Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CCOCC.Cl>O1CCCC1>[CH:7](/[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][OH:22])=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCC#Cc1ccccc1C=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCC/C=C/c1ccccc1CO
Temperature: 0 °C

Procedure:
To a suspension of lithium aluminum hydride (22.2 mmoles) in tetrahydrofuran (30 ml) under argon, cooled to 0° C., was added 2-(1-dodecyn-1-yl) benzaldehyde (11.1 mmoles, prepared as in Example 4a) in tetrahydrofuran (10 ml), dropwise with stirring. After coming to room temperature, the reaction mixture was refluxed for 18 hours. The reaction mixture was then cooled to 0° C., ice was added, followed by ether and dilute hydrochloric acid, and the layers were separated. The organic layer was washed with water and brine. The dried solution was concentrated to give 2-(1-trans-dodecenyl)benzyl alcohol, after recrystallization from acetonitrile. The benzyl alcohol (0.080 mmoles) was dissolved in ethyl acetate (10 ml) under argon and manganese dioxide (12.6 mmoles) was added. The reaction mixture was stirred for 18 hours at room temperature, filtered and the filtrate concentrated to leave an oil which is the desired product.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[N:12]=[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[N:10]=1.[OH:27][C@H:28]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:29](O)=[O:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.O>[OH:27][C@H:28]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:29]([N:7]1[CH2:6][CH2:5][N:4]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:10]=2)[CH:3]([CH2:2][OH:1])[CH2:8]1)=[O:30]
Reactant: Cc1ccc2c(N3CCNCC3CO)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)C[C@@H](O)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)C)CC3CO)nc(-c3ccccc3O)nc2c1

Procedure:
To 3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylic acid benzyl ester (200 mg, 0.41 mmol) in 1.7 mL of methanol was added 39 mg of Pd/C (10% weight Pd on carbon). The reaction mixture was subjected to hydrogenation using a H2 balloon for 3 h. The reaction mixture was filtered through Celite and the solvent was removed to give 2-[4-(2-hydroxymethyl-piperazin-1-yl)-7-methyl-quinazolin-2-yl]-phenol. This amine was treated with (R)-2-hydroxy-4-methyl-pentanoic acid (60 mg, 0.45 mmol), BOP (200 mg, 0.45 mmol) and 115 μL of triethylamine in 1.6 mL of DMF at room temperature for 12 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and 20 mL of water, and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was subjected to purification using 60-100% EtOAc-hexanes to give (R)-2-hydroxy-1-{3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one. LC/MS: m/z 465 (M+H)+ at 2.77 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[O:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)SC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(OCC(=O)O)c1
Yield: 57.1 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 39, but starting from 2.4 g of ethyl (2R,4R)-3-{3-[2-(4-tert-butoxycarbonyl-2-phenyl-3-thiazolidinyl)-2-oxoethyl]ureido}phenoxyacetate and 0.2 g of lithium hydroxide. The crude product is purified by chromatography on silica [eluent: ethyl acetate]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After vigorous stirring in diisopropyl ether, 1.3 g of (2R,4R)-3-{3-[2-(4-tert-butoxycarbonyl-2-phenyl-3-thiazolidinyl)-2-oxoethyl]ureido}phenoxyacetic acid are thus obtained in the form of an amorphous solid ([α]D20 =+63.7°±1.2° (C=0.96%; CHCl3)) [proton NMR (200 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 4.5 (bs, 2H, OCH2CO2); 6.5 (ddd, 1H, N--C6H4 --C in position 4); 6.9 (d, 1H aromatic); 7.1 to 7.7 (m, 7H, aromatic). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2975, 2930, 2630, 2550, 1735, 1640, 1600, 1555, 1490, 1370, 1240, 1150, 770, 730, 695].
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([O:19][CH2:20][CH2:21][OH:22])=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[CH:6]=1)C.[CH3:32][NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH3:32][N:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:4](=[O:3])[C:5]1[CH:6]=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[C:8]([O:19][CH2:20][CH2:21][OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)[CH:10]=1
Reactant: CNCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Product: CN(CCCCCCCCc1ccccc1)C(=O)c1cc(-c2ccc(F)c(Cl)c2)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1

Procedure:
N-Methyl-N-(8-phenyloctyl)-3,5-bis[m-chloro-p-fluoro-phenyl)-4-(2-hydroxyethoxy)-benzamide was prepared as a white solid (0.313 g, 78%) from 3,5-bis[(m-chloro)-(p-fluoro)-phenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester and N-methyl-N-(8-phenyloctyl)amine using a procedure similar to step 2 of Example 175. 1H NMR (CDCl3) δ 7.71-7.66 (dd, 2H); 7.52-7.45 (m, 2H); 7.36 (m, 2H); 7.30-7.12 (m, 7H); 3.52 and 3.28 (2bt, 2H); 3.27 (m, 4H); 3.04 (2s, 3H); 2.58 (m, 2H); 1.60 (m, 4H); 1.42-1.10 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][N:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(Cl)ncc1N
Temperature: 80 °C
Yield: 88.9 %

Procedure:
A mixture of 2-chloro-4-methoxy-5-nitropyridine (208 mg, 1.10 mmol), ammonium chloride (295 mg, 5.52 mmol) and iron powder (246 mg, 4.41 mmol) in ethanol (5 mL) and water (0.5 mL) was heated at 80° C. for 18 h. The mixture was cooled and filtered through a Celite cartridge and washed through with methanol. The combined filtrate and washing was evaporated, and the residue partitioned between DCM (10 mL) and water (10 mL), the organic phase was washed further with water (10 mL), and the aqueous washes were combined and extracted with DCM (3×5 mL). The organic extracts were combined and filtered through a hydrophobic frit, and the solvent was removed by evaporation to give the product as an off-white solid (155 mg, 89%). 1H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H); 6.71 (s, 1H); 3.90 (s, 3H); 3.71 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:16]([CH3:17])[C:3]=12.[OH-].[Na+].C(O)(=O)C>CS(C)=O.O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:16]([CH3:17])[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc(-c3cccnc3)c(C)c2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc2sc(-c3cccnc3)c(C)c2c(N)c1C(=O)O
Temperature: 120 °C
Yield: 89.2 %

Procedure:
A mixture of ethyl 4-amino-3,6-dimethyl-2-(3-pyridinyl)thieno[2,3-b]pyridine-5-carboxylate (120 mg, 0.367 mmol) (Description 32) in DMSO (3 mL) and 2M NaOH (0.916 mL, 1.833 mmol) was heated at 120° C. for 1 h. After cooling to RT, the mixture was diluted with water (20 mL), acidified with acetic acid to pH 6. The mixture was extracted with 10% MeOH in DCM (5×30 mL). The combined organics were dried and concentrated. The residue was passed through a C18 solid phase extractor cartridge, eluted with water (4×30 mL) followed by MeOH (4×30 mL). The combined organics were concentrated and dried at 55° C. in a vacuum oven, to afford the title compound (98 mg). LCMS (A) m/z: 300 [M+1]+, Rt 0.58 min (acidic).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl.CN(C)C.[CH3:24][C:25]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:26][CH2:27][CH2:28][OH:29].CN(C)CCCN>C(Cl)Cl.C(OCC)(=O)C>[CH3:24][C:25]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:26][CH2:27][CH2:28][O:29][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CC(=CCCO)CCCC(C)CCCC(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: CN(C)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.63 mL (4.6 mmol) of triethylamine, 0.87 g (4.6 mmol) of p-toluenesulfonyl chloride, 20 mg (0.21 mmol) of trimethylamine hydrochloride were added to a solution of 1.0 g (4.2 mmol) of 4,8,12-trimethyltridec-3-en-1-ol in dry methylene chloride (3 mL) at 0° C., sequentially. After being stirred for 2 hours at room temperature, N,N-dimethyl-1,3-propanediamine was added to the reaction mixture at 0° C. After being stirred for 30 min, the mixture was diluted with ethyl acetate. The resulting solution was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain (4,8,12-trimethyltridec-3-enyl)tosylate as a crude product.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][C:7]([CH:10](C(OCC)=O)[C:11]([O:13][C:14](C)(C)[CH3:15])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1cnc([N+](=O)[O-])cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1cnc([N+](=O)[O-])cn1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl ethyl (5-nitropyrazin-2-yl)propanedioate (10.7 g, 34.4 mmol) in 30 mL of TFA and 30 mL DCM was stirred at 35° C. for 3 hours before concentrated to dryness. The residue was dissolved in 200 mL of EtOAc and washed with water (25 mL) and brine (25 mL), dried over anhydrous Na2SO4 and concentrated to afford ethyl (5-nitropyrazin-2-yl)acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:20])[CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19].Cl[CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:20])[CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:22][CH2:23][CH2:24][C:25]1=[O:26]
Reactant: CN1Cc2c(Br)cc(Cl)cc2C(c2ccccc2N)C1
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1Cc2c(Br)cc(Cl)cc2C(c2ccccc2N2CCCC2=O)C1

Procedure:
Analogously to example 36, 2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (80 mg) was reacted with 4-chlorobutyryl chloride (35 mg) and the resulting amide was subsequently ring-closed with potassium carbonate in DMSO.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:35][CH2:34][CH2:33][S:32]1(=[O:37])=[O:36]>>[O:36]=[S:32]1(=[O:37])[CH2:33][CH2:34][CH2:35][N:31]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=S1(=O)CCCN1c1ccccc1Br
Product: Nc1ncc(-c2ccc(-c3ccccc3N3CCCS3(=O)=O)cc2F)cn1

Procedure:
Title compound was prepared using methods analogous to those described in Example 384 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-(2-bromophenyl)isothiazolidine 1,1-dioxide. MS (ESI): mass calcd. for C19H17FN4O2S, 384.11; m/z found, 385.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=1.4, 2H), 7.78-7.71 (m, 1H), 7.69-7.58 (m, 1H), 7.50-7.32 (m, 4H), 7.29-7.20 (m, 1H), 5.21 (s, 2H), 3.77 (t, J=6.8, 1H), 3.43-3.17 (m, 2H), 2.67-2.47 (m, 1H), 2.42-2.17 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:7]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:5])[CH3:2].[F:34][C:35]([F:46])([F:45])[C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:39]3[CH:40]=[CH:41][C:36]([C:35]([F:46])([F:45])[F:34])=[CH:37][CH:38]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:7]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(C2CCNCC2)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(C2CCNCC2)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-piperidin-4-ylphenyl)indole-3-carboxylic acid ethyl ester (203 mg, 0.45 mmol, see step (b) Example 17) and 4-trifluoromethylphenylboronic acid. Yield 160 mg (60%).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N=C(NO)c1ccncc1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccncc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-isonicotinamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.51 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:31]4[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:30]=4[CH3:29])=[CH:17][CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N(c2ccccc2)C(c2ccc(Br)cc2)CN1S(=O)(=O)c1ccccc1
Reactant: Cc1ccc(C)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C)c(-c2ccc(C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)cc2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(4-bromo-phenyl)-3-phenyl-imlidazolidin-2-one (example 1, step 2) was reacted with 2,5-dimethylphenylboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(2′,5′-dimethyl-biphenyl 4-yl)-3-phenyl-imidazolidin-2-one as a colorless solid. MS: 483.2 ([M+H]+)
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[NH2:5].CC(S(N)=O)(C)C.Cl[C:31]1[N:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:33][N:32]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([NH:5][C:31]1[N:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:33][N:32]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CC(C)CC(N)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1cnc(Cl)nc1
Agent: CC(C)(C)S(N)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 100 °C
Yield: 112.7 %

Procedure:
A solution of 3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine (307 mg, 1 mmol), prepared as in example 1.1 using racemic 2-methylpropane-2-sulfinamide, methyl 2-chloropyrimidine-5-carboxylate (186 mg, 1 mmol) and diisopropylethylamine (516 mg, 4 mmol) in 2-propanol (3 mL) was heated to 100° C. for 3 hours. The mixture was concentrated under reduced pressure and the crude residue was purified by column chromatography to give methyl 2-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)pyrimidine-5-carboxylate (500 mg, 87.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[F:19])=[CH:8][CH:7]=[N:6]2.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:27]([C:24]3[C:23](=[O:30])[N:22]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:21]([CH3:20])[C:25]=3[CH3:26])=[O:28])=[CH:14][C:13]=1[F:19])=[CH:8][CH:7]=[N:6]2
Reactant: Nc1ccc(Oc2ccnn3ccc(Br)c23)c(F)c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnn4ccc(Br)c34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of 4-(5-bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluoroaniline (57 mg, 0.178 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (124 mg, 0.534 mmol) prepared in Preparation Example 1 in dimethylformamide (2 mL), HATU (270 mg, 0.711 mmol) and triethylamine (0.1 mL, 0.711 mmol) were sequentially added and stirred at 50° C. overnight. The resulting reaction mixture was concentrated under reduced pressure and the resulting residue was extracted with dichloromethane and water. The organic layer was separated, dried with magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (10% ethyl acetate in dichloromethane) to give the target compound as a white solid (60 mg, 0.111 mmol, 63% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][CH:25]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:37]1[N:42]=[CH:41][C:40]([Br:43])=[CH:39][N:38]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:28][CH:29]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:37]1[N:42]=[CH:41][C:40]([Br:43])=[CH:39][N:38]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: Brc1cnc(Br)nc1
Reactant: CCOC(=O)c1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(OC2CCCC2)cc1
Product: CCOC(=O)c1cc2cc(-c3ncc(Br)cn3)ccc2n1-c1ccc(OC2CCCC2)cc1

Procedure:
The sub-title compound was prepared in accordance with Example 8(b), from 1-(4-cyclopentoxyphenyl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see step (d) above) and 2,5-dibromopyrimidine (see step (f) above).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[C:32]1([S:38]([O:24][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[O:22][CH3:23])[C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13]2)=[O:25])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OS(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
The compound of step 2 of example 15 (200 mg, 0.586 mmol) was dissolved in ACN (3 ml), potassium carbonate (243 mg, 1.7 mmol) and benzenesulfonyl chloride (155 mg, 0.88 mmol) were added, and the mixture was stirred for 30 min. The mixture was partitioned between EA and saturated sodium chloride solution, the aqueous phase extracted with EA, and the combined organic extracts were dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was dissolved in dioxane (0.8 ml), lithium hydroxide (0.8 ml of a 1 N aqueous solution) was added, and the mixture was stirred at room temperature for 2.5 h. The mixture was partitioned between 2 N hydrochloric acid and EA, the aqueous phase extracted with EA, and the combined organic extracts were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by preparative RP HPLC (water/ACN gradient) to give 115 mg of the title compound.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[CH:6]=1.[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:8]=[C:9]([CH3:23])[CH:10]=[C:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[N:12]=3)[CH:6]=2)=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c2)n1

Procedure:
N-tert-Butyl-4-{1-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 2-(4-iodo-imidazol-1-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyrimidine (example E.71) (0.43 g, 1.0 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.39 g, 1.5 mmol) according to the general procedure VI. Obtained as a light brown solid (0.2 g) which was subsequently deprotected.