08 mmol), molecular sieves 4A powder (204 mg) and copper (II) acetate (153 mg, 0.842 mmol) in methylene chloride (7 ml) and the mixture was stirred under air atmosphere (without argon) at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate (30 ml) and the insoluble materials were filtered off (celite (Trade mark)) and washed with ethyl acetate. The filtrate and washings were combined and washed with 10% hydrochloric acid and brine in turn and then dried. The solvent was distilled off under reduced pressure. The resultant residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=10) to give N-trifluoroacetyl-3-(2-naphthyloxy)-L-phenylalanine ethyl ester (200 mg, 89%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[I:12]Cl>C(Cl)Cl>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:12])[CH:9]=1)=[O:4]
Reactant: ClI
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl

Procedure:
At r.t. to a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone (10.0 g, 47.1 mmol) in methylene chloride (80 mL) was added dropwise a solution of iodine monochloride (8.406 g, 51.77 mmol) in methylene chloride (40 mL) with stirring. After completion of addition the mixture was stirred at r.t. for additional 2 h. The mixture was diluted with methylene chloride, quenched with saturated Na2S2O3 solution. After separation the organic solution was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the crude product which was directly used in the next reaction without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][N:2]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])C.[Cl:34][C:35]1[CH:43]=[C:42]2[C:38]([C:39]([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[CH:53]=3)([CH:45]3CCCNC3)[C:40](=[O:44])[NH:41]2)=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.ClCCl>[Cl:34][C:35]1[CH:43]=[C:42]2[C:38]([C:39]([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[CH:53]=3)([CH:45]3[CH2:31][CH2:30][N:29]([C:7]([C:4]4[CH:5]=[CH:6][N:1]=[N:2][CH:3]=4)=[O:9])[CH2:32][CH2:33]3)[C:40](=[O:44])[NH:41]2)=[CH:37][CH:36]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccnnc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1ccnnc1)N1CCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of pyridazine-4-carboxylic acid (0.37 g, 3 mmol) (Aldrich) in toluene (15 mL) was added diphenylphosphoryl azide (0.958 g, 3.5 mmol) (Aldrich), followed by the addition of triethylamine (0.35 g, 3.6 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes and the mixture became clear. Then the mixture was heated at 80° C. for 2 hours. After cooling to room temperature, the crude (0.8 mL, 0.16 mmol) was added to a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL), followed by the addition of triethylamine (46 ul, 0.32 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-{1-(pyridazine-4-carbonyl)-piperidin-4-yl}-1,3-dihydro-indol-2-one as fraction one and a white solid. (Yield 32 mg, 50%).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[N:22]1.O1CC(C2C3SC(NC(C4SC(C)=CC=4)=O)=NC=3C(OC)=CC=2)COCC1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:26]([C:24]4[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=4)=[O:27])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: Cn1cc(C(=O)O)cn1
Agent: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3cnn(C)c3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for 5-methyl-thiophene-2-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide and obtained as white solid. MS: m/e=389(M+H+).
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:15]1([C@H:21]2CCC[C@H:22]2[NH2:26])[CH2:20][CH2:19][CH2:18]CC1>>[ClH:1].[CH:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[N:13]=[C:22]2[CH2:21][CH2:15][CH2:20][CH2:19][CH2:18][NH:26]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Reactant: N[C@@H]1CCC[C@@H]1C1CCCCC1
Agent: Cl
Product: C1CCNC(=N[C@@H]2CCC[C@@H]2C2CCCCC2)CC1

Procedure:
By the procedure of Example 23, only employing a reaction time of 29 days and substituting for cis-2-phenylcyclopentylamine hydrochloride an appropriate amount of cis-2-cyclohexylcyclopentylamine hydrochloride, the desired product is obtained, M.P. 179°-180° C.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([P:11]([CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18])([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)C.[OH-].[Li+]>CO.O>[CH2:20]([O:19][P:17]([CH2:16][P:11]([O:13][CH2:14][CH3:15])([C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:25])=[O:3])=[CH:10][CH:9]=1)=[O:12])([O:22][CH2:23][CH3:24])=[O:18])[CH3:21]
Reactant: CCOC(=O)c1ccc(P(=O)(CP(=O)(OCC)OCC)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOP(=O)(CP(=O)(OCC)c1ccc(C(=O)O)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[(Diethoxyphosphorylmethyl)-ethoxyphosphinoyl]-benzoic acid ethyl ester (3c) (1 g, 2.55 mmol) in methanol (25 mL) was slowly added lithium hydroxide (monohydrate, 0.11 g, 2.55 mmol) in water (25 mL). The resulting reaction mixture was stirred, at room temperature for 4 hours. The reaction mixture was concentrated to remove methanol and diluted with brine, then extracted with EtOAc (3—100 mL) until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were dried over Na2SO4 and concentrated on rotary evaporator. The desired product (3d) was purified by silica gel flash chromatography as a pale yellow oil (0.91 g). 1H NMR (300 MHz, DMSO-d6) δ (ppm)): 1.13 (m, 9H), 2.94 (t, J=18.2 Hz, 2H), 3.85 (m, 6H), 7.88 (m, 2H), 8.02 (m, 2H), 12.60 (bs, 1H), 31P NMR (121 MHz, DMSO-d6) δ, 37.59 and 24.59
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:8]=[C:7]([OH:18])[C:4]=1[CH:5]=[O:6])[CH3:2].CCN(CC)CC.[O:26](S(C(F)(F)F)(=O)=O)[S:27]([C:30]([F:33])([F:32])[F:31])(=O)=[O:28]>ClCCl.O>[CH2:1]([C:3]1[C:4]([CH:5]=[O:6])=[C:7]([O:18][S:27]([C:30]([F:33])([F:32])[F:31])(=[O:28])=[O:26])[CH:8]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:10]=1)[CH3:2]
Reactant: CCc1cc(OC2CCCCO2)cc(O)c1C=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(OC2CCCCO2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 2-ethyl-6-hydroxy-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (1.56 g, 6.24 mmol) and Et3N (2.61 mL, 18.72 mmol) in dichloromethane (20 mL) was slowly added Tf2O (2.10 mL, 12.84 mmol) at −78° C. The mixture was stirred at −78° C. for 1 hour. The mixture was diluted with H2O and extracted with dichloromethane. The organic extracts were washed with brine, dried and concentrated in vacuo. The residue was dissolved in Hexane-EtOAc(4:1), filtered through a plug of silica gel and filtrate was concentrated to give trifluoro-methanesulfonic acid 3-ethyl-2-formyl-5-(tetrahydro-pyran-2-yloxy)-phenyl ester (2.06 g, quant.). 1H NMR (400 MHz, CDCl3δ 12.39 (s, 1H), 10.08 (s, 1H), 6.98 (s, 1H), 6.90 (s, 1H), 5.50 (s, 1H), 3.80 (m, 1H), 3.66 (m, 1H), 3.07 (m, 2H), 2.00-1.50 (m, 6H), 1.26 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(O)C>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Br)c1
Reactant: C[Si](C)(C)C#Cc1cc2c(Cl)c(C#N)cnc2cn1
Solvent: CCO
Product: C[Si](C)(C)C#Cc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1
Temperature: 25 °C

Procedure:
To 626 mg of 4-chloro-6-trimethylsilanylethynyl-[1.7]naphthyridine-3-carbonitrile in 20 mL of absolute ethanol was added 1 mL of 3-bromoaniline. After refluxing the reaction under an inert atmosphere for 18 hours, the reaction mixture was cooled to ambient temperature, concentrated to 5 mL, diluted with ether, and the product filtered and washed with ether. Drying in vacuo yielded 500 mg of 4-(3-bromo-phenylamino)-6-trimethylsilanylethynyl-[1.7]naphthyridine-3-carbonitrile as an off-white solid: melting point 125° C. (sublimed); mass spectrum (m/e): M+H 421.1, 423.2.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O>CN(C=O)C>[O:3]=[C:2]1[NH:1][CH2:7][C:5](=[O:6])[N:4]1[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1C(=O)CNC1=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of hydantoin (10.0 g, 0.10 mol) in DMF (100 ml) at 60° C. were added potassium carbonate (20.7 g, 0.15 mol) and benzyl bromoacetate (18.9 ml, 0.12 mol). After stirring the mixture at 60° C. overnight, the reaction mixture was poured into water (250 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with 5% aqueous citric acid solution and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crystalline residue was washed with diethyl ether, and dried to give phenylmethyl 2-(2,5-dioxoimidazolidinyl)acetate (14.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1([CH2:41][N:42]2[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH:35]1([CH2:41][N:42]2[CH2:46][CH2:45][CH:44]([NH:47][C:27]([NH:20][C:19]3[CH:21]=[CH:22][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)=[CH:17][CH:18]=3)=[O:33])[CH2:43]2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: NC1CCN(CC2CCCCC2)C1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NC4CCN(CC5CCCCC5)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) to prepare a solution. Triphosgene (110 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 1-(Cyclohexylmethyl)-3-pyrrolidinamine (74 mg) was then added thereto, and the mixture was stirred at room temperature for 3 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (94 mg, yield 55%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11](N)=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.ClC1C=C(CC(=O)C)C=CC=1[S:26]([NH2:29])(=[O:28])=[O:27].NC1C=CC(CC(=O)C)=CC=1Cl>>[Cl:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)c(Cl)c1
Reactant: Cc1nc(Cl)sc1-c1ccc(N)cc1
Agent: CC(=O)Cc1ccc(N)c(Cl)c1
Product: Cc1nc(Cl)sc1-c1ccc(S(N)(=O)=O)cc1

Procedure:
Starting from 4-(2-chloro-4-methyl-thiazol-5-yl)-phenylamine (25c) and following the two step process described for the preparation of 2-chloro-4-(2-oxo-propyl)-benzenesulfonamide (Example 23c) from 1-(4-amino-3-chloro-phenyl)-propan-2-one (Example 23a) gave the title compound.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=CN=[CH:4]1)=[O:2].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:30]=C(N)C=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CNC>CN1CCCC1=O.C1COCC1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[N:30]=[C:12]([NH:8][C:1](=[O:2])[N:3]([CH3:4])[CH3:7])[CH:11]=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(-n2nc(N)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(NC(=O)N(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Carbonyldiimidazole (1.26 g) was added to a solution of 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-amino-1H-pyrazole (2.4 g) in 1-methyl-2-pyrrolidinone (22 ml). After stirring at ambient temperature for 2 hour, 2M solution of dimethylamine in THF (7.4 ml) was added and the mixture was stirred ambient temperature for 2 hour. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=80% to give N′-[5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea (2.35 g) as amorphous powder.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([NH:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH2:11][Br:12])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)NCc1sccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)NCc1sccc1CBr

Procedure:
N-Acetyl-2-aminomethyl-3-methylthiophene is dissolved in carbon tetrachloride and treated with an equimolar amount of N-bromosuccinimide and a catalytic amount of dibenzoyl peroxide. The mixture is heated to reflux for 3 hours while irradiating with a 250 watt light. The mixture is cooled and the precipitated succinimide removed by filtration. The filtrate is washed with saturated sodium bisulphite solution, dried over magnesium sulfate and evaporated to yield the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]([CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([NH:9][CH:10]([CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(N)C1CCOCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(NCc1ccccc1)C1CCOCC1

Procedure:
0.53 ml (4.5 mmol) benzylbromide, 0.85 g (4.5 mmol) ethyl (rac)-amino-(tetrahydropyran-4-yl)-acetate and 1.9 g (13.7 mmol) potassium carbonate in 10 mL DMF were stirred for 2 h at 100° C. After cooling the mixture was mixed with water and extracted three times with ethyl acetate. The combined organic phases were extracted with saturated, aqueous saline solution, three times with 0.5 M hydrochloric acid and once more with saturated saline solution. The combined aqueous phases were adjusted to pH 9 with conc. aqueous ammonia solution and extracted three times with dichloromethane. The combined organic phases were washed with saturated saline solution, dried and concentrated by rotary evaporation.