Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=C[NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].Cl.[C:17]([C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2([NH2:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C([N:37](CC)CC)C>C(O)CCC>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:29]2[CH2:30][CH2:31][C:26]([NH2:32])([CH2:25][C:24]3[CH:33]=[CH:34][C:21]([C:17]([CH3:20])([CH3:18])[CH3:19])=[CH:22][CH:23]=3)[CH2:27][CH2:28]2)=[C:8]2[CH:14]=[N:37][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)c1ccc(CC2(N)CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1Cl
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCCCO
Product: CCOC(=O)c1cnc2[nH]ncc2c1N1CCC(N)(Cc2ccc(C(C)(C)C)cc2)CC1
Yield: 65 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (Example 68A) (50 mg, 0.22 mmol), 4-(4-tert-butyl-benzyl)-piperidin-4-ylamine hydrochloride (70.8 mg, 0.22 mmol) and triethylamine (150 μL) in n-butanol (1.5 mL) was irradiated in a microwave reactor (200 W) for 1 hour at 100° C. After cooling, the solvent was evaporated and the residue was purified by column chromatography (EtOAc-MeOH 4:1) to give an off-white solid (63 mg, 65%). LC-MS (LCT2) m/z 436 [M+H+], Rt 5.01 min.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:31][C:32]([O:34][CH2:35]I)=[O:33])[CH:28]([CH3:30])[CH3:29]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:35][O:34][C:32]([O:31][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:33])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(C)COC(=O)OCI
Agent: [Na+]
Product: CC(C)COC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 67.4 %

Procedure:
In the same manner as in Example 81, 294 mg of the title compound was prepared from 344 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 264 mg of isobutyloxycarbonyloxymethyl iodide.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:13][CH2:12][CH2:11][C:10]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:9]=2[CH:8]=1)(=O)=O.COC1C=CC2C=C([Sn](C)(C)C)CCCC=2C=1.[CH2:39]([O:46][C:47]1[CH:61]=[CH:60][C:50]([CH2:51][N:52]2[C:57](Br)=[CH:56][CH:55]=[CH:54][C:53]2=[O:59])=[CH:49][CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([O:46][C:47]1[CH:61]=[CH:60][C:50]([CH2:51][N:52]2[C:57]([C:7]3[CH2:13][CH2:12][CH2:11][C:10]4[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:9]=4[CH:8]=3)=[CH:56][CH:55]=[CH:54][C:53]2=[O:59])=[CH:49][CH:48]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=c1cccc(Br)n1Cc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc2c(c1)CCCC(OS(=O)(=O)C(F)(F)F)=C2
Agent: COc1ccc2c(c1)CCCC([Sn](C)(C)C)=C2
Product: COc1ccc2c(c1)CCCC(c1cccc(=O)n1Cc1ccc(OCc3ccccc3)cc1)=C2

Procedure:
Synthesized from 2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl trifluoromethanesulfonate according to an analogous synthetic method to Preparation Example 69, (2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)trimethyltin (3.25 g) and 1-(4-benzyloxybenzyl)-6-bromo-1H-pyridin-2-one (2.2 g) were used according to an analogous synthetic method to Example 1 to provide 1-(4-benzyloxybenzyl)-6-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-1H-pyridin-2-one (646 mg). The total amount of this compound was used according to an analogous synthetic method to Example 22 described below to provide the title compound (404 mg).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(Cl)(O[C:33](=[O:39])OC(Cl)(Cl)Cl)Cl.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C1COCC1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21][C:33]([N:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)=[O:39])[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(C(=O)Nc2cccc3nc(N[C@@H]4CCc5ccccc54)ccc23)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 32.5 %

Procedure:
To a stirred solution of (R)—N2-indan-1-yl-quinoline-2,5-diamine (example 16) (138 mg, 0.5 mmol) in THF (10 ml) was added at 0° C. triethylamine (56 mg, 0.55 mmol) and triphosgen (66.7 mg, 0.23 mmol). The white suspension was heated under reflux conditions for 3 h and triethylamine (56 mg, 0.55 mmol) and 1-methylpiperazine (55 mg, 0.55 mmol) were added at room temperature. The reaction mixture was allowed to stir at 50° C. for 16 h and was extracted with dichloromethane (2×30 ml). The combined organic layers were washed with water (2×20 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (dichloromethane/MeOH) and crystallization (diethyl ether/heptane) to yield the title compound as off-white solid (30 mg, 15%). M.p. 142° C.; MS: m/e=402.5 (M+H+)
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=[N:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24]C1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[C:33]1([C:41]2[CH:46]=[CH:45]C=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:36](NC)=[CH:35][CH:34]=1.[CH3:47][N:48]([CH:50]=[O:51])[CH3:49]>>[C:41]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:42]=[CH:43][C:47]([N:48]([CH3:49])[C:50]([C@@H:23]2[CH2:22][CH2:21][C@H:20]([NH2:25])[CH2:24]2)=[O:51])=[CH:45][CH:46]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CN(C)C=O
Reactant: CNc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)[C@@H]1CC[C@H](N)C1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
351.4 mg (1.00 mmol) (1S,3R)—(N)-Fmoc-1-aminocyclopentane-3-carboxylic acid is stirred in DMF at RT. 500.0 mg (4.00 mmol) DIPEA and 417.3 mg (1.3 mmol) TBTU are added. 219.0 mg (1.0 mmol) Biphenyl-4-yl-methyl-amine hydrochloride (II.1.c) is added and the mixture is stirred at RT over night. The solvent is evaporated. The product is purified by RP-HPLC (water+5-95% acetonitrile (with addition of 0.1% TFA)) and lyophilized. The residue is taken up in DCM and diethylamine is added. After 2 hours of stirring at RT the mixture is filtered and evaporated.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)(=[O:7])=[O:6].[I-].[Na+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C.C(Cl)Cl>[N:25]1([CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]3)(=[O:7])=[O:6])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cc2cc(NS(=O)(=O)CCCCl)ccc2[nH]1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(NS(=O)(=O)CCCN3CCCCC3)ccc2[nH]1
Reaction time: 8 h

Procedure:
Ethyl 5-[(3-chloropropyl)sulfonamido]indole-2-carboxylate (PREPARATION 82, 2.3 g) is dissolved in acetonitrile (10 ml) and piperadine (27 ml). Solid sodium iodide (1.0 g) is added and the reaction is stirred overnight at 20°-25°. The reaction is diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography, eluting with a gradient of 5% methanol/methylene chloride to 10% methanol/methylene chloride, pooling and concentration of the appropriate fractions gives the title compound, NMR (300 MHz, d4-CD3OD) 7.45, 7.32, 7.12, 7.03, 4.28, 2.96, 2.28, 1.18, 1.42, 1.33 and 1.30.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](#[N:13])[CH:11]=[CH2:12].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:12][CH2:11][C:10]#[N:13])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(C)c1O
Reactant: C=CC#N
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(CCC#N)cc(C)c1O

Procedure:
In a modification of this Friedel-Crafts reaction, 2,6-di-methylphenol is treated with acrylonitrile in the presence of aluminum chloride to yield 3-(3,5-dimethyl-4-hydroxyphenyl)propionitrile. Upon hydrolysis of this and esterification of the resulting free acid with methanol and p-toluenesulfonic acid, there is obtained methyl 3-(3,5-di-methyl-4-hydroxyphenyl)propionate, M.P. 70°-83° C.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[O-]CC.[Na+].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:31](OCC)=[O:32])[C:26](OCC)=[O:27])=[CH:20][CH:19]=1)#[N:11].O1CCOCC1>C(O)C>[OH:32][C:31]1[N:4]=[C:2]([CH3:3])[NH:5][C:26](=[O:27])[C:25]=1[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([C:10]#[N:11])=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nc(O)c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]1
Yield: 40 %

Procedure:
To a solution of acetamidine hydrochloride (2.68 g) in ethanol (30 mL) were added sodium ethoxide (20% ethanol solution, 14.5 g) and then a solution of diethyl [(2′-cyanobiphenyl-4-yl)methyl]malonate in ethanol (30 mL)-1,4-dioxane (15 mL) at 0° C., and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, and the residue was adjusted to pH 5 with water (50 mL) and 50% aqueous acetic acid solution. The obtained crystallized product was collected by filtration and washed with water to give the title compound as colorless crystals (1.8 g, 40%).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]>CO>[Br-:1].[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N+:11]=1[CH2:2][C:3](=[O:4])[CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: O=C(CBr)C1CCOCC1
Reactant: Cc1ccccn1
Solvent: CO
Product: Cc1cccc[n+]1CC(=O)C1CCOCC1
Product: [Br-]
Yield: 86.4 %

Procedure:
A mixture of 2-bromo-1-(tetrahydro-pyran-4-yl)-ethanone (0.6 g, 2.89 mmol) and 2-picoline (0.4 mL, 4.3 mmol) in methanol (10 mL) was heated to reflux and maintained overnight. The solvent was removed in vacuo to give a residue which was washed with 20% ethyl acetate in hexane to afford 2-methyl-1-[2-oxo-2-(tetrahydro-pyran-4-yl)-ethyl]-pyridinium bromide (0.75 g, 86%) as a semi-solid.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=C(OC)C=2)=CSC=1C([O:39][CH3:40])=O.C(OCC)(OCC)OCC.[Cl:51]C1C=CC(N)=CC=1>C(O)(=O)C>[Cl:51][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([O:39][CH3:40])[CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2cccc(OC)c2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: COc1cccc(-c2csc3c(=O)n(-c4ccc(Cl)cc4)cnc23)c1
Yield: 11.9 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(3-methoxyphenyl)thiophene-2-carboxylate (80 mg, 0.3 mmol), triethyl orthoformate (0.66 ml), 4-chloroaniline (72.1 mg, 0.57 mmol), and acetic acid (0.08 ml) were used to give 13.2 mg (0.04 mmol, 11.9% yield) of the title compound.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])=[C:13]([CH3:16])[CH2:14]O)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.P(Br)(Br)[Br:25]>CCCCC>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])=[C:13]([CH3:16])[CH2:14][Br:25])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCC(C)(C)c1ccc(C(C)=C(C)CO)cc1
Solvent: CCCCC
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(C(C)=C(C)CBr)cc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
A mixture of 72 g of 3-(p-tert.amyl-phenyl)-2,3-dimethyl-allyl alcohol and 7.2 ml of pyridine in 500 ml of n-pentane is cooled down to -5° C. At this temperature there are added dropwise while stirring over a period of 2 hours 40.2 g of phosphorus tribromide in 500 ml of n-pentane and the mixture is stirred at room temperature for 3 hours. The mixture is poured on to 500 g of ice and stirred up for 30 minutes. The pentane phase is separated and the aqueous phase is back-extracted with n-pentane. The combined n-pentane phases are washed neutral with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The crude 3-(p-tert.amyl-phenyl)-2,3-dimethyl-allyl bromide obtained [NMR: 60 Mc, CDCl3 →1-CH2 =3.9 and 4.1 ppm (2s)] was used in the process without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])SC)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH3:22]>>[C:1]([O:5][C:6]([NH:8][C:9](=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:21]([CH3:22])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CNC
Product: CN(C)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,3-Di-(tert-butoxycarbonyl)-2-methyl-isothiourea (Japanese Patent Unexamined Publication No. 2-3661) (3.00 g) was dissolved in a 50% aqueous dimethylamine solution (40 ml) and the resulting solution was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography to obtain the desired compound (2.58 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[N:3]=1.Cl.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(O)C.O1CCOCC1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=3[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[N:3]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(Br)cc2)nc(N)n1
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a stirred suspension of 4-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-2-yl-amine (0.054 g, 0.20 mmol) in ethanol (7.5 ml) was added a solution of hydrogen chloride in dioxane (4.0 M, 0.025 ml) followed by 4-bromoaniline (0.069 g, 0.40 mmol). After heating under reflux for 45 minutes, volatiles were removed under reduced pressure. The residue was treated with 1.0 M hydrochloric acid (10 ml) and stirred for 30 minutes. Filtration provided the hydrochloride salt of the title compound (0.08 g, 90% yield). 1H NMR (DMSO-d6) δ 3.90 (s, 3H, CH3), 6.71 (s, 1H, Ar), 7.30 (d, 1H, J=9.0 Hz, Ar), 7.57-7.59 (m, 2H, Ar), 7.65 (dd, 1H, J=9.0 Hz, J=2.4 Hz, Ar), 7.70 (d, 1H, J=2.4 Hz, Ar), 7.80-7.86 (m, 2H, Ar), 11.08 (s, 1H, NH).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].C(N(C(C)C)C(C)C)C.C(Cl)Cl.[CH2:23]([S:35](Cl)(=[O:37])=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O>[CH2:23]([S:35]([N:10]1[CH2:9][CH2:8][CH2:7][S:6][C:5]1=[CH:4][N+:1]([O-:3])=[O:2])(=[O:37])=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCS(=O)(=O)Cl
Reactant: O=[N+]([O-])C=C1NCCCS1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
1.6 g of 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine, 3.18 g of ethyldiisopropylamine and 20 ml of methylene chloride were mixed. The mixture was cooled to and stirred at -60° C. under a nitrogen atmosphere while 2.95 g of dodecanesulfonyl chloride was added in portions over a 10 minute period. The mixture was allowed to warm to 10° C. (2.5 hours), then stirred at 10° C. for 1 hour and at 20° C. for 1.5 hours. The resulting mixture was poured into water, and the organic phase was separated, dried (MgSO4), filtered and stripped of solvent. The residue, a gum, was chromatographed over silica gel, using methylene chloride as eluent. After workup the product was recrystallized from ethanol to give N-(dodecylsulfonyl)-2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (3A) as a solid, m.p.: 116°-117° C.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][O:7][CH2:8][CH:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[OH:10])=[CH:4][N:3]=[CH:2]1.[CH3:21]I>>[CH3:21][N:1]1[C:5]([CH2:6][O:7][CH2:8][CH:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[OH:10])=[CH:4][N:3]=[CH:2]1
Reactant: CI
Reactant: OC(COCc1cnc[nH]1)c1cccc2ccccc12
Product: Cn1cncc1COCC(O)c1cccc2ccccc12

Procedure:
2-(Imidazol-5-yl)methoxy-1-(1-naphthyl)ethanol was reacted with methyl iodide to obtain oily 2-(1-methylimidazol-5-yl)methoxy-1-(1-naphthyl)ethanol (compound No. 283).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:34][CH2:35][CH2:36][N:37]=[C:38]=[S:39].O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:38](=[S:39])[NH:37][CH2:36][CH2:35][Cl:34])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: S=C=NCCCl
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=S)NCCCl)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (18.18 mg, 0.18 mmol) in dichloromethane (6 ml) was added 1-chloro-2-isothiocyanatoethane (21.87 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 10 mg (15%); 1H NMR (CDCl3, 300 MHz): δ 9.945 (s, 1H), 7.966-7.996 (d, 1H, J=9 Hz), 7.745-7.773 (d, 2H, J=8.4 Hz), 7.615-7.645 (dd, 1H, J=9, 2.1 Hz), 7.516-7.544 (d, 2H, J=8.4 Hz), 7.082-7.089 (d, 1H, J=2.1 Hz), 4.289-4.344 (t, 2H), 3.411-3.467 (t, 2H), 1.82 (s, 6H); MS: m/z 491 (M−HCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH:10]([O:17]CC)([O:14][CH2:15][CH3:16])OCC.[C:20]([CH2:25][C:26](OCC)=O)(=[O:24])[CH2:21][CH2:22][CH3:23]>C(O)C>[C:20]([C:25](=[CH:26][NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:10]([O:14][CH2:15][CH3:16])=[O:17])(=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: COc1ccccc1N
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: CCCC(=O)C(=CNc1ccccc1OC)C(=O)OCC
Reaction time: 2.5 h
Yield: 27.2 %

Procedure:
A mixture of o-anisidine (22.6 ml, 0.2 mol), triethyl orthoformate (33.3 ml, 0.2 mol) and ethyl butyrylacetate (31.6 ml, 0.2 mol) was heated such that ethanol distilled over slowly. After 2.5 hours the mixture was allowed to cool, diluted with methanol (100 ml) and allowed to crystallise. The N-(2-methoxyphenyl)-2-butyryl-3-(2-methoxyphenylamino)acrylamide by-product was filtered off. Evaporation of the mother liquors and recrystallisation from petroleum ether (40-60) gave ethyl 2-butyryl-3-(2-methoxyphenylamino)acrylate (15.82 g, 27.2%), m.p. 74°-76°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[CH:5][O:4][N:3]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([C:49]3[CH:50]=[N:51][N:52]([CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[CH:53]=3)=[CH:45][C:41]=2[C:42](O)=[O:43])=[CH:34][CH:33]=1>CN(C)C=O>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([C:49]3[CH:50]=[N:51][N:52]([CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[CH:53]=3)=[CH:45][C:41]=2[C:42]([NH:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][CH:5]=2)=[O:43])=[CH:36][CH:37]=1
Reactant: Cc1nocc1N
Reactant: O=C(O)c1cc(-c2cnn(CCN3CCOCC3)c2)ccc1OCc1ccc(F)cc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nocc1NC(=O)c1cc(-c2cnn(CCN3CCOCC3)c2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methyl-4-isoxazolamine (38.0 mg, 0.28 mmol), 1-hydroxy-7-azabenzotriazole (30.7 mg, 0.23 mmol), EDC (43.3 mg, 0.23 mmol) and diisopropylethylamine (0.10 ml, 0.56 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-{1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl}benzoic acid (may be prepared as described in Description 114; 80 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) and the reaction mixture was stirred at room temperature overnight. The DMF was removed on a buchi. The residue was taken up into ethyl acetate (50 ml) and washed with water (1×25 ml). The ethyl acetate layer was evaporated on a buchi under reduced pressure and the residue was purified using the MDAP. The solid obtained after concentrating the appropriate sample was taken up into ethyl acetate (50 ml) and washed with saturated bicarbonate (10 ml). The organic phase was dried (MgSO4) and evaporated to yield the title compound as a white solid. 15 mg.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[Br:17][C:18]1[CH:22]=[C:21]([CH2:23]Cl)[O:20][N:19]=1>>[Br:17][C:18]1[CH:22]=[C:21]([CH2:23][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[O:20][N:19]=1
Reactant: ClCc1cc(Br)no1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cc(Br)no1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 3-bromo-5-(chloromethyl)isoxazole (Example 325A): MS (ES) m/z 382 (M−1) and 384 (M−1, isotope).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][O:10][C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=2[CH3:20])=[C:4]([CH3:21])[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:6]2[C:5]([CH2:9][O:10][C:11]3[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=3[CH3:20])=[C:4]([CH3:21])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,4-dichloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidine (978 mg, 3.01 mmol) in DMA (4 mL) is added piperazine-1-carboxylic acid tert-butyl ester (560 mg, 3.01 mmol) and potassium carbonate (832 mg, 6.02 mmol). The resulting colorless suspension is stirred at room temperature under nitrogen for 16 h. The reaction mixture is partitioned between EtOAc (60 mL) and water (20 mL), the organic layer is separated, washed with water (20 mL×2), brine (20 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to obtain a colorless oil consisting of a ˜2:1 mixture of isomeric addition products. Purification on a 30 g cartridge of silica gel (10-30% EtOAc/Hexanes) affords the title compound (lower Rf material) as a colorless solid foam. 1H NMR (CDCl3) δ=7.11 (d, 1H), 6.83 (d, 1H), 6.75 (s, 1H), 4.84 (s, 2H), 3.52 (m, 8H), 2.90 (m, 1H), 2.47, (s, 3H), 2.16, (s, 3H), 1.45, (s, 9H), 1.27 (d, 6H).