Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=1)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].[H-].[Na+]>CN(C)C=O>[C:22]([C:21]1[CH:20]=[C:19]([CH:32]=[CH:31][CH:30]=1)[NH:18][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CSc1nccc(-c2cnc3ccccn23)n1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1cccc(Nc2nccc(-c3cnc4ccccn34)n2)c1
Temperature: 130 °C
Yield: 11.9 %

Procedure:
To a solution of 2-methylsulfanyl-4-(imidazo-[1,2-a]pyridin-3-yl)pyrimidine (0.146 g, 0.60 mmol) and 3-aminobenzophenone (0.238 g, 1.21 mmol) in N,N-dimethylformamide (2.5 mL) was added sodium hydride (0.061 g, 1.52 mmol) and the mixture was heated at 130° C. for 4 hours. The mixture was allowed to cool to room temperature and the solvent was removed. The residue was dissolved in water and the resulting solid was washed with water and chloroform. The organic phase was dried over MgSO4 and the solvent was evaporated. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 9:1, as the eluent affording 0.028 g (12% yield) of the title compound as a yellow solid: mp (decomp.) 237-246° C.; MS (TSP) m/z 392 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 10.25 (d, J=6.3 Hz, 1 H), 10.15 (s, 1 H), 8.74 (s, 1 H), 8.55 (d, J=5.4 Hz, 1 H), 8.29 (s, 1 H), 8.25 (d, J=8.1 Hz, 1 H), 7.87 (m, 3 H), 7.78 (t, J=7.4 Hz, 1 H), 7.67 (m, 2 H), 7.60 (m, 2 H), 7.55 (d, J=5.4 Hz, 1 H), 7.44 (d, J=7.5 Hz, 1 H), 7.20 (m, 1 H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[CH3:54][N:55]1[CH:59]=[C:58]([C:60](Cl)=[O:61])[CH:57]=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:60]([C:58]2[CH:57]=[N:56][N:55]([CH3:54])[CH:59]=2)=[O:61])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cn1cc(C(=O)Cl)cn1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C(=O)N2CC[C@@H](CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)cn1
Yield: 72 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1-methyl-1H-pyrazole-4-carbonyl chloride as the starting materials in 72% yield. LCMS for C28H29ClN9O2 (M+H)+: m/z=558.1.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=O)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].O=S(Cl)Cl.[Cl-].[NH3:27]>C1(C)C=CC=CC=1.O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:27])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(CC(=O)O)cc2)cc1
Reactant: N
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCCCCc1ccc(-c2ccc(CC#N)cc2)cc1
Reaction time: 6 h

Procedure:
180 g of SOCl2 was added to a suspension of 281 g of 4'-pentylbiphenyl-4-ylacetamide [m.p. 185°; obtained by reaction of 4-acetyl-4'-pentylbiphenyl with morpholine/sulfur and subsequent hydrolysis to give 4'-pentylbiphenyl-4-ylacetic acid (m.p. 160°), reaction with SOCl2 to give the chloride and reaction with NH3 ] in 1 l of toluene at 80°. After stirring at 80° for 6 hours, cooling down and pouring into water, 4'-pentylbiphenyl-4-ylacetonitrile was obtained, m.p. 80°, c.p. -10°.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].CO>[CH2:1]([C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1=Cc1ccccc1
Agent: [Ni]
Solvent: CO
Product: O[C@@H]1CCCC[C@@H]1Cc1ccccc1
Product: O[C@@H]1CCCC[C@H]1Cc1ccccc1
Yield: 88 %

Procedure:
Then, 10 g of 2-benzylidenecyclohexanone were hydrogenated at room temperature using 1 g of Raney nickel in methanol under hydrogen pressure (3 kg/cm2) until the absorption of hydrogen was stopped. After an organic layer was collected by decantation and concentrated, the residue was purified by column chromatography, thereby obtaining 4.6 g of cis-2-benzylcyclohexanol and 4.4 g of trans-2-benzylcyclohexanol (yield: 88% in total).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[CH3:8][CH:9]([OH:11])C.[CH2:12]([OH:14])C>O.C(C(CCCC)C([O-])=O)C.[Co+2].C(C(CCCC)C([O-])=O)C>[C:9]([O:7][CH:5]([CH3:6])[CH2:4][O:14][CH3:12])(=[O:11])[CH3:8].[CH3:6][C:5](=[O:7])[CH2:4][C:1]([CH3:8])([OH:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)O
Reactant: CC(=O)CC(C)=O
Agent: [Co+2]
Agent: CCCCC(CC)C(=O)[O-]
Solvent: O
Product: CC(=O)CC(C)(C)O
Product: COCC(C)OC(C)=O
Reaction time: 0.33 h

Procedure:
Cobalt 2-ethylhexanoate was diluted with a solvent in a weight ratio of ethanol:acetylacetone=100:10 to a solid content of 5 wt % as calculated as oxide (solution J) Solution A1, solution C1, solution H and solution J were mixed in a weight ratio of solution A1 :solution C1 :solution H:solution J=40:15:30:15, and heat treatment was conducted at 40° C. for 20 minutes. Then, the solution was diluted with a solvent in a mixed solvent in a weight ratio of water:ethanol:propylene glycol monomethyl ether acetate:IPA:diacetone alcohol=5.3:22.5:38:23:10 to a solid content of 1.2 wt % to obtain a coating solution for a colored antistatic film.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17](B(O)O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([OH:33])[CH:26]=1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([O:23][CH3:22])=[O:34])=[CH:26][C:27]=1[O:33][C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B(O)O)cc2CC1
Product: COC(=O)c1ccc(OC)c(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1

Procedure:
The title compound was prepared from (3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid (E264, Step 2) and methyl-3-hydroxy-4-methoxybenzoate using the method of Example 264 Step 3; MS (ES+) m/e 328 [(M+H)—CO2tBu]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[CH:7]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:6]12>CO>[SH:4][CH2:3][CH2:2][NH:1][C:5](=[O:15])[CH:6]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:7]1[C:8]([OH:10])=[O:9]
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: NCCS
Solvent: CO
Product: O=C(O)C1CCCCC1C(=O)NCCS
Reaction time: 7 h
Yield: 99.4 %

Procedure:
To a solution of 7.72 g (0.1 mole) of cysteamine in 40 cm3 of methanol, maintained under an inert atmosphere and cooled to a temperature between 0° and 5° C., there are added, by portions, 15.43 g (0.1 mole) of hexahydrophthalic anhydride. After 7 hours of stirring at this temperature, there remains only traces of the starting cysteamine. The solution is evaporated to dryness under reduced pressure at ambient temperature. 23 g of N-(2-mercapto ethyl) hexahydrophthalamic acid are obtained in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[C:6]([NH2:8])[CH:7]=1.[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>C1C(Cl)=CC=C(Cl)C=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14](=[O:15])[NH:8]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Br)ccc1-n1ccnc1
Solvent: Clc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(Br)ccc2n2ccnc12
Temperature: 25 °C
Yield: 69.5 %

Procedure:
To a solution of 5-bromo-2-imidazol-1-yl-phenylamine (5.00 g; 21 mmol; 1 eq) in anhydrous dichlorobenzene (410 mL), is added carbonyldiimidazole (6.94 g; 42 mmol; 2 eq) under argon atmosphere. This reaction mixture is allowed to stir under reflux for 2 hours. The initial crystal clear solution quickly turns black after heating and become non homogeneous. This crude reaction mixture is allowed to cool to room temperature and the grey powder formed during the reaction is filtered off on a fritted glass. The filtrate is cooled down to 0° C. overnight to afford a second batch of grey powder. The combined 6.5 g of grey solid is transferred in a 1 L flask, diluted in fresh ethyl acetate (500 mL) and heated to gentle reflux for ten minutes. Hot filtration followed by concentration afforded the title compound as a grey powder (3.85 g; 14.6 mmol; 69%).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:23][C:24]#[N:25]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22](/[C:23](=[CH:5]/[C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=2[O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])/[C:24]#[N:25])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COCCOCCl
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cccc(F)c1O
Product: COCCOCOc1c(F)cccc1/C=C(\C#N)c1ccc(OC)c(OC)c1
Yield: 62.2 %

Procedure:
The hydroxyl group of 3-fluoro-2-hydroxybenzaldehyde (560 mg) was protected by use of 2-methoxyethoxymethyl chloride (500 mg) in accordance with (production process 1), to thereby produce an MEM form (660 mg, yield: 72%). The resultant MEM form (650 mg) and 3,4-dimethoxybenzyl cyanide (500 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxy-phenyl)-3-(3-fluoro-2-methoxyethoxymethoxy-phenyl)-acrylonitrile (680 mg, yield: 58%). The thus-produced (Z)-2-(3,4-dimethoxy-phenyl)-3-(3-fluoro-2-methoxyethoxymethoxy-phenyl)-acrylonitrile (670 mg) was subjected to deprotection in accordance with (production process 3), to therey produce the target product (140 mg, yield: 29%).
Reaction SMILES: Cl(O)(=O)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=NC)[C:14]2[N:18]([CH3:19])[C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=2[CH3:25])=[CH:9][CH:8]=1.C(=O)(O)[O-:29].[Na+].S(OC)(OC)(=O)=O.C([O-])(=O)C.[Na+]>CO.O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:14]2[N:18]([CH3:19])[C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=2[CH3:25])=[O:29])=[CH:9][CH:8]=1
Reactant: CN=C(c1ccc(Cl)cc1)c1c(C)cc(CC(=O)OC)n1C
Reactant: O=C([O-])O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CO
Product: COC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Yield: 65 %

Procedure:
Methyl 5-[(4-chlorophenyl)(methylimino)methyl]-1,4-dimethyl-1H-pyrrole-2-acetate perchlorate (1.5 g, 3.6 mmole) was treated with saturated aqueous sodium bicarbonate and extracted with chloroform (50 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was treated with dimethyl sulfate (0.62 g, 4.9 mmole) and heated at ~40° C. for one hour. The viscous reaction mixture was dissolved in methanol (10 ml) and treated with sodium acetate (2 g, 24 mmole) and water (2 ml) and heated at reflux overnight. The reaction was cooled and diluted with water (5 ml). The crystalline solid was isolated by filtration, washed with water, air dried, and recrystallized from methanol (10 ml) to yield 0.71 g (65%) of the title compound as a tan solid, m.p. 125°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[NH:7][CH:6]=[CH:5]2.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:14]([O:13][C:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([CH3:12])[CH:10]=2)[CH:5]=[CH:6][N:7]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc2c(=O)[nH]ccc2cc1F
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2c(OCc3ccccc3)nccc2cc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
6-Fluoro-7-methyl-2H-isoquinolin-1-one (prepared as described in WO2007012421, 13.2 g, mmol) was dissolved in tetrahydrofurane (175 mL). After addition of silver carbonate (41.2 g), benzyl bromide (15.3 g) was added dropwise. The mixture was stirred overnight. The mixture was heated to 70° C. and another 3 mL of benzyl bromide were added. Heating was continued until no further conversion was observed. The mixture was taken up in ethyl acetate, filtered over celite, evaporated and the residue was taken up in little ethyl acetate. The formed precipitate was filtered off to give 3.0 g of (2). The mother liquor was concentrated and chromatographed on silica gel to yield another 8.6 g of (2). Rt=4.00 min (Method 2). Detected mass: 268.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH:16]4[CH2:18][CH2:17]4)=[N:13][NH:12][C:11]=3[C:10](=[O:19])[N:9]2[C:20]2[CH:21]=[C:22]([CH3:30])[C:23]3[N:24]([C:26]([CH3:29])=[N:27][N:28]=3)[CH:25]=2)=[CH:4][CH:3]=1.[CH3:31]I>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:15]3[C:14]([CH:16]4[CH2:18][CH2:17]4)=[N:13][N:12]([CH3:31])[C:11]=3[C:10](=[O:19])[N:9]2[C:20]2[CH:21]=[C:22]([CH3:30])[C:23]3[N:24]([C:26]([CH3:29])=[N:27][N:28]=3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1cc(N2C(=O)c3[nH]nc(C4CC4)c3C2c2ccc(Cl)cc2)cn2c(C)nnc12
Product: Cc1cc(N2C(=O)c3c(c(C4CC4)nn3C)C2c2ccc(Cl)cc2)cn2c(C)nnc12

Procedure:
The title compound was prepared in analogy to the procedure described in Step 112.5 using 4-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 129.1) and MeI at RT for 30 min. The crude product was purified by preparative achiral SFC (column NH2, gradient 19-24% in 6 min_total 11 min). tR: 0.95 min (LC-MS 2); ESI-MS: 433.2 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm-0.10-0.07 (m, 1H) 0.50-0.78 (m, 3H) 1.59-1.76 (m, 1H) 1.92 (s, 3H) 3.36 (s, 3H) 3.92 (s, 3H) 6.09 (s, 1H) 7.27 (d, J=8.4 Hz, 2H) 7.32-7.45 (m, 3H) 7.68 (d, J=2.7 Hz, 1H).
Reaction SMILES: O.C([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1>[Pd].CO>[C:21]1([CH2:20][CH2:19][CH2:18][CH2:17][C:16]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:11]2[C:10]([OH:28])=[O:9])=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CCCCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
10% Pd-C (1.40 g) was added to a 1% water-containing methanol solution (150 ml) of N-(5-phenylpentanoyl)-L-proline benzyl ester (13.87 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for two hours. After the catalyst was filtered off, the filtrate was concentrated to obtain N-(5-phenylpentanoyl)-L-proline (10.04 g).
Reaction SMILES: [OH-].[Na+].[CH:3]1([N:6]2[C:14]3[N:13]=[CH:12][NH:11][C:10]=3[C:9](=[O:15])[NH:8][C:7]2=[O:16])[CH2:5][CH2:4]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CO>[CH2:17]([N:11]1[C:10]2[C:9](=[O:15])[NH:8][C:7](=[O:16])[N:6]([CH:3]3[CH2:5][CH2:4]3)[C:14]=2[N:13]=[CH:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c(=O)n(C2CC2)c2nc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]c(=O)n(C2CC2)c2ncn(Cc3ccccc3)c12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
10.4 g (0.26 mol) of sodium hydroxide dissolved in 110 ml of water were added to a suspension of 50 g (0.26 mol) of 3-cyclopropylxanthine in 300 ml of methanol and the reaction mixture was stirred for one hour at 70° C., then treated dropwise at the same temperature with 44.5 g (0.26 mol) of benzyl bromide and kept between 70° and 80° C. for 4 hours. 1.04 g (0.026 mol) of sodium hydroxide and 4.45 g (0.026 mol) of benzyl bromide were then added. After a further hour, the mixture was cooled and filtered cold on a suction filter and the product was washed with water on the suction filter. The crude product thus obtained could be employed without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:18])=[CH:8][CH:7]=1.C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:18])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CN1CCCCCC1Cc1ccc(N)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CC2CCCCCN2C)cc1

Procedure:
Add a solution of 0.75 g of acetyl chloride in 5 ml of benzene drop by drop to a solution of 1.9 g of the title compound of Example 22 and 1 g of triethylamine in 10 ml of benzene. After an hour concentrate the resulting product, take it up with water and diethyl ether, collect the organic phase and concentrate it to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C>[F:33][C:28]([F:34])([C:29]([F:32])([F:31])[F:30])[CH2:27][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
A solution of 4-hydroxybenzaldehyde (2 g, 16.7 mmol) in DMF (33 mL) was stirred as solid potassium carbonate (4.1 g, 29.7 mmol) was added, and the reaction mixture was then stirred at RT. After 30 min, solid 2,2,3,3,3-pentafluoropropyl 4-methylbenzenesulfonate (5 g, 16.4 mmol) was added into the reaction mixture. The mixture was stirred and heated at 100° C. for 7 h. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water (3×) and brine, and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexane afforded 4-(2,2,3,3,3-pentafluoropropoxy)benzaldehyde (1.26 g).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[NH:14][CH2:13][CH2:12]2.CCN(C(C)C)C(C)C>CO.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:14]1[CH:15]2[CH2:18][CH2:19][N:11]([CH2:17][CH2:16]2)[CH2:12][CH2:13]1
Reactant: C1CN2CCC(CC2)N1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2oc(N3CCN4CCC3CC4)nc2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 34.9 %

Procedure:
2-Chlorobenzoxazole (Aldrich, 99 μL, 0.87 mmol) was added to a solution of 1,4-diazabicyclo[3.2.2]nonane (100 mg, 0.79 mmol) in methanol (2.65 mL) at 0° C. The reaction mixture was allowed to slowly warm to RT. After a period of 16 h iPr2NEt (138 μL, 0.79 mmol) was added and the mixture was stirred at RT for 4.5 h at which time it was diluted with CHCl3 and NaHCO3. The layers were partitioned and the aqueous layer was extracted with CHCl3 (×3). The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by chromatography (Biotage, 12L) eluting with 4% MeOH in CHCl3 containing 20 drops of NH4OH per liter of eluent to afford 67 mg (35%) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.30 (d, 1H, J=7.5 Hz), 7.19 (d, 1H, J=7.9 Hz), 7.10 (t, 1H, J=7.5 Hz), 6.94 (t, 1H, J=7.9 Hz), 4.46, (s, 1H), 3.87, (t, 2H, J=5.8 Hz), 3.12-2.92 (m, 6H), 2.15-2.05 (m, 2H), 1.79-1.70 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 161.8, 148.9, 143.7, 124.1, 120.3, 116.1, 108.7, 57.3, 50.3, 46.5, 44.4, 27.1; MS (Cl) m/z 244.3 (M+1). The hydrochloride salt was prepared by dissolving the title compound in iPrOH and adding 0.1 mL of 6 M hydrochloric acid
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[C:24]([C:26]2[S:30][CH:29]=[N:28][CH:27]=2)[CH:23]=[C:22]([C:31](O)=[O:32])[CH:21]=1.C1C=[CH:36][C:37]2[N:42](O)N=N[C:38]=2C=1.CN1[C:49](=[O:50])CCC1>C(Cl)Cl.CN(C=O)C>[CH3:49][O:50][CH2:36][CH:37]([NH:42][C:31]([C:22]1[CH:21]=[C:20]([C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[Cl:12])[CH:25]=[C:24]([C:26]2[S:30][CH:29]=[N:28][CH:27]=2)[CH:23]=1)=[O:32])[CH3:38]
Reactant: On1nnc2ccccc21
Reactant: CN1CCCC1=O
Reactant: O=C(O)c1cc(-c2cncs2)cc(-c2ccc(F)cc2Cl)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCC(C)NC(=O)c1cc(-c2cncs2)cc(-c2ccc(F)cc2Cl)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
EDCI (293 mg, 1.53 mmol) was added in one portion to a stirred solution of 2′-Chloro-4′-fluoro-5-thiazol-5-yl-biphenyl-3-carboxylic acid (300 mg, 1.02 mmol), HOBt (207 mg, 1.53 mmol), 2-Amino-1-methoxy-1-propane (1.53 mmol) and NMP (0.5 ml, 4.08 mmol) in CH2Cl2 (5 ml) and DMF (1 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred over night. The reaction mixture was extracted with EtOAc and the combined organic layers were washed with 2N aqueous NaOH, saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 2′-Chloro-4′-fluoro-5-thiazol-5-yl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (0.347 g, 86%). MS (M+H)=405.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[C:8]2[N:10]=[C:11]([CH2:13][CH3:14])[NH:12][C:7]2=[C:6]([CH3:15])[CH:5]=1.[C:16]1([C:22]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=3)=[N:26][N:25]=[N:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH3:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:40][C:37]3[CH:36]=[CH:35][C:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:27]4[N:23]([C:22]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[N:24]=[N:25][N:26]=4)=[CH:39][CH:38]=3)[C:11]([CH2:13][CH3:14])=[N:12][C:7]2=[C:6]([CH3:15])[CH:5]=1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.6 %

Procedure:
To a stirred suspension of NaH (17.2 mmol of an 80% dispersion) in dry dimethylformamide (30 mL) at rt was added 5.7-dimethyl-2-ethylimidazo[4,5-b]pyridine (1.51 g, 8.62 mmol) in one portion. After 20 minutes, the mixture was cooled to 0° C. and N-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl)-tetrazole (5.29 g, 9.48 mmol) was added in one portion. The resulting mixture was warmed to rt and stirred for 15 hours. The excess NaH was quenched with water and the bulk of the DMF was removed in vacuo at 40°-50° C. The residue was extracted with EtOAc from brine, dried (K2CO3), and concentrated. Purification by flash chromatography (SiO2, solvent gradient: 80% EtOAc/hexanes, 100% EtOAc) gave 4.25 g of 5,7-dimethyl-2-ethyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine: 1H NMR (300 MHz, CDCl3) δ7.86 (dd, 1H, J=7, 2 Hz), 750-7.41 (m, 2H), 7.36-721 (m, 10 H), 7.05 (d, 2 H, J=4.5 Hz), 6.95-6.89 (m, 7 H), 6.86 (d, 2 H, J=4.5 Hz), 5.35 (s, 2H), 2.67 (q, 2 H, J=7.5 Hz), 2.65 (s, 3 H), 2.58 (s, 3 H), 1.25 (t, 3 H, J=7.5 Hz).