Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[F:16][C:17]([F:29])([F:28])[C:18]([C:20]1[N:21]=[CH:22][N:23]2[CH:27]=[CH:26][S:25][C:24]=12)=[O:19].[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:29][C:17]([F:16])([F:28])[C:18]([C:20]1[N:21]=[CH:22][N:23]2[CH:27]=[C:26]([Sn:34]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:30][CH2:31][CH2:32][CH3:33])[S:25][C:24]=12)=[O:19]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: O=C(c1ncn2ccsc12)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)C(F)(F)F)c2s1
Reaction time: 0.5 h

Procedure:
A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (2.0 ml) was added to a solution of 0.34 g of 7-trifluoroacetylimidazo[5,1-b]thiazole and 0.48 ml of tri-n-butylstannyl chloride in 16 ml of dry THF in an argon atmosphere at −40° C. The mixture was stirred at the same temperature for 30 min. A saturated aqueous ammonium chloride solution was added thereto. Ethyl acetate was then added, followed by washing with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give 0.14 g of the title compound.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14](CC2C=CC=CC=2)[CH3:15])=[O:9])[CH2:3]1>CO.[OH-].[Pd+2].[OH-].[C].[H][H]>[F:1][C:2]1([F:30])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]([O:10][CH2:11][CH2:12][CH2:13][NH:14][CH3:15])=[O:9])[CH2:3]1
Reactant: [H][H]
Reactant: CN(CCCOC(=O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNCCCOC(=O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 41 mg of 3-(benzyl(methyl)amino)propyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in 2 ml of methanol, 10 mg of palladium hydroxide-carbon catalyst was added, followed by 2 hours' stirring at ambient temperature and pressure in hydrogen atmosphere. The reaction liquid was filtered with Celite. Distilling the solvent off from the filtrate under reduced pressure, 32 mg of the title compound was obtained.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1[CH:22]=[C:21]2[C:10]([CH2:11][C:12]3[CH:16]=[CH:15][N:14]([CH2:17][C@H:18](O)[CH3:19])[C:13]=32)=[CH:9][CH:8]=1.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.CN(C)C=O.O>[N:30]([C@@H:18]([CH3:19])[CH2:17][N:14]1[CH:15]=[CH:16][C:12]2[CH2:11][C:10]3[C:21]([C:13]1=2)=[CH:22][C:7]([CH3:6])=[CH:8][CH:9]=3)=[N+:31]=[N-:32]
Reactant: Cc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)-c1c(ccn1C[C@H](C)N=[N+]=[N-])C2
Yield: 50 %

Procedure:
1.8 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 2.7 g of (R)-1-(7-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 6.7 ml of triethyl-amine in 75 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 200 ml of dichloromethane, washed twice with 90 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 90 ml of dichloromethane. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 70 ml of anhydrous dimethylformamide, treated with 1.55 g of sodium azide and the reaction mixture was heated to 60° for 15 hours while stirring. After cooling, the solution was poured into 150 ml of water and extracted twice with 150 ml of ethyl acetate each time. The combined organic phases were washed once with 120 ml of water and once with 120 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.5 g (50%) of (S)-1-(2-azido-propyl)-7-methyl-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a light yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=2)[C@H:10]([CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[Cl:29][C:30]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([NH:21][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:30]=3[Cl:29])[CH:18]=[CH:19][CH:20]=2)[CH:10]([CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1Oc1cccc(N)c1
Solvent: CO
Solvent: C1COCCO1
Product: CC1CN(Cc2ccccc2)CCC1Oc1cccc(NC(=O)c2ccc(F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine racemic 3-(1-benzyl-cis-3-methyl-piperidin-4-yloxy)-phenylamine (preparation 41, 0.80 g, 2.7 mmol), 1,4-dioxane (20 mL), and 2-chloro-4-fluoro-benzoyl chloride (0.625 g, 3.24 mmol), stir and heat at reflux. After 2 hr., cool to ambient temperature. Dilute with methanol and load the resulting solution on 210 g SCX columns. Wash each with methanol (2×50 mL). Elute product from each column with 2M ammonia/methanol (2×50 mL). Combine and concentrate the eluents. Purify residue by silica gel flash chromatography eluting with 5% (2M NH3/methanol)/methylene dichloride to obtain the title compound as a racemic mixture (1.07 g, 87.7%). Resolve using a Chiralpak AD™ 4.6×250 mm column eluting at 1.0 mL/min. with 10% absolute ethanol/90% Heptane with 0.2% DMEA to obtain of the title compound (0.524 g, 49.0%). Mass spectrum (electrospray): m/z=453.2 (M+1); 1H NMR (CDCl3): 7.85 (bs, 1H), 7.8 (dd, 1H), 7.45 (s, 1H), 7.3 (m, 7H), 7.1 (m, 1H), 7.0 (m, 1H), 6.75 (dd, 1H), 4.4 (m, 1H), 3.5 (m, 2H), 2.5 (m, 2H), 2.4 (m, 2H), 2.1 (m, 2H), 1.8 (m, 1H), 1.0 (d, 3H).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl:10][C:11]1[CH:31]=[CH:30][CH:29]=[CH:28][C:12]=1[C:13]([NH:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25](O)=[O:26])[CH:23]=2)[CH2:18][CH2:17]1)=[O:14].O.ON1C2C=CC=CC=2N=N1.[CH2:43]1[C:48]2([CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]2)[CH2:47][CH2:46][CH2:45][NH:44]1>C(Cl)Cl>[Cl:10][C:11]1[CH:31]=[CH:30][CH:29]=[CH:28][C:12]=1[C:13]([NH:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([N:44]3[CH2:45][CH2:46][CH2:47][C:48]4([CH2:49][CH2:50][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:52][CH2:53]4)[CH2:43]3)=[O:26])[CH:23]=2)[CH2:18][CH2:17]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Reactant: O=C(O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(C(=O)c3ccc4c(c3)[C@H](NC(=O)c3ccccc3Cl)CC4)C2)CC1
Temperature: 0 °C
Reaction time: 60 h
Yield: 70 %

Procedure:
N-Ethyl-diisopropylamine (4 eq.) was added to a solution of (3R)-3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid (E-03) (0.952 mmol, 1 eq.) in methylene chloride (18 ml). The reaction mixture was cooled to 0° C. and N-ethyl-N′-3-(dimethylamino)-propyl-carbodiimide hydrochloride (1.2 eq.) and 1-hydroxybenzotriazole hydrate (0.2 eq.) were then added. The mixture was stirred at this temperature for 15 min, before tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate (1.1 eq.) was added. The reaction mixture was stirred at room temperature for 2.5 d. Then, the reaction mixture was washed in each case 1× with 10% NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica; ethyl acetate/hexane/ammonia (25 aq.) 70:10:0.8). Yield: 70%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.Cl.C(N=C=N[CH2:21][CH2:22][CH2:23][N:24](C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.C1(N)CC1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:24][CH:23]1[CH2:21][CH2:22]1)=[O:14])[CH:6]=[CH:5]2
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc2cc(Br)ccc2c1
Yield: 70 %

Procedure:
6-Bromo-2-naphthoic acid (1.01 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.92 g) and 1-hydroxy-1H-benzotriazole monohydrate (0.735 g; HOBt) were dissolved in dimethylformamide (16 ml) under an argon atmosphere. N-Ethyldiisopropylamine (0.62 g) was added with stirring under ice-cooling. Cyclopropylamine (0.37 g) was added and the mixture was stood with stirring at room temperature for 18 h. The reaction mixture was poured into ethyl acetate (0.15 L) and the mixture was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate and the solvent was concentrated. The precipitated crystals were collected by filtration and dried to give the title compound (0.817 g) as colorless needle crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[K+].O1[CH2:18][CH2:17][NH:16]C1=O.C(O)C(O)C(O)C(O)C(O)C=O.[O-]S([O-])(=O)=O.[Mg+2]>C(N)CN>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:18][CH2:17][NH2:16]
Reactant: O=C1NCCO1
Reactant: Oc1ccc2ccccc2c1
Agent: O=CC(O)C(O)C(O)C(O)CO
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: NCCN
Product: NCCOc1ccc2ccccc2c1
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 97.6 %

Procedure:
2-naphthol (200 g, 1.39 mol) at room temperature. Potassium hydroxide pellets (8.99 g, 0.139 mol) and 2-oxazolidinone (181 g, 2.08 mol) were then added, and the reaction mixture was heated to reflux and stirred for 5.5 h. Reaction was monitored by TLC analysis. Additional 2-oxazolidinone (24.0 g, 0.277 mol) was added to ensure complete conversion of the 2-naphthol and the reaction mixture was heated to reflux temperature for 16 additional hours. The reaction mixture was cooled to 70° C. and ethylenediamine (18.5 mL, 0.277 mmole) was added. The reaction mixture was then reheated to reflux temperature (approximately 155° C.) under nitrogen and stirred for approximately 6 hours. The reaction mixture was cooled to room temperature and Magnesol® was added and stirred into the reaction mixture for 15 minutes. The reaction mixture was then filtered over Celite® and reaction flask was washed three times with ExxonMobil™ Aromatic 100 solvent. The filtrate was collected and the solvent was evaporated in vacuo to obtain 254.1 g (97%) of 2-(2-naphthoxy)ethylamine. Purity was determined by HPLC and NMR analysis to be ˜92%.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=1.Cl.[Li+].[OH-]>CN1C(=O)CCC1.C1COCC1.O>[O:12]=[C:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]2[C:8](=[N:9][CH:10]=[CH:11][C:2]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:22][CH:23]=2)[NH:7]1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: COC(=O)Cc1ccc(N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Temperature: 140 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
83 (550 mg, 2.17 mmol), methyl 2-(4-aminophenyl)acetate (376 mg, 2.28 mmol), and HCl (0.65 mL, 2.17 mmol, 4.0 M in dioxane) were suspended in NMP (5 mL), and stirred for 3 h at 140° C. The reaction mixture was quenched with saturated aqueous NaHCO3 (100 mL), and stirred for 30 min. The resulting precipitate was filtered, washed with H2O, and dried under vacuum. The methyl ester intermediate (750 mg, 2.09 mmol) and LiOH (150 mg, 6.26 mmol) were dissolved in THF (4 mL) and H2O (4 mL), and stirred for 48 h at room temperature. The THF was removed, the mixture was diluted with H2O, and acidified to pH=5 with 1M HCl. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to provide 302 (550 mg, 76% yield) as a white solid. 1HNMR(DMSO-D6): 3.52(s, 2H), 6.97 (d, 1H), 7.13 (m, 2H), 7.21 (m, 2H), 7.58 (m, 1H), 7.61 (m, 1H)m 8.10 (d, 1H), 8.34(d, 1H), 8.84-8.90 (m, 2H). LC-MS (M+H=346, obsd.=346).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[N:30]=[C:31]=S.C(O)C.CC(N=C=NC(C)C)C>CN(C=O)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[NH:30][C:31]1[N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:3]2[C:2]([N:1]=1)=[CH:7][N:6]=[C:5]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([OH:15])[CH2:13][CH2:14]1)[N:4]=2
Reactant: Fc1cccc(F)c1N=C=S
Reactant: Nc1cnc(N[C@H]2CC[C@H](O)CC2)nc1NC1CCCC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H]1CC[C@H](Nc2ncc3nc(Nc4c(F)cccc4F)n(C4CCCC4)c3n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-{[5-Amino-4-(cyclopentylamino)pyrimidin-2-yl]amino}trans-cyclohexan-1-ol (1.13 mmol, 330 mg) was dissolved in DMF (8.5 mL) and 2,6-difluorophenyl-isothiocyanate (1.13 mmol, 0.146 mL) was added. The reaction mixture was stirred at room temperature for about 90 minutes. Ethanol (2.5 mL) was added and the reaction mixture was stirred for about an additional 30 minutes. N,N-Diisopropylcarbodiimide (3.40 mmol, 0.532 mL) was added and the reaction mixture was stirred overnight. Solvent was removed and the residue was purified using column chromatography (SiO2, 1:1 n-hexanes/ethyl acetate→ethyl acetate→1% methanol/ethyl acetate) to give the desired product (222.5 mg, 46% yield). ES-MS: 429 (M+1). Tetrahydrofuran can also be used as solvent in this step.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl.O>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:4]
Reactant: NCCN1CCOCC1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)NCCN1CCOCC1
Temperature: 5 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
Chloroacetyl chloride (1.73 g, 15 mmol) was dissolved in 4 mL of dichloromethane and cooled to 5° C. in an ice-water bath. 4-(2-Aminoethyl)morpholine (2 g, 15 mmol) was dissolved in 4 mL of dichloromethane containing triethylamine (3.03 g, 30 mmol) which was then added to this cold solution at 5° C. A solid precipitate formed immediately after the triethylamine was added. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with 100 mL of dichloromethane and 20 mL of water. The organic solution was washed with 5% aqueous NaHCO3 (2×50 mL), brine (1×50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was dried in vacuo to give 2.57 g (83.7%) of N-(2-chloroacetyl)-2-(4-morpholinyl)ethylamine as a yellow solid. 1H NMR (300 MHz / CDCl3): ∂ 2.48-2.55 (m, 6H), 3.38 (dd, 2H, J=5.63 Hz), 3.71 (t, 4H, J=4.53 Hz), 4.04 (s, 2H); mass spectrum, m/z=207.1 (M+H); HRMS calcd for C8H15N2O2Cl1 206.0822, found 206.0814.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[N:13]1[N:14]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH2:23])[N:15]=[CH:16][CH:17]=1.N1C=CNN1S1C=CC(N)=C1>>[N:15]1[N:14]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH:23][C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:13]=[CH:17][CH:16]=1
Reactant: Nc1ccsc1-n1nccn1
Reactant: COc1ccc(CC(=O)O)cc1
Agent: NC1=C[SH](N2NC=CN2)C=C1
Product: COc1ccc(CC(=O)Nc2ccsc2-n2nccn2)cc1

Procedure:
The title compound was prepared from (2-(4-methoxyphenyl)acetic acid (1.21 g, 7.22 mmol) and a 1:1 mixture of 2-(2H-1,2,3-triazol-2-yl)thiophen-3-amine and 1-(1H-1,2,3-triazol-2-yl)thiophen-3-amine (431 mg, 2.61 mmol) according to protocol B to give N-(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide. Retention time (min)=5.712, method [7], MS (ESI) 315.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.99 (s, 1H), 8.06 (d, J=6.4 Hz, 1H), 7.67 (s, 2H), 7.28-7.31 (m, 2H), 7.02 (d, J=5.7 Hz, 1H), 6.98 (d, J=9.1 Hz, 2H), 3.88 (s, 3H), 3.76 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:15]=[CH:14][N:13]=1)[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[C:16]([C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)[CH:15]=[CH:14][N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OS(=O)(=O)C(F)(F)F)ccn1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(F)cc2)ccn1
Yield: 71.4 %

Procedure:
Compound II (54 mg, 0.113 mmol), Pd(PPh3)4 (13 mg, 0.011 mmol), 4-fluorophenylboronic acid (32 mg, 0.23 mmol) and potassium carbonate (63 mg, 0.45 mmol) were stirred in toluene (1.5 mL) and water (0.7 mL) at 120° C. under microwave irradiation (300 W) for 30 min. The reaction mixture was then poured onto brine (5 mL) and extracted with EtOAc (3×5 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 then 80:20) to furnish III as a colourless oil (34 mg, 71%).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[OH-].[K+].[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])[CH2:9][CH3:10]>C(O)(C)C>[CH3:10][CH2:9][CH:8]([OH:11])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC(=O)c1ccccc1
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: CC(C)O
Product: CCC(O)c1ccccc1
Reaction time: 4 h

Procedure:
24.4 mg (4×10-5 moles) of [Ir(PPEI)COD]+ClO4- (-) suspended in 100 ml of isopropanol were oxidized with air for 4 hours. The resulting yellow solution was degasified for 20 minutes at reflux in a nitrogen stream and treated with 1.94 ml of an isopropanol solution of KOH (4 mg of KOH). After a 30-minute reduction in a nitrogen stream, 5.3 ml of deaerated propiophenone were added. After a 240-minute reaction, a conversion to phenylpropanol (-) of 98.5% with an e.e. of 25.07% was obtained. The polarimetric determination was effected on the hydrogenation product distilled at reduced pressure. Ratios:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[N:22]1[CH:23]=[CH:24][C:19]([C:18]([N:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:16])=[O:25])=[CH:20][CH:21]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)C1CCCN1C(=O)c1ccncc1
Temperature: 10 °C
Reaction time: 5 h

Procedure:
L-Proline benzyl ester hydrochloride (2.42 g, 0.01 mol) dissolved in pyridine (80 ml) is treated in portions at 3° C. (ice-bath cooling) with isonicotinoyl chloride hydrochloride (1.78 g, 0.01 mol), the IT increasing to 10° C. After removing the ice bath, the mixture is stirred for 5 h, the batch turning greenish.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:4])#[N:2].C[O-].[Na+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1.[H-].[Na+]>C(#N)C.C(OCC)C>[C:1]([C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])[CH2:19][CH:20]1[CH2:22][CH2:21]1)#[N:2]
Reactant: BrCC1CC1
Reactant: COC(=O)c1cccc(C(C)C#N)c1
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)c1cccc(C(C)(C#N)CC2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.7 %

Procedure:
To a solution of methyl 3-(1-cyanoethyl)benzoate (1.5 g, 7.9=mol) in acetonitrile (20 mL) were added sodium methoxide (0.95 g, 17 mmol) and (bromomethyl)cyclopropane (1.3 g, 9.5 mmol), and the reaction mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium hydride (60% in oil, 0.7 g, 17 mmol) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with diethyl ether, and washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→40/60) to give the title compound (129 mg, 6.7%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[CH:27]1(B(O)O)[CH2:29][CH2:28]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:27]1([C:2]2[CH:3]=[C:4]([O:17][CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:5]3[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=3)[CH:7]=2)[CH2:29][CH2:28]1
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Br)cn12
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(C3CC3)cn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
500 mg of ethyl 6-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 21A; 1.18 mmol; 1 equivalent), 131 mg of cyclopropaneboronic acid (1.53 mmol, 1.3 equivalents), 873 mg of potassium phosphate (4.12 mmol, 3.5 equivalents), 33 mg of tricyclohexylphosphine (0.12 mmol, 0.1 equivalents) and 13 mg of palladium(II) acetate (0.059 mmol, 5 mol %) were initially charged in 10.5 ml of toluene/water 20:1 and stirred at 80° C. for 16 h.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:32])[C:18]([OH:31])([C:23]3[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=3)[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:33])[CH:12]=2)=[CH:7][C:6]=1[Cl:34])=[O:4].Cl.[OH-].[Na+]>O1CCOCC1.O1CCCC1.CO>[Cl:34][C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:32])[C:18]([OH:31])([C:23]3[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=3)[C:19]([F:21])([F:20])[F:22])=[C:13]([Cl:33])[CH:12]=2)[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc(OC)nc3)C(F)(F)F)c(Cl)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(c1ccc(-c2ccc(C(=O)O)c(Cl)c2)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F

Procedure:
In analogy to Example 175, step 6, 3,3′-dichloro-4′-[3,3,3-trifluoro-2-hydroxy-2-(6-methoxy-pyridin-3-yl)-1-methyl-propyl]-biphenyl-4-carboxylic acid methyl ester (Example 178) was treated first with aqueous HCl in dioxane, followed by aqueous NaOH in tetrahydrofuran/methanol to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=484.1 [M−H+].