Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]=[C:14]([N:16]4[CH2:20][CH2:19][C@@H:18]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)[CH2:17]4)[S:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.N>>[N:21]1([C@@H:18]2[CH2:19][CH2:20][N:16]([C:14]3[S:15][C:11]4[CH:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([OH:2])=[N:8][CH:7]=5)[CH:28]=[CH:27][C:12]=4[N:13]=3)[CH2:17]2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COc1ccc(-c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)cn1
Agent: N
Product: Oc1ccc(-c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared by the method of Example 73, substituting (R)-6-(6-methoxypyridin-3-yl)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 19) in place of (R)-6-(2-methoxypyrimidin-5-yl)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 15). 1H NMR (300 MHz, CD3OD) δ ppm 1.47-1.56 (m, 2H), 1.61-1.72 (m, 4H), 1.96-2.09 (m, 1H), 2.31-2.42 (m, 1H), 2.46-2.65 (m, 4H), 3.03-3.16 (m, 1H), 3.37-3.45 (m, 1H), 3.50-3.61 (m, 1H), 3.70-3.79 (m, 1H), 3.83-3.90 (m, 1H), 6.64 (dd, J=9.5, 0.7 Hz, 1H), 7.45 (dd, J=8.5, 1.7 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.96 (dd, J=9.5, 2.7 Hz, 1H); MS (DCI/NH3) m/z 381 (M+H)+.
Reaction SMILES: Br[C:2]1[O:11][CH2:10][C:9]2[CH:8]([N:12]([CH3:14])[CH3:13])[CH2:7][C:6]3=[CH:15][N:16]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:17]=[C:4]([C:5]=23)[CH:3]=1.[Li]CCCC.CN(C)[CH:35]=[O:36]>O1CCCC1.[Cl-].[NH4+]>[CH3:13][N:12]([CH3:14])[CH:8]1[C:9]2[CH2:10][O:11][C:2]([CH:35]=[O:36])=[CH:3][C:4]3=[CH:17][N:16]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:26])[CH3:27])[CH:19]([CH3:20])[CH3:21])[CH:15]=[C:6]([C:5]=23)[CH2:7]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1C=C2C=C(Br)OCC3=C2C(=C1)CC3N(C)C
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)N1C=C2C=C(C=O)OCC3=C2C(=C1)CC3N(C)C
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of compound (42) 750 mg in dry tetrahydrofuran 7 ml was cooled at −70° C. and n-BuLi (1.56 mol/l hexane solution) 2.2 ml was added dropwise to the solution. The mixture was stirred for 1 h. Dimethylformamide 257 μl was added and the mixture was stirred for 2 h. The reaction mixtures was diluted with an aqueous ammonium chloride solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:4) to give the titled compound as yellow oil, 556 mg. This was recrystallized from hexane to give the titled compound as colorless crystals, m.p. 104-106° C., 395 mg. Yield 59%
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[O:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[CH:36]=[C:35]1[CH:43]=O.C([O-])(O)=O.[Na+]>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([N:28]([CH2:43][C:35]2[O:34][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH:36]=2)[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1cc2ccccc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CCN(Cc1cc2ccccc2o1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.4 %

Procedure:
Sodium triacetoxyborohydride (0.88 g, 4.16 mmol) is added to a stirred solution of 4-(3-methyl-butylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.75 g, 2.77 mmol), benzofuran-2-carboxaldehyde (0.50 g, 3.46 mmol), and dichloromethane (14 ml). The reaction is stirred overnight at room temperature under nitrogen. The reaction is poured into aqueous saturated NaHCO3 (50 ml) and extracted with dichloromethane (25 ml×3). The organic layer is washed with aqueous saturated NaHCO3 and dried over Na2SO4, and filtered. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 0-30% (1:2 (10% NH4OH in methanol):ethanol) to yield (1.17 g) of 4-{[(benzofuran-2-yl)methyl]-(3-methylbutyl)-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=401 (M+1); 1H NMR (CDCl3): δ=7.57-7.41 (2H, m), 7.30-7.16 (2H, m), 6.55 (1H, s), 4.15 (2H, brs), 3.81 (2H, s), 2.75-2.56 (6H, m), 1.80 (2H, brd), 1.63-1.53 (3H, m), 1.46 (9H, s), 1.42-1.33 (1H, m), 0.92-0.85 (6H, m).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OC(C)(C)C)[C:12]1=[O:24])(C(C)(C)C)(C)C.O1CCOCC1.[ClH:31]>>[ClH:31].[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([CH2:10][CH2:9][OH:8])[C:12]1=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(CCO[Si](C)(C)C(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCN(CCO)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(S)-tert-Butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidin-3-ylcarbamate prepared according to Example 11; 200 mg, 0.558 mmol) was dissolved in 4M hydrogen chloride in dioxane (2.8 mL, 11.2 mmol), and the reaction mixture was allowed to stir at ambient temperature overnight. The reaction mixture was concentrated to yield (S)-3-amino-1-(2-hydroxyethyl)pyrrolidin-2-one hydrochloride (101 mg, 100%) which was taken on to the next step without further purification.
Reaction SMILES: N[C@H:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].N([O-])=[O:11].[Na+].[Cl-].[Na+]>S(=O)(=O)(O)O.O>[OH:11][C@H:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: O=N[O-]
Reactant: CC(C)(C)[C@@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 2(R)-amino-3,3-dimethylbutyric acid (5.0 g, 38.1 mmol) in 80 mL of 1 N sulfuric acid at −10° C. was slowly added a solution of sodium nitrite (5.26 g, 76.2 mmol) dissolved in 25 mL of water. After the addition was complete, the reaction was gradually warmed to ambient temperature and stirred for 20 h. Sodium chloride (10 g) was added and the solution was extracted twice with 100 mL portions of ether. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate solvent was removed under reduced pressure. The residue was purified by preparative HPLC using a Chiralpak AD column (5 cm×50 cm) using 5% ethanol in 95% hexanes with 0.2% TFA as the mobile phase at a flow rate of 80 mL/min. The product-containing fractions were concentrated in vacuo. 2(R)-Hydroxy-3,3-dimethylbutanoic acid was obtained as an oil that crystallized on standing (2.2 g; 44%); 1H NMR, 400 MHz, CDCl3, 6.0-7.0 ppm (v br s, 2H), 3.91 ppm (s, 1H), 1.03 ppm (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.[CH:21](OCC)(OCC)OCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:21]=[N:13][N:12]=[C:10]3[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: CCOC(OCC)OCC
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=CC1
Product: Brc1ccc2c(c1)C(c1ccccn1)=CCc1nncn1-2

Procedure:
In analogy to Example 16(b), by reacting 7-bromo-2-hydrazino-5-(2-pyridyl)-3H-1-benzazepine with triethyl orthoformate there is obtained 8-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1]benzazepine of melting point 219°.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH2:16][CH2:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22].[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33]O.N1(C2C=CN=CC=2)CCCC1>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH2:16][CH2:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([O:23][CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])=[O:22]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCOc3ccccc3C(=O)O)c2n1
Reactant: CN(C)CCCO
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCOc3ccccc3C(=O)OCCCN(C)C)c2n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The compound obtained in Example 2-9 step (iii) (50 mg) was dissolved in dichloromethane (5 ml), and thereto were added 3-(dimethylamino)propane-1-ol (0.016 ml), 4-pyrrolidin-1-ylpyridine (2 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbondiimide iodine methyl (42 mg). The mixture was stirred at room temperature for 96 hours and applied to a cartridge of SCX resin. The resin was washed with acetonitrile and the fractions were collected by application of 10% aqueous ammonium solution-acetonitrile, and purified by RPHPLC to give the titled compound. Yield: 8.9 mg (14%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][N:20]=2)[C:16]#N)[CH2:4][CH2:3]1.CC(C[AlH]CC(C)C)C.[OH:30]S(O)(=O)=O.[OH-].[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:16]=[O:30])[CH:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(CCCCOc2cc(C#N)ccn2)CC1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(CCCCOc2cc(C=O)ccn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a stirred solution of 2-[4-(1-methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile (0.44 g, 1.61 mmol) in toluene (5 mL) at 0° C. was added a 1.5 M DIBAL-H in toluene (2.41 mL, 2.41 mmol). The reaction mixture was allowed to warm to rt. After 3 h, methanol (8 mL) and 1.0 M H2SO4 (5 mL) were added dropwise. After 30 min, the mixture was neutralized with 1.0 M NaOH (10 mL) followed by addition of satd. aq. sodium potassium tartrate (40 mL) and CH2Cl2 (100 mL). After 30 min the mixture was extracted with CHCl3 (3×50 mL) and washed with brine. The organic layer was dried (Na2SO4), filtered, and concentrated. Purification of the mixture by Method 1 afforded 318 mg (64%) of the title compound. 1H NMR (400 MHz, CDCl3): 10.0 (s, 1H), 8.34 (d, J=5.3, 1H), 7.28 (d, J=1.3, 1H), 7.14-7.12 (m, 1H), 4.33 (t, J=6.6, 2H), 2.87-2.80 (m, 2H), 2.25 (s, 3H), 1.93-1.65 (m, 6H), 1.52-1.42 (m, 2H), 1.35-1.07 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][C:20]#[N:21])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][CH2:20][NH2:21])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(CC#N)ccc1OCC#Cc1ccccc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1cc(CCN)ccc1OCCCc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of [3-methoxy-4-(3-phenyl-prop-2-ynyloxy)-phenyl]-acetonitrile (2.0 g), liquid ammonia (5 g) and Raney-nickel (1 g) in methanol (100 ml) is shaken in an autoclave under hydrogen (100 bar) at +70° C. for 2 hours. The reaction mixture is filtered and evaporated. 2-[3-Methoxy-4-(3-phenyl-propoxy)-phenyl]-ethylamine is obtained as an oil.
Reaction SMILES: [Cl-].[NH4+].C(O)C.O.[CH2:7]([O:9][C:10]([C:12]1[NH:30][C:15]2[N:16]=[CH:17][N:18]=[C:19]([O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[C:14]=2[CH:13]=1)=[O:11])[CH3:8]>[Fe].O1CCCC1>[CH2:7]([O:9][C:10]([C:12]1[NH:30][C:15]2[N:16]=[CH:17][N:18]=[C:19]([O:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[C:14]=2[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cc2c(Oc3ccc([N+](=O)[O-])cc3)ncnc2[nH]1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2c(Oc3ccc(N)cc3)ncnc2[nH]1
Temperature: 82.5 °C
Reaction time: 2.5 h

Procedure:
After adding 110 mg of iron powder, 220 mg of ammonium chloride, 10 ml of ethanol and 2 ml of water to 4-(4-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, the mixture was stirred at 80-85° C. for 2.5 hours. After returning the mixture to room temperature, 20 ml of tetrahydrofuran was added, the mixture was stirred for 5 minutes and filtered with celite, and 100 ml of ethyl acetate and 50 ml of water were added to the filtrate for liquid separation and extraction. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered with plug cotton and concentrated to dryness to obtain 90 mg of the title compound.
Reaction SMILES: [CH2:1]([Sn:5](Cl)(Cl)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].CO.O.[F-:15].[F-:16].[NH4+].[NH4+]>>[CH2:1]([Sn:5]([F:16])([F:15])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Reactant: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCCC[Sn](F)(F)CCCC

Procedure:
Advantageously, dibutyl tin chloride and an ammonium difluoride are reacted to form a dibutyl tin difluoride precipitate. Dibutyl tin dichloride (DBTCl) is solubilized in an alcohol, preferably methanol, in a first reaction vessel. In a second such vessel, ammonium difluoride (NH4F, HF) is dissolved in a solvent which is preferably water. The contents of one reaction vessel are poured into the other and, on contact of the two solutions, a dibutyl tin difluoride precipitate is formed. The mixture is stirred to enhance the contact between the two solutions and to maximize the yield of precipitate. The resulting precipitate is recovered, drained, washed with water, washed with a solvent such as acetone to eliminate any remaining water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)=[C:22]=[O:23]>CN(C=O)C>[F:32][C:31]([F:33])([F:34])[O:30][C:27]1[CH:26]=[CH:25][C:24]([NH:21][C:22]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:23])=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(OC(F)(F)F)cc4)CC3)c2cc1OC
Yield: 52.1 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (20 mg, 0.0733 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 1-isocyanato-4-trifluoromethoxy-benzene (22 mg, 0.108 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a yellow solid (18.2 mg, 52%). 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 7.39 (m, 3H), 7.16 (m, 2H), 7.00 (m, 1H), 6.52 (br s, NH), 4.30-4.27 (m, 2H), 4.07 (s, 6H), 3.62 (m, 1H), 3.20 (m, 2H), 2.18-2.11 (m, 2H), 2.03-1.99 (m, 2H); LC/MS (ESI) calcd mass 476.2, found 477.3 [M+1]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[N:29][CH:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@H]1CCCC[C@@H]1NC>O1CCOCC1.[Cu](I)I>[CH3:22][N:8]1[C:6]2=[N:7][C:2]([N:34]3[CH:35]=[CH:36][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:38])[F:39])=[CH:30][N:29]=4)=[CH:32][C:33]3=[O:37])=[CH:3][CH:4]=[C:5]2[C:10]2[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:9]1=2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: I[Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 30 %

Procedure:
tert-Butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.19 g, 0.52 mmol), 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (0.14 g, 0.57 mmol), and K3PO4 (0.22 g, 1.0 mmol) were suspended in 1,4-dioxane (15 mL), and N2 was bubbled through the suspension for 45 min. To the suspension was added (1S,2S) N,N′-bismethyl-1,2-cyclohexane-diamine (20 μL, 0.14 mmol) and copper iodide (50 mg, 0.26 mmol). The reaction mixture was heated at reflux for 20 h under N2. The mixture was cooled, passed through a silica gel plug eluting with 80:18:2 CH2Cl2/MeOH/NH4OH, and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 4 column volumes) followed by additional flash chromatography (24 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 16 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) gave the title compound (82 mg, 30%) as a yellow film: 1H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.43-8.34 (m, 2H), 8.07 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 1H), 7.31 (d, J=1.5 Hz, 1H), 7.12 (dd, J=7.5, 2.0 Hz, 1H), 4.59 (s, 2H), 3.77 (t, J=5.5 Hz, 2H), 3.70 (s, 3H), 2.90 (t, J=5.5 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:43])[C@H:4]([OH:42])[CH2:5][NH:6][C:7](=[O:41])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][CH2:36][CH2:35]3)[C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[N:20]=2)=[CH:10][CH:9]=1.[OH-].[Na+].Cl.O>CO>[OH:42][C@H:4]([CH2:5][NH:6][C:7](=[O:41])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][CH2:36][CH2:35]3)[C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:30])([F:29])[F:31])=[CH:25][CH:26]=3)[N:20]=2)=[CH:10][CH:9]=1)[C:3]([OH:43])=[O:2]
Reactant: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(c2ccc3c(c2)CCC3)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NC[C@@H](O)C(=O)O)c1ccc(CN(c2ccc3c(c2)CCC3)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2(R)-Hydroxy-3-[4-({indan-5-yl-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]amino}methyl)benzoylamino]propionic acid methyl ester (0.10 g, 0.16 mmol) was dissolved in methanol (5 mL) and 1 N aqueous sodium hydroxide (0.16 mL, 0.16 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. 1 N hydrochloric acid (0.17 mL) and water (50 mL) were added and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with water (50 mL), dried (MgSO4) and concentrated in vacuo. This afforded 0.06 g (61%) of the title compound.
Reaction SMILES: CC[C:3](C1C=CC=CC=1)=[S:4].Cl[CH2:12][C:13]([C:15]1[CH:16]=[C:17]([OH:22])[C:18](=[CH:20][CH:21]=1)[OH:19])=[O:14].C[S-].[Na+]>CO>[CH3:3][S:4][CH2:12][C:13]([C:15]1[CH:16]=[C:17]([OH:22])[C:18](=[CH:20][CH:21]=1)[OH:19])=[O:14]
Reactant: CCC(=S)c1ccccc1
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Agent: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCC(=O)c1ccc(O)c(O)c1
Reaction time: 3 h

Procedure:
The procedure is as in Example 4 for the preparation of α-methylthioacetophenone, starting with a stirred solution of 4-(2-chloroacetyl)pyrocatechol (18.6 g) in methanol (200 cc). Sodium methanethiolate (7 g) is added in the course of 15 minutes at a temperature in the region of 20° C., and the mixture is left with stirring for 3 hours at the same temperature. 4-[2-(Methylthio)acetyl]pyrocatechol (14.5 g), m.p. 107° C., is thereby obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1.O1CCCC1>[C].[Pd].CO>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1
Reactant: COC(=O)/C=C/c1ccc(OC2Cc3ccccc3C2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1ccc(OC2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.3 %

Procedure:
A mixture of methyl (E)-3-[4-[(2,3-dihydro-1H-inden-2-yl)oxy]phenyl]-2-propenoate (0.76 g, 2.6 mmol), tetrahydrofuran (10 mL), methanol (5 mL) and 10% palladium carbon (50% water-containing product, 0.10 g) was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and concentrated. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate-methanol to give the title compound (0.85 g, yield 89%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:8]=1)=[O:5])[CH3:2].[Br:17]Br>CO>[CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([CH:12]([Br:17])[C:13]([O:15][CH3:16])=[O:14])[N:8]=1)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)Nc1nc(CC(=O)OC)ns1
Solvent: CO
Product: CCOC(=O)Nc1nc(C(Br)C(=O)OC)ns1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
Into a 1 L round bottom flask was charged methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetate (50.0 g, 0.204 mol, 1.0 eq) followed by methanol (500 mL). The resulting slurry was cooled to 0° C. To the cooled slurry was charged a pre-made solution of bromine (9.9 mL, 0.194 mol, 0.95 eq) in methanol (100 mL) dropwise over 30 minutes maintaining the temperature between 0-5° C. The cold bath was removed and the solution was allowed to warm to room temperature and stirred for two hours. Proton NMR analysis of the reaction mixture showed reaction completion. The orange solution was evaporated to an orange oil. The orange oil was taken up in diethyl ether (400 mL) and the organic was washed with water (2×100 mL), saturated 1:1 NaHCO3/Na2S2O4 (2×100 mL) and then brine (100 mL). The clear colorless ether layer was dried with sodium sulfate, filtered and evaporated in vacuo to give 54.5 grams of the title compound as a clear colourless oil. 1H NMR (CDCl3) δ 1.38 (t, 3H); 3.98 (s, 3H); 4.55 (q, 2H); 5.81 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.CCCCCC.C([Li])CCC.[CH3:20][C:21]1[CH:22]=[C:23]([O:26][C:27]=1[CH3:28])[CH:24]=[O:25]>O1CCCC1.O>[CH3:20][C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[OH:25])[O:26][C:27]=1[CH3:28]
Reactant: Cc1cccc(Br)n1
Reactant: Cc1cc(C=O)oc1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C(O)c2cc(C)c(C)o2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
2-Bromo-6-picoline (1.5 g) was dissolved in tetrahydrofuran (40 ml) under an argon atmosphere to prepare a solution. A 1.6 M hexane solution (5.6 ml) of n-butyllithium was added dropwise to the solution at −78° C., and the mixture was then stirred at −78° C. for 30 min. A solution of 4,5-dimethylfurfural (1 g) in tetrahydrofuran (20 ml) was added dropwise thereto, and the temperature of the mixture was raised to room temperature while stirring. Water was added to the reaction solution to stop the reaction, and the solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give (4,5-dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)-methanol (1.4 g, yield 74%).