Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][N:11]([C:21](=[O:24])[CH2:22]Cl)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:39])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:8][C:9](=[O:25])[CH2:10][N:11]([C:21](=[O:24])[CH2:22][N:31]([CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: O=C(CN(C(=O)CCl)C1Cc2ccccc2C1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CN(CC(=O)N(CC(=O)OCc1ccccc1)C1Cc2ccccc2C1)Cc1ccccc1
Yield: 69.5 %

Procedure:
N-Chloroacetyl-N-(indan-2-yl)glycine benzyl ester (3 g) and 2 g of N-benzylglycine ethyl ester are dissolved in 50 ml of methyl ethyl ketone, 10 g of potassium carbonate is added, and the mixture is refluxed for 24 hours with stirring. After cooling, the insoluble matter is filtered off, and the filtrate is distilled under reduced pressure to give an oil. This is purified by silica gel column chromatography to give 3 g of N-ethoxycarbonylmethyl-N-benzylglycyl-N-(indan-2-yl)glycine benzyl ester as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:29]=[C:30]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)[CH:31]=[CH:32][CH:33]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:42]1([C@@H:48]2[CH2:52][CH2:51][NH:50][CH2:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:50]4[CH2:51][CH2:52][C@@H:48]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:49]4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:29]=[C:30]([N:34]3[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]3)[CH:31]=[CH:32][CH:33]=2)[CH:17]=1
Reactant: c1ccc([C@@H]2CCNC2)cc1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)c2)S(=O)(=O)N1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CC[C@@H](c6ccccc6)C5)cc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (134 mg, 0.2 mmol) was treated as described in general procedure R using excess (S)-3-phenyl-pyrrolidine (147 mg, 1 mmol) to give the desired compound 5-(3-{4-(2,4-dichloro-phenyl)-2-{4′-[(3S)-3-phenyl-pyrrolidin-1-yl]-biphenyl-4-ylmethyl}-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1, 1-dioxide.
Reaction SMILES: [C:1]1([CH2:14][OH:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[C:25]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[C:1]1([CH2:14][O:15][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2c1Cc1ccccc1-2
Reactant: O=C1CCCC(=O)O1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: O=C(O)CCCC(=O)OCc1cccc2c1Cc1ccccc1-2
Reaction time: 8 h

Procedure:
Fluorenylmethanol (0.90 g, 4.5 mmol) and dimethylaminopyridine (50 mg) are dissolved in 10 ml dry pyridine. Glutaric anhydride (5.0 mmol) is added and the solution stirred overnight. The solvent is removed under reduced pressure, sodium bicarbonate added (50 ml), the solution extracted with ethyl acetate (50 ml), and the organic layer discarded. The aqueous layer is acidified to pH 2, extracted with ethyl acetate (2×100 ml), washed with brine, and the solvent removed under reduced pressure. The residue is purified by flash chromatography to give the product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.[OH:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[S:18]>C(O)C>[OH:13][CH2:14][CH2:15][NH:16][C:17]1[S:18][CH:2]=[C:3]([C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[N:19]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: NC(=S)NCCO
Solvent: CCO
Product: N#Cc1ccc(-c2csc(NCCO)n2)cc1
Yield: 39 %

Procedure:
In the same manner as described in step 3 of Example 81, a solution of 4-(2-bromo-acetyl)-benzonitrile (3.8 g, 17.1 mmol) and (2-hydroxy-ethyl)-thiourea, prepared in the previous step, in 50 mL of ethanol was heated at reflux for 2 h. The reaction was concentrated to a residue. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 6.2 g of crude product. The crude product was purified on silica gel using a stepwise gradient of 3:1 to 2:1 hexane:ethyl acetate to give 4-{2-[(2-hydroxyethyl)amino]-1,3-thiazol-4-yl}benzonitrile (1.6 g, 39%), mp 80-82° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Br:4][C:5]1[C:10]([N:11]([CH3:21])[C:12]([C:14]2[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:9][CH:8]=[C:7]([O:22][CH3:23])[N:6]=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Br:4][C:5]1[C:10]([N:11]([CH3:21])[C:12]([C:14]2[C:15]([NH:3][CH2:1][CH3:2])=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:9][CH:8]=[C:7]([O:22][CH3:23])[N:6]=1
Reactant: CCN
Reactant: COc1ccc(N(C)C(=O)c2cccnc2Cl)c(Br)n1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCNc1ncccc1C(=O)N(C)c1ccc(OC)nc1Br
Temperature: 150 °C
Yield: 77.1 %

Procedure:
Ethylamine (0.7 g) was added to a solution of N-(2-bromo-6-methoxy-3-pyridinyl)-2-chloro-N-methyl-3-pyridinecarboxamide (1.9 g) in xylene (5 ml), and the resulting mixture was sealed in a pressure bottle and heated at 150° C. for 4 hours. The solution was diluted with ethyl acetate, washed with water, dried (anhydrous magnesium sulfate), concentrated, and purified on a silica gel column (ethyl acetate/hexane, 1:4) to give 1.5 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([O:13][C:14](=[O:23])[NH:15][CH:16]1C[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([N:15]1[CH2:16][CH2:17][CH2:18][N:19]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH2:20][CH2:21]1)=[O:23])([CH3:10])([CH3:11])[CH3:12]
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)NC1CCCNCC1
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(Br)n2)CC1

Procedure:
The preparation is carried out analogously starting from 1.02 g (4.31 mmol) of 2,6-dibromopyridine and 856 mg (4.27 mmol) of azepan-4-ylcarbamic acid tert-butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-])=O.Cl.Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[N:18]1[CH:19]=[CH:20][C:15]([N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)=[CH:16][CH:17]=1
Reactant: Clc1ccncc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2c(ccn2-c2ccncc2)c1
Temperature: 100 °C
Yield: 58.6 %

Procedure:
To a solution of 5-nitroindole (7.0 g, 43.2 mmol) and 4-chloropyridine hydrochloride (7.8 g, 51.8 mmol) in DMF (43 mL) was added potassium tert-butoxide (12.1 g, 108.0 mmol), portionwise. The reaction was heated at 100° C. for 48 h. The mixture was allowed to cool to room temperature and poured into water (400 mL). The resulting solid was removed by filtration and dried under vacuum. Desired compound (6.04 g, 25.3 mmol; 58% yield); 1H NMR (DMSO-d6) δ 8.76 (dd, J=1.7, 4.5, 2H), 8.68 (d, J=2.2, 1H), 8.06-8.13 (m, 2H), 7.92 (d, J=9.2, 1H), 7.75 (dd, J=1.5, 4.6, 2H), 7.07 (dd, J=0.9, 3.5, 1H); ES MS [M+H]+=240. Step 2. Preparation of 1-(4-pyridinyl)-1H-indol-5-amine
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[CH2:11][CH:12]([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:22]([N:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[C:10](=[O:19])[CH2:11][CH:12]([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CC(C)CC(=O)Nc1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(C)CC(=O)N(Cc1ccccc1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
To a solution of the compound obtained in Step 1 (228 mg, 0.88 mmol) in DMF (6 mL) was added sodium hydride (60% in oil, 126 mg, 2.63 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 min, and benzyl bromide (0.156 mL, 1.31 mmol) was added thereto at 0° C. The reaction mixture was stirred at room temperature for 14 hr, to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 85% ethyl acetate/hexane) to give methyl 5-(benzyl(4-cyanophenyl)amino)-3-methyl-5-oxopentanoate (81 mg, 0.230 mmol, 26.3%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].Cl.[CH3:23]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:21])[C:18](=[CH2:23])[CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCCC(=O)c1ccc(OCCCCC(=O)O)c(Cl)c1Cl
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C(CC)C(=O)c1ccc(OCCCCC(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-(2,3-Dichloro-4-butyrylphenoxy)valeric acid (9.8 g, 0.029 mole), dimethylamine hydrochloride (15 g, 0.184 mole), paraformaldehyde (2.8 g, 0.09 equivalent) and acetic acid (1 ml) were united and stirred and heated on a steam bath for 3 hours. N,N-dimethylformamide (30 ml) was added and stirring and heating continued for another two hours. The reaction mixture was then poured into ice water and the solid that separated was removed by filtration, washed with water and dried. After recrystallization from butyl chloride the 5-[2,3-dichloro-(2-methylenebutyryl)phenoxy]valeric acid (5.4 g) melted at 107°-109° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH3:20])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:21]N(C=NC=[N+](C)C)C.[Cl-].C([O-])(=O)C.[Na+].C(O)(=O)C>O1CCOCC1>[CH2:12]([O:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][CH:21]=[N:1]2)=[CH:7][C:8]=1[O:19][CH3:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C=NC=[N+](C)C
Reactant: COc1cc(C(N)=O)c(N)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Yield: 77 %

Procedure:
A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10 g, 0.04 mol), (J. Med. Chem. 1977, vol 20, 146–149), and Gold's reagent (7.4 g, 0.05 mol) in dioxane (100 ml) was stirred and heated at reflux for 24 hours. Sodium acetate (3.02 g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol) were added to the reaction mixture and it was heated for a further 3 hours. The volatiles were removed by evaporation, water was added to the residue, the solid was collected by filtration, washed with water and dried. Recrystallisation from acetic acid gave 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84%).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4](O)=[O:5])[CH3:3]>O1CCCC1>[C:10]([O:9][C:7](=[O:8])[NH:1][C@H:2]([CH3:3])[CH2:4][OH:5])([CH3:13])([CH3:11])[CH3:12]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: C[C@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A solution of Boc-D-Ala—OH (1.0 g, 5.28 mmol) in tetrahydrofuran (10 ml) was added dropwise to a stirred solution of BH3, 1 M in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred for a further hour at 0° C., then quenched with 10% acetic acid in methanol. After solvent evaporation, the crude product was dissolved in ethyl acetate and washed with 1M HCl, water and then 1M sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield 0.39 g, 42%: NMR 1H (300 MHz, CDCl3): 0.97 (d, 3H), 1.36 (s, 9H), 3.14 (m, 1H), 3.29 (m, 1H), 3.40 (m, 1H), 4.57 (m, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:34][CH2:33][N:32]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:31]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C2CCNC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: O=C(O)C(=O)O
Product: COc1ccc(C2CCN(C(=O)c3cnoc3-c3ccc(C)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-methoxyphenyl)pyrrolidine oxalat (16.0 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.3 mg). Calcd for C22H22N2O3: 362.1630, found 362.1636.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:4]=1[CH:5]=O.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:4]=1[CH:5]=[N:14][OH:15]
Reactant: COc1ccc(F)c(F)c1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(F)c1C=NO
Reaction time: 16 h
Yield: 88.5 %

Procedure:
At 20-25° C., a solution of 29.4 g of 2-methoxy-5,6-difluorobenzaldehyde (according to Ex. 27 of WO 97/03071) was added dropwise with stirring to a mixture of 16.0 g of hydroxylamine hydrochloride, 18.9 g of sodium acetate and 110 ml of 90% strength aqueous methanol. The mixture was stirred for 16 hours, the methanol was evaporated, the mixture was made into a paste using 250 ml of water and then washed and dried, giving 28.3 g of the desired product of m.p. 199-201° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][C:11]1[N:12]([CH3:25])[N:13]=[C:14]2[C:23]=1[C:22]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=1[N:16]=[C:15]2[NH2:24].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>ClCCl>[NH2:24][C:15]1[C:14]2=[N:13][N:12]([CH3:25])[C:11]([CH2:10][CH2:9][NH:8][C:32]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:33])=[C:23]2[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N:16]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cn1nc2c(N)nc3c(c2c1CCN)CCCC3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nc2c(N)nc3c(c2c1CCNC(=O)N1CCOCC1)CCCC3
Temperature: 4 °C

Procedure:
Triethylamine (2.84 mL, 20.4 mmol) was added to a suspension of 1-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 50) (1.0 g, 4.08 mmol) in dichloromethane (50 mL) and cooled to 4° C. 4-Morpholinecarbonyl chloride (0.61 g, 4.08 mmol) was added in dichloromethane (5 mL) dropwise over 5 minutes to the reaction mixture and maintained at ambient temperature for 16 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed sequentially with water (50 mL), 4% sodium bicarbonate (2×50 mL), water (50 mL), and brine (50 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified via column chromatography on silica gel (80 g, eluting with mixtures of chloroform and CMA). The material was crystallized from acetonitrile to provide N-[2-(4-amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]morpholine-4-carboxamide as orange needles, mp 187-188° C.
Reaction SMILES: [CH2:1](C([SnH3])=C(CCCC)CCCC)[CH2:2]CC.Br[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[C:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=[C:20]2[O:35][C@H:36]1[CH2:40][N:39](C(OC(C)(C)C)=O)[C@H:38]([C:48]([O:50][CH3:51])=[O:49])[CH2:37]1.[ClH:52]>C1(C)C=CC=CC=1.O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[ClH:52].[CH3:28][O:27][C:26]1[CH:25]=[C:24]2[C:19]([C:20]([O:35][C@H:36]3[CH2:40][NH:39][C@H:38]([C:48]([O:50][CH3:51])=[O:49])[CH2:37]3)=[CH:21][C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:23]2)=[CH:18][C:17]=1[CH:1]=[CH2:2]
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: C=Cc1cc2c(O[C@H]3CN[C@H](C(=O)OC)C3)cc(-c3ccccc3)nc2cc1OC
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Tributylvinylstannane (1.15 eq.) and tetrakis(triphenylphosphine) palladium(0) (0.07 eq.) were added to a solution of compound 116 in toluene (0.09 M) and the reaction mixture was heated at 100° C. After 20 h volatiles were removed in vacuo and the residue was purified by column chromatography (SiO2, PE:EtOAc with EtOAc from 1 to 60%) to give a pale yellow solid, that was taken up in a 4N solution of HCl in dioxane (0.31 M). The reaction mixture was stirred for 1 h and the resulting white solid recovered by filtration, washed with EtOAc/petroleum ether affording the title compound 117 (99%) as a pale yellow solid. MS (ES+) m/z 405 (M+H)+.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][O:29][CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[N:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:35]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[O:29][CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ncn3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ncn3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-(4-[6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-ylcarbonyl)cyclopentanamine (120 mg, 0.30 mmol), 3-methoxytetrahydro-4H-pyran-4-one (120 mg, 0. 90 mmol), and triethylamine (0.12 mL, 0.90 mmol) in methylene chloride (20 mL) was added sodium triacetoxyborohydride (0.19 g, 0.90 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography to provide the desired product as a mixture of four isomers. LCMS calculated for C24H37F3N5O3:(M+H) 500.3; found 500.3 for four isomers.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:14][CH:13]=2)=[N:3]1.ClC(OCC(C)C)=O.C([N:33](CC)CC)C.[NH4+]>C1COCC1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([NH2:33])=[O:22])=[CH:14][CH:13]=2)=[N:3]1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1ccc(-c2nc(=O)c3ccccc3s2)nc1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC(=O)CCc1ccc(-c2nc(=O)c3ccccc3s2)nc1
Reaction time: 1 h
Yield: 54.6 %

Procedure:
3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propionic acid (0.31 g, 1.00 mmol), isobutyl chloroformate (0.22 ml, 1.50 mmol) and triethylamine (0.22 ml, 1.50 mmol) were dissolved in THF (10 ml), and the mixture was stirred under ice cooling condition for 1 hr. 25% aqueous ammonium solution was added to the mixture, and the mixture was stirred under ice cooling condition for 0.5 hr. The obtained precipitates were recrystallized from ethanol to give the titled compound (0.17 g, 55%) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
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: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2cncc(Cl)c2N2CCC(C(N)=O)CC2)cc1
Yield: 29.6 %

Procedure:
General procedure D (See Example 4) was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (24 mg, 0.088 mmol), 4-methoxybenzene boronic acid (16 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative hplc (CH3CN, H2O, 23:77) to furnish the title compound as a white solid (9 mg, 30%), LC-MS (ESI) Rt 1.67 min, m/z 346 (100%, [M+H]+); m/z (ESI) C18H21ClN3O2 requires 346.1317 found [M+H]+ 346.1317.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[CH3:17].I[CH2:19][CH2:20][CH3:21].O>CS(C)=O>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10](=[O:14])[N:11]2[CH2:19][CH2:20][CH3:21])=[CH:6][C:5]=1[CH3:17]
Reactant: CCCI
Reactant: Cc1cc2c(cc1Br)NC(=O)CC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 115.2 %

Procedure:
A mixture of powdered potassium hydroxide (1.26 g, 22.38 mmol) in DMSO (40 mL) was stirred at 0° C. for 10 min. 7-bromo-4,4,6-trimethyl-3,4- dihydro-1H-quinoline-2-one (Example 1e) (3.0 g, 11.19 mmol) was added cautiously, followed immediately by the addition of 1-iodopropane (5.5 mL, 55.95 mmol). The reaction mixture was warmed up to room temperature and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane washed with water and brine, dried (MgSO4), filtered and evaporated to give 4.0 g of 7-bromo-1-propyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one and used without further purification in the Suzuki coupling (step a). 1H NMR (300 MHz; CDCl3): 0.98 (t, J=7.5 Hz,1 H), 1.26 (s, 6 H), 1.65 (t, J=7.5 Hz, 1 H), 2.37 (s, 3 H), 2.46 (s, 2 H), 3.88 (t, J=7.8 Hz, 2 H), 7.13 (s, 1 H), 7.15 (s, 1 H).