Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:17](=O)[O:16]C(C)(C)[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([OH:14])[C:18]=1[CH:17]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2c(OCc3ccccc3)cccc2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1c(O)cccc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
A solution of 5-(benzyloxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (Example 38A, 4.00 g, 14.07 mmol) in dichloromethane (80 mL) was cooled to −78° C. and treated with a solution of diisobutylaluminum hydride (6.00 g, 42.2 mmol) in toluene (40 mL) added dropwise over 20 min. The resulting mixture was then stirred at −78° C. for 3 h. The reaction mixture was quenched by the careful addition of methanol (5 mL) added dropwise over 15 min, followed by 4 N hydrochloric acid (20 mL) added dropwise over 15 min. The cooling bath was then removed and an additional 80 mL of 4N hydrochloric acid was added over 10 min and the mixture was stirred vigorously at 22° C. for 4 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting oil was chromatographed on silica gel (4×10 cm, elution toluene) to give 2.25 g (70% yield) of the title material as a pale yellow solid. LC (Method A): 2.219 min. HRMS (ESI) calcd for C14H13O3 [M+H]+ m/z 229.0859, found 229.0859. 1H NMR (CDCl3, 600 MHz) δ ppm: 5.12 (s, 2H), 6.43 (d, J=8.25 Hz, 1H), 6.52 (d, J=8.46 Hz, 1H), 7.34-7.4 (m, 6H), 10.39 (s, 1H), 11.95 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:8][C:9]=1[N:10]([C:11]([CH:13]1[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[CH:20]1[CH2:29][CH2:28][C:23](=[O:24])[CH2:22][CH2:21]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.2 %

Procedure:
To 3-[(1,4-Dioxa-spiro[4.5]dec-8-yl)-(trans 4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (401 mg, 0.806 mmol) in tetrahydrofuran (4 ml) was added 3N HCl solution (4 ml) and the reaction was stirred at room temperature for 20 hours. It was then diluted with ethyl acetate (10 ml), the organic layer was separated, and the aqueous phase was washed twice with ethyl acetate (2×10 mL). The combined ethyl acetate layer was washed with brine (10 ml) and dried on Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0% to 40% EtOAc/Hexane) to obtain 315 mg (86%) of 3-[(4-Methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([CH3:21])[CH:20]=1)[N:17]=[C:16]([O:22][CH3:23])[CH:15]=[CH:14]2)(=O)[CH3:8].[C:24]([NH:27][NH2:28])(=O)[CH3:25]>C1(C)C=CC=CC=1>[CH3:8][C:7]1[N:10]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=2)[N:17]=[C:16]([O:22][CH3:23])[CH:15]=[CH:14]3)[C:24]([CH3:25])=[N:27][N:28]=1
Reactant: COc1ccc2cc(NC(C)=O)cc(C)c2n1
Reactant: CC(=O)NN
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc2cc(-n3c(C)nnc3C)cc(C)c2n1
Reaction time: 0.25 h
Yield: 26.3 %

Procedure:
Phosphorous pentachloride (1.0 g) was added to a stirred solution of 6-acetamido-2-methoxy-8-methylquinoline (1.0 g) in toluene (50 cm3) and the mixture was stirred at 50° for 15 minutes. Acetyl hydrazine (1.35 g) was then added and the mixture was stirred for 3 hours at 60°. The toluene was removed in vacuo, the residue dissolved in ethanol, and aqueous ammonia solution (S.G. 0.88) (25 cm3) was added. Dichloromethane (100 cm3) was added and the organic phase was separated. The aqueous phase was further extracted with dichloromethane (2×25 cm3), and the combined organic phases were dried (MgS04) and evaporated to give a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane:methanol, 19:1. Combination and evaporation of appropriate fractions afforded 6-[3,5-dimethyl-1,2,4-triazol-4-yl]-2-methoxy-8-methylquinoline (0.306 g), which was recrystallised from toluene to give microcrystals, m.p. 211°-213° (0.066 g).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH2:6][NH:7][C:8](=[S:19])[NH:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[N:15][NH:16]2)=[CH:12][CH:11]=1)C.[OH-].[Na+]>CO.O>[NH:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([NH:9][C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:20])=[O:3])=[S:19])[CH:18]=2)[CH:14]=[N:15]1
Reactant: CCOC(=O)CCNC(=S)Nc1ccc2cn[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCNC(=S)Nc1ccc2cn[nH]c2c1
Yield: 54.1 %

Procedure:
A solution of 0.6 g (2.05 mmol) of the ester thus obtained and 0.09 g (2.36 mmol) of sodium hydroxide in 15 ml of methanol and 0.1 ml of water is left at room temperature and under agitation for 20 hr. After concentration to dryness, 10 ml of water is added to the residue is obtained. After purification by extraction with ethyl acetate (3 × 20 ml), the aqueous phase is cooled and then acidified with a 3 N hydrochloric acid solution until a pH close to 3 is obtained 0.293 g (yield 56%) of (lH-indazol-6-yl)thiocarbamoyl-beta-alanine is obtained in the form of a solid having a melting point of 175° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[NH:30]1[C:34](C2C=C(C=CC=2)N)=[CH:33][CH:32]=[N:31]1>>[NH:30]1[C:34]([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[NH2:1])[N:14]=3)[CH:21]=[CH:20][CH:19]=2)=[CH:33][CH:32]=[N:31]1
Reactant: Nc1cccc(-c2ccn[nH]2)c1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-c2ccn[nH]2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(1H-pyrazol-5-yl)aniline in step 1. MS: 393.0 (M+H).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[N:23]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:27][NH:26][CH:25]([C:29]([O:31][CH3:32])=[O:30])[CH2:24]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:10]([N:8]1[CH2:9][CH:6]([N:26]2[CH2:27][CH2:28][N:23]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:24][CH:25]2[C:29]([O:31][CH3:32])=[O:30])[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 52.6 %

Procedure:
A mixture of 1-benzhydrylazetidin-3-yl methanesulfonate (2.4 g, 7.56 mmol), tert-butyl methyl piperazine-1,3-dicarboxylate (1.85 g, 7.56 mmol), K2CO3 (1.6 g, 11.34 mmol) in CH3CN (40 mL) was stirred at reflux for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% petroleum ether/ethyl acetate) to afford the desired product (1.85 g, 51% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(/C=C/C1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)/C=C/C2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 24 h

Procedure:
1.27 g of (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene was added to a mixed solution of 10 ml of acetic acid and 2 ml of hydrochloric acid, and then 1.38 g of stannous chloride was added thereto under ice cooling. The mixture was stirred for 24 hours. During the reaction, 0.69 g of stannous chloride was further added twice. After completion of the reaction, the reaction mixture was condensed under reduced pressure to obtain 5.50 g of a crude product of the title compound. This was used without purification for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][N:22]([CH3:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][NH:32][CH3:33])=[CH:25][CH:24]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:32]([CH3:33])[CH2:31][CH2:30][O:29][C:26]3[CH:27]=[CH:28][C:23]([N:22]([CH3:34])[CH3:21])=[CH:24][CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCOc1ccc(N(C)C)cc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCOc1ccc(N(C)C)cc1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane, N-[2-(4-dimethylaminophenyloxy)-ethyl]-methylamine and triethylamine analogously to Example 6.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].Br[C:17]1C2N(CCO)C=NC=2C=CC=1>>[OH:1][CH2:2][CH2:3][N:4]1[C:5]2[C:6]([C:7]#[N:8])=[CH:9][CH:10]=[CH:11][C:12]=2[N:13]=[CH:17]1
Reactant: N#Cc1cccc([N+](=O)[O-])c1NCCO
Reactant: OCCn1cnc2cccc(Br)c21
Product: N#Cc1cccc2ncn(CCO)c12

Procedure:
1-(2-Hydroxyethyl)-1H-benzimidazole-7-carbonitrile was prepared in two steps starting from 2-[(2-hydroxyethyl)amino]-3-nitrobenzonitrile (0.99 g) according to the procedure described for the synthesis of 2-(7-bromo-1H-benzimidazol-1-yl)ethanol. Yield 0.49 g (55 %). MS (ESI) m/z 188.1 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm: 3.81 (q, J=5.1 Hz, 2H), 4.53 (t, J=5.3 Hz, 2H), 5.03 (t, J=5.1 Hz, 1H) 7.36 (t, J=7.8 Hz, 1H), 7.76 (dd, J=7.6, 1.0 Hz, 1H), 8.04 (dd, J=8.1, 1.0 Hz, 1H), 8.37 (s, 1H).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[CH:8]=[C:9]2[CH:19]=[CH:18][S:17][C:10]2=[N:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[O:6].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:1][C:19]1[C:9]2[C:10](=[N:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([C:5]([O:4][CH3:3])=[O:6])[CH:8]=2)[S:17][CH:18]=1
Reactant: COC(=O)c1cc2ccsc2nc1C(=O)OC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(Br)csc2nc1C(=O)OC
Temperature: 75 °C
Reaction time: 6 h

Procedure:
Bromine (0.33, 0.00206 mol) in acetic acid (8 mL) is added to a stirred solution of dimethylthieno[2,3-b]pyridine-5,6-dicarboxylate (0.5 g, 0.00187 mol) in acetic acid containing sodium acetate (0.31 g, 0.00377 mol) at 40° C. The reaction mixture is heated at 75° C. for 18 hours. Evaluation of the mixture by tlc (silica gel) indicated incomplete reaction. Additional bromine (0.33 g) in acetic acid and sodium acetate (0.31 g) is added and heating at 75° C. continued for six hours. The reaction mixture is diluted with water and extracted into ethyl acetate. The separated organic layer is dried over anhydrous MgSO4, filtered, and the filtrate concentrated to an oil which solidifies on standing. Crystallization of the crude product from ethyl acetate-hexanes yields the dimethyl 3-bromothieno[2,3-b]pyridine-5,6-dicarboxylate as white needles mp 86°-87.5° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Reactant: C1COCCN1
Product: c1cc(N2CCC(N3CCOCC3)CC2)ccc1CN1CCOCC1

Procedure:
Prepared from the product of Example 19 and morpholine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33]C)=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[O:23])[O:21][N:20]=[C:19]([CH3:24])[C:18]=3[CH:25]=2)=[O:12])[CH:7]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl.B(Br)(Br)Br>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:27])([F:29])[F:28])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[O:23])[O:21][N:20]=[C:19]([CH3:24])[C:18]=3[CH:25]=2)=[O:12])[CH:7]=1
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(C(=O)Nc1ccc2c(=O)onc(C)c2c1)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(Br)ccc3O)C(F)(F)F)cc12
Yield: 80.8 %

Procedure:
43.2 mg of (+)-6-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeroylamino]-4-methyl-2,3-benzoxazin-1-one in 2.5 ml of dichloromethane and 0.4 ml of 1 M boron tribromide in dichloromethane are stirred for 1.5 hours at 0° C. and mixed with ethyl acetate and sodium bicarbonate solution. The organic phase is washed with water, dried, concentrated by evaporation, and the residue is chromatographed on silica gel (hexane/ethyl acetate, 1.5+1). After crystallization from diisopropyl ether, 34 mg of (+)-6-[4-(5-bromo-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeroylamino]-4-methyl-2,3-benzoxazin-1-one is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:9]([CH3:27])[C:8](=[O:28])[CH2:7][CH2:6]2.[C:29]([NH:36][CH2:37][CH2:38][N:39]=[C:40]=[S:41])([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C1C=CC=CC=1.C(OCC)C>[C:32]([O:31][C:29](=[O:30])[NH:36][CH2:37][CH2:38][NH:39][C:40]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][CH2:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:28])[N:9]3[CH3:27])=[CH:4][C:3]=2[O:2][CH3:1])[CH:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[S:41])([CH3:35])([CH3:33])[CH3:34]
Reactant: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)N(C)C(=O)CC2
Reactant: CC(C)(C)OC(=O)NCCN=C=S
Solvent: c1ccccc1
Solvent: CCOCC
Product: COc1cc2c(cc1CNC1CCCN(C(=S)NCCNC(=O)OC(C)(C)C)C1c1ccccc1)N(C)C(=O)CC2
Yield: 69.5 %

Procedure:
6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one (750 mg, 1.98 mmol) and N-BOC-2-isothiocyanatoethylamine (400 mg, 1.98 mmol) were stirred in 20 mL of benzene at room temperature for 16 hours. The reaction was diluted with diethyl ether and washed 1× with water, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (6:1 ethyl acetate/hexane) gave 800 mg (70% yield) of [2-({3-[(6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-amino]-2-phenyl-piperidine-1-carbothioyl}-amino)-ethyl]-carbamic acid tert-butyl ester. Rf=0.11 (6:1 ethyl acetate/hexane).
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11]C(=O)C(C)(C)C.C1(C)C=CC=CC=1.[ClH:31]>>[ClH:31].[ClH:31].[CH3:1][NH:2][CH:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CNC(Cc1ccccc1N)c1ccccc1
Temperature: 100 °C
Reaction time: 28 h
Yield: 92.9 %

Procedure:
N-[2-(2-methylamino-2-phenylethyl)phenyl]-2,2-dimethylpropanamide (155 g, 0.5 mol) was dissolved in 6N HCl (310 g) and stirred under a nitrogen atmosphere at 100° C. for 28 hours. The reaction mixture was cooled to 23° C. and toluene (200 ml) was added. Stirring was continued until the product had crystallized from the aqueous phase. The product was collected by filtration, washed with toluene (2×50 ml) and dried in vacuo (30 mm) at 60° C. for 60 hours to give N-methyl-2-amino-α-phenylphenethyl-amine dihydrochloride (139 g, 93% yield). The melting point of the product was 252°-254° C. The organic phase of the filtrate was concentrated in vacuo to give a 58% recovery of trimethylacetic acid. The aqueous phase of the filtrate afforded a second crop of N-methyl-2-amino-α-phenylphenethylamine dihydrochloride (9.3 g, 6%) The total yield of product was 99%.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([Br:14])=[CH:9][C:8]=1[F:15])(=O)=O.[Li+].[Br-:17]>CN(C=O)C.CCOC(C)=O>[Br:14][C:10]1[CH:9]=[C:8]([F:15])[C:7]([CH2:6][Br:17])=[C:12]([F:13])[CH:11]=1
Reactant: [Br-]
Reactant: CS(=O)(=O)OCc1c(F)cc(Br)cc1F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc(Br)cc(F)c1CBr
Temperature: 90 °C

Procedure:
To a solution of 4-bromo-2,6-difluorobenzyl methanesulfonate (from Step A above) in DMF (400 mL) was added LiBr (28.8 g, 335 mmol) and heated to 90° C. for 45 minutes. The reaction was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water (5×), brine (2×) dried over MgSO4, and concentrated in vacuo to yield a brown oil. The crude residue was purified via silica gel column chromatography (CH2Cl2/hexanes) to yield the title compound (24 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]2=[O:22].[CH3:23][C:24]1(OC)[CH2:28][CH2:27][CH:26](OC)O1>C(O)(=O)C>[CH3:23][C:24]1[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[C:12]([F:13])([F:15])[F:14])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]3=[O:22])[CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Reactant: COC1CCC(C)(OC)O1
Solvent: CC(=O)O
Product: Cc1cccn1-c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F

Procedure:
To a solution of 200 mg (0.59 mmol) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide in 10 ml of acetic acid, 87 mg (0.60 mmol) of 2-methyl-2,5-dimethoxy-tetrahydrofuran is added and the reaction mixture is stirred at reflux for 5 hours. Subsequently the solvent is evaporated and the residue is dried for I day at 60° C. and high vacuum to yield N-[6-(2-methyl-pyrrol-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide. 1H-NMR; DMSO-d6 (400 MHz, ppm): 7.69 (s, 1H, aromatic); 7.54 (s, 1H , aromatic); 6.6 (s, 1H, N-CH═CH in pyrrol); 5.97 (t, 1H, CH═CH═CH in pyrrol); 5.83 (m, 1H, CH═CH-C(CH3)-N in pyrrol); 3.05 (s, 3H, SO2-CH3); 1.82 (s, 3H, pyrrol-1-CH3). LC-MS: 403 [M+H]+; Agilent LC/MSD 1100 Series; LC-MS method: Column: SunFireC18, 4.6*50 mm, 3.5 μm; positive MS; water/acetonitril 95:5 to 5:95 in 5 min, flow: 1.5 ml/min.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][CH:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])=[CH:11][CH:10]=1)C1C=CC=CC=1.ClCCl>CO.[Pd]>[C:25]([Si:22]([CH3:24])([CH3:23])[O:21][CH:19]([CH3:20])[CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([OH:8])[CH:17]=2)[CH:13]=[N:14]1)([CH3:27])([CH3:28])[CH3:26]
Reactant: CC(Cn1ncc2ccc(OCc3ccccc3)cc21)O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(Cn1ncc2ccc(O)cc21)O[Si](C)(C)C(C)(C)C
Reaction time: 6 h
Yield: 84.6 %

Procedure:
A mixture of the product from Step A (10.6 g, 27 mmol) and palladium-on-carbon (10%, 0.26 g) in methanol (250 mL) was stirred under an atmosphere of hydrogen for 6 h, dichloromethane (100 mL) was added and the mixture filtered. Evaporation of the filtrate gave an off-white solid (7.0 g, 85%): mp 169-174° C.; LC/MS (+APCI) m/z 307 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:14][OH:15])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:16][O:17][C:18]1[CH:41]=[CH:40][C:21]([C:22](Cl)([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>N1C=CC=CC=1.O1CCOCC1>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([O:15][CH2:14][C:3]([CH2:2][OH:1])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:21]2[CH:40]=[CH:41][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Reactant: COc1ccc(C(Cl)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCOC(=O)C(CO)(COC(c1ccc(OC)cc1)(c1ccc(OC)cc1)c1ccc(OC)cc1)C(=O)OCC
Yield: 28.5 %

Procedure:
Referring to scheme 1, diethyl bis-(hydroxymethyl)malonate (11.5 g, 55 mmol) was treated overnight with 4,4′,4″-trimethoxytrityl chloride (19.2 g, 52 mmol) in pyridine (16 mL) and dioxane (100 mL), and the solvent was evaporated. The residue was dissolved in CH2Cl2 (500 mL), washed with 5% aqueous NaHCO3 (3×100 mL), washed with brine (2×100 mL), dried over Na2SO4 and evaporated. The residue was purified on a silica gel column using a step gradient of ethyl acetate (0 to 15%) in toluene to give 1 (8.2 g, 67.5%) as an oil. HR MALDI MS: calculated for C31H36O9 (M+H+) 553.2442, found 553.2438. 1H NMR (CDCl3) δ 7.29 (6H, d, J=8.8 Hz), 6.83 (6H, d, J=8.8 Hz), 4.26-4.11 (6H, m), 3.80 (9H, s), 3.62 (2H, s), 2.11 (1H, t, J=5.8 Hz), 1.24 (6H, t, J=7.0 Hz). 13C NMR (CDCl3) δ 169.3 (C), 158.5 (C), 136.1 (C), 129.8 (CH), 113.2 (CH), 86.0 (C), 63.7 (CH2), 61.9 (CH2), 61.6 (CH2), 60.6 (C), 55.2 (CH3), 14.1 (CH3).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[SH:5][CH:6]([CH2:14][CH2:15][SH:16])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:16][CH2:15][CH2:14][CH:6]([SH:5])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(O)CCCCC(S)CCS
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCCC(S)CCCCC(=O)O
Reaction time: 0.25 h
Yield: 5.4 %

Procedure:
Acetyl chloride (0.30 g, 3.8 mmol) in 4 mL of dry methylene chloride was added dropwise under a nitrogen atmosphere over 10 min to a stirred solution of 6,8-bismercaptooctanoic acid (0.80 g, 3.8 mmol) and triethylamine (1.16 g, 11.5 mmol) at 0. The solution was stirred at 0 a further 15 min then at room temperature for 2 hr. The solution was diluted to 75 mL with methylene chloride and extracted with 2×50 mL of 10% aqueous citric acid, then washed with 30 mL of saturated brine. The organic phase was dried (MgSO4), filtered and the solvent evaporated. The oil remaining was dissolved in 8 mL of 2-propanol and 8 mL of water added. The mixture was stirred under nitrogen at 40 for 4.5 hr. The solvent was evaporated in vacuo and the crude product mixture separated by column chromatography on silica gel first using ethyl acetate-hexane-acetic acid (100:100:1, v/v) as the eluting solvent, and then rechromatographed using hexane-ethyl acetate-acetic acid (150:100:1, v/v) as the solvent yielding 51 mg (5%) of pure 8-acetylmercapto-6-mercaptooctanoic acid as a colorless oil.