Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16][CH:15]2[NH:17][CH:11]([CH2:12][O:13][CH2:14]2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]1[NH:31][C:30]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)=[N:29][C@@H:28]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[Cl:44])[C:27]=1[C:45]([O:47][CH3:48])=[O:46].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][CH:11]2[N:17]([CH2:25][C:26]3[NH:31][C:30]([C:32]4[S:33][CH:34]=[CH:35][N:36]=4)=[N:29][C@@H:28]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[Cl:44])[C:27]=3[C:45]([O:47][CH3:48])=[O:46])[CH:15]([CH2:14][O:13][CH2:12]2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC1(NC(=O)OC(C)(C)C)CC2COCC(C1)N2
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1(NC(=O)OC(C)(C)C)CC2COCC(C1)N2CC1=C(C(=O)OC)[C@H](c2ccc(F)cc2Cl)N=C(c2nccs2)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of ethyl 2-[7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate 146a (0.1 g, 0.3 mmol) and methyl (4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate C (90 mg, 0.2 mmol), DIPEA (77.4 mg, 0.6 mmol) in DCM (5 mL) was stirred for 12 hours at room temperature. The mixture was concentrated to give crude methyl (4R)-6-[[7-(tert-butoxycarbonylamino)-7-(2-ethoxy-2-oxo-ethyl)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 146b. MS: calc'd (MH+) 692, exp (MH+) 692.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:13]([C:15]([O:17]C)=O)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8][CH:7]=1)([O-])=O.Cl>CO.[Zn]>[NH:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:15](=[O:17])[NH:1][CH2:4][CH2:5][C:6]([C:14]=23)=[CH:7]1
Reactant: COC(=O)c1cccc2[nH]cc(CC[N+](=O)[O-])c12
Agent: Cl
Agent: [Zn]
Solvent: CO
Product: O=C1NCCc2c[nH]c3cccc1c23

Procedure:
Methyl 3-(2-nitroethyl)-1H-indole-4-carboxylate, Intermediate 9 (7.38 g, 29.8 mmol) was dissolved in methanol (200 mL) by heating and aqueous 2M HCl (460 mL) was added. Zinc powder (46.2 g, 706 mmol) was added portion vise by vigorous stirring. The resulting mixture was heated under reflux for 2 h. The hot reaction mixture was filtered and the filtrate was treated with aqueous 2M NaOH (560 mL) and filtered again. The filter cake was washed with methanol. The methanol was removed under reduced pressure and the aqueous mixture was extracted three times with ethyl acetate. The organic solution was washed with water and brine dried with magnesium sulfate, filtered and evaporated to dryness. It was obtained a yellowish crystalline material with the yield of 4.62 g. Recrystallisation from the dichlomethane-methanol mixture gave the product of very high purity. Mp. 234° C. MS m/z 187 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.O.[C:17]([O:20][CH2:21][CH3:22])(=O)[CH3:18]>C1(C)C=CC=CC=1.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>[CH2:21]([O:20][C:17]([C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1)=[CH2:18])[CH3:22]
Reactant: COCCCn1ccc2ncc(Br)cc21
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(OCC)c1cnc2ccn(CCCOC)c2c1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-1-(3-methoxypropyl)-1H-pyrrolo[3,2-b]pyridine (1.5 g) in toluene (30 mL) were added tri-n-butyltin-1-ethoxyvinyl (5.65 mL) and dichlorobis(triphenylphosphine)palladium (II) (782 mg), and the mixture was heated to stir at 110° C. for 30 minutes. The reaction solution was cooled to room temperature, and then thereto was added water-ethyl acetate, and an insoluble was filtered through Celite. The organic layer was separated, and then washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1→1/1) to give 6-(1-ethoxyvinyl)-1-(3-methoxypropyl)-1H-pyrrolo[3,2-b]pyridine [REx(23-2)] (1.69 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:12])[CH3:11])=[C:4]([CH3:13])[CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.O>C(O)C>[CH3:8][C:6]1[CH:7]=[C:2]([NH:1][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:24])[F:25])=[CH:23][CH:22]=2)[CH:3]=[C:4]([CH3:13])[C:5]=1[NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Nc1c(C)cc(N)cc1C
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1c(C)cc(NCc2ccc(C(F)(F)F)cc2)cc1C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
N-(4-Amino-2,6-dimethyl-phenyl)-acetamide (1.2 g) and 4-trifluoromethyl-benzaldehyde (1.3 g) were dissolved in ethanol (100 mL) and refluxed for 16 h. The reaction mixture was poured into water (3 L) and the precipitate collected by filtration. Sodium cyanoborohydride (2 g) and acetic acid (2 mL) were added to the precipitate dispersed in methanol (50 mL) and stirred for 15 minutes. The reaction mixture was filtered, water (100 mL) was added and the organic solvent was removed in vacuo. The product was allowed to precipitate at 25° C. and collected by filtration and washed with water (200 mL) to furnish 0.68 g (30% yield) of the title compound as a pale yellow solid. LC-MS (m/z) 337 (MH+); tR=2.39, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.95 (s, 3H), 1.96 (s, 6H), 4.34 (d, 2H), 6.18 (t, 1H), 6.25 (s, 2H), 7.55 (d, 2H), 7.69 (d, 2H), 8.81 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:30][C:31]([F:46])([F:45])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)C.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>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:34]4[CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=[C:32]([C:31]([F:30])([F:46])[F:45])[CH:33]=4)[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)c3O2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 65.7 %

Procedure:
To a solution of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.0 g, 2.21 mmol) and 3,5-bis(trifluoromethyl)phenylboronic acid (0.86 g, 3.32 mmol) in dioxane (25 mL) heated to 90° C. was added tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.22 mmol) and potassium phosphate (0.94 g, 4.42 mmol). The reaction mixture was allowed to stir at 90° C. for 12 h. The reaction mixture was allowed to cool and was diluted with diethyl ether (100 mL), filtered (celite), and the solvent was removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethylacetate:hexanes 1:9) afforded 0.75 g (66%) of (±)-{7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.49 (silica, ethyl acetate:hexanes 1:3); mp 100-105° C.; Anal. calcd. for C24H18F6O4S2: C, 55.82; H, 3.51. Found: C, 55.75; H, 3.35.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CN(C(=O)OCc2ccccc2)C1
Reaction time: 5 h
Yield: 99.5 %

Procedure:
To a solution of phenylmethyl 3-hydroxyazetidine-1-carboxylate (3.5 g, 0.0168 mol) in dichloromethane (100 mL) was added Dess-Martin periodinane (10.7 g, 0.0.25 mol) at room temperature and stirred for 5 h. The reaction mixture was quenched with 1:1 ratio of saturated aqueous sodium bicarbonate and 1M sodium thiosulfate (200 mL) and then partitioned with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to afford phenylmethyl 3-oxoazetidine-1-carboxylate (3.43 g, 99% yield) as a clear and colorless oil without further purification. 1H NMR (400 MHz, CDCl3): 7.39-7.31 (m, 5H), 5.17 (s, 2H), 4.77 (s, 4H). MS (EI) for C11H11NO3: 205 (M+).
Reaction SMILES: [Br:1][C:2]12[CH2:12][C:6]3([C:13](O)=[O:14])[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([CH3:16])([CH2:5]3)[CH2:3]1)[CH2:9]2.O1CCCC1.B>O1CCCC1>[Br:1][C:2]12[CH2:12][C:6]3([CH2:13][OH:14])[CH2:5][C:4]([CH3:16])([CH2:10][C:8]([CH3:11])([CH2:7]3)[CH2:9]1)[CH2:3]2
Reactant: CC12CC3(C)CC(Br)(C1)CC(C(=O)O)(C2)C3
Agent: B
Solvent: C1CCOC1
Product: CC12CC3(C)CC(Br)(C1)CC(CO)(C2)C3
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5-bromo-3,7-dimethyltricyclo[3.3.1.13,7]decane-1-carboxylic acid (4.57 g, 15.9 mmol) in tetrahydrofuran (10 mL) was added borane tetrahydrofuran complex (50 mL, 1 M in THF) dropwise and the mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with methanol, concentrated and purified by normal phase chromatography to provide the title compound.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13](C(F)(F)F)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:42])C(=O)C1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([Cl:42])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CN(Cc2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)C1CN(Cc2ccc3c(Cl)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound methyl 1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylate (140 mg, 0.34 mmol) and NCS (90 mg, 0.68 mmol, 2.0 eq.) were dissolved in MeCN (5 mL). Then CF3COOH (12 mg, 0.1 mmol, 0.3 eq.) was added to the mixture at 0° C. The mixture was warmed to r.t. and stirred for 1 h. Then the pH of the solution was adjusted to 7 with saturated Na2CO3, concentrated and the mixture was extracted by EtOAc. The organic layer was concentrated and purified by silica gel chromatography using PE/EA (6/1) to give product methyl 1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-chloronaphthalen-2-yl)methyl)azetidine-3-carboxylate (65 mg, 43%) as a slight yellow oil. EDI-MS (M+1)+: 444.0. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, 1H), 7.69-7.66 (m, 2H), 7.50-7.47 (m, 1H), 7.28-7.27 (m, 1H), 4.25-4.19 (m, 1H), 3.77 (s, 2H), 3.72 (s, 3H), 3.59-3.58 (m, 2H), 3.38-3.37 (m, 3H), 2.23-2.20 (m, 2H), 1.88-1.85 (m, 2H), 1.61-1.52 (m, 2H), 1.12-1.07 (m, 3H), 0.87 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[O:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=1[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1ccccc1Oc1ccccc1
Product: N#Cc1cccnc1-c1ccccc1Oc1ccccc1
Yield: 50 %

Procedure:
Prepared in 50% yield from 2-chloro-3-cyanopyridine and 2-phenoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 273.0 (M+H)+; 1H NMR (CDCl3) δ 6.94 (d, J=7.1 Hz, 1H), 7.06-7.11 (m, 3H), 7.20-7.44 (m, 5H), 7.54 (dd, J=7.5, 1.7 Hz, 1H), 8.00 (dd, J=8.1, 2.0 Hz, 1H), 8.86 (dd, J=5.1, 1.7 Hz, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:19]([O:18][C:16]([CH:15]1[CH2:21][CH2:22][N:12]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:13][CH2:14]1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
A solution of benzyl chloroformate (95 g, 0.56 mol) in dichloromethane (200 ml) was added dropwise to an ice-bath-cooled, stirred mixture of ethyl isonipecotate (87 g, 0.55 mol), sodium carbonate (60 g, 0.57 mol) and dichloromethane (200 ml) over 70 minutes. The mixture was stirred at ambient temperature for 2.5 days and filtered though a pad of Celite™. The filtrate was concentrated in vacuo. The residue was partitioned between 2M aqueous hydrochloric acid and diethyl ether. Organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel (ethyl acetate/iso-hexane) to give the title product (152 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1CCCCN1c1ccc(Br)cc1C=O
Temperature: 120 °C
Yield: 88.8 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (13.20 g; 65.02 mmol) in DMSO (160 mL) and water (40 mL) were added 2-methylpiperidine (15.35 mL; 130.04 mmol) and anhydrous sodium carbonate (13.78 g; 130.04 mmol). The resulting mixture was heated at 120° C. for 16 h after which it was allowed to cool to RT. Reaction mixture was partitioned between H2O (1 L) and Et2O (2×750 mL) and the combined organic layers were washed with brine (500 mL, pH 5-6 adjusted with HCl), dried over MgSO4, filtered and dried under vacuum to give the title compound as a brown yellow oil (16.3 g, 89%). LC/MS (Method B): 282.1 (M+H)+. HPLC (Method A): Rt 2.20 min (Purity: 93.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1([CH3:15])[CH2:14][CH2:13]1)=[CH:6]2.[H-].[Na+].Cl[CH2:19][C:20]1[O:24][C:23]([C:25]#[N:26])=[CH:22][CH:21]=1.[Cl-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:19][C:20]1[O:24][C:23]([C:25]#[N:26])=[CH:22][CH:21]=1)[C:7]([C:12]1([CH3:15])[CH2:13][CH2:14]1)=[CH:6]2
Reactant: COc1ccc2[nH]c(C3(C)CC3)cc2c1
Reactant: N#Cc1ccc(CCl)o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)cc(C1(C)CC1)n2Cc1ccc(C#N)o1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 14.4 %

Procedure:
To a solution of 5-methoxy-2-(1-methylcyclopropyl)-1H-indole (155 mg) in N,N-dimethylformamide (3 mL) was added sodium hydride (dispersed in liquid paraffin, 50% or more, 39 mg) under ice-cooling. This mixture was stirred at room temperature for 50 minutes. Subsequently, a solution of 5-chloromethylfuran-2-carbonitrile (131 mg) in N,N-dimethylformamide (0.5 mL) was added thereto at room temperature, and the mixture was stirred at 80° C. for 14 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution and water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (34 mg). 1H-NMR (CDCl3) δ ppm: 0.70-1.00 (4H, m), 1.35 (3H, s), 3.83 (3H, s), 5.45 (2H, s), 5.95-6.00 (1H, m), 6.20-6.30 (1H, m), 6.75-6.85 (1H, m), 6.90-7.10 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])=[N:4][NH:5][CH:6]=1.[CH3:15]P(=O)(OC)OC.C([O-])(O)=O.[Na+]>>[CH3:15][N:5]1[CH:6]=[C:2]([Cl:1])[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])=[N:4]1
Reactant: COP(C)(=O)OC
Reactant: Clc1c[nH]nc1-c1cccc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(Cl)c(-c2cccc(Cl)c2Cl)n1

Procedure:
1.5 g of 4-chloro-3-(2,3-dichlorophenyl) pyrazole and 0.40 g of dimethyl methylphosphonate are heated at 150° C. for 1 hour. After returning to room temperature, the mixture is taken up in a saturated aqueous NaHCO3 solution and extracted with 2×50 ml of CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated under reduced pressure. The crude solid is purified by liquid chromatography on a silica column (eluent: heptane/ethyl acetate [80/20]).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[OH:9])[NH2:5].[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[NH2:1][C:2]1[CH:3]=[C:4]([NH:5][N:1]=[C:2]2[C:8](=[O:9])[N:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:17]=[C:3]2[CH3:4])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: Nc1ccc(O)c(N)c1
Reactant: NNc1ccccc1
Product: CC1=NN(c2ccccc2)C(=O)C1=NNc1ccc(O)c(N)c1

Procedure:
Compound 114 above was prepared according to the procedure described in Scheme III above from 3-amino-4-hydroxyaniline and phenylhydrazine. The molecular weight of C16H15N5O2 is 309.32; m/z (MH+): calculated 310.13 and observed 310.05.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21](/[C:24](/[CH3:31])=[CH:25]/[C:26](OCC)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21](/[C:24](/[CH3:31])=[CH:25]/[CH2:26][OH:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2cccc(OC)c2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: COc1cccc(-c2ccc(/C(C)=C/CO)cc2)c1

Procedure:
The colourless solid (E)-3-(3′-methoxy-biphenyl-4-yl)-but-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(3′-methoxy-biphenyl-4-yl)-but-2-enoate as described for example 52b.
Reaction SMILES: [CH3:1][N:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][NH:5][CH2:6][CH2:7]2.[S:11](N)([NH2:14])(=[O:13])=[O:12]>O1CCOCC1>[CH3:1][N:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][N:5]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:6][CH2:7]2
Reactant: CN1C2CCNCC1CC2
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CN1C2CCC1CN(S(N)(=O)=O)CC2
Yield: 15.4 %

Procedure:
To a solution of 9-methyl-3,9-diazabicyclo[4.2.1]nonane (0.56 g) in 1,4-dioxane (10 ml) was added sulfamide (0.37 g) and the reaction mixture was then heated at reflux in 1,4-dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with 7N NH3/MeOH (200 ml). The eluent was then reduced in vacuo to yield 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g) as a yellow solid. A mixture of 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.31 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 5 step i), 0.25 g) in 1,4-dioxane (10 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield 0.35 g
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][CH2:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:16]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6]C)=[O:4].C(CNCC1C=C(C2C=CC(C[C@@H](NC(OC(C)(C)C)=O)C(OC)=O)=CC=2)C=CC=1)(=O)C1C=CC=CC=1>>[NH2:1][C@H:2]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][CH2:23][C:24](=[O:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:16]=2)=[CH:13][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1
Agent: COC(=O)[C@@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)NC(=O)OC(C)(C)C
Product: COC(=O)[C@H](N)Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1
Yield: 92 %

Procedure:
In a manner similar to the preparation of ethyl (S)-2-amino-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}propionate (Example 28f), using 5.6 g of methyl (R)-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-tert-butoxycarbonylaminopropionate, 4.1 g of amine are obtained with a 92% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[CH3:24][N:25]([CH3:30])[CH2:26][C:27](O)=[O:28]>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:27](=[O:28])[CH2:26][N:25]([CH3:30])[CH3:24])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: CN(C)CC(=O)Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
55 mg of 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine was reacted with N,N-dimethylglycine via General Procedure I to give N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-(dimethylamino)acetamide. 70 mg of the crude N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-(dimethylamino)acetamide was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 3 mg of 152. MS (Q1) 514 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([Cl:12])=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>CC(C)=O>[Cl:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[O:1][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=2)[N:7]=1
Reactant: Oc1cccc2nc(Cl)ccc12
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(COc2cccc3nc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.7 %

Procedure:
5-Hydroxy-2-chloroquinoline (CAS 124467-35-2, 0.6 g, 3.0 mmol) was dissolved in 15 mL acetone and potassium carbonate (555 mg, 3.0 mmol) was added. Then 4-fluoro-benzylbromide (0.5 ml, 4.0 mmol) was added and the reaction mixture stirred for 18 hours at ambient temperature. The mixture was evaporated and the residue taken up in water and extracted (3×) with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. The residue was subjected to flash column chromatography on silica gel (heptane/ethyl acetate 90:10->80:20 gradient) to yield 2-chloro-5-(4-fluoro-benzyloxy)-quinoline as a white solid (420 mg, 44%), MS: m/e=289 (M+H+).