Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH:3]=1.[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1ccnc(Oc2cccc(N)c2)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(Oc2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 16 h
Yield: 77.5 %

Procedure:
To a suspension of 3-(4-methylpyridin-2-yloxy)aniline (264 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (474 mg) and diisopropylethyl-amine (0.529 ml) in dichloromethane (13.2 ml) was added 1-methyl-2-chloropyridinium iodide (438 mg), and the mixture was stirred for 16 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate 4:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(4-methylpyridin-2-yloxy)phenyl)-guanidine (452 mg).
Reaction SMILES: Br[C:2]1[S:16][C:5]2=[N:6][C:7]([CH3:15])=[CH:8][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.[NH:25]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH3:15][C:7]1[N:6]=[C:5]2[S:16][C:2]([C:28]3[CH:29]=[N:25][NH:26][CH:27]=3)=[C:3]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:4]2=[C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(C)(=O)=O)c23)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(-c3cn[nH]c3)sc3nc(C)cc(NS(C)(=O)=O)c23)c1
Temperature: 130 °C
Yield: 34.1 %

Procedure:
To a suspension of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}methanesulfonamide (Example 97) (109 mg, 0.255 mmol), 1H-pyrazol-4-ylboronic acid (60 mg, 0.536 mmol) and potassium carbonate (118 mg, 0.854 mmol) in 1,4-dioxane (1.5 mL) and water (0.6 mL), was added tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol). The reaction mixture was heated at 130° C. in a microwave reactor for 1 h, followed by the addition of another portion of 1H-pyrazol-4-ylboronic acid (41 mg, 0.366 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol). The reaction mixture was heated at 130° C. in a microwave reactor for another 1 h and was then directly loaded onto a silica column, eluting with a gradient of 0-75% of ethyl acetate in cyclohexane and then further purified by MDAP (acidic conditions), to give the title compound (36 mg). LCMS (A) m/z: 413 [M−1]−, Rt 0.97 min (acidic).
Reaction SMILES: FC(F)(F)C1C=CC(C(=O)C)=CC=1.C(O)(=O)C.[Br:18]Br.[Br:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:23]>C(#N)C.O.O>[Br:20][CH:21]([Br:18])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=1)=[O:23]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: BrBr
Agent: CC(=O)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(c1ccc(C(F)(F)F)cc1)C(Br)Br
Temperature: 25 °C

Procedure:
This compound was synthesised by the general procedure represented in Scheme 2, a stirred solution of 1-(4-trifluoromethyl-phenyl)-ethanone (1 g, 5.3 mmol) ) and acetic acid (50 ml) was refluxed 1 h, then bromine (0.35 ml, 6.9 mmol) was added dropwise and the mixture refluxed 3 h. After cooling at room temperature, water (50 ml) was added and the mixture extracted with CH2Cl2 (50 ml), the organic layer was washed with water (50 ml), a solution of NaHCO3 saturated (50 ml) and finally with NaCl solution (50 ml), the organic layer was dried over sodium sulphate and the solvent evaporated under reduced pressure. The resulting residue was purified by column chromatography, using a mixture of ethyl acetate:hexane (1:8) as eluent giving two compounds, the titled compound 41 as a yellow solid (45%) m.p.: 40-41° C., 1H-NMR (CDCl3): δ8.2 (d, J=8.3 Hz, 2H, Ar), 7.8 (d, J=8.3 Hz, 2H, Ar), 6.6 (s, 1H, CH); 13C-NMR (CDCl3): δ184.1 (CO), 134.7 (q, J=272.9 Hz, C—CF3), 132.7 (C—CO), 129.2 (CH), 124.8 (CH), 119.5 (q, J=33.09, CF3), 38.2 (CH); M/z (EI): 348, 346, 344 (M+, 1, 6, 1%), 173 (M-CHBr2, 100%); HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity 97%, r.t.=9.96 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50. The second compound was identified as 2-bromo-1-(4-trifluoromethyl-phenyl)-ethanone (0,6%), described as the example 40.
Reaction SMILES: ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH:23]1([C:26]2[CH:31]=[C:30]([O:32][CH2:33][C:34]3[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=3[F:41])[N:29]3[N:42]=[C:43]([CH3:48])[C:44]([C:45](O)=[O:46])=[C:28]3[CH:27]=2)[CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C.[C:58]([O:62][C:63](=[O:72])[NH:64][C:65]([CH3:71])([CH2:68][CH2:69][CH3:70])[CH2:66][NH2:67])([CH3:61])([CH3:60])[CH3:59]>O1CCCC1>[C:58]([O:62][C:63](=[O:72])[NH:64][C:65]([CH3:71])([CH2:68][CH2:69][CH3:70])[CH2:66][NH:67][C:45]([C:44]1[C:43]([CH3:48])=[N:42][N:29]2[C:30]([O:32][CH2:33][C:34]3[C:35]([F:41])=[CH:36][CH:37]=[CH:38][C:39]=3[F:40])=[CH:31][C:26]([CH:23]3[CH2:25][CH2:24]3)=[CH:27][C:28]=12)=[O:46])([CH3:61])([CH3:60])[CH3:59]
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Reactant: Cc1nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc2c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
76 mg (0.6 mmol) of 1-hydroxy-7-azabenzotriazole and 107 mg (0.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to a solution of 167 mg (0.5 mmol) of 5-cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 149A), 244 μl (1.4 mmol) of N,N-diisopropylethylamine and 121 mg (0.6 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 152A in 5 ml of tetrahydrofuran. The mixture was stirred at room temperature for 18 h and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was removed and washed with water and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel (40 g silica gel cartridge, mobile phase: cyclohexane/ethyl acetate, gradient 0% to 100%). This gave 125 mg of the target compound (48% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][NH:7][CH3:8])[CH3:2].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:32].[N:33]1([CH2:39][CH2:40][N:41]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53]([OH:55])=O)[CH:49]=[N:50][C:44]=3[NH:43][C:42]2=[O:56])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[ClH:32].[CH2:1]([O:3][C:4]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][N:7]([CH3:8])[C:53](=[O:55])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[N:41]([CH2:40][CH2:39][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[CH2:46][C:45]=2[CH:47]=1)[CH3:2]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Reactant: CCOc1cccc(CNC)c1OCC
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CCOc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)C(=O)N3)c1OCC
Yield: 56 %

Procedure:
According to the procedure of Example 1, except substituting 2,3-diethoxy-benzyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.18 g, 56%) was prepared as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.63-10.49 (m, 1H), 10.14-10.12 (m, 1H), 8.41-8.31 (m, 1H), 8.03-7.91 (m, 1H), 7.52-7.45 (m, 1H), 7.38-7.19 (m, 1H), 7.03-6.90 (m, 2H), 6.70-6.51 (m, 1H), 4.63-4.51 (m, 4H), 4.02-3.91 (m, 6H), 3.81-3.68 (m, 4H), 3.60-3.50 (m, 2H), 3.40-3.28 (m, 2H), 3.20-2.85 (m, 5H), 1.40-1.31 (m, 6H); MS (ESI) m/e 524 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:20]OS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:20][C:11]1[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:10]=1)[CH2:29][CH3:30])[CH3:27]
Reactant: CCNCC
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Product: CCN(CC)Cc1cc(-c2ccc(F)cc2F)nn(CC(C)C)c1=O

Procedure:
Following the procedure of Example 9(4), 6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethylamine were reacted to yield the title compound as a pale yellow oil (yield: quantitative)
Reaction SMILES: CC(N=C=NC(C)C)C.[CH3:10][O:11][C:12](=[O:25])[C@H:13]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[NH2:14].[CH3:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35](O)=[O:36])[CH:30]=[C:31]([CH3:33])[CH:32]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35]([NH:14][C@@H:13]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[C:12]([O:11][CH3:10])=[O:25])=[O:36])[CH:30]=[C:31]([CH3:33])[CH:32]=1
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)Cc1cc(C)cc(C)c1

Procedure:
DMAP (122.2 mg, 0.5 mmol) and DIC (N,N-diisopropylcarbodiimide) (235 μl, 1.5 mmol) were added to a solution of tryptophan methyl ester (255 mg, 1.0 mmol) and 3,5-dimethylphenylacetic acid (164 mg, 1.0 mmol) in dry DCM (11 ml). After 17 h at room temperature the solvent was removed under reduced pressure and the crude product was purified by flash chromatography (DCM containing 1% EtOH) to afford (S)-methyl 2-(2-(3,5-dimethylphenyl)acetamido)-3-(1H-indol-3-yl)propanoate. An aqueous solution of LiOH (1N, 4.5 ml, 4.5 mmol) was added to a solution of (S)-methyl 2-(2-(3,5-dimethylphenyl)acetamido)-3-(1H-indol-3-yl)propanoate (365 mg, 1 mmol) in methanol (24.5 ml) and the reaction mixture was stirred at room temperature for 4.5 h. Then water was added and methanol was removed under reduced pressure. The aqueous residue was washed with DCM (5×20 ml), treated with HCl 2N to obtain a pH 4 and extracted with DCM (3×25 ml). The organic phases were dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford (S)-2-(2-(3,5-dimethylphenyl)acetamido)-3-(1H-indol-3-yl)propionic acid (93% c.y.).
Reaction SMILES: Br[C:2]1[C:3]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=2[S:5][C:6]=1[CH3:7].[Li]CCCC.[F:19][C:20]1[C:24]([F:26])([F:25])[C:23]([F:28])([F:27])[C:22]([F:30])([F:29])[C:21]=1F.O>C1COCC1.CCCCCC>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([C:21]3[C:22]([F:30])([F:29])[C:23]([F:27])([F:28])[C:24]([F:25])([F:26])[C:20]=3[F:19])=[C:6]([CH3:7])[S:5][C:4]=2[CH:8]=1
Reactant: FC1=C(F)C(F)(F)C(F)(F)C1(F)F
Reactant: COc1ccc2c(Br)c(C)sc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1ccc2c(C3=C(F)C(F)(F)C(F)(F)C3(F)F)c(C)sc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a stirred solution of 7.61 g (0.03 mol) of 3-Bromo-6-methoxy-2-methylbenzo[b]thiophene (compound obtained in Step 2 of the synthesis of the compound 9) in 120 mL of anhydrous THF is added dropwise 11.90 mL (0.034 mol) of a 2.5M solution of nBuLi in hexane at −78° C. under nitrogen atmosphere. The resulting mixture is stirred for 30 min at −78° C., then 20 g (0.09 mol) of perfluorocyclopentene is added in a single portion. After the addition is completed, the mixture is allowed to return to room temperature, then hydrolysed with 120 mL of water. The mixture THF-water is extracted three times with 150 mL of Et2O. The resulting organic phase is washed several times with saturated aqueous NaCl solution, dried over magnesium sulfate and then concentrated under reduced pressure. The crude product purified by column chromatography on silica gel and eluted with mixtures consisting of pentane and CH2Cl2 of increasing polarity (100:0 to 80:20) gives an oily product (8.12 g, 72% yield), pure enough to be used in the next step without further purification.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[F:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]2[C:14]=1[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH:17]2[CH2:23][C:24](OCC)=[O:25]>>[F:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]2[C:14]=1[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:31])[CH3:32])[CH:17]2[CH2:23][C:24]([NH:10][C:9]([NH2:11])=[NH:8])=[O:25]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2c(F)ccc(F)c2C(=O)N1CC(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: CC(C)CN1C(=O)c2c(F)ccc(F)c2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 20 h
Yield: 10.3 %

Procedure:
N-[(4,7-Difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 2.68 g of potassium tert-butoxide, 2.74 g of guanidinium chloride and 1.49 g of ethyl (4,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then filtered. The filtrate is taken up in 80 cm3 of water and 120 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is separated out and the aqueous phase is extracted twice with 120 cm3 of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 40° C. The evaporation residue is purified by chromatography under argon pressure (50 kPa) on a column of silica gel (particle size 15-40 μm), eluting with successive mixtures of dichloromethane/methanol (95/5 and then 90/10 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. The residue is taken up in diethyl ether, triturated, filtered and then dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 0.16 g of N-[(4,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]-guanidine is thus obtained in the form of a pale yellow solid melting at 212° C. Mass spectrum: DCI: m/e 325 (M+H)+, m/e 263 (base peak).
Reaction SMILES: [NH:1]([C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O)[NH2:2].CO[C:20]1[CH:21]=[C:22]([C:26]#[N:27])[CH:23]=[N:24][CH:25]=1.[CH3:28][O-:29].[Na+].CO>C(OCCO)C.C(O)(=O)C>[CH3:28][O:29][C:25]1[N:24]=[CH:23][C:22]([C:26]2[NH:27][C:3]([CH:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)=[N:1][N:2]=2)=[CH:21][CH:20]=1
Reactant: COc1cncc(C#N)c1
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Agent: [Na+]
Solvent: CCOCCO
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-c2nnc(C3CCN(C(=O)OC(C)(C)C)CC3)[nH]2)cn1
Temperature: 130 °C

Procedure:
tert-Butyl 4-(hydrazinocarbonyl)-piperidine-1-carboxylate (800 mg, 3.29 mmol) was dissolved in anhydrous 2-ethoxyethanol (10 mL) and 5-methoxypyridine-3-carbonitrile (662 mg, 4.9 mmol) was added to the solution. A solution of 0.5M sodium methoxide in methanol (3 mL, ˜1.5 mmol) was added and the mixture was heated at 130° C. for 16 h. The cooled reaction mixture was neutralized with acetic acid and partitioned between ethyl acetate and aq. NaHCO3. The organic layer was dried over Na2SO4, the salts removed by filtration and the solvent evaporated under vacuum. This residue was triturated with diethyl ether to give tert-butyl 4-[5-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate as a white solid. This material was dissolved in methylene chloride (10 mL) and TFA (10 mL) was added. After one hour the solvent was evaporated under reduced pressure to give 2-methoxy-5-(5-piperidin-4-yl-4H-1,2,4-triazol-3-yl)pyridine. NMR (MeOD): δ 8.75 (1H, s), 8.19 (1H, d, J=6 Hz), 6.93 (1H, d, J=6 Hz), 3.95 (3H, s), 3.51 (2H, m), 3.22 (3H, m), 2.32 (2H, m), 2.11 (2H, m).
Reaction SMILES: S1(CCCC1)(=O)=O.[F-:8].[Cs+].Br[C:11]1[N:15]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:14]=[C:13]([C:28]#[N:29])[C:12]=1[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31]>CCOCC>[C:28]([C:13]1[C:12]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=[C:11]([F:8])[N:15]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:14]=1)#[N:29]
Reactant: [F-]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Agent: [Cs+]
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(F)c1S(=O)(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 9.6 %

Procedure:
A mixture of dry sulpholane (15 ml) and 4 Å molecular sieve (3.0 g) was stirred under nitrogen with caesium fluoride (2.4 g) at 60° C. for 1/2 hour. To this was added 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethanesulphonylpyrazole (2.0 g) and the mixture stirred at 60° C. for 2 hours, and left overnight at room temperature. This was diluted with ether (50 ml), filtered, and washed with water (100 ml). The aqueous layer was re-extracted with ether (3×50 ml ) and the combined organic solution re-washed with water (4×50 ml ), dried over anhydrous magnesium sulphate, and evaporated in vacuo to give an oil. Purification by chromatography, eluting with ether/hexane (1:4) gave 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-fluoro-4-trifluoromethanesulphonylpyrazole (0.17 g), m.p. 95°-98° C., in the form of a white solid, after recrystallisation from hexane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C@H:12]2[CH2:16][N:15]([C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[C:14](=O)[C@H:13]2[F:26])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1([C@H:12]2[CH2:16][N:15]([C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH2:14][C@H:13]2[F:26])[CH2:10][CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)N1C[C@H](C2(NC(=O)OC(C)(C)C)CC2)[C@H](F)C1=O
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1C[C@@H](F)[C@@H](C2(NC(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
Under a nitrogen atmosphere, a 1 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (120 ml) was added dropwise under ice cooling into a solution of 4-(R)-(1-tert-butoxycarbonylaminocyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidone in tetrahydrofuran (120 ml) and the mixture was stirred at room temperature for 5 hours. After evaporating the solvent under reduced pressure, a solvent mixture (200 ml) of ethanol with water (4:1) and triethylamine (20 ml) were added to the residue followed by heating under reflux for 2 hours. Then, the liquid reaction mixture was concentrated under reduced pressure and chloroform (400 ml) was added to the residue. After washing with a saturated aqueous solution of sodium chloride, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was subjected to flash silica gel column chromatography (eluent: n-hexane:ethyl acetate=1:2) to obtain 7.84 g (99.4%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:24]([C:23]2[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[O:25])=[CH:7][CH:8]=1
Reactant: COc1ccc(C2NCCc3ccsc32)cc1
Reactant: COc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)N2CCc3ccsc3C2c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
7-(4-methoxyphenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (80 mg) in toluene (10 ml), 4-methoxybenzoic acid (55 mg), EDAC (94 mg) and HOBt (44 mg) were mixed in DMF (3 ml). The mixture was stirred overnight, evaporated to dryness and dissolved in ethyl acetate (10 ml).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:11][C:12]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:15]([NH2:16])=[C:14]([Cl:23])[CH:13]=1.O>C(#N)C>[Br:11][C:12]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:15]([NH:16][C:8](=[O:9])[CH2:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:14]([Cl:23])[CH:13]=1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Nc1c(Cl)cc(Br)cc1C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(CCC1CCCC1)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Cyclopentyl propionyl chloride (1.28 g, 8.0 mmol) was added to a solution of 4-bromo-2-chloro-6-(trifluoromethyl)aniline (2.0 g, 7.3 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (100% DCM) afforded the title compound as a powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[C:18](=[CH:11]/[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)/[C:19]#[N:20])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: O=Cc1ccnc2ccccc12
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccnc3ccccc23)cc1OC
Yield: 51.9 %

Procedure:
4-Quinolinecarboxaldehyde (500 mg) was condensed with 3,4-dimethoxybenzyl cyanide (564 mg) through Method A (production step 2), to thereby yield the target product (yield: 522 mg, 52%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:14])=[CH:10][N:11]=[N:12][CH:13]=2)=[C:4]([O:15][CH3:16])[CH:3]=1.Cl[CH2:18]Cl.CO>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:14][CH3:18])=[CH:10][N:11]=[N:12][CH:13]=2)=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1cnncc1N
Reactant: ClCCl
Solvent: CO
Product: CNc1cnncc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 1, intermediate a, from 5-(4-fluoro-2-methoxy-phenyl)-pyridazin-4-ylamine and using a gradient of dichloromethane:methanol (100:0 to 90:10) for the chromatographic purification. Brown oil (5%). MS (ESI+): m/z=234.1 ([M+H]+).