Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:23][C:24]1[CH:29]=[C:28]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])=[CH:16][CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)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: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2cccc(Cl)c2)cc1
Yield: 65.2 %

Procedure:
3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.047 g (65%) of 3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:9](OCC)=[O:10].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: CCOC(=O)c1ccc(OC)c(OCc2c(C)cccc2C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1OCc1c(C)cccc1C
Reaction time: 4 h

Procedure:
To a solution of Ethyl 3-(2,6-dimethylbenzyloxy)-4-methoxybenzoate (Step B, 6.04 g, 19.23 mmol) in dry THF (30 ml) was added drop wise LiAlH4 (1M in THF, 0.803 g, 21.16 mmol) at 0° C. under argon. The reaction mixture was stirred for 4 hours or until all the starting material is consumed, then quenched slowly with 0.1N HCl, EtOAc (20 ml) was added to the reaction mixture. The reaction mixture was filtered and precipitate was washed with EtOAc (25 ml×2). The combined organic layer was washed with 0.1N HCl, brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3[F:28])=[O:9])=[CH:4][CH:3]=1.[C:31]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:28])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:31])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CN3CCOCC3)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(F)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide, (can be prepared according to the procedure described in PCT patent application, W099/32450) (147 mg) in anhydrous DMF (3 mL) is added K2CO3 (71.2 mg) followed by CH3I (0.026 mL). The reaction mixture is stirred at room temperature for 30 min, then poured into H2O (40 mL) to precipitate the product. The solid is collected, adsorbed onto silica, and chromatographed (1% MeOH in CH2Cl2 (2L)). Fractions homogenous by TLC are combined and concentrated to afford 55.3 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].[CH:18](NC(=O)C)([NH:25][C:26](=[O:28])[CH3:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.P(Cl)(Cl)(Cl)=O.O>C(Cl)Cl>[C:26]([NH:25][CH:18]([C:8]1[C:7]([OH:12])=[CH:6][C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])=[CH:11][C:9]=1[OH:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)NC(NC(C)=O)c1ccccc1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCC(C)C(C)c1cc(O)c(C(NC(C)=O)c2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 26.1 %

Procedure:
A stirred solution-suspension of 11.8 g (0.05 mol) of 5-(3-methyl-2-octyl)-resorcinol (4) (65% dl-erythro and 35% dl-threo) and 10.7 g (0.052 mol) of N,N'-benzylidenebisacetamide (2) in 60 ml of methylene chloride cooled to 2° in an ice bath was treated dropwise with 4.9 ml (0.05 mol) of phosphorus oxychloride over a period of 5 to 10 minutes. The stirring was continued in the melting ice bath. A clear solution formed after 2 to 2.5 hours and precipitation of produce occurred after 3 to 3.5 hours. After being stirred at room temperature overnight, the reaction mixture was treated with water (40 ml) and more methylene chloride (70 ml). After the slight exothermic reaction was complete, the organic layer containing suspended product was separated and washed successively with water (2 × 100 ml), 5% sodium bicarbonate (100 ml), and water (100 ml). Filtration of the organic layer gave 5.00 g of colorless crystalline powder, mp 204-208°. Concentration of the filtrate and cooling gave 2.58 g, mp 196-199°, as a second crop (7.58 g = 40% yield). Concentration to dryness left 10.8 g of an amorphous glassy solid which could not be crystallized. Its pmr spectrum was similar to that of the crystalline fraction, suggesting it consisted of a mixture of stereoisomers. Recrystallization from acetonitrile of a sample of the 7.58 g to constant mp gave pure 2-(α-acetylaminobenzyl)-5-(3-methyl-2-octyl)-resorcinol (6) mp 209°-210° (probably a single stereo-isomer); ir (Nujol) 3400 (νNH or OH), 3200 (broad, ν bonded OH), and 1610 cm-1 (νC=O); pmr (DMSO-d6) δ 9.0 -9.8 (m, 2H, OH), 7.98 (d, 1H, J = 9 Hz, NH), 7.0 - 7.5 (m, 5H, C6H5), 6.64 (d, 1H, J = 9 Hz, Ar2CHNH), 6.18 (s, 2H, C6H2) and 1.92 ppm (s, 3H, CH3CO); m/e (M+) 383.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:19][CH2:20]/[C:21](/B1OC2C=CC=CC=2O1)=[CH:22]\[CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH3:19][CH2:20]/[C:21](/[C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1)=[CH:22]\[CH2:23][CH3:24]
Reactant: CC/C=C(\CC)B1Oc2ccccc2O1
Reactant: Cn1c(=O)[nH]c2ccnc(Br)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC/C=C(\CC)c1nccc2[nH]c(=O)n(C)c12
Temperature: 90 °C
Yield: 57.6 %

Procedure:
A mixture of 0.68 g (3.0 mmol) of 4-bromo-3-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one and 0.17 g (0.20 mmol) of PdCl2dppf-dichloromethane complex was dissolved in 12 mL of toluene and treated with 3.8 mL (7.7 mmol) of 2N sodium carbonate and 0.72 g (3.6 mmol) of (Z)-2-(hex-3-en-3-yl)benzo[d][1,3,2]dioxaborole. The resulting mixture was heated to 90° C. for 5 h, partitioned between water and ethyl acetate, filtered to remove fine precipitates and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The brown oil thus obtained was purified by flash chromatography eluting with a 25% methanol/dichloromethane mixture to give 0.40 g (58%) of the title compound as a cream colored solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:21](=[O:22])[C:20]5=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]5[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH:21]([OH:22])[C:20]5[C:19](=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C1c2ccccc2C(O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a suspension of N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimide (7.8 g, 19.8 mmol) in methanol (250 ml) and DCM (30 ml) was added NaBH4 (1.7 g, 45.5 mmol) at room temperature under nitrogen. After stirring for 0.5 hours the homogeneous reaction mixture was concentrated. The remaining solid was purified on a flash chromatography column (SiO2, 1:1 EtOAc/DCM, increased to 10% MeOH) to give 7.0 g (90%) of the desired product as a solid which was recrystallized from EtOAc, m.p.=172°-173° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]([O:40]C)=[O:39])=[C:32]([CH3:42])[CH:31]=3)=[CH:20][CH:19]=2)=[CH:8][C:7]=1[CH3:43].[OH-].[Na+].O.Cl>C(O)C.C1COCC1>[CH3:1][O:2][C:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]([OH:40])=[O:39])=[C:32]([CH3:42])[CH:31]=3)=[CH:20][CH:19]=2)=[CH:8][C:7]=1[CH3:43])=[O:44]
Reactant: COC(=O)COc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(OCC(=O)OC)c(C)c3)cc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(OCC(=O)O)c(C)c3)cc2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a solution of (E)(E) [4-(5-{4-[5-(4-methoxycarbonylmethoxy-3-methyl-phenoxy)-pent-3-en-1-ynyl]-phenyl}-pent-2-en-4-ynyloxy)-2-methyl-phenoxy]-acetic acid methyl ester (example 17) (15 mg, 0.025 mmol) in ethanol (15 mL) and THF (5 mL) was added 1N sodium hydroxide (1.0 mL). After stirring at room temperature for 30 min., the reaction mixture was added water and 1N hydrochloride acid to pH 1. The product was extracted with dichloromethane (×3) and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give 10 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:6](Cl)=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:10].[Br:25]C1C=C(C(O)=O)NC=1C>>[Br:25][C:6]1[CH:2]=[C:3]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[O:10])[NH:4][C:5]=1[CH3:8]
Reactant: Cc1[nH]c(C(=O)O)cc1Br
Reactant: Cc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1Cl
Product: Cc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Intermediate 2, starting from 4-bromo-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 18).
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([CH2:24][CH3:25])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=O)[CH3:2].[CH2:26]([SH:29])[CH2:27][CH3:28].C[Si](Cl)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:24]([C:14]1[CH:15]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:22])[Cl:23])[CH:17]=[C:3]([CH2:1][CH3:2])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([S:29][CH2:26][CH2:27][CH3:28])[S:29][CH2:26][CH2:27][CH3:28])[CH3:25]
Reactant: CCCS
Reactant: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=O
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCSC(COCCCCOc1c(CC)cc(OCC=C(Cl)Cl)cc1CC)SCCC
Temperature: 25 °C
Yield: 38.1 %

Procedure:
To a mixture of 0.39 g of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde, 0.16 g of 1-propanethiol and 10 ml of chloroform was slowly added dropwise 0.16 g of trimethylsilyl chloride with stirring at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was poured into 5% aqueous sodium carbonate solution and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.20 g of 3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-di(propylthio)ethoxy)butyloxy)benzene (yield, 41%), nD26.4 1.5300.
Reaction SMILES: [C:1]1([C:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])([CH3:9])C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][C@H](N)CC1C=CC=CC=1.C1([C@H](N)CC)C=CC=CC=1.C1([C@@H](N)CC)C=CC=CC=1>>[C:1]1([CH:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[CH2:9][CH3:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](N)Cc1ccccc1
Reactant: CC(C)(Nc1nc(N)c2ncn([C@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Agent: CC[C@@H](N)c1ccccc1
Agent: CC[C@H](N)c1ccccc1
Product: CCC(Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Temperature: 130 °C
Reaction time: 4.5 h

Procedure:
In Scheme A, step b, the acetonide (2) is then treated with an appropriately substituted primary amine to provide the secondary amine of structure (3). More specifically, the acetonide (2) is combined with a large excess of an appropriately substituted primary amine, such as L-(-)-amphetamine, D-(+)-amphetamine, (R)-1-phenylpropylamine or (S)-1-phenylpropylamine, under an atmosphere of an inert gas such as nitrogen. The mixture is then heated to approximately 130° C. with stirring for approximately 3 to 6 hours. After cooling, the product can be isolated and purified by techniques well known to one skilled in the art. For example, the crude mixture can be directly purified by flash chromatography followed by radial chromatography using an appropriate eluent such as 3% to 6% methanol/chloroform to provide the secondary amine (3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[NH:17])[NH2:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl([O-])(=O)(=O)=O.[CH3:23][NH2+:24][CH3:25].C[O-].[Na+]>C(O)CC.CO>[CH3:23][N:24]([CH:10]=[N:9][C:6]1[CH:5]=[N:17][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[N:16][CH:7]=1)[CH3:25]
Reactant: C[NH2+]C
Reactant: COc1ccc(N2CCN(C(=N)N)CC2)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CCCO
Product: COc1ccc(N2CCN(c3ncc(N=CN(C)C)cn3)CC2)cc1
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a mixture of 20 g of 4-(4-methoxyphenyl)-1-piperazinecarboximidamide and 21 g of N-[3-(dimethylamino)methylene]amino]-2-propenylidene]-N-methylmethanaminium perchlorate in 200 ml of 1-propanol were added dropwise 70 ml of a solution of sodium methoxide in methanol (1M). After stirring for 2 hours there were added dropwise again 70 ml of a solution of sodium methoxide in methanol (1M). Then the mixture was stirred and refluxed for 2 hours. After cooling, the reaction mixture was evaporated and the residue was purified by column chromatography (eluent: CH2Cl2 /CH3OH 97:3). The eluent of the desired fraction was evaporated, yielding 15 g (62.5%) of N-[(dimethylamino)methylene]-2-[4-(4-methoxyphenyl)-1-piperazinyl]-5-pyrimidinamine (interm. 24);
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][CH:5]([CH3:14])[CH2:6][C:7]2=[O:13].C([Sn](CCCC)(CCCC)[C:20]1[S:21][CH:22]=[CH:23][N:24]=1)CCC>O1CCOCC1.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>[OH:12][C:9]1[CH:10]=[CH:11][C:2]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[C:3]2[C:8]=1[C:7](=[O:13])[CH2:6][CH:5]([CH3:14])[CH2:4]2
Reactant: CC1CC(=O)c2c(O)ccc(Br)c2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC1CC(=O)c2c(O)ccc(-c3nccs3)c2C1
Yield: 61.1 %

Procedure:
A solution of 5-bromo-8-hydroxy-3-methyl-1,2,3,4-tetrahydronaphthalen-1-one (3.0 g, 0.012 mol) and 2-(tri-n-butylstannyl)thiazole (6.4 g, 0.17 mol) in dioxan (100 mL) was degassed with nitrogen for 30 min. Tetrakis(triphenylphosphine)palladium(0) (1 g) was added and the mixture heated at reflux for 48 h. The solvent was evaporated and the residue chromatographed on silica gel, eluting with EtOAc:hexane (1:4). The title compound (1.9 g, 62%) was isolated as a yellow oil. 1H NMR (360 MHz, CDCl3) δ 1.13 (3H, d, J=6.5 Hz), 2.20-2.34 (1H, m), 2.39-2.47 (1H, m), 2.73-2.83 (2H, m), 3.34-3.49 (1H, m), 6.90 (1H, d, J=8.8 Hz), 7.40 (1H, d, J=3.3 Hz), 7.73 (1H, d, J=8.8 Hz), 7.89 (1H, d, J=3.3 Hz), 12.93 (1H, s). MS (ES+) 260 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.[CH3:41][NH:42][O:43][CH3:44]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:42]([O:43][CH3:44])[CH3:41])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: CNOC
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To the solution of compound 4-bromo-2-methylbenzoic acid D-1 (50 g, 0.23 mol) in DCM (500 mL) was added EDCI (48 g, 0.25 mol), HOBt (34.1 g, 0.25 mol), NMM (50.5 g, 0.50 mol) and N,O-dimethylhydroxylamine hydrochloride (24.3 g, 0.25 mol). The reaction mixture was stirred at room temperature overnight, diluted with DCM, washed with H2O (300 mL), 1 N HCl (300 mL), and saturated sodium bicarbonate solution (300 mL), dried over sodium sulfate, and concentrated to give the desired product D-2 (55 g, yield 91.6%) as yellow oil.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.Br[CH2:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[CH3:10][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:23][CH2:24][C:25](=[O:26])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCBr
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1ccc(N2CCC(=O)N2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19455.8 %

Procedure:
10 g of p-tolylhydrazine hydrochloride are dissolved in 100 ml of anhydrous CH2Cl2. The solution is cooled to 0° C. and 19 ml of DBU and then 6.5 mg of 3-bromopropionyl chloride are added. The mixture is stirred at ambient temperature for one hour. The reaction medium is poured onto water, extraction is carried out with CH2Cl2 and then purification is carried out by chromatography on a silica column eluted with an AcOEt/petroleum ether (v/v; 50/50) mixture. 1.3 g of crystals are obtained.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:36]=[CH:35][N:14]3[C:15](=[O:34])[C:16](/[CH:25]=[CH:26]/[C:27]([O:29]C(C)(C)C)=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[C:12]=2[O:37][CH3:38])[S:7][CH:8]=1)([CH3:3])[CH3:2]>FC(F)(F)C(O)=O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:36]=[CH:35][N:14]3[C:15](=[O:34])[C:16](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[C:17]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[N:18]=[C:13]3[C:12]=2[O:37][CH3:38])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1c(CCc2nc(C(C)C)cs2)ccn2c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N3CCOCC3)nc12
Solvent: O=C(O)C(F)(F)F
Product: COc1c(CCc2nc(C(C)C)cs2)ccn2c(=O)c(/C=C/C(=O)O)c(N3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
The tert-butyl (E)-3-{8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-9-methoxy-2-morpholino-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (209 mg) obtained in (I) was dissolved in trifluoroacetic acid (2 ml) and stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to obtain the title compound (180 mg) as yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.IC1C=C(NC(=O)C2C=CC(N3CCOCC3)=NC=2)C=CC=1C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([N:22]3[CH2:23][CH2:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21]3)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Cl)nc2)c1
Reactant: c1ccc2c(c1)CCNC2
Agent: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)nc2)cc1I
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCc4ccccc4C3)nc2)c1

Procedure:
N-(3-tert-Butyl-phenyl)-6-(3,4-dihydro-1H-isoquinolin-2-yl)-nicotinamide was synthesized from N-(3-tert-butyl-phenyl)-6-chloro-nicotinamide and 1,2,3,4-tetrahydro-isoquinoline in a method similar to the one described in the synthesis of N-(3-iodo-4-methyl-phenyl)-6-morpholin-4-yl-nicotinamide above. LCMS calcd for C25H27N3O (m/e) 385, obsd 386 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[S:21]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)([C:18]1[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.2 %

Procedure:
To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.9 g, 5.02 mmol) in anhydrous pyridine (10 mL) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (1.0 g, 5.27 mmol). The suspension was allowed to warm to room temperature and stirred for 24 h. After this time, the suspension was poured onto crushed ice and extracted with EtOAc. The organic layer was separated, washed with water, brine, dried (MgSO4) and concentrated under reduced pressure to give the title compound (15) (1.1 g, 69%) as a light yellow colored solid. 1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.94-5.17 (m, 1H), 3.33-3.56 (m, 4H), 2.46 (s, 3H), 1.79-2.28 (m, 2H), 1.43 (s, 9H); MS (APCI, M+H+) C16H24NO5S, calcd. 342.1. found 286.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH2:20]([O:19][C:17](=[O:18])[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To 2,4-difluoro-phenylamine (1, 7.0 mL, 70.0 mmol) in 100 mL of dichloromethane, pyridine (11 mL, 140.0 mmol) and benzyl chloroformate (2, 11.9 mL, 83.4 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate and potassium bisulfate solution. The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum and crystallized from hexanes to give the desired compound (3, 15.6 g, 85%).