Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]2=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[O:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][CH:57]=2)[CH2:52][CH2:51]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[N:53]1([C:56]2[CH:57]=[CH:58][C:59]([NH:60][C:12]([C:9]3[NH:10][C:11]4[C:6]([C:7](=[O:15])[CH:8]=3)=[CH:5][C:4]([O:16][CH3:17])=[CH:3][C:2]=4[Br:1])=[O:14])=[CH:61][CH:62]=2)[CH2:52][CH2:51][O:50][CH2:55][CH2:54]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COc1cc(Br)c2[nH]c(C(=O)O)cc(=O)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Br)c2[nH]c(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a yellow suspension of 8-bromo-6-methoxyoxo-1,4-dihydro-quinoline-2-carboxylic acid (Reference Example 27a) (3.446 g, 11.56 mmol), TBTU (9.039 g, 28.15 mmol), and HOBt (3.757 g, 27.8 mmol) in 100 mL dimethylformamide was added 4-morpholinoaniline (2.733 g, 15.3 mmol) and diisopropylethyl amine (8.2 mL, 50.2 mmol). The resulting marroon solution was stirred at room temperature under nitrogen for 16 hours during which time the reaction became greenish brown and formed a large amount of precipitate. The reaction mixture was filtered and the solids washed with dimethylformamide, water, and methanol; Drying under high vacuum afforded the desired product as a yellow solid (3.09 g, 58%). 1H NMR (300 MHz, DMSO, d6) δ 12.13 (s, 1 H, NH), 10.18 (s, 1 H, C(O)NH), 7.90 (d, 1 H, Jm=2.7 Hz, ArH5), 7.68 (d, 2 H, Jo=9.0 Hz, ArH2′ & H6′), 7.63 (s, 1 H, C═CH), 7.51 (d, 1 H, Jm=2.7 Hz, ArH7), 7.00 (d, 2 H, Jo=9.0 Hz, ArH3′ & H5′), 3.94 (s, 3 H, OCH3), 3.75 (t, 4 H, J=4.8 Hz, OCH2CH2N), 3.10 (t, 4 H, J=4.8 Hz, OCH2CH2N); Mass Spec.: calc. for [C21H20BrN3O4+H]+ Theor. m/z=458, 460; Obs.=458, 460.
Reaction SMILES: [C:1]([C:3]1[N:4]=[N:5][N:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1)#[N:2].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH3:20])[CH:19]=[C:8]([N:6]1[CH:7]=[C:3]([C:1]#[N:2])[N:4]=[N:5]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Cn1cc(C#N)nn1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)n1cc(C#N)nn1

Procedure:
1.3 g (7.5 mmol) of the compound from Example 4A and 1.4 ml (1.2 g, 8.2 mmol) of N,N-dimethylformamide diethyl acetal are stirred at a bath temperature of 100° C. for 16 h. For work-up, the cooled reaction solution is concentrated on a rotary evaporator and the residue is dried under reduced pressure. Yield: 1.5 g (86% of theory)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1.[CH2:20]=[C:21]([CH3:23])[CH3:22].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:18]([C:14]1[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=1)[CH2:20][C:21]2([CH3:23])[CH3:22])=[O:11]
Reactant: O=Cc1cccnc1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccnc1)N2
Temperature: 85 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
To a stirred solution of 4-amino-benzoic acid methyl ester (11.3 g, 78.4 mmol) and pyridine-3-carbaldehyde (8.4 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 4,4-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (9.2 g, 40.0%) as a light yellow solid: MS (ESI) M+1=297.3.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:22])([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:13][OH:14]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:22])([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:13][O:14][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: Cc1ccc(C(C)(CO)CCCCBr)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(C)(CCCCBr)COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
Under N2 atmosphere, 3,4-dihydro-2H-pyran (6.39 g, 76.09 mmol) was added drop-wise to a stirred solution of 6-bromo-2-methyl-2-p-tolyl-hexan-1-ol (18.20 g, 63.86 mmol) and p-toluenesulfonic acid hydrate (0.43 g, 2.26 mmol) in dichloromethane (300 mL) at −5° C. The reaction mixture was allowed to warm to rt and stirred for 3 h. The solution was filtered through aluminum oxide (160 g), which was washed with CH2Cl2 (500 mL). The filtrate was concentrated in vacuo to furnish 2-(6-bromo-2-methyl-2-p-tolyl-hexyloxy)-tetrahydropyran (22 g, 93.4%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.25-7.05 (m, 4H), 4.60-4.48 (m, 1H), 3.82 (m, 2H), 3.48-3.37 (m, 2H), 3.35-3.26 (m, 2H), 2.30 (s, 3H), 1.90-1.40 (m, 11H), 1.40-1.33 (s, 3H), 1.40-1.08 (m, 1H), 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 142.78, 135.22, 128.81, 126.39, 99.09, 61.99, 41.67, 38.12, 37.87, 33.68, 30.99, 25.96, 23.08, 22.89, 21.12, 20.97, 19.41. HRMS (LSIMS, nba): Calcd. for C19H30O2Br (MH+): 369.1429, found: 369.1451.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CN(C)C(CCCC1C=C2C(=CC=1)N(CCC)C=C2C[C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=1[O:42][CH3:43])=O.CI>O1CCCC1>[CH3:43][O:42][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:33]=1)[C:37]([OH:39])=[O:38]
Reactant: CCCn1cc(Cc2ccc(C(=O)O)cc2OC)c2cc(CCCC(=O)N(C)C)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CC(C)NC(C)C
Product: COc1cccc(C(=O)O)c1
Reaction time: 0.25 h
Yield: 222.7 %

Procedure:
To a mixture of diisopropylamine (2.92 ml) and tetrahydrofuran (17.5 ml), at -78°, under nitrogen, was added 1.17 M n-butyllithium (16.3 ml). After stirring for 15 min, a solution of 4-[5-[3-(dimethylcarbamoyl)propyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoic acid (3.8 g) in tetrahydrofuran (50 ml) was added. The reaction was allowed to warmed to -30° and stirred for 45 min. Methyl iodide (2.71 ml) was added and the mixture stirred for 90 min. The reaction was quenched with saturated ammonium chloride (100 ml) and the organic layer was partitioned between ethyl acetate and saturated ammonium chloride. The organic phase was washed (saturated ammonium chloride, water), dried (MgSO4), and evaporated. The residue was dissolved in saturated sodium bicarbonate. The solution was washed with diethyl ether and acidified to pH 2 with 6N hydrochloric acid. The product was extracted into ethyl acetate, and the organic layer was dried (MgSO4) The solvent was evaporated and the residue was triturated with hexane, powderized and vacuum dried at 40° for 18 hr to afford 4-[5-[3-dimethylcarbamoyl)butyl]1-propylindol-3-ylmethyl]-3methoxybenzoic acid (2.95 g, 75%) as a pale pink solid; mp 60.0°-64.0°.
Reaction SMILES: Cl[Si:2]([CH3:13])([CH3:12])[C:3]1(C)[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]1[CH3:10].[CH2:14]([NH-:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Li+].[CH3:23]COCC>>[CH2:14]([NH:21][Si:2]([CH3:12])([CH3:13])[C:3]1[CH:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH3:8])[C:7]=1[CH3:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [NH-]Cc1ccccc1
Reactant: CCOCC
Reactant: CC1=CC(C)([Si](C)(C)Cl)C(C)=C1C
Agent: [Li+]
Product: CC1=C(C)C(C)C([Si](C)(C)NCc2ccccc2)=C1C
Reaction time: 8 h

Procedure:
To a solution of 1.000 g (4.651 mmol) (chloro)(dimethyl)(tetramethylcyclopentadienyl)silane in 70 mL ether was slowly added 0.526 g (4.651 mmol) lithium benzylamide. The reaction mixture was stirred overnight, then the solvent was removed, the residue was extracted with pentane and filtered. The pentane was removed under reduced pressure to give the product as a pale yellow oil. The yield was 1.234 g (93.3%). Mass spec. m/e 285 (18%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:9]([C:10]([N:12]([O:14]C(C)(C)C)[CH3:13])=[O:11])[N:8]=[C:7]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[S:6]1.C(O)(C(F)(F)F)=O>>[NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:9]([C:10]([N:12]([OH:14])[CH3:13])=[O:11])[N:8]=[C:7]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[S:6]1
Reactant: CN(OC(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(O)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Reaction time: 18 h
Yield: 49.2 %

Procedure:
To 2-(3-aminopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (0.023 g, 0.05 mmol) was added TFA (2 mL). After stirring for 18 hours, the mixture was concentrated and chromatographed (10:1:0.2 dichloromethane/methanol/30% NH4OH) to provide the product (0.01 g, 49%). MS ESI (+) m/z 407 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 2H), 7.36 (m, 3H), 7.29 (m, 1H), 7.11 (m, 2H), 3.28 (s, 3H), 3.12 (m, 1H), 2.90 (m, 1H), 2.78 (m, 1H), 2.24 (m, 1H), 1.98 (m, 1H), 1.62 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.N12CCCN=C1CCCCC2.Br[CH2:22][CH:23]([CH3:25])[CH3:24]>CC#N>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH:7]=1
Reactant: CC(C)CBr
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Cn1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
To a solution of 5-fluoropyrimidine-2,4(1H,3H)-dione (5.0 g, 38 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 6.4 g, 42 mmol) in dry CH3CN (150 mL) at room temperature and under nitrogen was added 1-bromo-2-methylpropane (5.3 g, 38 mmol) dropwise. The reaction was then heated to reflux for 18 h. After cooling to room temperature, the solvent was removed in vacuo. The crude residue was purified by normal phase chromatography (gradient, 0 to 20% EtOAc/Petroleum ether), providing 5-fluoro-1-isobutylpyrimidine-2,4(1H,3H)-dione (2.5 g, 35%) as a white solid: mp 173-174° C.; 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.21 (d, J=5.5 Hz, 1H), 3.53 (d, J=7.5 Hz, 2H), 2.13-2.01 (m, 1H), 0.98 (d, J=6.7 Hz, 6H); ESIMS m/z 185 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](C)[C:8]=1I)([CH3:4])([CH3:3])[CH3:2].[CH2:16](N(CC)CC)C.[CH3:23][C:24]1([CH3:31])[C:28]([CH3:30])([CH3:29])[O:27][BH:26][O:25]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[B:26]1[O:27][C:28]([CH3:30])([CH3:29])[C:24]([CH3:31])([CH3:23])[O:25]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1cccc(C(=O)OC(C)(C)C)c1I
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)OC(C)(C)C)c(B2OC(C)(C)C(C)(C)O2)c1
Yield: 64 %

Procedure:
The procedure used in Example 3: step b was followed using 2-iodo-3-methyl-benzoic acid tert-butyl ester ((Example 4: step a) 960 mg, 3 mmol), PdCl2(PPh3)2 (126 mg, 0.18 mmol), triethylamine (1.25 mL, 9 mmol), and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (660 μL, 4.5 mmol) in dioxane (12 mL) at a reaction temperature of 80° C. Analogous aqueous workup and purification by SiO2 flash chromatography yielded the title compound (618 mg, 64%). 1H-NMR (CDCl3): δ 7.67 (m, 1H), 7.25 (m, 2H), 2.43 (s, 3H), 1.57 (m, 9H), 1.44 (m, 12H).
Reaction SMILES: Br[CH2:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[N:15]([CH2:2][CH3:3])[N:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=c1ccc(-c2cccc(Cl)c2)n[nH]1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1nc(-c2cccc(Cl)c2)ccc1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
Under nitrogen atmosphere bromoethane (18.31 g, 0.168 mol) was added dropwise to a solution of 6-(3-chlorophenyl)-2H-pyridazin-3-one (4.96 g, 0.024 mol) and potassium carbonate (19.90 g, 0.144 mol) in N,N-dimethylformamide (100 ml). The mixture was stirred at room temperature for 4 hours and then water (150 ml) and ethyl acetate (300 ml) were added. The organic layer washed with water and brine, dried over sodium sulfate anhydride and evaporated. The oil obtained solidified in the vacuum oven to yield the title compound (96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:32](O)[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.P([N:62]=[N+:63]=[N-:64])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.CCOC(C)=O>[N:62]([CH:32]([C:18]1[CH:17]=[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]3[CH:44]=[CH:45][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:35][C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)[N:10]=2)[C:21]([NH:22][C:23]2[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=2)=[N:20][CH:19]=1)[CH3:33])=[N+:63]=[N-:64]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N=[N+]=[N-])cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 16 h
Yield: 105.7 %

Procedure:
A glass microwave reaction vessel was charged with 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (0.9 g, 1.635 mmol) in toluene (15 mL). The tube was sealed under inert atmosphere. To this suspension, diphenyl azidophosphate (0.9 mL, 4.2 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.64 mL, 4.3 mmol) were mixed, the solution was stirred for 16 h. The mixture was diluted with EtOAc, washed by saturated NH4Cl and brine, concentrated under a vacuum to provide 4-(5-(1-azidoethyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.1 g, 92% purity, 100% yield) as a yellow solid, which was used in next step without further purification. MS (ESI positive ion) m/z: 637 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[F-].[K+].C(=O)([O-])[O-].[K+].[K+].Br[C:20]1[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][N:21]=1>C(OCC)(=O)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:20]2[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:5][CH:4]=1
Reactant: Oc1cccnc1Br
Reactant: COc1ccc(CS)cc1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CSc2ncccc2O)cc1
Temperature: 150 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
4-Methoxy-α-toluenethiol (9.4 mL), potassium fluoride (3.34 g) and potassium carbonate (10.3 g) were added to a DMF (100 mL) solution of 2-bromo-3-hydroxypyridine (10 g, 57.5 mmol), and stirred at 150° C. for 3 days. The reaction liquid was diluted with ethyl acetate, and washed three times with distilled water. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate and hexane to obtain the intended compound (6.2 g, 43%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]([O:17]CC)=[O:16])[CH:3]=1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C.O>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4]([C:15]([OH:17])=[O:16])[CH:3]=1
Reactant: CCOC(=O)c1cc(C)n(CCc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)nn1CCc1ccccc1
Yield: 94.7 %

Procedure:
Ethyl 5-methyl-1-phenethylpyrazole-3-carboxylate (3.84 g, 14.9 mM) in ethanol (30 ml) with sodium hydroxide (0.6 g 14.9 mM) was stirred at room temperature for 3 days. The mixture was then diluted with ethyl acetate and water and the layers separated. The organic phase was further extracted with water. The combined aqueous extracts were acidified to pH 2.0 with 5M hydrochloric acid and extracted with dichloromethane. The organic extracts were dried (MgSO4) and evaporated to give the title compound (3.24 g, 95%); υmax(CH2Cl2) 1759 and 1699 cm−1; δH(CDCl3) 1.91 (3H, s), 3.16 (2H, t, J7 Hz), 4.31 (2H, t, J7 Hz), 6.54 (1H, s), 6.98-7.10 (2H, m), and 7.20-7.37 (3H, m).
Reaction SMILES: FC(F)(F)S(O[C@@H:7]([CH3:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=O)=O.[CH2:18]([Mg]Cl)[CH2:19][CH2:20]C.[Cl-].[NH4+].O1CCC[CH2:27]1>[Cl-].[Zn+2].[Cl-].O>[CH3:27][C@@H:7]([CH2:15][CH2:18][CH2:19][CH3:20])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: C[C@H](OS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C
Reactant: CCCC[Mg]Cl
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: O
Product: CCCC[C@H](C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In a 10 ml Schlenk tube, 3.5 mg of dry zinc chloride was dissolved in 3.0 ml of absolute tetrahydrofuran and cooled to 0° C. under argon. Thereafter, 279 mg of tert-butyl (S)-2-trifluoromethanesulphonyloxypropionate (ee>99%) and 0.700 ml of n-butylmagnesium chloride (2.00 M solution in THF) were added in succession and the reaction was stirred for 3 h at 0° C. Thereafter, the reaction mixture was diluted with petroleum ether, first water and then saturated ammonium chloride solution were added and the organic phase was separated off. This was applied directly to a silica gel filter and washed with petroleum ether. The product was then washed off with a petroleum ether/diethyl ether mixture (10:1) from the filter and freed from the solvent. The pure tert-butyl (S)-2-methylhexanoate (entry 3 in table 1)(ee>99%) was obtained in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(O)(=O)C.[CH:15](OCC)(OCC)OCC.[N-:25]=[N+:26]=[N-:27].[Na+].Cl.N([O-])=O.[Na+]>O>[N:1]1([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:7])=[O:6])[CH:15]=[N:27][N:26]=[N:25]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1cccc(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)c1cccc(-n2cnnn2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a round bottom flask was added 3-aminobenzamide (1.36 g, 10.0 mmol, 1.0 eq.), acetic acid (9.1 mL, 160 mmol, 16.0 eq.), triethyl orthoformate (5.4 mL, 32.0 mmol, 3.2 eq.), and sodium azide (0.812 g, 12.5 mmol, 1.25 eq.). The reaction mixture was then heated to 80° C. until all solids were dissolved. The reaction was stirred at 80° C. for an additional 2 h before cooling to RT. Water (6.0 mL,) was added, followed by 6N HCl (5.3 mL), and then 25% NaNO2 (2.1 mL). The resulting precipitate was filtered and rinsed with water to give pure tetrazole 38 (1.5 g, 80% yield). LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 189.9 (M+H)+1, 187.9 (M−H)+1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 10.1 (s, 1H), 8.39 (t, 1H), 8.20 (br. s, 1H), 8.05 (m, 2H), 7.72 (t, 1H), 7.55 (s, 1H) ppm.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([N:19]4[CH2:23][CH2:22][C@@:21]5([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[C:25](=[O:32])[O:24]5)[CH2:20]4)=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.CS(C)=O>>[N:33]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]4([C:17]([N:19]5[CH2:23][CH2:22][C@@:21]6([C:27]7[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=7[C:25](=[O:32])[O:24]6)[CH2:20]5)=[O:18])[CH2:16][CH2:15]4)=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C1CCNC1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccc(F)nc5)cc4)CC3)C2)c2ccccc21
Solvent: CS(C)=O
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccc(N6CCCC6)nc5)cc4)CC3)C2)c2ccccc21
Temperature: 100 °C

Procedure:
A mixture of (1R)-1′-({1-[4-(6-fluoropyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (20.0 mg, 0.0000467 mol, example 250), pyrrolidine (7.8 μL, 0.000093 mol) in dimethyl sulfoxide (0.5 mL, 0.007 mol) was heated at 100° C. in a sealed tube for 5 hours. The product was purified by prep-HPLC. LC-MS: 480.2 (M+H+)
Reaction SMILES: C1COCC1.[BH4-].[Na+].[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH:10]=[C:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21].N>O.C(O)(=O)C>[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH2:10][CH:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -7.5 °C
Reaction time: 2.5 h

Procedure:
In a 250 mL round bottom flask dry THF (35 mL) was taken. It was cooled to −10 to −5° C. and NaBH4 (2.0 g) was added. After that acetic acid (33.7 mL) was added dropwise at −5 to 0° C. over a period of 15-30 min. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazol o[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (5.0 g) was added into the reaction mixture, keeping the temperature between −2 to 0° C. It was stirred for 2-3 h at −5 to 0° C. Reaction mixture was poured into cold water. It was basified by adding aq. ammonia solution. Product was extracted in ethyl acetate. The organic layer was collected. It was washed with water and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-4.2 g, % Y-83.6%, % Purity by HPLC-60.1%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2cccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3cccnc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a solution of quinoline-8-carboxylic acid (421 mg, 2.43 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (500 mg, 2.43 mmol), HATU (1.39 g, 3.65 mmol) in anhydrous DMF (15 mL) is added DIPEA (603 μL, 3.65 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (47) as white solid (281 mg, 32%).