Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=[C:18]4[Cl:31])[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:31][C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([C:12]3[N:11]=[C:10]([C:4]4[CH:3]=[C:2]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=4)[O:14][N:13]=3)[CH:16]=2)[N:20]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=1
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(OC)c(Br)c4)n3)ccc21
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: COCCOC
Product: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(OC)c(-c5ccccc5)c4)n3)ccc21
Temperature: 90 °C

Procedure:
Ethyl 3-(5-{5-[3-bromo-4-(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-3-chloro-1H-indol-1-yl)propanoate (D106) (212 mg, 0.42 mmol), phenyl boronic acid (104 mg, 0.84 mmol), Pd(PPh3)4 (20 mg) and 2N aq. sodium carbonate solution (3 ml, 6 mmol) were suspended in DME (6 ml) and heated at 90° C. for 2 hours. Added phenyl boronic acid (30 mg, 0.24 mmol) and Pd(PPh3)4 (20 mg) and heated at 90° C. for a further 2 hours. Added EtOAc (70 ml) and washed with water (100 ml). Dried over MgSO4 and evaporated off the solvent. The residue was crystallised from ethanol to yield the title compound as 90 mg of light tan solid. MS (ES) C28H2435ClN3O4 requires 501; found 502 (MH+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:29])[C:18]1[C:23]([Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:28])[CH3:12].[CH2:30](I)[CH3:31]>C1COCC1>[Cl:28][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18]=1[C:17]([N:16]([CH2:15][CH2:14][O:13][CH2:11][CH3:12])[CH2:30][CH3:31])=[O:29]
Reactant: CCI
Reactant: CCOCCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCCN(CC)C(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A 1M THF solution of sodium bis(trimethylsilyl)-amide (7.7 mL, 7.7 mmol) was added dropwise over 5 min to a solution of N-(2-ethoxyethyl)-2-chloro-6-(trimethylsilyl)benzamide (2.1 g, 7 mmol) in THF (30 mL). The resulting mixture was stirred for 1 h at RT, then a solution of ethyl iodide (1.31 g, 8.4 mmol) in THF (15 mL) was added with a mild exotherm. The resulting reaction mixture was stirred overnight, then was partitioned between ethyl acetate and dilute aq citric acid. The ethyl acetate phase was washed with sat aq NaHCO3 followed with brine, then was dried (MgSO4) and concentrated to afford 1.9 g of the title compound as an amber oil, an 83% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].C(N(C(C)C)CC)(C)C.[CH3:38][O:39][CH2:40][CH2:41][O:42][CH2:43]Cl.C(Cl)Cl>CCCCC>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:27][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: COCCOCCl
Solvent: CCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCO[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)OC)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A 100 ml round bottom flask, equipped with a mercury relief valve and magnetic stirrer, was flame-dried and flushed with nitrogen. The flask was charged with 2.57 mmoles (1.0 g) of 3β-hydroxy-5-cholenic acid methyl ester, 3.86 mmoles (0.50 g) of diisopropylethylamine, 3.86 mmoles (0.48 g) of methoxyethoxymethyl chloride and 10 ml of CH2Cl2. The reaction mixture was stirred for 48 hours at room temperature. After stirring, the reaction mixture was diluted with 25 ml of pentane, washed with 20 ml of 10% acetic acid and 20 ml of saturated sodium bicarbonate. The combined aqueous layers were extracted with two twenty ml portions of ether and the organic layers separated and dried with MgSO4. Concentration of the ether solution left an oily crude product (96%) which was isolated as a pure white solid (84%) by dissolving the oil in pentane, cooling to -78° C., and filtering. The pure solid had mp 44°-46° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([P:13]([O:24][CH2:25][CH3:26])([CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[O:14])=[CH:9][C:8]=1[C:27]([CH3:40])([CH3:39])[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(OCC)(=O)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([P:13]([O:24][CH2:25][CH3:26])([CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[O:14])=[CH:9][C:8]=1[C:27]([CH3:40])([CH3:39])[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: CCOP(=O)(CP(=O)(OCC)c1ccc(O)c(C(C)(C)CC(=O)OCc2ccccc2)c1)OCC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOP(=O)(CP(=O)(OCC)c1ccc(OC(=O)CC)c(C(C)(C)CC(=O)OCc2ccccc2)c1)OCC
Reaction time: 3 h
Yield: 66.2 %

Procedure:
Proprionyl chloride (190 μL, 2.17 mmol) was added drop-wise to a stirring solution of crude phenol 122 (880 mg, 1.67 mmol) and DMAP (2 mg, 0.016 mmol) in pyridine (5 mL). The reaction was continued for 3 hr at room temperature followed by the addition of ethyl acetate (100 mL). The organic layer was washed with cold aqueous HCl (0.5 N), H2O and saturated aqueous NaCl then dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (0 to 20% methanol in ethyl acetate) using a Biotage Horizons™ system, resulting in 123 as a pale yellow liquid (644 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 1.25 (t, J=7.0, 3H), 1.26 (t, J=7.5, 3H), 1.30 (t, J=7.0, 3H), 1.46 (s, 3H), 1.48 (s, 3H), 2.50-2.63 (m, 4H), 2.82 (AB q, J=14.4, 2H), 3.93-4.16 (m, 6H), 4.93 (s, 2H), 7.12-7.18 (m, 3H), 7.26-7.32 (m, 3H), 7.70 (ddd, J=1.8, 8.4, 11.6, 1H), 7.86 (dd, J=1.8, 13.4, 1H): 31P (162 MHz, CDCl3) δ 20.21 (d, J=9.7, 1 P), 34.03 (d, J=9.7, 1 P).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:35])[N:12]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH3:9])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:58][O:59][C:60](=[O:64])[CH2:61][CH2:62][NH2:63].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:58][O:59][C:60](=[O:64])[CH2:61][CH2:62][NH:63][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([CH2:25][N:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:17][CH:18]=2)[C:11]([NH:10][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:9])=[O:35])=[CH:27][CH:28]=1
Reactant: COC(=O)CCN
Reactant: C[C@H](NC(=O)N(Cc1ccc(C(=O)O)cc1)c1ccc(C2CCCCC2)cc1)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1ccc(CN(C(=O)N[C@@H](C)c2ccc(Cl)cc2)c2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
4-[3-[1(S)-(4-Chlorophenyl)ethyl]1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid (1.0 g, 2.04 mmol) was dissolved in DMF (8 ml) and HOBt (410 mg, 3.05 mmol), and EDAC (580 mg, 3.05 mmol) were added. The solution was stirred at room temperature for 30 min. A solution of 3-aminopropionic acid methyl ester hydrochloride (310 mg, 3.05 mmol) and N,N-diisopropylethylamine (530 μl, 3 mmol) in DMF (2 ml) was added, and the reaction mixture was stirred at ambient temperature over night. The reaction mixture was partitioned between ethyl acetate (70 ml) and water (3×50 ml). The organic phase was dried with anhydrous sodium sulfate and evaporated to dryness to afford 1.17 g (99%) of 3-{4-[3-[1(S)-(4-chloro-phenyl)ethyl]1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}propionic acid methyl ester. HPLC-MS (method A): m/z=576 (M+1); Rt=5.47 min.
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:26])=[C:18]([CH2:20][NH:21][C:22](=[O:25])[CH2:23][Cl:24])[CH:19]=1)(OC(C)(C)C)=O.Cl.Cl.CCOCC>CO>[ClH:24].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:26])=[C:18]([CH2:20][NH:21][C:22](=[O:25])[CH2:23][Cl:24])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CNC(=O)CCl)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(CCl)NCc1cc(OC[C@@H]2CCN2)cnc1Cl
Yield: 37 %

Procedure:
The product of step 211a (0.34 g, 0.80 mmol) was deprotected and isolated as the free base in 37% yield according to the procedure of Example 20b, followed by conversion to the monohydrochloride with HCl/Et2O: [α]D23 +16.82 (c 0.3, MeOH); 1H NMR (D2O, 300 MHz) δ 2.72 (q, J=8.5, 16.5 Hz, 2H), 4.07-4.43 (m, 4H), 4.45 (s, 2H), 4.48 (d, J=4.5 Hz, 2H), 4.81 (m, 1H), 7.53 (d, J=3.0 Hz, 1H), 8.08 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z 304 (M+H)+. Anal. Calcd for C12H15Cl2N3O2.HCI: C, 42.31; H, 4.73; N, 12.33. Found: C, 42.34; H, 5.00; N, 12.25.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]1[S:30][C:10]2=[N:11][CH:12]=[C:13]([C:28]#[N:29])[C:14]([NH:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[C:9]2[CH:8]=1.[BH4-].[Li+].CO>O1CCCC1>[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:30][C:10]2=[N:11][CH:12]=[C:13]([C:28]#[N:29])[C:14]([NH:15][C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[C:9]2[CH:8]=1
Reactant: COC(=O)CCCc1cc2c(Nc3cc(OC)c(OC)c(OC)c3)c(C#N)cnc2s1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3sc(CCCCO)cc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To a solution of 4-[5-cyano-4-(3,4,5-trimethoxyphenylamino)-thieno[2,3-b]pyridin-2-yl]-butyric acid methyl ester (1.10 g, 2.5 mmol) in 15 mL of tetrahydrofuran at room temperature is added dropwise lithium borohydride in tetrahydrofuran (10 mL, 2.0 M, 20 mmol). The mixture is heated at reflux for 1 hour, and cooled to room temperature. Methanol (20 mL) is added, and stirring is continued at room temperature overnight. The reaction mixture is partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic layer is dried, and concentrated. The residue is purified by flash column chromatography eluting with with 2:1 ethyl acetate:hexane to provide 563 mg of 2-(4-hydroxybutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile as a white solid, mp 125–127° C.; 1H NMR (DMSO-d6) δ 1.50 (m, 2H), 1.72 (m, 2H), 2.91 (t, J=7 Hz, 2H), 3.42 (m, 2H), 3.68 (s, 3H), 3.76 (s, 6H), 4.42 (t, J=5 Hz, 1H), 6.75 (s, 2H), 7.44 (s, 1 H), 8.45 (s, 1H), 10.23 (s, 1H); MS 414.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[C:23](=[O:24])[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[O:20][CH2:19]2)=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:2].C[O-].[Na+:31].C(OCC)C>CO>[CH2:1]([O:3][CH:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][N:18]2[C:23](=[O:24])[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[O:20][CH2:19]2)=[CH:13][CH:14]=1)[C:5]([O-:7])=[O:6])[CH3:2].[Na+:31]
Reactant: CCOC(Cc1ccc(OCCN2COc3ccccc3C2=O)cc1)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCOC(Cc1ccc(OCCN2COc3ccccc3C2=O)cc1)C(=O)[O-]
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirred suspension of (±)-2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoic acid (100 mg, 0.26 mmol), obtained in Example 3 in methanol (3 mL) was added a solution of sodium methoxide (54 mg, 1.0 mmol) in methanol (1 mL) dropwise at 30° C. The reaction mixture was stirred for further 1 h. Diethylether (5 mL) was added and the white solid precipitated was filtered and dried to afford the title compound (85 mg, 80%): mp 186-188° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:34]=[CH:33][C:20]([C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>C1COCC1>[O:32]=[C:28]1[CH2:27][C:26]2[C:30](=[CH:31][C:23]([C:21]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=4)=[O:10])=[CH:34][CH:33]=3)=[O:22])=[CH:24][CH:25]=2)[NH:29]1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Reactant: CCn1nc(C)cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Temperature: 79 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
A dry 25 mL flask was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (0.887 g, 5.16 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride then was removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (1.00 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a precipitate. The solids were filtered to afford the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.741 g, 1.94 mmol, 49%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:6]([C:22]([O:24]C)=[O:23])[CH2:5]1.[Li+].[OH-].C(O)(=O)C.C1(C)C=CC=CC=1>CO.O>[C:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][C:8]2([O:7][CH:6]([C:22]([OH:24])=[O:23])[CH2:5][N:4]([CH2:3][C:2]([F:27])([F:1])[F:26])[CH2:9]2)[CH2:14][CH2:13]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C1CN(CC(F)(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)(F)F)CC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
9-Tert-butyl 2-methyl 4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate (197 mg, 0.48 mmol) was dissolved in MeOH (1 mL)/H2O (1 mL), followed by the addition of LiOH (46 mg, 1.92 mmol) and the reaction mixture was stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in water (2 mL) and cooled to 0° C., then acetic acid (115 mg, 109 μL, 1.92 mmol) was added dropwise (pH=5). The product was partitioned between EtOAc/water, the layers were separated and the aqueous layer was extracted once more with EtOAc. The organics were dried over Na2SO4, filtered and concentrated in vacuo to yield an oil. The oil was co-evaporated twice with toluene and dried under high vacuum to yield 9-(tert-butoxycarbonyl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylic acid (142 mg, 77%) as a white foam. ESI-MS m/z calc. 382.4. Found 383.5 (M+1)+; Retention time: 1.58 minutes (3 min run).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH:20]1([CH2:23][NH:24][C:25](=[O:42])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][NH:24][C:25]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[C:30]([C:2]3[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:31]=2)=[O:42])[CH2:22][CH2:21]1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)NCC4CC4)ccc3C)nc2)c1

Procedure:
6-[5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl]-N-(3-methoxybenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 3.07 min, MH− 430. NMR: δH [2H6]-DMSO 9.30, (1H, t), 9.16, (1H, d), 8.62, (1H, t), 8.36, (1H, dd), 7.94, (1H, s), 7.85, (1H, d), 7.74, (1H, d), 7.43, (1H, d), 7.27, (1H, t), 6.94-6.92, (2H, m), 6.84, (1H, d), 4.51, (2H, d), 3.75, (3H, s), 3.14, (2H, t), 2.39, (3H, s), 1.03, (1H, m), 0.43, (2H, m), 0.23, (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(F)cc2)cc1
Temperature: 77.5 °C
Yield: 53 %

Procedure:
To a mixture of 4-fluoro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Step 1) (4.5 g. 15.4 mmol) and sodium bicarbonate (2.59 g, 30.8 mmol) in isopropanol (200 mL), 3-bromo-1,1,1-trifluoroacetone (3.2 mL) was added. After heating the reaction mixture at 75-80° C. for 22 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture (7.2 g) was purified by chromatography (silica gel, toluene/ethyl acetate, 1/1) to give 2-(4-fluorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole (3.28 g, 53%) as a white solid: mp (DSC) 203° C. Anal. Calc'd for C17H14N2F4SO3: C, 50.75; H, 3.51; N, 6.96. Found: C, 51.16; H, 3.69; N, 6.54.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([OH:48])[CH:39]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:49](O)[CH2:50][C:51]#[CH:52]>>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:41]=[C:40]([O:48][CH2:52][CH2:51][C:50]#[CH:49])[CH:39]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(O)cc(C(F)(F)F)c1)N(C(=O)OC(C)(C)C)C2=O
Reactant: C#CCCO
Product: C#CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)OC(C)(C)C)cc4C)CC3)C(=O)N2C(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Yield: 71 %

Procedure:
8-[2-(4-tert-Butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-2-(3-but-3-ynyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester (37.9 mg, 71%) was obtained by the same method as in Reaction 366-9 using 8-[2-(4-tert-butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-2-(3-hydroxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester and 3-butyn-1-ol as starting materials.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[OH:18].C(N(CC)CC)C>ClCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:18][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)c(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl chloride (4.22 g, 30 mmol) was added dropwise with a syringe to a solution of 2-fluoro-5-methylphenol (3.784 g, 30 mmol) and triethylamine (5 mL) in dichloromethane (50 mL), The mixture was stirred for 18 h at room temperature and concentrated under reduced pressure. Diethyl ether (200 mL) and water (100 mL) were added, the organic layer was separated and extracted with 2N NaOH (2×30 mL) and brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure to give a white solid. Yield: 6.601 g (96%). 1H-NMR (400 MHz, CDCl3) δ=2.36 (s, 3H, —CH3), 7.01-7.12 (m, 3H), 7.49-7.55 (m, 2H), 7.63-7.68 (m, 1H), 8.19-8.23 (m, 2H). LRMS (FAB+): 231.1 (100, [M+H]+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]([CH:28]([CH3:30])[CH3:29])[C:11]([O:13]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:12].[OH-].[K+].C(O)C.Cl>O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[C:2]1[CH:10]([CH:28]([CH3:30])[CH3:29])[C:11]([OH:13])=[O:12]
Reactant: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)C1=Cc2ccccc2C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(C(=O)O)C1=Cc2ccccc2C1

Procedure:
A mixture of m-phenoxylbenzyl 2-(2-indenyl)-3-methylbutanoate (8 mmol), potassium hydroxide (24 mmol), ethanol (25 ml) and water (4 ml) is heated to reflux for about 3 hours. After cooling, the reaction is acidified with dilute hydrochloric acid. The mixture is extracted with ether, and the ether phase is washed to neutrality with saturated NaCl solution. Removal of solvent by evaporation yields 2-(2-indenyl)-3-methylbutanoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([NH:14][CH3:15])=[CH:7][C:6]=1[N:16]1[CH2:21][CH2:20][CH:19]([C:22]([F:25])([F:24])[F:23])[CH2:18][CH2:17]1)[CH3:2]>[Ni].C1COCC1>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:14][CH3:15])=[CH:7][C:6]=1[N:16]1[CH2:17][CH2:18][CH:19]([C:22]([F:23])([F:24])[F:25])[CH2:20][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1N1CCC(C(F)(F)F)CC1
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(N)c(NC)cc1N1CCC(C(F)(F)F)CC1
Reaction time: 8 h

Procedure:
A mixture of ethyl-2-[4-trifluoromethyl-piperidinyl]-4-methylamino-5-nitro-benzoate (380 mg, 1.01 mmol), Ra—Ni (500 mg) and THF (20 mL) is stirred overnight under 10 bar H2-atmosphere. The mixture is filtered, and the filtrate is concentrated.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([C:29]#[C:30][C:31]([CH3:34])([OH:33])[CH3:32])[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([C:29]#[C:30][C:31]([OH:33])([CH3:32])[CH3:34])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)C#Cc1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)C#Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 4-(6-bromopyridin-2-yl)-2-methylbut-3-yn-2-ol (115 mg, 0.48 mmol) as starting materials.