Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)#[CH:15].ClC1N=CC(C2N=NN(C3C=C(C=CC=3C)C(O)=O)C=2)=CC=1>>[Cl:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:1]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1cc(C(=O)O)ccc1Cl
Reactant: C#Cc1cccnc1
Agent: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(Cl)nc2)nn1
Product: O=C(O)c1ccc(Cl)c(-n2cc(-c3cccnc3)nn2)c1

Procedure:
4-Chloro-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid was prepared from 3-azido-4-chloro benzoic acid (U.S. Ser. No. 04/102,492) and 3-ethynyl pyridine (Aldrich) in the same manner as 3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid (Example 1).
Reaction SMILES: C([NH:4][C:5]12[CH2:18][C:9]3([CH3:19])[CH2:10][C:11]([NH:14]C(=O)C)([CH2:13][C:7]([CH3:20])([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.C(O)COCCO>O>[NH2:4][C:5]12[CH2:18][C:9]3([CH3:19])[CH2:10][C:11]([NH2:14])([CH2:13][C:7]([CH3:20])([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: CC(=O)NC12CC3(C)CC(C)(C1)CC(NC(C)=O)(C3)C2
Solvent: O
Solvent: OCCOCCO
Product: CC12CC3(C)CC(N)(C1)CC(N)(C2)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
Diamide 3 (1.56 g) was added to diethyene glycol (25 mL). The reaction mixture was stirred at 175˜180° C. for 16 h. The brown solution was cooled to room temperature, and water was added (100 mL). The reaction mixture was extracted with a solvent consisting of ethyl acetate (80%) and t-butylmethyl ether (20%) (70 mL×7). The combined organic solvent was washed with water and brine, and dried over sodium sulfate. The solution was concentrated to approximately 20 mL. Anhydrous hydrogen chloride in ethyl acetate was added. The precipitate was filtered. The product was then dissolved in water (10 mL). The product was extracted with ethyl acetate (10 mL×6). Solvent was removed to afford diamine 4 as an off-white solid (767 mg).
Reaction SMILES: [NH2:1][CH:2]1[C:31](=[O:32])[N:4]2[C:5]([C:15]([O:17]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:16])=[C:6]([C:9]3[S:10][C:11]([CH3:14])=[N:12][N:13]=3)[CH2:7][S:8][C@H:3]12.FC(F)(F)C([O-])=O>C1(OC)C=CC=CC=1>[NH2:1][CH:2]1[C:31](=[O:32])[N:4]2[C:5]([C:15]([OH:17])=[O:16])=[C:6]([C:9]3[S:10][C:11]([CH3:14])=[N:12][N:13]=3)[CH2:7][S:8][C@H:3]12
Reactant: Cc1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)s1
Agent: O=C([O-])C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1nnc(C2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To a suspension of 0.443 g of the 7-amino-3-thiadiazole benzyhydryl ester obtained in Example 78 in 2 ml of anisole is added 3 ml of trifluoroacetate acid under stirring and ice-cooling. After 30 minutes, the solvent is distilled off under reduced pressure. The residue is dissolved in 10% hydrochloric acid and the solution is neutralized with a saturated aqueous solution of sodium bicarbonate. The formed precipitates are filtered, and washed with water, acetone and then ether to give 0.21 g of 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][C:6]2(OCC[O:7]2)[C:5]([C:12]2[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=2)=[CH:4][CH2:3]1.Cl>C1COCC1>[CH3:1][C:2]1([CH3:18])[CH2:11][C:6](=[O:7])[C:5]([C:12]2[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=2)=[CH:4][CH2:3]1
Reactant: Cn1nccc1C1=CCC(C)(C)CC12OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: Cn1nccc1C1=CCC(C)(C)CC1=O
Yield: 93.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 67c by using the 5-(9,9-dimethyl-1,4-dioxaspiro[4.5]dec-6-en-6-yl)-1-methyl-1H-pyrazole (758 mg, 3.05 mmol) prepared in Example 72b, 2 M hydrochloric acid (2.0 mL) and THF (5.0 mL), to yield the title compound (581 mg, 93%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[S:4][C:3]=1[CH:15]=[O:16].[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl-].[NH4+].C[N+]1([O-])CCOCC1>O1CCCC1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C>[CH:17]1([C:15]([C:3]2[S:4][C:5]3[C:6](=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=3)[C:2]=2[CH3:1])=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1c(C=O)sc2cc(C(F)(F)F)cnc12
Reactant: Br[Mg]C1CCCCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1c(C(=O)C2CCCCC2)sc2cc(C(F)(F)F)cnc12
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution (15 mL) of 3-methyl-6-(trifluoromethyl)thieno[3,2-b]pyridine-2-carbaldehyde (1.44 g) synthesized above in tetrahydrofuran was added 1.0M solution (8.81 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr under argon atmosphere. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-50% ethyl acetate/hexane) to give a yellow oil. To a mixture of the obtained oil, 4-methylmorpholine N-oxide (817 mg) and acetonitrile (20 mL) was added tetrapropylammonium perruthenate (108 mg), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% ethyl acetate/hexane) to give the title object compound (805 mg, 42%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[CH:20]=1>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:21]3[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=3)[C:18]([OH:27])=[O:17])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COc1ccc(-c2ccc(OCc3cccc(C(=O)O)c3)cc2)cc1

Procedure:
3-(4′-Methoxy-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4-hydroxy-4′-methoxybiphenyl (available from TCI America, Portland, Oreg.) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd. Morcambe, Lancashire, UK). Yield: 73 mg. Mass spectrum (ES) MH+=335.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])[C:3]([OH:5])=[O:4].[CH2:25](O)[CH3:26]>C1C=CC=CC=1>[CH3:25][CH2:26][O:4][C:3]([CH:2]([Cl:1])[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[N:14]=[C:15]([CH3:22])[N:16]([CH:19]([F:20])[F:21])[C:17]2=[O:18])[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])=[O:5]
Reactant: CCO
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Solvent: c1ccccc1
Product: CCOC(=O)C(Cl)Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl

Procedure:
adding 1 mol of the 2-chloro-3-{2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorophenyl}propionic acid of the step (1), 4˜10 mol of ethanol and 0.03˜0.2 mol of an acid catalyst into 6˜12 mol of the solvent of benzene class; refluxing the reaction mixture until an esterification is completed; washing successively with water, with aqueous alkali base and then with water; and removing the solvent totally from the organic layer, to give the product carfentrazone-ethyl;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][OH:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:31](I)[CH2:32][CH3:33]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][O:28][CH2:31][CH2:32][CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCO
Agent: [H-]
Agent: [Na+]
Product: CCCOCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C(=O)OC(C)(C)C

Procedure:
The product from Step B was reacted with sodium hydride (0.220 g, 60% dispersion in oil, 5.4 mmol) and n-propyl iodide (0.375 mL, 3.85 mmol) according to the procedure described in Example 7, Step C. The crude product was chromatographed on silica gel with 30% ethyl acetate in hexane. The title compound was obtained as a foam, (0.400 g).
Reaction SMILES: C1([N:4](CCCO)[C:5]([CH2:7][C@H:8]([NH:26][S:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)(=[O:29])=[O:28])[C:9]([NH:11]C[C@@H]2CCCN(N(C=N)C(=O)OC)C2)=[O:10])=[O:6])CC1.CI.C(Cl)Cl>C1COCC1.C1CCN2C(=NCCC2)CC1>[CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[CH:39][C:30]=1[S:27]([NH:26][CH:8]([CH2:7][C:5]([NH2:4])=[O:6])[C:9]([NH2:11])=[O:10])(=[O:29])=[O:28]
Reactant: COC(=O)N(C=N)N1CCC[C@@H](CNC(=O)[C@H](CC(=O)N(CCCO)C2CC2)NS(=O)(=O)c2ccc3ccccc3c2)C1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CI
Product: NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)C(N)=O

Procedure:
274 mg of methyl [(S)-3-[(S)-3-[cyclopropyl-(3-hydroxypropyl)-carbamoyl]-2-(naphthalen-2-ylsulfonylamino)-propionylaminomethyl]-piperidin-1-yl]-imino-methylcarbamate (Example 63), 1 ml of 1N methyl iodide in THF, 2 ml of 1 molar DBU solution in THF and 2 ml of methylene chloride are stirred together at room temperature. The mixture is concentrated and the residue is chromatographed over silica gel with ethyl acetate-methanol 9:1. There are obtained 120 mg of (S)-N1-cyclopropyl-N4-[(S)-1-(iminomethoxycarbonylamino-methyl)-piperidin-3-ylmethyl]-N1-(3-methoxy-propyl)-2-(naphthalen-2-ylsulfonylamino-succinamide, MS (ISO): 631.6 (M+H).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:21]=1[C:22](O)=[O:23].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.CN1CCOCC1>CN(C=O)C.CO>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:21]=1[C:22]([NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[NH:10][C:7]1[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=1)=[O:23]
Reactant: COc1cccc(F)c1C(=O)O
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cccc(F)c1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
A solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 14 mg, 0.05 mmol), 2-fluoro-6-methoxybenzoic acid (CAS number 137654-21-8; 8.5 mg, 0.05 mmol), TOTU (20 mg, 0.06 mmol) and 4-methylmorpholine (0.008 ml, 0.075 mmol) in DMF (0.25 ml) was stirred at room temperature for 1 hour. The reaction was then diluted with methanol and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (eluted with acetonitrile/water with 0.1% ammonia) to afford the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:33][C@@H:34]([C@@H:36]4[CH2:40][C:39](=[O:41])[NH:38][CH2:37]4)[CH3:35])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH:23]6[CH2:25][CH:21]([N:22]6C(OC(C)(C)C)=O)[CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH:23]12[CH2:25][CH:21]([NH:22]1)[CH2:20][N:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]3[N:10]=[C:9]([O:33][C@@H:34]([C@H:36]4[CH2:37][NH:38][C:39](=[O:41])[CH2:40]4)[CH3:35])[C:8]4[N:4]([CH:1]5[CH2:3][CH2:2]5)[CH:5]=[N:6][C:7]=4[CH:12]=3)=[CH:18][CH:17]=1)[CH2:24]2
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CC4CC(C3)N4C(=O)OC(C)(C)C)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1nc(-c2ccc(N3CC4CC(C3)N4)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
In a round-bottomed, 100-mL, single-necked flask was placed tert-butyl 3-(4-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (200.0 mg, 0.27 mmol) in dichloromethane (1 mL). To this was added trifluoroacetic acid (3.1 ml, 40.81 mmol). The mixture was stirred at room temperature for 3 h. Then, it was neutralized with sat. NaHCO3 and the organic layers were extracted with dichloromethane (3×5 mL). The combined organic layers were washed with water (2×5 mL) and brine (1×5 mL), dried (Na2SO4), concentrated, and purified by flash chromatography (100% dichloromethane to 25% MeOH in dichloromethane) to give 124.8 mg (71%) of (4R)-4-((1R)-1-((6-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)phenyl)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.22 (s, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.61 (s, 1H), 7.57 (s, 1H), 6.78 (d, J=9.1 Hz, 2H), 5.57 (m, 1H), 3.57 (m, 8H), 2.84 (m, 2H), 2.57 (m, 1H), 2.39 (m, 3H), 1.53 (m, 1H), 1.41 (d, J=6.3 Hz, 3H), 1.18 (m, 4H). MS (ESI+) m/z 459.1 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][C:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH2:4]1>Br.CCO>[CH3:29][N:2]([CH3:1])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CC=C(c2[nH]c3ccccc3c2CCCCO)CC1
Agent: Br
Solvent: CCO
Product: CN(C)C1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCCCO)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(±)-4-[2-(4-Dimethylamino-4-phenylcyclohex-1-enyl)-1H-indol-3-yl]butan-1-ol (600 mg, 1.54 mmol) was dissolved in HBr/glacial acetic acid (33% HBr, 10 ml). Sn powder (1.81 g, 15.4 mmol) was then added to the mixture in portions at RT in the course of 2 h. When the addition had ended, the reaction mixture was stirred at RT for a further 16 h. For working up, the mixture was diluted with EtOH (10 ml) and concentrated to dryness on a rotary evaporator. The residue which remained was rendered basic by addition of 5 N NaOH (40 ml). The aqueous mixture obtained was extracted with methylene chloride (3×30 ml). The combined organic phases were dried over Na2SO4 and then concentrated. It was possible for the crude product obtained to be purified by column chromatography [silica gel 60 (50 g); MeOH (500 ml)]. 4-[2-(4-Dimethylamino-4-phenylcyclohexyl)-1H-indol-3-yl]butan-1-ol (less polar diastereomer) was obtained in a yield of 173 mg (29%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:37]2[N:42]=[C:41]([O:43]C)[C:40]([C:45]#[N:46])=[CH:39][CH:38]=2)=[CH:19]\[C@H:20]2[CH2:24][CH2:23][C:22](=[O:25])[N:21]2CC2C=CC(OC)=CC=2OC)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>C1(OC)C=CC=CC=1>[C:8]([C:12]1[CH:13]=[CH:14][C:15](/[C:18](/[C:37]2[NH:42][C:41](=[O:43])[C:40]([C:45]#[N:46])=[CH:39][CH:38]=2)=[CH:19]\[C@H:20]2[CH2:24][CH2:23][C:22](=[O:25])[NH:21]2)=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C#N)c(OC)n2)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(C#N)c(=O)[nH]2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-carbonitrile (32 mg) in anisole (1 mL), and the mixture was stirred at 85° C. overnight. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:5). The resulting compound was dissolved in 1,4-dioxane (1 mL) and 48% hydrobromic acid (1 mL) was added, after which the mixture was stirred at 65° C. for one hour. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:5→chloroform:methanol=5:1) to give the title compound (8 mg, 36%) as a colorless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][N:24]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)CBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc2CC1
Yield: 67.2 %

Procedure:
7-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 17) (100 mg, 0.238 mmol), ethyl bromoacetate (0.043 ml, 0.391 mmol) and cesium carbonate (170 mg, 0.521 mmol) were stirred at room temperature in DMF for 5 hours. The reaction mixture was diluted with diethyl ether (˜20 ml) and washed with water (2×˜20 ml), the organic layer was passed through a phase separating cartridge to dry and concentrated in vacuo to yield the title compound (77 mg, 0.16 mmol, 60% yield) as a yellow oil. δH (d6DMSO, 400 MHz): 8.19 (1H, s), 8.11 (1H, dd), 7.81-7.85 (2H, m), 7.45 (1H, d), 7.34 (1H, d), 4.89 (1H, sept), 4.07 (2H, q) 3.42 (2H, s), 3.00-291 (4H, m), 2.77-2.72 (4H, m), 1.36 (6H, d), 1.19 (3H, t). MS (ES): C25H2835ClN3O4 requires 469; found 470 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([N+:12]([O-])=O)[CH:3]=1>CC(O)=O.O.[Fe]>[NH2:12][C:4]1[CH:3]=[C:2]([Br:1])[C:10]([Cl:11])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1cc(Cl)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)c1cc(Cl)c(Br)cc1N
Temperature: 70 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 4-bromo-5-chloro-2-nitrobenzamide (900 mg, 3.2 mmol) in AcOH (20 mL) and water (5 mL) at 70° C., Fe powder (900 mg, 16.1 mmol) was added and the resulting mixture was stirred at 70° C. for 1 h. The mixture was allowed to cool to RT and poured into ice-water. The precipitate was collected by filtration and rinsed with water. This crude product was dissolved with ethyl acetate and filtered. The filtrate was washed with saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (770 mg, 97% yield). ESI-MS m/z: 250.1[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:13]Br>C(O)(=O)C>[NH2:1][C:2]1[C:11]([Br:13])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Nc1ccc2c(c1)C(=O)CCC2
Solvent: CC(=O)O
Product: Nc1ccc2c(c1Br)C(=O)CCC2
Reaction time: 0.17 h
Yield: 102.4 %

Procedure:
7-Amino-1-tetralone (457 mg, 2.83 mmol) was dissolved in acetic acid (8 mL) and treated with bromine (150 mL, 2.91 mmol) dropwise. After 10 min., more bromine (17 mL) was added. Then the solvent was evaporated off to give a light brown solid. It was partitioned between Na2CO3 solution and EtOAc. From the organic phase was obtained a semi-solid (696 mg). It was dissolved in CHCl3 and flash chromatographed over silica gel (50 g) eluting with EtOAc/hexane (1:4) to afford a yellow solid (320 mg, 47% yield): mp 93-96° C.
Reaction SMILES: Cl.[O:2]([CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)OCC[O:18]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCCCCC.CCOCC>C1COCC1>[O:2]([CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(COc1ccccc1)OCCCCC1(c2ccccc2)OCCO1
Agent: Cl
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(COc1ccccc1)OCCCCC(=O)c1ccccc1

Procedure:
This compound was synthesised as described under 1.e) with 1.45 ml of a 1N solution of HCl, 2.90 g (8.1 mmol) of 4-(2-phenyl-1,3-dioxolan-2-yl)butyl phenoxyacetate obtained under a) in 13 ml of THF for 17 h. Column chromatography (SiO2, heptane/ether 8:2) afforded 1.98 g (78%) of a slightly yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2([C:27](=[O:28])[NH:26][C:25](=[O:29])[NH:24]2)[C:16]1=[O:30].C(N(CC)CC)C>COCCOC.C1(C)C=CC=CC=1>[C:1]([N:24]1[C:17]2([C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([CH2:14][C:13]3[CH:31]=[CH:32][C:33]([Cl:34])=[C:11]([Cl:10])[CH:12]=3)[C:16]2=[O:30])[C:27](=[O:28])[NH:26][C:25]1=[O:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C2(C(=O)N(Cc3ccc(Cl)c(Cl)c3)c3ccccc32)N1C(=O)c1ccccc1
Reaction time: 3 h
Yield: 15.8 %

Procedure:
A solution of benzoyl chloride (0.63 g.) in 1,2-dimethoxyethane (10 ml.) was added dropwise to a stirred mixture of 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.8 g.) and triethylamine (0.51 g.) in 1,2-dimethoxyethane (50 ml.) cooled at 0°-5° C. When the addition was completed, the solution was stirred at 20°-25° C. for three hours. Silica gel (5 g., Merck type 7734) was added to the solution and the mixture was evaporated The residue obtained was added to the top of a column of silica gel (75 g., Merck type 7734) made up in toluene. The column was eluted with increasing concentration of ethyl acetate in toluene up to 25% v/v and the fractions containing the major product [Relative flow value: 0.4, on Merck SiO2TLC plates No. 5715; eluant: EtOAc/Toluene, 1:1 v/v] were collected, combined and evaporated. The solid thereby obtained was recrystallised from ethyl acetate/petrol 60-80 to give 3-benzoyl-1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (0.34 g.), m.p. 251°-253° C.
Reaction SMILES: [SH-].[Na+].[CH3:3][C:4]1([CH3:13])[O:8][N:7]=[C:6]([S:9]([CH3:12])(=O)=O)[CH2:5]1.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].[Cl:26][C:27]1[S:31][N:30]=[C:29]([CH3:32])[C:28]=1CCl>CN(C)C=O.O>[Cl:26][C:27]1[S:31][N:30]=[C:29]([CH3:32])[C:28]=1[CH2:12][S:9][C:6]1[CH2:5][C:4]([CH3:13])([CH3:3])[O:8][N:7]=1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: Cc1nsc(Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nsc(Cl)c1CSC1=NOC(C)(C)C1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
0.82 g of sodium hydrosulfide (purity: 70%, 10.00 mmoles) was added at the room temperature to a solution of 0.89 g (5.00 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto were added 0.70 g (5.00 mmoles) of anhydrous potassium carbonate, 0.78 g (5.00 mmoles) of Rongalit and 0.91 g (5.00 mmoles) of 5-chloro-4-chloromethyl-3-methylisothiazole. The resulting mixture was stirred at room temperature overnight to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.38 g (yield: quantitative) of [(5-chloro-3-methyl-isothiazol-4-yl)methylthio]-5,5-dimethyl-2-isoxazoline.