Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7]P(=O)(OCC)OCC)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH:20]([C:22]1[C:31]([CH3:32])=[CH:30][C:29]2[C:28]([CH3:34])([CH3:33])[CH2:27][CH2:26][C:25]([CH3:36])([CH3:35])[C:24]=2[C:23]=1[O:37][CH3:38])=O.Cl>CS(C)=O.O>[CH3:38][O:37][C:23]1[C:24]2[C:25]([CH3:35])([CH3:36])[CH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]=2[CH:30]=[C:31]([CH3:32])[C:22]=1/[CH:20]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:17][CH:16]=1
Reactant: CCOP(=O)(Cc1ccc(C#N)cc1)OCC
Reactant: COc1c(C=O)c(C)cc2c1C(C)(C)CCC2(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1c(/C=C/c2ccc(C#N)cc2)c(C)cc2c1C(C)(C)CCC2(C)C
Yield: 76.8 %

Procedure:
A solution of 25.2 g (0.1 mole) of diethyl 4-cyanobenzylphosphonate in 50 ml of dimethyl sulfoxide was added dropwise to a suspension of 3 g (0.1 mole) of sodium hydride (80% strength, freed beforehand from the 20% of paraffin using petroleum ether) in 100 ml of absolute dimethyl sulfoxide at from 25° to 40° C. The mixture was stirred for a further hour, after which a solution of 12 g (50 millimoles) of 2-formyl-5,6,7,8-tetrahydro-1-methoxy-3,5,5,8,8-pentamethylnaphthalene in 100 ml of dimethyl sulfoxide was added dropwise, and the mixture was stirred overnight at room temperature. Thereafter, the reaction mixture was poured onto 1.2 l of water and acidified with 2N hydrochloric acid, the resulting oily product was separated off and stirred with a little methanol, the crystals obtained were filtered off and the solid was washed on the filter with methanol and dried to give 13.8 g of the title compound of melting point 120° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][CH2:16][C:17]4[C:22]([C:13]=3[O:12][N:11]=2)=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=4)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH:25]1[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]1.C([BH3-])#N.[Na+]>ClC(Cl)C.CO.C(O)(=O)C>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][CH2:16][C:17]4[C:22]([C:13]=3[O:12][N:11]=2)=[CH:21][CH:20]=[C:19]([CH2:23][N:25]2[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]2)[CH:18]=4)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(-c2noc3c2CCc2cc(C=O)ccc2-3)cc1
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: CCCc1ccc(-c2noc3c2CCc2cc(CN4CC(C(=O)O)C4)ccc2-3)cc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 37.1 %

Procedure:
To 3-(4-propylphenyl)-4,5-dihydronaphtho[2,1-d]isoxazole-7-carbaldehyde (Preparation 20E, 0.191 g, 0.602 mmol) in dichloroethane (2 mL) and methanol (2.0 mL) was added azetidine-3-carboxylic acid (0.073 g, 0.722 mmol) and 8 drops of acetic acid. The reaction mixture was heated at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature and sodium cyanoborohydride (0.045 g, 0.722 mmol) was added in one lot. The reaction mixture was stirred at room temperature for 20 min., and then concentrated. Acetonitrile (10 mL) was added to the resulting residue. The contents were sonicated for ˜2 min. and filtered. The solid was washed with acetonitrile (2×10 mL), water (2×10 mL), acetonitrile (5 mL), and dried to yield 1-((3-(4-propylphenyl)-4,5-dihydronaphtho[2,1-d]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid as a grey solid (90 mgs). The compound had an HPLC retention time=3.08 min (condition C); LC/MS M+1=403.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19]2)[CH2:14]1)=[O:11])=[O:7].[H][H]>CO.[Pd]>[N:15]1([CH:18]2[CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:16][CH2:17][C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:33]=[CH:34][CH:35]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:4]=2)[CH2:14]1
Reactant: [H][H]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3)C2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCNC2)C1
Yield: 96.9 %

Procedure:
In a round-bottom flask, a slurry of benzyl (3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidine-1′-carboxylate (0.765 g, 1.48 mmol) and Palladium (10%) on Carbon (0.200 g) in methanol (10 mL) was purged with hydrogen gas for 2 min.; the reaction was then subjected to 1 atm of hydrogen gas for 3 h. The flask was purged with Argon, then the mixture was filtered and concentrated to afford N-{2-[(3R)-1,3′-bipyrrolidin-3-ylamino]-2-oxoethyl}-3-(trifluoromethyl)benzamide (0.551 g, 97%) as an off-white solid. 1H-NMR (CDCl3) δ: 1.32-1.53 (m, 2H), 1.52-2.04 (m, 6H), 2.15-2.40 (m, 2H), 2.40-2.70 (m, 3H), 2.80-3.00 (m, 3H), 4.00-4.20 (m, 2H), 4.42 (bs, 1H), 6.77 (m, 1H), 7.40-7.55 (m, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.73 (d, J=7.2 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 8.08 (s, 1H). MS m/z: 399 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:31]
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC(F)(F)F)c2)CCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)C1(c2cc(Br)c(N)c(OCC(F)(F)F)c2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 4.0 mmol) in dry CCl4 (60 mL), NBS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (920 mg) as a yellow solid.
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6](=O)[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])C.[CH3:15][S:16][CH:17]([CH3:25])/[CH:18]=[CH:19]/[N:20]1CCCC1.C([O-])(=O)C.[NH4+].O>C(OCC)C>[CH3:15][S:16][CH:17]([C:18]1[CH:4]=[CH:5][C:6]([C:7]([F:12])([F:13])[C:8]([F:9])([F:10])[F:11])=[N:20][CH:19]=1)[CH3:25]
Reactant: CCO/C=C/C(=O)C(F)(F)C(F)(F)F
Reactant: CSC(C)/C=C/N1CCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CSC(C)c1ccc(C(F)(F)C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.8 %

Procedure:
(E)-1-Ethoxy-4,4,5,5,5-pentafluoropent-1-en-3-one (1.09 g, 5 mmol) in anhydrous ethyl ether (5 mL) was treated with 1-((E)-3-methylthiobut-1-enyl)pyrrolidine (0.85 g, 5 mmol) in 2 mL dry ether at −15° C. over a period of 5 min and the reaction was continued for 20 min. Then the temperature was allowed to rise to room temperature and the reaction continued for 3 h. The solvent was removed under reduced pressure and the residue re-dissolved in anhydrous DMF (5 mL). Ammonium acetate (0.58 g, 7.5 mmol) was added and the mixture stirred at room temperature over a weekend. Water was added and mixture extracted with ether three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified on silica gel eluted with 8% EtOAc in hexane (v/v) to give 0.16 g of the desired 5-(1-methylthioethyl)-2-pentafluoroethylpyridine (A) as brownish colored oil in 12% yield. GC-MS: mass calcd for C10H11F2N3S [M]+ 271. Found 271.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][C:10]([OH:14])([C:12]#[CH:13])[CH3:11].CN(C)C(N(C)C)=N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>Cl[Cu].Cl[Pd]Cl.C(Cl)Cl.O.CN(C)C=O>[NH2:5][C:4]1[CH:3]=[C:2]([C:13]#[C:12][C:10]([CH3:11])([OH:14])[CH3:9])[CH:8]=[CH:7][CH:6]=1
Reactant: C#CC(C)(C)O
Reactant: Nc1cccc(Br)c1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)C#Cc1cccc(N)c1
Yield: 71 %

Procedure:
A 250 ml round bottomed flask fitted with refrigerator, under nitrogen stream, is loaded with 3-bromoaniline (16 ml), dimethylformamide (80 ml), 2-methyl-3-butyn-2-ol (21.3 ml), 1,1,3,3-tetramethyl guanidine (20.3 ml), CuCl (0.044 g), PdCl2 (0.156 g) and triphenyl phosphine (0.925 g), in this order. The mixture is heated to 70°-75° C., keeping this temperature until completion of the reaction. H2O (250 ml) and CH2Cl2 (100 ml) are added at a temperature of 35°-30° C. The organic phase is dried, then evaporated to dryness. The residue is purified by chromatography to obtain 18.5 g of 4-(3-aminophenyl)-2-methyl-3-butyn-2-ol. Yield: 71% with HPLC purity ≥99%.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:29]2[CH:30]=[C:25]([CH3:24])[CH:26]=[CH:27][CH:28]=2)=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: Cc1cccc(B(O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C)c3)c2cc1OC
Reaction time: 3 h
Yield: 93.6 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 3-methylphenylboronic acid (136 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at +80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (72 mg, yield 94%).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:26][CH2:27][N:28]([C:11]([C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:16])=[CH:15][CH:14]=2)=[O:13])[CH2:29][CH2:30]1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 88.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (253 mg) described in Preparation Example 16 and 1-(2,4-dimethylphenyl)piperazine (199 mg) and by the reaction and treatment in the same manner as in Example 87, [4-(2,4-dimethylphenyl)piperazin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]methanone (384 mg) was obtained. Using the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]methanone (303 mg) and by the reaction and treatment in the same manner as in Example 123, the title compound (264 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:25]O.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:25])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C#N)ccc1OCc1ccccc1
Yield: 79.2 %

Procedure:
A mixture of 4-benzyloxy-3-methoxybenzaldehyde (157 g, 649 mmol), sodium acetate (106 g, 1.29 mol), hydroxylamine hydrochloride (90 g, 1.29 mol) and acetic acid (500 ml) was heated at reflux for 21 hours. The solvent was evaporated and ice/water (1000 ml) was added to the residue forming a sticky solid. The mixture was neutralised with aqueous sodium hydroxide solution then extracted with dichloromethane (2×500 ml). The organic solution was washed with 1.0 N sodium hydroxide (100 ml), brine (100 ml) and then dried over magnesium sulphate. Solvent evaporation in vacuo, trituration of the residue with hexane:ethyl acetate (3:1) and collection of the solid by suction filtration yielded 4-benzyloxy-3-methoxybenzonitrile (123 g, 80% yield) as a brown solid:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15]1([CH:18]=O)[CH2:17][CH2:16]1.[BH4-].[Na+].O>C(O)C>[CH:15]1([CH2:18][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:18][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)[CH2:17][CH2:16]1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=CC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C(CNCC1CC1)CN1CCN(CCCNCC2CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.51 mL, 2.5 mmol) and cyclopropanecarboxaldehyde (6392 μL, 5.24 mmol) in absolute ethanol (20 mL), 3 Å molecular sieves are added. After stirring the mixture at room temperature for 12 h, NaBH4 (1.9 g, 49.92 mmol) was added portionwise and the mixture was stirred for 12 h at room temperature. The reaction was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL). Combined organic layers were extracted with HCl 1M. The combined aqueous layers were neutralized with NaOH 1M and extracted with CH2Cl2. Combined organic layers were dried over MgSO4. Crude compound is purified by flash chromatography on neutral aluminium oxide (CH2Cl2/MeOH).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1ccc(CO)cc1[N+](=O)[O-]
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(COC2CCCCO2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of 9.85 g of 4-methyl-3-nitrobenzyl alcohol in 200 ml of dichloromethane is admixed successively with 10.9 ml of 3,4-dihydro-2H-pyran and 1.12 g of p-toluenesulphonic acid monohydrate. The reaction mixture is stirred at room temperature over 18 hours. The solution is poured onto 1M sodium hydrogencarbonate solution (300 ml) and extracted with tert-butyl methyl ether (2×300 ml). The organic phase is washed with brine (300 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.49 (1:2 EtOAc-heptane); Rt=4.73.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.Cl[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl.[I-].[K+]>CN(C=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: ClCCOCCCl
Reactant: Nc1ccc(CCCCO)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCCc1ccc(N2CCOCC2)cc1

Procedure:
A mixture of 4-aminobenzenebutanol (7.5), 2-chloroethyl ether (6.5 g, 5.32 ml), DEA (11.74 g) and finely ground potassium iodide (15.0 g) was stirred in DMF (500 ml) at 100° under nitrogen for 65 h. The mixture was cooled, the solvent removed in vacuo at 55° and the residue partitioned between EA (250 ml) and water (100 ml). The aqueous layer was extracted with further EA (100 ml), the combined organic solutions washed with brine (150 ml), dried and evaporated onto FCC silica (15 g). The impregnated material was applied to an FCC column, elution with ER-CX (2:1) affording the title compound as a waxy cream solid (6.13 g) m.p. 51°-52°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]=O.[C:13]([NH2:17])(=[O:16])[CH2:14][SH:15].B(F)(F)F.CCOCC>CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]1[NH:17][C:13](=[O:16])[CH2:14][S:15]1
Reactant: NC(=O)CS
Reactant: O=CCOc1ccc(Cl)cc1Cl
Agent: FB(F)F
Solvent: CCOCC
Product: O=C1CSC(COc2ccc(Cl)cc2Cl)N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 20.1 %

Procedure:
To a solution containing 5.25 g (0.025 mole) of (2,4-dichlorophenoxy)acetaldehyde and 5.0 g (0.055 mole) of thioglycolamide in 100 ml of anhydrous ether was added 14.2 g (0.10 mole) of boron trifluoride etherate. The resulting solution was stirred at ambient temperature for 6 hours, washed with water, dried (MgSO4), and concentrated to dryness. The residual solid was purified by silica chromatography to give 1.4 g of 2-(2,4-dichlorophenoxymethyl)-4-thiazolidinone as a white crystalline solid melting at 134°-136°.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)(=[O:9])=[O:8].CCN(CC)CC.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[F:60][C:61]([F:71])([F:70])[C:62]1[CH:69]=[CH:68][C:65]([CH2:66][NH2:67])=[CH:64][CH:63]=1>C1COCC1>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:67][CH2:66][C:65]1[CH:64]=[CH:63][C:62]([C:61]([F:60])([F:70])[F:71])=[CH:69][CH:68]=1)=[O:15])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cccc(C(=O)O)c2)c(OC)c1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1cccc(S(=O)(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-{[(2,4-Dimethoxybenzyl)(1,3-thiazol-2-yl)amino]sulfonyl}benzoic acid (Preparation 23, 90 mg, 0.207 mmol, 1 eq) THF (2 ml) was added Et3N (0.04 ml, 0.311 mmol, 1.5 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl, 52 mg, 0.27 mmol, 1.3 eq) and 1-hydroxybenzotriazole hydrate (HOBt, 28 mg, 0.207 mmol, 1 eq) at 0° C. and the reaction mixture stirred for 10 minutes before the addition of 4-(trifluoromethyl)benzylamine (0.032 ml, 0.228 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 18 hours. The mixture was extracted from water into DCM, dried over magnesium sulphate, filtered and evaporated in vacuo. The residue was dissolved in 4M HCl in dioxane (2 ml) and the reaction mixture stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration and washed with dioxane. The material was purified further by preparative HPLC to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:9]2=[O:37])[CH:3]=1.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:38].[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:9]2=[O:37])[CH:3]=1
Reactant: Cc1cc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)no1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)no1

Procedure:
A solution of tert-butyl 4-{1-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (841 mg; compound B6) in DCM (15 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (1.5 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[C:17]#[CH:18].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CC#N.CC#N.Cl[Pd]Cl.O.C(#N)C>[CH2:8]([C:4]1[CH:3]=[C:2]([C:18]#[C:17][CH2:16][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:7]=[CH:6][CH:5]=1)[CH3:9]
Reactant: C#CCOC1CCCCO1
Reactant: CCc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CCc1cccc(C#CCOC2CCCCO2)c1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
A mixture of 1-bromo-3-ethylbenzene (9.79 g), cesium carbonate (45.0 g), 2-(2-propynyloxy)tetrahydropyran (11.2 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.51 g), bis(acetonitrile)palladium(II) dichloride (274 mg) and acetonitrile (300 ml) was stirred at 90° C. for 10 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-95:5) to give the object product (5.25 g) as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([N+:24]([O-])=O)=[CH:22][N:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1>[Pd].CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cncnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1cncnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A mixture of N-1,3-benzoxazol-2-yl-N′-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (54 mg) and 5% palladium on carbon (22 mg, 50% water by weight) in methanol (5 mL) was stirred under an atmosphere of hydrogen (balloon) for 1 h. After this time, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford N4-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyrimidine-4,5-diamine (49 mg) as a brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]2=[O:18])=[CH:7][N:6]=1)=O.CO.[BH4-].[Na+]>C(Cl)Cl>[Cl:17][C:15]1[CH:14]=[CH:13][C:12](=[O:18])[N:11]([C:8]2[CH:7]=[N:6][C:5]([CH2:3][OH:2])=[CH:10][N:9]=2)[CH:16]=1
Reactant: COC(=O)c1cnc(-n2cc(Cl)ccc2=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=c1ccc(Cl)cn1-c1cnc(CO)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the ester from step 2 (1.41 g, 5.317 mmol), in CH2Cl2 and methanol (1:1 50 ml) at 0° C. was treated with sodium borohydride (2.01 g, 53.17 mmol) and the reaction was stirred at room temperature for 18 hrs. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc and sat. NaHCO3. The aqueous layer was extracted with EtOAc and the combined extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (silica gel, MeOH: CH2Cl2 2:98 to 5:95 gradient elution) to afford the title compound.