Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:43]>>[ClH:43].[NH2:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]4[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=4)=[O:13])[C:4]=23)[CH2:22]1
Reactant: ClCCl
Reactant: Cc1cnc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)cn1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](N)C4)c23)cn1
Product: Cl
Reaction time: 1 h
Yield: 56 %

Procedure:
A solution of crude (R)-tert-butyl 1-(5-bromo-3-(5-methylpyrazine-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (75 mg, 0.14 mmol) in DCM (3 mL) was treated with TFA (1 mL) at room temperature. After 1 hour, the mixture was concentrated in vacuo. The resulting residue was dissolved in a minimal amount of DCM and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylpyrazine-2-carboxamide hydrochloride (40 mg, 56% yield). 1H NMR (400 MHz, D2O) δ 8.47 (s, 1H), 8.30 (s, 1H), 8.08 (s, 1H), 7.56 (s, 1H), 3.61-3.59 (m, 1H), 3.51-3.46 (m, 1H), 3.42-3.36 (m, 1H), 3.31-3.30 (m, 1H), 2.87-2.84 (m, 1H), 2.40 (s, 3H), 2.16-2.13 (m, 1H), 1.90-1.87 (m, 1H), 1.74-1.71 (m, 1H), 1.49-1.46 (m, 1H); LCMS (APCI+) m/z 430, 432 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]([NH:15]C(=O)OC(C)(C)C)[CH2:10][C:11]([F:14])([F:13])[CH3:12])=[O:8])[CH2:5][CH2:4]1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:3]1([NH:6][C:7](=[O:8])[C@@H:9]([NH2:15])[CH2:10][C:11]([F:14])([F:13])[CH3:12])[CH2:4][CH2:5]1)#[N:2]
Reactant: CC(F)(F)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(C#N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(F)(F)C[C@H](N)C(=O)NC1(C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To detach the Boc protecting group, the compound from example 17 (580 mg, 1.83 mmol) was admixed with 10 ml of 1:1 TFA/DCM and stirred at RT for 30 min. Subsequently, the mixture was concentrated by evaporation under reduced pressure and subjected to azeotropic distillation with dichloromethane and toluene, and solvent residues were removed under high vacuum. The product was present as the trifluoroaceate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][OH:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH:21]=[O:22].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]=[O:11].[CH3:25][N:26]([CH3:28])[CH:27]=[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])[CH:21]=[O:22]
Reactant: COc1ccccc1CCO
Reactant: COC(OC)N(C)C
Agent: COc1ccccc1CC=O
Product: COc1ccccc1C(C=O)=CN(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
(2-Methoxyphenyl)acetaldehyde is prepared by oxidation of 2-(2-methoxyphenyl)ethanol according to the procedure disclosed in J. Org. Chem., 49:1720, 1999. A mixture of (2-methoxyphenyl)acetaldehyde (3.8 g, 25.3 mmol) and dimethylformamide dimethyl acetal (4.52 g, 37.9 mmol) is stirred at room temperature for 1 hour. Excess of the acetal is removed under reduced pressure to leave 4.68 g of 3-dimethylamino-2-(2-methoxyphenyl)propenal (90%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@@H:7]([CH3:16])[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[C:3]1=[O:17].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][C:23]=2[CH:31]=1.[Cl-].[NH4+]>C(#N)C.N1C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([S:27]([NH:1][C@H:2]3[CH2:6][CH2:5][N:4]([C@@H:7]([CH3:16])[C:8]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[O:9])[C:3]3=[O:17])(=[O:29])=[O:28])=[CH:24][C:23]=2[CH:31]=1
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2o1
Reactant: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N)C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: c1ccncc1
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2cc3cc(Cl)ccc3o2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.1 %

Procedure:
To a solution of (3S)-3-amino-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]pyrrolidin-2-one (0.077 g) in anhydrous acetonitrile (2 ml) were added 5-chloro-1-benzofuran-2-sulfonyl chloride (0.043 g) in acetonitrile (2 ml) and pyridine (0.057 ml), and the mixture was stirred at room temperature for 72 h. Saturated ammonium chloride solution (2 ml) was added and the resultant mixture stirred at room temperature for 20 min. The mixture was concentrated under reduced pressure and the residue partitioned between chloroform and hydrochloric acid (2M). The organic layer was washed with saturated sodium bicarbonate and brine. The organic layer was isolated, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.043 g) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][NH2:13])[N:7]=1)=[O:5].C(N(CC)CC)C.C[O:22][C:23](=O)[N:24]=[C:25](SC)[C:26]([C:40]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH2:49][CH2:50][F:51])[C:41]=1[F:52])=[N:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=[C:37]([CH3:39])[O:36][N:35]=2)=[CH:30][CH:29]=1>CN(C=O)C>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[C:23](=[O:22])[NH:24][C:25]([CH:26]([C:40]3[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH2:49][CH2:50][F:51])[C:41]=3[F:52])[NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]4[N:38]=[C:37]([CH3:39])[O:36][N:35]=4)=[CH:32][CH:33]=3)=[N:13]2)[N:7]=1)=[O:5]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCF)c1F
Reactant: COC(=O)c1cccc(NN)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-n2nc(C(Nc3ccc(-c4noc(C)n4)cc3)c3cc(OC)cc(OCCF)c3F)[nH]c2=O)n1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
After adding 149 mg of 6-hydrazinopyridine-2-carboxylic acid methyl ester hydrochloride and 92 μl of triethylamine to a solution of 255 mg of {2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (3e)) in 5 ml of DMF, the mixture was stirred at 85° C. for 24 hours under a nitrogen atmosphere.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[C:16](=O)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)=[O:4].[NH3:27]>CO.ClCCl>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[Cl:24])[CH2:17][C:16]1[C:7]2[CH:8]=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:6]=2[NH:5][C:3](=[O:4])[CH2:2][N:27]=1
Reactant: COc1cc(NC(=O)CBr)c(C(=O)Cc2ccc(Cl)c(Cl)c2)cc1OC
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1OC)C(Cc1ccc(Cl)c(Cl)c1)=NCC(=O)N2
Temperature: 40 °C
Yield: 35 %

Procedure:
2-Bromo-N-{2-[2-(3,4-dichloro-phenyl)-acetyl]-4,5-dimethoxy-phenyl}-acetamide (5.25 g, 11.39 mmol) was placed at −10° C. under nitrogen. Ammonia in methanol (7N, 55 ml) was added dropwise at −10° C. and the reaction mixture was heated at 40° C. for 2.5 h, and then at reflux (75° C.) for 1 h. The solvent was evaporated under vacuum yielding a yellow solid which was dissolved in dichloromethane and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. Flashchromatography (dichloromethane/methanol, 18/1) yielded the expected product as a yellow solid (1.5 g, 35%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)[CH3:2].[Br:30]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][C:10]=1[Br:30])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)Cc1nc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)sc1Br
Reaction time: 8 h
Yield: 21.9 %

Procedure:
To a solution of {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (0.05 g, 0.12 mmol) in 2 ml of acetonitrile was added N-bromosuccinimide (0.024 g, 0.13 mmol). The reaction mixture was stirred under nitrogen in a pressure bottle excluded from light overnight at 25° C. The mixture was diluted with 15 ml of DCM, washed (1N HCl, saturated NaHCO3, water), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound (0.013 g, 21%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>O1CCOCC1>[F:12][C:13]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:14]=1[C:15]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:16]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(F)cc1F
Yield: 84 %

Procedure:
Using a method similar to Preparation 13, using 4-fluoro-3-nitroaniline (1.0 g, 6.4 mmol), dioxane (20 mL), and 2,4-difluorobenzoyl chloride (1.46 g, 8.3 mmol) gives the title intertermediate (1.6 g, 84% yield): mass spectrum (ion spray): m/z=297.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28](O)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:32][N:33]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([NH:38][C@H:35]5[CH2:36][CH2:37][N:33]([CH3:32])[CH2:34]5)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CN1CC[C@H](N)C1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CC[C@H](NC(=O)c2ccc3c(n2)CCC2C3=NN(c3ccc(C#N)c(Cl)c3)C2C2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), the crude (S)-1-methylpyrrolidine-3-amine hydrochloride (0.235 g), DIEA (0.26 mL, 1.5 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 2 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to produce a crude yellow solid, which was washed with methanol to produce a purified product (0.13 g) in 25.8% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH2:35][CH:36]1[CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:36]1([CH2:35][O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]3[CH3:33])=[CH:6][CH:7]=2)[CH2:38][CH2:37]1
Reactant: BrCC1CC1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OCC3CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and (bromomethyl)cyclopropane (0.70 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 70° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.93 g, 83%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:18]1[N:22]3[CH:23]=[CH:24][C:25]([CH2:27][N:28]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:29]4=[O:38])=[CH:26][C:21]3=[N:20][N:19]=1)[CH:14]=[CH:13]2.Br[CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43]>CC(N(C)C)=O.CCOC(C)=O.O>[OH:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:18]1[N:22]3[CH:23]=[CH:24][C:25]([CH2:27][N:28]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:29]4=[O:38])=[CH:26][C:21]3=[N:20][N:19]=1)[CH:14]=[CH:13]2
Reactant: CC(C)(CO)CBr
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccn2c(-c3ccc4cccc(O)c4n3)nnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(CO)COc1cccc2ccc(-c3nnc4cc(CN5C(=O)c6ccccc6C5=O)ccn34)nc12
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Cs2CO3 (0.513 g, 1.57 mmol) was added to a solution of 2-((3-(8-hydroxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)isoindoline-1,3-dione (0.221 g, 0.524 mmol) and 3-bromo-2,2-dimethylpropan-1-ol (0.350 g, 2.10 mmol) in DMA (2 mL). The reaction was sealed and heated at 100° C. and stirred for 30 minutes. The reaction was cooled to ambient temperature and diluted with EtOAc/H2O (2:1). The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (eluting with a 20:1 mixture of DCM/MeOH), to afford the desired product.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26](=[O:28])N)[CH:24]=4)[NH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:29].[Na+].C(OCCOCCO)C>O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([OH:28])=[O:29])[CH:24]=4)[NH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: NC(=O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Agent: [Na+]
Solvent: O
Solvent: CCOCCOCCO
Product: O=C(O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Reaction time: 16 h

Procedure:
A mixture of 37.3 g of 3-[4-(4-phenyl-1,2,3,6tetrahydropyridyl)-butyl]-5-carbamoylindole, 27.1 g of NaOH, 525 ml of water and 450 ml of diethylene glycol monoethyl ether is boiled with stirring for 16 hours. The mixture is cooled, worked up in the customary manner and acidified to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylic acid, m.p. 284°-285°.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[C:18](O)=[O:19])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][N:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][OH:19])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)c1c(-c2c(Cl)cncc2Cl)noc1C1CCC1
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCc1c(-c2c(Cl)cncc2Cl)noc1C1CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a solution of 5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylic acid (808 mg, 2.59 mmol) in THF (13 mL) at 0° C. was added triethylamine (0.361 mL, 2.59 mmol) followed by isopropyl chloroformate (1 M in toluene, 2.59 mL, 2.59 mmol). The solution was stirred at 0° C. for approximately 1 hour and then was filtered into a solution of sodium borohydride (127 mg, 3.37 mmol) in water (1 mL) at 0° C. The solution was allowed to warm to ambient temperature and was then concentrated. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 0-40% ethyl acetate in hexanes gradient elution) to afford [5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methanol (478 mg, 62%). 1H-NMR (400 MHz, DMSO-d6) δ 8.79 (s, 2H), 4.97-4.94 (m, 1H), 4.16-4.15 (m, 2H), 3.92-3.83 (m, 1H), 2.40-2.30 (m, 4H), 2.10-2.01 (m, 1H), 1.99-1.89 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7]O)[CH3:5].[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][N:16]2S(C)(=O)=O)=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][N:16]2[CH2:7][CH2:6][N:4]([CH3:5])[CH3:3])=[CH:12][CH:11]=1
Reactant: CN(C)CCO
Reactant: CS(=O)(=O)n1ccc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)CCn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
To a powdered suspension of NaH (55 mg, 4.8 mmol) in toluene (4 mL) was added 2-(N,N-dimethylamino)ethanol (321 mg, 3.6 mmol). The mixture was stirred for 10 minutes, after which compound (i), above, (751 mg, 2.4 mmol) was added and the mixture refluxed 16 h. The mixture was allowed to cool to room temperature and then diluted with CH2Cl2. The organic extract was washed with water and brine and dried over anhydrous Na2SO4. The crude residue was purified by flash chromatography to give the title product as a white solid (390 mg, 61% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].C([O:23][CH2:24][CH3:25])C>CCCCCC>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[CH:24]([OH:23])[CH2:25][CH2:19][CH2:18][CH2:17][C:16]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[N:13]1
Reactant: COc1ccc(C2=NC(C)(C)CO2)cc1
Reactant: [Li]CCCC
Reactant: CCOCC
Solvent: CCCCCC
Product: COc1ccc(C2=NC(C)(C)CO2)c(C(O)CCCCc2ccccc2)c1
Reaction time: 4 h
Yield: 35 %

Procedure:
A solution of 2-(4-methoxy-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (1.85 g, 9 mmoles), prepared as described in example 1, in dry ethyl ether (37 ml), at 0° C. was added with 2.5M n-butyl lithium (4 ml, 9.9 mmoles) in hexane, keeping the temperature below 5° C. The mixture was left at 0° C. for 4 hours, then dropwise added with a solution of 5-phenyl-pentanale (3.25 g, 20 mmoles) in dry ethyl ether (10 ml), keeping the temperature below 5° C. The mixture was kept at room temperature for 2 days, then poured into water/ice. The phases were separated and the aqueous one was extracted again with ethyl ether. The organic ones were discoloured with charcoal, anhydrified and concentrated to give an oil which was purified by flash chromatography (eluent: petrolatum/ethyl acetate 8:2, then 7:3) to give 1.17 g of the title compound (yield: 35%).
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([O:33]C)=[O:32])=[C:27]([F:35])[CH:26]=4)[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12.O1CCCC1.Cl>CO.O>[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[C:27]([F:35])[CH:26]=4)[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12
Reactant: COC(=O)c1ccc(-c2c(C)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Lithium hydroxide, monohydrate (13 mg, 0.31 mmol) was added to a solution of methyl 3′-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylate made above (0.030 g, 0.062 mmol) in methanol (0.2 mL)/tetrahydrofuran (0.2 mL)/water (0.09 mL). The reaction was stirred at room temperature for 1.5 h, then treated with conc. HCl (60 uL) to adjust pH to 2, The solvent was removed to provide the crude product which was used in next step without further purification. LCMS calculated for C23H22ClFN5O3 (M+H)+: m/z=470.1; Found: 470.2
Reaction SMILES: C(OP([CH2:9][C:10]1[S:11][C:12]([Br:15])=[CH:13][CH:14]=1)(=O)OCC)C.[H-].[Na+].[CH3:18][C:19]([CH3:21])=O.O>O1CCCC1>[Br:15][C:12]1[S:11][C:10]([CH:9]=[C:19]([CH3:21])[CH3:18])=[CH:14][CH:13]=1
Reactant: CCOP(=O)(Cc1ccc(Br)s1)OCC
Reactant: CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=Cc1ccc(Br)s1
Temperature: 25 °C
Yield: 2.7 %

Procedure:
(5-Bromothiophen-2-ylmethyl)phosphonic acid diethyl ester described in Preparation Example 142 (3.13 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL), sodium hydride (0.40 g, 10 mmol, 60% in oil) was added to this solution under stirring at room temperature. The solution was stirred for 30 minutes at 60° C., then, acetone (1 g, 17.2 mmol) was added, and the solution was further stirred for 30 minutes. Water (100 mL) was added to the reaction solution, which was then extracted with hexane (50 mL), the organic layer was washed with water, dried over anhydrous magnesium sulfate, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane), and the title compound (60 mg, 0.27 mmol, 2.7%) was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Br)cc2)cc1-c1c(Br)cnn1C
Yield: 72.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 4-bromophenyl isocyanate (0.022 g, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 5 (0.040 g, 0.08 mmol, 75%) as a white solid. LCMS m/z (%)=479 (M+H79Br79Br, 51), 481 (M+H79Br81Br, 100), 483 (M+H81Br81Br, 50). 1H NMR (400 MHz, acetone-d6) δ: 8.22 (s, 1H), 8.14 (s, 1H), 7.68 (dd, J=2.7, 9.0 Hz, 1H), 7.48-7.54 (m, 313), 7.39-7.46 (m, 3H), 7.14 (d, J=9.0 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)[CH2:6]2)#[N:2].[ClH:25]>O1CCOCC1>[Cl-:25].[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:12]1[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]1)[CH2:6]2)#[N:2]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C2Cc3ccc(C#N)cc3C2)CC1
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)CC(N1CC[NH2+]CC1)C2
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 4 mL reaction vial, was added tert-butyl 4-(5-cyano-2,3-dihydro-1H-inden-2-yl)piperazine-1-carboxylate. To above vial was added 4 N HCl in dioxane (1 mL), let stirred at RT for 2 hr. The reaction mixture was concentrated to give the desired product. LC-MS (IE, m/z): 228.3 [M+1]+.