Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.[C:3]([NH:11][C:12]1[CH:17]=[C:16]([CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=O)[CH:15]=[CH:14][N:13]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:29][C:30]([NH2:32])=[S:31].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)(=O)C>[NH2:32][C:30]1[S:31][C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:17]=2)=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:29]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)cc1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(N)sc2-c2ccnc(NC(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
Bromine (0.11 mL, 2.1 mmol) was added to a solution of 2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (0.72 g, 2.1 mmol) in acetic acid (20 mL) at 0° C. and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was dissolved in acetonitrile (20 mL), to the solution were added thiourea (0.17 g, 2.2 mmol) and triethylamine (0.35 mL, 2.5 mmol) and the mixture was stirred at 80° C. for 5 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (200 mL) was added and the resulting solid was filtered and washed with water. The resulting crude crystals were collected by filtration and washed with water. The crude crystals were recrystallized from ethanol to obtain 0.17 g (0.43 mmol, yield 21%) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]([CH3:12])[C@H:3]([NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.C(=O)(O)[O-].[Na+].Cl[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:20]>O1CCCC1.O1CCOCC1>[CH2:22]([O:21][C:19]([NH:11][C@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1)[C@H:2]([CH3:12])[OH:1])=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C[C@H](O)[C@H](N)c1cccc(O)c1
Reactant: CCCCCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCCCCCOC(=O)N[C@H](c1cccc(O)c1)[C@H](C)O
Temperature: 0 °C
Yield: 96.3 %

Procedure:
To a solution of (1R,2S)-2-hydroxy-1-(3-hydroxyphenyl)propylamine (17.2 g) in tetrahydrofuran (500 ml) was added 0.5M aqueous solution of sodium bicarbonate (500 ml) and the mixture was stirred at 0° C. To the mixture was added a solution of hexyl chloroformate (14 g) in dioxane (20 ml) and the mixture was stirred for 30 minutes at 0° C. The reaction mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1→2:1→3:2) to give the title compound (24.2 g) having the following physical data.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:52]=[CH:51][C:33]([O:34][CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:52]=[CH:51][C:33]([O:34][CH2:35][CH2:36][CH2:37][N:38]5[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:42][CH2:43]5)=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3CCNCC3)cc2)CC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
DIPEA (2.417 mL, 13.88 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (2.059 g, 9.25 mmol) and tert-butyl 4-[3-[4-(piperidin-4-yl)phenoxy]propyl]piperazine-1-carboxylate (3.92 g, 9.71 mmol) in DMF (30 mL). The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and evaporated to dryness. The resulting solid was triturated with water, then collected by filtration, washed with ether and dried to afford tert-butyl 4-[3-[4-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]propyl]piperazine-1-carboxylate (4.67 g, 86%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@H:11]([CH2:21][O:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=2[N+:33]([O-:35])=[O:34])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([CH2:21][O:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=2[N+:33]([O-:35])=[O:34])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OC[C@@H]2C[C@@H](OCc3ccccc3)CN2)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a stirred solution of methyl (2S, 4R)4-[4-benzyloxy-1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-nitrobenzoate (681 mg, 1.4 mmol) in CH2Cl2 (2 mL) was added TFA (2 mL), and the resulting mixture was stirred for 2 hr. After the reaction mixture was concentrated, the residue was made basic by the addition of sat. NaHCO3 and extracted with CHCl3. The extract was washed with H2O, dried over MgSO4, and evaporated to give 511 mg (95%) methyl (2S,4R)-4-[4-benzyloxy-2-pyrrolidinyl]methoxy-3-nitrobenzoate as a yellow oil.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:19])=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].N([CH2:24][C@H]1OC(=O)N(C2C=CC(SCC)=C(F)C=2)C1)=[N+]=[N-].ClC1C=C(C=CC=1)C(OO)=O>>[N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:19][CH3:24])=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CCSc1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Reactant: CS(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Agent: O=C(OO)c1cccc(Cl)c1
Product: CCS(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F

Procedure:
This compound was prepared analogously to the synthesis of 5-(S)-azidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one from 5-(S)-azidomethyl-3-[4′-ethylthio-3′-fluorophenyl]oxazolidine-2-one (0.250 g, 0.844 mmol) and m-chloroperoxybenzoic acid (77%, 0.189 g, 0.844 mmol). Yield 0.235 g (89%). MS (m/z): [M+H]+=313.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][O:4][CH2:5][C:6](=[NH:9])OC.[NH3:12]>C(O)C>[F:1][C:2]([F:11])([F:10])[CH2:3][O:4][CH2:5][C:6]([NH2:12])=[NH:9]
Reactant: COC(=N)COCC(F)(F)F
Reactant: N
Solvent: CCO
Product: N=C(N)COCC(F)(F)F

Procedure:
Obtained using the procedure described in section b of Example 2, starting with 15.6 g (0.091 mole) of methyl 2-(2,2,2-trifluoroethoxy)acetimidate and 7.7 g (0.455 mole) of ammonia in 225 ml of absolute ethanol. Reaction time: 24 hours. Yld: 14.2 g (quantitative).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH:18]1([C:23](N(OC)C)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:23]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)C1CCCC1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)C2CCCC2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with cyclopentyl-N-methoxy-N-methylcarboxamide. It is used in crude form in the following reaction.
Reaction SMILES: [CH2:1]([N:3]([CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:4][CH3:5])[CH3:2].C([OH:19])C>>[CH2:1]([N+:3]([O-:19])([CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:4][CH3:5])[CH3:2]
Reactant: CCO
Reactant: CCCCC/C=C\C/C=C\CN(CC)CC
Product: CCCCC/C=C\C/C=C\C[N+]([O-])(CC)CC
Reaction time: 1 h
Yield: 95 %

Procedure:
4 G (18 mmole) of N,N-diethyl-undeca-2Z,5Z-dienyl-amine in 10 ml of ethanol were placed in a 25 ml flask under nitrogen and 4 ml of 70% oxygenated water were added thereto. The reaction mixture was maintained under stirring for 1 h and then left to rest at room temperature for 18 h. After evaporation, it was retaken with ethyl acetate and the organic phase, once separated, was washed with a saturated solution of NaCl, dried over Na2SO4 and evaporated to provide 4.09 g of N,N-diethyl-undeca-2Z,5Z-dienyl-amine N-oxide (yield: 95%).
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([C:10]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=2[Cl:36])=[CH:21][C:11]=1[O:12][CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14](Cl)=[O:15])#[N:9]>C(Cl)Cl>[CH2:1]([NH:7][C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:21]=[C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][C:27]=2[Cl:36])[CH:23]=[CH:24][C:10]=1[C:8]#[N:9])[CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: CCCCC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N)C(=O)Cl
Solvent: ClCCl
Product: CCCCC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N)C(=O)NCc1ccco1
Temperature: -15 °C

Procedure:
Furfurylamine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-cyano-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]hexanoyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. This residue is then purified by subjecting it to elution chromatography using mixtures of ethyl acetate and hexane with increasing concentrations of ethyl acetate as the eluant. The desired fractions determined by IR spectroscopy are then stripped of solvent to yield the desired product N-furfuryl-2-[2-cyano-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]hexanamide.
Reaction SMILES: [OH:1]O.[O-]Cl=O.[Na+].[Br:7][C:8]1[C:15]([CH3:16])=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([F:17])[CH:9]=1.Cl>O.CC#N>[Br:7][C:8]1[C:15]([CH3:16])=[CH:14][C:11]([C:12]([OH:1])=[O:13])=[C:10]([F:17])[CH:9]=1
Reactant: OO
Reactant: Cc1cc(C=O)c(F)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(=O)O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 100.3 %

Procedure:
NaH2PO4 (418 mg, 3.48 mmol) in H2O (17.6 ml), a 35% aqueous H2O2 solution (2.5 ml, 25.7 mmol) and NaClO2 (2.23 g, 24.7 mmol) in H2O (34.9 ml) were sequentially added to a mixture of 4-bromo-2-fluoro-5-methyl-benzaldehyde (3.74 g, 17.2 mmol) in MeCN (52 ml) at 0° C. The mixture was stirred at room temperature for 14 hours, and then made acidic (pH 3) with a 10% aqueous HCl solution and extracted with ethyl acetate (3×100 ml). The organic layers were washed with H2O (70 ml), and then dried over MgSO4 and concentrated under reduced pressure to give 4-bromo-2-fluoro-5-methyl-benzoic acid as a pale orange solid (4.02 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[CH:18]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:20])[CH3:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(OC(C)C)cc2)cn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 9.67 (br s, 1H, NH), 8.45 (d, 1H, J=1.8 Hz), 7.75 (d, 1H, J=8.8 Hz), 7.68 (dd, 1H, J=8.0 Hz, J=2.2 Hz), 7.55 (d, 2H, J=9.0 Hz), 7.50 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.32 (d, 1H, J=2.6 Hz), 7.24 (d, 1H, J=8.0 Hz), 6.68 (d, 2H, J=9.0 Hz), 4.43 (septet, 1H, J=6 Hz), 2.65 (s, 3H), 1.28 (d, 3H, J=6 Hz). MS: m/z 445 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].O.[OH-].[Li+].Cl>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1

Procedure:
Methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoate (3.02 g, 0.0064 mol) in MeOH (30 mL) was stirred with lithium hydroxide monohydrate (1.36 g, 0.032 mol) in H2O (15 mL) overnight at room temperature. The solution was treated with 3N HCl to adjust the pH to about 2.0 and cooled in an ice bath. Solid was collected and dried (2.4 g). The filtrate was treated with sat. aq. NaCl and extracted with EtOAc (2×). The extract was dried (Na2SO4) and concentrated to a residue. It was triturated with ether to afford the title compound as a white solid (143 mg only slightly inferior to the main product by LC-MS). Total product 2.56 g (88.7%). LC-MS m/z 452.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:1][C:2]1[CH2:10][CH:6]2[CH2:7][CH2:8][O:9][C:5]2=[CH:4][C:3]=1[CH:11]=[O:12])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc2c(cc1O)CCO2
Solvent: c1ccncc1
Product: CC(=O)OC1=C(C=O)C=C2OCCC2C1
Reaction time: 18 h
Yield: 73.6 %

Procedure:
A solution of 5-hydroxy-2,3-dihydrobenzofuran-6-carboxaldehyde (5.0 g, 0.030 mol) in pyridine (10 ml) was cooled to an internal temperature of -5° C. Acetic anhydride (3.2 g, 0.03 mol) was added dropwise. The cooling bath was removed and the mixture was allowed to stir under nitrogen for 18 hours. The reaction was quenched into water (50 ml) at which time the product crystallized and was collected by filtration. The product was dissolved in methylene chloride (100 ml) and was washed with water (25 ml), saturated sodium bicarbonate (25 ml) saturated sodium chloride (25 ml), dried (MgSO4) and concentrated to a dark oil which solidified on standing. The product was ground, washed with ethyl ether and dried to afford 5-acetoxy-3,4-dihydrobenzofuran-6-carboxaldehyde (4.6 g, 74%). m.p. 68°-70° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH3:10].[Br:11]Br>C(O)(=O)C>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([S:9][CH3:10])[CH:4]=[CH:5][C:6]=1[Br:11]
Reactant: CSc1cccc(C)c1C
Reactant: BrBr
Solvent: CC(=O)O
Product: CSc1ccc(Br)c(C)c1C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
510 g (3.33 mol) of 2,3-dimethylthioanisole are initially charged in 3 l of glacial acetic acid, and a solution of 592 g (7.4 mol) of bromine in 1 l of glacial acetic acid is added dropwise at room temperature over a period of three hours. The reaction is slightly exothermic. The reaction mixture is stirred at room temperature for another 3.5 hours. The precipitate is then filtered off with suction and the filtrate is admixed with 270 g of sodium acetate and concentrated. The residue is taken up in 2 l of dichloromethane and washed twice with 2 l of sodium bicarbonate solution and twice with sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated.
Reaction SMILES: Br.[OH:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].Br[CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1.O>CS(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: O=C(c1ccc(O)cc1)C1CCNCC1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccc(O)cc1)C1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 9.7 g of 4-(4-hydroxybenzoyl)piperidine hydrobromide, 6.4 g of sodium bicarbonate and 7.0 g of 3-(2-bromoethyl)indole in 90 ml of dimethylsulfoxide is stirred overnight under nitrogen at 50° C. After cooling to ambient temperature, water is added dropwise, precipitating a gummy brown solid. The supernatant solution is decanted from the solid, triturated with water, collected, and dried. Recrystallization from an ethanol-water mixture gives an off-white solid, mp 212°-214° C. (dec.) of 3-{2-[4-(4-hydroxybenzoyl)piperidyl]ethyl}indole.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O.[OH-].[Na+]>>[N+:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][NH:1]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(c1)NCC2
Temperature: 10 °C
Yield: 95 %

Procedure:
5.96 g (50 mmol) of indoline were dissolved in 25 ml of concentrated sulfric acid, and a mixture of 3.75 ml of concentrated nitric acid (61%) and 25 ml of concentrated sulfuric acid was added to the solution while ice-cooling so that the internal temperature was maintained at 10° C. or lower. The mixture was then stirred while ice-cooling for 2 hours. At the end of this time, a 75% w/v aqueous solution of sodium hydroxide was added to the reaction mixture while ice-cooling to neutralize the reaction mixture, while maintaining the internal temperature at 60° C. or lower. The mixture was then extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and, after filtration, the solvent was removed from the filtrate by distillation under reduced pressure to obtain 7.8 g (47.5 mmol) of the title compound as crystals, melting at 65-68° C. (yield: 95%).
Reaction SMILES: [O:1]1[CH2:6][C:2]1([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH2:3][C:4]#[CH:5].O>OS(O)(=O)=O.C(O)C>[CH3:5][C:4]1[O:1][CH:6]=[C:2]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[CH:3]=1
Reactant: C#CCC1(c2ccc(F)cc2)CO1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2ccc(F)cc2)co1
Temperature: 23 °C
Yield: 56.8 %

Procedure:
To a solution of 0.46 g (1.5 mmol) of mercuric sulfate in 28 mL of 2N H2SO4 at 0° C. was added 4.0 g (22 mmol) of 4,5-epoxy-4-(4'-fluorophenyl)-1-pentyne in 20 mL of ethanol over a 0.5 hour period. The mixture was warmed to 23° C. for 0.25 hour and refluxed for 0.25 hour. After cooling, the mixture was poured into 50 mL of H2O and extracted three times with hexanes. The organic layer was dried (MgSO4), concentrated under reduced pressure, and the solid sublimated (97°-105° C. at 15 mmHg) to yield 2.2 g (55%) of 2-methyl-4-(4'-fluorophenyl)furan as a solid (m.p. 95°-97° C.), homogeneous by spectroscopic criteria; IR (KBr) 1548, 1495, 1240 cm-1 ; 1HNMR (300 MHz, CDCl3) δ 7.55 (s, 1H), 7.43 (m, 2H), 7.07 (t, 2H, J=9 Hz), 6.27 (s, 1H), 2.33 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([CH3:27])[CH:21]=2)[C:13]=1[F:29])[CH:9]1[CH2:11][CH2:10]1)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:7][C@H:8]([CH:9]1[CH2:11][CH2:10]1)[C:12]1[C:13]([F:29])=[C:14]([C:19]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([CH3:27])[CH:21]=2)=[O:28])[C:15]([Cl:18])=[CH:16][CH:17]=1
Reactant: Cc1cc(C(=O)c2c(Cl)ccc([C@H](NC(=O)OC(C)(C)C)C3CC3)c2F)ccc1N
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C(=O)c2c(Cl)ccc([C@H](N)C3CC3)c2F)ccc1N
Reaction time: 18 h
Yield: 102.7 %

Procedure:
Step 3 To a solution of {(R)-[3-(4-amino-3-methyl-benzoyl)-4-chloro-2-fluoro-phenyl]-cyclopropyl-methyl}-carbamic acid tert-butyl ester (570 mg, 1.32 mmol) in DCM (6 mL) was added 4M HCl in dioxane (1.65 mL, 6.58 mmol, 5 eq) and the reaction stirred for 18 hours. The resulting mixture was partitioned between DCM (50 mL) and water (20 mL) and basified with NaOH. Not all of the compound dissolved and so the aqueous phase was extracted with 4:1 CHCl3:IPA (2×30 mL). The combined organics were washed with brine (20 mL) and then dried (MgSO4), filtered and concentrated to give [3-((R)-amino-cyclopropyl-methyl)-6-chloro-2-fluoro-phenyl]-(4-amino-3-methyl-phenyl)-methanone (451 mg).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:13]1(=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.Cl.C(O)C.O>C(O)C>[CH:2]([C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:15]3[C:16]4[C:21]([CH2:13][C:14]=3[C:7]=2[CH:6]=1)=[CH:20][CH:19]=[CH:18][CH:17]=4)([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc(NN)cc1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-isopropylphenylhydrazine hydrochloride (6.3 g, 34 mmol) and 1-indanone (4.5 g, 34 mmol) were heated to reflux in ethanol (40 cm3) containing concentrated hydrochloric acid (2 cm3). Heating was continued for 4 hours, and then the reaction mixture was cooled to room temperature during which time the product crystallised out of solution as colourless crystals. This compound was filtered off, dried in a vacuum oven, and recrystallised from ethanol/water to yield colourless prisms. Yield: 6.59 g, (79%). M.p. 193° C. (from ethanol/water). 1H NMR (DMSO-d6) δ: 1.27 (6H, d,), 2.96 (1H, septet,), 3.65 (2H, s,), 6.9-7.6 (7H, m,), 11.2 (1H, br,).
Reaction SMILES: C([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)(OC(C)(C)C)=O>C(Cl)Cl>[NH2:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Solvent: ClCCl
Product: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reaction time: 0.17 h

Procedure:
While maintaining the nitrogen gas atmosphere, 3 fold molar excess of the benzyl ester of Boc-L-Histidine (Vega, supra.) dissolved in 15 ml. of methylene chloride is added to the residue of Step (H) above. The resulting mixture is shaken and after about 10 minutes, 3 fold molar excess of N,N-dicyclohexylcarbodiimide in 15-20 ml. of methylene chloride is added with stirring. The resulting mixture is shaken at room temperature for 4.5 to 5 hours. At the end of this period, the reaction mixture is filtered and the residue washed and dried.