Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH:2]1([CH2:8][NH2+:9][CH2:10][CH2:11]Cl)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]=[S:25]>>[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]1[N:9]([CH2:8][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:10][CH2:11][S:25]1
Reactant: ClCC[NH2+]CC1CCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclohexylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-(cyclohexylmethyl)-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+].CCOCC>C1COCC1>[NH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([OH:18])[CH2:13][CH2:12]1
Reactant: N#CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a stirred solution of 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]propionitrile (3.51 g, 13.2 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0M, 46.4 mL, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6N, 30 mL) was added and stirring was continued for 2 hours at 55°-60° C. The mixture was basified to pH 9 by addition of 6N aq. NaOH and extracted with CH2Cl2 (3×150 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved on CH2 Cl2 (20 mL) and treated with HCl in ether (1.0M, 27.7 mL, 2.1 equiv). The solvents were removed, ether (60 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2×20 mL). Water (40 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1M NaOH, and the aqueous phase was extracted with CH2Cl2 (3×80 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 3.10 g (87%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [C:1]([C:6]1[CH:34]=[CH:33][C:9]2[N:10]([CH2:14][CH2:15][O:16][C:17]3[CH:32]=[CH:31][C:20]([CH2:21][CH:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)[C:11](=[O:13])[S:12][C:8]=2[CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4]>CCCCCC>[CH2:1]([C:6]1[CH:34]=[CH:33][C:9]2[N:10]([CH2:14][CH2:15][O:16][C:17]3[CH:32]=[CH:31][C:20]([CH2:21][CH:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)[C:11](=[O:13])[S:12][C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1
Solvent: CCCCCC
Product: CCCCc1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1

Procedure:
The procedure is as in Example 48, starting from the compound obtained in Example 53. The recrystallisation solvent is hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[Cl-].[NH4+]>C(Cl)Cl>[C:41]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
1.00 gram (2.21 mmol) of (−)-2-amino-2′-diphenylphosphino-1,1′-binaphthyl (the formula (1-1a)) was dissolved in 44 ml of methylene chloride, followed by the addition of 0.21 ml (2.65 mmol) of pyridine and 0.28 ml (2.43 mmol) of benzoyl chloride under 0° C. The reaction mixture was stirred at room temperature for 5 hours. To the reaction solution, 30 ml of saturated aqueous solution of ammonium chloride was added and extracted with 100 ml of methylene chloride. The extract was washed with 70 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:6 mixture of ethyl acetate and hexane) to obtain 1.16 gram of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][CH2:27][C:28](=[O:30])[CH3:29])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][Mg]Br.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(=O)CCn1cnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(CCC(C)(C)O)cn1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(3-oxobutyl)-1H-imidazole-4-carboxamide (100 mg, 1.18 mmol) in dry THF (3 ml) was added to 3.0 M methylmagnesium bromide solution in ether (0.39 ml) at 30-40° C. Thereafter the reaction mixture was stirred at 45° C. for 3 h. The cooled reaction mixture was poured into saturated NH4Cl solution. Solvents were evaporated and the product was extracted into ethyl acetate. The combined organic layers were washed with water, dried and concentrated. The crude product was purified by flash chromatography on silica gel by using EtOAc-MeOH (9:1) as an eluent. The final purification was made by preparative HPLC to obtain the title compound. 1H NMR (400 MHz, CDCl3): 1.22 (3H, d), 1.30 (6H, s), 1.97 (2H, m), 4.14 (2H, m), 4.28 (1H, distorted dd), 4.41 (1H, distorted dd), 4.56 (1H, m), 6.60 (1H, d), 7.48 (2H, m), 7.56 (1H, d), 7.61 (1H, distorted d), 7.79 (1H, distorted dd), 7.86 (1H, d), 8.17 (1H, d).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[F:27])=[N:11][CH:12]=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[F:27][C:20]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[C:10]1[C:9]([OH:8])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1
Reactant: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.3 %

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 5-(benzyloxy)-6-(2-fluoro-5-methoxyphenyl)nicotinate (1.50 g) in ethyl acetate (20 mL) was added 10% palladium-activated carbon (433 mg) and the mixture was stirred under a hydrogen atmosphere at room temperature for 20 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (1.00 g) as a yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: Br.Br.[CH3:3][C@@H:4]1[CH2:9][NH:8][C@H:7]([CH3:10])[CH2:6][NH:5]1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](Cl)=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C(OCC)(=O)C>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([N:5]2[CH2:6][C@@H:7]([CH3:10])[NH:8][CH2:9][C@H:4]2[CH3:3])=[N:14][N:13]=1
Reactant: C[C@@H]1CN[C@H](C)CN1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2nnc(Cl)c3ccccc23)[C@H](C)CN1

Procedure:
(2R,5R)-2,5-dimethylpiperazine dihydrobromide (2.08 g, 7.54 mmol), 1,4-dichlorophthalazine (0.500 g, 2.52 mmol), potassium carbonate (2.08 g, 15.0 mmol), and N-methylpyrrolidinone (7 mL) were heated at 120° C. for 6 hours. The reaction was taken up in ethyl acetate (75 mL) washed with aqueous K2CO3 (10%), water, and then saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-40% ethyl acetate gave a yellow oil. MS (M+H)+=277.2.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([NH:16][CH:13]([CH3:15])[CH3:14])[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1
Reactant: O=c1[nH]nc2c(Cl)nc(Br)cn12
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)Nc1nc(Br)cn2c(=O)[nH]nc12

Procedure:
A solution of 0.50 g of the product of Step D and 0.59 g of isopropylamine in THF (20 mL) was heated to reflux. After one h, the reaction was concentrated and the residue partitioned between EtOAc and water. The layers were separated and the organic phase was washed with sat sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to provide 6-bromo-8-isopropylamino-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one as a light tan solid. MS (M+H−)=271.2.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1)=O.[CH:10]1([CH2:13][NH2:14])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][N:14]=[CH:1][C:3]2[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=2)[CH2:12][CH2:11]1
Reactant: NCC1CC1
Reactant: Cc1cc(C=O)ccn1
Product: Cc1cc(C=NCC2CC2)ccn1

Procedure:
Reaction of 4-formyl-2-methylpyridine [prepared in Example 33(a)] and cyclopropylmethyl amine by the procedure of example 1(c) affords the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][C:15]4[O:16][C:17]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[N:18][N:19]=4)=[CH:6][CH:7]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Cc1nnc(-c2ccccc2)o1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cc4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 4, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-5-phenyl-[1,3,4]oxadiazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](Cl)=[N:10][C:4]=2[CH:3]=1.[CH2:18]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:30]3[CH2:31][CH2:32][N:27]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29]3)=[N:10][C:4]=2[CH:3]=1
Reactant: ClC1=Nc2cc(Cl)ccc2Oc2ccccc21
Reactant: CCCCCCCCCN1CCNCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCCN1CCN(C2=Nc3cc(Cl)ccc3Oc3ccccc32)CC1

Procedure:
The mixture of 8,11-dichlorodibenz[b,f][1,4]oxazepine (0.32 g, 1.19 mmol), 1-nonylpiperazine (0.38 g, 1.79 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.72 mL, 0.73 g, 4.77 mmol) in acetonitrile (15 mL) was heated at reflux for 6 h. After the mixture was concentrated, water (20 mL) and ethyl acetate (20 mL) were added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate solution was dried over magnesium sulfate and filtered. The filtrate was then concentrated in vacuo to dryness and the residue was subjected to column chromatography using ethyl acetate/hexane (1/2) as the eluent. The compound 8-chloro-11-(4-nonyl-1-piperazinyl)dibenz[b,f][1,4]oxazepine was obtained as a white solid (0.15 g, 28%), m.p. 64°-66° C., MS 440 (M+ +1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:32][CH2:31][C:26]4(OCC[O:27]4)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:32][CH2:31][C:26](=[O:27])[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccc(N3CCC4(CC3)OCCO4)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCN(c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)CC1
Temperature: 90 °C
Reaction time: 7 h
Yield: 78.7 %

Procedure:
To a solution of 4-[4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl]piperazine-1-carboxylic acid benzyl ester (30 g) in 1,4-dioxane (450 ml) was added 1N-hydrochloric acid (240 ml) at ambient temperature, and the mixture was stirred for 7 hours at 90° C. The reaction mixture was poured into water. The mixture was adjusted to pH 10-12 with 1N-sodium hydroxide (480 ml), and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried, and evaporated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methyl alcohol (50:1) to give 4-[4-(4-oxopiperidin-1-yl)phenyl]piperazine-1-carboxylic acid benzyl ester (21.22 g).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@@H:44]([CH2:54][S:55][C:56]6[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=6)[CH2:45][CH2:46][N:47]6[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]6)=[C:39]([S:62]([C:65]([F:68])([F:67])[F:66])(=[O:64])=[O:63])[CH:38]=5)(=[O:36])=[O:35])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)[C:5]([C:69]([OH:71])=[O:70])=[C:4]1[CH3:72].O[CH:74]1[CH2:79][CH2:78][CH:77]([C:80]([O:82]C(C)(C)C)=[O:81])[CH2:76][CH2:75]1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:3]([CH2:2][CH3:1])[C:4]([CH3:72])=[C:5]([C:69]([O:71][CH:74]3[CH2:79][CH2:78][CH:77]([C:80]([OH:82])=[O:81])[CH2:76][CH2:75]3)=[O:70])[C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@H:44]([CH2:45][CH2:46][N:47]6[CH2:48][CH2:49][CH:50]([OH:53])[CH2:51][CH2:52]6)[CH2:54][S:55][C:56]6[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=6)=[C:39]([S:62]([C:65]([F:66])([F:67])[F:68])(=[O:63])=[O:64])[CH:38]=5)(=[O:36])=[O:35])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[CH:16]=2)=[CH:9][CH:10]=1
Reactant: CCn1c(C)c(C(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C1CCC(O)CC1
Product: CCn1c(C)c(C(=O)OC2CCC(C(=O)O)CC2)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1

Procedure:
7 was prepared from BM-957 and tert-butyl 4-hydroxycyclohexanecarboxylate according general procedure IV. MS (ESI): m/z 1192.25 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-:22])=O)[C:5]([NH:12][C:13]([C:15](OCC)=[O:16])=[O:14])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C)C=O.N.[H][H]>O1CCCC1.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:12][C:13](=[O:14])[C:15](=[O:16])[N:20]2[OH:22])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Agent: [Pt]
Agent: N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1[nH]c2c(C(F)(F)F)cc(Cl)cc2n(O)c1=O
Yield: 80 %

Procedure:
To a solution of 1.0 g (2.94 mmol) 5-chloro-2-ethoxalylamino-3-nitrobenzotrifluoride in 75 ml tetrahydrofuran was added 25 ml dimethylformamide and 1.0 ml 25% aqueous ammonia. The mixture was hydrogenated at atm. pressure by using 100 mg 5% Pt-C as a catalyst. When the hydrogen uptake was completed, the catalyst was filtered off, and the filtrate was evaporated in vacuo. The residue was stirred with 1N aqueous hydrochloric acid to give 0.66 g (80%) of 7-chloro-1-hydroxy-5-trifluoromethylquinoxaline -2,3(1H,4H)-dione. M.P. 275° C. decomp. 1H-NMR (DMSO-d6): 11.7 (2H, m), 7.60 (1H, d), 7.43 (1H, d).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14]C(C)C)=[CH:9][C:8]=1[N:18]1[C:22](=[O:23])[N:21]([CH2:24][F:25])[C:20]([CH3:26])=[N:19]1>>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([OH:14])=[CH:9][C:8]=1[N:18]1[C:22](=[O:23])[N:21]([CH2:24][F:25])[C:20]([CH3:26])=[N:19]1
Reactant: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c(=O)n1CF
Agent: O=S(=O)(O)O
Product: Cc1nn(-c2cc(O)c(Cl)cc2Cl)c(=O)n1CF
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 72.8 %

Procedure:
To 5 mL of stirring concentrated sulfuric acid was added portionwise 0.53 g (0.0016 mole) of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-4-fluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one. After complete addition, the mixture was stirred at room temperature for 2.5 hours. The mixture was poured into 100 mL of ice water and stirred for 30 minutes. The aqueous mixture was extracted with diethyl ether, and the extract was washed with water. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 0.34 g of 1-(2,4-dichloro-5-hydroxyphenyl)-4-fluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]([NH:28][CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:18]=[C:19]([CH2:21][N:28]([CH:29]([CH3:31])[CH3:30])[CH:25]([CH3:27])[CH3:26])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NC(C)C
Reactant: CN1Cc2c(-c3nc(CCl)co3)ncn2-c2cccc(Cl)c2C1=O
Solvent: C1CCOC1
Product: CC(C)N(Cc1coc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1)C(C)C
Yield: 31.3 %

Procedure:
0.30 g (0.00082 mol) of 7-chloro-3-(4-chloromethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one was dissolved in 40 ml of tetrahydrofuran, treated with 2.3 ml (0.0165 mol) of diisopropylamine and boiled at 150° in an autoclave for 20 hrs. The solution was completely freed from the solvents, the residue was chromatographed over silica gel with ethyl acetate/ethanol 9:1 as the eluent and recrystallized from hot diisopropyl ether. There was obtained 0.11 g (31%) of 7-chloro-3-(4-diisopropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 164°-166°.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=2)=[C:6]([C:16]#[N:17])[C:5]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])(=[O:3])[CH3:2].OI(C1C=CC=CC=1)[O:28][S:29]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30].C(#N)C>>[CH3:36][C:35]1[CH:34]=[CH:33][C:32]([S:29]([O:31][CH2:2][C:1]([C:4]2[S:8][C:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=3)=[C:6]([C:16]#[N:17])[C:5]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[O:3])(=[O:30])=[O:28])=[CH:38][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Reactant: CC(=O)c1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCC(=O)c2sc(-c3ccnc(F)c3)c(C#N)c2-c2ccc(Cl)cc2Cl)cc1
Temperature: 90 °C
Yield: 46 %

Procedure:
A mixture of 5-acetyl-4-(2,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)thiophene-3-carbonitrile (0.48 g, 1.2 mmol) and [hydroxy(tosyloxy)iodo]benzene (0.819 g, 2.09 mmol) in ACN (20 mL, 400 mmol) was heated at 90° C. overnight. The mixture was cooled down to rt. The solvent was evaporated and the residue was purified by column chromatography to afford the title compound (0.31 g, 45%). 1H NMR (300 MHz, d1-chloroform) δ: 8.44 (1H, d, J=5.27 Hz), 7.69 (2H, d, J=8.34 Hz), 7.62 (2H, ddd, J=6.91, 3.43, 1.72 Hz), 7.47 (1H, dd, J=8.25, 2.02 Hz), 7.39-7.33 (3H, m), 7.30 (1H, d J=5.79), 4.47 (2H, s), 2.47 (3H, s)
Reaction SMILES: Cl.[C:2]1([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C1COCC1.C(OCC)(=O)C>[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:12][CH2:11]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring suspension of phenyl(piperidin-4-yl)methanone hydrochloride 86 (1.97 g, 8.73 mmol) and potassium carbonate (3.62 g, 26.2 mmol) in THF (40 mL) at 0° C. was added benzyl chloroformate (1.433 mL, 10.04 mmol) and the reaction mixture was allowed to slowly warm to room temperature and stirred for 2 h. The mixture was diluted with ethyl acetate, washed with brine, water, dried over Na2SO4, filtered and concentrated to afford compound 87 quantitative yield. LRMS (ESI): (calc) 323.39 (found) 324.31 (MH)+
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[C:20]2[S:24][C:23]([CH3:25])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(C(OCC)=O)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].Cl>C1C=CC=CC=1>[CH3:25][C:23]1[S:24][C:20]([C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[CH:14][CH:15]=2)=[O:26])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(C(=O)c2ccc(C)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)c2ccc(C(C)C(=O)O)cc2)s1
Reaction time: 0.17 h

Procedure:
A mixture of 15.5 parts of diethyl 2-methyl-2-[p-(5-methyl-2-thenoyl)phenyl]malonate and 120 parts of sodium hydroxide solution 5% is stirred and refluxed for 5 hours. The reaction mixture is cooled and shaken twice with 80 parts of benzene. The aqueous phase is acidified with concentrated hydrochloric acid solution. After standing for 10 minutes, the product is extracted with chloroform. The extract is washed with water, dried, filtered and evaporated. The residue is triturated in petroleumether. The crude product is filtered off and purified by column-chromatography using a mixture of chloroform and 10% of methanol. The pure fractions are collected and the solvent is evaporated. The residue is crystallized from acetonitrile at -20° C, yielding p-(5-methyl-2-thenoyl)hydratropic acid; mp. 93.7° C.