Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[CH:6]1([CH2:12][NH:13][CH2:14][C@H:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:22][CH:21]=3)[C:18](=[O:36])[CH2:17][CH2:16]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH:6]1([CH2:12][N:13]([CH2:14][C@H:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][CH2:33][CH:34]4[CH3:35])=[CH:22][CH:21]=3)[C:18](=[O:36])[CH2:17][CH2:16]2)[CH2:2][CH:3]2[CH2:5][CH2:4]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CC[C@@H](CNCC2CCCCC2)N1c1ccc(OCCCN2CCCCC2)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CN(CC2CCCCC2)CC2CC2)cc1
Temperature: 50 °C
Yield: 42 %

Procedure:
(Bromomethyl)cyclopropane a48 (47 μl, 0.48 mmol, 2.1 eq) is added to a solution of (5S)-5-{[(cyclohexylmethyl)amino]methyl}-1-[4-(3-piperidin-1-ylpropoxy)phenyl]pyrrolidin-2-one 2 in acetonitrile (4 ml), then cesium carbonate (150 mg, 0.46 mmol, 2 eq) and potassium iodide (8 mg, 0.05 mmol, 0.2 eq) are added and the mixture is heated at 50° C. for 24 h. The precipitate is filtered and the solvent is removed in vacuo. The residue is dissolved into dichloromethane and washed with a saturated solution of aqueous ammonium chloride. The aqueous layer is then extracted with dichloromethane, the organic layers are dried over magnesium sulfate and concentrated in vacuo to give 109 mg of a yellow oil. This oil is purified by chromatography over silicagel (dichloromethane/methanol/ammonia 92/8/0.8) to obtain 47 mg of (5S)-5-{[(cyclohexylmethyl)(cyclopropylmethyl)amino]methyl}-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 3 as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:15])=O)=[CH:9]2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:36])[NH2:15])=[CH:9]2)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Solvent: C1CCOC1
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Temperature: 55 °C
Reaction time: 2 h
Yield: 152.8 %

Procedure:
A mixture of 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (0.43 g) and Lawesson's reagent (0.28 g) in tetrahydrofuran (30 mL) was stirred at 55° C. for 2 h. The reaction mixture was concentrated to give a light yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (414 mg, 92%) as light yellow crystals. MS 392 (MH+).
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[N:13]1([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(Cl)(Cl)Cl>C1C=CC=CC=1>[N:13]1([CH:18]2[CH2:23][CH2:22][N:21]([C:2]([Cl:1])=[O:4])[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCN(C2CCNCC2)C1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cl)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 29.2 %

Procedure:
Triphosgene (742 mg, 2.5 mmol) was dissolved in benzene (60 ml), followed by the addition of a solution of 4-pyrrolidinopiperidine (1.00 g, 6.5 mmol) in benzene and triethylamine (7.5 mmol). The resulting mixture was stirred at room temperature for 17 hours. Chloroform was added to the reaction mixture, and the thus-obtained mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (chloroform-acetone mixed solvent [1:2]), whereby 4-pyrrolidinopiperidinocarbonyl chloride (158 mg, 11%) was obtained.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH3:14][N:15]([CH3:25])[CH2:16][CH2:17][C@H:18]([OH:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].O>CN(C=O)C.CCOC(C)=O>[Si:10]([O:24][C@@H:18]([CH2:17][CH2:16][N:15]([CH3:25])[CH3:14])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: CCOC(=O)[C@@H](O)CCN(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@H](CCN(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 18 h
Yield: 60.8 %

Procedure:
Imidazole (1.98 g, 29.10 mmol) and TBDMSCl (2.34 g, 15.52 mmol) was added to a stirred solution of ethyl (2S)-4-(dimethylamino)-2-hydroxybutanoate (Step 1) (3.20 g, 19.97 mmol) in DMF (25 mL). The reaction mixture was kept at ambient temperature for 18 hrs. Water and EtOAc were added and the two phases were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined and washed three times with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with heptane/EtOAc:2/1) to give the title compound as a colourless oil (2.73 g), 1H NMR (300 MHz, DMSO) δ 4.28 (m, 1H), 4.18 (m, 2H), 2.44 (m, 1H), 2.30 (m, 1H), 2.22 (s, 6H), 1.87 (m, 2H), 1.28 (t, 3H), 0.90 (s, 9H), 0.08 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[NH:17][CH:16]=[C:15]([C:18]([NH:20][CH2:21][CH2:22][CH:23]=O)=[O:19])[CH:14]=3)[CH:8]=2)=[CH:4][C:3]=1[NH:27][C:28]([C:30]1[O:31][CH:32]=[CH:33][C:34]=1[CH3:35])=[O:29].Cl.[CH3:37][O:38][C:39](=[O:45])[C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1.C(N(CC)CC)C.C([BH3-])#N.[Na+].C1COCC1>CN(C=O)C.O>[F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[NH:17][CH:16]=[C:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:41]4[CH2:42][CH2:43][CH2:44][CH:40]4[C:39]([O:38][CH3:37])=[O:45])=[O:19])[CH:14]=3)[CH:8]=2)=[CH:4][C:3]=1[NH:27][C:28]([C:30]1[O:31][CH:32]=[CH:33][C:34]=1[CH3:35])=[O:29]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: Cc1ccoc1C(=O)Nc1cc(Oc2ccnc(-c3cc(C(=O)NCCC=O)c[nH]3)c2)ccc1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1CCCN1CCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(F)c(NC(=O)c4occc4C)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide (140 mg, 0.29 mmol) in 10 ml of anhydrous DMF were added L-proline methyl ester hydrochloride (96 mg, 0.58 mmol) and triethylamine (58 mg, 0.58 mmol). The mixture was stirred at room temperature for 30 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.60 ml, 0.60 mmol) and stirring was continued for another 30 minutes. The mixture was poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel flash chromatography eluting with 5% of MeOH in CHCl3 to give methyl 1-[3-({[5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)propyl]pyrrolidine-2-carboxylate as light beige solid. Yield: 70 mg, 40%.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:14])[NH:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13].[C:17]1([C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:12][C:9]1[C:8]([CH3:13])=[C:7]([NH:6][C:5]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:28][N:27]=3)[CH2:30][CH2:31]2)=[O:14])[O:11][N:10]=1
Reactant: c1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3ccc(-c4ccccc4)cn3)CC2)c1C
Yield: 45.6 %

Procedure:
A solution of 2,2,2-trichloroethyl(3,4-dimethylisoxazol-5-yl)carbamate (251 mg, 0.872 mmol), 1-(5-phenylpyridin-2-yl)piperazine (200 mg, 0.872 mmol), diisopropylethylamine (0.304 ml, 1.74 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, then the reaction solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduce pressure, and the residue was recrystallized from ethyl acetate to give the titled compound 150 mg (45.6%) as solid product.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][C:6]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].C(N(C(C)C)C(C)C)C.[F:32][C:33]([F:51])([F:50])[C:34]1[CH:35]=[C:36]([C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:32][C:33]([F:51])([F:50])[C:34]1[CH:35]=[C:36]([C:44]([CH3:49])([CH3:48])[C:45]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][C:6]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:46])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1
Reactant: CNc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 37.5 °C
Yield: 80.9 %

Procedure:
A solution of 20 g (67.5 mmol) methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine and 17.5 ml (101 mmol) N-ethyldiisopropylamine in 200 ml dichloromethane was cooled in an ice bath and a solution of 24 g (75 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 50 ml dichloromethane was added dropwise. The reaction mixture was warmed to 35-40° C. for 3 h, cooled to room temperature again and was stirred with 250 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 31.6 g (81%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl)propanamide as white crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)=O.O.[NH2:24][NH2:25].CC(O)=O>CCO.O>[NH:24]([C:3]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)=[O:2])[NH2:25]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2)cc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NNC(=O)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
To a suspension of 4-{[4-(methoxycarbonyl)benzoyl]amino}benzoic acid (300 mg g, 1 mmol) in EtOH (4.5 mL) was added hydrazine hydrate (0.73 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (3×1 mL) and drying under vacuo at 70° C. for 2 hrs gave a white solid. This residue was taken up in water (25 mL) and AcOH (5 mL) was added. A white solid precipitated out which was further washed with water (3×2 mL). Drying at 80° C. for 1 hr gave 220 mg of the title compound (73%) as a white solid in 91.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.[CH3:21][N:22]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[N:23]1.CC([O-])=O.[K+].C(Cl)Cl>CN(C=O)C.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]>[F:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:25]3[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=3)=[CH:3][N:4]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:9][CH:8]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2ccc(F)cc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 90 °C
Yield: 20.1 %

Procedure:
A mixture of 3-bromo-6-fluoro-1-(phenylsulfonyl)-1H-indole (Intermediate 2; 1.0 g; 2.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.7 g; 8.4 mmol), KOAc (1.4 g; 14.0 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.15 g; 0.18 mmol) in DMF (25 mL) flushed with nitrogen was heated to 90° C. overnight. The mixture was filtered through Celite, diluted with EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by a silica gel chromatography (petroleum ether/EtOAc=1/1) to afford 0.20 g (23%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][OH:22])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:25]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][OH:22])[CH:17]=3)[N:12]([CH3:25])[N:11]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(CO)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Temperature: 25 °C
Yield: 35.2 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-cinnolinecarboxamide (Prep. 6, 0.12 g), K2CO3 (0.21 g) and iodomethane (26 μL) in 5 mL anhydrous DMF is heated at 90° C. for 1.5 h. The reaction is cooled to room temperature and poured into 50 mL water. The resulting solid is filtered and dried, then dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1L), 0.5% MeOH/CH2Cl2 (2L), 1% MeOH/CH2Cl2 (1L), 1.5% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 2.5% MeOH/CH2Cl2 (3L), 3% MeOH/CH2Cl2 (1L), 4% MeOH/CH2Cl2 (1L), 6% MeOH/CH2Cl2 (1L), 8% MeOH/CH2Cl2 (1L)) affords the desired product as a white solid (0.044 g, 36%). Physical characteristics are as follows: m.p. 203-205° C.; 1H NMR (300 MHz, DMSO-d6) δ10.11, 8.23, 7.95, 7.92, 7.40, 5.54, 4.68, 4.56, 4.26; IR (drift) 3380, 1653, 1600, 1551, 1482, 1406, 1351, 1107, 1090, 1015, 813, 801, 727, 709, 659 cm−1; MS (FAB) m/z 358 (MH+), 511, 361, 360, 359, 358, 217, 127, 125, 123, 39; HRMS (FAB) calcd for C18H16ClN3O3+H1 358.0958, found 358.0961.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][O:8][C:9]2=[O:10])=[CH:5][CH:4]=1.C1C(=O)N(Br)C(=[O:16])C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC1C=CC=CC=1>[CH:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:11]=1[C:9]([OH:8])=[O:10])=[O:16]
Reactant: COc1ccc2c(c1)C(=O)OC2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: COc1ccc(C=O)c(C(=O)O)c1
Temperature: 85 °C

Procedure:
10 g (61 mmol) of 6-methoxyphthalide, 11.4 g (64.0 mmol) of NBS and 200 ml of chlorobenzene are mixed, while stirring, the suspension is heated to 85° C. and 2 ml of a solution of 100 mg of AIBN in 10 ml of chlorobenzene are added. In the course of a few minutes, the temperature rises to 110° C. and a red solution forms. After the rise in-temperature has subsided, the remaining 8 ml are added and the mixture is stirred at 85° C. for 40 min. After cooling to 0° C., the succinimide which has precipitated out is filtered off and rinsed with chlorobenzene. The filtrate is concentrated until an oily residue forms, which is taken up in 10% strength NaOH solution, and the mixture is washed three times with 300 ml of methylene chloride each time. After acidification of the aqueous phase with concentrated HCl, the mixture is stirred at 0° C. for 1 hour. The acid thereby precipitates out in the form of a white precipitate, which is filtered off.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15](O)=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:27])=O.CN(C=O)C>C(Cl)Cl>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([Cl:27])=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: -10 °C
Yield: 100 %

Procedure:
Intermediate VIII (Scheme 3), e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (1.747 g, 5 mmol) was dissolved in DCM (20 mL). The resulting solution was cooled down to −10° C. and oxalyl chloride (0.645 mL, 7.5 mmol) was added slowly. DMF (0.1 mL) was added carefully. The reaction mixture was allowed to warm to RT over 1 h and stirred an additional hour at RT. As the reaction was complete, the solvents were evaporated. Toluene was added and evaporated to remove residual oxalyl chloride. This process was repeated twice, affording intermediate XXX, e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride as a yellow solid (1.839 g, quantitative yield). α-Aminophenylacetic acid (831 mg, 5.5 mmol) was dissolved in water (20 mL). TEA (2.77 mL, 20 mmol) was added carefully. THF (25 mL) was added to reaction mixture. The reaction mixture was cooled to 0° C. Acid chloride previously prepared XXX, e.g. 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride dissolved in THF (25 mL) was added dropwise. The reaction mixture was stirred 15 min at 0° C. and overnight at RT. Solvents were concentrated and the resulting aqueous fraction was acidified with HCl 5N and extracted with 3 portions of EtOAc. Combined organic phases were dried over MgSO4, filtrated and evaporated. The crude product was recrystallized in acetone/Et2O mixture, affording carboxylic acid Ia, e.g., ({[3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)(phenyl)acetic acid in 97% purity by HPLC (943 mg, 39% yield).
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[N:10]=[C:11]([CH3:14])[NH:12][CH:13]=1)=[O:6])([CH3:4])[CH3:3].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1.C1COCC1>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:8]([C:9]2[N:10]=[C:11]([CH3:14])[NH:12][CH:13]=2)[NH:7][S:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])=[CH:19][CH:18]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: Cc1nc(/C=N/S(=O)C(C)(C)C)c[nH]1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(NS(=O)C(C)(C)C)c2c[nH]c(C)n2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a 100 ml round bottom flask containing −78° C. solution of 2-methyl-N-((1E)-(2-methyl-1H-imidazol-4-yl)methylene]propane-2-sulfinamide (1.170 g, 5.490 mmol) in 25.0 ml of CH2Cl2 was added dropwise 1.0 N 4-methoxyphenylmagnesium bromide in THF (8.230 ml, 8.230 mmol). The resulting solution was stirred at −78° C. for 1 hour. The reaction mixture was quenched with saturated NH4Cl and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by flash chromatography (SiO2, 0-4% methanol in CH2Cl2, gradient) gave the title compound as a white solid (0.735 g, 42%). 1H NMR (CDCl3, 400 MHz) δ 7.270 (m, 2H), 6.849 (m, 2H), 6.405 (s, 1H), 5.451 (d, J=6.04 Hz, 1H), 4.307 (d, J=6.05 Hz, 1H), 3.791 (s, 3H), 3.433 (s, 1H), 2.282 (s, 3H), 1.251 (s, 9H). ES-MS [M+1]+: 322.3.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[N:17][C:18]=1[Cl:19].O.[Cl-].[NH4+]>C(OCC)(=O)C.CN(C)C(=O)C>[Cl:19][C:18]1[C:13]([Cl:12])=[CH:14][C:15]([O:20][CH2:4][CH2:3][O:2][CH3:1])=[CH:16][N:17]=1
Reactant: Oc1cnc(Cl)c(Cl)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCCOc1cnc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
2-Bromoethyl methyl ether (0.44 ml, 4.57 mmol) and cesium carbonate (2.48 g, 7.62 mmol) were added to an N,N-dimethylacetamide solution (5 ml) of 5,6-dichloropyridin-3-ol (500 mg, 3.05 mmol), and stirred under a nitrogen atmosphere at 80° C. for 5 hours. The reaction solution was cooled with ice, then ammonium chloride water and ethyl acetate were added, the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, hexane:ethyl acetate=9:1) to obtain 2,3-dichloro-5-(2-methoxyethoxy)pyridine (573 mg, yield: 85%) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5](N)=[C:4]([Cl:10])[CH:3]=1.Br.N([O-])=O.[Na+].[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>CC(C)=O.O>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5](/[CH:18]=[CH:17]/[C:16]([O:20][CH3:21])=[O:19])=[C:4]([Cl:10])[CH:3]=1
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Reactant: C=CC(=O)OC
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1c(Cl)cc(Br)cc1Cl
Temperature: 0 °C

Procedure:
4-Bromo-2,6-dichloroaniline (5, 80 g) was dissolved in acetone (640 mL), and a 48% hydrogen bromide aqueous solution (120 mL) was added, followed by stirring at 0° C. A sodium nitrite (32 g) aqueous solution (160 mL) was added dropwise thereto, the mixture was stirred for 30 minutes, and methyl acrylate (200 mL), and water (200 mL) were added, followed by stirring for 1 hour. At room temperature, cuprous oxide (2 g) was added, followed by stirring for 2 hours. The reaction solution was extracted with ethyl acetate, and purified by column chromatography to obtain methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g). Methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g) was dissolved in dichloromethane, an ozone gas was introduced at −70° C., and ozone oxidization was performed. To the reaction solution was added dimethyl sulfide (40 mL), and this was extracted with ethyl acetate to obtain 4-bromo-2,6-dichlorobenzaldehyde (6, 37.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][C:12]([NH2:14])=[NH:13].O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:13][C:12](=[NH:14])[N:11]=[CH:1][C:2]2[CH:9]=[CH:8][C:5]([CH3:6])=[CH:4][CH:3]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C=NC(=N)N=Cc2ccc(C)cc2)cc1

Procedure:
4-Methylbenzaldehyde (MBA) (0.50 mols-60 grams) is admixed with guanidine hydrochloride (0.25 mols, 25 grams) in molar ratio of 2:1. They are then heated under reflux in 150 ml of toluene under a Dean Stark water collector trap for approximately 17 hours to collect the theoretical amount of H2 0 evolved. The hot solution is rapidly decanted to ensure the removal of insoluble residues. The solution is then evaporated to dryness on a rotary evaporator. The crude immine is then recrystalized twice from absolute ethanol.