Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:29]5[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=5)=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Product: CC(C)(C)c1ccc(-c2ccc(N3CCCN(c4ccc(-c5ccc(C(C)(C)C)cc5)cn4)CC3)nc2)cc1
Yield: 45.1 %

Procedure:
Following the procedure of Example 1, crude crystals were obtained from the 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol) synthesized in Reference Example 1 and 4-t-butylphenylboronic acid (226.0 mg, 1.20 mmol). The crude crystals were recrystallized from chloroform-hexane to yield the title compound as colorless needles (melting point: 268.0-270.0° C.) (117.0 mg, yield: 42%).
Reaction SMILES: [O:1]=[C:2]1[N:11]2[CH2:12][CH2:13][N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[H-].[Na+].[CH3:17][CH2:18][CH2:19]CCC.C(Br)C=C>CC(N(C)C)=O>[O:1]=[C:2]1[N:11]2[CH2:12][CH2:13][N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]1[CH2:19][CH:18]=[CH2:17]
Reactant: O=C1Nc2ccccc2C2=NCCN12
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C=CCBr
Product: C=CCN1C(=O)N2CCN=C2c2ccccc21
Temperature: 80 °C

Procedure:
6.9 g (0.037 mol) of 5-oxo-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline in 60 ml of absolute dimethylacetamide were added to 1.75 g (0.058 mol) of an 80% strength suspension of NaH in oil (Schuchardt), after the suspension had been thoroughly stirred twice with 20 ml of n-hexane in each case and the solvent had been decanted, and the mixture was heated to 80° C. for 1 hour. During this process, a clear solution was gradually formed. The solution was cooled, and 4.6 ml (0.053 mol) of allyl bromide were added dropwise. The mixture was then heated to 100° C. for 4 hours. It was concentrated in a rotary evaporator to one third of its volume and was poured onto ice-water. The precipitated product was filtered off under suction and was recrystallised from methanol/water.
Reaction SMILES: C(O[C:5]1([C:11]#[CH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)(=O)C.[CH3:13][NH2:14].CO>>[C:11]([C:5]1([NH:14][CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)#[CH:12]
Reactant: C#CC1(OC(C)=O)CCCCC1
Reactant: CN
Solvent: CO
Product: C#CC1(NC)CCCCC1

Procedure:
This was synthesized in the same manner as in Production Example 18 except that 1-acetoxy-1-ethynylcyclohexane (Production Example 17) and a 40% methylamine/methanol solution were used.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([C:11]#[N:12])=[CH:4][N:3]=1.[S:13]([F:23])(=[O:22])([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14]>CC(O)CC>[C:11]([C:5]1[C:6]([NH:8][CH2:9][CH3:10])=[N:7][C:2]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([S:13]([F:23])(=[O:22])=[O:14])=[CH:16][CH:17]=2)=[N:3][CH:4]=1)#[N:12]
Reactant: CCNc1nc(Cl)ncc1C#N
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Solvent: CCC(C)O
Product: CCNc1nc(Nc2ccc(S(=O)(=O)F)cc2)ncc1C#N
Reaction time: 48 h
Yield: 93.3 %

Procedure:
2-Chloro-5-cyano-4-ethylaminopyrimidine (Method 56; 6.35 g, 34.88 mmol) and sulphanilyl fluoride (6.11 g, 34.88 mmol) in 2-butanol (120 ml) were heated at 95° C. for 4 hours and then stirred at ambient temperatures for 48 hours. The volatiles were evaporated and the residue triturated with ether to give the title compound (10.46 g, 93%). NMR: 1.20 (t, 3H), 3.45 (m, 2H), 8.00 (d, 2H), 8.13 (d, 2H), 8.41 (s, 1H), 10.52 (s, 1H); m/z: 321.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:32])=[CH:26]2>>[ClH:1].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[CH:20][CH:19]=1)[C:27]([CH3:32])=[CH:26]2
Reactant: COc1ccc2[nH]c(C)cc2c1
Reactant: O=C(O)c1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Product: COc1ccc2c(c1)cc(C)n2C(=O)c1ccc(OCCCN2CCCCC2)cc1

Procedure:
The title compound (E7) was prepared from 4-(3-piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2) and 5-methoxy-2-methyl-indole using the method described in Example 5 (E5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([CH3:33])(=[O:32])=[O:31])=[N:17][C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([CH3:33])(=[O:32])=[O:31])=[N:17][C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:35]([F:38])([F:36])[F:37]
Reactant: COCN(c1cc(Cl)c(C)nc1C(=O)c1ccccc1S(C)(=O)=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C(=O)c2ccccc2S(C)(=O)=O)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture 4-chloro-N-[5-chloro-2-(2-methanesulfonyl-benzoyl)-6-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (40 mg, 0.07 mmol) in 4 M HCl in dioxane (2 mL), and water (1 mL) was heated at 100° C. for 4 h and then it was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and it was treated with aqueous NaHCO3 to adjust pH to 5-6 and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide the desired product. 1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1 H), 8.21 (s, 1 H), 8.15 (s, 1 H), 7.98-7.96 (m, 2 H), 7.70-7.62 (m, 3 H), 7.33-7.31 (m, 1 H); Mass spectrum m/z: 567.4.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:10]([O:17][CH3:18])[N:9]=[CH:8][N:7]=1.[H-].[Na+].COS(OC)(=O)=O.[CH3:31][O:32][CH2:33]COC>C(OC)=O.CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:11]([C:12](=[CH:31][O:32][CH3:33])[C:13]([O:15][CH3:16])=[O:14])=[C:10]([O:17][CH3:18])[N:9]=[CH:8][N:7]=1
Reactant: COCCOC
Reactant: COC(=O)Cc1c(OC)ncnc1Oc1cccc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: COC=O
Solvent: CCOCC
Product: COC=C(C(=O)OC)c1c(OC)ncnc1Oc1cccc(C)c1

Procedure:
Methyl 4-(3-methylphenoxy)-6-methoxy-pyrimidin-5-yl-acetate (12.1 g, 42 mmol) is dissolved in a mixture of 1,2-dimethoxyethane (120 ml) and methyl formate (50 ml). Sodium hydride (2.5 g, 80% in oil, 84 mmol) is added in one portion, the temperature being kept at room temperature. After 5 hours dimethylsulfate (6.6 ml, 70 mmol) is added with cooling. After an additional 5 hours the reaction mixture is diluted with ether and washed with brine. Drying and chromatography on silicagel (eluant:hexane/ethyl acetate 1:1) gives the E-isomer of methyl α-[4-(3-methylphenoxy)-6-methoxy-pyrimidin-5-yl)-β-methoxyacrylate as a crystalline solid, m.p. 107° C.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:18][CH2:19][C:20](O)=[O:21])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OCC)=O.[CH3:31][NH2:32]>O1CCCC1.C(N(CC)CC)C>[N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:18][CH2:19][C:20]([NH:32][CH3:31])=[O:21])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)CC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)CC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
To a solution of (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-carboxyethyl)-4-hydroxypyrrolidine (57.73 g) in dry tetrahydrofuran (500 ml), triethylamine (29.27 ml) was added, and ethyl chloroformate (18.74 ml) was further added thereto at -20° to -25° C. under nitrogen stream. The resulting mixture was stirred at the same temperature for 15 minutes and 30% (w/w) ethanolic solution of methylamine (57.5 g) was added thereto, followed by stirring at the same temperature for 1 hour. The solvent was removed, and the residue was combined with water and ether. The precipitated crystals were collected by filtration to give (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-methylaminocarbonylethyl)-4-hydroxypyrrolidine.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.O.[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>ClCCl>[CH3:2][N:3]([O:4][CH3:5])[C:20]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:21]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CNOC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCCCC1
Temperature: 0 °C
Yield: 80 %

Procedure:
In a dried, flushed with nitrogen round bottom flask, N,O-dimethyl hydroxylamine hydrochloride (0.1 mol, 13.3 ml) was suspended in 200 ml anhydrous dichloromethane. To the resulting mixture triethylamine (0.22 mol, 30 ml) was added dropwise in ˜5 min while cooling by water (stirring became difficult because of salts formation). To the resulting mixture, while stirring under nitrogen and cooling by ice water, cyclohexanecarbonyl chloride was added dropwise in ˜15 min. The mixture was stirred overnight, washed with water (50 ml), saturated aqueous NH4Cl (50 ml), then brine (50 ml), dried over Na2SO4, and concentrated to give 17.8 g of crude product. Purification on 150 g silica gel, eluent hexanes-ethyl acetate, from 100:0 to 50:50, afforded 13.6 g (80%) of N-methyl-N-methoxy-cyclohexanecarboxamide as clear oil, Rf 0.44 (hexanes-EtOAc 1:1), 1H NMR (400 MHz, CDCl3) δ 3.67 (s, 3H, OCH3), 3.15 (s, 3H, NCH3), 2.65 (m, 1H, CH—CO), 1.8-1.6 (m, 5H, cyclohexyl), 1.5-1.4 (qm, 2H, cyclohexyl), 1.3-1.2 (m, 3H, cyclohexyl).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:25][NH:26][O:27][CH3:28].CN1CCOCC1>C(Cl)Cl>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([N:26]([O:27][CH3:28])[CH3:25])=[O:17])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)Cc1ccc(OC2CCCCC2)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)Cc1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (4-cyclohexyloxy-phenyl)-acetic acid (181 mmol, 42.4 g) in anhydrous DCM (200 mL) at 0° C. was added oxalyl chloride (362 mmol, 36.6 mL) and continued stirring for 12 h during which time the reaction mixture slowly attained room temperature. The reaction mixture was concentrated in vacuo to remove volatile impurities and dried under high vacuum. To a stirred solution of N,O-dimethylhydroxylamine hydrochloride (226 mmol, 22.1 g) and N-methylmorpholine (407 mmol, 44.8 mL) in anhydrous DCM (200 mL) at 0° C. was added the acid chloride obtained above, dissolved in DCM (50 mL) dropwise. The reaction mixture was stirred for 12 h allowing it to slowly attain room temperature. The reaction mixture was washed with water (2×200 mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified on a 330 g SiO2 cartridge with 20-30% ethyl acetate in hexanes to provide 2-(4-cyclohexyloxy-phenyl)-N-methoxy-N-methyl-acetamide.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13].[CH2:22]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31]I)[CH2:27][CH2:26]1)[CH2:23][CH3:24].Cl>CN(C)C=O.CCCCCCC.C1(C)C=CC=CC=1>[F:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:31][C@H:28]3[CH2:29][CH2:30][C@H:25]([CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27]3)=[C:16]([F:21])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13]
Reactant: CCC[C@H]1CC[C@H](CI)CC1
Reactant: CCCOc1ccc(-c2ccc(O)c(F)c2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2ccc(OC[C@H]3CC[C@H](CCC)CC3)c(F)c2)cc1F
Reaction time: 1 h

Procedure:
In a mixture of 0.7 g (60% oiliness, corresponding to 18.2 mmol) of sodium hydride and 5 ml of dimethyl formamide (DMF) was added by drops a solution of 4.0 g (15.1 mmol) of the 3,3′-difluoro-4′-hydroxy-4-propoxybiphenyl obtained in the previous step in 20 ml of DMF at room temperature, and then stirred at the same temperature for 1 hour. Subsequently, a solution of 6.0 g (22.7 mmol) of trans-4-propyl-l-iodomethylcyclohexane in 20 ml of DMF was added by drops to the reaction solution at room temperature, stirred at the same temperature for 1 hour, and then heated to reflux for 3 hours. After finishing of the reaction, the reaction solution was poured into 50 ml of a diluted hydrochloric acid and then extracted with 150 ml of toluene. The organic layer thus obtained was washed with a diluted aqueous sodium hydroxide solution thrice and with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (eluent: heptane/toluene=7/3) to obtain 2.3 g of a crude 3,3′-difluoro-4′-((trans-4-propylcyclohexyl)methoxy)-4-propoxybiphenyl. This product was recrystallized from mixed solvent of ethanol/ethyl acetate (7/3) to obtain 1.8 g of the subject compound. (Yield: 48.2%)
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH2:15][CH:14]([OH:16])[CH:13](OC)[CH2:12][C:11]1([CH2:20][S:21][CH3:22])[OH:19])[CH3:9].[Cl:23][CH2:24][C:25]([N:27]=[C:28]=[O:29])=[O:26].[C:30](OCC)(=[O:32])C>ClCCl>[Cl:23][CH2:24][C:25]([NH:27][C:28]([O:16][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][S:21][CH3:22])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[CH:15]1[O:32][CH3:30])=[O:29])=[O:26]
Reactant: CCOC(C)=O
Reactant: COC1CC(O)(CSC)C(C2(C)OC2CC=C(C)C)CC1O
Reactant: O=C=NC(=O)CCl
Solvent: ClCCl
Product: COC1C(OC(=O)NC(=O)CCl)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
In dichloromethane (15 ml) was dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-5-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (1.50 g). To the solution was added dropwise, under ice-cooling, chloroacetyl isocyanate (0.46 ml). The mixture was stirred for 20 minutes, which was diluted with ethyl acetate (60 ml) and washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 75 g, developing solvent : ethyl acetate - hexane=1:2), followed by crystallization from ether-hexane to afford 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (1.70 g: yield 83%) as colorless crystals, m.p. 101° to 102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH3:17])[NH:10][CH3:11].[Br:18]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:18])=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH3:17])[NH:10][CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(Cc1ccccc1N)c1ccsc1C
Solvent: CN(C)C=O
Product: CNC(Cc1cc(Br)ccc1N)c1ccsc1C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
A stirred solution of 3.0 g of 2-amino-N-methyl-α-(2-methyl-3-thienyl)benzeneethanamine in 50 ml of N,N-dimethylformamide was treated with a solution of 2.6 g of N-bromosuccinimide in 50 ml of N,N-dimethylformamide and allowed to stand overnight at room temperature. Evaporation of the volatiles afforded an oil which was purified by HPLC (Water's Associates Prep LC/System 500, silica gel, elution with methanol). The resultant oil was dissolved in diethyl ether, filtered and concentrated. Trituration with diethyl ether afforded 1.2 g of 2-amino-5-bromo-N-methyl-α-(2-methyl-3-thienyl)benzeneethanamine, mp 72.5°-74° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]3[C:7]=2[NH:6][CH:5]=[CH:4]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1ccc(F)c2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2ccc(F)c3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of 59 mg (0.33 mmol) of 4-fluoro-1H-indole-7-carboxylic acid and 91 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine in 3 ml DCM 63 mg (0.33 mmol) of EDC.HCl were added and the reaction mixture was stirred over night at rt. The product was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 113 mg (81%) product as a colorless viscous oil. MS (ISP) 463.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[C:30]2[CH3:34])[N:25]=[N:26][CH:27]=1>>[ClH:21].[F:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:23]=[C:24]([CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[N:25]=[N:26][CH:27]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC1(C)OB(c2cc(F)cc(C(F)(F)F)c2)OC1(C)C
Product: Cc1nccn1Cc1cc(-c2cc(F)cc(C(F)(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e 337.2 (M+H+), was prepared from 2-(3-fluoro-5-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: CC(C)=O.[F:5][C:6]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]([OH:12])[NH:10][C:9](=[O:13])[NH:8][C:7]1=O.C(OC(=O)C)(=O)C.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>N1C=CC=CC=1>[F:5][C:6]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[NH:8][C:9](=[O:13])[NH:10][C:11]1=[O:12]
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1O
Reactant: C1CCNCC1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1N1CCCCC1
Reaction time: 24 h

Procedure:
In 20 ml. of acetone is dissolved 4.40 g. of ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxo-pyrimidine-5-carboxylate, followed by the addition of 2.5 ml. of acetic anhydride. To this is further added dropwise 2 ml. of pyridine and the mixture is allowed to stand at room temperature for 24 hours. To the colorless reaction mixture thus obtained is added dropwise 5.9 ml. of piperidine, whereby the reaction takes place with evolution of heat. After 5.5 hours' standing at room temperature, volatiles are distilled off under reduced pressure and the yellow oily residue is dissolved in chloroform. The solution is subjected to column chromatography on silica gel (80 g., solvent:chloroform). The fractions rich in the desired compound are concentrated under reduced pressure to recover 5.20 g. of a white solid. Upon recrystallization from chloroform-hexane, 3.0 g. of ethyl 5-fluoro-6-piperidino-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate is obtained as colorless needles.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].CO[C:15](OC)([CH3:17])[CH3:16].Cl>CC(C)=O>[CH3:16][C:15]1([CH3:17])[O:10][CH:9]([CH:7]2[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]2[OH:6])[CH2:11][O:12]1
Reactant: COC(C)(C)OC
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: Cl
Solvent: CC(C)=O
Product: CC1(C)OCC(C2OC(=O)C(O)=C2O)O1
Reaction time: 1 h

Procedure:
In a 12-L round bottom flask was placed 8,000 mL acetone, 1,600 g L-ascorbic acid, 1,880 mL 2,2-dimethoxypropane and the mixture was stirred for 1/4 hr; hydrogen chloride was added slowly through bubbler over 2-4 min (color of solution changed from colorless to dark yellow). The mixture was stirred for 1 hr and became very viscous. The product was filtered, washed with cold acetone and the solid was then air dried in hood to give 1,521 g of 1st crop of 5,6-O-isopropylidene-L-ascorbic acid. The mother liquor was concentrated to give 225 g of 2nd crop and 162 g of 3rd crop of 5,6-O-isopropylidene-L-ascorbic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)=[O:32]>>[C:37]1([CH3:40])[CH:38]=[CH:39][C:34]([O:33][C:31](=[O:32])[N:14]([C@@H:13]2[C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])=[CH:35][CH:36]=1.[C:6]1([CH3:5])[CH:7]=[CH:2][CH:3]=[CH:4][C:40]=1[C:37]1[CH:38]=[CH:39][C:34]([O:33][C:31](=[O:32])[N:14]([C@@H:13]2[C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:12]2)[CH3:15])=[CH:35][CH:36]=1
Reactant: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Product: Cc1ccc(OC(=O)N(C)[C@H]2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)C[C@@H]2c2ccc(Cl)c(Cl)c2)cc1
Product: Cc1ccccc1-c1ccc(OC(=O)N(C)[C@H]2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)C[C@@H]2c2ccc(Cl)c(Cl)c2)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid p-tolyl-phenyl ester was prepared from rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using p-tolyl chloroformate instead of 4-fluorophenyl chloroformate and was obtained as a light brown foam. MS m/e: 572.2 [M]+.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][Cl:23]>CCO>[ClH:23].[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: Cc1ccccc1CCl
Solvent: CCO
Product: Cc1ccccc1CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Product: Cl
Temperature: 25 °C
Yield: 56 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-methylbenzyl chloride (0.204 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 174 mg of the product 227. 1H NMR (DMSO-d6) δ 11.28 (s, 2 H), 7.68 (m, 1 H), 7.55-7.20 (m, 3 H), 7.20-7.00 (m, 6 H), 7.00-6.90 (m, 4 H), 5.82 (s, 2 H), 4.81 (s, 2 H), 2.44 (s, 3 H); MS: m/z 359 (M++1).