Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Mg+2:2].[OH-].[C:4](=[O:7])([OH:6])[O-:5].[Na+:8]>>[C:4](=[O:5])([O-:7])[O-:6].[Mg+2:2].[C:4](=[O:5])([O-:7])[O-:6].[Na+:8].[Na+:8]
Reactant: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])[O-]

Procedure:
In one embodiment, the invention relates to a process of producing magnesium metal in which the sodium hydroxide used as a reactant in an initial step of the process is recovered in a later step of the process and recycled. For example, steps 5-7 in FIGS. 1-4 illustrate this use and recovery of sodium hydroxide. The process comprises: (a) reacting a magnesium silicate with sodium hydroxide to produce magnesium hydroxide; (b) reacting the magnesium hydroxide with sodium bicarbonate to produce magnesium carbonate and sodium carbonate; (c) reacting the magnesium carbonate in one or more reactions to produce magnesium metal; (d) reacting the sodium carbonate with a metal hydroxide to produce sodium hydroxide; and (e) recycling the sodium hydroxide from step (d) into step (a). In one embodiment the metal hydroxide of step (d) is calcium hydroxide.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19]C1C=CC(C(N)=O)=C(F)C=1>>[CH2:1]([S:8][C:9]1[CH:17]=[C:16]([Cl:19])[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(Cl)ccc1SCc1ccccc1
Reactant: NC(=O)c1ccc(Cl)cc1F
Product: NC(=O)c1ccc(Cl)cc1SCc1ccccc1

Procedure:
A method similar to the preparation of 2-benzylsulphanyl-5-chlorobenzamide (see page 17 above) was followed using 4-chloro-2-fluorobenzamide (400 mg, 2.31 mmol). The title compound was isolated as a white solid (376 mg, 59%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)=[O:8].S(Cl)([Cl:20])=O>ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([Cl:20])=[O:17])[CH2:10]1)=[O:8]
Reactant: O=C(O)C1CCCN(C(=O)Cc2cccs2)C1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C1CCCN(C(=O)Cc2cccs2)C1
Temperature: 25 °C

Procedure:
1-(2-thiopheneacetyl)-3-piperidine carboxylic acid (1.3 g; 5.1 mmol) was dissolved in dry dichloromethane (35 ml) under a nitrogen atmosphere. Thionyl chloride (3 ml. 41.3 mmol) was added and the mixture was heated to reflux for approximately 1 hour. It was then cooled to ambient temperature and evaporated under reduced pressure, giving 1-(2-thiopheneacetyl)-3-piperidinecarbonyl chloride as a brownish oil. MS m/z (positive ion; run in CH3CN) 274 ([M+2]H+; 50), 272 (MH+; 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.CS(O[CH2:17][CH2:18][CH2:19][O:20][CH3:21])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Reactant: COCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCCn1c(=O)oc2ccc(Br)cc21
Temperature: 70 °C
Yield: 102 %

Procedure:
A mixture of 5-bromobenzo[d]oxazol-2(3H)-one (1.1 g), 3-methoxypropyl methanesulfonate (1.297 g) and potassium carbonate (2.131 g) in acetonitrile (25 mL) was heated at 70° C. for 16 h. Water was added and the mixture was extracted with ethyl acetate (3 times). The organic layers were dried (MgSO4), evaporated and purified by flash chromatography (silica, isohexane-acetone (5:1) as eluent) to give the sub-titled compound (1.50 g) as an oil.
Reaction SMILES: C([Mg]Cl)(C)C.Cl.[CH3:7][NH:8][O:9][CH3:10].[CH:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]([C:18]([O:20]CC)=O)[N:12]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C1COCC1>[CH3:10][O:9][N:8]([CH3:7])[C:18]([CH:13]1[CH:14]2[CH2:17][CH:11]([CH2:16][CH2:15]2)[N:12]1[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[O:20]
Reactant: CCOC(=O)C1C2CCC(C2)N1C(=O)OC(C)(C)C
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C1C2CCC(C2)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
Isopropylmagnesium chloride (41.3 mL of a 2 M solution in THF, 82.6 mmol) was added dropwise to a cooled 0° C. mixture of N,O-dimethylhydroxylamine hydrochloride (4.0 g, 41.3 mmol) and 2-tert-butyl 3-ethyl 2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (prepared according to procedures described in EP 947506) (7.9 g, 29.5 mmol) in THF (50 mL). The mixture was stirred for 30 min and quenched with saturated aqueous ammonium chloride (50 mL) and 33% aqueous ammonia (50 mL). The mixture was extracted into ethyl acetate (2×100 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified on silica gel eluting with iso-hexane on a gradient of ethyl acetate (0-60%) to give the title product (6.17 g, 73%). 1H NMR (400 MHz, CDCl3, δ 1:1 mixture of rotamers): δ 4.37 (0.5H, s), 4.24 (0.5H, s), 4.13 (0.5H, s), 4.06 (0.5H, s), 3.78-3.71 (3H, m), 3.21-3.19 (3H, m), 2.58 (1H, m), 2.10-2.00 (1H, m), 1.80-1.40 (4H, m), 1.44 (4.5H, s) and 1.39 (4.5H, m), 1.19 (1H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2].C1C(=O)N([Br:33])C(=O)C1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:33])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Solvent: ClCCl
Product: CCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Yield: 72.2 %

Procedure:
A mixture of 4-hydroxy-7-(4-fluoro-2-chloro-phenoxy)-isoquinoline-3-carboxylic acid ethyl ester (610 mg, 1.69 mmol) and NBS (331 mg, 1.86 mmol) in CH2Cl2 (17 mL) was refluxed for 3 h and then concentrated. Residue was triturate with acetone (15 mL). Solid was collected and dried to provide the title compound 540 mg (1.22 mmol) in 73% yield. 1H NMR (200 MHz) in CDCl3, δ ppm: 11.90 (s, 1H), 8.37 (d, J=8.8 Hz, 1H), 7.47 (m, 2H), 7.15 (m, 3H), 4.54 (br q, J=7.3 Hz, 2H), 1.49 (br t, J=7.3 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Br)c4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-bromophenyl)-5-oxopentyl]-4-piperidinyl]phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 572.0 (M+H)+.
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:15])([F:14])[C:8](=[O:13])[CH2:9][CH2:10][CH2:11]O.[Br:16]Br>CCOCC>[F:6][C:7]([F:15])([F:14])[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][Br:16]
Reactant: O=C(CCCO)C(F)(F)F
Reactant: BrBr
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(CCCBr)C(F)(F)F
Temperature: -5 °C
Reaction time: 8 h

Procedure:
A 500 mL three neck round bottom flask, fitted with dropping funnel, magnetic stirrer, ice-salt bath, and argon inlet is charged with 125 mL of dry dimethylformamide, 29 g(35.7 mM) of trifluoro-5-hydroxy-2-pentanone. This mixture was cooled to -5° C. and 11.5 g(71.6 mM) of bromine was added dropwise over a two hour period. After stirring overnight at ambient temperature the reaction mixture was distilled through a 30 cm vigreaux column at 2.0 mm of pressure. Two fractions were collected; the first fraction from 27°-35° C. and the second fraction at 35°-70° C. The second fraction was partitioned between water and ethyl ether, the organic layer was washed with water (3×100 mL, dried (anhydrous MgSO4), and evaporated under reduced pressure at ambient temperature to give 40 g of a colorless oil mixture of dimethyl formamide, ether, and the desired product which was used in the next reaction without further purification.
Reaction SMILES: [C:1]([C:4](=[CH:8][CH2:9][CH2:10][CH3:11])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:6][C:5]([C:4]1[CH:8]=[C:9]([CH2:10][CH3:11])[O:3][C:1]=1[CH3:2])=[O:7]
Reactant: CCCC=C(C(C)=O)C(C)=O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1cc(C(C)=O)c(C)o1
Yield: 99.9 %

Procedure:
A mixture of 3.56 g (0.02 mole) 3-acetyl-3-hepten-2-one and 3.55 g (0.02 mole) N-bromosuccinimide in 50 ml of carbon tetrachloride was heated at reflux for 2 hours. After cooling, the succinimide was removed by filtration and the solution concentrated in vacuo. Distillation of the crude product gave 3.04 g (86%) of 5-ethyl-2-methyl-3-furyl methyl ketone, bp 84°-87° C. (9 mm).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[NH2:14])=[CH:6][CH:5]=1.[CH3:15][S:16][C:17](SC)=[N:18][C:19]#[N:20]>C(O)C>[C:19]([N:18]=[C:17]([S:16][CH3:15])[NH:14][CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1)#[N:20]
Reactant: CSC(=NC#N)SC
Reactant: COc1ccc2c(c1)C(N)CCC2
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)C(NC(=NC#N)SC)CCC2
Reaction time: 48 h
Yield: 86.8 %

Procedure:
To a stirred solution of 17.8 g of 7-methoxy-1,2,3,4-tetrahydro-1-naphthylamine hydrochloride in 150 ml of ethanol at 0° C. was added 15.5 g of dimethyl cyanodithioiminocarbonate over a period of 30 minutes. The mixture was then allowed to remain at room temperature for 2 days after which the reaction mixture was cooled and the resulting crystals were collected by filtration. Concentration of the mother liquor gave a second crop of crystals. The combined product was recrystallized from ethanol to give 19.9 g of N'-cyano-N-(7-methoxy-1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea as colorless plates, mp 131°-132° C.
Reaction SMILES: F[C:2]1[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:12]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>C(O)C>[CH:12]1([NH:21][C:2]2[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Reactant: NC1CCc2ccccc21
Solvent: CCO
Product: O=[N+]([O-])c1cc[n+]([O-])cc1NC1CCc2ccccc21
Yield: 95.7 %

Procedure:
A solution of 3-fluoro-4-nitropyridine-1-oxide (5.6 g) and indan-1-amine (6 g) in 100 ml ethanol was stirred at reflux for one hour and thereafter cooled and concentrated to 12 g of solid. This solid was purified by flash chromatography (silica, ethyl acetate in dichloromethane) to give 9.2 g solid, m.p. 137°-138°. An analytical sample was obtained by recrystallizing 2.7 g from ethanol to give 2.5 g crystals, m.p. 141°-142°.
Reaction SMILES: [CH3:1][N:2]1[C@:6]([CH2:13][OH:14])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)[C:3]1=[O:28].CN(C1C=CC=CN=1)C.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH2:40][CH2:39]1>N1C=CC=CC=1>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:4]2[C:5](=[O:15])[C:6]([CH2:13][O:14][C@@H:40]([CH2:39][CH:38]=[O:44])[C:41]([OH:43])=[O:42])([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:2]([CH3:1])[C:3]2=[O:28])=[CH:17][C:18]=1[C:24]([F:25])([F:27])[F:26])#[N:21]
Reactant: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)[C@@]1(CO)c1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO[C@@H](CC=O)C(=O)O)c1ccccc1
Temperature: 110 °C
Reaction time: 7 h

Procedure:
To a solution of 0.60 g of (S)-4-[3-methyl-4-hydroxymethyl-2,5-dioxo-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile in 24 mL of pyridine was added 19 mg of dimethylaminopyridine and 1.54 g of succinic anhydride. The mixture is stirred at 110° C. for 7 hours then evaporated to dryness. The crude product is washed with water and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 50/50 heptane/ethyl acetate to give the desired compound.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][S:8]([CH3:11])(=[O:10])=[O:9].[NH2:12][C:13]([CH3:30])([CH3:29])[CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](OC)=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1.C(O)(C(F)(F)F)=O>CS(C)=O>[NH2:12][C:13]([CH3:30])([CH3:29])[CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](=[O:26])[CH2:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1
Reactant: CS(C)(=O)=O
Reactant: COC(=O)c1ccc2c(ccn2CCC(C)(C)N)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)(N)CCn1ccc2cc(C(=O)CS(C)(=O)=O)ccc21
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Potassium tert. butoxide (741 mg, 6.62 mmol) is added in two batches to a solution of dimethylsulphone (661 mg, 7.03 mmol) in 5 ml DMSO. After 10 minutes stirring at RT a solution of methyl 1-(3-amino-3-methyl-butyl)-indole-5-carboxylate (Component IV) (520 mg, 2.00 mmol) in 2 ml DMSO is added dropwise over 10 minutes. The reaction mixture is stirred for 16 hours at 70° C., acidified with TFA while cooling with ice and chromatographed on Microsorb C18-reverse-phase [acetonitrile (0.1% TFA)/water (0.13% TFA)=10:90→100:0]. Then the residue is chromatographed again on silica gel (DCM/methanol/ammonia=90:9:1).
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14]C1C=CC=CC=1C(=O)C>CCOC(C)=O>[Cl:14][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10]
Reactant: CCC(=O)CC(=O)c1ccccc1
Reactant: CC(=O)c1ccccc1Cl
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1ccccc1Cl

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 2.0 g of 2′-chloroacetophenone and 2.53 mL of EtOAc to yield 0.5 g of Intermediate 30: TLC analysis: Rf=0.76 (2/1, hexanes/EtOAc); 1H NMR (400 MHz, CDCl3, enol form) δ7.6-7.55 (m, 1H), 7.45-7.43 (m, 1H), 7.4-7.32 (m, 1H), 6.05 (s, 1H), 2.18 (s, 3H).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH2:43][CH:42]([C:46]([NH2:48])=[O:47])[CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH2:43][CH:42]([C:46]([NH2:48])=[O:47])[CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: NC(=O)C1CCCNC1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1CCCC(C(N)=O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and piperidine-3-carboxamide (49 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (45 mg, yield 72%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH:7]2[CH2:12][OH:13].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:19]([O:18][C:16]([CH2:15][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH:7]2[CH2:12][OH:13])=[O:17])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: OCC1CCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2c1CCCC2CO

Procedure:
A suspension of (5-hydroxy-1,2,3,4-tetrahydro-1-naphthyl)methanol (0.20 g), ethyl bromoacetate (0.15 ml), potassium iodide (catalytic amount) and potassium carbonate (0.20 g) in acetonitrile (10 ml) was stirred under reflux for 2.5 hours. The solvent was removed and the residue was partitioned between ether and 1N hydrochloric acid. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (n-hexane-ethyl acetate) over silica gel to afford (5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-1-naphthyl)methanol (0.29 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=1[F:12].[OH:14]OS([O-])=O.[K+]>CN(C=O)C>[F:12][C:5]1[CH:6]=[CH:7][C:8]([C:10]([OH:14])=[O:11])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:13]
Reactant: O=S([O-])OO
Reactant: COC(=O)c1cc(C=O)ccc1F
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a solution of methyl-2-fluoro-5-formylbenzoate (2 g, 0.0109 mol) in dry DMF (75 mL) was added oxone (Aldrich, 6.75 g, 0.0109 mol) and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was then quenched with 1.5M.HCl (50 mL) and the product was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, brine, dried over magnesium sulfate filtrated and concentrated to give 1.7 g (78%) of the titled compound as a solid. TLC: Chloroform/methanol (9/1), Rf=0.2, HPLC purity >99%. 1H NMR (DMSO) δ: 8.44 (m, 1H), 8.19 (m, 1H), 7.48 (m 1H), 3.88 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C@H:18]([CH3:27])[CH2:19][N:20]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)=[CH:15][C:14]([C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=O)=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[CH:35]12[NH:41][CH:38]([CH2:39][CH2:40]1)[CH2:37][CH2:36]2.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(N(CC)CC)C>[CH:38]12[N:41]([C:29](=[O:31])[C:28]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[NH:10][C:9]([C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[C:17]4[C@H:18]([CH3:27])[CH2:19][N:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)([CH3:33])[CH3:32])[CH:35]([CH2:40][CH2:39]1)[CH2:36][CH2:37]2
Reactant: C1CC2CCC1N2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2[C@H](C)CN2CCC(=O)CC2)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN2CCC(=O)CC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.5 %

Procedure:
To a solution of (S)-2-{2-(3,5-dimethylphenyl)-3-[1-methyl-2-(4-oxo-piperidin-1-yl)-ethyl]-1H-indol-5-yl}-2-methylpropionic acid (148 mg in 2 mL dry methylene chloride) was added 58 mg 7-aza-bicyclo[2.2.1]heptane hydrochloride followed by 0.185 mL triethylamine and 173 mg of the PyBOP reagent and the mixture stirred at room temperature. After 14 hours, the mixture was concentrated in vacuo and the residue dissolved in ethyl acetate, washed with water and brine and the organic portion dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 3:2) gave the title compound (128 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:52])[CH:22]([N:29]3[C:33]4[CH:34]=[C:35]([C:38]#[N:39])[CH:36]=[CH:37][C:32]=4[N:31]([S:40]([C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)(=[O:42])=[O:41])[C:30]3=[O:51])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>C(Cl)Cl>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[CH3:50][O:49][C:46]1[CH:45]=[CH:44][C:43]([S:40]([N:31]2[C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][C:33]=3[N:29]([CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:21](=[O:52])[N:18]3[CH2:17][CH2:16][CH:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH2:20][CH2:19]3)[C:30]2=[O:51])(=[O:41])=[O:42])=[CH:48][CH:47]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(NC4CCN(C(=O)OC(C)(C)C)CC4)CC3)c3ccccc3)c3cc(C#N)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(NC4CCNCC4)CC3)c3ccccc3)c3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 4-(1-{2-[6-cyano-3-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-2-phenyl-acetyl}-piperidin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.14 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 hours, concentrated in vacuo and co-evaporated the solvent with toluene (3×). The residue was purified by preparative RP-HPLC (eluent: gradient from 10% to 80% acetonitrile in water, 0.1% trifluoroacetic acid as modulator) to afford 1-(4-methoxy-benzenesulfonyl)-2-oxo-3-{2-oxo-1-phenyl-2-[4-(piperidin-4-ylamino)-piperidin-1-yl]ethyl}-2,3-dihydro-1H-benzoimidazole-5-carbonitrile; compound with trifluoroacetic acid (70 mg, 67%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:40]>C(O)C>[ClH:40].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([Br:34])=[CH:32][CH:33]=2)=[C:20]([C:35]([F:38])([F:36])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc(Br)cc3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc(Br)cc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 41-4 (820 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (600 mg) as a white powder.