Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25]>>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[N:25]([CH2:24][C:23]([F:27])([F:26])[F:22])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(=O)c(OCc2ccccc2)cn1CC(F)(F)F
Temperature: 70 °C
Reaction time: 17 h
Yield: 42.9 %

Procedure:
5-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (10.5 g, 42.7 mmol) was dissolved in sodium hydroxide solution (1.71 g, 42.7 mmol in 77 mL de-ionized water). 2,2,2-Trifluoroethylamine hydrochloride (23.1 g, 171 mmol) was added and the resulting suspension was stirred at 70° C. (oil-bath temperature) in the sealed flask for 17 hours. The reaction mixture was then filtered and the off-white solid was washed with de-ionized water (20 mL×5) to give 5-(benzyloxy)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydropyridine-2-carboxylic acid (6.00 g). Yield=43%; 1H NMR (MeOD-D4, 90 MHz) δ 7.30 (s, 1H), 6.76-7.09 (m, 5H), 6.71 (s, 1H), 4.93 (d, J=8.4 Hz, 2H) and 4.65 (s, 2H); MS m/z 328 [M+1]+. (b) 5-(Benzyloxy)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydropyridine-2-carboxylic acid (4.70 g, 14.4 mmol) was mixed with DMF (25 mL) and heated to 130° C. (bath temperature) for 3 hours. The mixture was concentrated under reduced pressure using a rotary evaporator and the residue was mixed with ethyl acetate (50 mL). It was then stirred for 2 hours at room temperature and filtered. The filtrate was concentrated to give 3-(benzyloxy)-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (3.58 g). Yield=69%; 1H NMR (DMSO-D6, 400 MHz) δ (ppm) 7.57-7.84 (m, 2H), 7.22-7.57 (m, 5H), 6.25 (br. s, 1H) and 4.69-5.28 (m, 4H); MS m/z 284 [M+1]+. (c) 3-(Benzyloxy)-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (1.2 g, 4.2 mmol) was mixed with 10% Palladium on charcoal (wet, 0.12 g) in ethanol (70 mL). The resulting mixture was hydrogenated at 15 psi of hydrogen pressure for 1.5 hours. Palladium was removed by filtration through a layer of Celite™ and the Celite™ cake was washed with methanol (5 mL×3). The filtrate was evaporated to give 3-hydroxy-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (0.78 g) as white solid. Yield=95%; 1H NMR (DMSO-D6, 400 MHz) δ (ppm) 7.60 (d, J=7.1 Hz, 1H), 7.46 (s, 1H), 6.23 (d, J=7.1 Hz, 1H) and 4.80-5.00 (m, 2H); MS m/z 194 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[NH:19][C:24]2=[S:25])=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2c(N)c1OC
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc2ncnc3c2c(c1OC)NC(=S)N3c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of N4-(4-chloro-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (120 mg, 0.36 mmol) (from Example 13, Step B, supra) in 1,2-dichloroethane (30 mL) was added 1,1′-thiocarbonyldiimidazole (0.65 g, 3.63 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The solvents were evaporated and the residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:3:0.05) as eluent to give the desired 3-(4-chloro-phenyl)-8,9-dimethoxy-1H,3H-1,3,4,6-tetraaza-phenalene-2-thione as a yellow solid. (Yield 110 mg, 82%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:43])[CH2:31][O:32][C:33]1[C:38]([F:39])=[C:37]([F:40])[CH:36]=[C:35]([F:41])[C:34]=1[F:42])[CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:43])[CH2:31][O:32][C:33]1[C:38]([F:39])=[C:37]([F:40])[CH:36]=[C:35]([F:41])[C:34]=1[F:42])[CH2:22][C:23]([OH:25])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)O)C(=O)COc1c(F)c(F)cc(F)c1F
Yield: 94.3 %

Procedure:
Treatment of N-[(1-methyl-indole-2-carbonyl)valinyl]-3-amino-4-oxo-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid, tert-butyl ester (120 mg, 0.20 mmol) with TFA as described in Example 80 gave the titled product (104 mg, 95%) as a white powder. MS C26H25F4N3O6, [M+Na]+ =574, [M−H]− =550.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH2:19][CH3:20])[C:11]3=[O:21])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:23]1[NH:31][C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[N:24]=1.O>CN1C(=O)CCC1>[CH2:19]([N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:23]2[NH:31][C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:25]4[N:24]=2)[CH2:2][CH2:3]3)[C:11]1=[O:21])[CH3:20]
Reactant: CCn1c(=O)n(-c2ccc3c(c2)CCN3)c2ncccc21
Reactant: Clc1nc2cccnc2[nH]1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCn1c(=O)n(-c2ccc3c(c2)CCN3c2nc3cccnc3[nH]2)c2ncccc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
Under nitrogen atmosphere, a mixture of 3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and 2-chloro-3H-imidazo[4,5-b]pyridine (60.3 mg) in NMP (4 mL) was stirred at 150° C. for 2 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC. Crystallization from EtOH/H2O to give the title compound (18.0 mg).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][C:27]([CH3:29])=[CH2:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([O:32]C)=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][C:27]([CH3:29])=[CH2:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C)CN1CCCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)CN1CCCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To methyl 8-(4-(2-butoxyethoxy)phenyl)-1-(2-methyl-2-propen-1-yl)-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (1.65 g) were added tetrahydrofuran (45 ml) and methanol (45 ml), followed by adding an aqueous 1N sodium hydroxide solution (15 ml), and the mixture was stirred at 60° C. overnight. After cooling down to 0° C., water was added and the mixture was neutralized with 1N hydrochloric acid. After extracting with ethyl acetate, the organic layer was washed with saturated water and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from hexane-ethyl acetate to give 8-(4-(2-butoxyethoxy)phenyl)-1-(2-methyl-2-propen-1-yl)-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (0.97 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:3]=1[NH2:4]>CO.[Pd]>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(Cl)c1N

Procedure:
A solution of 2-chloro-6-nitroaniline (1.0 g, 5.81 mmol, commercially available from Apollo International) in methanol (20 mL) was passed through the H-Cube® (Thales Nanotechnology Inc.) operating at 40 bars and ambient temperature with a flow rate of 1 mL/min. The H-Cube® was equipped with a 10% Pd/C cartridge (Catcart™). The reaction mixture was collected and concentrated after being exposed to the hydrogenation conditions. The crude 3-chlorobenzene-1,2-diamine was carried on without further purification. MS (EI): 145 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([CH3:22])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][C:14](Br)=[CH:13][C:12]=3Br)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([CH3:22])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c1cc(Br)cc(Br)c1n2C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1ncc2c(c1O)c1ccccc1n2C

Procedure:
Prepared in analogy to that of Example 6(a) from 6,8-dibromo-4-hydroxy-9-methyl-9H-beta-carboline-3-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound: 1H NMR (200 MHz, CDCl3): δ (ppm)=11.71 (s, 1H), 8.51 (s, 1H), 8.41 (d, 1H, J=7.8 Hz), 7.64-7.24 (m, 3H), 4.56 (q, 2H, J=7.1 Hz), 3.97 (s, 3H), 1.52 (t, 3H, J=7.1 Hz).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:31][CH2:30]3)=O)[CH2:22][CH2:21]2)=[CH:12]1.[OH-].[Na+]>O1CCCC1.O>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[N:32]1[CH2:33][CH2:34][N:29]([CH2:27][CH2:26][C@H:23]2[CH2:24][CH2:25][C@H:20]([C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:11][CH:12]=3)[CH2:21][CH2:22]2)[CH2:30][CH2:31]1
Reactant: O=C(C[C@H]1CC[C@H](c2c[nH]c3ccccc32)CC1)N1CCN(c2ccccn2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(N2CCN(CC[C@H]3CC[C@H](c4c[nH]c5ccccc54)CC3)CC2)nc1
Reaction time: 0.33 h

Procedure:
A slurry of lithium aluminum hydride (0.472 g, 12.4 mmol) in 20 mL of tetrahydrofuran at 0° C. is treated with aluminum chloride (0.553 g, 4.15 mmol) and the mixture is stirred for 20 minutes. A slurry of trans 1-(2-{4-[1H-3-indolyl]-cyclohexyl}acetyl)-4-(2-pyridinyl)piperazine (1.67 g, 4.15 mmol) in 20 mL of tetrahydrofuran is added and the reaction is stirred at ambient temperature for 18 hours. Water (1 mL) and 10% sodium hydroxide solution (2 mL) is added the mixture is stirred for 2 hours, then filtered through celite and the volatiles are removed under reduced pressure. The resulting oil is triturated with diethyl ether to give the product as a white solid (1.57 g); mp 147°-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.O[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:14][O:15][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: Oc1ccccn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3ccccn3)C3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 2-hydroxypyridine (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The crude product was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 50:50). White solid (79%). MS (Turbo Spray): m/z=468.3 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:15][C:16]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:20])[CH2:17][CH:18]=O>CCCCCC.CCOC(C)=O>[OH:14][C:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH2:18][CH2:17][C:16]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:20])[CH3:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Reactant: Nc1ccccc1C1(O)CCCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(CCNc1ccccc1C1(O)CCCCC1)NC(=O)OC(C)(C)C

Procedure:
The product is prepared analogously to intermediate product 1b starting from 1-(2-aminophenyl)cyclohexanol and tert-butyl (1,1-dimethyl-3-oxopropyl)carbamate. After column chromatography (silica gel, hexane/EtOAc 7:1) the product is obtained as a colorless oil. Yield: 2.65 g (66%); Rf=0.50 (silica gel, hexane/EtOAc 4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:28][O:29][NH2:30]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12]([NH:30][O:29][CH3:28])=[O:14]
Reactant: CON
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CONC(=O)Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
2-(2-Chloro-5-nitrophenyl)acetic acid (49.9 mmol) and CDI (59.9 mmol) were dissolved in DMF (300 mL) to give a yellow solution. O-Methylhydroxylamine hydrochloride (59.9 mmol) was added. The mixture was stirred at room temperature for 4 h. The reaction mixture was then concentrated under reduced pressure to approximately 50 mL and diluted with 300 mL of ethyl acetate. The organic layer was washed twice with 250 mL of water. The aqueous layer was then saturated with brine and back-extracted with ethyl acetate. The organic layers were combined and subsequently washed with 300 mL of 1 M aq. HCl, 300 mL of sat. aq. NaHCO3, and 300 mL of brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 2-(2-chloro-5-nitrophenyl)-N-methoxyacetamide as a solid (69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:20]([OH:23])[C:21]#[CH:22].Cl>O1CCCC1.[Cu]I.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.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:22]#[C:21][CH2:20][OH:23])=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: OCC#Cc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A solution of 1-chloro-4-iodobenzene (23.9 g, 100.0 mmol) in dry tetrahydrofuran (100 mL) was degassed and copper(I)iodide (570 mg, 3.0 mmol), tetrakis(triphenylphosphine)palladium (3.4 g, 3.0 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (18.2 g, 120.0 mmol) were added. The reaction solution was degassed again and propargyl alcohol (6.7 g, 120.0 mmol) was added under inert atmosphere at ambient temperature. The reaction mixture was stirred (initially under cooling with ice water) for 24 h, then treated with water (20 mL) and acidified with 2 M hydrochloric acid (20 mL). The organic phase was separated and the aqueous phase was extracted with ether (4×30 mL). The combined organic phases were dried with anhydrous magnesium sulfate and concentrated in vacuo yielding brown solid. The residue was purified by column chromatography (silica gel Fluka 60, chloroform) yielding 3-(4-chlorophenyl)prop-2-yn-1-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[CH2:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl.CCN(C(C)C)C(C)C>[O:15]=[S:14]1(=[O:16])[CH2:13][CH2:12][CH2:11][N:1]1[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: N#Cc1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(N2CCCS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g of 3-Aminobenzonitril were dissolved in 10 ml DCM and 2.2 ml of DIPEA. 1.3 ml of 3-Chloro-propane-1-sulfonyl chloride were added and the reaction mixture stirred at rt overnight. The organic layer was evaporated, the crude taken up in DMF and 1.5 ml DBU added. The reaction mixture was stirred at rt overnight. DCM was added and the organic phase washed with water. The organic layer was separated, dried over Na2SO4 and evaporated. MS(ISO): 232.2 (MH+)
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([F:25])[CH:18]=3)[NH:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[CH3:26]I>>[F:25][C:19]1[CH:18]=[C:17]([C:15]2[N:16]=[C:12]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=3)[CH:2]=[O:1])[N:13]([CH3:26])[N:14]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: CI
Reactant: COc1ccc(-c2nc(-c3cccc(C4OCCO4)c3)n[nH]2)cc1F
Product: COc1ccc(-c2nc(-c3cccc(C=O)c3)n(C)n2)cc1F

Procedure:
Using 3-(3-[1,3]dioxolan-2-yl-phenyl)-5-(3-fluoro-4-methoxy-phenyl)-1H-[1,2,4]triazole (mixture of tautomers) and methyl iodide the title compound was obtained as an orange solid (34% yield), MS: m/e=311.1 (M+).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH2:10]1[CH2:14]OC[CH2:11]1>[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:6]1[N:7]=[C:2]([C:11]#[C:10][CH3:14])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C1CCOC1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC#Cc1nc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a solution of 3,5-dibromopyrazin-2-amine (10.0 g, 39.5 mmol) in THF (200 mL) was added copper (I) iodide (0.377 g, 1.98 mmol), bis(triphenylphosphine)palladium (II) dichloride (1.39 g, 1.98 mmol) and TEA (16.5 mL, 119 mmol). The reaction mixture was cooled to about 0° C. and degassed with Ar. The reaction mixture was stirred for about 5 min and then the reaction mixture was sparged with propyne and a propyne atmosphere was maintained via balloon. The reaction mixture was stirred for about 30 min at about 0° C. and then was allowed to warm to ambient temperature. The reaction mixture was stirred for about 2 h and then EtOAc (100 mL) and water (100 mL) were added to the reaction mixture. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concd in vacuo. The crude mixture was purified by chromatography on silica gel (120 g) eluting with 10-60% EtOAc in DCM (dry loaded) to provide 5-bromo-3-(prop-1-ynyl)pyrazin-2-amine (7.05 g, 84%) as a yellow solid: LC/MS (Table 1, Method a) Rt=1.79 min; MS m/z: 212, 214 (1:1) (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].Br[C:31]1[CH:32]=[CH:33][C:34]([CH2:37][OH:38])=[N:35][CH:36]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:31]3[CH:36]=[N:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:27])[CH3:28])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: OCc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CO)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 80 °C
Yield: 48.6 %

Procedure:
To as solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (200 mg, 0.48 mmol) in toluene (3.2 ml) and ethanol (2.4 ml) is added (5-Bromo-pyridin-2-yl)-methanol (91 mg, 0.48 mmol); aqueous sodium bicarbonate solution (1.94 mmol, 2M, 1 ml) and [1,1′Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (18 mg, 0.02 mmol). The reaction is heated at 80° C., under nitrogen, for 45 minutes. The reaction mixture is concentrated under reduced pressure and purified by column chromatography (40 g silica gel, 0-100% ethyl acetate/heptane) to give the title compound (92 mg): 1H NMR (400 MHz, CDCl3) 1.61-1.79 (m, 6H), 3.7-3.81 (m, 1H), 4.50-4.88 (m, 5H), 5.24-5.31 (m, 1H), 6.13 (t, 1H), 7.36 (d, 1H), 7.55 (d, 2H), 7.63 (d, 2H), 7.87-7.92 (m, 1H), 8.78-8.82 (m, 1H). m/z M+H 395.
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.[CH3:10][C:11]([CH:13](OC(=O)C)[O:14][C:15](=[O:17])[CH3:16])=[CH2:12]>>[C:15]([O:14][CH:13]=[C:11]([CH3:12])[CH2:10][C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:1][O:9][C:4]=2[CH:5]=1)(=[O:17])[CH3:16]
Reactant: C=C(C)C(OC(C)=O)OC(C)=O
Reactant: c1ccc2c(c1)OCO2
Product: CC(=O)OC=C(C)Cc1ccc2c(c1)OCO2

Procedure:
The production process (A) comprises the steps of (1) reacting 1,2-methylenedioxybenzene and 2-methyl-3,3-diacetoxypropene with each other to produce 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene; and (2) subjecting the obtained 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene to hydrolysis reaction or to transesterification reaction with an alcohol, followed by subjecting the resulting reaction mixture to distillative purification, to thereby adjust a content of 1-acetyl-3,4-methylenedioxybenzene as a by-product in the 2-methyl-3-(3,4-methylenedioxyphenyl)propanal to from 50 to 3000 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[H-].[Na+].[CH3:12][C:13]1[C:18]([CH3:19])=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N+:14]=1[O-:23]>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:16]=[CH:15][N+:14]([O-:23])=[C:13]([CH3:12])[C:18]=2[CH3:19])=[C:4]([F:9])[CH:3]=1
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: Oc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1c(Oc2ccc(Br)cc2F)cc[n+]([O-])c1C
Temperature: 180 °C
Yield: 45.9 %

Procedure:
To a room temperature solution of 4-bromo-2-fluorophenol (1 g, 5.23 mmol) in N-methylpyrrolidone (10 ml) was added sodium hydride (0.27 g, 6.79 mmol, 60% in mineral oil) portionwise. After stirring for 10 minutes 2,3-dimethyl-4-nitro-pyridine 1-oxide (1.05 g, 6.28 mmol) was added The reaction mixture was heated at 180° C. for 60 minutes under microwave irradiation. After cooling to room temperature the mixture was filtered through a diatomaceous earth pad and the filtrate was then diluted with EtOAc and washed with water. The solution was then extracted with additional EtOAc (2×150 ml). The organic layer was dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM to DCM/MeOH up to 3% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 23 (0.75 g, 46%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([O:17][CH3:18])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[OH-].[K+]>C1COCC1.CCOCC>[CH3:18][O:17][C:8]1[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(OC)c(-c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1c(-c2ccccc2)cc(C(=O)O)cc1-c1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
At ambient temperature, to a stirred solution of 2'-methoxy-[1,1';3',1"]terphenyl-5'-carboxylic acid methyl ester (1.148 g, 3.606 mmol) in THF (36.06 mL) was added 1N KOH (36.06 mL) and the reaction was stirred for 16 h. The reaction was heated at 100° C. for an additional 24 h. The reaction was cooled to ambient temperature, diluted with ether (100 mL) and extracted with 0.1N NaOH. The aqueous extracts were washed with ether (3×), acidified with 6N HCl and extracted with EtOAc. The organic extracts were dried (MgSO4) and concentrated to give 1.043 g (95%) of the title compound. 1H NMR (DMSO-d6) δ 3.15 (s, 3 H), 7.40-7.52 (m, 6 H), 7.58-7.60 (m, 4 H), 7.88 (s, 2 H), 13.04 (s, 1 H).