Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:40](=[O:39])[CH2:41][OH:42])[CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f38) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:22]([O:24]C)=[O:23])(=[O:10])=[O:9].C(N(CC)CC)C.[CH2:33]([NH2:37])[CH2:34][CH2:35][CH3:36].[Li+].[OH-]>C(#N)C>[CH2:33]([NH:37][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9])[CH2:34][CH2:35][CH3:36]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2ccccc12
Reactant: CCCCN
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCNc1ccccc1S(=O)(=O)Nc1ccc2ccccc2c1C(=O)O
Temperature: 65 °C

Procedure:
A solution of Example 133B (0.060 g, 0.17 mmol), triethylamine (0.070 mL, 0.50 mmol), and butylamine (0.088 mL, 0.85 mmol) in anhydrous acetonitrile (0.6 mL) was heated to 200° C. for 20 minutes in a microwave reactor and concentrated. The concentrate was dissolved in 9:1 methanol/water (1 mL), treated with LiOH (25 mg, 0.6 mmol), and heated to 65° C. for 16 hours. The reaction mixture was concentrated and the concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 399 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 13.73 (br s, 1H), 10.30 (br s, 1H), 8.16 (br s, 1H), 7.88 (m, 2H), 7.57 (m, 2H), 7.49 (t, 1H), 7.34 (m, 1H), 7.26 (d, 1H), 6.72 (d, 1H), 6.59 (t, 1H), 5.87 (br s, 1H), 3.04 (t, 2H), 1.41 (quint, 2H), 1.26 (sext, 2H), 0.82 (t, 3H).
Reaction SMILES: [N:1]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:2]1[C:3]([N:5]([CH3:12])[CH2:6][C:7]([O:9]CC)=[O:8])=[O:4].O[Li].O>O1CCOCC1.O>[N:1]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:2]1[C:3]([N:5]([CH3:12])[CH2:6][C:7]([OH:9])=[O:8])=[O:4]
Reactant: CCOC(=O)CN(C)C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CN(CC(=O)O)C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 90.1 %

Procedure:
To a solution of Cbz-D-hPro-N(Me)Gly-OEt (6 g, 16.6 mmol) in p-dioxane (200 mL) was added a solution of LiOH.H2O (2.78 g, 66.2 mmol) in water (100 mL) with vigorous stirring. After stirring for 12 hours, the solution was concentrated to a volume of 50 mL, diluted with water (100 mL), and extracted twice with diethyl ether (200 mL). The aqueous phase was adjusted to pH 2 with 5N aqueous HCl and extracted three times with ethyl acetate (150 mL). The combined ethyl acetate extracts were dried with MgSO4, filtered, and concentrated to give a white solid (5 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:25]([O:27]C)=[O:26])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:12].[OH-].[Na+:30]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:25]([O-:27])=[O:26])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:12].[Na+:30]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1c(F)cccc1F)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)[O-]
Yield: 68 %

Procedure:
The same procedures as in Example 60 were carried out from the compound obtained in Example 13 (3.9 g), 1 mol/L of an aqueous sodium hydroxide solution (15 mL), and methanol (150 mL), to give the captioned compound (2.7 g, 68%) as an amorphous solid product.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12](O)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH2:15][C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[CH:20][C:21]=1[NH2:22]>>[CH3:23][C:18]1[CH:19]=[CH:20][C:21]2[N:22]=[C:12]([C:11]3[C:2](=[O:1])[NH:3][C:4]4[C:9]([CH:10]=3)=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:15][C:16]=2[CH:17]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C(O)c1cc2ccccc2[nH]c1=O
Product: Cc1ccc2nc(-c3cc4ccccc4[nH]c3=O)[nH]c2c1
Temperature: 200 °C

Procedure:
A suspension of 2-oxo-1,2-dihydro-quinoline-3-carboxylic acid 1-1 (500 mg, 2.64 mmol, 1 equiv) and 3,4-diaminotoluene (646 mg, 5.29 mmol, 2.00 equiv) in polyphosphoric acid (10 mL) was heated under argon at 200° C. for 2 h. The hot reaction mixture was poured over ice (200 g), and the resulting mixture was allowed to stand until all polyphosphoric acid had dissolved. The precipitate was filtered, washed with water (200 mL), and air dried. The olive-colored solid was partitioned between aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL). The organic layer was dried over sodium sulfate and concentrated to give 1-3 as a yellow solid. 1H NMR (300 MHz, CDCl3) major hydrogen-bonded rotational isomer: δ 15.20 (br s, 1H), 14.30 (br s, 1H), 9.18 (s, 1H), 7.77 (br d, 1H, J=7.6 Hz), 7.61 (br d, 1H, J=7.5 Hz), 7.60 (br t, 1H, J=7.5 Hz), 7.37 (br s, 1H), 7.36 (br d, 1H, J=7.5 Hz), 7.32 (br t, 1H, J=7.6), 7.14 (br d, 1H, J=8.2 Hz), 2.52 (s, 3H); HRMS (electrospray FT/ICR) calcd for C17H14N3O [M+H]+ 276.1131, found 276.1132; TLC (40% EtOAc in hexane) Rf=0.10.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[N:10]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2cccc(Cl)c2)n1
Yield: 71.3 %

Procedure:
The title compound was prepared from 3-chlorophenylhydrazine hydrochloride (1.43 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedure in Example 161A Step 3 to give 3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-amine (1.42 g, 5.70 mmol, 71%). 1H NMR (300 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.61 (d, 1H), 7.46 (t, 1H), 7.30 (d, 1H), 5.42 (s, 1H), 5.34 (s, 2H), 1.09 (s, 9H); LC-MS (ESI) m/z 250 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](N)c1nc2cccnc2n1-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccnc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 7.9 %

Procedure:
A mixture of (S)-1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine from Example 10 (270 mg, 1.13 mmol), 6-chloro-9H-purine (250 mg, 1.59 mmol) and DIPEA (0.36 mL, 2.04 mmol) in n-butanol (1.5 mL) was stirred in a sealed tube for 48 h at 120° C. After cooling to RT, the crude reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM), then triturated with diethyl ether and then submitted to preparative HPLC (Phenomenex Gemini 5 μm C18 on a 60 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) affording 114 as an off-white solid (32 mg, 8%). LCMS: RT 2.64 min [M+H]+ 357.0. 1H NMR (DMSO, 400 MHz): δ 8.23 (1H, dd, J=4.76, 1.48 Hz), 8.18-7.97 (4H, m), 7.67-7.41 (5H, m), 7.29 (1H, dd, J=7.99, 4.76 Hz), 1.57 (3H, d, J=6.83 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[N:9][N:10]=2)[CH:7]=1.Cl.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:29]3[CH2:28][CH2:27][CH:26]([C:20]4[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=4[Cl:18])[CH2:31][CH2:30]3)=[O:13])=[N:9][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc2ccc(Br)cn12
Reactant: Fc1ccc(Cl)c(C2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cc(F)ccc2Cl)CC1
Reaction time: 0.33 h
Yield: 42.3 %

Procedure:
To a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (73 mg, 0.27 mmol) in THF (2.2 mL) was added a solution of LiOH monohydrate (13 mg, 0.30 mmol) in H2O (1.5 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (2.9 mL) under an atmosphere of N2. To this mixture was added 4-(2-chloro-5-fluorophenyl)piperidine hydrochloride (17, 68 mg, 0.27 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (240 mg, 0.54 mmol), and diisopropylethylamine (0.14 mL, 0.81 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL) and the resulting precipitate was collected by filtration. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0 to 50% EtOAc in hexanes) to provide (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-chloro-5-fluorophenyl) piperidin-1-yl)methanone as a white solid (50 mg, 42%): 1H NMR (500 MHz, DMSO-d6) δ 9.13-9.11 (m, 1H), 7.98 (dd, J=9.5, 1.0 Hz, 1H), 7.71 (dd, J=9.5, 1.5 Hz, 1H), 7.50 (dd, J=9.0, 5.5 Hz, 1H), 7.28 (dd, J=25, 3.0 Hz, 1H), 7.15-7.10 (m, 1H), 5.28-5.20 (m, 1H), 4.76-4.70 (m, 1H), 3.42-3.29 (m, 2H, overlaps with H2O), 3.07-2.98 (m, 1H), 1.96-1.65 (m, 4H).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH:30][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH3:29])=[CH:24][CH:23]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: COc1ccc([C@H](C)N)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@H](C)NC2=NC(=O)/C(=C/c3ccc4ncccc4c3)S2)cc1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-(S)-(4-methoxy-phenyl)-ethylamine and DIEA to give 2-[(S)-1-(4-methoxy-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:31](=[O:32])[CH:5]2[CH:6](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23](C(F)(F)F)[CH:22]=4)=[CH:17][N:16]=3)[N:7]3[CH:12]([CH:4]2[C:3]1=[O:33])[CH2:11][CH2:10][CH2:9][CH2:8]3.BrC1C=CC(/C=C/C2N3C(CCCC3)C3C(=O)N(C)C(=O)C23)=NC=1.[Cl:58]C1C=CC=CC=1B(O)O>>[Cl:58][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]/[CH:6]2[N:7]3[CH:12]([CH2:11][CH2:10][CH2:9][CH2:8]3)[CH:4]3[C:3](=[O:33])[N:2]([CH3:1])[C:31](=[O:32])[CH:5]23)=[N:16][CH:17]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)cn1
Agent: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(Br)cn1
Product: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(-c2ccccc2Cl)cn1

Procedure:
The title compound is prepared analogously to the compound from Example 17 from 42 mg of 4-[(E)-2-(5-bromopyridin-2-yl)vinyl]-2-methyloctahydropyrrolo[3,4-a]-indolizine-1,3-dione (from Example 6, racemic mixture 3) and 18 mg of 2-chloro-phenylboronic acid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[S:11]C(=S)N[C:8]2=[O:13])=[CH:4][C:3]=1[O:16][CH3:17].[OH-:18].[Na+]>Cl>[OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]([SH:11])[C:8]([OH:18])=[O:13])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(C=C2SC(=S)NC2=O)ccc1O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1cc(C=C(S)C(=O)O)ccc1O
Reaction time: 1 h

Procedure:
The product from Step A was added to 20% sodium hydroxide solution (250 mL) and heated to 70°-75° C. with stirring for one hour. The resulting solution was chilled in an ice bath and added rapidly, with stirring, to cold 10% hydrochloric acid (350 mL). The yellow solid was collected, washed with water and dried at 50° C.; yield 36 g.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:8][O:9][N+:10]=2[O-:11])[N:5]=[CH:6][N:7]=1.[H-].[Li+].Cl[CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17]>C1COCC1>[CH3:19][N:18]([C:16]([CH2:15][N:7]1[C:2](=[O:1])[C:3]2=[N+:10]([O-:11])[O:9][N:8]=[C:4]2[N:5]=[CH:6]1)=[O:17])[CH3:20]
Reactant: CN(C)C(=O)CCl
Reactant: [O-][n+]1onc2ncnc(O)c21
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1cnc2no[n+]([O-])c2c1=O
Reaction time: 2 h

Procedure:
4.6 g (30 mmol) of 7-hydroxy-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide and 0.28 g (35 mmol) of lithium hydride are heated at 50° C. for 30 minutes in 65 ml of THF. A solution of 4.6 g (38 mmol) of 2-chloro-N,N-dimethylacetamide in 10 ml of THF is then added dropwise and the mixture is heated under reflux for 4 hours. The solvent is completely stripped off in a rotary evaporator and the residue is stirred with 30 ml of water for 2 hours. The precipitate is filtered off with suction and recrystallised from THF, and 2.4 g (33%) of 6-(N,N-dimethylaminocarbonylmethyl)[1,2,5]oxadiazolo[3,4-d]pyrimidine-7(6H)-one-1-oxide are obtained.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@@:4]([CH2:1][CH3:3])([OH:12])[CH2:8][CH2:7][N:6]1[C:20]1[CH:21]=[C:14]([F:13])[C:15]([C:16]#[N:17])=[C:18]([F:23])[CH:19]=1)[CH3:11]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2cc(F)c(C#N)c(F)c2)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (197 mg), 2,4,6-trifluorobenzonitrile (295 mg) and lithium carbonate (192 mg), the title compound was obtained as a colorless solid (yield: 157 mg, yield: 54%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:8]([CH:22]=O)=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]1[CH2:24][C@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1.[CH3:30][NH:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:30][N:31]([CH2:22][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10]1([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]1=3)[CH2:19][CH2:18][O:17]4)[C:2](=[O:1])[N:3]2[CH2:24][C@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1)[CH3:32]
Reactant: CNC
Reactant: O=Cc1cccc2c1C1(COc3cc4c(cc31)CCO4)C(=O)N2C[C@H]1CCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN(C)Cc1cccc2c1C1(COc3cc4c(cc31)CCO4)C(=O)N2C[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
To a stirred solution of 2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-4′-carbaldehyde (0.10 g, 0.26 mmol) and dimethylamine (0.19 mL, 0.38 mmol) in dichloroethane was added sodium triacetoxyborohydride (0.10 g, 0.46 mmol) at 0° C. The mixture was stirred at ambient temperature for 18 h, and quenched with water. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (methanol/ethyl acetate, 5/100) to afford 4′-[(dimethylamino)methyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.05 g, 46%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.29-7.20 (m, 1H), 7.07 (d, J=7.9 Hz, 1H), 6.98 (t, J=7.0 Hz, 1H), 6.45-6.39 (m, 1H), 6.38 (s, 1H), 5.07 (dd, J=8.8, 2.1 Hz, 1H), 4.88 (d, J=8.8 Hz, 1H), 4.52 (t, J=8.6 Hz, 1H), 4.33-4.21 (m, 1H), 3.98-3.62 (m, 4H), 3.33 (dd, J=13.2, 3.3 Hz, 1H), 3.03-2.88 (m, 2H), 2.80 (d, J=13.2 Hz, 1H), 2.09-1.63 (m, 10H); MS (ES+) m/z 421.0 (M+1).
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[CH:22]([NH:25][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:24])[CH3:23]
Reactant: CC(C)N
Reactant: CCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: CCCc1noc(C)c1COc1ccc(C(=O)NC(C)C)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 29.9 %

Procedure:
A mixture of 6-(5-methyl-3-propyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (290 mg, 1.0 mmol), isopropylamine (71 mg, 1.2 mmol) and TBD (42 mg, 0.30 mmol) was stirred for 15 h at ambient temperature under argon. The reaction mixture was concentrated onto silica then purified by chromatography (silica, 0 to 60% ethyl acetate in heptane) to give the title compound (95 mg, 30%) as a white solid after trituration with diisopropyl ether. MS: m/e=318.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=O)[NH:11][C:7]=2[CH:6]=1)=[O:4].P(Cl)(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10]([Cl:17])=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2[nH]c(Cl)nc2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester (3.00 g, 15.6 mmol) and phosphorus oxychloride (30 mL) were combined and heated to 100° C. for 48 h. The mixture was cooled to 23° C. and concentrated under reduced pressure. The residue was cooled to 0° C., and cold, saturated aqueous NaHCO3 (60 mL) was added cautiously. After stirring at 23° C. for 15 min, the mixture was sonicated and the resulting residue was filtered to yield the titled compound (3.13 g, 95%), which was used in the next step without further purification. MS (ESI/CI): mass calcd. for C9H7ClN2O2, 210.02; m/z found, 211.0 [M+H]+.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC.O>[CH2:22]([O:21][C:19]([NH:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A)a) 3.7 g of tetrabutylammonium hydrogen sulphate and 100 ml of 1N sodium hydroxide solution are added to a solution of 10.0 g of t-butyl (S)-3-aminomethyl-1-piperidinecarboxylate (Example 6d) in 400 ml of hexane and 100 ml of water. 9.3 ml of benzyl chloroformate are added dropwise to this mixture and the mixture obtained is stirred at room temperature for 3 hours. Subsequently, the organic phase is separated, washed with water, 10% citric acid, water and saturated sodium bicarbonate solution, dried and evaporated. t-Butyl (S)-3-[(1-(benzyloxy)formamido]-methyl]-1-piperidinecarboxylate is obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH2:30][O:31]S(C)(=O)=O)[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CC(C)CO>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH2:30][O:31][CH2:2][CH:3]([CH3:8])[CH3:4])[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(COS(C)(=O)=O)c3)n2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CO
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)cc1COCC(C)C
Temperature: 130 °C

Procedure:
Methyl 2-fluoro-4-[5-(2′-methyl-2-{[(methylsulfonyl)oxy]methyl}biphenyl-4-yl)-1,2,4-oxadiazol-3-yl]benzoate, prepared as in example 58, step 1, (75 mg; 0.15 mmol) was dissolved in 2-methyl-1-propanol (5 mL). The solution was then heated in the microwave at 130° C. for 10 min. Sodium hydroxide (151.05 μL; 5 M; 0.76 mmol) was added and the mixture was heated at 60° C. for 10 min in the microwave. Hydrogen chloride (151.05 μL; 5 M; 0.76 mmol) was added and the mixture was evaporated to dryness. The crude was purified with MD Autoprep, to afford the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 13.63 (br s, 1H), 8.34 (d, J=1.5 Hz, 1H), 8.18 (dd, J=8.0, 1.8 Hz, 1H), 8.13-8.08 (m, 1H), 8.03 (dd, J=8.1, 1.4 Hz, 1H), 7.95 (dd, J=11.0, 1.2 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.36-7.25 (m, 3H), 7.15 (d, J=7.0 Hz, 1H), 4.23 (s, 2H), 3.10 (d, J=6.4 Hz, 2H), 2.04 (s, 3H), 1.77 (sept, J=6.6 Hz, 1H), 0.84 (d, J=6.6 Hz, 6H). LC/MS (Method B): 459.4 (M−H)−, 461.3 (M+H)+. HPLC (Method A) Rt 6.04 min (Purity: 99.3%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17]([CH2:25][O:26][C:27]4[C:32]([F:33])=[CH:31][C:30]([CH2:34][CH2:35][C:36](OCC)=[O:37])=[CH:29][C:28]=4[F:41])=[C:18]([C:21]([F:24])([F:23])[F:22])[S:19][CH:20]=3)=[CH:15][C:10]=2[CH2:9][CH2:8]1>>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17]([CH2:25][O:26][C:27]4[C:28]([F:41])=[CH:29][C:30]([CH2:34][CH2:35][CH2:36][OH:37])=[CH:31][C:32]=4[F:33])=[C:18]([C:21]([F:24])([F:22])[F:23])[S:19][CH:20]=3)=[CH:15][C:10]=2[CH2:9][CH2:8]1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc4c(c3)CCO4)csc2C(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1cc(F)c(OCc2c(-c3ccc4c(c3)CCO4)csc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-((4-(2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-3,5-difluorophenyl)propanoate to give the desired product as off-white oil. 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.3 (s, 1H), 7.26 (m, 1H), 6.82 (d, J=8.6 Hz, 1H), 6.72 (d, J=9.5 Hz, 2H), 5.04 (s, 2H), 4.62 (t, J=10.5 Hz, 2H), 3.68 (t, J=7.5 Hz, 2H), 3.25 (t, J=10.2 Hz, 2H), 2.65 (t, J=7.2 Hz, 2H), 1.84 (m, 2H), 1.55 (br, s, 1H).