Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][C:3]1=2.Cl.C(Cl)Cl>CO>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)nc31)CNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
tert-Butyl 9-methyl-2-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.14 g, 0.26 mmol) was treated with 1.25 M HCl in MeOH (6.0 mL), and the resulting suspension was stirred at ambient temperature for 18 h. To the suspension was added CH2Cl2 (1.0 mL) and 1.25 M HCl in MeOH (2.0 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was concentrated, diluted with CH2Cl2 (30 mL), washed with saturated NaHCO3 solution (2×10 mL), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 30 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (51 mg, 46%) as a yellow powder: 1H NMR (500 MHz, DMSO-d6) δ 8.06-8.00 (m, 3H), 7.93 (d, J=8.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 1H), 6.89 (d, J=1.5 Hz, 1H), 6.76 (dd, J=7.5, 2.0 Hz, 1H), 3.89 (s, 2H), 3.67 (s, 3H), 3.08 (t, J=5.5 Hz, 2H), 2.75 (t, J=5.5 Hz, 2H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>S(=O)(=O)(O)O>[CH:5]1([C:11]2[CH:12]=[CH:13][C:14]([C:17](=[O:19])[CH3:18])=[CH:15][C:16]=2[N+:1]([O-:4])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)c1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
A mixture of concentrated sulfuric acid & nitric acid (68-72%) (1.7:6, 15 mL) is added drop wise to a cold solution of 1-(4-cyclohexylphenyl)ethanone (6 g, 0.03 mol) in concentrated sulfuric acid (15 mL) at 0-5° C. Reaction mixture is allowed to stir at this temperature for 30 minutes & is then poured into crushed ice. It is then extracted with ethyl acetate (3×40 mL). Combined organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, 230-400 mesh, ethyl acetate:n-hexane 1:9) to yield 1-(4-cyclohexyl-3-nitrophenyl)ethanone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].CCO[C:14]([CH3:16])=[O:15]>CO>[OH:15][C:14]1[CH:16]=[CH:5][C:4]([C:7]2[NH:10][C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[N:1]=2)=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc(N)c(N)c1
Solvent: CO
Product: N#Cc1ccc2[nH]c(-c3ccc(O)cc3)nc2c1
Reaction time: 4 h
Yield: 85 %

Procedure:
A mixture of 3,4-diaminobenzonitrile (3.0 g, 0.023 mol) and the imidate in 500 mL of methanol was heated at 70° C. under nitrogen. The reaction was followed by TLC with 1:1 Hex/EtOAc. After 4 h the reaction solution was place under vac cuo to remove all solvents. The residue was recrystallized from ethyl acetate to afford 4.5 g (85%) of 2-(4-hydroxyphenyl)-1H-benzimidazole-5-nitrile.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].Cl[CH2:14][C:15]#[N:16]>[OH-].[Na+].CN(C)C=O>[C:15]([CH2:14][N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)#[N:16]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: N#CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2CC#N

Procedure:
35.0 g (0.25 mole) of 3-methyl-xanthine (Chem. Ber. 83, 209 1950) are dissolved in 81.4 ml (0.25 mole) of a 10% sodium hydroxide solution under shaking; crystallization takes place within some minutes. Water is distilled off in vacuo and the traces of water are removed by azeotropic distillation with toluene. The residue is suspended in 35 ml of dimethyl formamide, whereupon a solution of 18.9 g (0.25 mole) of chloroacetonitrile in 80 ml of dimethyl formamide is added dropwise at 100° C. within 30 minutes. The reaction mixture is stirred at 100° C. for a further hour, filtered until hot, the precipitate (sodium chloride) is washed with hot dimethyl formamide and the united solutions are evaporated to dryness under reduced pressure. The residue is treated with 100 ml of acetone, the crystals are filtered by suction and throughly washed with acetone. The 7-cyanomethyl-3-methyl-xanthine (m.p.: 285°-287° C.) thus obtained can be used in further reactions.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]2[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.[H-].[Na+]>CS(C)=O>[CH3:1][C:2]1[C:3]([N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:31][CH2:30][CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2)c(C)c1
Reactant: OCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cnc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a solution of N-(3,5-dimethylpyridin-2-yl)-4-fluoro-N-isobutylbenzenesulfonamide (53.7 mg, 0.160 mmol) and (tetrahydro-2H-pyran-4-yl)methanol (18.54 mg, 0.160 mmol) in dimethyl sulfoxide (DMSO) (1 mL) stirred at room temperature, was added sodium hydride (4.79 mg, 0.160 mmol, 60% wt in mineral oil). The reaction mixture was stirred at 20° C. for 2 hour, then left to stand overnight. Additional sodium hydride (4.79 mg, 0.160 mmol, 60% wt in mineral oil) was added and the reaction stirred for a further 2 hours. The reaction was quenched with methanol (0.5 mL) and water (0.5 mL), then concentrated in vacuo. The crude was purified by mass directed autoprep (formic acid modifier) to give the title compound (31.3 mg). LCMS (2 min, formic) Rt 1.38 min, m/z (ES+) 433 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[H-].[Na+].[O:13]1[CH:20]2[CH:14]1[CH2:15][CH2:16][O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=12>CN1C(=O)N(C)CCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2](=[O:1])[N:3]([C@@H:20]2[C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[O:17][CH2:16][CH2:15][C@H:14]2[OH:13])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: c1ccc2c(c1)OCCC1OC21
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: O=c1ccc([N+](=O)[O-])cn1[C@@H]1c2ccccc2OCC[C@H]1O
Temperature: 95 °C
Reaction time: 0.33 h

Procedure:
7.85 g (56 mmol) of 2-hydroxy-5-nitro-pyridine are added in portions to 1.61 g (56 mmol) of sodium hydride (80% dispersion in mineral oil) in 30 ml of DMPU (1,3-dimethyl-tetrahydro-2(1H)-pyrimidinone) under argon. After evolution of gas has ceased the mixture is stirred for 20 minutes. Then, at room temperature, a solution of 4,5-epoxy-2,3,4,5-tetrahydro-1-benzoxepin in 10 ml of DMPU is added dropwise. The mixture is subsequently heated at 95° C. for 6 hours. The mixture is poured into ice/water, stirring vigorously, and precipitated solid is filtered off with suction. The solid is chromatographed on silica gel (ethyl acetate/cyclohexane 2:1), and the pale yellow oil obtained in this way is crystallized in methyl tert.-butyl ether. Melting point 152°-155° C.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[N:9][OH:10])[S:2]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:10][N:9]=[C:3]1[CH:4]2[CH2:7][CH2:8][CH:1]([CH:6]=[CH:5]2)[S:2]1
Reactant: ON=C1SC2C=CC1CC2
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C1=CC2CCC1SC2=NOC1CCCCO1
Yield: 93.4 %

Procedure:
A solution of 10 g (0.06 m) of 2-thiabicyclo[2.2.2]oct-5-en-3-one oxime, 9 g (0.1 m) of 98% dihydropyran, and a catalytic amount of ptoluenesulfonic acid in 30 ml of methylene chloride was heated under reflux overnight. Sodium bicarbonate was added to neutrality. The residue after removal of solvent was purified by dry column chromatography (silica gel-ethyl acetate:hexane::1:1) to give 14.4 g of yellow solid. Recrystallization from etherhexane yielded 10.1 g of the title compound as a white solid, m. 84°-5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:10])[CH3:11])[CH:3]=1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)C(O)(c1cccc(-c2ccc(F)cc2F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 100.3 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 1-(3-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (6.00 g), 2,4-difluorophenylboronic acid (2.82 g), 2M aqueous sodium carbonate solution (45 ml) and tetrakis(triphenylphosphine)palladium(0) (647 mg), the yellow amorphous title compound (6.39 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:10])=[O:9])[S:4][N:3]=1.Cl.O.C([O-])(O)=O.[Na+].[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([O:10][CH2:18][CH3:19])=[O:9])[S:4][N:3]=1
Reactant: CCO
Reactant: O=C(O)c1snc(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1snc(Cl)c1Cl
Yield: 83 %

Procedure:
3,4-Dichloro-5-isothiazolecarboxylic acid (55 g; 0.278 mol) was dissolved in 500 ml of ethanol. The solution was saturated with hydrochloric acid and then refluxed for 3 hrs. The ethanol was distilled on a rotary evaporator leaving a residue which was then charged into 200 ml of water and neutralized with NaHCO3. The water layer was extracted with 2x200 ml of Ch2CL2. The extracts were combined, dried over MgSO4, filtered and the solvent distilled. The remaining liquid was distilled to yield 52.3 g (83%) of ethyl 3,4-dichloroisothiazol-5-carboxylate by 92° (3.0 mm).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([O:7][P:8]([O:12]CC)[O:9][CH2:10][CH3:11])[CH3:6]>>[CH2:1]([P:8](=[O:12])([O:9][CH2:10][CH3:11])[O:7][CH2:5][CH3:6])[CH:2]=[CH2:3]
Reactant: CCOP(OCC)OCC
Reactant: C=CCBr
Product: C=CCP(=O)(OCC)OCC

Procedure:
Allyl bromide was treated with triethylphosphite in the absence of solvent using microwave conditions at 150° C. to give diethyl allylphosphonate. Diethyl allylphosphonate was combined with bromotrimethyl silane and subsequently quenched with methanol to afford diethyl allylphosphonic acid according to Scheme 7.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([OH:11])=[N:5][NH:6]2.[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1>N1C=CC=CC=1>[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:11][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[NH:6][N:5]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: Oc1n[nH]c2cccc(F)c12
Solvent: c1ccncc1
Product: CC1CCN(C(=O)Oc2n[nH]c3cccc(F)c23)CC1
Reaction time: 8 h

Procedure:
100 mg (0.66 mmol) of 4-fluoro-1H-indazol-3-ol and 116.8 mg (0.72 mmol) of 4-methylpiperidine-1-carbonyl chloride (Example 2) in 10 ml of pyridine were heated under reflux for 4 h and left to stand overnight. Addition of 24 mg of 4-methyl-piperidine-1-carbonyl chloride was followed by heating under reflux for a further 2 h while the pyridine was distilled off in vacuo, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 56 mg (31%), M+H+: 278.1.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O>C(#N)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[N:7]=[C:6]2[N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1n[nH]c2nc(F)ccc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nn(C(=O)OC(C)(C)C)c2nc(F)ccc12
Reaction time: 1 h

Procedure:
A stirred solution of 6.67 g (44.2 mmol) of 6-fluoro-3-methyl-1H-pyrazolo[3,4-b]pyridine in 100 mL of acetonitrile under nitrogen was treated with 5.40 g (44.2 mmol) of DMAP and 6.46 mL (46.4 mmol) of triethylamine. A solution of 11.56 g (53.0 mmol) of (BOC)2O in 20 mL acetonitrile was added dropwise via a cannula and the resulting reaction mixture stirred for 1 hour until completion as determined by LC/MS analysis. The reaction was quenched with brine and extracted with EtOAc (3×). The combined organic layers were washed with H2O, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified via silica gel chromatography (0-70% EtOAc/hexane) to yield the title compound. 1H NMR (CDCl3): 1.74 (s, 9H), 2.60 (s, 3H), 6.95 (d, 1H), 8.08 (t, 1H).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:3][C:2]#[CH:1])[CH2:8][CH2:7]1
Reactant: CC1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN1CCC(C)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
At 0–5° C., propargyl bromide (12.01 g) was added dropwise with stirring to a suspension of 4-methylpiperidine (10.0 g) and potassium carbonate (13.96 g) in dry acetone (80 ml). The mixture was stirred at 50° C. for 6 hours and then filtered. The filtrate was concentrated under reduced pressure and the residue was taken up in dichloromethane. The organic phase was washed with water (3×15 ml), dried with sodium sulfate and concentrated under reduced pressure. Distillation of the residue under reduced pressure gave 12.73 g of an oil of boiling point 60° C./16 mm Hg.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([F:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:14][CH2:12][C:11]1[C:2]([F:1])=[C:3]([C:8]([F:13])=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)ccc(C)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(F)ccc(CBr)c1F
Temperature: 25 °C
Yield: 107 %

Procedure:
To a room temperature solution of methyl 2,6-difluoro-3-methylbenzoate (9.35 g, 50.2 mmol, 1.0 equiv) and N-bromosuccinimide (11.6 g, 65.3 mmol, 1.3 equiv) in carbon tetrachloride (230 mL) was added catalytic AIBN (−200 mg) as a solid in one portion. The resulting reaction mixture was heated to reflux overnight. After the reaction mixture was allowed to cool to room temperature, it was washed with aq. satd. NaHCO3. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide 14.24 g (>100% mass recovery) of unpurified bromide, which was taken on to the next step without purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[F:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([N:16]([CH3:23])[C@@H:17]([CH:20]([CH3:22])[CH3:21])[CH:18]=O)=[O:15])=[CH:12][C:11]=1[CH3:26].[Na].[BH4-].[Na+]>CCO.C(Cl)Cl>[C:7]([CH:4]1[CH2:5][CH2:6][N:1]([CH2:18][C@@H:17]([N:16]([CH3:23])[C:14](=[O:15])[C:13]2[CH:24]=[CH:25][C:10]([F:9])=[C:11]([CH3:26])[CH:12]=2)[CH:20]([CH3:21])[CH3:22])[CH2:2][CH2:3]1)#[N:8]
Reactant: N#CC1CCNCC1
Reactant: Cc1cc(C(=O)N(C)[C@H](C=O)C(C)C)ccc1F
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C(=O)N(C)[C@H](CN2CCC(C#N)CC2)C(C)C)ccc1F
Reaction time: 1 h
Yield: 4 %

Procedure:
TEA (0.552 mL, 3.98 mmol) was added to a mixture of piperidine-4-carbonitrile (0.132 g, 1.19 mmol) in EtOH (2 mL) and DCM (3 mL). To the mixture was added (S)-4-fluoro-N,3-dimethyl-N-(3-methyl-1-oxobutan-2-yl)benzamide (Compound A2.1) (0.2 g, 0.80 mmol). The resultant mixture was stirred at rt for 15 min before sodium triacetoxyhydroborate (0.337 g, 1.59 mmol) was added. The stirring was continued at rt over night. Sodium tetrahydroborate (0.015 g, 0.40 mmol) was added and the mixture was stirred for 1 h. The solvents were removed on a vacuum centrifuge. The residue was diluted with DCM and washed with NaOH (aq., 1M). The organic phase was filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The product containing fractions was concentrated and the residue was purified a second time by preparative HPLC using Chiralpak IC 5 μm 20×250 mm column and Heptan/EtOH/TEA 60/40/0.1, as mobile phase to give the title compound (11 mg, 4%). Enantiomeric excess: 98.2%. Mixture of rotamers: (400 MHz, CD3OD) δ 0.85-1.08, 1.69-2.02, 2.12-2.96, 3.37-3.50, 4.41-4.59, 7.07-7.16, 7.19-7.36.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]([CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:22][CH2:21]4)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[C:34]([BH3-])#N.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1COCC1.C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:34])[CH:23]([CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[CH2:22][CH2:21]4)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc4c(c3)CCC(CN3CCCC3)N4)nc2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2CCC1CN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
37 mg (1.23 mmol) paraformaldehyde in 1.8 mL THF are added to a solution of 350 mg (0.82 mmol) 6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline (see Example 3.46) in 1.6 mL THF. 0.24 mL acetic acid and 1.2 mL THF are added to this mixture. Finally, 1.00 g (2.05 mmol) cyanoborohydride resin (macroporous polystyrene, load: 2.04 mmol/g) are added and the mixture is stirred for 16 h at RT. After filtration the filtrate is combined with 1.50 g (2.15 mmol) toluenesulphonic acid resin (macroporous polystyrene, load: 1.43 mmol/g), shaken for 30 min and suction filtered. The solvent is eliminated i.vac. and purification is carried out by column chromatography using HPLC-MS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:29])[CH2:20][CH2:19]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 70 mL of a chloroform solution containing 9.53 g of tert-butyl (1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 20 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 10 hours. The solvent was removed under reduced pressure, the reaction mixture was alkalified with an aqueous saturated sodium hydrogen carbonate solution, and then the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Chromatorex-NH, manufactured by Fuji Silysia Chemical Ltd., eluent; chloroform:methanol=50:1] to obtain 5.97 g of a brown oily substance, 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one.
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH:12]=[C:11]([CH:13]3[CH:15]([C:16](O)=[O:17])[CH2:14]3)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.C([N:39](CC)CC)C>>[C:19]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH:12]=[C:11]([CH:13]3[CH:15]([C:16]([NH2:39])=[O:17])[CH2:14]3)[N:10]=[CH:9]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)C1CC1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Product: NC(=O)C1CC1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
According to the foregoing reaction scheme I 3-[1-(triphenylmethyl)-1H-imidazol4-yl]-cyclopropanecarboxylic acid (1), prepared as a racemic mixture of trans cyclopropanes using the method of Burger, et al., J. Med. Chem., (1970), 13: 33-35, is converted to an activated ester through the action of ethyl chloroformate and triethylamine. The activated ester is reacted in situ with amine (2) to provide the 3-[1-(triphenylmethyl)-1H-imidazol-4-yl]-cyclopropanecarboxamide (3). The trityl group can be removed with acid, preferably aqueous 2N HCl, to give 3-[1H-imidazol-4-yl]-cyclopropanecarboxamide (4).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:12]=[C:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:44][CH2:45][C:46]([NH:48][CH:49]1[CH2:52][N:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:50]1)=[O:47]>O1CCOCC1>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:12]=[C:11]([NH:44][CH2:45][C:46]([NH:48][CH:49]2[CH2:52][N:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:50]2)=[O:47])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=1
Reactant: Oc1cc(C(F)(F)F)nc2ccc(C(F)(F)F)cc12
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2cc(C(F)(F)F)nc3ccc(C(F)(F)F)cc23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of commercially available 2,6-bis(trifluoromethyl)quinolin-4-ol (291 mg, 1.04 mmol) in dry dioxane (5 mL) was treated sequentially with TEA (0.36 mL, 2.58 mmol) and PyBrOP (586 mg, 1.26 mmol). After stirring 1 hour at room temperature under argon, a solution of tert-butyl 3-(2-aminoacetamido)azetidine-1-carboxylate (352, 1.54 mmol), prepared as described in Example 1, Step E in dry dioxane (5 mL) was introduced and the reaction mixture was stirred overnight at room temperature. After concentration in vacuo, the residue was purified by flash chromatography (silica gel, 0-5% MeOH/ethyl acetate) to afford the product.