Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])[CH:7]=1.[N:24]#[C:25]Br>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:21]=[C:25]([NH2:24])[N:9]([CH2:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:8]2
Reactant: N#CBr
Reactant: COc1cccc(OC)c1CNCc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COc1cccc(OC)c1CN1Cc2cc(Cl)ccc2N=C1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 122.3 %

Procedure:
1-(5-Chloro-2-nitrophenyl)-N-(2,6-dimethoxybenzyl)methanamine (6.50 g, 21.2 mmol) was dissolved in 160 mL dioxane and cyanogen bromide (3.24 g, 29.6 mmol) dissolved in 20 mL dioxane was added. A slightly yellowish suspension was formed immediately. The reaction mixture was heated for 2 hours at reflux. The entire reaction mixture was completely dissolved at 85° C. and a colorless precipitate began to form at 75° C. The mixture was cooled to room temperature and stirring was continued for 12 hours. The resulting precipitate was filtered out and rewashed with dioxane (2×), isolating the crude product (8.6 g) after drying in a vacuum drying cabinet at 40° C. For purification and release of the hydrobromide salt, the solids were dissolved in dichloromethane again and alkalized with 2N sodium hydroxide solution. A portion of the product was precipitated immediately, filtered out and dried. The two phases of the mother liquor was separated and the resulting organic phase was washed with water (3×), whereupon a crystal product was again formed from it. The organic aqueous phase was concentrated in vacuo and the solids were filtered out. The two solids that were isolated in succession were combined.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O>[Si:16]([O:15][CH2:14][CH2:13][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:13])[CH:5]=[CH:4]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)c1cccc2ccn(CCO[Si](C)(C)C(C)(C)C)c12
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Add sodium hydride (2.75 g, 24 mmol, 35% in mineral oil) to 1-(tert-butyldimethylsilyloxy)eth-1-yl)indole (5.5 g, 20 mmol) in N,N-dimethylformamide (50 ml) and stir for 15 minutes at 20° C. Add (2-bromoethoxy)-tert-butyldimethylsilane and stir at 20° C. for 4 hours. Dilute with hexanes. Wash with 0.25 M aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. Dry over magnesium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with hexane containing 30% ethyl acetate to provide the desired compound (8.0 g, 89%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]([C:8]([NH:10][CH2:11][CH2:12][S:13][C:14]([CH3:16])=[O:15])=[O:9])[CH2:6][SH:7])=[O:3].N[C@H](C(O)=O)CS.C(N[C@H](C(O)=O)CS[C:31]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)C.Cl.C(SCCN)(=O)C>>[C:2]([NH:4][C@H:5]([C:8]([NH:10][CH2:11][CH2:12][S:13][C:14](=[O:15])[CH3:16])=[O:9])[CH2:6][S:7][C:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CC(=O)N[C@@H](CS)C(=O)NCCSC(C)=O
Agent: CC(=O)SCCN
Agent: Cl
Agent: N[C@@H](CS)C(=O)O
Product: CC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(C)=O

Procedure:
The first process for the preparation of the compound I-152 (scheme 1) corresponds to the process for the preparation of the compound of general formula (I) described above and involves correctly protected L-cysteine. This preparation process is characterized in that it comprises the following stages (i) of coupling of N-acetyl-S-trityl-L-cysteine (7) with S-acetylcysteamine hydrochloride to provide the compound N-(N-acetyl-S-trityl-L-cysteinyl)-S-acetylcysteamine (8); then (ii) of S-detritylation reaction of the compound N-(N-acetyl-S-trityl-L-cysteinyl)-S-acetylcysteamine, in solution in methanol and chloroform, with a mixture of silver nitrate, pyridine and methanol to provide the corresponding silver sulfide (9); then (iii) of suspending said corresponding silver sulfide in chloroform; then (iv) of release of the free thiol in the presence of HCl or H2S.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].Br[CH2:12][C:13]1[C:23]([F:24])=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([F:25])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH2:12][C:13]2[C:23]([F:24])=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([F:25])[CH:14]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(O)cc1Cl
Reactant: CCOC(=O)c1cc(F)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(F)c(COc2cnc(OC)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
To a solution of 5-chloro-6-methoxypyridin-3-ol (Preparation 56, 98 mg, 0.612 mmol) in acetone (10 mL) were added ethyl 4-(bromomethyl)-2,5-difluorobenzoate (Preparation 19, 171 mg, 0.612 mmol) and potassium carbonate (170 mg, 1.224 mmol). The mixture was stirred for 18 hours at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with water (20 mL), and extracted with DCM (2×30 mL). Combined organic extracts were dried over sodium sulphate, and evaporated to a yellow solid. The solid was purified by silica gel chromatography eluting with DCM/heptanes (3:2) to afford the title compound as a white solid (112 mg, 51%).
Reaction SMILES: [O:1]=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([OH:18])=[O:17].S(=O)(=O)(O)O.[CH3:24]O>CCOCC>[O:1]=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17]
Reactant: CO
Reactant: O=C(O)CCC1CCCCCCCCCCC1=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)CCC1CCCCCCCCCCC1=O
Yield: 83 %

Procedure:
A solution of 3-(2-oxocyclododecyl)-propionic acid (7.0 g, 27.5 mmol) in methanol (80 mL) was treated with concentrated sulfuric acid (0.3 mL, 5.4 mmol) and the mixture heated under reflux for 1 hour. After concentration of the reaction mixture in vacuo the residue was diluted with ether (1.1L) and washed sequentially with saturated sodium bicarbonate (100 mL) and water (2×100 mL). The organic phase was dried over magnesium sulfate and evaporated in vacuo to a crude oil (7.1 g, 96%). Purification by flash column chromatography on silica gel (100:1 ratio) by elution with hexane/ethyl acetate (95/5) afforded 6.1 g (83% yield) of the title compound as a waxy solid on cooling, m.p. 33°-35° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[N:4][CH:3]=1.[Cl:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]2[C:16]=1[CH:17]=[C:18]([C:26]1[C:27]([NH2:41])=[N:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=1)[N:19]=[CH:20]2.C(=O)([O-])[O-].[K+].[K+].[ClH:48]>C(Cl)Cl.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[ClH:14].[ClH:48].[ClH:14].[Cl:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]2[C:16]=1[CH:17]=[C:18]([C:26]1[C:27]([NH2:41])=[N:28][CH:29]=[C:30]([C:2]3[S:6][C:5]([N:7]4[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]4)=[N:4][CH:3]=3)[CH:31]=1)[N:19]=[CH:20]2
Reactant: CC1(C)OB(c2cnc(N)c(-c3cc4c(Cl)ccc(F)c4cn3)c2)OC1(C)C
Reactant: CN1CCN(c2ncc(Br)s2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CN1CCN(c2ncc(-c3cnc(N)c(-c4cc5c(Cl)ccc(F)c5cn4)c3)s2)CC1
Temperature: 100 °C

Procedure:
A solution of 1-(5-bromothiazol-2-yl)-4-methylpiperazine (45 mg, 0.17 mmol), 3-(5-chloro-8-fluoroisoquinolin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB5) (89.2 mg, 0.223 mmol), potassium carbonate (71.2 mg, 0.515 mmol), and Pd(PPh3)4 (11.9 mg, 0.0103 mmol) in previously degassed DME/Water (4:1) (3.0 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 45 min. The reaction mixture was partitioned between CHCl3 and H2O, and the layers were separated. The aqueous layer was re-extracted with CHCl3 (3×), and the combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 1% MeOH in CHCl3] resulting in a pure yellow solid. This sample was then dissolved in a minimum of DCM then charged with 3 equiv of 1M HCl in ether and the reaction mixture was concentrated in vacuo resulting in the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.83 (d, J=4.0 Hz, 3H), 3.13-3.28 (m, 2H), 3.45-3.60 (m, 4H), 4.07 (d, J=14.3 Hz, 2H), 7.67 (t, J=8.0 Hz, 1H), 7.84 (s, 1H), 8.11 (dd, J=8.4, 4.8 Hz, 1H), 8.27 (d, J=2.2 Hz, 1H), 8.54 (s, 1H), 8.61 (s, 1H), 9.67 (s, 1H), 11.05 (br. s., 1H). MS (ES+): m/z=455.07/457.08 (76/24) [MH+]. HPLC: tR=1.99 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:7][CH:8]([CH:10]([OH:13])[CH2:11][CH3:12])[CH3:9].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH2:11]([CH:10]([O:13][C:1](=[O:5])[CH2:2][CH:3]=[CH2:4])[CH:8]([CH3:9])[CH3:7])[CH3:12]
Reactant: CCC(O)C(C)C
Reactant: C/C=C/C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(=O)OC(CC)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Crotonoyl chloride (21.5 g) in dichloromethane (CH2Cl2) (100 mL) was charged into a 2-L reaction flask and cooled to 0° C. 2-Methyl-pentan-3-ol (prepared as above in EXAMPLE IV) (21 g) was added followed by diisopropylethylamine (31.9 g). The reaction mixture was aged at about 0-10° C. for about 30 minutes and poured into dilute hydrochloric acid (HCl) (33 g in 170 g water). Hexanes were added and the aqueous and organic layers were split. The organic layer was separated and subsequently purified via liquid chromatography to provide but-3-enoic acid 1-ethyl-2-methyl-propyl ester (28 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[C:29]([F:32])([F:31])[F:30])[CH:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[C:29]([F:30])([F:31])[F:32])[CH:20]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: FC(F)(F)c1cccc2cc(CBr)ccc12
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Product: COC1(c2cc(F)cc(OCc3ccc4c(C(F)(F)F)cccc4c3)c2)CCOCC1
Yield: 36 %

Procedure:
Using the procedure described in Example 5, 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran was reacted with 2-bromomethyl-5-trifluoromethylnaphthalene to give 4-[5-fluoro-3-(5-trifluoromethylnaphth-2-ylmethoxy)phenyl]-4-methoxytetrahydropyran in 36% yield, as an oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:35]([C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=5)(=[O:37])=[O:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, white solid (119 mg, 97%), MS (ISP) m/z=489.3 [(M+H)+], mp 148° C., was prepared in accordance with the general method of example 26 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH2:1]1[CH2:28][O:27][CH:3]([CH2:4][C@H:5]2[C@H:9]([O:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH2:8][C@H:7]([OH:17])[C@@H:6]2[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[O:2]1.[N+](=[CH2:31])=[N-]>CCOCC>[CH2:28]1[CH2:1][O:2][CH:3]([CH2:4][C@H:5]2[C@H:9]([O:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH2:8][C@H:7]([OH:17])[C@@H:6]2[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:31])=[O:25])[O:27]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](CC2OCCO2)[C@H](OC2CCCCO2)C[C@@H]1O
Solvent: CCOCC
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](CC2OCCO2)[C@H](OC2CCCCO2)C[C@@H]1O

Procedure:
The carboxylic acid (59) was treated with diazomethane in ether (150 ml) to give the methyl ester (60). The crude product obtained after the work-up was chromatographed on a column of silica gel (hexane/ethyl acetate =3/2).
Reaction SMILES: C(O[CH:4](O)[C:5]([C:7]1[CH:8]=[C:9]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=1)=[O:6])C.[I:24][C:25]1[N:26]=[CH:27][N:28]([CH2:30][CH2:31][C:32]([NH2:35])([CH3:34])[CH3:33])[CH:29]=1.[BH4-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:6][CH:5]([C:7]1[CH:8]=[C:9]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH:10]=[CH:11][CH:12]=1)[CH2:4][NH:35][C:32]([CH3:34])([CH3:33])[CH2:31][CH2:30][N:28]1[CH:29]=[C:25]([I:24])[N:26]=[CH:27]1
Reactant: CCOC(O)C(=O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Reactant: CC(C)(N)CCn1cnc(I)c1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(CCn1cnc(I)c1)NCC(O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 45.1 %

Procedure:
7.81 g (23.3 mmol) N-[3-(2-ethoxy-2-hydroxy-acetyl)-phenyl]-benzenesulphonamide and 6.50 g (23.3 mmol) 3-(4-iodo-imidazol-1-yl)-1,1-dimethyl-propylamine in 40 mL ethanol were refluxed for 15 h. The reaction mixture was cooled to 0° C. and then combined with 3.70 g (97.9 mmol) sodium borohydride. It was stirred for a further 24 h at ambient temperature stirred and then combined with 20 mL saturated aqueous potassium carbonate solution. The aqueous phase was separated from the organic phase and extracted twice with 50 mL ethyl acetate. The combined organic phases were washed with 20 mL saturated, aqueous sodium chloride solution, dried over magnesium sulphate and freed from the solvent using the rotary evaporator. The residue was purified by flash column chromatography [methylene chloride/methanol/ammonia (90:10:1)]. 12.9 g (10.5 mmol, 45%) N-(3-{1-hydroxy-2-[3-(4-iodo-imidazol-1-yl)-1,1-dimethyl-propylamino]-ethyl}-phenyl)-benzenesulphonamide were obtained as a colourless solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH:12]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[S:15][CH:14]([CH:28]([N:36]2[C:40](=[O:41])[C:39]3=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]3[C:37]2=[O:46])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:13]1)([OH:11])=[O:10]>CN(C)C=O>[CH2:1]([O:11][C:9]([CH:12]1[C:16]2([CH2:17][CH2:18][N:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]2)[S:15][CH:14]([CH:28]([N:36]2[C:37](=[O:46])[C:38]3=[CH:45][CH:44]=[CH:43][CH:42]=[C:39]3[C:40]2=[O:41])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(C1NC(C(=O)O)C2(CCN(c3ccccc3)CC2)S1)N1C(=O)c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
17 g (0.10 mole) of benzyl bromide, dissolved in 20 ml of N,N-dimethylformamide are added to 24 g (0.0447 mole) of the alpha-isomer of tert-butyl 4-carboxy-8-phenyl-alpha-phthalimido-1-thia-3,8-diazaspiro[4.5]decane-2-acetate, obtained in 2.3, dissolved in 200 ml of N,N-dimethylformamide. The reaction mixture is stirred overnight at ambient temperature and is then poured onto ice, extracted three times with 500 ml amounts of ethyl acetate and the organic phase washed successively with a little water, with a saturated aqueous solution of sodium hydrogen carbonate and again with a little water. The solution is then dried and evaporated to dryness. After recrystallization from ethyl acetate, there are obtained 18.8 g tert-butyl 4-benzyloxycarbonyl-8-phenyl-alpha-phthalimido-1-thia-3,8-diazaspiro[4.5]decane-2-acetate. Yield: 66%; M.P. 184°-185° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(F)cc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21
Temperature: 0 °C
Yield: 96 %

Procedure:
In 15 ml of concentrated sulfuric acid, under below 0° C., 1.20 g of ethyl 2-(7-fluoro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate were added to dissolve the latter in the former. While stirring, 0.21 ml of fuming nitric acid (d=1.52) was added dropwise to the resulting solution and they were stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice water. The crystals so precipitated were collected by filtration, washed with water and then, dried under reduced pressure to give 1.35 g (96%) of ethyl 2-(7-fluoro-6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][OH:10].Cl.[OH-].[Na+]>C(O)C.O>[CH:1](=[N:9]/[OH:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C\c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of benzaldehyde (3 g, 28.3 mmol) in ethanol (50 mL) and water (30 mL), NH2OH hydrochloride (3.9 g, 56.6 mmol) and sodium hydroxide (2.26 g, 56.6 mmol) were added. The mixture was heated at reflux for 6 hours. The resulting mixture was cooled to room temperature and extracted with EtOAc, and the organic layer was dried over anhydrous sodium sulfate. The solution was then concentrated under vacuum to give the title compound as an oil-like solid (3.4 g), which was used in the next step without further purification. MS (ESI) m/z 121 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:29])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:10]=2)[CH:8]=1.[CH3:30][O:31][C:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38])=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[F:29][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:37]([C:36]2[CH:40]=[CH:41][CH:42]=[C:34]([C:32]([O:31][CH3:30])=[O:33])[CH:35]=2)=[O:38])=[CH:8][C:7]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CN)ccc3F)c2)CC1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.6 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.200 g, 0.5 mmol) in CH2Cl2 (5 mL) was added 3-[(methyloxy)carbonyl]benzoic acid (0.0901 g, 0.5 mmol), HBTU (0.19 g, 0.5 mmol), and Et3N (0.0703 mL, 0.5 mmol). The mixture was stirred at room temperature for 18 h and then quenched with H2O. The organic layer was separated, concentrated and purified by CombiFlash chromatograph to afford the title compound 0.26 g (93%). LC-MS m/z 562 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:8][CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:5][CH:4]=1.Br.[OH-].[NH4+]>O>[NH:16]1[CH:17]=[C:13]([CH2:12][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([OH:2])[CH:11]=3)[CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:8]2)[N:14]=[CH:15]1
Reactant: COc1ccc2c(c1)C(Cc1c[nH]cn1)CC2c1ccccc1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc2c(c1)C(Cc1c[nH]cn1)CC2c1ccccc1

Procedure:
A mixture of 4-(6-methoxy-3-phenylindan-1-ylmethyl)-1H-imidazole (500 mg) and 48% hydrobromic acid (20 ml) was heated at reflux for 1 hr with stirring. The cooled reaction mixture was poured into water and made basic with ammonium hydroxide solution. The resulting precipitate was filtered and washed with water. The product was purified by flash chromatography (elution with a dichloromethane—methanol gradient).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.C(NC1C=CC([O:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([O:36][Si](C(C)(C)C)(C)C)[CH2:32][CH2:31]2)=O)=NC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.F>C(#N)C.CCCCCCC>[F:10][C:8]([F:9])([F:11])[C:5]1[CH:6]=[CH:7][C:2]([O:1][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)=[O:27])=[N:3][CH:4]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C(=O)Oc2ccc(NC(=O)c3ccccc3)cn2)CC1
Reactant: Oc1ccc(C(F)(F)F)cn1
Agent: F
Solvent: CC#N
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(C(F)(F)F)cn1)N1CCC(O)CC1
Reaction time: 18 h
Yield: 46.5 %

Procedure:
A solution of 2-hydroxy-5-trifluoromethylpyridine (0.32 g, 2.00 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester (0.90 g, 2.00 mmol) and triethylamine (0.20 g, 2.00 mmol) in acetonitrile (10 mL) was stirred at room temperature for three days. Hydrofluoric acid (min. 40% in water, 0.50 mL) was added and stirring was continued for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 75:25), followed by crystallisation from ethyl acetate:heptane, yielding the title compound (0.27 g, 47% yield) as a white solid.