Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)(=O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=CC=CC=1)([O-])=O.C1([S-])C=CC=CC=1.[Na+]>O>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:30][CH:29]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2S(=O)(=O)c2ccccc2-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Na+]
Agent: [S-]c1ccccc1
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ccccc2Sc2ccccc2-c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
An amount of 21.4 g (0.08 mole) of the thus obtained 4-nitrophenylphenyl sulfone was dissolved in a two phase solvent composed of a mixture of 80 g of nitrobenzene and 80 g of water, and was reacted with sodium thiophenolate in the same manner as in Example 1.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[S:10][C:11]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[S:10][C:11]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: C(=Cc1nc2cnc3ccccc3c2s1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: c1ccc(CCc2nc3cnc4ccccc4c3s2)cc1
Yield: 75.3 %

Procedure:
A small amount of catalyst (5% palladium on activated carbon) was added to a suspension of 2-(2-phenyl-1-ethenyl)thiazolo[4,5-c]quinoline (1.16 g, Example 21 Part B) in acetic acid (200 mL). The mixture was reduced on a Parr apparatus under a 50 psi (3.5 Kg/cm2) hydrogen atmosphere for 1 day. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, washed with sodium bicarbonate then with water, dried over magnesium sulfate and then concentrated under vacuum to provide 0.88 g of 2-(2-phenyl-1-ethyl)thiazolo[4,5-c]quinoline as an oily solid.
Reaction SMILES: [S:1](=[O:4])([OH:3])[O-:2].[Na+:5].[CH:6]1([CH2:12]Br)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>O>[Na+:5].[CH:6]1([CH2:12][S:1]([O-:3])(=[O:2])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: BrCC1CCCCC1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CC1CCCCC1
Temperature: 25 °C
Yield: 39.3 %

Procedure:
To a solution of sodium bisulfite (32 g, 307 mmole) in H2O (200 mL) was added cyclohexylmethyl bromide (21 mL, 150 mmole). The mixture was then stirred vigorously while heated at reflux for 48 hours. Upon cooling to room temperature, a white precipitate formed. The precipitate was collected on a Buchner funnel and washed with diethyl ether to wash away residual cyclohexylmethyl bromide. The white plate-like solid was dried under high vacuum overnight to provide 11.8 g (39%) of the title compound which had a m.p. >400° C.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][CH3:30])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][CH3:30])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
A suspension of 7-[2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (0.7 ml.) and methanol (30 ml.) was stirred at room temperature for 1.5 hours. After removing methanol from the resultant solution in vacuo, water (30 ml.) was added to the residue. After the solution was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate, the insoluble substance was removed by filtration. The filtrate was adjusted to pH 3 with 10% hydrochloric acid. The precipitates were collected by filtration and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 0.6 g.).
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[CH:25]1([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1.[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[CH:43][C:44]=1[Cl:45].[BH4-].[Na+]>>[CH:25]1([C:30]2[CH:37]=[CH:36][C:33]([CH2:34][NH:48][CH2:47][CH2:46][C:41]3[CH:42]=[CH:43][C:44]([Cl:45])=[C:39]([Cl:38])[CH:40]=3)=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(C2CCCC2)cc1
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: Clc1ccc(CCNCc2ccc(C3CCCC3)cc2)cc1Cl

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 160 mg of 4-cyclopentyl-benzaldehyde (0.92 mmol), 175 mg of 2-(3,4-dichloro-phenyl)-ethylamine (0.92 mmol) and 52 mg of sodium borohydride (1.38 mmol). The isolated light yellow oil (183 mg, 57%) was used in the following step without further purification. MS (ISP) 348.2 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]([C:25]([O:27][CH3:28])=[O:26])[CH:8]=1)(=O)=O.[Li+].[Cl-].[CH:33]([Sn](CCCC)(CCCC)CCCC)=[CH2:34]>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:33]([C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]([C:25]([O:27][CH3:28])=[O:26])[CH:8]=1)=[CH2:34]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c2ccc(OCc3ccccc3)cc2c1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1cc(C(=O)OC)cc2cc(OCc3ccccc3)ccc12
Yield: 67.3 %

Procedure:
A solution of 0.5 g (1.4 mmol) of 1-trifluoromethylsulfonyloxy-3-carbomethoxy-6-benzyloxynaphthalene in 20 ml of DMF is stirred at 25° C. for 18 hours with 0.18 g (4.27 mmol, 3 eq) of LiCl, 0.46 ml (1.57 mmol, 1.1 eq) of vinyl-tributyltin and 0.019 g (0.03 mmol, 0.02 eq) bis(triphenyl-phosphine) palladium (II) chloride. The mixture is partitioned between ethyl acetate and 1N HCl. The organics are dried (MgSO4) and concentrated in vacuo. Purification by flash silica gel chromatography using 5% ethyl acetate in hexanes as an eluent affords 0.3 g of 1-vinyl-3-carbomethoxy-6-benzyloxynaphthalene in the form of a yellow oil which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:15])=[N:12][CH:13]=2)[CH:7]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]=1[CH3:42].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[C:34]([CH3:42])[CH:35]=3)=[CH:27][CH:26]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:15])=[N:12][CH:13]=2)[CH:7]=1
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: COC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(I)cc2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(F)c(C)c3)cc2)cn1

Procedure:
Methyl 3-(5-(5-chloro-2-(((4-iodophenyl)amino)methyl)phenyl)picolinamido)propanoate (83 mg, 0.15 mmol), (4-fluoro-3-methylphenyl)boronic acid (31 mg, 0.20 mmol), Pd(dppf)Cl2 (12 mg, 0.02 mmol), and K2CO3 (55 mg, 0.40 mmol) were dissolved in 1,4-dioxane (1.5 mL) and water (0.5 mL) and heated to 90° C. After 1.5 h the resulting mixture was diluted with DCM, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([N:9]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)[C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1>C(O)C.[Pd]>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([N:9]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)[C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)N(c1cccc(C(F)(F)F)c1)c1ccc([N+](=O)[O-])cc1-c1nnn[nH]1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)N(c1cccc(C(F)(F)F)c1)c1ccc(N)cc1-c1nnn[nH]1
Yield: 103.2 %

Procedure:
A solution of 3-trifluoromethylphenyl-4-nitro-2-(5-tetrazolyl)phenyl urea (0.8 g, 2.0 mmol) in 96% ethanol was hydrogenated over 5% palladium on charcoal for 3 hours at room temperature. The reaction mixture was filtered through a pad of celite and the solvent evaporated off to give 0.75 g of the desired product. M.p. 175-180° C.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=S)[NH:17][CH2:16]2>>[CH:2]1([NH:1][C:18]2[NH:17][CH2:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc2c(c1)CNC(=S)N2
Reactant: NC1CCc2ccccc21
Product: COc1ccc2c(c1)CNC(NC1CCc3ccccc31)=N2

Procedure:
The title compound (MS: m/e=294.2 [M+H+]) was prepared in analogy to example 1(b) from (+/−)-1-aminoindan and 6-methoxy-3,4-dihydro-1H-quinazoline-2-thione. 6-Methoxy-3,4-dihydro-1H-quinazoline-2-thione can be prepared by the method of Manetsch, Roman; Zheng, Lei; Reymond, Martine T.; Woggon, Wolf-Dietrich; Reymond, Jean-Louis Chemistry—A European Journal 2004, 10(10), 2487-2506.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]3[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=3[CH2:21][CH2:22][CH3:23])=[O:12])[CH:10]=1)[N:7]([CH3:26])[CH:6]=[C:5]2[CH:27]([CH3:29])[CH3:28].Cl.[CH3:31][N:32]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1)[CH3:33]>>[CH3:31][N:32]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]4[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=4[CH2:21][CH2:22][CH3:23])=[O:12])[CH:10]=2)[N:7]([CH3:26])[CH:6]=[C:5]3[CH:27]([CH3:28])[CH3:29])=[CH:37][CH:36]=1)[CH3:33]
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c(C(C)C)cn(C)c12
Agent: Cl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(CN(C)C)cc2)cc2c(C(C)C)cn(C)c12
Yield: 47.7 %

Procedure:
The title compound was prepared in the same manner as described for Example 2 using 5-bromo-1-methyl-3-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indole-7-carboxamide (300 mg, 0.65 mmol) and 4-(N,N-dimethylaminomethyl)phenylboronic acid pinacol ester hydrochloride (250 mg, 0.84 mmol). Obtained 159 mg of the title compound (47% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (s, 1H), 8.48 (t, J=4.80 Hz, 1H), 7.83 (d, J=1.77 Hz, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 7.33 (d, J=1.52 Hz, 1H), 7.10 (s, 1H), 5.90 (s, 1H), 4.38 (d, J=4.80 Hz, 2H), 3.70 (s, 3H), 3.34 (br. s., 2H), 3.22 (dt, J=6.82, 13.64 Hz, 1H), 2.52-2.59 (m, 2H), 2.25 (s, 6H), 2.13 (s, 3H), 1.52-1.63 (m, 2H), 1.31 (d, J=6.82 Hz, 6H), 0.94 (t, J=7.33 Hz, 3H). MS (ES) [M+H]+ 513.3.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=[O:21])[C:11]#[C:12][C:13]([CH3:20])([O:15][Si](C)(C)C)[CH3:14])[CH:7]=[CH:6][C:5]=12.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=[O:21])[C:11]#[C:12][C:13]([OH:15])([CH3:14])[CH3:20])[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C#CC(=O)c1ccc2nsnc2c1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)C#CC(=O)c1ccc2nsnc2c1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a stirred solution of 1-(benzo[c][1,2,5]thiadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (0.80 g, 2.515 mmol) in DCM (15 mL) was added p-TSA (0.574 g, 3.018 mmol) at RT. The reaction mixture was stirred for 2 h and diluted with water (5 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 1-(benzo[c][1,2,5]thiadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-1-one (0.6 g, 100%) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:29]=1[F:36])=[O:25])[C:21](O)=[O:22]>>[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:29]=1[F:36])=[O:25])[C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1F
Product: CC(C(=O)NCc1cc(F)cc(F)c1F)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=482.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(2,3,5-trifluoro-benzyl)-malonamic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18]#[N:19].CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][CH2:17][C:18]#[N:19]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCOc1ccc(Cl)c(Cl)c1
Temperature: 70 °C
Yield: 90.6 %

Procedure:
A mixture of 81.5 g of 3,4-dichlorophenol, 98.0 g of anhydrous K2CO3, 40.0 g of chloroacetonitrile and 100 ml of DMSO was stirred and heated to 70° C. after an initial period of ice cooling. The reaction mixture was heated at 70°-80° C. for 3 hours and the reaction mixture was then poured into 2500 ml of ice and water which resulted in crystal formation. The crystals were removed by filtration, washed with water and then dried overnight in a vacuum oven. The resulting solids were put in approximately 1 liter of boiling cyclohexane and treated with activated charcoal and then filtered. The filtrate was cooled to 10° C. and filtered, which gave 91.5 g of 3,4-dichlorophenoxyacetonitrile, m.p. 61°-62° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH3:19])C=C.[C:20]1(C)[CH:25]=C(C)C=C(C)[CH:21]=1>>[CH2:25]([C:10]1[CH:9]=[CH:8][C:7]([F:11])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[CH3:19])[C:5]=1[OH:4])[CH:20]=[CH2:21]
Reactant: C=CCOc1cccc(F)c1-c1ccc(Cl)cc1C
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1ccc(F)c(-c2ccc(Cl)cc2C)c1O
Yield: 95 %

Procedure:
A solution of 2′-allyloxy-4-chloro-6′-fluoro-2-methylbiphenyl (2.1 g, 7.6 mmol) in mesitylene (70 mL) was refluxed for 24 h. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes provided 2.0 g (95%) of 3-allyl-4′-chloro-6-fluoro-2′-methylbiphenyl-2-ol as a pale yellow oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:27])=[C:7]([CH:24]=[CH:25][CH:26]=1)[C:8]([NH:10][C@@H:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:12]([OH:16])[C:13](O)=[O:14])=[O:9])(=[O:3])[CH3:2].[CH2:28]([NH:31][C:32]([C@@H:34]1[C:38]([CH3:40])([CH3:39])[S:37][CH2:36][NH:35]1)=[O:33])[CH:29]=[CH2:30].O.C(N=C=NC(C)C)(C)C>CC1CCCO1>[CH2:28]([NH:31][C:32]([C@@H:34]1[C:38]([CH3:40])([CH3:39])[S:37][CH2:36][N:35]1[C:13](=[O:14])[C@@H:12]([OH:16])[C@@H:11]([NH:10][C:8]([C:7]1[C:6]([CH3:27])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:26]=[CH:25][CH:24]=1)=[O:9])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:33])[CH:29]=[CH2:30]
Reactant: CC(=O)Oc1cccc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)O)c1C
Reactant: C=CCNC(=O)[C@H]1NCSC1(C)C
Agent: CC(C)N=C=NC(C)C
Solvent: CC1CCCO1
Solvent: O
Product: C=CCNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc(OC(C)=O)c2C)CSC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(2S,3S)-3-(3-Acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyric acid (271 g; 731 mmol) was added to a 5-L flask containing a solution of (4R)-5,5-Dimethyl-thiazolidine-4-carboxylic acid allylamide (161 g; 804 mmol) in 2-methyltetrahydrofuran (1.20 L total solution), while using 2-methyltetrahydrofuran (500 mL) for rinsing. HOBt.H2O (32.6 g; 241 mmol) was added, using 2-methyltetrahydrofuran (50 mL) for rinsing. The white suspension was allowed to stir at room temperature for 10 min. Diisopropylcarbodiimide (119 mL; 760 mmol) was added in three portions (40 mL+40 mL+39 mL) at 30 min intervals. One hour after the final DIC addition, Celite (100 g) was added and the suspension was allowed to stir at room temperature for 3 h. The mixture was vacuum-filtered, while 2-methyltetrahydrofuran (400 mL) was used to rinse over the solids and wash the resulting filter cake. The filtrate was transferred to 4-L separatory funnel, using 2-methyltetrahydrofuran (50 mL) for rinsing. The solution was washed with 1 N HCl (1.25 L), and then with an aqueous solution of NaHCO3 (27 g), NaCl (134 g) and H2O (1.25 L). The resulting organic phase was transferred to a 3-L distillation flask and the solution was then reduced to a volume of 1.12 L by distillation of 2-methyltetrahydrofuran at one atmosphere. The solution was then diluted with 2-methyltetrahydrofuran (230 mL) to bring the total volume to 1.35 L. After cooling the solution to 23° C., the solution of crude acetic acid 3-{(1 S,2S)-3-[(4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl]-1-benzyl-2-hydroxy-3-oxo-propylcarbamoyl}-2-methyl-phenyl ester on directly into the next step.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([O:14][CH3:15])=[O:13])[NH:3]1.C(N(CC)CC)C.N#N.Cl.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH:34]=[C:33]([S:40]([NH:43][C@H:44]([C:52](Cl)=[O:53])[CH2:45][CH2:46][CH2:47][NH:48][C:49](=[NH:51])[NH2:50])(=[O:42])=[O:41])[CH:32]=[CH:31]2>C(Cl)(Cl)Cl>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH:34]=[C:33]([S:40]([NH:43][C@H:44]([C:52]([N:3]1[CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]1)=[O:53])[CH2:45][CH2:46][CH2:47][NH:48][C:49](=[NH:50])[NH2:51])(=[O:41])=[O:42])[CH:32]=[CH:31]2
Reactant: COC(=O)C1Cc2ccccc2CN1
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Agent: Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1Cc2ccccc2CN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Reaction time: 8 h

Procedure:
To a stirred solution of 1.8 g of methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride and 8 ml of triethylamine in 50 ml of chloroform which was cooled in an ice bath, there was carefully added N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloride hydrochloride obtained above. The reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was washed twice with 50 ml of saturated sodium chloride solution and evaporated to dryness. The residue was dissolved in water-ethanol and ajusted to pH 12 with 5N NaOH solution at a temperature below 0° C to precipitate a solid. This was collected by filtration to give 3 g of methyl 2-[N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.
Reaction SMILES: ClC[CH2:3][N:4]1[C:8](=O)[O:7][N:6]=[C:5]1[C:10]1[C:14]2[CH:15]=[C:16]([CH:33]3[CH2:35][CH2:34]3)[C:17]([N:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:13]=2[O:12][C:11]=1[C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1.[OH-].[Na+]>C(O)C>[CH:33]1([C:16]2[C:17]([N:19]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:13]3[O:12][C:11]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)=[C:10]([C:5]4[NH:4][CH2:3][CH2:8][O:7][N:6]=4)[C:14]=3[CH:15]=2)[CH2:34][CH2:35]1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(-c4noc(=O)n4CCCl)c3cc2C2CC2)S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C4=NOCCN4)c3cc2C2CC2)S(C)(=O)=O)cc1
Yield: 67 %

Procedure:
A mixture of Example 8E (3.54 g, 5.78 mmol) and 1.0 M aqueous sodium hydroxide (14.46 mL, 14.46 mmol) in ethanol (50 mL) was refluxed for 2 hours, cooled, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel eluting with methanol (2% to 4%) in dichloromethane to give the title compound as a solid (2.13 g, 67%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.16-0.27 (m, 1H) 0.65-0.82 (m, 2H) 0.85-1.00 (m, 1H) 2.15-2.25 (m, 1H) 3.20 (s, 3H) 3.66-3.69 (m, 3H) 4.54 (s, 2H) 4.69-4.91 (m, 2H) 6.77-6.82 (m, 2H) 7.03 (s, 1H) 7.10-7.16 (m, 2H) 7.37-7.45 (m, 2H) 7.80 (s, 1H) 7.83-7.91 (m, 2H) 11.32 (s, 1H); MS (ESI+) m/z 550.1 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[S:8][N:7]=2)=[CH:2]1.Cl.CCCCCC>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]=[C:9]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[S:8][N:7]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccsc3)ns2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1cc(-c2nsc(N3CCNCC3)n2)cs1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of tert-butyl 4-[3-(3-thienyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxylate (3.70 g, 10.5 mmol) in ethyl acetate (60 ml) was added a solution of 4 N hydrochloric acid in ethyl acetate (30 ml), and the mixture was stirred at room temperature for 22 hours. Hexane (200 ml) was poured to the reaction mixture, and a solid was separated by filtration. The obtained solid was dissolved in an aqueous saturated sodium hydrogen carbonate solution, followed by stirring at room temperature for 2 hours. Water was poured to the reaction mixture, and 1.86 g (70.4%) of the desired product as a solid was separated by filtration.