Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:30]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:31])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)C3CCCCC3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and cyclohexanecarbonyl chloride provided the title compound. ESMS [M+H]+: 414.4
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1.[CH2:20]([O:22][CH2:23][CH2:24]Br)[CH3:21]>>[CH3:19][O:18][C:4]1[CH:3]=[C:2]([O:1][CH2:21][CH2:20][O:22][CH2:23][CH3:24])[CH:7]=[CH:6][C:5]=1[CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(CC(C)C)c1ccc(O)cc1OC
Reactant: CCOCCBr
Product: CCOCCOc1ccc(C(CC(=O)OC)CC(C)C)c(OC)c1

Procedure:
Following a similar procedure to that described in Preparation 45A(i), but using methyl 3-(4-hydroxy-2-methoxyphenyl)-5-methylhexanoate (prepared as described in Preparation 58B) and 2-ethoxyethyl bromide, the title compound was obtained as an oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](O)[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:28])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([Cl:28])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cl[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a stirred 0° C. solution of (1R)-1-(4-Bromophenyl)-2-(4-morpholinyl)ethanol (48.5 g, 0.17 mol) in 200 mL CH2Cl2 was added 52 mL of triethylamine (0.37 mol, 2.2 equiv). Following the addition of triethylamine, 15.8 mL of methanesulfonyl chloride (0.2 mol, 1.2 equiv) was added to the reaction mixture through an addition funnel. After the addition, the reaction mixture was stirred at room temperature overnight. HPLC analysis indicated a 5:1 ratio of starting material to product and an additional 6.58 mL of methanesulfonyl chloride (0.085 mols) and 11.8 mL of triethylamine (0.085 mol) were added. After stirring overnight at ambient temperature, the reaction was heated to 40° C. and stirred for 48 h. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude brown oil was purified by silica gel chromatography (800 g silica gel 60, 230-400 mesh, 20-50% EtOAc/CH2Cl2 as eluent). Concentration of the pure fractions yielded the title compound as a yellow oil (34.5 g, 67%). MS (ES) m/e 304, 306 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1F)[C:25]([OH:27])=[O:26])#[N:21]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:30]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[C:20]#[N:21])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Reactant: CC(C)COc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)COc1ncc(Oc2ccc(C(=O)O)cc2C#N)cc1Cl
Temperature: 90 °C
Reaction time: 16 h
Yield: 118.7 %

Procedure:
5-Chloro-6-isobutoxypyridin-3-ol (Preparation 16, 0.124 g, 0.62 mmol) and potassium carbonate (0.28 g, 2.03 mmol) were suspended in DMSO (3.0 mL). Then 3-cyano-4-fluorobenzoic acid (0.0835 g, 0.51 mmol) was added portionwise. The reaction was then stirred at 90° C. under nitrogen for 16 hours, diluted in EtOAc (15 mL) and washed twice with an aqueous solution of HCl (2.0 M, 10 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase column chromatography (ISCO®, gradient of 5-95% acetonitrile in water, 13 g C18 column) to afford the title compound as an orange oil (0.21 g, 120%):
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[S:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[S:21].NCCC(O)=O>>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[C:25]4[S:19][C:20](=[S:21])[NH:22][C:23]4=[O:24])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: O=C1CSC(=S)N1
Agent: NCCC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Yield: 66.2 %

Procedure:
A mixture of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) (4.96 g, 20 mol), rhodanine (2.66 g, 20 mmol), and β-alanine (2.0 g, 22.5 mmol) in 50 ml of acetic acid(AcOh) was refluxed for 2 hours. The solid which was formed on cooling the solution was collected to give the title compound as a red solid (4.8 g, 66%); 1H NMR (300 MHz, CDCl3) δ 1.81 (t, J=5.5 Hz, 4 H), 3.55 (t, J=5.5 Hz, 4 H), 4.00 (s, 4 H), 6.92 (d, J=8.9 Hz, 2 H), 7.58 (d, J=8.9 Hz, 2 H), 7.38 (s, 1 H); MS (ES) m/z: 362.8 (MH+); HRMS Calcd. for C17H19N2O3S2(MH+): 363.0837. Found: 363.0852. Anal. Calcd. for C17H18N2O3S2: C, 56.33; H, 5.01; N, 7.73. Found: C, 56.28; H, 4.89; N, 7.73.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[CH2:21][C:22]34[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]3)[CH2:29]4)=[C:15]([CH3:33])[CH:14]=2)[CH2:9]1)(C)(C)C.[ClH:35]>CO.O1CCOCC1>[ClH:35].[ClH:35].[NH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[CH2:21][C:22]34[CH2:23][CH:24]5[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]5)[CH2:31]3)[CH2:29]4)=[C:15]([CH3:33])[CH:14]=2)[CH2:9]1
Reactant: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)C2)ccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(N2CCC(N)C2)ccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
{1-[4-(2-(tricyclo[3.3.1.13,7]dec-1-yl)acetylamino)-3-methylphenyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (0.20 g, Example 35c) was dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml of a 4N solution in dioxane) was added. After stirring at room temperature for 14 h, the mixture was evaporated to 2/3 original volume under reduced pressure. Diethyl ether was gradually added to the solution and the resulting precipitate collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound as a solid (0.15 g)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][N:12]=2)[CH:7]=[CH:6]1.Cl[C:15](=[O:20])[C:16]([O:18][CH3:19])=[O:17].CO>C(Cl)Cl>[O:20]=[C:15]([C:7]1[C:8]2[C:13](=[N:12][CH:11]=[CH:10][CH:9]=2)[NH:5][CH:6]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(=O)Cl
Reactant: c1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(=O)c1c[nH]c2ncccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a suspension of aluminum chloride (56.4 g, 423 mmol, 5 equiv.) in DCM (50 mL) was added 7-azaindole (10.0 g, 85 mmol). After 1 h at room temperature the resulting mixture was cooled to 0° C. and methyl chlorooxoacetate (51.9 g, 423 mmol, 5 equiv.) was added dropwise. After a period of 18 h at room temperature the reaction mixture was cooled to 0° C. and methanol (300 mL) was added. After a period of 0.5 h at room temperature, the solvents were evaporated. DCM (500 mL) and saturated NaHCO3 (600 mL) were added. The organic layer was separated and the water extracted with DCM (250 mL). The organic phases were combined and stirred for 18 h with a solution of potassium sodium tartrate (166 g in 500 mL of water). The organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography with 50% ethyl acetate in hexane to provide 13 g of the title compound.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C(O[C:12]([C:14]1[O:15][C:16]2[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=2[C:18]=1[N:19]=[CH:20]N(C)C)=[O:13])C.C(O)(=O)C>O1CCCC1>[OH:13][C:12]1[C:2]([C:1]#[N:3])=[CH:20][N:19]=[C:18]2[C:17]3[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=3[O:15][C:14]=12
Reactant: CC#N
Reactant: CCOC(=O)c1oc2ccccc2c1N=CN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cnc2c(oc3ccccc32)c1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
A solution of 1.5 mL (30.0 mmol) of acetonitrile in 30 mL of tetrahydrofuran is added to a −78° C. solution of 11.4 mL of 2.5 M n-butyllithium (29.00 mmol) in 35 mL of tetrahydrofuran. After stirring at −78° C. for 15 min a solution of 3.7 g (14.2 mmol) of 3-(dimethylaminomethyleneamino)benzofuran-2-carboxylic acid ethyl ester in 50 mL of tetrahydrofuran is added dropwise. After stirring at −78° C. for 30 minutes, the reaction mixture is allowed to warm to 0° C. The reaction mixture is cooled to −78° C. and 3 mL of acetic acid is added. The solution is warmed to room temperature and the resulting precipitate is collected. This solid is combined with 20 mL of acetic acid and heated at reflux temperature for 1.5 hours. The mixture is cooled to room temperature and the solid is collected by filtration washing with saturated sodium bicarbonate, water, diethyl ether and ethyl acetate to provide 2.45 g of a red solid, mp>310° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[C:4]([C:15]2(O)[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)[CH:3]=1.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:15]2[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[CH2:17][CH:16]=2)[CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1(O)CCN(C/C=C/c2ccc(Cl)cc2)CC1
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Cl)cc1C1=CCN(C/C=C/c2ccc(Cl)cc2)CC1

Procedure:
A suspension of N-(4-chloro-2-{1-[(E)-3-(4-chloro-phenyl)-allyl]-4-hydroxy-piperidin-4-yl}-phenyl)-2,2-dimethyl-propionamide (1.00 g) in 3NH2SO4 (7.5 ml) and DMSO (3 ml) was heated to reflux temperature for 48 hours. Then, water was added and the mixture extracted three times with CH2Cl2, the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (CH2Cl2:MeOH 95:5) to afford 4-chloro-2-{1-[(E)-3-(4-chloro-phenyl)-allyl]-1,2,3,6-tetrahydro-pyridin-4-yl}-phenylamine (0.205 g; viscous oil; Retention Time HPLC 2.15 min; MS (ES+) 359 (M+H+) and 4-(2-amino-5-chloro-phenyl)-1-[(E)-3-(4-chloro-phenyl)-allyl]-piperidin-4-ol (0.182 g; M.p. 168-170° C.; Retention Time HPLC 1.95 min; MS (ES+) 377 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.F[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=1[F:30]>CN(C)C=O>[F:30][C:21]1[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[N:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=[C:2]1[CH3:1]
Reactant: Cc1nc(C(=O)O)c[nH]1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)O)cn1-c1ccc(S(C)(=O)=O)cc1F

Procedure:
A mixture of 2-methyl-1H-imidazole-4-carboxylic acid (500 mg), N,N-diisopropyl-ethyl-amine (4 mL), and 1,2-difluoro-4-methanesulfonylbenzene (1.2 g), in N,N-dimethylformamide (6 mL) is heated to 120° C. overnight. The crude product is purified by HPLC. LC (method 20): tR=0.90 min; Mass spectrum (APCI): m/z=299 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1[O:16][CH3:17].C([Li])CCC.[P:23](Cl)([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:24]>>[CH3:17][O:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[P:23](=[O:24])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]
Reactant: COc1cccc(OC)c1-c1ccccc1Br
Reactant: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Product: CCOP(=O)(OCC)c1ccccc1-c1c(OC)cccc1OC
Temperature: -78 °C
Yield: 65 %

Procedure:
To a 250-mL round-bottom flask equipped with a magnetic stir bar was added 2′-bromo-2,6-dimethoxybiphenyl (see Buchwald S L, Journal of the American Chemical Society 2005; 127:4685-4696) (7.02 g, 24.0 mmol, 1 equiv). Degassed, anhydrous tetrahydrofuran was added (80 mL) followed by N,N,N′,N′-tetramethylethylene-1,2-diamine (4.31 mL, 28.7 mmol, 1.2 equiv). The resulting solution was cooled to −78° C., and then n-butyllithium (11.5 mL, 28.7 mmol, 1.2 equiv, 2.5 Min hexanes) was added in a dropwise fashion. After the addition of 5 mL of n-butyllithium the reaction slurry could no longer be stirred. The reaction flask was warmed to 0° C. at which point the slurry became free-flowing. The remainder of the n-butyllithium (−6.5 mL) was added over the course of 10 minutes. The reaction was stirred for 90 minutes at 0° C., and then the aryllithium intermediate was quenched with diethyl chlorophosphate (4.15 mL, 28.7 mmol, 1.2 equiv). The reaction was re-cooled to −78° C. and stirred for 1 hour, then the cooling bath was removed and the flask was warmed to room temperature. At that point, the reaction solution was diluted with pH 7 phosphate buffer (100 mL). The reaction mixture was worked up by separating the phases and washing the aqueous layer with ethyl acetate (4×60 mL). The combined organic fractions were then washed once with brine (150 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by column chromatography (120-g column; gradient: 1.5 column volumes dichloromethane, ramp up to 88:12 dichloromethane:acetone over 10.5 column volumes, hold at 88:12 for 6 column volumes), the product was isolated as a white solid (5.49 g, 78 area % by HPLC, 65% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.07 (dd, J=14.1, 7.7 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 7.46-7.37 (m, 1H), 7.30 (t, J=8.3 Hz, 1H), 7.24-7.18 (m, 1H), 6.60 (d, J=8.4 Hz, 2H), 3.98-3.77 (m, 4H), 3.70 (s, 6H), 1.17 (t, J=7.1 Hz, 6H). 31P NMR (CDCl3, 202 MHz) δ ppm 15.2 (s).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[C:11]12([CH:21]3[CH2:25][CH2:24][CH2:23][NH:22]3)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C>[C:11]12([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:6]3[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[C:3]=3[C:4]#[N:5])[CH2:20][CH:15]3[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]3)[CH2:18]1)[CH2:12]2
Reactant: C1CNC(C23CC4CC(CC(C4)C2)C3)C1
Reactant: N#Cc1c(F)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1c(Br)cccc1N1CCCC1C12CC3CC(CC(C3)C1)C2
Temperature: 130 °C

Procedure:
2-Bromo-6-fluorobenzonitrile (900 mg), 2-adamantan-1-yl-pyrrolidine (924 mg), and potassium carbonate (1244 mg) were added to dimethyl sulfoxide and the mixture was heated at 130° C. for 16 hours. The solution was cooled, diluted with ethyl acetate, washed twice with 1M HCl, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the crude material was concentrated under vacuum and purified on silica gel using 5% ethyl acetate (hexanes) to provide the title compound.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[CH3:17].[CH2:18](I)C.O>CS(C)=O>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10](=[O:14])[N:11]2[CH3:18])=[CH:6][C:5]=1[CH3:17]
Reactant: Cc1cc2c(cc1Br)NC(=O)CC2(C)C
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(cc1Br)N(C)C(=O)CC2(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 104.5 %

Procedure:
A mixture of powdered potassium hydroxide (3.35 g, 59.67 mmol) in DMSO (40 mL) was stirred at 0° C. for 10 min. 7-bromo-4,4,6-trimethyl-3,4- dihydro-1H-quinoline-2-one (Example 1e) (8.0 g, 29.83 mmol) was added cautiously, followed immediately by the addition of ethyl iodide (12 mL, 149.17 mmol). The reaction mixture was kept at 0° C. for 30 min then slowly warmed up to room temperature and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane washed with water and brine, dried (MgSO4), filtered and evaporated to give 8.8 g of 7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one and used without further purification in the Suzuki coupling (step a): 1H NMR (300 MHz; CDCl3): 1.24 (t, J=7.2 Hz, 1 H), 1.25 (s, 6 H), 2.37 (s, 3 H), 2.45 (s, 2 H), 3.98 (q, 2 H), 7.13 (s, 1 H), 7.18 (s, 1 H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7](C(O)=O)=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]>C1(C)C=CC=CC=1.CCOCC>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[CH:7]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-n2cccc2)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCc1nc(-n2cccc2)cn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A suspension of 2-butyl-4-(1H-pyrrol-1-yl)-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylic acid (Example 16, 50 mg) in toluene (10 mL) was heated at reflux for 1 hour. Evaporation gave a gummy solid that was redissolved in ether and evaporated again to give the title compound as a colorless powder. 1H-NMR (CDCl3) δ 7.9 (d, 1H), 7.6 (m, 2H), 7.4 (d, 2H), 7.1 (d, 2H), 6.9 (d, 2H), 6.8 (s, 2H), 6.5 (s, 1H), 6.1 (s, 2H), 5.0 (s, 2H), 2.4 (t, 2H), 1.6 (m, 2H), 1.3 (m, 2H), 0.9 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[C:15]2[N:20]=[C:19]([N:21]3[C:25]([C:26]([F:29])([F:28])[F:27])=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=[N:22]3)[CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:45]2[CH2:46][CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH:50]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[CH2:33]([O:32][C:30]([C:24]1[CH:23]=[N:22][N:21]([C:19]2[N:20]=[C:15]([C:9]3[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=3[O:7][CH2:6][C:5]3[CH:35]=[CH:36][C:2]([C:45]4[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH:46]=4)=[CH:3][CH:4]=3)[CH:16]=[CH:17][CH:18]=2)[C:25]=1[C:26]([F:29])([F:28])[F:27])=[O:31])[CH3:34]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OCc3ccc(Br)cc3)n2)c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OCc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)F
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A vial was charged with the title compound from Example 12 Step C (375 mg, 0.669 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (310 mg, 1.00 mmol; Tetrahedron Lett, 2000, 41, 3705-3708) and trans-dichlorobis(triphenylphosphine)palladium (II) (47 mg, 0.067 mmol). Acetonitrile (2.2 mL) and sodium carbonate (1.7 mL, 1.0 M aqueous, 1.7 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70° C. for 15 h, then was allowed to cool to ambient temperature and was loaded directly onto a silica gel column. Purification by chromatography on silica gel (0 to 50% EtOAc in hexanes, then 50 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 663.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 7.16 (dd, J=8.5, 2.0 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.08-6.02 (m, 1H), 5.11 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 4.08-4.06 (m, 2H), 3.65-3.63 (m, 2H), 2.54-2.50 (m, 2H), 2.35 (s, 3H), 1.49 (s, 9H), 1.41 (q, J=7.0 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C[O-].[Na+].[CH3:17][S-:18].[Na+].O>CO>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[S:18][CH3:17])[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: C[S-]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 57.5 °C

Procedure:
0.75 mol of 4-fluoro-3-nitrobenzoic acid was charged in 2 l of methanol, and 0.75 mol of sodium methoxide was added dropwise. 0.83 mol of sodium thiomethoxide was then added and the reaction mixture was heated at from 55 to 60° C. for 5 hours. After cooling, 1 l of water was added, the precipitate was filtered off with suction and washed with 100 ml of methylene chloride. The residue was then taken up in 500 ml of 2 N hydrochloric acid and the precipitate formed was filtered off with suction and washed with water. The residue was then taken up in tetrahydrofuran and dried over sodium sulfate and the solvent was distilled off.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.Cl[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>C(O)(C)C>[S:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: Clc1nc2ccccc2s1
Reactant: NCCCCCSc1nc2ccccc2[nH]1
Solvent: CC(C)O
Product: c1ccc2[nH]c(SCCCCCNc3nc4ccccc4s3)nc2c1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
0.6 g of the compound obtained in Example 17c and 0.34 g of 2-chloro-benzothiazole were refluxed for 23 hours in 15 ml of isopropanol. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 0.32 g of the title compound (yield: 43%).