Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH3:20]>C1(C)C=CC=CC=1.CN(C)C=O>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([NH2:20])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NC(=O)C=Cc1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
4-(Trifluoromethyl)cinnamic acid (64.85 g, 300 mmol) was added in toluene (325 ml) and dimethylformamide (2.2 ml). Thionyl chloride (26.3 ml, 361 mmol) was added dropwise at room temperature, and the mixture was heated at 45° C. for 2 hours. The obtained reaction mixture was added dropwise to 25% aqueous ammonia (325 ml) while keeping the mixture at 5-20° C. The mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with 20 water and isopropyl ether and dried under reduced pressure to give 4-(trifluoromethyl)cinnamamide (60.76 g, yield 94%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C@@:12]([C:27]1[CH:32]=[C:31]([O:33][C:34]([F:39])([F:38])[CH:35]([F:37])[F:36])[CH:30]=[C:29]([F:40])[CH:28]=1)([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])#[N:2].[Si]([N:45]=[N+:46]=[N-:47])(C)(C)C>COCCOC>[N:2]1[NH:45][N:46]=[N:47][C:1]=1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C@@:12]([C:27]1[CH:32]=[C:31]([O:33][C:34]([F:38])([F:39])[CH:35]([F:36])[F:37])[CH:30]=[C:29]([F:40])[CH:28]=1)([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: N#CCCCCCNC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: COCCOC
Product: O=C(NCCCCCc1nn[nH]n1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 150 °C
Yield: 47 %

Procedure:
To a solution of (R)-1-(5-cyanopentyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea, prepared by the method described in Procedure 12 (45 mg, 0.080 mmol) in DME (161 μL) at rt was added TMSN3 (0.013 mL, 0.16 mmol), followed by n-Bu2SnO2 (2 mg, 0.008 mmol). The reaction mixture was heated at 150° C. for 10 min under microwave irradiation. An additional amount of TMSN3 (0.013 mL, 0.16 mmol) and n-Bu2SnO2 (2 mg, 0.008 mmol) was added, and the reaction mixture was heated at 150° C. for an additional 10 min under microwave irradiation. The reaction mixture was concentrated and the residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18, eluting with MeCN/H2O containing 0.1% TFA, monitoring at 220 nm) to provide (R)-1-(5-(2H-tetrazol-5-yl)pentyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea (23 mg, 47% yield) as a white solid. 1H NMR (500 MHz, MeOH-d4) δ 7.18-6.89 (m, 11H), 6.71 (d, J=5 Hz, 2H), 6.37-6.16 (m, 1H), 3.93 (d, J=15 Hz, 1H), 3.81 (d, J=15.0 Hz, 1H), 3.08 (t, J=5 Hz, 2H), 2.94 (t, J=5 Hz, 2H), 1.83-1.76 (m, 2H), 1.55-1.48 (m, 2H), 1.41-1.35 (m, 2H); LC/MS: RT=3.736 min [M+H] 607.3 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeCN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O.N1C(=O)C2NC=NC=2NC1=O.[N+:31]([C:34]1[CH:35]=[N:36][C:37]2[C:42]([C:43]=1O)=[CH:41][CH:40]=[CH:39][CH:38]=2)([O-:33])=[O:32].P(Cl)(Cl)([Cl:47])=O>>[N+:31]([C:34]1[CH:35]=[N:36][C:37]2[C:42]([C:43]=1[Cl:47])=[CH:41][CH:40]=[CH:39][CH:38]=2)([O-:33])=[O:32]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Product: O=[N+]([O-])c1cnc2ccccc2c1Cl

Procedure:
Compound 6 was prepared as described elsewhere [Van Galen, P. J. M. et. al. 1-H-imidazo[4,5-c]quinolin-4-amines: Novel Non-Xanthine Adenosine Antagonists. J. Med. Chem. 1991, 34, 1202-1206]. In brief, 3-Nitro-4-hydroxyquinoline 5 (5.7 g, 30 mmol) was added to phosphorus oxychloride (70.0 g, 41.2 ml, 450 mmol) with stirring. The mixture was refluxed for 30 minutes. After cooling the solvent was poured over crushed ice while stirring. After 1 hour the solid that was formed was filtered off, washed with cold water and dissolved in ethyl acetate. The solution was extracted with ice-cold NaOH (1 M) till pH=8-9 and dried over MgSO4. The solvent was evaporated and the residue was dried. Yield: 5.05 g (81%). Mp.: 118°-119° C. 1H NMR (DMSO-d6): δ 7.94-8.11 (m, 2H, Ar); 8.25 (d, 1H, J=8.0 Hz, Ar); 8.47 (d, 1H, J=9.5 Hz, Ar); 9.42 (s, 1H, Ar).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH2:18][O:19][CH2:20][CH:21]([CH3:22])[C:15]=3[N:14]=2)=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C(Cl)CCl>CN(C=O)C.C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH2:18][O:19][CH2:20][CH:21]([CH3:22])[C:15]=3[N:14]=2)=[CH:8][C:4]=1[C:5]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:6])[CH3:2]
Reactant: CCc1cc(C)c(-c2nc3c([nH]2)COCC3C)cc1C(=O)O
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCc1cc(C)c(-c2nc3c([nH]2)COCC3C)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 8 h
Yield: 6.8 %

Procedure:
Into around-bottom flask, was placed a solution of 2-ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid (compound 400.3, 30 mg, 0.10 mmol, 1.0 equiv) in DMF/DCM (5/5 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 50 mg, 0.22 mmol, 2.2 equiv), EDC (40 mg, 2.0 equiv) and 4-dimethylaminopyridine (28 mg, 2.0 equiv) were added. The resulting solution was stiffed overnight at 25° C., then quenched with water (10 mL). The mixture was extracted with ethyl acetate (3×5 mL), and the combined organic layers was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatraphy with ethyl acetate/petroleum ether (2:1) as the eluent to obtain the title compound as a light yellow solid (3.2 mg, 7%). m/z (ES+) 469 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]([C:21]#[C:22][Si](C)(C)C)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.C1C(=O)N([Br:35])C(=O)C1>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]([C:21]#[C:22][Br:35])=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C#C[Si](C)(C)C)c(C)cc(Br)c32)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C#CBr)c(C)cc(Br)c32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 7-bromo-5-methyl-1-tosyl-4-((trimethylsilyl)ethynyl)-1H-indole (70 mg, 0.152 mmol) and AgNO3 (7.75 mg, 0.046 mmol) in acetone (0.8 mL) at 0° C. was added a solution of NBS (38 mg, 0.213 mmol) in acetone (0.8 mL) and the mixture was warmed to room temperature. After stirring overnight the reaction was purified directly by flash chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (d, J=3.79 Hz, 1H) 7.72 (d, J=8.59 Hz, 2H) 7.37-7.48 (m, 3H) 6.91 (d, J=3.79 Hz, 1H) 2.38 (s, 3H) 2.37 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH:63]([F:65])[F:64])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH:63]([F:65])[F:64])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)F)c2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.4 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 100 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-difluoromethoxy-phenyl)-ethyl]-amine in 2 ml DMF was added. After 2.5 h stirring at rt, the reaction mixture was diluted with 50 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 105 mg colorless viscous oil (73%). MS (EI) 477.4 (M)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[O-]CC.[Na+]>C(O)C>[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:27](/[CH:28]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: COc1cccc(C=O)c1OCC(C)(C)C
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC(C)(C)C
Yield: 49.2 %

Procedure:
The title compound was prepared by condensation of Intermediate 15 (400 mg, 1.225 mmol) with 3-methoxy-2-neopentyloxybenzaldehyde (353 mg, 1.50 mmol) in the presence of sodium ethoxide (163 mg, 2.40 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to afford 320 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.01 (s, 9H), 3.52 (s, 2H), 3.77 (s, 3H), 6.82 (d, J=16.2 Hz, 1H), 6.92-6.94 (m, 1H), 6.99 (s, 2H), 7.48 (m, 5H), 7.98 (d, J=5.1 Hz, 1H), 8.22 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 531.35 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([F:21])[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=2[F:21])=[CH:6][N:7]=1
Reactant: N#Cc1nc(Br)cnc1N
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1nc(-c2ccc(Cl)cc2F)cnc1N
Temperature: 80 °C
Yield: 83.8 %

Procedure:
To a solution of 3-amino-6-bromopyrazine-2-carbonitrile (2.00 g, 9.55 mmol) in 1,4-dioxane (48 mL), were added (4-chloro-2-fluorophenyl)boronic acid (1.66 g, 9.55 mmol) and aqueous Na2CO3 (2 M, 24 mL, 48 mmol) and the reaction mixture sparged with N2 gas for 10 min. Pd(dppf)Cl2.CH2Cl2 (0.349 g, 0.477 mmol) was then added and the reaction mixture sparged for an additional 10 min with N2 gas. The reaction vessel was sealed and heated for 3 hours at 80° Celsius. The mixture was cooled to rt, filtered through celite, and the filter cake washed with EtOAc (300 mL). The filtrate was washed with a 1:1 mixture of brine/H2O (2×100 mL). The organic phase was concentrated to dryness and subjected to FCC to give the title compound (1.99 g, 84%). MS (ESI): mass calcd. for C11H6ClFN4, 248.03; m/z found 249.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J=2.0, 1H), 7.83 (m, 1H), 7.25-7.08 (m, 2H), 5.36 (s, 2H).
Reaction SMILES: C(OC([NH:11][NH:12][C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:12]([C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:14])[NH2:11]
Reactant: [H][H]
Reactant: COC(=O)c1cccc(C(=O)NNC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(C(=O)NN)c1

Procedure:
14.6 g (44.5 mmol) methyl 3-[N′-benzyloxycarbonyl-hydrazinocarbonyl)-benzoate are dissolved in 75 mL methanol and hydrogenated in the presence of palladium on charcoal (10%) at ambient temperature and 3 bar hydrogen pressure. The catalyst is filtered off and the filtrate is freed from solvent. White solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:18]([C:22]1[CH:23]=[CH:24][C:25]([O:31][CH2:32][O:33][CH3:34])=[C:26](B(O)O)[CH:27]=1)([CH3:21])([CH3:20])[CH3:19]>C(COC)OC.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>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([O:31][CH2:32][O:33][CH3:34])=[C:24]([C:2]2[N:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: COCOc1ccc(C(C)(C)C)cc1B(O)O
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+]
Solvent: COCCOC
Product: COCOc1ccc(C(C)(C)C)cc1-c1ncc(C(F)(F)F)cn1
Temperature: 80 °C
Yield: 44.8 %

Procedure:
To a solution of 2-chloro-5-(trifluoromethyl)pyrimidine (0.300 g, 1.64 mmol) in dimethoxyethane (9 mL) was added a 2 M aqueous solution of sodium carbonate (3.7 mL, 7.4 mmol) and (5-(tert-butyl)-2-(methoxymethoxy)phenyl)boronic acid (0.500 g, 2.14 mmol). The solution was degassed with nitrogen for five minutes and tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.082 mmol) was added and the reaction mixture heated to 80° C. in a sealed vial for 16 hours. The cooled reaction mixture was partitioned between ethyl acetate (25 mL) and 1 M aqueous sodium hydroxide solution (25 mL), the organic phase separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give 2-(5-(tert-butyl)-2-(methoxymethoxy)phenyl)-5-(trifluoromethyl)pyrimidine (0.25 g, 44% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.C1(N)CCCCC1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2cccc(Cl)c2Cl)cc1
Solvent: NC1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2cccc(Cl)c2Cl)cc1
Yield: 75 %

Procedure:
Prepared analogous to Example 25 from 4-(2',3'-dichloro-4-biphenylyl)-4-oxo-butyric acid. Yield: 75% of theory, m.p. 134°-135° C. (decomp.). Melting point of the cyclohexylamine salt: 158° C. (decomp.).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:37]=[CH:36][C:22]4[CH2:23][N:24]([CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH2:25][CH2:26][O:27][C:21]=4[CH:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:37]=[CH:36][C:22]4[CH2:23][N:24]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:25][CH2:26][O:27][C:21]=4[CH:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCCN1CCOc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)OCCN(CCCC(=O)O)C4)no2)cc1Cl
Reaction time: 2 h

Procedure:
2M Sodium hydroxide (aq) (0.5 ml, 1.000 mmol) was added to a solution of ethyl 4-[8-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]butanoate (Preparation 36) (0.103 g, 0.206 mmol) in ethanol (4 ml) and left at room temperature for 2 hours. The reaction mixture was evaporated and the residue dissolved in water/EtOAc (30 ml of each) and acidified with acetic acid. The organic layer was collected, dried (magnesium sulphate), evaporated and azeotroped with 15 ml of toluene. The title compound was obtained by triturating with ether and filtering off as a white solid (65 mg). δH (400 MHz, d6DMSO) 1.36 (6H, d), 1.70 (2H, m), 2.23 (2H, t), 2.33 (2H, t), 3.02 (2H, m), 3.84 (2H, s), 4.06 (2H, m), 4.89 (1H, m), 7.44 (2H, m), 7.61 (1H, d), 7.72 (1H, dd), 8.10 (1H, dd), 8.18 (1H, d); MS (ES) C24H2635ClN3O5 requires 471; found 472 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:34][NH2:35]>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([NH:35][CH3:34])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: CN
Product: CNc1ccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(COC)C2)cn1

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and methylamine. LCMS (Method C): 484 (M+H)+, Retention time 9.8 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH2:56]([O:55][CH2:54][CH2:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:51][CH:50]=1)[CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: CCCCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (310 mg) was added toluene/ethanol/water (10/1/1, 19.8 ml) and then were added 4-(2-hexyloxyethoxy)phenyl borate (190 mg) and potassium carbonate (181 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (28 mg), and the mixture was refluxed for 8 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/2) and recrystallized from ethanol to give 7-[4-(2-hexyloxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 107) (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH2:12][CH:13]([OH:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[CH:10][CH:11]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH2:12][C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCC(O)Cc1cccc(/C=C/c2c(Cl)cccc2Cl)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Cc1cccc(/C=C/c2c(Cl)cccc2Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (E)-tert-butyl 3-(3-(2,6-dichlorostyryl)phenyl)-2-hydroxypropylcarbamate (1.08 g, 2.56 mmol) in CH2Cl2 (20 mL) was added Celite (0.8 g) and pyridinium chlorochromate (0.661 g, 3.06 mmol). The reaction mixture was stirred at room temperature for 1.5 h then additional Celite (0.70 g) and pyridinium chlorochromate (0.552 g, 2.56 mmol) were added. The mixture was stirred for 1 h then the solids were removed by filtration through Celite. The filtrate was concentrated under reduced pressure then purified by flash chromatography (10 to 70% EtOAc-hexanes gradient) to give (E)-tert-butyl 3-(3-(2,6-dichlorostyryl)phenyl)-2-oxopropylcarbamate. Yield (0.49 g, 45%): 1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J=8.4 Hz, 2H), 7.48 (d, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.29-7.36 (m, 2H), 7.15 (d, J=7.4 Hz, 1H), 7.12 (d, J=16.6 Hz, 1H), 7.04 (d, J=16.6 Hz, 1H), 7.05-7.06 (m, 1H), 3.88 (d, J=6.0 Hz, 2H), 3.78 (s, 2H), 1.36 (s, 9H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[Cl:16][C:17]1[N:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=1>>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=2)=[O:26])=[C:19]([C:28]([F:31])([F:29])[F:30])[CH:18]=1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: O=C(O)C=Cc1cnc(Cl)cc1C(F)(F)F
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2cnc(Cl)cc2C(F)(F)F)cc1F
Yield: 52.3 %

Procedure:
N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide HCl salt (59 mg, 0.23 mmol) was reacted with 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 1.0 eq) to give 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (47 mg, 49.0%) after purification by column chromatography (Hex/EtOAc=4/5).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:4][C:5]([CH2:8]O)=[CH:6][CH:7]=1.[BrH:16].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)C>[CH3:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:4][C:5]([CH2:8][Br:16])=[CH:6][CH:7]=1
Reactant: Cc1ccc(CO)nc1-c1ccccn1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(CBr)nc1-c1ccccn1

Procedure:
0.9 g (4.5 mmols) of 3-methyl-6-hydroxymethyl-2,2'-bipyridine are boiled under reflux for 6 hours, together with 5 ml of 62% hydrobromic acid. After cooling, 10 ml of water and 20 ml of diethyl ether are added. The water phase is rendered alkaline with potassium carbonate, separated from the ether phase and washed with a further 10 ml of diethyl ether. The combined ether phases are dried over sodium sulfate and concentrated to dryness in vacuo (maximum bath temperature: 30° C.). 1.16 g (98% of theory) of 3-methyl-6-bromomethyl-2,2'-bipyridine remains as an oily product which decomposes at room temperature, giving a red colouration, and crystallises at 0° C. The 3-methyl-6-bromomethyl-2,2'-bipyridine is immediately used further.