Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.CC[N:14]([CH:18]([CH3:20])[CH3:19])C(C)C.C1(N)CC1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:14][CH:18]2[CH2:20][CH2:19]2)[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NC1CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To solution of 4-bromo-2-fluoronitrobenzene (2M g, 0.0091 mol) in DMF (10 ml) was added carefully DIPEA (3.25 ml, 0.0182 mol) and cyclopropylamine (0.7 ml, 0.0091 mol) and the resulting solution was stirred at room temperature for 14 h. The reaction was quenched with ice-water and extracted with diethyl ether (3×100 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford the title compound (5-bromo-2-nitro-phenyl)-cyclopropylamine as a yellow solid. C9H9BrN2O2; 1H NMR (400 MHz, DMSO-d6), δ: 8.08 (brs, 1H), 8.02-7.99 (d, J=8.8 Hz, 1H), 7.47 (s, 1H), 7.26 (s, 1H), 6.82-6.79 (dd, J=8.8 Hz, 1.6 Hz, 1H), 2.58-2.54 (m, 1H), 0.97-0.88 (m, 2H), 0.69-0.65 (m, 2H). MS (M+1): 258.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:34]=[CH:35][C:36]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][C:7]=4[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:37][CH:38]=3)=[CH:31][CH:32]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]
Reactant: OC(CCCc1ccccc1)c1ccncc1Br
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnccc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-(3-bromo-pyridin-4-yl)-4-phenyl-butan-1-ol and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH:7]([CH2:11][C:12]#[N:13])[C:8]([OH:10])=[O:9].[OH-].[Na+].Cl>C1COCC1>[C:12]([CH2:11][CH:7]([NH:6][C:2]([O:4][CH3:5])=[O:3])[C:8]([OH:10])=[O:9])#[N:13]
Reactant: N#CCC(N)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)NC(CC#N)C(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 19.6 %

Procedure:
Methyl chloroformate (0.81 mL, 10.51 mmol) was added dropwise to a stirred suspension of 2-Amino-3-cyano-propionic acid (1.00 g, 8.76 mmol) and NaOH (5 N in H2O, 4.2 mL, 21.0 mmol) in THF (20 mL). After stirring at room temperature for 7 h, the reaction mixture was poured into 10% HCl and the aqueous phase was extracted 3× with diethyl ether. The combined organics were dried over MgSO4, filtered and concentrated to afford 3-Cyano-2-methoxycarbonylamino-propionic acid (295 mg, 20%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([CH:11]([C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[C:12]#[N:13])[CH:8]=[CH:7][N:6]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[S:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[CH:11]([C:12]#[N:13])[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([Cl:23])=[CH:25][CH:26]=2)[N:10]=1
Reactant: N#CC(c1ccnc(NCCN)n1)c1nc2ccccc2s1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC(c1ccnc(NCCNC(=O)c2ccc(Cl)cc2)n1)c1nc2ccccc2s1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of 46 (0.1 g, 0.32 mmol) in DCM/DMF 3/1 (4 ml) was added p-chloro benzoylchloride (0.056 g, 0.32 mmol) and triethylamine (0.09 ml, 0.64 mmol) and the solution was shaken overnight at r.t then at 40° C. for 3 h. After cooling down to r.t, the precipitate formed was filtered off then washed with DCM then water. After recrystallization in acetonitrile, 98 mg (68%) of the title compound (base) was obtained as a yellow powder.
Reaction SMILES: [CH2:1](OC(ON1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=C1.[CH3:28][NH:29][CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([N:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([CH2:30][NH:29][CH3:28])=[CH:32]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1c[nH]c2ccccc12
Agent: c1ccc2[nH]ccc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCc1cn(Cc2ccccc2)c2ccccc12
Reaction time: 8 h
Yield: 86 %

Procedure:
3-IN-(Benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole N-(Benzyloxycarbonyloxy)succinimide (8.9 g, 35.7 mmole) was added to a solution of 3-(methylaminomethyl)-1H-indole (5.2 g, 32.5 mmole) and triethylamine (5.0 mL, 65.7 mmole) in DMF (100 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (33% ethyl acetate/hexanes) gave the title compound (7.0 g, 74%) as an off-white solid: MS (ES) m/e 295 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl.[CH3:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:5]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:14]
Reactant: COc1c(B(O)O)ccc2ccccc12
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1-c1ccc2ccccc2c1OC
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A solution of 2-chloro-3-nitrobenzoic acid methyl ester, (2.16 g, 10.0 mM), 1-methoxynaphthalene-2-boronic acid, (2.22 g, 11.0 mM), tetrakis(triphenylphosphine) palladium(0)(0.584 g, 0.5 mM), and 2M aqueous sodium carbonate solution (10.5 mL, 21.0 mM) in THF (50 mL) was stirred at reflux for 31 h in the absence of light. The mixture was cooled to room temperature, the THF removed in vacuo, and the resulting aqueous residue dissolved in ethyl acetate and brine. The solvent layers were separated, the aqueous layer extracted with ethyl acetate (4×25 mL), the combined ethyl acetate extracts washed successively with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resultant oil was purified by column chromatography on silica gel (elution with 1:1 chloroform/toluene) to afford 2.54 g (75%) of the title compound 2-(1-methoxynaphthalen-2-yl)-3-nitrobenzoic acid, methyl ester as a yellow solid (MP 139–141° C., MW 337.34).
Reaction SMILES: COC1CCCC1.[NH2:8][C@H:9]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13].C1C=CC2N(O)N=NC=2C=1.[NH:36]([C:48]([O:50][CH2:51][CH:52]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:58]2[C:53]1=[CH:54][CH:55]=[CH:56][CH:57]=2)=[O:49])[C@H:37]([C:45](O)=[O:46])[C@@H:38]([CH3:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].CCN=C=NCCCN(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].[Na+].O.CN(C=O)C>[NH:36]([C:48]([O:50][CH2:51][CH:52]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:58]2[C:53]1=[CH:54][CH:55]=[CH:56][CH:57]=2)=[O:49])[C@H:37]([C:45]([NH:8][C@H:9]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:10][O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:46])[C@@H:38]([CH3:44])[O:39][C:40]([CH3:42])([CH3:43])[CH3:41]
Reactant: CC(C)(C)OC[C@H](N)C(=O)OCc1ccccc1
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COC1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](COC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the CPME solution (35 mL) of H-Ser(tBu)-OBzl (2-OBzl(3,4,5-OPhy)-4-OMe) was added HOBt (71 mg, 0.43 mmol), Fmoc-Thr(tBu)-OH (1.00 g, 2.51 mmol), EDC.HCl (529 mg, 2.76 mmol) and DMF (10 ml) were added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, to the reaction solution was added 20% brine (30 ml) to give an organic layer and an aqueous layer. While stirring the obtained organic layer and aqueous layer, 10% aqueous sodium carbonate solution was added dropwise until the pH of the aqueous layer became 6.0, and the organic layer and the aqueous layer were partitioned (hereinafter this operation is sometimes to be abbreviated as “pH=6.0 washing”). The pH-6.0 washing was further repeated twice. The solvent in the obtained organic layer was evaporated under reduced pressure, the residue was dissolved in cyclohexane (40 ml), and the mixture was washed four times with 80% by volume of aqueous acetonitrile solution (30 ml) with stirring, and the organic layer and the aqueous layer were partitioned. The obtained organic layer was dried over sodium sulfate and filtered. The solvent in the obtained filtrate was evaporated under reduced pressure to give Fmoc-Thr(tBu)-Ser(tBu)-OBzl (2-OBzl(3,4,5-OPhy)-4-OMe).
Reaction SMILES: BrCCBr.Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[O:28][C:27]([C:29](OC)=[O:30])=[N:26][N:25]=1>C1COCC1>[C:12]1([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:29]([C:27]2[O:28][C:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[N:25][N:26]=2)=[O:30])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCCCCc1ccccc1
Reactant: COC(=O)c1nnc(-c2ccccn2)o1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=C(CCCCCCc1ccccc1)c1nnc(-c2ccccn2)o1
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A dry vial was charged with freshly activated Mg turnings (115 mg, 5 mmol), 100 μL of anhydrous THF and a drop of 1,2-dibromoethane under Ar. This mixture was treated dropwise with a solution of 6-bromohexylbenzene (240 mg, 1 mmol) in THF (1 mL) at 23° C. The mixture was warmed and sonicated repeatedly until Grignard formation occurred. The gray solution of the Grignard reagent was added to a solution of methyl 5-(pyridin-2-yl)-1,3,4-oxadiazole-2-carboxylate (S7, 40 mg, 0.17 mmol) in THF (2 mL) at −40° C. Stirring was continued for 2 h before the reaction was quenched by the addition of MeOH at −40° C. The mixture was extracted with EtOAc and washed with water, saturated NaHCO3 and saturated aqueous NaCl followed by separation and evaporation. Flash chromatography (SiO2, 1×4 cm, 40% EtOAc-hexanes) afforded the title compound (30 mg, 51%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.85 (d, 1H, J=4.7 Hz), 8.30 (d, 1H, J=7.9 Hz), 7.93 (td, 1H, J=1.5, 7.8 Hz), 7.54 (ddd, 1H, J=0.9 4.7, 7.6 Hz), 7.26-7.30 (m, 2H), 7.16-7.19 (m, 3H), 3.31 (t, 2H, J=7.3 Hz), 2.62 (t, 2H, J=7.6 Hz), 1.82 (quintet, 2H, J=7.3 Hz), 1.66 (quintet, 2H, J=7.5 Hz), 1.43 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 187.1, 165.0, 161.2, 150.8, 142.6 (2C), 137.3, 128.3, 128.2, 126.7, 125.6, 124.0, 40.0, 35.8, 31.2, 28.9, 28.8, 23.5; IR (film) νmax 2927, 2856, 1709, 1589, 1442, 1398, 1038, 986, 798, 754, 710 cm−1; HRMS-ESI-TOF m/z 336.1717 ([M+H]+, C20H21N3O2 requires 336.1706).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:35]([OH:38])[C:36]#[CH:37].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[F:13][C:12]([F:15])([F:14])[C:4]1[CH:3]=[C:2]([C:37]#[C:36][CH2:35][OH:38])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: C#CCO
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: OCC#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-iodo-3,5-bis(trifluoromethyl)benzene (5.00 g), copper(I) iodide (56.0 mg), triphenylphosphine (193 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (304 mg), propargyl alcohol (0.954 ml), diisopropylethylamine (10.2 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 6 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.81 g) as a brown oil.
Reaction SMILES: [CH2:1]([NH:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14])[CH2:2][CH3:3].C1(O)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.Cl[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][C:37]=1[F:42].ClC1C=CN=CC=1F.C(=O)(O)[O-].[Na+]>ClCCl>[F:42][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][C:36]=1[N:4]([CH2:1][CH2:2][CH3:3])[N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14]
Reactant: Fc1cnccc1Cl
Reactant: CCCNN1C(=O)Cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: CCCN(c1ccncc1F)N1C(=O)Cc2ccccc21
Temperature: 150 °C
Reaction time: 6.5 h

Procedure:
To a stirred solution consisting of 1,3-dihydro-1-propylamino-2H-indol-2-one (5.06 g), phenol (13.2 g) and p-toluenesulfonic acid hydrate (0.25 g), heated at 150° C., was added 4-chloro-3-fluoropyridine hydrochloride (5.37 g). Heating was continued at 150° C. for 10.75 hours at which time additional 4-chloro-3-fluoropyridine (2.05 g) was added and heating continued an additional 6.5 hours. Upon cooling to room temperature, the reaction mixture was dissolved in dichloromethane and dilute aqueous sodium bicarbonate. The layers were separated and the organic layer extracted with dilute aqueous sodium bicarbonate (2×). The combined aqueous layers were back-extracted with dichloromethane and ether. The combined organic layers were washed with brine, dried (K2CO3), filtered, and concentrated. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) and another column (silica gel, EtOAc) afforded the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[CH:15])[CH:8]=2)[O:3]1.Cl[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[C:15][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]=3)[CH:8]=2)[O:3]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)nc1
Temperature: 55 °C
Reaction time: 80 h

Procedure:
A solution of 233 mg (1.09 mmol) of 2,2,4,4-tetramethyl-6-ethynylchroman (Compound 5) and 209 mg (1.09 mmol) of ethyl 6-chloronicotinate (Compound 98) in 1 ml of triethylamine was degassed and then treated under argon with a powdered mixture of 50 mg (0.26 mmol) of cuprous iodide and 100 mg (0.14 mmol) of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was heated under argon at 55 degrees C. for 80 h and then cooled to room temperature. The triethylamine was then removed under vacuum and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as a yellow oil. PMR (CDCl3): δ 1.36 (12H, s), 1.42 (3H, t, J~7.2 Hz), 1.85 (2H, s), 4.37 (2H, q, J~7.2 Hz), 6.79 (1H, d, J~.4 Hz), 7.34 (1 H, dd, J~2.1 Hz), 7.56 (1H, d, J~8.7 Hz), 7.60 (1H, d, J~2.1 Hz), 8.27 (1H, dd, J~8.7 Hz, 2.4 Hz), 9.19 (1H, d, J~2.4 Hz). MS exact masss, m/e 363.1837 (calcd. for C23H25O3N, 363.1834).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].CCCCCC.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:22](=[O:24])[CH3:23])[S:5][C:6]=1[CH3:7]
Reactant: CON(C)C(C)=O
Reactant: Cc1ncsc1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1nc(C)c(C)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Commercially available 4,5-dimethyl-1,3-thiazole (453 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution which was then cooled to −78° C. A hexane solution (1.56 M) (2.8 ml) of n-butyllithium was slowly added over a period of 10 min, and the mixture was stirred at −78° C. for 2 hr. N-Methoxy-N-methylacetamide (454 mg) was dissolved in tetrahydrofuran (2 ml) to prepare a solution which was then slowly added over a period of 10 min, and the mixture was stirred at −78° C. for 2 hr. The cooling bath was removed, an aqueous saturated ammonium chloride solution (10 ml) was added, and the mixture was stirred for 30 min. Further, water (10 ml) was added, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over sodium sulfate. The solvent was removed, and the residue was purified by chromatography on silica gel using hexane/ethyl acetate for development to give the title compound (609 mg, 98%).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][N:5]([CH3:32])[C:6]1[C:7]([NH2:31])=[CH:8][C:9]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH3:30])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)=[C:10]([O:12][CH3:13])[CH:11]=1.C([O-])([O-])=O.[K+].[K+].[Cl:40][CH2:41][CH2:42][C:43](Cl)=[O:44].[OH-].[Na+]>CC(C)=O.CO>[Cl:40][CH2:41][CH2:42][C:43]([NH:31][C:7]1[CH:8]=[C:9]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH3:30])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)[C:10]([O:12][CH3:13])=[CH:11][C:6]=1[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:33])[CH3:32])=[O:44]
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: COc1cc(N(C)CCN(C)C)c(NC(=O)CCCl)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a stirred suspension of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 175, 33 g, 62.29 mmol) and K2CO3 (6.09 g, 43.6 mmol) in acetone (300 mL) was added 3-chloropropanoyl chloride (9.78 g, 74.74 mmol) at −50° C. The resulting mixture was heated to −20° C. and stirred for 0.5 h. CH3OH (27.75 mL) and NaOH solution (2.24 g, 56.06 mmol in 300 mL water) were added. The resulting mixture was stirred for 3-4 h at r.t. Solid was collected by filtration and dried at 50° C. to give the title compound (32.5 g, 95%). 1H NMR: (CDCl3) 2.95 (2H, t), 3.04 (6H, d), 3.50 (3H, s), 3.63 (2H, s), 3.81 (2H, t), 4.01 (6H, s), 4.33-4.37 (2H, m), 7.33-7.42 (3H, m), 7.47 (1H, t), 7.51-7.55 (1H, m), 8.11-8.21 (3H, m), 8.48 (1H, s), 8.87 (1H, s), 9.17 (1H, s); m/z: ES+ MH+ 536.24.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C@:5]2([NH:22][S@@](C(C)(C)C)=O)[C:17]([F:21])([F:20])[CH2:18][OH:19]>CCCCCCC.C(OCC)(=O)C>[NH2:22][C@@:5]1([C:17]([F:21])([F:20])[CH2:18][OH:19])[C:4]2[C:14](=[CH:15][CH:16]=[C:2]([Br:1])[CH:3]=2)[O:13][C@:7]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[CH2:6]1
Reactant: CC(C)(C)[S@@](=O)N[C@]1(C(F)(F)CO)CC2(CCCOC2)Oc2ccc(Br)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: N[C@]1(C(F)(F)CO)C[C@@]2(CCCOC2)Oc2ccc(Br)cc21
Yield: 47 %

Procedure:
Starting from (R)—N-((4R)-6-bromo-4-(1,1-difluoro-2-hydroxyethyl)-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-yl)-2-methylpropane-2-sulfinamide (intermediate B4.7), and after chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to =:100 as the eluent the 2-((2R,4R)-4-amino-6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-yl)-2,2-difluoroethanol (47% yield) (intermediate B5.7A) was obtained as the first eluting isomer as a white foam; MS (ISP): m/z=378.0 [M+H]+ and 380.0 [M+2+H]+. The second eluting isomer, 2-((2S,4R)-4-amino-6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-yl)-2,2-difluoro ethanol (27% yield) (intermediate B5.7B) was also obtained as a white foam; MS (ISP): m/z=378.0 [M+H]+ and 380.0 [M+2+H]+.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][CH2:5][N:4]([C:8]([CH3:12])([CH3:11])[C:9]#N)[CH2:3]1.C[Mg]Br>O1CCCC1.C(OCC)C>[C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C:2]([NH2:1])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1)([CH3:12])([CH3:9])[CH3:11]
Reactant: CC(C)(C#N)N1CCCC(N)(c2ccccc2)C1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)N1CCCC(N)(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
To a solution of 100 mg (0.411 mmol) rac-2-(3-Amino-3-phenyl-piperidin-1-yl)-2-methyl-propionitrile in 2.0 ml tetrahydrofuran over mol-sieve at 0° C. under nitrogen, was added dropwise 1.4 ul (4.11 mmol) of a 3M methylmagnesium bromide solution in diethyl ether. The mixture was stirred at 0° C. for 10 minutes, and then at 60° C. for 30 hours. The mixture was cooled in an ice bath and quenched with a saturated ammonium chloride solution. The mixture was extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to provide 60 mg (63%) of the title compound as a yellow gum. MS (m/e): 233.2 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:42]([O:47][CH2:48][O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH2:67])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)(=[O:46])[CH2:43][CH2:44][CH3:45]>CN(C=O)C>[C:42]([O:47][CH2:48][O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH:67][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:59][CH:60]=1)(=[O:46])[CH2:43][CH2:44][CH3:45]
Reactant: O=C(O)c1c[nH]nn1
Reactant: CCCC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
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: CCCC(=O)OCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 1.6 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid butyryloxymethyl ester (51 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (1 mg; purity 95%). MS m/z [M+H]+ calc'd for C27H32N4O6, 509.23. found 509.4.