Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]3[C:17]([O:19][C:20](=O)[C:8]=23)=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>O>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:17][OH:18])[C:8]=2[CH2:20][OH:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OC(=O)c2c1cc1ccccc1c2-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2ccccc2c(-c2ccccc2)c1CO

Procedure:
1-Phenyl-2,3-naphthalenedicarboxylic anhydride (VII) (25 g) was added to lithium aluminium hydride (10.4 g) in refluxing tetrahydrofuran (500 ml) over 30 min. and the reactants were refluxed for a further 1 hr. Water was added and the precipitate formed was filtered off and washed with ether (3 × 500 ml). The filtrate and the combined ether washings were dried (Mg2SO4) and evaporated to dryness. The residue was recrystallised from toluene to give 1-phenyl-2,3-bis(hydroxymethyl)naphthalene (VIII) m.p. 150°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[N+:11]([CH:13](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:14])#[C-:12].C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[O:7][CH:12]=[N:11][C:13]=2[CH3:14])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of 4-bromo-3-fluorobenzaldehyde (1.02 g, 5.0 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.05 g, 5.0 mmol), and K2CO3 (0.83 g, 6.0 mmol) in methanol (20 mL) was heated to reflux. After 2.5 hr the mixture was cooled to ambient temperature and the volatiles evaporated. The residue was partitioned between Et2O and H2O. The separated aqueous phase was extracted with Et2O, and the combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280™; 10% to 20% EtOAc/hexanes eluant; SF25-80 g column) yielded 1.04 g (81%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.83 (dd, J=8.3, 7.5 1H), 7.57 (dd, J=10.1, 2.0 1H), 7.42 (dd, J=8.5, 2.0 1H), 2.38 (s, 3H). MS (DCI+) m/z 256/258 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([C:14]2[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:19])=[CH:16][N:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:29])[C:3]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.[Li+].[OH-].Cl>O.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([C:14]2[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[CH:16][N:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:29])[C:3]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(NC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cn2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 13 %

Procedure:
Methyl 3-(6-(1-(2,6-dimethyl-4′-(trifluoromethyl) biphenyl-4-yl amino)-3-methylbutyl)nicotinamido)propanoate (400 mg, 0.74 mmol) was dissolved in H2O (3 mL) and tetrahydrofuran (3 mL). Then 1N LiOH (93.0 mg, 2.2 mmol) was added. The mixture was stirred at ambient temperature for 5 hours. The mixture was neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Boston Analytics Symmetrix ODS-H 150×30 mm, 5 μm; modifier: formic acid 0.225%; gradient: 10 to 80% MeCN in water) gave (+/−)-3-(6-(1-(2,6-dimethyl-4′-(trifluoromethyl)biphenyl-4-ylamino)-3-methylbutyl)nicotinamido)propanoic acid (50.7 mg, 13%) as a yellow solid. 1H NMR (400 MHz, CD3CN, 6): 8.85 (s, 1H), 8.02 (m, 1H), 7.64 (d, 2H), 7.46 (d, 1H), 7.22 (d, 3H), 6.32 (s, 2H), 4.59 (m, 1H), 3.54 (m, 2H), 2.55 (m, 2H), 1.93 (m, 6H), 1.78 (s, 2H), 1.72 (m, 2H), 1.60 (m, 1H), 0.96 (d, 3H), 0.91 (d, 3H). MS (M+1): 528.2.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[CH3:12][C@H]1CN(C2C=CC(OC(F)(F)F)=CC=2)C[C@@H](C)N1S(C1C=CC=C2C=1C[C@@H](C(O)=O)C2)(=O)=O.[S:46]([C:50]1[CH:56]=[CH:55][C:53]([CH3:54])=[CH:52][CH:51]=1)([O-:49])(=[O:48])=[O:47]>>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].[CH3:12][O:47][S:46]([C:50]1[CH:56]=[CH:55][C:53]([CH3:54])=[CH:52][CH:51]=1)(=[O:49])=[O:48]
Reactant: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1C[C@@H](C(=O)O)C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: COS(=O)(=O)c1ccc(C)cc1

Procedure:
The methyl ester precursor of (S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid tosylate (hereinafter optionally referred to as “Compound 1 tosylate”) was used for this experiment instead of Compound 1 tosylate due to the unsuitability of the Compound 1 tosylate crystals for X-ray structure determination. Compound 1 tosylate methyl ester was prepared via an esterification of Compound 1 tosylate followed by recrystallization from isopropanol. Other experiments have established that the stereochemistry is retained in converting the methyl ester to Compound 1 tosylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C@H:26]4[C@@H:31]([CH3:32])[O:30][CH2:29][CH2:28][NH:27]4)[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C=O.[CH3:35]N(CCO)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C@H:26]4[C@@H:31]([CH3:32])[O:30][CH2:29][CH2:28][N:27]4[CH3:35])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: C[C@H]1OCCN[C@H]1CN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Reactant: CN(C)CCO
Agent: C=O
Solvent: CCO
Product: C[C@H]1OCCN(C)[C@H]1CN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a stirred solution of the product of Step C (21 mg, 0.048 mmol) in 2 mL ethanol was added formaldehyde (37% in H2O, 20 ul, 0.24 mmol), followed by borane-pyridine complex (12 ul, 0.097 mmol). After stirring overnight, the reaction was treated with dimethylaminoethanol (1 mL) and heated for 2 hours. Solvent was removed in vacuo. Purification by prep-TLC afforded the desired product (120 mg, 83%).1.2(d, J=6.3 Hz, 3H), 1.9(m, 1H), 2.1(m, 2H), 2.4(s, 3H), 2.5(m, 1H), 2.7(m, 1H), 3.4(m, 1H), 3.6(m, 1H), 3.8(m, 1H).
Reaction SMILES: [Na:1].[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[O:6])[CH3:3].[C:18](O)(=[O:23])[CH2:19][C:20](O)=[O:21].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:2]([N:4]1[C:18](=[O:23])[CH2:19][C:20](=[O:21])[N:7]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([OH:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)[C:5]1=[O:6])[CH3:3].[Na:1]
Reactant: CCNC(=O)Nc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CC(=O)O
Agent: [Na]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCN1C(=O)CC(=O)N(c2ccc(S(=O)(=O)O)cc2)C1=O
Temperature: 95 °C
Yield: 93.5 %

Procedure:
A mixture of 26.6 g of N-ethyl-N'-(4-sulfophenyl)urea sodium salt, 13.5 g of malonic acid and 150 ml of glacial acetic acid was heated and dissolved at 60° to 70° C. Acetic anhydride (200 ml) was added dropwise to the solution with stirring. After addition of the acetic anhydride, the temperature of the reaction solution increased to 95° C. The reaction solution was stirred for 6 hours and then condensed under reduced pressure so as to precipitate crystals. 700 ml of ethanol was added to the condensed solution and the crystals were completely precipitated. The precipitated crystals were collected by filtration, washed thoroughly with ethanol and dried by heating under reduced pressure to obtain 31.2 g of crystals. The crystals obtained were recrystallized using a 90% methanol aqueous solution and, thereby, 23.5 g of white crystals was obtained. Melting point: 290° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:10](=[O:12])[CH3:11])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(C#N)c1
Temperature: 5 °C
Reaction time: 12 h

Procedure:
3-Aminobenzonitrile (5.70 g) and N,N-dimethylaminopyridine (20 mg) were dissolved in pyridine (40 ml) and the mixture was cooled to 5° C. Acetic anhydride (5.8 ml) was added and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and 1N hydrochloric acid were added to the residue, and the organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried, concentrated and recrystallized from hexane-ethyl acetate to give the title compound (5.78 g) as pale-brown powder crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:14][CH:15]=2)=[O:9])[CH:7]=1.[CH3:27][S:28][C:29]1[N:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][N:30]=1>>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:13]1[N:12]=[CH:11][C:10]([C:8]([C:6]2[CH:7]=[C:2]([C:31]3[CH:32]=[CH:33][N:34]=[C:29]([S:28][CH3:27])[N:30]=3)[CH:3]=[CH:4][C:5]=2[O:25][CH3:26])=[O:9])=[CH:15][CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)nc1
Product: COc1ccc(-c2ccnc(SC)n2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)nc1
Yield: 45 %

Procedure:
[6-(2,4-Difluoro-phenylamino)-pyridin-3-yl]-[2-methoxy-5-(2-methylsulfanyl-pyrimidin-4-yl)-phenyl]-methanone is prepared in analogy to example 11 from (5-bromo-2-methoxy-phenyl)-[6-(2,4-difluoro-phenylamino)-pyridin-3-yl]-methanone and 2-methylsulfanyl-4-tributylstannanyl-pyrimidine in 45% yield:
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]=[CH2:4].[F:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH:13]=[O:14])=[CH:9][CH:8]=1.S(=O)(=O)(O)O>CCOCC.C(Br)C=C>[F:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH:13]([OH:14])[CH2:4][CH:3]=[CH2:2])=[CH:9][CH:8]=1
Reactant: O=CCOc1ccc(F)cc1
Reactant: C=CCBr
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: C=CCC(O)COc1ccc(F)cc1
Yield: 77.1 %

Procedure:
Allyl bromide (~0.5 g.) is added to a stirred suspension of magnesium turnings (4.49 g., 0.185 mole) in dry ether (50 ml.) at 25° C. Upon initiation of reflux, the reaction suspension is stirred and treated with a solution of allyl bromide (24.2 g., 0.2 mole) and 4-fluorophenoxyacetaldehyde (19 g., 0.123 mole) in dry ether (110 ml.) added at such a rate as to maintain a gentle reflux. The resulting reaction mixture is heated at reflux for 1 hour, cooled to 0°-5° C., and treated with 3.2 N sulfuric acid (70 ml.), providing a heterogeneous mixture. After separating the phases, the aqueous phase is extracted with ether three times. The organic phase is combined with the ethereal extracts and washed with 5% aqueous sodium bicarbonate, dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo affords an oily residue which is distilled to provide the title compound as a colorless oil (18.6 g., 77%), bp0.03 73° C.; pmr (CCl4) δ2.32 (2H, t), 2.54 (H, m) 3.6-4.1 (3H, m), 4.8-5.05 (H, m) 5.05-5.25 (H, m), 5.4-6.3 (H, m) and 6.6-7.1 (4H, m).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)[NH:21][C:22]3=[O:25])=[CH:17][CH:16]=2)[CH2:10]1>ClCCl>[OH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[NH:21][C:22]3=[O:25])=[CH:17][CH:16]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2-c2cc3ccc(N4CCCC(O)C4)cc3c(=O)[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(-c2ccccc2N2CCNCC2)cc2ccc(N3CCCC(O)C3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Trifluoroacetic acid (0.2 ml) was added to a dichloromethane solution (0.3 ml) containing 11.5 mg (0.0227 mmol) of t-butyl 4-{2-[7-(3-hydroxypiperidin-1-yl)-1-oxo-1,2-dihydroisoquinolin-3-yl]phenyl}piperazin-1-carboxylate obtained in Example 101. The obtained mixture was stirred at a room temperature for 30 minutes. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified using BondElute NH2 (register trade mark; Varian; 1 g; dichloromethane:methanol=20:1), so as to obtain 8.9 mg (97%) of 7-(3-hydroxypiperidin-1-yl)-3-(2-piperazin-1-ylphenyl)-2H-isoquinolin-1-one in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:12]=2)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:22]1[C:23]2[C:30]([CH3:31])=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:1][C:2]1([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:12]=2)=[O:9])[CH2:3][CH2:4][N:5]([C:22]2[C:23]3[C:30]([CH3:31])=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:6][CH2:7]1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CC1(C(=O)Nc2cccc(S(N)(=O)=O)c2)CCNCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(S(N)(=O)=O)c4)CC3)c12
Temperature: 105 °C
Yield: 21 %

Procedure:
4-Methyl-N-(3-sulfamoylphenyl)piperidine-4-carboxamide from step B (33 mg, 0.098 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (16 mg, 0.098 mmol), N,N-diisopropylethylamine (51 mg, 0.39 mmol), and isopropanol (1.0 mL) were combined in a pressure rated sealed tube and heated at 105° C. for 18 hours. The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound in 21% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][CH2:14][C:15]([CH3:23])([N:20]([CH3:22])[CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:13]([CH3:12])[CH2:14][C:15]([CH3:23])([N:20]([CH3:21])[CH3:22])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:6]
Reactant: CCCCC(C)(CNC)N(C)C
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: CCCCC(C)(CN(C)C(=O)c1ccc(Cl)c(Cl)c1)N(C)C

Procedure:
A solution of 3,4-dichlorobenzoyl chloride (1.048 g., 5 mmole) in dry benzene (25 ml.) was added to a solution of N-methyl-2-methyl-2-dimethylamino hexylamine (0.754 g., 4.4 mmole) in dry benzene (25 ml.) and the solution heated under reflux for 1 hr.. The cooled solution was washed with 2N sodium hydroxide solution (4 × 100 ml.), water (4 × 100 ml.), dried (Na2SO4) and evaporated to a colourless oil (1.612 g.). The oil was dissolved in benzene, chromatographed on a column of alumina (25 × 3.0 cm.) eluting with benzene/ether 1:1, and fractions (9 × 100 ml.) were collected. Fractions 2-8 were combined and, on evaporation, afforded 3,4-dichloro-N-methyl-N-[2-methyl-2-dimethylamino-hexyl]benzamide as a colourless oil (1.282 g., 84%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([CH3:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:42])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[C:32]([CH2:33][O:34]C3CCCCO3)=[CH:31][N:30]=[N:29]2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([CH3:17])=[CH:10][C:9]2[NH:18][C:19](=[O:42])[CH2:20][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[C:32]([CH2:33][OH:34])=[CH:31][N:30]=[N:29]4)[CH:23]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1N(C)C)N=C(c1cccc(-n3nncc3CO)c1)CC(=O)N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-4-methyl-2-(3oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example M77) (0.42 g, 0.71 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale yellow solid (200 mg, 72%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12]CC)=[O:11])=[C:6]([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:21][CH:20]=2)[CH:5]=1.Cl>>[CH3:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[C:6]([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:21][CH:20]=2)[CH:5]=1
Reactant: CCOC(=O)COc1ccc(C)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(OCC(=O)O)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To 20 ml of a 10% potassium hydroxide-90% methanol solution was added 1.5 g of ethyl 4-methyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Example 24 followed by stirring at 50° to 60° C. for 1 hour. After adding 10 ml of a saturated saline aqueous solution, the reaction mixture was rendered acidic with diluted hydrochloric acid followed by extraction with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 1.12 g of 4-methyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>C1COCC1>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([B:22]([OH:27])[OH:23])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: OCCc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCCc1ccc(B(O)O)cc1
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a stirred solution of 4-bromophenethylalcohol (5.00 g, 24.9 mmol) in THF (80 ml) was added a solution of 1.5M n-BuLi in hexane (39.8 ml, 59.7 mmol) at −78° C. over 30 min. After 1 hour, a solution of B(OiPr)3 (8.61 ml, 37.3 mmol) in THF (20 ml) was added slowly to the mixture at −78° C. The resultant mixture was warmed to room temperature, and treated with 2M HCl (100 ml) for 1 hour. This was extracted with CH2Cl2 and dried over MgSO4, then filtered. After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluting with CH2Cl2/MeOH=20/1 to afford 2.61 g (63%) of the title compound.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:30]=[CH:29][C:9]([C:10]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]3[N:25]=[C:26]([CH3:28])[CH:27]=[C:15]3[N:14]=2)=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].[H][H]>CO.[Ni]>[NH2:2][CH2:1][C:3]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]3[N:25]=[C:26]([CH3:28])[CH:27]=[C:15]3[N:14]=2)=[O:11])=[CH:29][CH:30]=1)([CH3:4])[CH3:5]
Reactant: [H][H]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)C#N)cc3)cc(-c3ccccc3)n2n1
Agent: [Ni]
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CN)cc3)cc(-c3ccccc3)n2n1
Yield: 59.3 %

Procedure:
4-(2-Cyanopropan-2-yl)-N-(2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzamide (Compound 343 (Example 357), 75 mg, 0.19 mmol) was dissolved in methanol (5 ml). The solution was subjected to hydrogenation conditions in a flow-hydrogenator, using Raney nickel cartridge, with 30 bar of hydrogen pressure, 50° C. temperature and a flow rate of 0.5 ml/min. The reaction mixture was concentrated in vacuo to obtain the titled product 4-(1-amino-2-methylpropan-2-yl)-N-(2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzamide (45 mg, 59% yield). 1H NMR(CHLOROFORM-d) δ: 8.59 (br. s., 1H), 8.07-8.20 (m, 3H), 7.91 (d, J=8.3 Hz, 2H), 7.46-7.61 (m, 5H), 6.29 (s, 1H), 2.87 (br. s., 2H), 2.50 (s, 5H), 1.36 (s, 8H), 0.87 (br. s., 3H); ESI-MS: m/z 400.4 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[CH:10]=[CH:9][C:8]=1[O:17][CH3:18])[OH:6])=[N+]=[N-].[CH3:19][S:20](O)(=[O:22])=[O:21]>>[CH3:19][S:20]([O:6][CH:5]([CH2:4][NH2:1])[C:7]1[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[CH:10]=[CH:9][C:8]=1[O:17][CH3:18])(=[O:22])=[O:21]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(O)CN=[N+]=[N-]
Reactant: CS(=O)(=O)O
Product: COc1ccc(S(N)(=O)=O)cc1C(CN)OS(C)(=O)=O

Procedure:
Starting from (+)-α-azidomethyl-2-methoxy-5-sulphamoylbenzenemethanol, hydrogenated under the conditions described in step 6 of Example 2 and then treated with 1 equivalent of methanesulphonic acid, (+)-α-aminomethyl-2-methoxy-5-sulphamoylbenzenemethanol methanesulphonate was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[O:10]([C:17]1[CH:18]=[C:19]([CH2:23][CH:24]([CH3:27])[CH2:25]I)[CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[O:10]([C:17]1[CH:18]=[C:19]([CH2:23][CH:24]([CH3:27])[CH2:25][N:6]2[CH2:7][CH2:8][CH:9]=[C:4]([CH2:3][O:2][CH3:1])[CH2:5]2)[CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCc1cccnc1
Reactant: CC(CI)Cc1cccc(Oc2ccccc2)c1
Product: COCC1=CCCN(CC(C)Cc2cccc(Oc3ccccc3)c2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 20 %

Procedure:
3-Methoxymethylpyridine (1.75 g) was added to 3-(m-phenoxyphenyl)-2-methylpropyl iodide (1.0 g) at room temperature, and the resultant mixture was stirred at 120° C. for 4 hours. The reaction mixture was cooled to room temperature and washed with diethyl ether three times. Methanol (20 ml) was added thereto, and after addition of sodium borohydride (0.21 g) at room temperature, the resultant mixture was stirred at the same temperature for 15 hours. The resultant mixture was admixed with water (200 ml) and 15% aqueous sodium hydroxide solution (20 ml) and extracted with diethyl ether (50 ml×3). The extracts were combined together, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give N-[3-(m-phenoxyphenyl)-2-methylpropyl]-3-methoxymethyl-1,2,5,6-tetrahydropyridine (0.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][C:16]([OH:18])=[O:17])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>ClCCl.CO>[C:16]([CH2:15][C:11]1[CH:12]=[C:13]([CH3:14])[C:8]([C:6]2[CH:5]=[CH:4][N+:3]([O-:27])=[C:2]([CH3:1])[CH:7]=2)=[N:9][CH:10]=1)([OH:18])=[O:17]
Reactant: Cc1cc(-c2ncc(CC(=O)O)cc2C)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)cnc1-c1cc[n+]([O-])c(C)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)acetic acid 156-5 (100 mg, 0.41 mmol) in dichloromethane (3 mL) and methanol (0.5 mL) was added mCPBA (91 mg, 0.41 mmol) in small portions at 0° C. The mixture was stirred for 3 hours at 0° C., and then was concentrated to dryness to give 4-(5-(carboxymethyl)-3-methylpyridin-2-yl)-2-methylpyridine 1-oxide 156-6 as white solid, which was used for next step without further purification. MS m/z 259.1 (M+1).