Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([CH2:13]O)=[CH:10][CH:9]=[CH:8]2)[CH3:2].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:16][CH2:13][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:8]=[CH:9][CH:10]=1
Reactant: CCc1cccc2cccc(CO)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cccc2cccc(CBr)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A solution of (8-ethyl-naphthalen-1-yl)-methanol (760 mg) in dichloromethane (15 ml) was cooled to 0° C. and treated with carbon tetrabromide (2.03 g). A solution of triphenylphosphine (1.28 g) in dichloromethane (15 ml) was added dropwise. The reaction mixture was stirred at r.t. overnight, then concentrated. The crude product was purified by column chromatography (silica gel; cyclohexane→cyclohexane/EtOAc 4:1) to give 1-bromomethyl-8-ethyl-naphthalene (670 mg) as light yellow liquid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30]Br>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:14][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCC(CNC(=O)OCc2ccccc2)CC1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCC1CCC(N2CCCC2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.8 %

Procedure:
To a solution of (4-amino-cyclohexylmethyl)-carbamic acid benzyl ester (350 mg, 1.34 mmol) in DMF (5 mL) was added K2CO3 (924 mg, 6.70 mmol) and 1,4-dibromobutane (160 mL, 1.34 mmol). The reaction mixture was stirred at room temperature for 14 h before diluting with EtOAc (100 mL). The reaction solution was washed with water (2×100 mL) and brine before concentrating in vacuo. The residue was purified by chromatography using a 12 g ISCO combi-flash cartridge (silica gel, 95:4.75:0.25 DCM/MeOH/NH4OH) to afford (4-pyrrolidin-1-yl-cyclohexylmethyl)-carbamic acid benzyl ester (351 mg, 83%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:43])[NH2:42])[CH:37]=2)[CH:32]=1)(=O)=O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:42])[NH2:43])[CH:37]=2)[CH:32]=1)=[O:5]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: Cc1ccccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
To 50 ml of anhydrous pyridine, was added 2.4 g of 2-methylbenzoic acid followed by 4.4 g of DCC under cooling in ice. After stirring for 30 minute and adding 5.0 g of 6amidino-2-naphthol methanesulfonate, the mixture was stirred overnight at room temperature. The precipitate was collected by filtration and washed with a small volume of pyridine, then successively with ethylether and acetone. The precipitate was dissolved in DMF and the insolubles were removed by filtration. Ethylether was added to the filtrate and the precipitated crystals were recrystallized from ethanol to obtain 1.4 g of flaky colorless crystals of 6amidino-2-napthyl 2-methyl benzoate methanesulfonate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:45]=[CH:44][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:19]2=[O:43])=[CH:15][CH:14]=1>[Pd].CO>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:43])=[CH:44][CH:45]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cccnc21
Yield: 25.5 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 500 mg of 5-[4-(3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 16), 1 g of 10% w/w palladium-on-charcoal and 100 ml of methanol were used, to give 77 mg of the title compound, melting at 223-225° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[Br-].[CH2:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CCc1ccc(O)c(Br)c1
Reactant: C1CCCC1
Agent: [Br-]
Product: CCOC(=O)CCc1ccc(OC2CCCC2)c(Br)c1

Procedure:
According to the procedure described in the synthesis method of Intermediate 8 in Reference Example 2 (Step e-1), ethyl 3-(3-bromo-4-hydroxyphenyl)propionate and cyclopentane bromide were reacted and treated to obtain ethyl 3-(3-bromo-4-cyclopentyloxyphenyl)propionate (410 mg). According to the procedure described in the synthesis method of Compound of Example 001 (Preparation Method 4, Step d-1) with the modifications that the reaction was carried out for 18 hours, and the purification was performed by flash column chromatography (hexane:ethyl acetate=8:1), the above product was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (396 mg), 2 M aqueous sodium carbonate (1.0 ml) and (Ph3P)4Pd (110 mg) and treated to obtain the title compound (Intermediate 67, 313 mg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][CH:37]=[CH:36][N:35]=1>C(#N)C>[N+:40]([C:39]1[C:34]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[N:35][CH:36]=[CH:37][CH:38]=1)([O-:42])=[O:41]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccnc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 107.8 %

Procedure:
To a stirred solution of {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (320 mg, 1.0 mmol) in acetonitrile (˜5 mL), was added Hunig's base (190 μL, 1.1 mmol, 1.1 eq.) and 2-chloro-3-nitropyridine (175 mg, 1.1 mmol, 1.1 eq.) and the mixture stirred at reflux for 4 hours. The reaction mixture was then concentrated in vacuo and partitioned between saturated NaHCO3 solution (20 mL) and DCM (2×20 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound (475 mg, 100%) as a yellow oil. LRMS APCI+ m/z 441 [MH]+.
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[Cl:7][C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[NH:10][C:9]=1[C:15]([NH:17][C@H:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]([C:32]([CH:35]=[O:36])=[CH:33][N:34]=2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][C@H:19]1[O:37][CH3:38])=[O:16]>O.CC(C)=O>[Cl:7][C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[NH:10][C:9]=1[C:15]([NH:17][C@H:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([C:35]([OH:1])=[O:36])=[CH:33][N:34]=2)[CH2:20][C@H:19]1[O:37][CH3:38])=[O:16]
Reactant: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 133 mg (0.84 mmol) KMnO4 in 5 ml water was added to a solution of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-formylisonicotinate (Example 154) in 20 ml acetone, and the mixture was stirred at room temperature for 4 h. After quenching with aqueous NaHSO3, the mixture was acidified to about pH=4 with 1N HCl and extracted twice with EtOAc. The EtOAc extracts were washed with brine, dried (MgSO4) and concentrated to give a solid that was triturated with MeOH to give 175 mg of product. MS (ES) MH+: 499 for C21H24Cl2N4O6; NMR: 1.25 (t, 3H), 1.5-1.8, (m, 3H), 2.1 (s, 3H), 3.1 (m, 3H), 3.3 (s, 3H), 3.5 (m, 1H), 4.2 (m, 2H), 4.4 (m, 1H), 4.9 (m, 1H), 6.9 (s, 1H), 7.1 (d, 1H), 8.6 (s, 1H), 12.1 (s, 1H), 13.3 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]([Sn](CCCC)(CCCC)CC=C)[CH2:20][CH2:21]C>C(#N)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([CH2:21][CH:20]=[CH2:19])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Solvent: CC#N
Product: C=CCc1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C

Procedure:
A 9 g portion of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was combined with 11.1 g of tri-n-butyl-2-propenylstannane and 1.69 g of tetrakis(triphenylphosphene) palladium in 40 mL of acetonitrile in a sealable tube. Argon was bubbled through the mixture, the cap replaced, and the reaction heated at 90° for 18 h. Upon cooling, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was triturated with diethyl ether to obtain 4.23 g of crystalline product, and a second crop of 1.31 g of product was also obtained. mp 144°-146°. FDMS 255 M+. Calcd for C17H21N1O2 :
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][C@@H:30]([CH3:60])[C@@H:31]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[C:49]([C:55]([F:58])([F:57])[F:56])[C:48]=1[CH3:59])[C:32]([NH:34][NH:35][C:36](=O)[C:37]1[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=1)=[O:33])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[Si:22]([O:29][C@@H:30]([CH3:60])[C@@H:31]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[C:49]([C:55]([F:58])([F:56])[F:57])[C:48]=1[CH3:59])[C:32]1[O:33][C:36]([C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)=[N:35][N:34]=1)([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:23])[CH3:24]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Yield: 98.8 %

Procedure:
Triphenylphosphine (374 mg, 1.43 mmol) was dissolved in 25 mL of DCM followed by addition of I2 (362 mg, 1.43 mmol) and TEA (289 mg, 2.85 mmol) at 0° C. N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)butanoyl)-4-cyanobenzohydrazide (400 mg, 0.71 mmol) in 15 mL DCM was added to the precooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to rise to room temperature and stirred for an additional 10 min. The reaction was quenched with 50 mL saturated sodium thiosulfate and extracted with EtOAc. The crude mixture was chromatographed to give the product (380 mg)1H NMR(400 MHz, acetone-d6, δ in ppm): 8.39 (d, J=9 Hz, 2H), 8.19 (d, J=9 Hz, 2H), 7.79 (d, J=9 Hz, 1H), 7.32 (d, J=9 Hz, 1H), 5.88 (d, J=9 Hz, 1H), 5.53 (m, 1H), 4.99 (m, 1H), 2.61 (m, 3H), 1.67 (d, J=6 Hz, 3H), 1.02 (s, 9H), 0.29 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].Cl[C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:17][CH:16]=2)[C:11]([Cl:34])=[CH:10][N:9]=1.O>CC(O)C>[Cl:34][C:11]1[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C@@H:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:19][CH:20]=2)=[N:13][C:8]([O:4][CH:2]([CH3:3])[CH3:1])=[N:9][CH:10]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3nc(Cl)ncc3Cl)cc2)C1
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(Cl)c(Nc2ccc([C@H]3CN(C(=O)OC(C)(C)C)CCO3)cc2)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a stirred solution of potassium tert.-butoxide (116 mg, 1.03 mmol) in propan-2-ol (2 mL) was added (S)-tert-butyl 2-(4-(2,5-dichloropyrimidin-4-ylamino)phenyl)morpholine-4-carboxylate (110 mg, 0.26 mmol) and the mixture was shaken at 90° C. overnight. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated. The residue was purified by column chromatography (silica gel, 5 to 15% ethyl acetate in heptan, 10 g ISCO column). White foam (58 mg, 50%). MS (ISP): 449.3 ([{35Cl}M+H]+), 451.1 ([{37Cl}M+H]+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:11]([O:13]CC)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[OH-].[K+]>O.C(O)C>[CH3:1][C:2]1[S:3][C:4]([C:11]([OH:13])=[O:12])=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=1
Reactant: CCOC(=O)c1sc(C)nc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C(F)(F)F)c(C(=O)O)s1
Reaction time: 8 h
Yield: 77.6 %

Procedure:
1.3 g of ethyl 2-methyl-4-trifluoromethylthiazole-5-carboxylate and 0.4 g of potassium hydroxide were dissolved in a mixture of 5 ml each of water and ethanol and reaction was effected at room temperature overnight. After the reaction, the reaction mixture was concentrated and acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was concentrated to obtain 0.89 g of 2-methyl-4-trifluoromethylthiazole-5-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C[O-].[Na+].O.[C:19](OCC)(=[O:21])C>CO>[CH3:19][O:21][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2
Reactant: CCOC(C)=O
Reactant: FC(F)(F)c1nc(Cl)c2[nH]cnc2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(C(F)(F)F)nc2nc[nH]c12
Temperature: 20 °C
Yield: 49 %

Procedure:
6-Chloro-2-trifluoromethylpurine (1.10 g, 5.0 mmol) in 25 ml of methanol was treated with 1.35 g (25 mmol) of sodium methoxide at 80° C. for 60 hours. Water (50 ml) and ethyl acetate (50 ml) were added after the reaction mixture was cooled to 20° C. The organic layer was separated and concentrated. Chromatography gave 535 mg (49%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:9])=[CH:4][N:3]=1
Reactant: Cc1ccc(Br)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)nc1
Yield: 110.3 %

Procedure:
A solution of 296.3 g (1.72 mol) of 2-bromo-5picoline from step 3 in 6 L of carbon tetrachloride was treated with 306.5 g (1.72 tool) of N-bromosuccinimide (NBS) and 28.3 g 173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCl3) 6 4.42 (s, 2H), 7.48 (d, J=9Hz, 1H), 7.60 (dd, 2=9 and 3Hz, 1H), 8.37 (d, J=3Hz, 1H).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][C:10]1[S:11][C:12]([CH3:15])=[N:13][N:14]=1)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:15][C:12]1[S:11][C:10]([CH2:9][NH2:8])=[N:14][N:13]=1
Reactant: Cc1nnc(CNC(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nnc(CN)s1
Reaction time: 1 h

Procedure:
Upon cooling in an ice-water bath, to a 6 mL 4M hydrogen chloride solution in 1,4-dioxane was added the tert-butyl[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]carbamate (391 mg, 1.71 mmol). After the stirring for 1 hr, the reaction mixture was concentrated to give the title compound as white solid (351 mg).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]3[CH:30]=[CH:29][S:28][CH:27]=3)=[CH:22][C:20]=2[CH:21]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+].Cl>CO.O>[S:28]1[CH:29]=[CH:30][C:26]([C:23]2[CH:24]=[CH:25][C:19]3[O:18][C:17]([CH2:16][O:15][C:13]([NH:12][C@H:4]([CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:3]([OH:31])=[O:2])=[O:14])=[CH:21][C:20]=3[CH:22]=2)=[CH:27]1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccsc3)ccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1cc2cc(-c3ccsc3)ccc2o1
Temperature: 50 °C
Yield: 65.9 %

Procedure:
A solution of (R)-2-(5-thiophen-3-yl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid methyl ester 23 (0.23 g, 0.54 mmole) in methanol (10 ml) was treated with a solution of lithium hydroxide monohydrate (25 mg, 0.59 mmole) in water (1 ml) and heated to 50° C. for 4 hrs, cooled, acidified with 1M HCl, evaporated, partitioned between ethyl acetate and 1M HCl, separated, washed, dried, and evaporated. The residue was crystallized giving about 0.15 g of (R)-2-(5-thiophen-3-yl-benzofuran-2-ylmethoxycarbonylamino)-3-phenylpropionic acid 24, mp. 169-170° C.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:28]=[CH:27][CH:26]=[CH:25][C:9]=1[NH:10][C:11]1[S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]=1[C:20](OCC)=[O:21].Cl>COCCOC>[CH:19]1[C:13]2[C:12]3[C:20](=[O:21])[NH:7][C:8]4[CH:28]=[CH:27][CH:26]=[CH:25][C:9]=4[NH:10][C:11]=3[S:15][C:14]=2[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1c(Nc2ccccc2N)sc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Product: O=C1Nc2ccccc2Nc2sc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
Potassium tert-butoxide (718 mg) was suspended in 1,2-dimethoxyethane (35 ml) and the mixture was refluxed under heating. Thereto was added dropwise ethyl 2-(2-aminoanilino)benzo[b]thiophene-3-carboxylate (1.0 g) dissolved in 1,2-dimethoxyethane (35 ml) over 15 minutes. After 30 minutes, potassium tert-butoxide (359 mg) was added and the mixture was refluxed under heating for 1 hour. After the completion of the reaction, the reaction mixture was allowed to cool to room temperature and poured into 0.5N hydrochloric acid. The mixed solution was extracted 3 times with chloroform, and washed with water and dried over magnesium sulfate. The solution was filtered and the solvent was evaporated under reduced pressure. The precipitated crude crystals were washed with ethyl acetate and diisopropyl ether to give 6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one (300 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:43][CH:44](OCC)OCC)[C:9]([CH:11]([NH:24][C:25](=[O:42])[CH2:26][CH:27]([NH:31][C:32]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:28][CH:29]=[CH2:30])[CH2:12][C:13]1[CH:18]=[CH:17]C(OC(C)(C)C)=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:51]([OH:53])=O>>[CH2:35]([NH:34][C:32]([N:31]1[CH:27]([CH2:28][CH:29]=[CH2:30])[CH2:26][C:25](=[O:42])[N:24]2[CH:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:51]([OH:53])=[CH:17][CH:18]=3)[C:9](=[O:10])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:43][CH:44]12)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1ccccc1)CC(OCC)OCC)NC(=O)NCc1ccccc1
Reactant: O=CO
Product: C=CCC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3ccccc3)CC2N1C(=O)NCc1ccccc1
Yield: 38 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-hex-5-enoic acid [1-[benzyl-(2,2-diethoxy-ethyl)-carbamoyl]-2-(4-tert-butoxy-phenyl)-ethyl]-amide (2.9 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and Hexane to give the 2-Allyl-8-benzyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic acid benzylamide (1.18 g, 3 step yield: 38%). 1H NMR (CDCl3, 300 MHz) δ 7.5˜7.26 (m, 5H), 7.25 (d, J=7.01, 2H), 6.85 (m, 5H), 6.55 (d, J=8.76, 2H), 5.7 (m, 1H), 5.3 (t, J=4.7, 1H), 5.05 (d, J=10.75, 1H), 5.0 (d, J=18.54, 1H), 4.87 (d, J=14.51, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H, OH), 3.5˜3.3 (m, 2H), 3.25-3.1 (m, 2H), 2.6˜2.4 (m, 2H), 2.2 (t, J=7.2, 2H) MS ESI 539 (M+H), 561 (M+Na).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(OO)(=[O:16])C.O>C(Cl)Cl>[C:8]1([CH2:7][CH:1]2[CH2:6][CH2:5][CH:4]3[CH:3]([O:16]3)[CH2:2]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1=CCC(Cc2ccccc2)CC1
Reactant: CC(=O)OO
Solvent: O
Solvent: ClCCl
Product: c1ccc(CC2CCC3OC3C2)cc1

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 9.55 g (0.056 mol) of (3-cyclohexen-1-ylmethyl)benzene, and 90 mL of methylene choride. Peracetic acid (17.5 g, 35 wt. % in acetic acid; 0.073 mol) in methylene chloride (70 mL) was added dropwise to the above mixture over 25 min. in an ice bath. After the above mixture was reacted at room temperature for 7 hrs., 200 mL of water was added to the above reaction mixture, the water layer was extracted with chloroform (2×150 mL). The organic layer was combined, washed with saturated sodium carbonate solution (2×150 mL), then with water (2×150 mL), and dried with sodium sulfate. The solvent was evaporated and the residue was vacuum distilled to give pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([OH:13])[C:7](O)=[N:6]2.O=S(Cl)[Cl:17].Cl>CN(C=O)C>[Cl:17][C:7]1[C:8]([OH:13])=[N:9][C:10]2[C:5]([N:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: COc1ccc2nc(O)c(O)nc2c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc2nc(O)c(Cl)nc2c1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A solution (1.53 M) of 6-methoxyquinoxaline-2,3-diol in DMF was treated with SOCl2 (1 eq) and heated at 110° C. After 1.5 h, the reaction mixture was cooled and poured into aqueous HCl (1 N). The resulting precipitate was filtered and washed with H2O and Et2O. The dried solid contained predominantly the title compound as a mixture with 6-methoxyquinoxaline-2,3-diol and 2,3-dichloro-6-methoxyquinoxaline. This material was used directly in the subsequent step. MS (ES+) m/z 211 (M+H)+
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:14])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CC(C)=O>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CC(=O)NC1Cc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2c(c1)CC(NC(C)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
1.05 g of 2-acetylamino-5-hydroxyindan are dissolved in 15 ml of acetone, and 1.14 g of powdered potassium carbonate and 1.01 g of methyl bromoacetate are added to the solution. The mixture is stirred overnight at room temperature and the reaction mixture is evaporated to remove solvent. The residue is extracted with ethyl acetate and the extract is washed successively with water and an aqueous sodium chloride solution, dried and evaporated to remove solvent. The residue is recrystallized from ethyl acetate-isopropyl ether-n-hexane to give 1.243 g of methyl (2-acetylaminoindan-5-yl)oxyacetate as colorless prisms. Yield: 86%