Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CCOCC.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[CH2:38][CH3:39].C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].CC(O)(C)C.ClCCCl>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:29][CH2:30]3)=[CH:21][C:20]=2[CH2:38][CH3:39])[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CCOCC
Product: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A solution of 2,4-dichloro-5-(trifluromethyl)pyrimidine (166 mg, 0.766 mmol) in 1:1 DCE:t-BuOH (5 mL) was stirred at 0° C. under nitrogen. 1.0 M Zinc(II) chloride in ether (0.77 mL, 0.77 mmol) was added and the mixture stirred for one hour. tert-Butyl 4-(4-amino-3-ethylphenyl)piperidine-1-carboxylate (I40) (212 mg, 0.70 mmol) in 1:1 DCE:t-BuOH (5 mL) was added dropwise, and after 30 minutes triethylamine (146 μL, 1.05 mmol) in 1:1 DOE:t-BuOH (5 mL) was added and the mixture allowed to slowly come to room temperature. After 18 hours the mixture was concentrated, and chromatography (12 g silica cartridge, 0-50% ethyl acetateicyclohexane) gave the title compound (I41) (283 mg, 84% yield) as a pale pink solid; 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=0.6 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.15-7.07 (m, 3H), 4.25 (s, 2H), 2.80 (t, J=12.1 Hz, 2H), 2.69-2.59 (m, 3H), 1.83 (d, J=12.9 Hz, 2H), 1.69-1.59 (m, 2H), 1.49 (s, 9H), 1.23 (t, J=7.6 Hz, 3H), LCMS Method C: rt. 6.94 min; m/z 429.1 [M-tBu+2H]+, 385.1 [M-Boc+2H]+; m/z 483.1 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([O:22][CH3:23])=[C:15]([O:24][CH3:25])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[Cl:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[C:13]2[CH:14]=[C:15]([O:24][CH3:25])[C:16]([O:22][CH3:23])=[C:17]([NH:19][S:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=3)(=[O:37])=[O:36])[CH:18]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3cccc(Cl)c3)c(OC)c(OC)c2)cc1

Procedure:
4-[3-(3-Chloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid, MS (ISP): m/e=489.2 (M+H+), was prepared in analogy to example 1, steps A to D. Step A was performed using 3,4-dimethoxy-5-nitro-benzoyl chloride and yielded 4-(3,4-dimethoxy-5-nitro-benzoylamino)-benzoic acid ethyl ester. This was reduced to 4-(3,4-dimethoxy-5-nitro-benzoylamino)-benzoic acid ethyl ester in step B. This was coupled with 3-chloro-benzenesulfonyl chloride in step C, yielding 4-[3-(3-chloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].CC[O-].[Na+].[C:10]1([N:16]2[C:22]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=3[NH:20][C:19](=O)[CH2:18][C:17]2=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([N:16]2[C:22]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=3[N:20]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: CCCCBr
Agent: CC[O-]
Agent: [Na+]
Product: CCCCN1CCCN(c2ccccc2)c2cc(Cl)ccc21

Procedure:
In the same manner, by acting butyl bromide in the presence of sodium ethylate, starting from 1-phenyl 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine, there is obtained 1-phenyl 5-butyl 8-chloro 1,2,4,5-tetrahydro 3H-1,5-benzodiazepine (R1 = H, R2 = Cl, R3 = C4H9, R4 = C6H5) melting at 159°-161° C., upon recrystallisation in 50% ethanol.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@@:5]([C:17]2([OH:21])[CH2:20][CH2:19][CH2:18]2)([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:4]=[CH:3]1.[CH3:22][O:23][C@H:24]1[C:29](=O)[CH2:28][CH2:27][O:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].[OH-].[Na+]>ClCCl>[CH2:10]([O:9][C:7]([C@:5]1([C:17]2([OH:21])[CH2:18][CH2:19][CH2:20]2)[CH2:6][C@H:2]([NH:1][C@@H:29]2[C@H:24]([O:23][CH3:22])[CH2:25][O:26][CH2:27][CH2:28]2)[CH:3]=[CH:4]1)=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(O)CCC2)C1
Reactant: CO[C@@H]1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(O)CCC2)C1
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
A solution of 3.83 g (13.3 mmol) of benzyl (1R,4S)-4-amino-1-(1-hydroxycyclobutyl)cyclopent-2-ene-1-carboxylate (Preparation SRT-0235) and 1.89 g (14.5 mmol) of (3R)-3-methoxytetrahydro-4H-pyran-4-one in 26 mL of dichloromethane was stirred with activated 3 A molecular sieves for 10 min, then cooled to 0 C. Sodium triacetoxyborohydride (3.35 g, 15.8 mmol) was added in several portions ever 10 min, and the mixture was stirred for 1.5 h. The cloudy mixture was added to dichloromethane and aqueous NaHCO3+NaOH (pH ˜14), and the aqueous phase was extracted with several additional portions of dichloromethane. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 3-5% methanolic ammonia (7 M) in dichloromethane afforded 3.94 g (74%) of the title compound as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41-1.52 (m, 1H) 1.55-1.64 (m, 1H) 1.64-1.79 (m, 2H) 1.86-2.09 (m, 5H) 2.19-2.29 (m, 1H) 2.41 (dd, J=14.2, 7.7 Hz, 1H) 2.84-2.91 (m, 1H) 3.17-3.44 (m, 4H) 3.34 (s, 3H) 3.88-3.96 (m, 2H) 4.00 (dd, J=12.3, 4.4 Hz, 1H) 5.10-5.20 (m, 2H) 5.88-5.93 (m, 1H) 6.00 (dd, J=5.6, 1.9 Hz, 1H) 7.28-7.39 (m, 5H). TLC Rf 0.41 (4% 7 M methanolic ammonia in dichloromethane). LC-MS ES+ 402.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH3:7][C:8]([CH3:10])=O>C(O)C.[Pt](=O)=O>[CH:8]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])([CH3:10])[CH3:7]
Reactant: NCCCCO
Reactant: CC(C)=O
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)NCCCCO
Reaction time: 48 h

Procedure:
100.40 g of 4-amino-1-butanol was dissolved in a mixed solvent of 108 ml of acetone and 160 ml of ethanol and, after adding 2.1 g of platinum (IV) oxide, hydrogenation was carried out under the pressure of 2 to 3 atms for 48 hours. A catalyst was removed by filtering the reaction solution and the filtrated was concentrated to obtain 147.64 g of the desired compound as a colorless oily substance.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]([F:30])([F:29])[C@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1>CCCCO>[C:16]1([C:3]2[C:2]([N:25]3[CH2:26][CH2:27][CH2:28][C@@H:24]3[C:23]([F:30])([F:29])[F:22])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)[C@H]1CCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CCCCO
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3C(F)(F)F)nc2c1
Temperature: 110 °C
Reaction time: 72 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv), (R)-2-(trifluoromethyl)pyrrolidine (95 mg, 0.68 mmol, 2.36 equiv), n-BuOH (1.5 mL). The resulting solution was stirred for 3 days at 110° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 30 mg (26%) of (R)-methyl 2-phenyl-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=O)=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=2)[CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32]>N1C=CC=CC=1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[S:32])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc(C(=O)N4CCCC4)ccc3n2CC2CC2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCOc1ccc(Cc2nc3cc(C(=S)N4CCCC4)ccc3n2CC2CC2)cc1
Temperature: 100 °C

Procedure:
To a solution of free base 1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-5-(1-pyrrolidinylcarbonyl)-1H-benzimidazole (Example 21, from 80 mg 1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-1H-benzimidazole-5-carboxylic acid) in pyridine (2 mL) was added P2S5 (507 mg, 1.14 mmol). The mixture was heated at 100° C. for 24 h and cooled to room temperature. After being decanted, the supernatant was concentrated and the residue was diluted with EtOAc (20 mL), washed with 1 N NaOH (2×10 mL) and then H2O (2×10 mL). The organic layer was dried over MgSO4 and was evaporated. The crude residue was purified by silica gel column chromatography to give an oil (59 mg, 62% for 2 steps). 1H NMR (400 MHz, CD3OD): δ 7.70 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 4.27 (s, 2H), 4.08–3.95 (m, 4H), 3.89 (d, J=6.8 Hz, 2H), 3.57 (t, J=7.2 Hz, 2H), 2.14–2.03 (m, 2H), 2.00–1.92 (m, 2H), 1.38 (t, J=7.2 Hz, 3H), 1.06–0.98 (m, 1H), 0.54–0.48 (m, 2H), 0.28–0.22 (m, 2H). MS (ESI) (M+H)+=420.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:29])[C:13](=[N:26][C:27]#[N:28])[N:14]([C:15]4[CH:16]=[N:17][C:18]([C:21]([C:24]#[N:25])([CH3:23])[CH3:22])=[CH:19][CH:20]=4)[C:5]=3[C:4]=2[CH:3]=1.[B:30]1(B2OC(C)(C)C(C)(C)O2)[O:34]C(C)(C)C(C)(C)[O:31]1.C([O-])(=O)C.[K+].C(Cl)Cl>O1CCOCC1.C(OCC)(=O)C>[C:27]([N:26]=[C:13]1[N:12]([CH3:29])[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([B:30]([OH:34])[OH:31])=[CH:3][C:4]=3[C:5]=2[N:14]1[C:15]1[CH:16]=[N:17][C:18]([C:21]([C:24]#[N:25])([CH3:23])[CH3:22])=[CH:19][CH:20]=1)#[N:28]
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)nc2)c2c3cc(Br)ccc3ncc21
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)nc2)c2c3cc(B(O)O)ccc3ncc21

Procedure:
N-(8-bromo-1-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (2.463 mmol) was dissolved in 15 mL of dioxane under argon atmosphere. Bis(pinacolato)diboron (1.347 mmol), potassium acetate (2.246 mmol) and (1,1-bis(diphenylphosphino)ferrocene)-dichloropalladium (II) complex with DCM (50 mg) while stirring. The reaction mixture was refluxed for 8 h. After completion of the reaction, the reaction mixture was cooled and diluted with 15 mL ethyl acetate and filtered through celite. The filtrate was concentrated and the crude product was purified (silica gel column, ethyl acetate/petroleum ether as eluent) to obtain the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
73 mg (52%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(4-chlorophenyl)piperazine (74 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: Br[C:2]1[C:3]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[Zn]C>C1COCC1.[Pd]>[CH3:27][C:2]1[C:3]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(Br)c(C(=O)Nc3ccccc3)n2)cc1
Agent: [Pd]
Agent: C[Zn]Cl
Solvent: C1CCOC1
Product: Cc1ncc(-c2ccc(S(C)(=O)=O)cc2)nc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 819.5 %

Procedure:
A solution of 3-bromo-6-(4-methylsulfonylphenyl)-N-phenyl-pyrazine-2-carboxamide (89.4 mg, 0.1634 mmol) and palladium; triphenylphosphane (9.441 mg, 0.008170 mmol) in THF (1 mL) was treated with chloro(methyl)zinc (490.2 μL of 2 M, 0.9804 mmol) and left to stir for 16 hours at ambient temperature. The reaction was treated with further chloro(methyl)zinc (490.2 μL of 2 M, 0.9804 mmol) and allowed to heat at 60° C. for 7 hours. The mixture was allowed to cool to ambient temperature and concentrated in vacuo. The resultant residue was dissolved in DMSO and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (24.6 mg, 41% Yield). 1H NMR (400.0 MHz, DMSO) δ 2.81 (s, 3H), 3.31 (s, 3H), 7.15-7.19 (m, 1H), 7.39-7.43 (m, 2H), 7.82 (d, J=7.6 Hz, 2H), 8.11 (d, J=8.5 Hz, 2H), 8.56 (d, J=8.5 Hz, 2H), 9.44 (s, 1H) and 10.71 (s, 1H) ppm; MS (ES+) 367.98. LCMS retention time, 3.37 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17](I)[C:16]([Cl:20])=[C:15]([O:21][CH2:22][CH3:23])[N:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(OC(C)(C)C)(=O)C=C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:16]1[CH:17]=[CH:18][C:13]([C:11]([NH:10][CH2:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:25][CH:24]=2)=[O:12])=[N:14][C:15]=1[O:21][CH2:22][CH3:23]
Reactant: CCOc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cc(I)c1Cl
Agent: [Pd+2]
Agent: C=CC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)ccc1Cl
Temperature: 100 °C
Yield: 10.8 %

Procedure:
This material obtained from step A (50 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (0.1 mL) followed by addition of t-butyl acrylate (25 mg, 0.2 mmol), (Tol)3P (6 mg, 0.02 mmol), palladium(II) acetate (2 mg, 0.01 mmol), and triethylamine (20 mg, 0.2 mmol). The mixture was heated to 100° C. for 2 h, cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was washed with brine, drived over Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% ethyl acetate to provide the title compound (4 mg, 10%). 1H NMR (500 MHz, DMSO-d6) δ 9.29 (t, J=6.0 Hz, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.88 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 4.60 (d, J=7.0 Hz, 2H), 4.59 (q, J=7.0 Hz, 2H), 3.18 (s, 3H), and 1.38 (d, J=7.0, 3H). MS (m/e) positive mode: 369, 71 (3:1, M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)cc(-c2nc(NC(=O)c3ccccc3)sc2-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 25.9 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.51 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.52 mmol) in N,N-dimethylacetamide (20 mL) was added benzoyl chloride (0.30 g, 2.15 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.18 g, yield 26%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[O:44])[CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[C:32](Cl)=[N:31][C:30]=2[N:29]([CH3:43])[C:27]1=[O:28])([O-:17])=[O:16].C(=O)([O-])[O-].[Na+].[Na+].O>CS(C)=O>[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[O:44])[CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH2:37][CH:38]=[C:39]([CH3:40])[CH3:41])[C:32]([N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]3)=[N:31][C:30]=2[N:29]([CH3:43])[C:27]1=[O:28])([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Temperature: 65 °C
Reaction time: 16 h

Procedure:
2.20 g of 3-tert-butyloxycarbonylaminopiperidine is added at 65° C. to 4.40 g of 1-[2-(2-nitrophenyl)-2-oxoethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloroxanthine and 1.30 g of sodium carbonate in 50 mL of dimethylsulfoxide. The reaction mixture is stirred for approximately 16 hours at 65° C. After cooling to ambient temperature, it is poured onto a mixture of 600 mL of water and 100 g of ice. The precipitate formed is suction filtered and washed with water. The filter cake is dissolved in diethyl ether, and the solution is dried and evaporated down. The brown resinous flask residue is brought to crystallization with diisopropylether. Yield: 3.30 g (54% of theory); Rf value: 0.52 (silica gel, cyclohexane/ethyl acetate (3:7)); mass spectrum (ESI+): m/z=596 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[N:6][N:7]=1.NC(N)=[S:18]>C(O)C>[SH:18][C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[N:6][N:7]=1
Reactant: NC(N)=S
Reactant: Cc1ccc2c(n1)sc1c(Cl)nnnc12
Solvent: CCO
Product: Cc1ccc2c(n1)sc1c(S)nnnc12

Procedure:
A mixture of 7 g. (0.03 M) of 4-chloro-7-methylpyrido[3',2':4,5]thieno[3,2-d]-1,2,3-triazine, and 7 g. (0.09 M) of thiourea in 350 ml. ethanol was refluxed for 2 hours. It was then cooled and filtered. The crude product was dissolved in 5% NaOH, and treated with charcoal and filtered. Acidification with HOAC followed by filtration yielded yellow solid, m.p. 205°-208° C.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH:17]([CH2:19][CH3:20])[C:16](=O)[CH:15]([CH2:22][CH3:23])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:25].[Na+]>CO>[NH2:25][CH:16]1[CH:17]([CH2:19][CH3:20])[CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][CH:15]1[CH2:22][CH3:23]
Reactant: CCC1CN(Cc2ccccc2)CC(CC)C1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC1CN(Cc2ccccc2)CC(CC)C1N
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Ammonium acetate (10 g, 130 mmol) was added to the stirred solution of 1-benzyl-3,5-diethyl-4-piperidone (3.5 g, 14.3 mmol) in methanol (50 ml) and stirring was continued for 4 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.45 g, 7.14 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 10 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 2) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1M sodium hydroxide solution (pH 10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3,5-diethylpiperidine. Yield 3.4 g (97%), C16H26N2, m/z 247 (M+1).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[N:6]#[C:7][NH2:8].[CH3:9][OH:10].OS(O)(=O)=O>CO>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH3:9][O:10][C:7](=[NH:8])[NH2:6]
Reactant: CO
Reactant: N#CN
Agent: O=S(=O)(O)O
Product: COC(=N)N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sulfuric acid (112.7 g, 0.97 mol) was added carefully to a cooled CH3OH (150 mL) solution. In a separate flask, cyanamide (50 g, 1.19 mol) was dissolved in methanol (100 mL) and chilled to ca 5° C. in ice-water. Over 2 h, the MeOH—H2SO4 solution was added such that the reaction temperature did not rise above 10° C. After the last addition, the solution was stirred for an additional 1 h and then concentrated in vacuo to give O-methylisourea hydrogen sulfate as a thick-viscous syrup with an assumed quantitative yield which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9](Br)[C:8]([Cl:12])=[CH:7][C:6]=1[O:13][CH3:14])[CH3:2].[Cu][C:17]#[N:18].CN(C)C=O.Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([C:17]#[N:18])[C:8]([Cl:12])=[CH:7][C:6]=1[O:13][CH3:14])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1cc(Br)c(Cl)cc1OC
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C#N)c(Cl)cc1OC

Procedure:
14.7 g (0.05 mol) of 5-bromo-4-chloro-2-methoxybenzoic acid ethyl ester, 5.4 g (0.06 mol) of copper(I) cyanide and 8 ml of dimethylformamide are heated at 190° for three hours while stirring under a nitrogen atmosphere. After cooling, the reaction mixture is stirred well with 250 ml of methylene chloride and 250 ml of 2N hydrochloric acid. The insoluble portions are filtered off with suction and the layers are separated in a separating funnel. The methylene chloride solution is washed neutral with water and then concentrated by evaporation. 4-Chloro-5-cyano-2-methoxybenzoic acid ethyl ester is obtained as residue which, after recrystallisation from methylene chloride/hexane, melts at 102°-103°.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a stirred, cooled solution of 15.0 g. of 4-bromo-3-trifluoromethylaniline in 75 ml. of dry pyridine add 6.8 g. of isobutyrylchloride and heat the resulting mixture at 70° C. for 2 hours. Allow the reaction mixture to cool to room temperature and then pour the mixture into 600 ml. of ice-water, filter and dry the precipitate which is recrystallized from 1:1 petroleum etherdichloromethane to yield 4'-bromo-3'-trifluoromethylisobutyranilide, m.p. 126.5°-128° C.