Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-:3])=[O:2].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>C(Cl)CCl>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[C:5]=1[O:14][CH3:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
The recovered 2-nitro-4-tertbutylanisole is then again subjected to nitration. Specifically, the 2-nitro-4-tertbutylanisole intermediate is mixed with between 2-9 parts (by volume) organic solvent such as ethylene dichloride. Next is the cooling of the reaction mixture of 2-nitro-4-tertbutylanisole and organic solvent in an ice-water bath to a temperature below 5° C. This is followed by the adding of a mixture of 70% nitric acid and 98% sulfuric acid while maintaining a temperature below 10° C. Following the acid mixture addition, the cooling bath is removed and the temperature of the reaction mixture is increased to 50° C. and maintained there for 2-10 hours to produce 2,6-dinitro-4-tertbutylanisole and a 2,4-dinitrophenol byproduct.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH2:11])[CH2:5]2.[C@:12]12([CH2:22][S:23]([OH:26])(=[O:25])=[O:24])[C:19]([CH3:21])([CH3:20])[CH:16]([CH2:17][CH2:18]1)[CH2:15][C:13]2=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH2:11])[CH2:5]2.[C@:12]12([CH2:22][S:23]([OH:26])(=[O:24])=[O:25])[C:19]([CH3:21])([CH3:20])[CH:16]([CH2:17][CH2:18]1)[CH2:15][C:13]2=[O:14].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH2:11])[CH2:5]2
Reactant: NC1Cc2ccc(Br)cc2C1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Product: N[C@@H]1Cc2ccc(Br)cc2C1

Procedure:
The title compound was prepared using a similar method to that described in Prashad et al, Adv. Synth. Catal. 2001, 343, No. 5, pp 461-472: ie by resolution of the free base form of racemic 5-bromo-2-aminoindan using (1S)-(+)-10-camphorsulphonic acid to obtain (R)-5-bromo-2-aminoindan (1S)-(+)-10-camphorsulfonate salt. The enantiomeric purity of (R)-5-bromo-2-aminoindan (1S)-(+)-10-camphorsulfonate salt was checked by HPLC using the following conditions:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:14]=[C:13]([CH2:15][Br:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1OC(C)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC(C)=O
Temperature: 25 °C

Procedure:
A solution of methyl 2-acetoxy-4-methylbenzoate (24.5 g, 0.118 mole) in carbon tetrachloride (700 ml) was treated with N-bromosuccinimide (20.96 g, 0.118 mole), benzoyl peroxide (0.5 g, catalytic) and AIBN (0.03 g). The reaction mixture was heated to reflux, held at reflux for 1 hour and then allowed to cool to ambient temperature, filtered and evaporated to give methyl 2-acetoxy-4-bromomethylbenzoate which was used without further purification (34 g, 63% of mixture is desired product).
Reaction SMILES: [CH:1]1[C:9]2[C@H:10]3[O:15][CH2:14][CH2:13][NH:12][C@@H:11]3[CH2:16][C:7]3[C:8]=2[C:4]([NH:5][CH:6]=3)=[CH:3][CH:2]=1.[CH:17](=O)[CH3:18]>[Pd].C(O)C>[CH2:17]([N:12]1[C@@H:11]2[CH2:16][C:7]3[C:8]4[C:4]([NH:5][CH:6]=3)=[CH:3][CH:2]=[CH:1][C:9]=4[C@H:10]2[O:15][CH2:14][CH2:13]1)[CH3:18]
Reactant: CC=O
Reactant: c1cc2c3c(c[nH]c3c1)C[C@H]1NCCO[C@H]21
Agent: [Pd]
Solvent: CCO
Product: CCN1CCO[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Yield: 58.5 %

Procedure:
A suspension of trans-4,6,6a,8,9,10a-hexahydro-7H-indolo-[3,4 gh]-[1,4]-benzoxazine (650 mg, 0.03 m) acetaldehyde (260 mg, 0.006 m) and Pd/c (10%, 700 mg) in abs. ethanol (50 ml) is hydrogenated at room temperature for 4 hours. The catalyst is removed by filtration, and the solvent is removed under reduced pressure (20 mm). The oil is recrystallized from methanol to yield 430 mg of trans 4,6,6a,8,9,10a-hexahydro-7-ethyl-7H-indolo-[3,4 gh]-[1,4]benzoxazine, m.p. turns brown 200° melt 210°-213°.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:4]=1)=[O:2].N#N.[BH4-].[Na+].Cl>CCO.O>[OH:2][CH2:1][C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:4]=1
Reactant: Cc1ccc(-c2nc3c(C=O)cn(CCCCCCC(=O)O)c3nc2-c2ccc(C)cc2)cc1
Agent: Cl
Agent: N#N
Agent: [BH4-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc3c(CO)cn(CCCCCCC(=O)O)c3nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-(7-Formyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic acid (Example 2.1) (42 mg, 0.092 mmol) in EtOH (1 ml) was degassed with N2 and treated with sodium borohydride (5.23 mg, 0.138 mmol). After stirring at RT for 16 hours, the mixture was added to water (30 ml) and the pH was adjusted to pH 1 using 2M HCl. The aqueous portion was extracted with DCM (×3) and the combined extracts were concentrated under reduced pressure. The crude product was triturated with EtOAc/iso-hexane to afford the titled compound as an orange solid;
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][C:12]([OH:14])=[O:13])#[N:10].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C(O)C>[C:9]([C:11](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]([OH:14])=[O:13])#[N:10]
Reactant: O=Cc1ccccc1
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCO
Product: N#CC(=Cc1ccccc1)C(=O)O
Yield: 81.2 %

Procedure:
200 g of benzaldehyde, 176 g of cyanoacetic acid, 30 ml of acetic acid and 14.5 g of ammonium acetate were refluxed for 4 hours in 800 ml of ethyl alcohol with heating. After the reaction, the mixture was concentrated to 400 ml by removing the ethyl alcohol under a reduced pressure, followed by pouring into 1 liter of ice water to separate crystals. The resulting crystals were recrystallized from 250 ml of acetonitrile to obtain 265 g of 2-cyano-3-phenylacrylic acid having a melting point of 184° to 188° C. 150 g of the resulting compound and 176 g of thionyl chloride were dissolved in 100 ml of acetonitrile with heating for 1 hour. After the reaction, the acetonitrile and the thionyl chloride were distilled off under a reduced pressure, and the resulting solid was added to a solution containing 124 g of hydroxyethyl methacrylate, 75 g of pyridine and 1 liter of acetonitrile. The reaction was carried out for 2 hours while maintaining the reaction temperature below 40° C. After the reaction, the reacting solution was poured into ice water to separate crystals, and the resulting crystals were recrystallized from 1 liter of ethyl alcohol to obtain 205 g of the desired compound having a melting point of 68° to 70° C. The identification of the compound was carried out using IR spectrum, NMR spectrum and elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)=[O:11].C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br>ClCCl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)=[O:11]
Reactant: COc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: Clc1cccc(CBr)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NCc2cccc(Cl)c2)c(C(=O)c2ccc(C(C)C)cc2)c1

Procedure:
To a solution of 100 mg (0.327 mmol) (2-amino-5-methoxy-phenyl)-(4-isopropyl-phenyl)-methanone in 1 ml dichloromethane is added 140 μl (0.818 mmol) N,N-diisopropyl-ethylamine and 48.7 μl (0.360 mmol)3-chloro-benzyl bromide. The reaction mixture is heated under reflux for 4 days and extracted with water/dichloromethane. The organic residue is chromatographed. For further purification the corresponding hydrochloride is precipitated form an etheric solution by addition of gaseous hydrochloric acid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Cl[CH2:6][C:7](=O)[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([F:22])[CH:11]=1)[CH3:9]>O.[OH-].[Na+]>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:12]([F:22])[CH:11]=2)[CH3:9])[N:4]=1
Reactant: NC(N)=S
Reactant: CC(C(=O)CCl)c1ccc(-c2ccccc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
To thiourea (1.77 g, 23.3 mmol) in water (50 ml) was added 1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (5.25 g, 19.0 mmol). After addition, the mixture was heated for 3 hr, and the solution was cooled to room temperature, then added IN sodium hydroxide to pH 8. The mixture was extracted with chloroform and the chloroform extracts were washed with water, dried over, and evaporated under reduced pressure to a residue, which was chromatographed to afford 2-amino-4-[1-(2-fluoro-4-biphenylyl)ethyl] thiazole (4.12 g, 73% yield) as crystalline material: mp 167°-168° C.
Reaction SMILES: [CH2:1]=O.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[C:16]([CH3:25])[CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[BH4-].[Na+]>CO>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:24][CH2:23][N:22]([CH3:1])[CH2:21]3)=[C:16]([CH3:25])[CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: C=O
Reactant: COc1ccc(S(=O)(=O)c2ccc(C3CCNC3)c(C)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(=O)(=O)c2ccc(C3CCN(C)C3)c(C)c2)cc1
Temperature: 0 °C
Yield: 76.7 %

Procedure:
A solution of formaldehyde (37% in water, 1.47 mL, 19.53 mmol) was added to a solution of 3-[4-(4-methoxy-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidine (0.20 g, 0.6301 mmol) in MeOH (2 mL) and the reaction mixture was heated at reflux for 30 minutes. The mixture was cooled to 0° C. and NaBH4 (0.833 g, 22.05 mmol) was slowly added. The mixture was allowed to reach room temperature and it was stirred for an additional hour. The solvent was evaporated under reduced pressure and the residue was partitioned between water and DCM. The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.167 g (77% yield) of 3-[4-(4-methoxy-benzenesulfonyl)-2-methyl-phenyl]-1-methyl-pyrrolidine as a white foam: MS (M+H)=346.
Reaction SMILES: [I-:1].C([N:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[C:18]([CH2:36][CH3:37])[C:19]3[C:28]([CH:29]=2)=[S+:27][C:26]2[C:21](=[C:22]([CH3:35])[CH:23]=[C:24]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:25]=2)[N:20]=3)[CH2:11][CH2:10]1)(OC(C)(C)C)=O>ClCCl.FC(F)(F)C(O)=O>[I-:1].[N:12]1([C:16]2[CH:17]=[C:18]([CH2:36][CH3:37])[C:19]3[C:28]([CH:29]=2)=[S+:27][C:26]2[C:21](=[C:22]([CH3:35])[CH:23]=[C:24]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:25]=2)[N:20]=3)[CH2:13][CH2:14][CH2:15][NH:9][CH2:10][CH2:11]1
Reactant: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc2[s+]c3cc(N4CCCC4)cc(C)c3nc12
Agent: [I-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(N2CCCNCC2)cc2[s+]c3cc(N4CCCC4)cc(C)c3nc12

Procedure:
A solution of 3-(4-Boc-1,4-diazepan-1-yl)-1-ethyl-9-methyl-7-(pyrrolidin-1-yl)-phenothiazin-5-ium iodide (65 mg, 0.01 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (1.0 mL) was stirred for 3 h at 50° C. The resulting mixture was washed by toluene (2×5 mL), pentane (2×5 mL) and concentrated to dryness.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[C:12]([O:16][C:17]([N:19]([CH3:30])[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[C:21]=1[CH3:29])=[O:18])([CH3:15])([CH3:14])[CH3:13]>O1CCCC1.O>[C:12]([O:16][C:17]([N:19]([CH3:30])[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27][C:8](=[O:10])[CH3:9])=[C:22]([CH3:28])[C:21]=1[CH3:29])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1cc(N(C)C(=O)OC(C)(C)C)c(C)c(C)c1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Oc1c(C)cc(N(C)C(=O)OC(C)(C)C)c(C)c1C
Reaction time: 1 h

Procedure:
5.64 ml of dehydrated triethylamine and 2.9 ml of acetyl chloride were added at room temperature to a solution of 7.2 g of N-t-butoxycarbonyl-N-methyl-4-hydroxy-2,3,5-trimethylaniline [prepared as described in step (f) above] in 100 ml of dehydrated tetrahydrofuran, and the resulting mixture was stirred for 1 hour, after which it was allowed to stand overnight. The reaction mixture was then diluted with water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, after which the residue was triturated with ice-cooled hexane to cause crystallization. The crystals were collected by filtration and washed with ice-cooled hexane to give 6.25 g of the title compound, melting at 103-104° C.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1.[CH2:32]([CH:37]=O)[CH2:33][C:34](O)=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C=O.C(N(CC)CC)C>[O:35]=[C:34]1[CH2:33][CH2:32][CH2:37][N:3]1[C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1
Reactant: O=CCCC(=O)O
Reactant: N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)[C@H]1CC[C@H](N2CCCC2=O)CC1

Procedure:
Trans-3-(4-aminocyclohexylcarbonylamino)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride (150 mg) obtained in Example 219 is suspended in dichloromethane (5 ml), and thereto is added triethylamine (129 μl) under ice-cooling, and the mixture is stirred for several minutes. Then, 15% aqueous succinic semialdehyde solution (290 μl) and sodium triacetoxy borohydride (131 mg) are successively added thereto, and under ice-cooling, the mixture is stirred for 0.5 hour. Then, 1-hydroxybenzotriazole (63 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118 mg) and N,N-dimethylformamide (3 ml) are successively added thereto, and the mixture is stirred at room temperature for 15 hours. The reaction solution is concentrated under reduced pressure, and thereto is poured chloroform. The mixture is washed successively with a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, then ethyl acetate), and the resulting residue is suspended in n-hexane, and collected by filtration to give the title compound (29 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30](C3C=CC(OC(C)C)=CC=3)=[CH:29][C:28]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.C(OC1C=CC(B(O)O)=CC=1)(C)C.[F:62][C:63]1[CH:64]=[C:65](B(O)O)[CH:66]=[CH:67][C:68]=1[O:69][CH2:70][CH2:71][CH3:72]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:65]3[CH:66]=[CH:67][C:68]([O:69][CH2:70][CH2:71][CH3:72])=[C:63]([F:62])[CH:64]=3)=[CH:29][C:28]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:23]([F:24])([F:26])[F:25])[N:3]=1
Reactant: CCCOc1ccc(B(O)O)cc1F
Reactant: CC(C)Oc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(-c3ccccc3)c2)cc1
Agent: CC(C)Oc1ccc(B(O)O)cc1
Product: CCCOc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(-c3ccccc3)c2)cc1F

Procedure:
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by replacing the 4-isopropoxyphenyl boronic acid in Step 2 with (3-fluoro-4-propoxyphenyl)boronic acid (CAS#192376-68-4).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]([Si](C)(C)C)([F:18])[F:17].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:16]([F:18])([F:17])[F:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-benzyl-4-piperidone (2.2 g, 11.67 mmole) and (trifluoromethyl)-trimethyl silane (2.37 g, 16.7 mmole) in dry THF (10 ml) at 0° C. was treated with tetrabutylammonium fluoride (0.02 g) in THF. The mixture was stirred at 0° C. for 15 min and allowed to stir at 25-30° C. for 2 hr. THF (10 ml) and 3N HCl were added and stirred for 2 hr. The reaction mixture was extracted with ethyl acetate (3×25 ml), washed with water (2×10 ml) and brine (20 ml), dried (Na2SO4). Residue obtained after evaporation of solvent was purified by column chromatography over silica gel. Elute from a mixture of 5% methanol in chloroform gave 1-benzyl-4-hydroxy-4-trifluoromethylpiperidine as an oil. Yield 2.2 g, (73%), C13H24NOF3, m/z 260 (M+1), PMR (CDCl3): 1.7 (2H, d, CH2, j=10 Hz), 1.85 (1H, bs, OH, D2O exchangeable), 1.9 (2H, t, CH2, j=10 Hz), 2.3 (2H, t, CH2, j=10 Hz), 2.8 (2H, d, CH2, j=10 Hz), 3.55 (2H, s, CH2Ar), 7.2-7.4 (5H, m, ArH).
Reaction SMILES: OO.[O:3]=[C:4]([CH3:19])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:7].[Br-:20].[K+].Cl>C1(C)C=CC=CC=1.O>[Br:20][CH:5]([C:4](=[O:3])[CH3:19])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)=[O:7]
Reactant: [Br-]
Reactant: CC(=O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C(Br)C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 48.5 %

Procedure:
Hydrogen peroxide (8.096 ml) was added dropwise to the well stirred solution of 3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide (10 g) [obtained from above step-a], potassium bromide (4.85 g) and conc. HCl (7.446 ml) in toluene (100 ml) at room temperature. Reaction was monitored by TLC. D.M water was added to the reaction mixture and organic layer was separated. Aqueous layer was extracted with ethyl acetate (50 ml×2). Combined organic layer was washed with brine, dried over sodium sulfate and concentrated to give crude compound. The crude was purified by column chromatography to give pure 2-bromo-3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide (6.4 g).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[CH2:36]O>C(Cl)Cl>[Br:5][CH2:1][CH2:36][C:27]1[CH:28]=[C:29]([C:32]([F:33])([F:35])[F:34])[CH:30]=[CH:31][C:26]=1[I:25]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(C(F)(F)F)ccc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(I)c(CCBr)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Carbon tetrabromide (1.86 g; 5.6 mmol) and triphenylphosphine (1.47 g; 5.6 mmol) were added successively to a stirred solution of [2-iodo-5-(trifluoromethyl)phenyl]methanol (1.13 g; 3.74 mmol) in CH2Cl2 (25 mL) at 0° C. under N2. The reaction was stirred at room temperature for 48 h. A second equivalent of carbon tetrabromide (1.2 g; 3.74 mmol) and triphenylphosphine (0.98 g; 3.74 mmol) was added and the reaction was stirred an additional 14 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (0-25% EtOAc/hexanes gradient) to afford 2-(bromoethyl)-1-iodo-4-(trifluoromethyl)benzene as a clear oil. 1H NMR (CDCl3, 500 MHz): δ 8.02 (d, J=8.2 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.26 (dd, J=8.3, 1.8 Hz, 1H), 4.64 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([NH:23][CH3:24])=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([NH:23][CH3:24])=[O:22])=[O:18])[CH2:13][CH2:12]3)[CH:3]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CNC(=O)COC(=O)N1CCN(CCCc2cccc(Br)c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNC(=O)COC(=O)N1CCN(CCCc2cccc(-c3cccc(Cl)c3)c2)CC1
Temperature: 150 °C
Yield: 51.4 %

Procedure:
A suspension of 0.14 g (0.35 mmol) of 2-(methylamino)-2-oxoethyl 4-[3-(3-bromophenyl)propyl]piperazine-1-carboxylate, prepared in step 7.2., in a mixture of 4 ml of toluene and 0.6 ml of ethanol is admixed with 0.08 g (0.07 mol) of the tetrakis(triphenylphosphine)palladium complex, 1.05 ml (2.1 mmol) of a 2M aqueous solution of sodium carbonate and 0.22 g (1.4 mmol) of 3-chlorobenzeneboronic acid. The mixture is heated to 150° C. under microwave irradiation for 5 minutes and the organic phase is recovered by filtration on a cartridge equipped with a frit and containing celite and sodium sulphate. The cartridge is rinsed with toluene and the filtrate is concentrated under reduced pressure. The product is purified by chromatography on silica gel, eluting with a 90/10 mixture of ethyl acetate and methanol. The eluate is subsequently taken up in n-heptane, to give 0.086 g (0.18 mmol) of product in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][CH2:27][C:22]([OH:28])([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=3)[CH2:23]2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(Cl)c([N+](=O)[O-])c3)C2)c1

Procedure:
The compound of Example 18 was prepared according to the general preparation protocol A from 4-chloro-3-nitrobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.