Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH:12](=O)/[CH:13]=[CH:14]/[CH3:15].C(OCC)(=O)C>Cl.O>[CH3:15][C:14]1[CH:13]=[CH:12][C:7]2[C:5](=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: C/C=C/C=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc2ccc(C(F)(F)F)cc2n1
Temperature: 25 °C
Yield: 28.9 %

Procedure:
To a solution of 3-(trifluoromethyl)aniline (12.43 mL, 99.92 mmol) in 6 N HCl (50 mL) in water was added (E)-but-2-enal (18.77 mL, 229.8 mmol) dropwise at reflux. The reaction was stirred at reflux for 3 hours. After cooling to ambient temperature, ethyl acetate (200 mL) was added. The aqueous layer was separated, basified with ammonium hydroxide to about pH 9, and extracted with DCM (2×200 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 2-methyl-7-(trifluoromethyl)quinoline (6.1 g, 28.9%) as a solid.
Reaction SMILES: CN(C)C=O.[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].CS[C:13]1[S:17][CH:16]=[CH:15][S+:14]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CC(C)=O>[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].[S:14]1[CH:15]=[CH:16][S:17][C:13]1=[N+:19]([CH3:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CSc1scc[s+]1
Reactant: CNc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[N+](c1ccccc1)=c1sccs1
Temperature: 25 °C

Procedure:
To 2 ml of dimethylformamide, 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was suspended, and 1.1 ml of N-methylaniline was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and then after an addition of 30 ml of ethyl acetate, the precipitated crystals were collected by filtration. The product was recrystallized from acetone, whereby 1.7 g (yield: 69%) of N-(1,3-dithiol-2-ylidene)-N-methyl-N-phenylammonium perchlorate (Compound No. 8) was obtained as crystals having a melting point of 169° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC/C=C/CCc1ccccc1
Agent: [Pd]
Product: O=C(O)CCCCCCc1ccccc1

Procedure:
7-Phenylheptanoic acid was prepared from E-7-phenylhept-4-enoic acid by hydrogenation at 40 psi using 5% palladium on carbon as the catalyst. Quantitative conversion of the alkene to the alkane was observed by thin layer chromatographic analysis. The product acid was purified by chromatography on silica gel and fully characterized by spectroscopic methods (infrared and nuclear magnetic resonance) and combustion analysis.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35](=[O:40])[NH:36][CH2:37][CH2:38][OH:39]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[C:27]([CH:28]=4)[C:35]([NH:36][CH2:37][CH2:38][OH:39])=[O:40])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: O=C(NCCO)c1cc(B(O)O)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(F)c(C(=O)NCCO)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 12.2 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-fluoro-3-(2-hydroxyethylcarbamoyl)phenylboronic acid (23 mg, 0.106 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 5-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-2-fluoro-N-(2-hydroxyethyl)benzamide (3.1 mg, 12%). 1H-NMR (MeOD): 2.48 (m, 1H), 2.61 (m, 1H), 3.34 (s, 3H), 3.57 (m, 2H), 3.72 (m, 2H), 5.27 (d, 0.3H), 5.89 (d, 0.8H), 7.18 (m, 1H), 7.30 (m, 1H), 7.45 (m, 1H), 7.52 (m, 4H), 7.67 (m, 1H), 7.79 (m, 1H), 8.01 (m, 1H), 8.32 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([C:22](O)=[O:23])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH2:22][OH:23])[CH2:11]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@H](CO)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 45.2 %

Procedure:
A solution of trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-D-proline (1.0 g, 2.9 mmol) in anhydrous THF (24 mL) was cooled to -10° C. and borane in THF (1M, 26 mL) was added at that temperature. The reaction was left to stir for 5 hours at 0° C. The reaction was quenched with methanol (100 mL) at 0° C. and left for 1.5 hours to stir at 20° C. The solvents were removed in vacuo , and EtOAc (100 mL) was then added to the reaction mixture and the organic phase washed with 1M NaOH (2×50 mL), brine (2×50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (50% EtOAc:Hexanes) to give the title compound (433mg, 45%). Rf(60% EtOAc-Hexanes; ninhydrin)=0.29. 1H NMR (CDCl3, 300 MHz) δ 1.45 (s, 9 H), 1.47 (s, 9 H), 1.69 (m, 1 H), 2.01 (m, 1 H), 2.47 (m, 1 H), 3.16 (m, 3 H), 3.55-3.77 (m, 2 H), 3.60 (m, 1 H), 3.85 (br m, 1 H). MS: 353.2 (M+Na).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].C(N(CC)CC)C>C(O)CC>[OH:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH:31][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: NCc1ccccc1O
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCCO
Solvent: CCN(CC)CC
Product: Oc1ccccc1CNc1ncnc2c1ncn2C1CCCCO1
Yield: 90 %

Procedure:
A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) 2-hydroxybenzylamine, and 5 mL of triethylamine was refluxed in n-propanol for 3 hrs. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate solvent was evaporated and the residuum subsequently washed with 30 ml of diethylether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 90%, white solid. TLC (EtOAc:hexane (1:1) (v:v): single spot; HPLC: purity>98%. 1H-NMR (400 MHZ, DMSO): 1.58m (2H); 1.70m (1H); 1.95m (2H); 2.26qq (1H, Ja=11.8 Hz, Jb=4.0 Hz); 3.67m (1H); 4.0d (1H, J=11.3 Hz); 4.64bs (2H); 5.63dd (1H, Ja=11.3 Hz, Jb=1.8 Hz); 6.73t (1H, J=7.5 Hz); 6.82 (d, 1H, J=7.9 Hz); 7.06t (1H, J=7.5 Hz); 7.14d (1H, J=7.5 Hz); 8.21s (1H); 8.35bs (1H); 8.37bs (1H); 9.82bs (1H). MS (ES): [M+H]+=326 (100).
Reaction SMILES: [C:1]1([C:7]2[N:15]=[C:14]3[C:10]([NH:11][C:12](=[O:16])[NH:13]3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCN(CC1)CC2.CN(C)C=O.[N:30]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>O>[C:1]1([C:7]2[N:15]=[C:14]3[C:10]([N:11]([C:35]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:36])[C:12](=[O:16])[NH:13]3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=c1[nH]c2cnc(-c3ccccc3)nc2[nH]1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N1CCCC1)n1c(=O)[nH]c2nc(-c3ccccc3)ncc21
Reaction time: 10 h

Procedure:
To a mixture of 2-phenyl-7,9-dihydro-8H-purine-8-one <prepared according to the similar method to those of Reference Example 19> (4.0 g), 1,4-diazabicyclo[2.2.2]octane (2.2 g) and N,N-dimethylformamide (50 ml) was added dropwise 1-pyrrolidinecarbonyl chloride (2.6 g) at room temperature and the mixture was stirred for 10 hours. To the reaction mixture was added water (100 ml), and the crystals precipitated were collected by filtration and was dried to give the title compound 4.8 g.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=[O:11].[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([O:12][CH3:17])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C)c(F)c1
Yield: 73 %

Procedure:
Sulfuric acid (2 mL) was added to the solution of 3-fluoro-4-methylbenzoic acid (0.831 g, 5.23 mmol) in methanol (30 mL). The mixture was refluxed for 24 hours. After cooling, the solution was made alkaline by addition of an aqueous solution of sodium carbonate, concentrated under reduced pressure in order to remove methanol, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and was evaporated to give 0.641 g (73%) of methyl 3-fluoro-4-methylbenzoate as an oily residue which was directly used in the next step.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].Cl>CO.O>[N+:3]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 134.6 %

Procedure:
To a solution of KOH (0.46 g, 8.16 mmol) in methanol (30 mL) and water (30 mL) was added Compound 258a (1.14 g, 4.08 mmol). The solution was stirred at r.t. for 1.5 hours, poured into water, acidified with 2M HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford the title product (1.38 g).
Reaction SMILES: C(OC([N:8]1[C:17]2[N:16]=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]([O:22]CC3C=CC=CC=3)=[O:21])=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.[Li+].[OH-]>Cl.O1CCOCC1>[N:16]1[C:17]2[NH:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[C:14](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(/C=C/C(=O)OCc3ccccc3)cnc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1cnc2c(c1)CCCN2
Temperature: 25 °C
Yield: 28.7 %

Procedure:
Benzyl (E)-3-[8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro1,8-naphthyridin-3-yl]acrylate (1.21 g, 3.07 mmole) was dissolved in 4 N HCl in dioxane (15 mL). After 18 hr the mixture was concentrated. The residue was taken up in 1:1 MeOH/H2O (15 mL). 1.0 N LiOH (15 mL, 15 mmole) was added and the mixture heated to reflux. After 18 hr the mixture was cooled to RT and concentrated to approximately ⅓ volume. The mixture was adjusted to pH 6 using 10% HCl. The solid was collected by filtration, washed with H2O, and dried in vacuo to give the title compound (180 mg, 29% over 2 steps): MS (ES) m/e 205 (M+H)+.
Reaction SMILES: CN.[CH3:3][N:4](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[C:33]1[CH:34]=[N:35][C:36]([N:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48]([N:50]([CH2:52][C:53]([OH:55])=O)[CH3:51])=[O:49])[CH:46]=3)[C:41]([S:56][CH3:57])=[CH:40]2)=[N:37][CH:38]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[C:33]1[CH:38]=[N:37][C:36]([N:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48]([N:50]([CH3:51])[CH2:52][C:53]([NH:4][CH3:3])=[O:55])=[O:49])[CH:46]=3)[C:41]([S:56][CH3:57])=[CH:40]2)=[N:35][CH:34]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CSc1cn(-c2ncc(-c3cc(C)ccc3F)cn2)c2cc(C(=O)N(C)CC(=O)O)ccc12
Agent: CN
Agent: F[B-](F)(F)F
Product: CNC(=O)CN(C)C(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C)ccc4F)cn3)c2c1

Procedure:
Methylamine (2M in THF, 1.54 ml, 3.09 mmol) was coupled with TBTU to 304c) (0.48 g, 1.03 mmol). Light yellow solid. Yield: 0.22 g (45% of theory)
Reaction SMILES: COC1C=CC([CH2:7][N:8]([C@H:19]2[CH2:23][CH2:22][C@H:21]([N:24](C(OC)=O)C)[C@H:20]2[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:9]([O:11][CH2:12]C2C=CC=CC=2)=[O:10])=CC=1>CO.[Pd]>[NH2:24][C@H:21]1[CH2:22][CH2:23][C@H:19]([N:8]([C:9]([O:11][CH3:12])=[O:10])[CH3:7])[C@H:20]1[C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1
Reactant: COC(=O)N(C)[C@H]1CC[C@H](N(Cc2ccc(OC)cc2)C(=O)OCc2ccccc2)[C@@H]1c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N(C)[C@H]1CC[C@H](N)[C@@H]1c1ccc(F)cc1

Procedure:
A solution of the product from Step C in 10 mL of methanol was hydrogenated over 200 mg of 10% Pd/C at 40 psi for 3 days to remove first the CBz and then the PMB group. The reaction was filtered and evaporated to give 550 mg of title compound. T.l.c. (5% Methanol in methylene chloride) Rf =0.5 (PMB intermediate) and 0.2 (amine product).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C(N(CC)CC)C.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([O:23][C:24]([NH:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ncc(C=O)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=Cc1cnc(NC(=O)OCc2ccccc2)s1
Yield: 63.5 %

Procedure:
1 g (7.8 mmol) of 2-amino-5-formyl-1,3-thiazole was dissolved in 25 ml of tetrahydrofuran and 1.35 ml (9.36mmol) of triethylamine and 1.33 ml (9.36 mmol) of benzylchloroformate were added at 0° C. under stirring. After 8 hours at room temperature the solvent was evaporated, the residue redissolved with methylene chloride and washed with saturated tartaric acid and then with water. The solvent was dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography on silica gel using cyclohexane-ethylacetate as eluent to give 1.3 g (65% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18][NH:19]C)[C:12]=2[F:21])[CH:9]=1)[C:5]#[N:6].[Cl:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28]([OH:30])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:12]=1[F:21])=[O:30]
Reactant: CNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 56.2 %

Procedure:
4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide was prepared in a similar manner as described herein from 3-chloro-5-({6-chloro-2-fluoro-3-[(methylamino)methyl]phenyl}oxy)benzonitrile (0.062 g, 0.20 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (0.032 g, 0.20 mmol), HATU (0.091 g, 0.24 mmol), DIPEA (0.042 mL, 0.24 mmol) and DMF (2 mL). Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.051 g, 56%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (br. s., 1H), 8.08 (br. s., 1H), 7.80-7.84 (m, 1H), 7.44-7.53 (m, 3H), 7.36 (t, 1H), 4.49-4.56 (m, 2H), 2.26 (s, 3H). ES-LCMS: m/z 453.0, 454.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([CH3:22])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O.Cl[Pd]Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:7])=[C:15]([CH3:22])[CH:14]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(C(=O)c2ccc(Cl)cc2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a chilled stirred solution of 3-methoxybenzoyl chloride (5.0 g, 29.3 mmole) in acetone/water (3:1) was added 4-chloro-2-methylphenylboronic acid (5.0 g, 29.3 mmole) followed by PdCl2 (0.259 g, 5 mole %) and sodium carbonate (23.87 mL, 47 mmole). The solution was allowed to stir at room temperature overnight. The reaction workup and purification was conducted according to Example 9a, Step 1 producing the title compound (5.8 g, 76%). This ester was of suitable purity to use without further purification: ESLRMS m/z 261.1 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:38][C:39](=[O:57])[NH:40][C:41]1[CH:46]=[N:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)=[CH:43][N:42]=1)([CH3:37])([CH3:36])[CH3:35].O[CH:59]([C:63]1[CH:73]=[CH:72][C:66]([C:67]([O:69][CH2:70][CH3:71])=[O:68])=[CH:65][CH:64]=1)[CH2:60][CH2:61][CH3:62]>C(Cl)Cl.[Cl-].[NH4+].C1COCC1>[C:34]([O:38][C:39]([N:40]([C:41]1[CH:46]=[N:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:54])[F:55])=[CH:49][CH:48]=2)=[CH:43][N:42]=1)[CH:59]([C:63]1[CH:73]=[CH:72][C:66]([C:67]([O:69][CH2:70][CH3:71])=[O:68])=[CH:65][CH:64]=1)[CH2:60][CH2:61][CH3:62])=[O:57])([CH3:37])([CH3:35])[CH3:36]
Reactant: CCCC(O)c1ccc(C(=O)OCC)cc1
Reactant: CC(C)(C)OC(=O)Nc1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCC(c1ccc(C(=O)OCC)cc1)N(C(=O)OC(C)(C)C)c1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
A round bottom flask was charged with triphenylphosphine (2.64 g, 10.0 mmol), diisopropylazodicarboxylate (1.99 mL, 10.0 mmol) and THF (23 mL) at 0° C. After the ylid crashed out of solution (less than 10 minutes), tert-butyl(5-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)carbamate (3.10 g, 9.10 mmol) and (±)-ethyl 4-(1-hydroxybutyl)benzoate (2.03 g, 9.14 mmol) followed by THF (10 mL). Reaction stirred at room temperature overnight. Reaction diluted with DCM and ammonium chloride solution (aq. sat.) and transferred to an extraction funnel. Aqueous extracted twice with DCM. Combined organic layers washed with brine (1×), dried over sodium sulfate, filtered and concentrated to provide the crude material. Purification by silica gel flash chromatography (MeOH/DCM) provide the title compound as a yellow gum (4.86 g, 98.0%). 1H NMR (400 MHz, CHLOROFORM-d) δ 0.96 (t, 3H) 1.36 (s, 9H) 1.37-1.54 (m, 5H) 2.06-2.18 (m, 1H) 2.23-2.35 (m, 1H) 4.38 (q, J=7.24 Hz, 2H) 5.77 (dd, J=9.10, 6.55 Hz, 1H) 7.51 (d, J=8.61 Hz, 2H) 7.76 (d, J=8.61 Hz, 2H) 7.95-8.02 (m, 2H) 8.12 (d, J=8.22 Hz, 2H) 8.74 (d, J=1.37 Hz, 1H) 8.83 (d, J=1.56 Hz, 1H); MS (M+1): 544.5.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C.[Br:29][C@H:30]([CH3:34])[C:31](Cl)=[O:32]>ClCCl>[Br:29][C@H:30]([CH3:34])[C:31]([N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:32]
Reactant: C[C@@H](Br)C(=O)Cl
Reactant: O=C(OCc1ccccc1)[C@@H]1CC2=C(CCCC2)N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Br)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Introduce 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate and 1.5 litres of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 201 ml of diisopropylethylamine followed by 132 g of (2R)-2-bromopropionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S)-1-[(2R)-2-bromopropionyl]-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate solution so obtained is used as it is in the following Step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH2:41][CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([C:38]1[N:37]=[CH:36][C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:23])([F:21])[F:22])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:40][CH:39]=1)[CH3:42]
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M175) (387 mg, 0.619 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (191 mg, 61%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[CH:23]=[C:22]([C:24](O)=[O:25])[S:21][C:20]=2[CH:27]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:24]([C:22]2[S:21][C:20]3[CH:27]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=3[CH:23]=2)=[O:25])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc3ccc(Cl)cc3s2)C1

Procedure:
65.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 6-chloro-benzo[b]thiophene-2-carboxylic acid (prepared according to WO 2001007436) to give (R)-3-{[(6-chloro-benzo[b]thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. White solid. MS 392.9 ([M−H]−)
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.Br[CH2:24][CH2:25][F:26].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(OCC)C.CN(C)C=O>[F:26][CH2:25][CH2:24][N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1
Reactant: FCCBr
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)CC(c2ccccc2N2CCN(CCF)CC2)CC(C)(C)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30 mg, 0.1 mmol) produced in Example (8b), 1-bromo-2-fluoroethane (16.2 mg, 0.125 mmol), sodium iodide (1.5 mg, 0.01 mmol), potassium carbonate (20.8 mg, 0.15 mmol) and dimethylformamide (1 mL) was stirred for 2 hours at an external temperature of 80° C. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with diethyl ether. The solvent was distilled off by nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-(2-fluoroethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.