Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: COC(=O)c1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 43 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 653 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and 567 mg of methyl 3-aminobenzoate in place of the 3-(tert-butyl)aniline. 400 mg of methyl 3-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoate are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([S:1][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Sc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
Combine 4-mercapto-benzaldehyde (0.45 g, 3.3 mmol), 6-chloro-nicotinamide (0.52 g, 3.3 mmol), potassium carbonate (0.7 g, 5.1 mmol), and dimehtylformamide (15 mL) then heat at 70° C. overnight. Cool to room temperature, pour into water, and then extract with dichloromethane (3×75 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (1 g). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 6-(4-formyl-phenylsulfanyl)-nicotinamide (120 mg). 1H NMR (DMSO-D6, 300.00 MHz): 10.08 (s, 1H), 8.91 (dd, 1H, J=2.3, 0.7 Hz), 8.18-8.12 (m, 2H), 8.03-7.98 (m, 2H), 7.83-7.78 (m, 2H), 7.61 (s, 1H), 7.34 (dd, 1H, J=8.4, 0.8 Hz). Step 3 6-[4-(Benzylamino-methyl)-phenylsulfanyl]-nicotinamide
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH3:23][C:5]1[NH:4][CH:3]([O:2][CH3:1])[N:8]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(OC)N(S(=O)(=O)c2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
A solution of 1, 4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl) -5-pyrimidinecarboxylic acid, ethyl ester (3.19 g, 10.0 mmole; see Example 5A) and distilled triethylamine (4.18 ml, 30.0 mmol) in distilled dichloromethane (20 ml) in an ice bath under argon was treated dropwise via syringe with benzenesulfonyl chloride (1.53 ml, 12.0 mmol). The reaction was then stirred at room temperature overnight; and then over the weekend. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium chloride and flash chromatographed to give the title compound as a light brown oil (2.94 g).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:40][CH:39]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)=[O:15]>>[C:45]([O:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][C@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[O:15])=[CH:39][CH:40]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NOCC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 48 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([CH:19]=O)=[CH:15][CH:16]=[CH:17][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.ClCCl.C([O-])(O)=O.[Na+]>[C:13]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.3 %

Procedure:
1-Phenylpiperazine (266 mg, 1.64 mmol) was dissolved in methanol (7 mL) in a reaction vessel and, after adding biphenyl-2-carbaldehyde (150 mg, 0.82 mmol), the mixture was stirred at room temperature for 2 hours. 2 hours later, NaBH(OAc)3 (529 mg, 2.46 mmol) was added and the mixture was further stirred for 8 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane and saturated NaHCO3 solution was added. After extraction, organic layer was dried with anhydrous MgSO4 and then filtered. The filtrate was concentrated and the concentrate was purified by column chromatography (hexane:diethyl ether=8:1) to obtain 50 mg of the target compound (0.15 mmol, 18.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:27])[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([N:19]([CH3:27])[CH3:18])[CH2:21][CH2:22]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (870 mg, 2.80 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine (400 mg, 2.80 mmol) to afford the desired product (398 mg, 36%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.12 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 7.85 (dd, J=8.9, 2.0 Hz, 1H), 7.76 (d, J=8.9 Hz, 1H), 4.10-3.84 (m, 1H), 2.93-2.70 (m, 1H), 2.56-2.40 (m, 1H), 2.37 (s, 6H), 2.25 (d, J=12.0 Hz, 2H), 2.05 (d, J=11.4 Hz, 2H), 1.62-1.31 (m, 4H), 1.31-1.01 (m, 4H).
Reaction SMILES: C(=O)([O-])OC.[Mg+2].COC(=O)[O-].[CH3:12][C:13]([C:15]1[N:16]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])[CH:17]=[CH:18][CH:19]=1)=[O:14].[N:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=1.Cl>CO.CN(C)C=O>[NH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:35]1[CH2:12][C:13]([C:15]1[N:16]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])[CH:17]=[CH:18][CH:19]=1)=[O:14]
Reactant: C1=NCCCC1
Reactant: CCc1cccc(CC)c1-n1cccc1C(C)=O
Agent: COC(=O)[O-]
Agent: Cl
Agent: [Mg+2]
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1cccc(CC)c1-n1cccc1C(=O)CC1CCCCN1
Temperature: 120 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of 186 g (0.5 mole) of magnesium methyl carbonate reagent (2.69 millimoles/g) and 300 ml of dry dimethylformamide are heated to 120°C. under an atmosphere of carbon dioxide. The compound 1-(2,6-diethylphenyl)pyrrol-2-yl methyl ketone, 36.1 g (0.15 mole), is added and the mixture stirred at 120°C. for a period of 4 hours under a stream of nitrogen to form the chelate, allowing the methyl alcohol that forms to escape. The mixture is cooled to room temperature under an atmosphere of carbon dioxide and 15.1 g (0.18 mole) of 2,3,4,5-tetrahydropyridine (as α-tripiperidein) is added and stirring continued at room temperature for a period of 40 hours under an atmosphere of carbon dioxide. The reaction mixture is poured into a solution of 2 N hydrochloride acid and extracted with ethyl ether. The combined extracts are washed with water, dried over sodium sulfate and the solvent removed. The remaining aqueous phase is made alkaline using a solution of 2 N sodium carbonate and extracted with ethyl ether. The ether extract is washed, dried over sodium sulfate and the solvent removed. The residue is converted to the hydrochloride salt, triturated with ether to solidify and the crude 1-(2,6-diethylphenyl)pyrrol-2-yl 2-piperidylmethyl ketone recrystallized from a methylene dichloride-ethyl ether mixture to yield 16.4 g (30% yield) of a product having a M.P. of 162-4°C.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.Cl.[CH3:40][NH:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46]>C(Cl)Cl>[C:2]([O:4][CH:5]1[C:14]2[C:15]3([CH3:30])[C:16]([C:17](=[CH:18][N:41]([CH3:40])[CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])[C:23](=[O:24])[O:25][CH:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: CNCCCC(=O)O
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1OC(=O)C(=CN(C)CCCC(=O)O)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added 4-(methylamino)butyric acid hydrochloride (71 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 549 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18].Cl.[CH:31]([C:34]1[CH:35]=[C:36]([C@@H:40]([NH2:42])[CH3:41])[CH:37]=[CH:38][CH:39]=1)([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:20]([O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](=[O:15])[NH:42][C@H:40]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([CH:31]([CH3:33])[CH3:32])[CH:35]=3)[CH3:41])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1
Reaction time: 15 h

Procedure:
The (S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (71 mg, 0.17 mmol), the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride (53 mg, 0.27 mmol) and HATU (88 mg, 0.23 mmol) were dissolved in DMF (3 mL) and DIEA (0.15 mL). It was stirred for 15 h. The solution was filtered and purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][C@@H:4]([CH3:7])[C:3]=1[C:8]([O:10]CC)=O.C([O-])=O.[NH4+].[CH:17]([NH2:19])=O>>[CH3:7][C@H:4]1[C:3]2[C:8]([OH:10])=[N:19][CH:17]=[N:1][C:2]=2[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1=C(N)CC[C@H]1C
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Product: C[C@@H]1CCc2ncnc(O)c21
Temperature: 150 °C
Reaction time: 17 h
Yield: 65 %

Procedure:
A solution containing (R)-ethyl 2-amino-5-methylcyclopent-1-enecarboxylate (161.61 g, 955.024 mmol) and ammonium formate (90.3298 g, 1432.54 mmol) in formamide (303.456 mL, 7640.19 mmol) was heated to an internal temperature of 150° C. and stirred for 17 hours. The reaction mixture was cooled, and transferred to a 2 L single extracted flask. Then excess formamidine was removed by high vacuum distillation. Once formamidine stopped coming over, the remaining oil in the still pot was dissolved in DCM and washed with brine (3×200 mL). The combined aqueous washes were extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated. The resulting oil was dissolved in minimal DCM, and this solution was added using a separatory funnel to a stirred solution of ether (about 5 volumes of ether vs. DCM solution), causing some precipitate to form. This precipitate was removed by filtration through a medium fit funnel which was rinsed with ether and disposed. The filtrate was concentrated, the trituration from ether repeated two more times and then dried on high vacuum line to give (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (93.225 g, 65.00% yield) as a pasty solid. LC/MS (APCI−) m/z 149.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[O:13]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:18][CH:15]1[CH2:16][CH2:17][O:13][CH2:14]1
Reactant: CS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: NC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(NC2CCOC2)c(Br)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 69.2 %

Procedure:
A mixture of 2-bromo-1-fluoro-4-methylsulfonylbenzene (0.8 g, 3.16 mmol), oxolan-3-amine (1.38 g, 15.8 mmol) and K2CO3 (0.87 g, 6.32 mmol) in DMSO (15 mL) was stirred at 100° C. for 5 hrs. It was cooled to r.t. and water (50 mL) was added. The mixture was extracted with EtOAc (50 mL×3) and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE: EA=50:1˜3:1) to give the title compound (0.7 g, yield: 69.16%). 1H NMR (CDCl3, 400 MHz) δ 8.00 (d, J=1.2 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 5.03 (d, J=6.4 Hz, 1H), 4.23-4.13 (m, 1H), 4.07-3.98 (m, 2H), 3.96-3.87 (m, 1H), 3.83-3.76 (m, 1H), 3.03 (s, 3H), 2.43-2.32 (m, 1H), 1.98-1.88 (m, 1H). LCMS (M+H)+=320.0 (M+H)+, 322.0
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH3:10])=[O:9])[C:5](Br)=[CH:4][C:3]=1[S:12]([CH3:14])=[O:13].[CH2:15]([C:18]1[S:19][C:20]([Sn](C)(C)C)=[CH:21][CH:22]=1)[CH2:16][CH3:17]>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>[CH3:14][S:12]([C:3]1[CH:4]=[C:5]([C:20]2[S:19][C:18]([CH2:15][CH2:16][CH3:17])=[CH:22][CH:21]=2)[C:6]([S:8]([CH3:10])=[O:9])=[CH:7][C:2]=1[C:20]1[S:19][C:18]([CH2:15][CH2:16][CH3:17])=[CH:22][CH:21]=1)=[O:13]
Reactant: CCCc1ccc([Sn](C)(C)C)s1
Reactant: CS(=O)c1cc(Br)c(S(C)=O)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCc1ccc(-c2cc(S(C)=O)c(-c3ccc(CCC)s3)cc2S(C)=O)s1
Temperature: 100 °C
Yield: 80.9 %

Procedure:
1,4-dibromo-2,5-bis(methylsulfinyl)benzene 3 (2.60 g, 7.21 mmol) was added to a solution of 2-propyl-5-trimethylstannylthiophene (5.0 g, 17.3 mmol) in anhydrous Toulene (48 mL), and the resulting mixture was purged with nitrogen for 30 min. Pd(PPh3)4 (0.833 g, 0.072 mmol) was then added, and the reaction mixture was heated to 100° C. overnight. Excess Toulene was removed under high vacuum, and the residue was dissolved in ethyl acetate and treated with 10% aqueous KF. The mixture was filtered through a pad of Celite. The filtrate was dried over Mg2SO4, filtered, and the solvent removed in vacuo. The crude product was purified by flash chromatography (silica gel, eluent:hexane/EA) 2:1) to afford 2.63 g (81%) of 2c.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:7]([O:23][CH3:24])=[CH:8][C:9]([O:21][CH3:22])=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.I[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[C:7]([O:23][CH3:24])=[CH:8][C:9]([O:21][CH3:22])=[C:10]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[CH:11]=1
Reactant: COc1cc(OC)c(C2OCCO2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Ic1cnccn1
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: O
Solvent: COCCOC
Product: COc1cc(OC)c(C2OCCO2)cc1-c1cnccn1
Yield: 59 %

Procedure:
Ex-46C: 2-(5-[1.3]Dioxolan-2-yl-2,4-dimethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Ex-46B, 2.22 g, 6.60 mmol, containing borolane impurity) was dissolved in DME (60 mL) and 2-iodopyrazine (0.59 mL, 6.0 mmol) was added. 2M aqueous Na2CO3 (17.8 mL, 35.6 mmol) was added and the mixture was purged with nitrogen for 20 min. Tetrakis(triphenylphosphine)palladium(0) (0.69 g, 0.60 mmol) was added and the mixture was heated at reflux for 2.5 h. After cooling, water (50 mL) was added and the mixture was extracted with CH2Cl2 (2×30 mL). The organic phase was washed with brine (1×20 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the resulting yellow-orange solids via silica chromatography (50–80% EtOAc/hexanes) provided 1.02 g of 2-(5-[1,3]dioxolan-2-yl-2,4-dimethoxy-phenyl)-pyrazine as a yellow solid (59% yield). 1H-NMR (CDCl3) δ 9.10 (d, J=2 Hz, 1H), 8.61 (m, 1H), 8.39 (d, J=3 Hz, 1H), 8.07 (s, 1H), 6.57 (s, 1H), 6.14 (s, 1H), 4.13–4.18 (m, 2H), 4.01–4.05 (m, 2H), 3.95 (s, 3H), 3.93 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][O:14]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:21]1[NH:20][CH:19]=[C:18]2[C:13](=[O:12])[O:14][CH2:15][CH2:16][C:17]=12
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-Chloro-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:8]2[C:9]3[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=3[O:11][C:12]3([CH2:17][CH2:16][N:15]([C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH3:30])[CH:21]=4)=[O:19])[CH2:14][CH2:13]3)[C:7]2=[CH:6][CH:5]=1.[CH:35](OCC)=[O:36]>>[CH:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([N:15]2[CH2:16][CH2:17][C:12]3([O:11][C:10]4[CH:31]=[CH:32][CH:33]=[CH:34][C:9]=4[N:8]4[C:4]([CH2:3][NH:2][CH:35]=[O:36])=[CH:5][CH:6]=[C:7]34)[CH2:13][CH2:14]2)=[O:19])=[CH:21][C:22]=1[CH3:30])([CH3:28])[CH3:29]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(CN)ccc23)ccc1OC(C)C
Reactant: CCOC=O
Agent: Cl
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(CNC=O)ccc23)ccc1OC(C)C

Procedure:
A solution of (1-(aminomethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-isopropoxy-3-methylphenyl)methanone hydrochloride (60 mg, 0.13 mmol) in ethyl formate (109 μL, 1.35 mmol) was heated at 50° C. overnight. The solvent was removed under reduced pressure and the product was purified by reverse phase HPLC 10-99% acetonitrile in water (HCl modifier) to give N-((1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]pyrrolo-[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl)formamide. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.30-7.22 (m, 1H), 7.20-7.01 (m, 3H), 6.83 (d, J=8.1 Hz, 1H), 6.28 (d, J=3.5 Hz, 1H), 5.99 (d, J=3.6 Hz, 1H), 5.89 (s, 1H), 4.77 (d, J=5.0 Hz, 2H), 4.62-4.52 (m, 1H), 3.50 (s, 2H), 2.21 (s, 3H), 2.17-1.78 (m, 4H), 1.70 (s, 2H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z talc. 473.6, found 474.5 (M+1)+; Retention time: 1.80 minutes (3 min run).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH:14]=[CH2:15])[CH:6]=1)=[S:3].[S:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C(N(CC)CC)C>C(OCC)C>[S:16]1[CH2:20][CH2:19][N:18]([C:2](=[S:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH:14]=[CH2:15])[CH:6]=2)[CH2:17]1
Reactant: C1CSCN1
Reactant: C=CCOc1cc(OC(=S)Cl)ccc1Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCOc1cc(OC(=S)N2CCSC2)ccc1Cl
Reaction time: 4 h
Yield: 66.5 %

Procedure:
O-(3-Allyloxy-4-chlorophenyl) chlorothioformate (2.63 g) was dissolved in 60 ml of diethyl ether. To this solution were added with stirring 1.01 g of thiazolidine and 1.42 ml of triethylamine. The resulting mixture was stirred for 4 hours and then washed with water. The solvent was distilled off from the ether layer. The residue was recrystallized from methanol to give 2.1 g of O-(3-allyloxy-4-chlorophenyl) 3-thiazolidinecarbothioate [Compound (33)]. The product had a melting point of 103.6°-105.6° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[C:25](#[N:27])[CH3:26]>>[N:27]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:10][CH2:9][CH2:26][CH2:25]1
Reactant: CC#N
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cc(OCCN2CCCCCCC2)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, heptamethyleneimine and acetonitrile essentially as described above in example 40. Purity by LC/MS (APCI)=99%, [M+H]+=357.