Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[Br:1][C:2]1[C:3]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][OH:28])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CCNCCO
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 185.2) and 2-ethylamino-ethanol to afford a white crystalline solid. (Reaction Time was 10 h). HPLC (Condition 4) tR=6.33 min, UPLC-MS (Condition 3) tR=1.25 min, m/z=466.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]([CH:18]2[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]2=O)=[O:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14].C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C)C=O>[Cl:29][C:19]1[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:18]=1[C:16]([C:3]1[C:2]([Cl:1])=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][S:10]2(=[O:13])=[O:12])=[CH:5][CH:4]=1)=[O:17]
Reactant: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1C(=O)CCCC1=O)c2Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Cl)CCCC1=O)c2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g (5.2 mmol) of 2-(8-chloro-4,4-dimethyl-1,1-dioxothiochroman-7-yl)carbonyl-1,3-cyclohexanedione were dissolved in 30 ml of methylene chloride and 2.2 g (17.3 mmol) of oxalyl chloride and 2 drops of dimethylformamide were added. After 1 hour of stirring at 25° C., the solvent was removed. This gave 2.1 g of colored crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4]C(O)C.[OH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:4][CH2:3][CH2:2][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=1
Reactant: CC(O)OCCCl
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCO)cc1
Temperature: 80 °C
Reaction time: 17 h
Yield: 134.4 %

Procedure:
104.9 g (842.5 mmol) 2-chloroethoxyethanol, 500 ml dimethylformamide (DMF), 70 g (421.2 mmol) ethyl 4-hydroxybenzoate, and 116.3 g (842.5 mmol) potassium carbonate were introduced into a flask in a nitrogen stream and stirred at 80° C. for 17 hours. The insolubles were filtered off, and the filtrate was concentrated, then introduced into a saline solution, extracted with ethyl acetate, washed with water and dried over magnesium sulfate anhydride, and the solution was concentrated to give 119 g crude ethyl 4-(2-hydroxyethoxy)benzoate. Subsequently, 150 ml ethanol and 200 ml aqueous solution of 33.7 g sodium hydroxide were added thereto, and the mixture was stirred at 70° C. for 2 hours. After the reaction solution was left and cooled, 72 ml conc. hydrochloric acid was added thereto on an iced bath, and the precipitates were filtered, and washed with water to give 89 g (76.2 mmol) 4-(5-hydroxy-3-oxapentyloxy) benzoic acid (compound (XIII) [R9, R10, R11, R12=H; X1=—(CH2CH2O)2—] in scheme (3)). Then, 800 ml toluene, 76.5 g (1060 mmol) acrylic acid and 10.1 g(53mmol)p-toluenesulfonicacidmonohydrate(referred to hereinafter as “PTSA”) were added thereto, and the mixture was esterified for 3 hours in a Dean-Stark tube. The insolubles were filtered, and washed with toluene, then suspended in water, filtered and dried to give 86 g of the desired product. The yield was 78%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:20])=[C:5]([O:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:6]([CH3:9])=[N:7][CH:8]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)#[N:22]>>[CH3:20][C:4]1[C:5]([O:10][CH2:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:14]([C:15]#[N:16])[CH:13]=2)=[C:6]([CH3:9])[N:7]=[CH:8][C:3]=1[CH2:2][O:1][C:26]1[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=1
Reactant: Cc1ncc(CO)c(C)c1OCc1cccc(C#N)c1
Reactant: N#Cc1ccc(O)cc1
Product: Cc1ncc(COc2ccc(C#N)cc2)c(C)c1OCc1cccc(C#N)c1
Yield: 47.3 %

Procedure:
The coupling of 3-(5-hydroxymethyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (26) (1.0 mg, 3.70 mmol) and 4-cyanophenol (885 mg, 7.40 mmol), as described in Example 9, gave 4-[4,6-dimethyl-5-(3-cyano-benzyloxy)-pyridin-3-ylmethoxy]-benzonitrile (69) (646 mg, 47% yield).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27].O>CN1C(=O)CCC1>[CH2:25]([NH:29][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CN
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)CNc1nc(-c2ccc(S(C)(=O)=O)cc2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (1 g, 2.629 mmol) and isobutylamine(0.52 ml) in NMP (10 ml) was stirred at ambient temperature for 18 h. Water (100 ml) was then added and the resulting precipitate was collected by filtration and dried (0.85 g). Trituration of this material with ether/cyclohexane gave the title compound as a colourless solid (0.62 g).
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:18][CH2:17][CH2:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=2[CH:23]=1>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]([CH:1]=[O:3])[CH2:17][CH2:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=2[CH:23]=1
Reactant: CC(=O)O
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.84 ml) was added dropwise formic acid (0.4 ml), under ice-cooling, and the mixture was stirred, under nitrogen atmosphere, at 50° C. for 2 hours. To the mixture was added THF (5 ml), and to the mixture was added dropwise, under ice-cooling, a solution of methyl 7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0 g) in THF (15 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.07 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:11][CH2:10][CH2:9][N:8]([C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:24](=[O:25])[CH3:23]
Reactant: O=C(Cl)CCl
Reactant: CCCNc1c(C)cccc1OCCOCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCN(C(C)=O)c1c(C)cccc1OCCOCCOC
Reaction time: 0.17 h
Yield: 39 %

Procedure:
A mixture containing a portion of the 6-methyl-2-[2-(2-methoxyethoxy)ethoxy]-N-2-methylethyl aniline (5.34 g; 0.02 mole) and sodium hydroxide (0.88 g; 0.22 mole) in 150 ml. of methylene chloride was cooled to 10° C. To the reaction mixture was added dropwise chloroacetyl chloride (2.5 g; 0.022 mole) and the resulting mixture was stirred for 10 minutes. The layers were separated and the organic methylene chloride layer was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield a crude product. The crude product was separated on a silica gel column using a 2:5 ethyl acetate:cyclohexane mixture as the eluant to yield N-2-methylethyl-N-[6-methyl-2-(2-(2-methoxyethoxy)ethoxy)phenyl]acetamide (Compound No. 102) (2.7 g; 39% yield) as a clear yellow oil having a boiling point of 163° C. (0.13 mmHg) and the following analysis:
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:24])[C:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:20]([CH3:21])=[CH:19][S:18][CH:17]=2)=[C:12]([O:22]C)[CH:11]=1)([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].B(Br)(Br)Br.Cl>C(Cl)Cl>[OH:22][C:12]1[CH:11]=[C:10]([C:7]([CH3:8])([CH3:9])[C:6]([NH:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:24])[CH:15]=[CH:14][C:13]=1[C:16]1[C:20]([CH3:21])=[CH:19][S:18][CH:17]=1
Reactant: COc1cc(C(C)(C)C(=O)NCC(C)C)ccc1-c1cscc1C
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Cc1cscc1-c1ccc(C(C)(C)C(=O)NCC(C)C)cc1O
Temperature: -78 °C
Reaction time: 72 h
Yield: 69.4 %

Procedure:
N-isobutyl-2-(3-methoxy-4-(4-methylthiophen-3-yl)phenyl)-2-methylpropanamide (example 35a) (103 mg, 0.3 mmol) was dissolved in dry DCM (5 mL), the mixture was under argon cooled to −78° C. and BBr3 (1.69 mL of 1M solution in DCM) was added drop-wise and the mixture was stirred at room temperature for 72 hrs. The solution was diluted with DCM and treated with 1M aq. HCl. The organic phase was washed with water and brine, dried over MgSO4 filtered and evaporated. The residue was purified on preparative RP HPLC (acetonitrile/water) and on silica gel (EtOAc/hexanes) and the product was co-evaporated with ethanol to give 2-(3-hydroxy-4-(4-methylthiophen-3-yl)phenyl)-N-isobutyl-2-methylpropanamide (69 mg, 70%). 1H NMR (400 MHz, dMSO): δ 0.74-0.76 (d, 6H), 1.42 (s, 6H), 1.67-1.74 (m, 1H), 2.09 (s, 3H), 2.83-2.86 (t, 2H), 6.76-6.78 (dd, 1H), 6.87-6.88 (d, 1H), 7.01-7.03 (d, 1H), 7.13-7.14 (m, 1H), 7.21-7.22 (d, 1H), 7.27-7.29 (t, 1H), 9.38-9.39 (b, 1H); MS (332).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[NH2:14][C:15]1[N:19]=[CH:18][NH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:14][C:15]1[N:16]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:6]=2[Cl:9])[N:17]=[CH:18][N:19]=1
Reactant: Nc1nc[nH]n1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.0 g) in dimethylformamide (5 ml) was added 3-amino-1,2,4-triazole (360 mg) and potassium carbonate (296 mg), the mixture was heated at 100° C. for 2 hrs. The reaction was cooled to room temperature, diluted with water (100 ml) and extracted with ether (100 ml). The organic extracts were evaporated to dryness to give the title compounds as pale yellow crystals.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:15]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(CBr)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1

Procedure:
4-(bromomethyl)benzoic acid was coupled to 4-chloro-3-(pyridin-2-yl)aniline as described in general procedure E to yield 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[C:14]([O:19][CH3:20])[CH:13]=[CH:12][CH:11]=3)=[O:4].[OH-].[Na+].O.Cl>O1CCOCC1>[CH2:27]([N:24]1[CH2:23][CH2:22][CH:21]([N:9]2[C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:18][C:17]=3[O:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[O:19][CH3:20])[CH2:26][CH2:25]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc2c1Oc1cc(C(=O)O)ccc1N2C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic acid methyl ester, 2d (270 mg, 0.7 mmol) in dioxane (15 mL) was added sodium hydroxide (31 mg, 0.77 mmol) and the mixture was heated to reflux for 4 h. The mixture was allowed to cool to rt, water (15 mL) was added, and the solution was acidified with 1N HCl to pH 2. The mixture was extracted with methylene chloride, the organic phase was separated, dried, and evaporated to yield 245 mg (94%) of title compound 10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic acid, 3d.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([Cl:22])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Solvent: ClCCl
Product: Cc1ccc(OCc2ccccc2)cc1C(=O)Cl
Temperature: 25 °C

Procedure:
To a mixture of 3.3 g 5-(benzyloxy)-2-methylbenzoic acid (compound F1) in 80 ml DCM are added 1.4 ml of oxaloylchloride, and the reaction is stirred at RT over night under a blanket of nitrogen. The solvent is removed under reduced pressure yielding the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1.[NH2:12][C@H:13]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH3:1][C:2]1[C:6]([S:7]([NH:12][C@H:13]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Product: Cc1noc(C)c1S(=O)(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 3,5-dimethyl-4-isoxazolesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 2H), 7.3-7.1 (m, 5H), 7.05 (t, 2H, J=6.5 Hz), 6.81 (d, 1H, J=7.1 Hz), 4.65 (dd, 1H, J=6.3, 2.2 Hz), 3.11 (t, 2H, J=7.2 Hz), 2.4 (m, 4H), 2.2 (s, 3H), 2.05 (m, 2H), 2.01 (s, 3H), 2.0-1.8 (m, 7H), 1.21 (d, 6H, J=7.1 Hz); ESMS m/e: 539.5 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:10]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:11]2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:6]1.[C:34](#[N:36])C>CN.CCO>[CH3:34][NH:36][CH2:2][CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:10]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:11]2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:6]1
Reactant: Fc1ccc(-c2nc3nn(CCCCl)cc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: CC#N
Agent: CN
Solvent: CCO
Product: CNCCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Temperature: 60 °C
Yield: 29 %

Procedure:
To a solution of 2-(3-chloropropyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (0.07 g, 0.1 mmol, obtained in example 16) in acetonitrile (0.3 mL), methylamine (1.8 mL of a 33% solution in EtOH, 14.6 mmol) was added under argon atmosphere. This was heated to 60° C. for 3 days, adding methylamine (0.9 mL and 3.6 mL of a 33% solution in EtOH) after 24 and 48 h respectively. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by silica gel EtOAc-MeOH mixtures of using increasing polarity as eluent, to afford 24 mg of the title compound in solid form (yield: 29%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][C:10]2=[O:20])=[CH:6][CH:5]=1.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].CCOCC>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][C:10]2=[O:20])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium hydride (18g.; 60% w/w dispersion in oil, washed as described in Example 1) was stirred in dry dimethylformamide (300 ml.), and 1-(4-chlorobenzyl)-1,2-dihydro-4-methyl-2-oxoquinoline (64.7 g.) was added, followed by diethyl oxalate (55 g.). The mixture was stirred at room temperature for 2.5 hours with occasional external cooling to keep the temperature below 25° C. Ether (2 1.) was added, and the mixture was filtered. The solid residue was washed with ether (500 ml.), and then suspended in dimethylformamide (200ml.) nd acidified to pH 2 by the addition of concentrated hydrochloric acid. The resultant mixture was added to water (3 1.), and the mixture filtered, and the solid residue washed with water (2 1.), drained well, and crystallised from ethanol to give ethyl 1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylpyruvate, m.p. 180°-182° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[N:38][C:37]=1OS(C(F)(F)F)(=O)=O.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:37]4[N:38]=[CH:39][C:40]5[C:45]([C:36]=4[CH3:35])=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ncc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)ncc2ccccc12
Temperature: 100 °C

Procedure:
To a solution of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (86.3 mg, 0.184 mmol), trifluoromethanesulfonic acid 4-methylisoquinolin-3-yl ester (54.8 mg, 0.188 mmol), and Pd(PPh3)4 (14 mg, 0.012 mmol) in 1,4-dioxane (2.8 mL, 36 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (118 mg, 0.361 mmol) in H2O (0.80 mL, 44 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 100° C. for 30 min. The reaction mixture was diluted with DCM, washed with water and brine, and dried over MgSO4. The crude material was chromatographed on silica gel [20 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM→2.5% MeOH in DCM→3% MeOH in DCM→3.5% MeOH in DCM→4% MeOH in DCM]. Fractions containing the title compound were combined and dried in vacuo, giving the title compound as a glassy solid. 1H NMR (400 MHz, CDCl3): δ=9.22 (s, 1H), 8.30 (d, J=2.4 Hz, 1H), 8.08 (dd, J=0.8, 8.6 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.81 (ddd, J=1.2, 6.8, 8.3 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.68 (ddd, J=0.8, 7.0, 8.0 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J=2.4 Hz, 1H), 4.85 (brs, 2H), 4.42-4.13 (m, 3H), 2.90 (brt, J=11.2 Hz, 2H), 2.62 (s, 3H), 2.15 (brdd, J=2.0, 12.4 Hz, 2H), 1.95 (dq, J=4.0, 12.0 Hz, 2H), 1.48 (s, 9H). MS(ES+): m/z=485.14 (100) [MH+], 429.12 (66) [MH+-isobutene]. HPLC: tR=2.62 min (polar—5 min, ZQ3).
Reaction SMILES: [CH2:1]([O:3][CH:4]([PH:8](=[O:12])OCC)[O:5][CH2:6][CH3:7])[CH3:2].[CH2:13]([Mg]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O>[CH2:13]([PH:8](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[O:5][CH2:6][CH3:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(OCC)[PH](=O)OCC
Reactant: Cl[Mg]Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(OCC)[PH](=O)Cc1ccccc1

Procedure:
By a procedure analogous to that of Example 1, but using 1.96 g of ethyl diethoxymethylphosphinate and 20 ml of a molar solution of benzylmagnesium chloride in diethyl ether and adding 4.14 g of potassium carbonate in 5 ml of water to precipitate inorganic salts, benzyl(diethoxymethyl)phosphine oxide is obtained as a colourless oil.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:8]2)[S:4][N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])O1.C([O-])([O-])=O.[K+].[K+].CC#N>O>[OH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:8]2)[S:4][N:3]=1
Reactant: CC(C)COC(=O)NC1CCN(c2nc(Br)ns2)CC1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)COC(=O)NC1CCN(c2nc(-c3ccccc3O)ns2)CC1
Temperature: 175 °C

Procedure:
A mixture of isobutyl 1-(3-bromo-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate (0.38 g, 1.1 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol (0.35 g, 1.6 mmol), Pd(Ph3)4 (12 mg, 11 μmol), K2CO3 (0.29 g, 2.1 mmol), CH3CN (3.0 mL), and H2O (0.3 mL) was sealed in a microwave vessel and heated by microwave irradiation at 175° C. for 15 minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to yield isobutyl 1-(3-(2-hydroxyphenyl)-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate. LC/MS: m/z 377.3 (M+H)+ at 3.77 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).