Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[S:16][CH3:17])[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]([O:33]C)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(O)C.P([O-])([O-])(O)=O.[Na+].[Na+]>O>[CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[S:16][CH3:17])[N:7]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:26]([C:31]([OH:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c2cccc(SC)c2c1=O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2cccc(SC)c2c1=O
Reaction time: 2 h
Yield: 34.4 %

Procedure:
A mixture of 270 mg of the product of Example 7, 5 ml of a 5N sodium hydroxide solution and 5 ml of ethanol was stirred for 2 hours at reflux and the mixture was poured into water and acidified with sodium hydrogen phosphate. Extraction was carried out with ethyl acetate and the extracts were washed with water, dried and evaporated to dryness. The residue was chromatographed on silica (eluant: methylene chloride-methanol (9-1)) and the product was impasted in a mixture of 5 ml of ethyl acetate and 5 ml of isopropyl ether to obtain 90 mg of the desired compound melting at 155° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#N)=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C.C[OH:20].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[N:4][C:5]([CH:8]=[O:20])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(F)cn1
Reactant: CO
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ncc(F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 5-fluoropyrimidine-2-carbonitrile (Method 6, 1.0 g, 8.1 mmol) in anhydrous THF at −78° C. was added a solution of DIBAL-H (8.1 mL) over a period of 20 minutes. The resulting mixture was stirred at this temperature for 2 hours whereupon MeOH was added. The solution was allowed to warm to room temperature whereupon a solution of conc. HCl was added. The resulting mixture was stirred for 2 hours at ambient temperature and the aqueous layer was washed with EtOAc (3×). The combined organic extracts were washed with brine and dried (MgSO4). Evaporation of the solvent afforded the titled compound (780 mg, 76%). MS: [M+H]+ 127.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]1[S:10](=[O:12])(=[O:11])[C:9]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:8]=2[CH:7](O)[CH2:6]1)[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:32]([NH2:34])[CH3:33]>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][C@H:5]1[S:10](=[O:12])(=[O:11])[C:9]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:8]=2[C@@H:7]([NH:34][CH2:32][CH3:33])[CH2:6]1)[CH3:2]
Reactant: CCN
Reactant: CCOCC1CC(O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCN[C@H]1C[C@@H](COCC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: -10 °C
Reaction time: 5 h

Procedure:
5,6-Dihydro-6-ethoxymethyl-4-hydroxy-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (4.25 g, 0.0123 mol) was dissolved in dry pyridine (25 ml) and the solution was cooled to -10° C. p-Toluenesulfonyl chloride (5.14 g, 0.027 mol) was added and the mixture was stirred at -10° C. for 5 hours. Anhydrous ethylamine (26 ml, 0.4 mol) was added and the mixture was stirred for 2 hours at room temperature. Finally, 70% ethylamine (32 ml. 0.40 mol) was added and the mixture was heated at 50° C. overnight. The dark mixture was concentrated in vacuo and the residual oil was taken up in ethyl acetate (100 ml) and saturated sodium bicarbonate (100 ml). The aqueous layer was separated and extracted with ethyl acetate. The combined ethyl, acetate solutions were washed with saturated sodium chloride, dried, filtered and concentrated in vacuo. The oil obtained was a 2:1 mixture of cis and trans isomers which were separated by silica gel chromatography using 7.5% methanol-chloroform. Total recovery was 2.43 g. Yield of 33 was 54%.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].N1C=CN=C1.C1COCC1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(OC)(C)C>[Si:18]([O:1][C@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7])([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1OCC[C@@H]1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@H]1CCOC1=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
To a stirred solution of (S)-3-hydroxydihydrofuran-2(3H)-one (5.24 g, 51.4 mmol), imidazole (3.8 g, 56 mmol), and THF (70 mL) at 0° C., under N2, was added t-butyldiphenylsilyl chloride (11.8 g, 43 mmol) dropwise. The mixture was stirred at 0° C. for 6 hours. TBME (150 mL) was added and the solution was washed with water (2×100 mL), brine (100 mL), dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure to afford (S)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (13.9 g, 95%) as a slightly yellow oil. 1H-NMR (400 MHz, CDCl3) δ 7.84-0.82 (m, 2H), 7.73-7.71 (m, 2H), 7.50-7.40 (m, 6H), 4.41-4.31 (m, 2H), 4.06-4.00 (m, 1H), 2.29-2.19 (m, 2H), 1.10 (s, 9H).
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[CH2:31]([NH2:34])[CH2:32][CH3:33]>CCCCCC.C(OCC)(=O)C>[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:5]([NH:34][CH2:31][CH2:32][CH3:33])=[O:4])[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]=3[O:14][CH2:13]2)=[CH:20][CH:19]=1)([CH3:23])[CH3:22]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: CCCN
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCNC(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Yield: 53 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 1-propylamine, the title compound was synthesized in the same manner as in Example 143. Yield: 53%. Melting point: 177-178° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[NH:14][CH:13]=[C:12]([S:15](Cl)(=[O:17])=[O:16])[CH:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-]S([O-])=O.[Na+].[Na+].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>O.CC(C)=O>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][S:15]([C:12]2[CH:11]=[C:10]([C:8]([C:7]3[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[NH:14][CH:13]=2)(=[O:17])=[O:16])=[CH:28][CH:27]=1
Reactant: O=C(c1cc(S(=O)(=O)Cl)c[nH]1)c1cccnc1Cl
Reactant: Clc1ccc(CBr)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1cc(S(=O)(=O)Cc2ccc(Cl)cc2)c[nH]1)c1cccnc1Cl
Temperature: 60 °C
Yield: 99.7 %

Procedure:
5-[(2-chloropyridin-3-yl)carbonyl]-1H-pyrrole-3-sulfonyl chloride (500 mg, 1.64 mmol), Na2SO3 (413 mg, 3.28 mmol), Na2HPO4 (233 mg, 1.64 mmol) were mixed in 4 mL of water and heated to 60° C. overnight (16 hour). The initial creamy suspension became clear and then cloudy. A solution of 4-chlorobenzyl bromide (337 mg, 1.64 mmol) in acetone (4 mL) was added to the reaction solution dropwise with stirring. The mixture was stirred at 60° C. for 4 hour and then cooled down to room temperature. Quenched with 4 mL of water and stirred for another 1 hour. Filtered and washed with water and acetone to afford the product, {4-[(4-chlorobenzyl)sulfonyl]-1H-pyrrol-2-yl}(2-chloropyridin-3-yl)methanone as white solid 646 mg (90% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14](OC(C)(C)C)=O)=[CH:8][CH:7]=2.[C:21]1([C:27]2[N:32]=[N:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.[OH-].[Na+]>>[C:21]1([C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:14]([CH2:13][C:9]4[CH:10]=[C:11]5[C:6](=[CH:7][CH:8]=4)[N:5]=[CH:4][C:3]([OH:2])=[CH:12]5)=[N:34][N:33]=3)[N:32]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cnc2ccc(Cc3nnc4ccc(-c5ccccc5)nn34)cc2c1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a 5 ml CEM microwave tube was added tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (0.3 g, 1 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.3 g, 2 mmol), and HYDROCHLORIC ACID (0.3 ml, 11 mmol) as solvent. The vial was sealed and first heated at 100° C. for 20 min then placed into CEM microwave for 20 min. at 180° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH. The ppt. was collected by filtration. The ppt. was washed with water and dried. The solid was purified using SiO2 chromatography (TELEDYNE ISCO REDISEP®, P/N 68-2203-027, 40 g SiO2, DCM:MeOH=95%:5%, Flow=40 mL/min) to afford the desired product as gray solid. MS m/z: 354.2 (M+H). Calc'd. for C21H15N5O−353.37.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[O:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:15]3([OH:22])[C:14]4[C:18](=[CH:19][CH:20]=[C:12]([CH3:11])[CH:13]=4)[NH:17][C:16]3=[O:21])[C:10]=2[O:9][CH2:8]1
Reactant: Brc1cccc2c1OCO2
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Product: Cc1ccc2c(c1)C(O)(c1cccc3c1OCO3)C(=O)N2
Yield: 68.9 %

Procedure:
With 7.80 g of 4-bromo-1,3-benzodioxol and 1.61 g of 5-methyl isatin as starting materials, 1.95 g of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10](=O)[CH3:11])[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:14][C:15]1[CH:16]=[C:17]([NH:21]N)[CH:18]=[CH:19][CH:20]=1>CC(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:18]3[C:17](=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=3)[NH:21][C:10]=2[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CC(=O)CSc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-(3-Bromo-phenylsulfanyl)-propan-2-one (1.5 g, 6.12 mmol) and 3-chlorophenylhydrazine hydrochloride (1.21 g, 6.73 mmol) were combined in t-BuOH (50 mL) and the reaction was heated to 80° C. and stirred overnight. After cooling the reaction was worked-up using standard procedures to afford a crude mixture of two regioisomers which was then purified using silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([CH3:22])[CH:16]=1)[CH:7]=[CH:6]2.[CH3:23][C:24]1[O:25][C:26](=O)[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[C:26](=[O:25])[C:27]4[C:28](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:29]=[C:24]3[CH3:23])=[C:17]([CH3:22])[CH:16]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C#Cc3ccc(N)c(C)c3)ccc2c1
Reactant: Cc1nc2ccccc2c(=O)o1
Solvent: CC(=O)O
Product: COc1ccc2cc(C#Cc3ccc(-n4c(C)nc5ccccc5c4=O)c(C)c3)ccc2c1

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with 2-ethynyl-6-methoxynaphthalene (25c, 182 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 4-((6-methoxynaphthalen-2-yl) ethynyl)-2-methyl benzenamine (26c) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl-4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 4-((6-methoxynaphthalen-2-yl)ethynyl)-2-methylbenzenamine (26c) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h After completion of the reaction as indicated by TLC. then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 3-(4-((6-methoxynaphthalen-2-yl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29c). Reaction of 3-(4-((6-methoxynaphthalen-2-yl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29c, 430 mg, 1 mmol) with 3,4,5-trimethoxybenzaldehyde (30l, 196 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (61) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[N:8][C:6]=2[N:7]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1.[Na]>O1CCCC1>[N:15]1([C:4]2[C:5]3[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[N:8][C:6]=3[N:7]=[C:2]([O:29][CH2:28][CH2:27][N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)[N:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: OCCN1CCOCC1
Reactant: O=[N+]([O-])c1cnc2nc(Cl)nc(N3CCOCC3)c2c1
Agent: [Na]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc2nc(OCCN3CCOCC3)nc(N3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Chloro-4-morpholino-6-nitro-pyrido[2,3-d]pyrimidine (4.4 g; 15 mmol) was dissolved in tetrahydrofuran (100 mL). To the solution was added morpholino-2-ethanol (2.4 g; 18 mmol), and it was chilled in a dry ice bath. Sodium 400 mg; 18 mmol) was then added, and it was allowed to warm to room temperature and stirred overnight. The solvent was then evaporated, and the solid was dissolved in dichloromethane (50 mL), washed with water (3×10 mL), dried over magnesium sulfate, and purified by column chromatography to give 4-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-6-nitro-pyrido[2,3-d]pyrimidine (3.35 g).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:31]([O:38][C:39](=[O:46])[C@H:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:31]([O:38][C:39](=[O:46])[CH:40]([NH:41][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:8])=[O:9])=[O:18])[CH2:42][CH:43]([CH3:44])[CH3:45])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)NC(CC(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.432 g (1.1 mmol) of L-leucine benzyl ester p-toluenesulfonic acid salt, 0.227 g (1.2 mmol) of DCC and 0.122 g (1 mmol) of DMAP were dissolved in 30 mL of CH2Cl2, 0.2 ml (1.4 mmol) of TEA was added. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: CH2Cl2:CH3Cl=1:1) to obtain the product as a oil (0.48 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.O.[NH3:26]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH2:26])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: N
Solvent: O
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN

Procedure:
Using 5 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 100 ml of methylisobutylketone, and 200 ml of 28% ammonia water, a reaction similar to that conducted in Example 107 was carried out. The crystal procipitated was filtered out, yielding 0.9 g of N-(trans-4-methylcyclohexyl)-4-(2-aminoethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:51])([CH3:50])[CH2:38][CH2:39][S:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([S:40][CH2:39][CH2:38][C:37]([CH3:51])([CH3:50])[CH3:36])[CH:46]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: CC(C)(C)CCSc1cccc(B(O)O)c1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: CC(C)(C)CCSc1cccc(-c2ccc(Cc3nc(-c4ccc(F)cc4F)cn3-c3cccc(N4CC(=O)NS4(=O)=O)c3)cc2)c1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (prepared according to general procedures A, J and C stepwise) (112 mg, 0.2 mmol) was treated as described in general procedure G using 3-(3,3-dimethyl-butylsulfanyl)phenylboronic acid (96 mg, 0.4 mmol, prepared according to general procedure I) to give 5-(3-{4-(2,4-difluoro-phenyl)-2-[3′-(3,3-dimethyl-butylsulfanyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[H-].[Na+].[C:17]1([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[C:23]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:24]=[CH:25][C:26]([CH2:27][N:6]2[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:29][CH:30]=1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1ccccc1n2Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 3-bromo-9H-carbazole (7.38 g, 30 mmol, prepared as described in Tetrahedron (1992), 48, 4779) in N,N-dimethylformamide (200 ml) was added portion wise sodium hydride (1.6 g, 39 mmol, 60% in mineral oil) during 15 min. After stirring at room temperature for 1 h, 4-phenyl-benzylchloride (6.21 g, 30 mmol) was added portion wise during 10 min. The resulting reaction mixture was stirred at room temperature for 20 h poured onto water (300 ml) and stirred for 4 h. The precipitate was filtered off, washed with water (3×150 ml) and dried in vacuo at 50° C. for 18 h. The crude product was washed with heptane, filtered off and dried in vacuo at 50° C. affording 12 g (100%) of 9-(biphenyl-4-ylmethyl)-3-bromo-9H-carbazole as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH:9]=[CH:10][N:11]([CH3:13])C)[CH:5]=[CH:6][CH:7]=1.N[C:16]1[C:20]([C:21]#[N:22])=C[NH:18][N:17]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:18]3[N:17]=[CH:16][C:20]([C:21]#[N:22])=[C:13]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1cccc(Cl)c1
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3cccc(Cl)c3)ccnc12
Yield: 83.2 %

Procedure:
A mixture of 50.0 g of 3'-chloro-3-dimethylaminoacrylophenone, 25.0 g of 3-aminopyrazole-4-carbonitrile and 500 ml of glacial acetic acid was heated at reflux for 2 hours. The mixture went into solution upon heating and a precipitate formed after one hour of refluxing. The reaction mixture was filtered and the crystals collected were triturated with saturated aqueous sodium bicarbonate, filtered and washed with water and then dried to give 49.0 g of the product of the example as colorless crystals, mp 238°-240° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][NH2:31])=[CH:24][CH:23]=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:31][CH2:30][CH2:29][O:28][C:25]4[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: COc1ccc(OCCN)cc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: COc1ccc(OCCNc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2-(4-methoxyphenyloxy)ethyl amine were reacted to give N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[(4-methoxyphenyloxy)ethyl]-2,4-pyrimidinediamine. LCMS: ret. time: 22.74 min.; purity: 91.9%; MS (m/e): 413.05 (MH+).
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[CH2:6]1[C@@H:16]2[C@H:10]([CH:11]=[CH:12][C:13]3[C:14]4[N:15]2[C:17]2[CH:26]=[CH:25][N:24]=[CH:23][C:18]=2[C:19]=4[CH2:20][CH2:21][CH:22]=3)[CH2:9][CH2:8][CH2:7]1>C(O)C>[CH2:6]1[CH:16]2[CH:10]([CH:11]=[CH:12][C:13]3[C:14]4[N:15]2[C:17]2[CH:26]=[CH:25][N:24]=[CH:23][C:18]=2[C:19]=4[CH2:20][CH2:21][CH:22]=3)[CH2:9][CH:8]([CH2:2][CH2:1][C:3](=[O:4])[CH3:5])[CH2:7]1
Reactant: C1=C[C@@H]2CCCC[C@H]2n2c3c(c4cnccc42)CCC=C13
Reactant: C=CC(C)=O
Solvent: CCO
Product: CC(=O)CCC1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1
Reaction time: 96 h
Yield: 86.5 %

Procedure:
2.3 grams of methyl vinyl ketone was added to a solution of 8.3 grams of (±)-trans-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine in 400 ml. of ethanol. The mixture was permitted to stand at room temperature for four days, after which an additional 2.6 grams of methyl vinyl ketone was added. This mixture was permitted to stand at room temperature for three days, and was then filtered, evaporated to dryness in vacuo, and triturated with pentane. The resulting solid was recrystallized from ethanol to yield 9 grams of the title compound with m.p. 102.5° C.