Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[OH-].[Na+]>C(O)C>[N:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1
Yield: 74.5 %

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4.5]decane (150 g), 4-chloropyridine hydrochloride (190 g) and triethylamine (320 g) in ethanol (800 ml) was reacted in a sealed tube at 150° C. for 15 hours. The reaction mixture was concentrated to obtain a residue, which was made alkaline by an addition of a 6N aqueous solution of sodium hydroxide, and then extracted with dichloromethane. After drying and concentrating, the resultant residue was triturated from hexane, collected by filtration and then dried to obtain 8-(4-pyridyl)-1,4-dioxa-8-azaspiro[4.5]decane (172 g) as a pale yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:14]=[C:13](Cl)[C:12]3[C:16](=[O:30])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH3:29])[CH2:18][C:11]=3[C:10]=2[F:31])[CH2:6][CH2:5][O:4][CH2:3]1.[N:32]1[N:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]2=[C:34](B(O)O)[CH:33]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:14]=[C:13]([C:34]3[CH:33]=[N:32][N:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=34)[C:12]3[C:16](=[O:30])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH3:29])[CH2:18][C:11]=3[C:10]=2[F:31])[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4N)nc(Cl)c3C2=O)c(OC)c1
Reactant: OB(O)c1cnn2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4N)nc(-c4cnn5ccccc45)c3C2=O)c(OC)c1
Temperature: 120 °C
Yield: 100.7 %

Procedure:
To a 5 mL microwave vial with a stir bar was added bis(triphenylphosphine)palladium chloride (11.68 mg, 0.017 mmol), 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (75 mg, 0.166 mmol), pyrazolo[1,5-a]pyridin-3-ylboronic acid (135 mg, 0.832 mmol) in dioxane (2 mL), and saturated aq NaHCO3 (2 mL). The mixture was heated in a Biotage Initiator microwave at 120° C. for 30 min. The mixture was concentrated and purified via preparative HPLC to give the title compound (89 mg, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.84 (m, 1H), 2.10-2.12 (m, 1H), 3.68-3.72 (m, 3H), 3.75 (s, 3H), 3.82 (s, 3H), 3.92-3.95 (m, 1H), 4.01-4.02 (m, 1H), 4.39 (s, 2H), 4.55-4.58 (m, 1H), 4.59 (s, 2H), 6.50 (dd, J=8.30, 1.95 Hz, 1H), 6.60 (d, J=2.44, 1H), 7.04-7.08 (m, 2H), 7.16 (d, J=5.86 Hz, 1H), 7.48-7.51 (m, 1H), 7.93 (br s, 1H), 8.37 (d, J=9.27 Hz, 1H), 8.79 (d, J=6.83 Hz, 1H), 9.36 (s, 1H). [M+H] calc'd for C28H29FN6O4, 533; found, 533.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)(=O)C>[C:14]1([C:3]2[C:4]([CH3:13])=[N:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]=2[NH2:1])[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Reactant: O=C1CCCCC1
Solvent: CC(=O)O
Product: Cc1nn(-c2ccccc2)c(N)c1C1=CCCCC1
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A solution of 5-amino-3-methyl-1-phenylpyrazole (8.66 g, 50 mmol) in acetic acid (70 mL) was treated with cyclohexanone (10.6 mL, 100 mmol) at ambient temperature for 40 hours. The volatiles were removed and the residue diluted with water and 10% sodium hydroxide added until the pH=12. The mixture was stirred with 10 mL of hexane for 30 minutes and the solid collected by filtration, washed with water and hexane and dried to give 9.43 g (74%) of the title compound. MS (DCI): m/z 254 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:19])[C@@H:4]([NH2:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Br:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([C:31](O)=[O:32])[N:27]=[CH:28]2)=[CH:23][CH:22]=1>>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH:18][C:31]([C:26]2[N:27]=[CH:28][C:29]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[C:21]([Br:20])[CH:30]=3)=[O:32])[C:3]([OH:2])=[O:19])=[CH:7][CH:8]=1
Reactant: O=C(O)c1cc2ccc(Br)cc2cn1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1cc2ccc(Br)cc2cn1
Yield: 2 %

Procedure:
(2S)-amino-3-biphenyl-4yl-propionic acid methyl ester (340 mg, 13.9 mmol) was reacted with 7-bromo-isoquinoline-3-carboxylic acid (350 mg, 13.9 mmol) as described in general procedure A. The resulting compound was hydrolyzed by following general procedure C yielding the title compound (132 mg, 81%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:8]([C:7]1[CH:11]=[C:3]([C:1]#[C:2][C:18]2[C:19]([C:20]([F:22])([F:21])[F:23])=[CH:14][N:15]=[C:16]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([N:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[CH:29][CH:30]=3)[N:17]=2)[CH:4]=[CH:5][C:6]=1[CH3:12])(=[O:9])[NH2:10]
Reactant: C#Cc1ccc(C)c(C(N)=O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C#Cc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cc1C(N)=O
Temperature: 120 °C
Yield: 68.9 %

Procedure:
To a mixture of 5-ethynyl-2-methylbenzamide (I71) (0.041 g, 0.25 mmol), tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I3) (0.105 g, 0.230 mmol), PdCl2(PPh3)2 (0.011 g, 0.016 mmol), triphenylphosphine (0.010 g, 0.038 mmol) and copper(I) iodide (0.010 g, 0.53 mmol) in DMF (2 mL) was added triethylamine (0.091 mL, 0.65 mmol). The mixture was then heated under microwave irradiation at 120° C. for 30 minutes. The resulting mixture was concentrated under reduced pressure then purified using silica gel column chromatography (0-100% EtOAc/petroleum benzine 40-60° C.) to give title compound (I72) (0.092 g, 69%); 1H NMR (400 MHz, d5-DMSO) δ 10.24 (s, 1H), 8.75 (s, 1H), 8.31 (s, 1H), 7.90 (s, 1H), 7.58 (m, 4H), 7.39 (m, 1H), 6.96 (d, J=9.0 Hz, 2H), 3.46 (dd, J=6.3, 3.3 Hz, 4H), 3.06 (m, 4H), 2.42 (s, 3H), 1.42 (s, 9H). LCMS Method C: rt 6.22 min; m/z 581.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13].Br[CH2:15][CH2:16]Br>CN(C=O)C>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([CH2:16][CH2:15]2)[C:5]1=[O:13]
Reactant: BrCCBr
Reactant: CN1C(=O)Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
Add sodium hydride (60%, 1.4 g, 35.4 mmol) portionwise to the solution of 1-methylindolin-2-one (2.6 g, 17.7 mmol) in DMF (10 mL) at 0° C., stir for 30 min. Then add 1,2-dibromoethane (3.31 g, 17.7 mmol) to the mixture, stir the resulting mixture at room temperature overnight. Pour the reaction mixture to ice water, extract with ethyl acetate (100 mL×2), and wash the combined organic layers with brine (50 mL), dry over anhydrous sodium sulfate. Concentrate under reduced pressure, purify the residue by chromatography (silica gel, EtOAc:PE=1:3) to provide the title compound (1.5 g, 50.0%). MS: (M+1): 174.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][O:15]C(=O)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC[C@@H]1CN(Cc2ccccc2)CCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC[C@@H]1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
5 g of (S)-4-benzyl-2-acetoxymethylmorpholine was dissolved in 10 ml of ethanol. To the solution was added a solution of 1 g of sodium hydroxide dissolved in 5 ml of water with ice cooling. The mixture was stirred at room temperature for 10 minutes. The reaction mixture was added to 50 ml of ice water and extracted with 50 ml of chloroform. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=30/1) to obtain 3.6 g of oily (S)-4-benzyl-2-hydroxymethylmorpholine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.C=O.[OH-].[Na+].CCCCCC.[C:34]([O:37][CH2:38]C)(=[O:36])[CH3:35]>CC(O)=O>[C:34]([O:37][CH2:38][C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]=1[CH3:23])(=[O:36])[CH3:35]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(=O)OCc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1C
Temperature: 52.5 °C
Yield: 22 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (Example 1) (500 mg, 2.87 mmol) in AcOH (5 ml), formaldehyde (0.22 ml, 40% solution in water, 2.87 mmol) was added. After heating at 50-55° C. for 90 minutes, the reaction mixture was cooled and poured over ice. The solution was made alkaline with 2N NaOH and extracted with methylene chloride. The organic fractions were washed with water and with brine, dried (MgSO4), filtered and concentrated to give the crude product (780 mg) as a yellowish liquid. Chromatography (silica gel, hexane/ethyl acetate, 6/4) gave [1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]methyl acetate (250 mg, 22%) as a white solid: mp (DSC) 151° C. Anal Calc'd. for C21H20NSFO4 : C, 62.83; H, 5.02; N, 3.49. Found: C, 62.48; H, 5.16; N, 3.37.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1.C(N(CC)CC)C>C(O)CCC>[Cl:14][C:15]1[N:16]=[N:17][C:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)nn2)CC1
Yield: 64.6 %

Procedure:
A mixture of 13.52 g of tert-butyl 1-piperazinecarboxylate, 10.81 g of 3,6-dichloropyridazine and 20 ml of triethylamine in 100 ml of n-butanol is refluxed for 5 hours. The mixture is concentrated under vacuum and the residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture (90/10; v/v). 14 g of the expected product are obtained, and are used without further purification.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:30][C:29]4[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: COc1ccc(CCl)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: COc1ccc(COC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 72.4 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 4-methoxybenzyl chloride (16.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(4-methoxybenzyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (29.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][CH2:38][OH:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][N:25]5[CH2:37][CH2:38][OH:39])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN1
Reactant: OCCBr
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN1CCO

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S)-1-(2-hydroxyethyl)pyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2S)-pyrrolidin-2-ylmethyl]-1,3-thiazolidine-2,4-dione (Example 145) and 2-bromoethanol following General Procedure S.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]3)=[CH:4][C:3]=1[C:34]1[CH:35]=[N:30][CH:31]=[N:32][CH:33]=1
Reactant: OB(O)c1cncnc1
Reactant: O=S(=O)(Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F)C(F)(F)F
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1cncnc1
Yield: 40.9 %

Procedure:
Trifluoromethanesulfonic acid 2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenyl ester (30.0 mg, 0.068 mmol) was coupled to 5-pyrimidinylboronic acid (prepared as described in WO 9411372; 11.0 mg, 0.089 mmol) as described in Example 35 part c), affording 5-(4-fluoro-3-pyrimidin-5-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (10.3 mg, 41%). δH (360 MHz, CDCl3) 7.49 (1H, t, J 9.5), 7.55-7.61 (3H, m), 7.86 (1H, d, J 8.4), 8.51 (1H, d, J 8.4), 9.01 (2H, d, J 1.1), 9.28 (1H, s), 9.32 (1H, d, J 4.6). m/z (ES+) 371 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH:10]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=[C:31]([CH3:39])[CH:30]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:40][OH:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[NH:40][OH:41])[CH:10]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=[C:31]([CH3:39])[CH:30]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CN(C(=O)OC(C)(C)C)CCC3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3CN(C(=O)OC(C)(C)C)CCC3C(=O)NO)cc2)c2ccccc2n1
Yield: 5.3 %

Procedure:
According to the procedure of Example 24, Step 3, 0.55 g (0.99 mmol) of 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester and hydroxylamine afforded 4-hydroxycarbamoyl-3-[4-(2-methyl-quinolin-4-yl methoxy)-benzenesulfonylamino]-piperidine-1-carboxylic acid tert-butyl ester as an amorphous white solid (0.030 g, 5.3%) after purification using reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column, eluting an acetonitrile:water gradient. MS: 571 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([OH:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(F)c(OCC(=O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(OC[C@H](O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Reaction time: 0.5 h

Procedure:
100 mL dry THF, 75 mL of 1M (R)-CBS reagent in toluene, and 26.7 mL borane-diethylaniline complex were stirred together 20 min at room temperature. 3-{2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-ethoxy}-4-fluoro-benzonitrile (31.7 g) in 700 mL dry THF was then added through an addition funnel at rt over 30 minutes. The mixture stirred for 30 min, then was quenched by slow addition of 100 mL MeOH. After gas evolution ceased the mixture was evaporated to a yellow oil. The oil was dissolved in 200 mL ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated. The residue was stirred with hexanes and the hexanes layer removed. The resulting residue was purified over silica gel (DCM). 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.38 (m, 2H), 7.3-7.15 (m, 4H), 6.97 (m, 2H), 5.13 (m, 1H), 5.03 (s, 2H), 4.10 (m, 2H), 2.64 (d, 1H).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:23]=[CH:22][C:13]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.B.[Na]>O1CCOCC1.O>[N:1]1([CH:6]([C:10]2[CH:23]=[CH:22][C:13]([CH:14]([OH:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1ccc(C(=O)c2ccccc2)cc1)n1ccnc1
Agent: B
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(c1ccc(C(O)c2ccccc2)cc1)n1ccnc1

Procedure:
By reduction of the ketone of example 17 with sodium boron hydride in dioxane/water (90:10); boiling point 250° C./0.03 mbar.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C@H:4]([CH2:12][O:13][CH3:14])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:16])=[O:15])[CH2:12][O:13][CH3:14])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:24][CH2:23]1
Reactant: COC[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: COC[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a solution of N,N,O-trimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-serinamide (434 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (780 mg) in 2-propanol (10 mL) was added piperidinium acetate (334 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (409 mg).
Reaction SMILES: [F-].[Cs+].[F:3][C:4]([F:41])([F:40])[C:5]1[CH:6]=[C:7]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:8][N:9]([C@H:16]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]2[C:23](Br)=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]1=2)[C:10]1[N:11]=[N:12][N:13]([CH3:15])[N:14]=1.[CH3:42]B(O)O.ClCCl>O1CCOCC1>[F:3][C:4]([F:41])([F:40])[C:5]1[CH:6]=[C:7]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:8][N:9]([C@H:16]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]2[C:23]([CH3:42])=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]1=2)[C:10]1[N:11]=[N:12][N:13]([CH3:15])[N:14]=1
Reactant: Cc1cc2c(c(Br)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CB(O)O
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc2c(c(C)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Yield: 83 %

Procedure:
Add cesium fluoride (2.44 g, 16.1 mmol) to a mixture of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(9-bromo-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine and methyl boronic acid (0.820 g, 13.8 mmol) in dioxane (50.0 mL). Purge the mixture with nitrogen for 15 min. Add 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride, complex with dichloromethane (0.290 g, 0.355 mmol) under nitrogen. Heat the reaction mixture for 3 h. Cool down to room temperature and then evaporate the solvent under reduced pressure. Partition the residue between ethyl acetate (100 mL) and water (100 mL). Separate the layers and extract the aqueous with more ethyl acetate (2×50 mL). Combine the organic layers, dry over Na2SO4, filter and concentrate. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0-35%), to provide the title compound as an off-white solid (2.16 g, 83%). MS (ES+): 567 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:6]([Br:18])[CH:5]=1.[OH-].[Na+].Cl>CO.O>[Br:18][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]([OH:19])=[O:2]
Reactant: COC(=O)c1ccc(Oc2ccc(Cl)cc2)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Oc2ccc(Cl)cc2)c(Br)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
To a solution of methyl-3-bromo-4-(4-chlorophenoxy)-benzoate (Preparation 28, 2 g, 6 mmol) in 40 mL methanol was added sodium hydroxide (0.486 g, 11.7 mmol) in 10 mL water. The reaction mixture was stirred at 50° C. for 16 hours and then acidified to pH 4 with 1M hydrochloric acid, stirred for 1 hour, filtered and dried in vacuo to afford the title compound (1.53 g, 78%).