Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[N:14][CH:15]=1)#[CH:9].Br[C:18]1[C:26]2[NH:25][C:24]3[CH2:27][CH2:28][N:29]([CH3:31])[CH2:30][C:23]=3[C:22]=2[CH:21]=[CH:20][CH:19]=1>O1CCCC1.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.[Cu]I>[CH3:31][N:29]1[CH2:28][CH2:27][C:24]2[NH:25][C:26]3[C:18]([C:9]#[C:8][C:10]4[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][CH:11]=4)=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]=2[CH2:30]1
Reactant: CN1CCc2[nH]c3c(Br)cccc3c2C1
Reactant: C#Cc1ccc(C)nc1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C#Cc2cccc3c4c([nH]c23)CCN(C)C4)cn1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Triethylamine (1.5 mL) was added to a mixture of bis(tri-t-butylphosphino)palladium (12.3 mg, 0.024 mmol; Aldrich), 5-ethynyl-2-methylpyridine (85 mg, 0.72 mmol; International Publication No. WO2005090333), CuI (4.6 mg, 0.024 mmol; Aldrich) and the product of Example 1A (128 mg, 0.48 mmol) in anhydrous tetrahydrofuran (1.5 mL). The mixture was purged with a nitrogen stream for 2 minutes, then stirred under nitrogen at 75° C. for 2 hours and then at 35° C. for 18 hours in a sealed tube. The mixture was filtered through a glass microfiber frit, rinsed with CH3OH (3 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 50-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)]. Fractions containing the product were concentrated under vacuum and the residue was further purified by flash chromatography (silica gel, eluted with CHCl3—CH3OH-14.8 M aqueous NH4OH (90:10:1)) to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.55 (s, 3H), 2.56 (s, 3H), 2.89 (t, J=5.8 Hz, 2H), 2.98 (t, J=5.5 Hz, 2H), 3.69 (s, 2H), 6.97-7.04 (m, 1H), 7.25 (dd, J=7.3, 0.9 Hz, 1H), 7.33 (d, J=7.9 Hz, 1H), 7.41 (dd, J=7.8, 1.1 Hz, 1H), 7.94 (dd, J=7.9, 2.1 Hz, 1H), 8.68 (d, J=1.8 Hz, 1H); MS (DCI) m/z 302 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.C(O)(C)C.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1csc2cnc(Cl)nc12
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 2,4-dichloro-7-methyl-thieno[3,2-d]pyrimidine (2.5 g), palladium hydroxide on carbon (20%, 0.5 g) and sodium acetate (2.0 g) in a mixture of ethyl acetate (40 mL) and isopropyl alcohol (5 mL) was shaken in a Parr apparatus under hydrogen atmosphere (50 PSI) overnight. The reaction mixture was filtered on a CELITE™ pad and the filtrate was evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM) to give 1.8 g of 2-chloro-7-methyl-thieno[3,2-d]pyrimidine.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([O:36]CC)=O)=[N:28][C:27]=3[S:26][CH:25]=2)=[CH:20][CH:19]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:82]2[CH:86]=[N:85][C:84]([O:87][CH2:88][CH2:89][O:90][C:91]3[CH:92]=[C:93]([CH2:97][NH2:98])[CH:94]=[CH:95][CH:96]=3)=[N:83]2)C=CC=CC=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([NH:98][CH2:97][C:93]4[CH:94]=[CH:95][CH:96]=[C:91]([O:90][CH2:89][CH2:88][O:87][C:84]5[N:85]=[CH:86][NH:82][N:83]=5)[CH:92]=4)=[O:36])=[N:28][C:27]=3[S:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3ccc(Cl)cc3)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3ccc(Cl)cc3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(4-chlorophenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 78 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (180.0 mg, 80%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:17]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]3)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:17]5[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]5)=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CN1CCC(N(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)S(C)(=O)=O)C1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CN1CCC(N(Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)S(C)(=O)=O)C1

Procedure:
N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(1-methyl-pyrrolidin-3-yl)-methanesulfonamide was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in General Procedure A to yield 195. NMR: (CDCl3): 1.96 (1H, m); 2.19 (2H, m); 2.33 (4H, m); 2.48 (1H, m); 2.90 (5H, m); 3.94 (4H, m); 4.10 (4H, m); 4.57 (1H, m); 4.90 (2H, s); 7.50 (1H, s); 7.53 (1H, d, J=7.4 Hz); 7.10 (1H, d, J=8.2 Hz); 8.30 (1H, d, J=7.1 Hz); 9.03 (1H, s); 10.14 (1H, br s). MS: (ESI+): MH+=528
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][N:17]=2)=[O:15])=[N:2]1.O.[OH-].[Li+]>O1CCCC1.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=2)=[O:15])=[N:2]1
Reactant: COC(=O)c1ccc(C(=O)NCCNc2nsc3ccccc23)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C(=O)NCCNc2nsc3ccccc23)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
Methyl 6-(2(benzo[d]isothiazol-3-ylamino)ethylcarbamoyl)nicotinate (211 mg, 0.6 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and water (0.5 mL) and treated with lithium hydroxide monohydrate (100 mg, 2.4 mmol). The reaction mixture was stirred at room temperature overnight. The tetrahydrofuran was removed under vacuum and the residue was diluted with water. Dropwise addition of 50% aqueous hydrochloric acid gave a white solid, which was collected by vacuum filtration and dried to yield 6-(2-(benzo[d]isothiazol-3-ylamino)ethylcarbamoyl)nicotinic acid (130 mg) as a white solid. 1H NMR (300 MHz, CDCl3/DMSO-d6): 9.02 (m, 1H), 8.83 (broad s, 1H), 8.32 (m, 1H), 8.10 (d, 1H), 7.95 (d, 1H), 7.68 (d, 1H), 7.39 (t, 1H), 7.25 (t, 1H), 3.71 ppm (m, 4H). MW=342 confirmed by LC-MS, tr=10.56 min (Method Y) MH+=343
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[C:4]([CH3:11])[CH:3]=1.Cl[CH:13]([CH:16]=O)[CH:14]=[O:15].C(=O)([O-])[O-].[Mg+2]>C(COC)OC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:13]([CH:14]=[O:15])=[CH:16][N:8]=2)=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(N)=S
Reactant: O=CC(Cl)C=O
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: COCCOC
Product: Cc1cc(Br)ccc1-c1ncc(C=O)s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a suspension of 4-bromo-2-methyl-thiobenzamide (3.11 g, 13.5 mmol) and 2-chloromalonaldehyde (2.16 g, 20.3 mmol) in dimethoxyethane (20 ml) is added magnesium carbonate (567 mg, 6.75 mmol) and the resulting mixture stirred at 60° C. under N2 for 3 hours. The crude reaction is then filtered through a plug of silica, washed with EtOAc and the filtrate concentrated to give 2-(4-bromo-2-methyl-phenyl)-thiazole-5-carbaldehyde (3.8 g).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:6]=1)=[N+]=[N-]>CCOC(C)=O.[Pd]>[C:10]([C:8]1[N:7]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][CH:15]=2)[N:6]=[C:5]([CH2:4][NH2:1])[CH:9]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1cc(CN=[N+]=[N-])nn1-c1ccc(S(C)(=O)=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(CN)nn1-c1ccc(S(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
To a solution of 9h (0.4 g, 1.2 mmol) in EtOAc was added 10% palladium on carbon. The solution was filled with H2 and the reaction mixture was stirred for 2 hours. After the solution was filtered through Celite, the filtrate was concentrated in vacuo. Purification by recrystallization with DCM/hexanes gave the title compound 10h, 0.35 g (95%) as a white solid. mp 137.5-145.1° C. 1H NMR (300 MHz, DMSO-d6): δ 8.05 (d, J=8 Hz, 2H), 7.67 (d, J=8 Hz, 2H), 6.27 (s, 1H), 3.62 (s, 2H), 3.32 (s, 3H), 2.07-1.83 (m, 2H), 1.14 (s, 9H).
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([CH2:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:12])[CH:7]=[CH:6][C:5]=12.Br.C([O-])([O-])=[O:22].[K+].[K+]>CS(C)=O>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10](=[O:22])[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:12])[CH:7]=[CH:6][C:5]=12
Reactant: Cc1cccc(C(=O)Cc2ccc3ncnn3c2)n1
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc(C(=O)C(=O)c2ccc3ncnn3c2)n1
Temperature: 65 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a stirred suspension of 2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(6-methylpyridin-2-yl)ethanone (6.20 g, 24.57 mmol) in DMSO (48 mL) was added dropwise HBr (48 wt. % in water, 5.96 g, 12.4 mL) at 0° C., and the mixture was heated at 60-70° C. After 2 h, the reaction mixture was cooled to 0° C., poured onto ice water (20 mL), and basified to pH 10 with solid K2CO3. The mixture was extracted with CHCl3 (2×250 mL), and the organic phase was washed with water (2×100 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of MeOH and CH2Cl2 as eluent to give the titled compound (6.02 g, 92%) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.11 (dd, 1H, J=1.6, 1.2 Hz), 8.47 (s, 1H), 8.14 (dd, 1H, J=9.2, 1.6 Hz), 8.04 (br d, 1H, J=7.6 Hz), 7.88 (dd, 1H, J=9.2, 1.2 Hz), 7.84 (t, 1H, J=7.8 Hz), 7.42 (br d, 1H, J=8.0 Hz), 2.49 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH:20]=[CH2:21])[C:10](=[O:12])[CH3:11])[C:5](I)=[CH:4][N:3]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:21]=[CH:20][C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:9]([C:10](=[O:12])[CH3:11])[CH2:8][C:6]=2[CH:7]=1
Reactant: C=Cc1cc(Cl)ccc1N(Cc1cc(Cl)ncc1I)C(C)=O
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cc(Cl)ncc2C=Cc2cc(Cl)ccc21
Yield: 62.7 %

Procedure:
Compound 77C (26 mg, 73%) was prepared from 77B (50 mg, 0.13 mmol) by a route analogous to that used for the preparation of 1D.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.Cl.[S:19]1[CH:23]=[CH:22][C:21]2[C:24]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:25][CH:26]=[CH:27][C:20]1=2.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN(C)C=O>[S:19]1[CH:23]=[CH:22][C:21]2[C:24]([N:28]3[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]4[CH:16]=[C:15]5[C:10]([CH:11]=[CH:12][C:13](=[O:17])[NH:14]5)=[CH:9][CH:8]=4)[CH2:30][CH2:29]3)=[CH:25][CH:26]=[CH:27][C:20]1=2
Reactant: O=c1ccc2ccc(OCCCCCl)cc2[nH]1
Reactant: c1cc(N2CCNCC2)c2ccsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 9.0 g of 7-(4-chlorobutoxy)-1H-quinolin-2-one, 10 g of 1-benzo[b]thiophene-4-yl-piperazine hydrochloride, 14 g of potassium carbonate, 6 g of sodium iodide and 90 ml of dimethylformamide was stirred for 2 hours at 80° C. Water was added to the reaction solution and precipitated crystals were separated by filtration. The crystals were dissolved in a mixed solvent of dichloromethane and methanol, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:3). Recrystallized from ethanol, 13.6 g of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one in the form of a white powder was obtained.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([OH:22])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][S:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[C:38]([OH:45])[C:37]=1[CH2:46][CH2:47][CH3:48]>CC(C)=O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:32][CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[C:38]([OH:45])[C:37]=2[CH2:46][CH2:47][CH3:48])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(O)ccc(C(C)=O)c1OCCCC(=O)OCC
Reactant: CCCc1c(SCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(SCCCOc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
To a stirred mixture of ethyl 4-(6-acetyl-3-hydroxy-2-propylphenoxy)butyrate (1.6 g), potassium iodide (0.5 g) and potassium carbonate (1.45 g) in acetone (30 ml) was added drop wise a solution of 4-(3-bromopropylthio)-2-hydroxy-3-propylphenyl-ethanone (1.9 g) in acetone (10 ml) with heating to reflux. After refluxing six hours the mixture was cooled to room temperature and inorganic materials were separated by filtration. The filtrate was concentrated and the residue was separated and purified by silica-gel column chromatography (eluting with benzene:ethyl acetate=9:1) to give the title compound as crude crystals (2.1 g, 72.4%) which were recrystallized from ethanol to give colorless crystals, mp 65–66° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[CH:10]([S:12]([OH:15])(=[O:14])=[O:13])[CH3:11].Cl.[NH2:17][CH2:18][CH:19]([SH:24])[CH2:20][C:21]([OH:23])=[O:22]>O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[CH:10]([S:12]([OH:15])(=[O:14])=[O:13])[CH3:11].[NH2:17][CH2:18][C@H:19]([SH:24])[CH2:20][C:21]([OH:23])=[O:22]
Reactant: NCC(S)CC(=O)O
Agent: CC(c1ccc(Cl)c(Cl)c1Cl)S(=O)(=O)O
Agent: Cl
Solvent: O
Product: NC[C@H](S)CC(=O)O

Procedure:
(-)-1-(2,3,4-Trichlorophenyl)ethanesulfonic acid (3.18 g) is dissolved in water (17.4 ml), and thereto is added aqueous solution of racemic 4-amino-3-mercaptobutyric acid hydrochloride (3.77 g)in water (24.6 ml). The mixture is dissolved at 70° C.-80° C., and allowed to cool. After cooling, the mixture is stirred under ice-cooling for one hour, and the precipitated crystals are collected by filtration, washed, and dried to give (3R)-4-amino--3-mercaptobutyric acid (-)-1-(2,3,4-trichlorophenyl)ethanesulfonate (3.8 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:7]([C:20]([NH2:22])=[O:21])=[CH:6]2.[NH2:25][C:26]1[CH:31]=[C:30](Br)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu](I)I.O.O1CCOCC1>[NH2:25][C:26]1[CH:31]=[C:30]([NH:22][C:20]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:2]([F:1])([F:23])[F:24])=[CH:11][CH:10]=3)=[O:21])[CH:29]=[CH:28][N:27]=1
Reactant: Nc1cc(Br)ccn1
Reactant: NC(=O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(NC(=O)c2cc3cc(C(F)(F)F)ccc3n2Cc2cccc(F)c2)ccn1
Temperature: 170 °C
Yield: 73.6 %

Procedure:
0.056 g (0.30 mmol) of copper iodide, 0.2 g (0.59 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 17.1, 0.12 g (0.71 mmol) of 2-amino-4-bromopyridine, 0.33 g (2.38 mmol) of potassium carbonate and 4 mL of anhydrous dioxane are placed in a 10 mL pressure tube specific for microwave reactors. The suspension is degassed for a few minutes and 0.04 mL (0.3 mmol) of trans-1,2-cyclohexanediamine is then added. The tube is then sealed and heated in the microwave reactor at 170° C. for 45 minutes. After this time, the suspension cooled to room temperature is poured into 30 mL of water and then extracted with 2×40 mL of dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.186 g of the expected product is thus obtained.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([CH2:20][CH3:21])[CH:4]=1)#[N:2].[NH2:22][OH:23]>C(O)C>[NH2:2][C:1](=[N:22][OH:23])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[C:5]([CH2:20][CH3:21])[CH:4]=1
Reactant: NO
Reactant: CCc1cc(C#N)ccc1CN(C)CC(=O)OC(C)(C)C
Solvent: CCO
Product: CCc1cc(C(N)=NO)ccc1CN(C)CC(=O)OC(C)(C)C
Yield: 103.4 %

Procedure:
A solution of tert-butyl N-(4-cyano-2-ethylbenzyl)-N-methylglycinate (570 mg, 1.98 mmol) and 50% aqueous hydroxylamine (0.6 mL, 10 mmol) in ethanol (10 mL) was heated at 80° C. for 18 hours. The solvent was evaporated in vacuo. The residue was partitioned between DCM and water. The organic phase was passed through a hydrophobic frit and evaporated in vacuo to afford the title compound (658 mg, quantitative). 1H NMR (CDCl3, 400 MHz) δ 7.46 (1H, s), 7.39 (2H, s), 4.85 (2H, br s), 3.73 (2H, s), 3.16 (2H, s), 2.73 (2H, q, J=7.6 Hz), 2.37 (3H, s), 1.47 (9H, s), 1.25-1.19 (3H, m).
Reaction SMILES: C[O:2][C:3](=[O:42])[C@@H:4]1[CH2:8][CH:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:27]5[O:28][C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=6[C:26]=5[CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][N:5]1[C:35]([O:37]C(C)(C)C)=[O:36].[OH-].[K+].Cl.[CH2:46]1[CH2:50]O[CH2:48][CH2:47]1>CO.C(OCC)(=O)C>[CH:25]1[C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][C:27]=2[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH:7]4[CH2:6][N:5]([C:35]([O:37][CH2:50][CH2:46][CH2:47][CH3:48])=[O:36])[C@H:4]([C:3]([OH:2])=[O:42])[CH2:8]4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)=[CH:23][CH:24]=1
Reactant: C1CCOC1
Reactant: COC(=O)[C@@H]1CC(Oc2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CC(Oc2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)C[C@H]1C(=O)O
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 4-(4′-dibenzofuran-4-yl-bipheny-4-yloxy)-N-tert-butoxycarbonyl-proline methyl ester (400 mg, 0.71 mmol) in THF (3 mL) and methanol (4 mL) was cooled to 0° C. and treated with 2 N KOH (1.25 mL). After stirring at room temperature for 1 H the solution was acidified with 10% HCl to pH 2 and diluted with 25ml of ethyl acetate. After being separated, the aqueous layer was extracted with ethyl acetate (3×15 mL) and the combined organic layers were dried over MgSO4 and concentrated. Purification by flash column chromatography (2-5% methanol in dichloromethane) provided 4-(4′-dibenzofuran-4-yl-bipheny-4-yloxy)-N-butoxycarbonyl-proline (320 mg, 82%) as pale yellow solid. 0.320 g (yield 82.1%). 1H NMR (DMSO-d6), δ 8.16 (dd, J=8, 12 Hz, 2H), 7.98 (d, J=9 Hz, 2H), 7.80 (m, 6H), 7.47 (m, 3H), 6.97 (d, J=9 Hz, 2H), 5.08 (m, 1H), 4.29 (t, J=9 Hz, 1H), 3.72 (m, 1H), 3.42 (dd, J=6, 9 Hz, 1H), 2.62 (m, 1H), 2.20 (m, 1H), 1.44 (s, 9H). LCMS 450 (M+−100).
Reaction SMILES: Br[C:2]1[C:3]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]2[CH2:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17]>CN(C)C=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([C:2]1[C:3]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]2[CH2:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1)[CH:16]=[CH2:15]
Reactant: C[Si](C)(C)c1c(Br)cnc2c1CCO2
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1cnc2c(c1[Si](C)(C)C)CCO2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
A mixture of 5-bromo-4-(trimethylsilyl)-2,3-dihydrofuro[2,3-b]pyridine (37.5 g, 138 mmol), allyltributyltin (65.8 mL, 212 mmol) and trans-dichlorobis(triphenylphosphine)palladium(II) (9.9 g, 14.1 mmol) in N,N-dimethylformamide (500 mL) was stirred at 100° C. for 1.5 hr. The reaction solution was diluted with water, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=25/75→33/67) to give the title compound (30.9 g, yield 96%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:17]=[C:18](I)[CH:19]=[CH:20][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:12])=[N:8][N:9]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:13])([F:23])[F:24])[CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: FC(F)(F)Oc1cccc(I)c1
Reactant: CCOC(=O)c1c(C)n[nH]c1C
Product: CCOC(=O)c1c(C)nn(-c2cccc(OC(F)(F)F)c2)c1C
Yield: 73.6 %

Procedure:
The title compound was prepared in analogy to intermediate 6A by reaction of 3,5-Dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2 g, 12 mmol) with 3-trifluoromethoxyiodobenzene (6.7 g, 14 mmol) affording the desired product (2.9 g, 73%) as a colourless liquid. MS: 329.2 (MH1).
Reaction SMILES: O[C:2]1[C:11]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:16]1([CH3:20])[CH:17]=[CH:18][CH:19]=[C:14]([C:13]2[O:21][C:2]3[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=3[N:12]=2)[CH:15]=1
Reactant: COC(=O)c1cccc(NC(=O)c2cccc(C)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2nc(-c3cccc(C)c3)oc12
Yield: 7.1 %

Procedure:
Methyl 2-hydroxy-3-(3-methylbenzamido)benzoate (1.8 mg, 6.29 mmol) and 4-methylbenzenesulfonic acid (1.61 g, 9.4 mmol) were added to toluene (10 mL) and the mixture was stirred at reflux for 10 hr. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated to obtain methyl 2-m-tolylbenzo[d]oxazole-7-carboxylate as a solid (120 mg, yield 64%). LC-MS (ESI) m/z 269 [M+1]−.