Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([C:40]#[N:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]#[N:41])[CH2:38][CH2:39]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: N#CC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Product: N#CC1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)piperidine-4-carbonitrile. MS (ESI): mass calcd. for C22H20FN5O2S, 437.13; m/z found, 438.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.29 (d, J=1.1, 1H), 8.12-8.09 (m, 1H), 7.99 (m, 1H), 7.74-7.69 (m, 1H), 7.65-7.60 (m, 1H), 7.45-7.42 (m, 1H), 7.34 (s, 1H), 7.32-7.30 (m, 1H), 3.10-3.02 (m, 2H), 2.86-2.73 (m, 3H), 1.82-1.73 (m, 2H), 1.64-1.53 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(Cl)Cl.[Cl:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:8]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: Nc1ccccc1Cl
Reactant: Nc1nccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nccnc1C(=O)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A mixture of 3-aminopyrazine carboxylic acid (7.0 g, 50.32 mmol), methylene chloride (60 mL), dimethylformamide (40 mL), 4-dimethylaminopyridine (15.37 g, 126 mmol), 2-chloroaniline (5.82 mL, 55.35 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.58 g, 60.38 mmol) was stirred overnight at ambient temperature. The solvent was removed and the residue was mixed with ethyl acetate and 1 N lithium chloride. The precipitate which formed was filtered and rinsed with 1 N lithium chloride, ethyl acetate, and ether and then air dried to afford 6.22 g (50%) of 3-aminopyrazine-2-carboxylic acid 2-chlorophenylamide as fluffy yellow crystals.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=[O:25])[O:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[C:16]([O:21]C(=O)C)[CH:15]=3)=[CH:7][CH:6]=1)(=O)C.[OH-].[Li+].O.Cl>CN(C=O)C>[OH:21][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=3)[C:12](=[O:25])[O:13]2)=[CH:18][CH:17]=1
Reactant: CC(=O)Oc1ccc(-c2cc3ccc(OC(C)=O)cc3oc2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1oc2cc(O)ccc2cc1-c1ccc(O)cc1
Temperature: 65 °C

Procedure:
To a solution of 4-(7-acetoxy-2-oxo-2H-chromen-3-yl)phenyl acetate of formula (3) (80 gm) in DMF (400 mL) an aqueous solution of lithium hydroxide (29.8 g, 0.71 mol) was added at RT and maintained at 60-70° C. for 1-2 hours. After the completion of the reaction, water (800 mL) and dilute hydrochloric acid (112 mL) was added to the reaction mass. The reaction mass was maintained at RT for 1-2 hours. The solid was filtered and dried at 70-75° C. for 6-8 hours to afford the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])(C(C)(C)C)(C)C>C(O)(=O)C.O>[OH:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19]
Reactant: CCOP(=O)(/C=C\CCO[Si](C)(C)C(C)(C)C)OCC
Solvent: O
Solvent: CC(=O)O
Product: CCOP(=O)(/C=C\CCO)OCC
Yield: 58.7 %

Procedure:
A solution of diethyl (Z)-4-(t-butyldimethylsilyloxy)but-1-enylphosphonate (1.32 g, 4.09 mmol) in acetic acid-water (2:1) (35 ml) was stirred at room temperature for 2 hr. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with dichloromethane-methanol (19:1) to give diethyl (Z)-4-hydroxybut-1-enylphosphonate as a colourless liquid (0.5 g, 59%); νmax (film) 3380, 2980, 1720, 1620, 1390, 1230 and 1020 cm-1 ; δH (CDCl3) 1.33 (6H, t, J 7 Hz, CH3), 2.70 (2H, m, CH2), 3.15 (1H, s, OH), 3.73 (2H, t, J 7 Hz, CH2O ), 4.00 (4H, qu, J 7 Hz, CH3CH2), 5.70 (1H, dd, J 14 Hz and 20 Hz, PCH=CH), 6.60 (1H, ddt, J 7 Hz, 14 Hz and 54 Hz, PCH=CH) (Found: MH+ 209.0942. C8H17O4P requires MH+ 209.0943).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:22]([O:24][CH3:25])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:26][C:27](OC(C)=O)=[O:28]>N1C=CC=CC=1>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:27](=[O:28])[CH3:26])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:20])([CH3:21])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:22]([O:24][CH3:25])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H]1C[C@H](NC2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@H](N(C(C)=O)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Methyl (2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidine-2-carboxylate (1.01 g, 2.84 mmol) obtained in Step A, was dissolved in pyridine (5 mL), and Ac2O (1.34 mL, 14.20 mmol) was added thereto at room temperature. The reaction solution was heated to 90° C. and was stirred for 2 hours. After the reaction was completed, CuSO4.5H2O aqueous solution was added and the solution was extracted with EtOAc. The extracted organic solution was dried over MgSO4 and concentrated in vacuo. The obtained residue was purified by column chromatography (eluent: EtOAc/Hex=1/1) to give the title compound (0.98 g, 87%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:14]([N:16]([C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:15]
Reactant: CCNCCCCCCC(=O)OCC
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(CC)c1ccc(C(F)(F)F)cc1C=O
Temperature: 25 °C
Yield: 66.4 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzaldehyde (1 g) is dissolved in toluene (5 ml) and thereto are added ethyl 7-ethylamino-heptanoate (3.98 g) and potassium carbonate (2.88 g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=97:3→83:17) to give ethyl 7-[ethyl-(2-formyl-4-trifluoromethyl-phenyl)-amino]-heptanoate (1.29 g). MS (m/z): 374 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A mixture of 4-Fluoro-3-nitro aniline (0.5 g, 3.2 mmol), 4-bromobenzoyl chloride (0.702 g, 3.2 mmol), diisopropylethylamine (0.56 ml, 3.2 mmol) in dichloromethane (10 mL) was stirred at room temperature for 2 hr. The mixture was diluted with dichloromethane (50 mL) and washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated under vacuum giving the title compound as a yellow solid (0.89 g, 82%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=S)[C:2]([NH2:4])=O.F[B-](F)(F)F.C([O+:16](CC)CC)C.[CH2:21]([NH:28][NH:29][C:30](=O)[C:31]([CH3:34])([CH3:33])[CH3:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[C:31]([C:30]1[N:4]=[C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:16])[N:28]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:29]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=S)C(N)=O
Reactant: CC(C)(C)C(=O)NNCc1ccccc1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C(C)(C)C)nn1Cc1ccccc1
Yield: 40 %

Procedure:
A solution of ethyl thiooxamate (0.27 g, 2.0 mmol) and triethyloxonium tetrafluoroborate (0.40 g, 2.1 mmol) in CH2Cl2 (25 mL) was stirred at room temperature 2 h. The reaction was cooled in an ice bath, and a solution of N′-benzylpivalohydrazide (0.41 g, 2.0 mmol) and triethylamine (0.28 mL, 2.0 mmol) in CH2Cl2 (10 mL) was slowly added. The cooling bath was removed, and the reaction was heated to reflux for 90 min. The solvent was removed under vacuum, and the residue was purified by silica gel chromatography (0%-25% EtOAc-hexanes) to obtain ethyl 5-tert-butyl-2-benzyl-2H-1,2,4-triazole-3-carboxylate (0.23 g, 40% yield). 1H NMR (400 MHz, CDCl3) δ 7.34-7.28 (m, 5H), 5.73 (s, 2H), 4.43 (q, J=7.1 Hz, 2H), 1.40 (s, 9H), 1.38 (t, J=7.7 Hz, 3H) ppm. LC/MS: m/z 288.2 (M+H)+ at 3.51 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[NH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][N:39]=1>CN(C=O)C.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:7][O:6][C:1](=[O:5])[CH:2]=[C:3]([C:41]1[CH:40]=[N:39][C:38]([NH2:37])=[CH:43][CH:42]=1)[CH3:4]
Reactant: Nc1ccc(Br)cn1
Reactant: C/C=C/C(=O)OC
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C=C(C)c1ccc(N)nc1
Temperature: 120 °C
Yield: 40.6 %

Procedure:
Methyl crotonate (1.35 ml, 12.8 mmol), tris(dibenzylideneacetone)-dipalladium(0) (106 mg, 0.12 mmol), tri-o-tolylphosphine (1.41 g, 4.6 mmol), and triethylamine (3.22 ml, 23.1 mmol) were added to a solution of 2-amino-5-bromo pyridine (2 g, 11.6 mmol) in DMF (25 mL). The reaction mixture was heated to 120° C. in a nitrogen atmosphere overnight, then cooled to ambient temperature and diluted with ethyl acetate (50 mL). The reaction was filtered, then washed with saturated ammonium chloride solution (2×25 mL), and the organic layer dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash column (2% methanol in dichloromethane) to give 3-(6-amino-pyridin-3-yl)-but-2-enoic acid methyl ester as a yellow solid (904.7 mg, 41%). 1H NMR (250 MHz, DMSO): δ 8.22 (d, 1H, J=3.1), 7.68 (dd, 1H, J=7.5, J=3.1), 6.46 (d, 1H, J=7.5), 6.40 (bs, 2H), 6.11 (d, 1H, J=0.62), 3.65 (s, 3H), 2.48 (d, 3H, J=0.62). MS [EI+] 193 (M+H)+.
Reaction SMILES: FC1C=C(OC)C=C(F)C=1C1SC=C(C(O)=O)N=1.[F:19][C:20]1[CH:21]=[C:22]([C:36]([OH:39])([CH3:38])[CH3:37])[CH:23]=[C:24]([F:35])[C:25]=1B1OC(C)(C)C(C)(C)O1.Br[C:41]1[N:46]=[C:45]([C:47]([O:49]C)=[O:48])[CH:44]=[CH:43][C:42]=1[F:51]>>[F:35][C:24]1[CH:23]=[C:22]([C:36]([OH:39])([CH3:37])[CH3:38])[CH:21]=[C:20]([F:19])[C:25]=1[C:41]1[N:46]=[C:45]([C:47]([OH:49])=[O:48])[CH:44]=[CH:43][C:42]=1[F:51]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CC(C)(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 2-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (Intermediate 107) and replacing methyl 2-bromothiazole-4-carboxylate with methyl 6-bromo-5-fluoropicolinate (see US2012/225062) gave the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][CH2:39][C@H:40]([NH2:44])[C:41]([OH:43])=[O:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34]([NH:44][C@@H:40]([CH2:39][CH3:38])[C:41]([OH:43])=[O:42])=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](N)C(=O)O
Reactant: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(I)cc3)cc2)cc1
Product: CC[C@H](Nc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O

Procedure:
2-(4′-tert-Butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1-(4-iodo-phenyl)-1H-imidazole (191 mg, 0.3 mmol) was treated as described in general procedure R using L-2-aminobutyric acid (310 mg, 3 mmol) to give (S)-2-{4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-butyric acid, which was then treated as described in general procedure F to give (4S)-5-{4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-ethyl-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[Cl:12]C(OCC)=O.Cl.[NH2:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[OH:34])[CH:23]([OH:30])[CH2:24][NH:25][C:26]([CH3:29])([CH3:28])[CH3:27]>CC(C)=O.O>[ClH:12].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:19][C:20]2[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=2[OH:34])[CH:23]([OH:30])[CH2:24][NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:9])=[CH:10][CH:11]=1
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(N)c1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Nc2cc(C(O)CNC(C)(C)C)ccc2O)cc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methoxybenzoic acid (0.76 g, 0.0050 mole) and of triethyl amino (0.70 ml, 0.0050 mole) in dry acetone (8 ml) was cooled to -15° C and ethyl chloroformate (0.54 g, 0.0050 mole) was added dropwise. The mixture was stirred 30 minutes at -15° C, and 30 minutes at 0° C, and then cooled to -15° C. A solution of 3-amino-4-hydroxy-α-(tert.butylaminomethyl)benzylalcohol hydrochloride in acetone (10 ml) and water (1.7 ml) was cooled to -15° C and added to the reaction mixture in one portion. The solution obtained was stirred at -15° C for 30 minutes, at 0° C for 30 minutes, and at room temperature for 1 hour. The solution was evaporated in vacuum and the residue was recrystallized from water yielding 1.02 g (52%), m.p. 224°-225° C of the title compound, identical to the compound prepared in Example 5.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[OH:17])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[O:17][CH2:19][CH2:20][CH2:21][OH:22])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc2nn(Cc3ccccc3)cc12
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCOc1cccc2nn(Cc3ccccc3)cc12

Procedure:
A mixture of 24 g. 2-benzyl-4-hydroxyindazole, 10.4 ml. 3-bromopropan-1-ol and 16 g. potassium carbonate in 100 ml. dimethylformamide is stirred for 30 hours at 70° C. After dilution with methylene chloride, the reaction mixture is filtered with suction, the filtrate is evaporated and the evaporation residue is purified chromatographically on silica gel (elution agent methylene chloride-ethyl acetate 9:1 v/v), 2-benzyl-4-(3-hydroxypropoxy)-indazole being obtained in the form of an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([NH:14][C:15]([NH:17]C3C=CC=CC=3)=[O:16])[C:7]=2[CH:24]=1)#[N:2].[CH2:25](N=C=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[CH2:9][CH:8]([NH:14][C:15]([NH:17][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:16])[C:7]=2[CH:24]=1)#[N:2]
Reactant: O=C=NCc1ccccc1
Reactant: CC1(C)CC(NC(=O)Nc2ccccc2)c2cc(C#N)ccc2O1
Solvent: CCO
Product: CC1(C)CC(NC(=O)NCc2ccccc2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A solution of the title D compound from Example 8 (0.50 g, 2.47 mmoles) and benzyl isocyanate (0.33 g, 2.47 mmoles) in anhydrous ethanol (4 ml) was heated at reflux for 3 hours and cooled to room temperature. The reaction product precipitated from solution. It was collected by suction filtration; the solid was triturated with diisopropyl ether and dried under vacuum to obtain 0.71 g of the title compound as a white solid, m.p. 168°-169° C. 1H NMR (DMSO-d6) δ7.59 (s, 1H), 7.56 (s, 1H), 7.38-7.24 (m, 5H) 6.89 (d, J=8.21 Hz, 1H), 6.56 (t, J=5.87 Hz, 1H), 6.50 (d, J=8.21 Hz, 1H), 4.94 (M, 1H), 4.30 (d, J=5.86 Hz, 2H), 2.10 (m, 1H), 1.74 (m, 1H), 1.41 (s, 3H), 1.28 (s, 3H). 13C NMR (DMSO-d6) δ158.11, 157.19, 140.78, 132.25, 132.08, 128.22, 126.93, 126.61, 126.12, 119.18, 118.03, 102.02, 77.28, 43.01, 41.95, 38.81, 29.08, 24.42.
Reaction SMILES: [OH:1][CH:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:5](=[O:13])[NH:4][C:3]1=[O:14].[CH3:15]I>CO.C[O-]>[OH:1][CH:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:5](=[O:13])[N:4]([CH3:15])[C:3]1=[O:14]
Reactant: O=C1NC(=O)N(C2CCCCC2)C1O
Reactant: CI
Agent: C[O-]
Solvent: CO
Product: CN1C(=O)C(O)N(C2CCCCC2)C1=O
Reaction time: 1 h

Procedure:
2.0 g of 5-hydroxy-1-cyclohexylhydantoin were dissolved in 30 ml of methanol containing 600 mg of sodim methoxide. 20 minutes thereafter, 0.7 ml of methyl iodide were added dropwise to the solution and the reaction was continued at 50° C. for 1 hour. The solvent was removed by distillation and the residue was purified by thin layer chromatography on silica gel (ethyl acetate:hexane=1:1). The obtained crude product was recrystallized from benzene to give 500 mg of 5-hydroxy-1-cyclohexyl-3-methylhydantoin (compound 21) in the form of colorless needle crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]2)[N:3]=1
Reactant: CN1CCCC(O)C1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CN1CCCC(Oc2nc(N)nc(-c3ccco3)c2C#N)C1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 3-hydroxy-1-methylpiperidine and DBU in DME. ES-MS m/e (%): 300 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Br[CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH:24]([C:25]([O:27][CH3:28])=[O:26])[CH3:29])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C(C)Br
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)OC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
3.3 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetic acid and 1.7 g of methyl α-bromopropionate were dissolved in 30 ml of acetone. Then, to the obtained solution was added 1.4 g of anhydrous potassium carbonate and stirred at room temperature for 30 minutes. Then, the reaction mixture was heated under reflux for 30 minutes. After completion of the reaction, the formed solid substance was filtered off and the acetone was distilled off under reduced pressure to obtain 4 g of 1-methoxycarbonylethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[C:13]([Cl:17])[CH:12]=[C:11]([Cl:18])[C:10]=2[O:19][CH3:20])=[O:5])[CH3:2].C(O)(=O)C.C(OCC)(=O)C>O1CCOCC1.[Zn]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([Cl:17])[CH:12]=[C:11]([Cl:18])[C:10]=2[O:19][CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)c(Cl)cc(Cl)c2c1Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2c(OC)c(Cl)cc(Cl)c2c1
Reaction time: 0.33 h
Yield: 39.7 %

Procedure:
A suspension of zinc powder (0.70 g) was stirred at 20° C. in a solution of 4,5,7-trichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester 26 (364 mg, 1.09 mmol) and acetic acid (2.2 ml) in 1,4-dioxane (15 ml). After 20 minutes, ethyl acetate (20 ml) was added and the resultant mixture filtered through a pad of celite. The filtrate was washed with saturated aqueous sodium chloride solution (10 ml), dried (MgSO4), filtered, and the solvent removed under vacuum. The residue was chromatographed on flash silica (ethyl acetate/hexane, 1:9), yielding 130 mg (39%) of the title compound 27 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 9.51 (d, J=2.0, 1 H), 9.15 (d, J=2.0, 1 H), 7.72 (s, 1 H), 4.51 (q, J=7.2, 2 H), 4.18 (s, 3 H), 1.47 (t, J=7.2, 3 H).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C@H:14]3[CH2:17][CH2:18][CH2:19][C@H:13]3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C@H:14]3[CH2:17][CH2:18][CH2:19][C@H:13]3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[CH:6][CH:5]=1
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 70.9 %

Procedure:
(3aR*,10aS*)-9-(4-Nitrobenzyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (5.06 g, 15 mmol) and 10% palladium-carbon (hydrous) (0.5 g) were suspended in a mixture of tetrahydrofuran (15 mL) and methanol (15 mL). The suspension was stirred for 4.5 hours at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was crystallized from ethyl acetate-hexane to give 3.27 g (yield 71%) of the titled compound, m.p. 149.1°-149.6° C.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]([NH:8][CH2:9][C:10]#[CH:11])=[O:7])([O-])=O.[N+](C1C=CC=CC=1C(Cl)=O)([O-])=O.C(N)C#C.C(O)C>CO.O>[CH:9]([N:8]1[C:6](=[O:7])[C:5]2[C:4](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:1]1)=[C:10]=[CH2:11]
Reactant: C#CCNC(=O)c1ccccc1[N+](=O)[O-]
Agent: C#CCN
Agent: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: C=C=Cn1[nH]c2ccccc2c1=O
Yield: 12 %

Procedure:
Using a similar procedure to that described in Examples 2-16, but starting from 2-nitro-N-(prop-2-ynyl)benzamide (itself prepared from 2-nitrobenzoyl chloride and prop-2-ynylamine using the process described for the preparation of the starting material for Ex. 24), using a mixture of ethanol and water (95/5 v/v) in place of aqueous methanol as the reaction solvent and having a reaction duration of 3 hours, there was obtained 1,2-dihydro-2-allenyl-3H-indazol-3-one (Ex. 177) as a solid, m.p. 126-130° C. in 12% yield.