Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[C@H:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(=O)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a stirred yellow solution of methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (1 g, 2.61 mmol) in anhydrous toluene (25 mL) was added 1.1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (0.947 mL, 1.042 mmol). The mixture was cooled to −35° C. and a solution of 1M catechoborane/THF (3.65 mL, 3.65 mmol) was added over 10 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 30 min. Then, diluted with EtOAc (30 mL) and sat. Na2CO3 (10 mL), and the mixture was stirred vigorously for 30 min. The organic phase washed with sat Na2CO3 (2×5 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford desired (S)-methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (888 mg, 2.301 mmol, 88% yield) as off-white solid. EE=95.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.Cl.[CH:20](=[NH:24])OCC>C1COCC1>[NH:24]=[CH:20][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Reactant: CCOC=N
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(NC=N)cc2)cs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
N-(4-[2-(4-Aminophenyl)ethyl]-1,3-thiazol-2-yl)acetamide (150 mg) was dissolved in THF (2 ml) and pH=7 buffer (2 ml). Then, ethyl imidoformate hydrochloride (1.26 g) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 2 hours, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with CH3CN/water (7:3) as an eluent. The oil was purified again by preparative silica gel chromatography with CHCl3/MeOH (5:1) as an eluent to give N-[4-(2-{4-[(iminomethyl)amino]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide (110 mg) as pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:9]1[C:14]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:53]1[CH:58]=[CH:57][C:56]([S:59]([CH:62]([CH3:64])[CH3:63])(=[O:61])=[O:60])=[CH:55][N:54]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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]([N:8]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[C:9]1[C:14]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[CH:13][C:12]([C:53]2[CH:58]=[CH:57][C:56]([S:59]([CH:62]([CH3:64])[CH3:63])(=[O:60])=[O:61])=[CH:55][N:54]=2)=[CH:11][N:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)S(=O)(=O)c1ccc(Br)nc1
Reactant: CN(Cc1ccc(-c2nnc(-c3cc(B4OC(C)(C)C(C)(C)O4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)o3)c2)nc1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
The reaction mixture from Method F Step 1 was diluted with DMF (2 mL) an 2-bromo-5-isopropylsulfonyl-pyridine [Compound I-7a; prepared according to Method F-1] (48 mg, 0.1817 mmol), Pd(PPh3)2Cl2 (6.263 mg, 0.01514 mmol) and 2M aqueous Na2CO3 (227.1 μL, 0.4542 mmol) were added. The reaction was degassed with nitrogen and stirred at 95° C. for 2 hours in a sealed tube. The reaction mixture was partitioned between EtOAc and brine and the aqueous layer extracted with EtOAc (×2). The combined organic extracts were washed with brine (×3), dried (MgSO4), filtered and concentrated in vacuo. The crude residue was used in the deprotection step without further purification.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10]1.N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:1]([Si:5]([CH3:7])([CH3:6])[O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccsc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccsc1
Reaction time: 16 h

Procedure:
tert-Butylchlorodimethylsilane (3.88 g) was added to a stirred solution of 2-(thiophen-3-yl)ethanol (3.00 g) and 1H-imidazole (4.78 g) in DMF (30 mL) cooled in ice bath. After 16 h, the reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3×150 mL) and evaporated in vacuo. Purification was by silica gel chromatography eluting with isohexane and then 1:5 ethyl acetate:isohexane, to collect the subtitled compound as an oil. Yield 5.2 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2.C(O)(=O)C.O>C1(C)C=CC=CC=1.CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:34])[NH:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Temperature: 100 °C

Procedure:
300 mg (0.88 mmol) of (2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 140 mg (0.88 mmol) of 5-aminoquinolin-2(1H)-one are dissolved in 19 ml of toluene and the solution is admixed with 0.55 ml (1.75 mmol) of titanium tert-butoxide and 0.1 ml of acetic acid. The reaction mixture is heated at 100° C. for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 539 mg of (5-{[(2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one as a crude product. The imine is dissolved in 44 ml of CH2Cl2 and the solution is cooled to −30° C. 8.9 ml (8.9 mmol) of a 1M BBr3 solution in dichloromethane are added slowly dropwise over 15 minutes and the mixture is allowed to warm to room temperature over 22 hours. The reaction solution is poured onto a mixture of saturated NaHCO3 solution and ice. It is extracted repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/ethyl acetate 0-100%) yields 134 mg of the title compound.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]1[N:30]=[CH:29][C:28]2[CH:27]([NH2:31])[CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O.CCOC(C)=O.CO>C1COCC1.CO>[NH2:31][CH:27]1[CH2:26][CH2:25][CH2:24][C:23]2[N:22]=[C:21]([CH2:20][CH2:19][OH:18])[N:30]=[CH:29][C:28]1=2
Reactant: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2N)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1CCCc2nc(CCO)ncc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazolin-5-amine (570 mg, 1.32 mmol) in 10 mL of THF at 0° C. was treated with a 1M TBAF solution in THF (1.56 mL, 1.56 mmol). After stirring at room temperature overnight, the reaction mixture was directly submitted to flash chomatograph (SiO2, EtOAc to EtOAc/MeOH=100:15 to EtOAc/2M NH3 in MeOH=1:1) to give crude product as a white solid.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]1([C:10](=O)[CH:11]([CH2:20][CH3:21])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(C)C>[C:4]1([C:10]2[C:11]([CH2:20][CH3:21])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:2]([CH3:1])[N:3]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCC(C(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: CNN
Solvent: CC(C)O
Product: CCc1c(-c2ccccc2)nn(C)c1-c1ccccc1
Temperature: 80 °C

Procedure:
Methylhydrazine (2.86 g, 0.06 mole) is added to an isopropanol (100 ml) solution of 1,3-diphenyl-2-ethyl-1,3-propanedione (11.0 g, 0.044 mole) with constant stirring at 80°C. The reaction mixture is heated at reflux for 31/2 hours, then stirred at room temperature overnight. The reaction mixture is poured into ice water, stirred for 1/2 hour, and the resulting mixture extracted with chloroform (3×50 ml). Evaporation of the organic layer gives an oil which is crystallized from hexane with cooling to give 6.47 g (56%) or product, m.p. 80°C to 81°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][C:10]2=[O:16])=[CH:5][CH:4]=1.[CH3:17][CH2:18][CH2:19][C:20](Cl)=[O:21].COC1C=CC(C2CCC(OC(=O)CCC)=CC2=O)=CC=1.COC1C=CC(C2C(OC(=O)CCC)=CC(=O)CC2)=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:20]([C:11]1[C:12](=[O:15])[CH2:13][CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]=1[OH:16])(=[O:21])[CH2:19][CH2:18][CH3:17]
Reactant: COc1ccc(C2CCC(=O)CC2=O)cc1
Reactant: CCCC(=O)Cl
Agent: CCCC(=O)OC1=CC(=O)C(c2ccc(OC)cc2)CC1
Agent: CCCC(=O)OC1=CC(=O)CCC1c1ccc(OC)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC(=O)C1=C(O)C(c2ccc(OC)cc2)CCC1=O
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Triethylamine (11.1 g) was added dropwise to a stirred solution of 4-(4-methoxyphenyl)cyclohexane-1,3-dione (21.8 g) and n-butyryl chloride (17.6 g) in methylene chloride (100 ml) at ambient temperature. After stirring for a further 1 hour, the reaction solution was washed with water, brine and dried over anhydrous magnesium sulphate. The methylene chloride was removed in vacuo to give a mixture of 4-(4-methoxyphenyl)-1-butyryloxycyclohex-1-en-3-one and 6-(4-methoxyphenyl)-1-butyryloxycyclohex-1-ene-3-one. Toluene (150 ml) was added followed by 4-(N,N-dimethylamino) pyridine (0.5 g) and the mixture refluxed for 8 hours. Evaporation of the toluene in vacuo gave a red oil. Purification on a silica gel column using 5% v/v diethyl ether-methylene chloride as eluant gave the title compound (25 g) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>C(O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8](=[N:12][OH:13])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: CC(=O)c1ccnc(N)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a suspension of 1-(2-aminopyrimidin-4-yl)ethanone (3a) (4 g) in ethanol (70 mL) and water (14 mL) was added hydroxylamine hydrochloride (4.05 g) followed by sodium acetate (7.18 g) and the mixture was stirred at room temperature for one hour. After this time the reaction mixture was concentrated in vacuo, water was added and stirred for 15 minutes. The precipitate was collected by filtration and washed with water and dried in vacuo at 40° C. overnight to afford the title product (4.29 g) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20])[CH:23]=[CH2:24]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: C=CCOC(=O)Cl
Product: C=CCOC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 70.8 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 5.5 mg (0.0458 mMol) allyl chloroformate, 9.7 mg (71%) of the title compound were recovered.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:13]1[CH:30]=[CH:29][C:16]([O:17][CH2:18][CH2:19][N:20]([CH2:26][CH2:27][OH:28])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[CH:15][CH:14]=1)#[N:12].C(N(CC)CC)C>ClCCl>[C:11]([C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][N:20]([CH2:26][CH:27]=[O:28])[C:21]([N:23]([CH3:24])[CH3:25])=[O:22])=[CH:29][CH:30]=1)#[N:12]
Reactant: CN(C)C(=O)N(CCO)CCOc1ccc(C#N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN(C)C(=O)N(CC=O)CCOc1ccc(C#N)cc1
Temperature: -30 °C
Reaction time: 3 h
Yield: 50.3 %

Procedure:
Oxalyl chloride (6.3 g, 0.0497 mol) was added dropwise to a stirred solution of DMSO (7.6 g, 0.094 mol) and dichloromethane (100 mL) at −78° C. After stirring for 15 min at the same temperature, 1-[2-(4-cyanophenoxy)ethyl]-1-(2-hydroxyethyl)-3,3-dimethylurea (6 g, 0.0325 mol; see step (i) above) in dichloromethane was added and stirring continued for 3 h under a nitrogen atmosphere. Triethylamine (16.4 mL, 0.1625 mol) was added dropwise and the reaction mixture was then warmed slowly to −30° C. The reaction mixture was quenched with an aqueous solution of citric acid, and the resulting mixture extracted with dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure yielded 4.5 g of the crude title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(O)(O)(=O)=O.[NH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:3]=1[C:4]([NH:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)=[O:6]
Reactant: Nc1ncc[nH]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a thermally controlled reaction vessel, add 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid (420 g, 1.56 mol, 1.0 equiv), 2-aminoimidazole monosulfate (349 g, 1.87 mol, 1.2 equiv), N,N-dimethylformamide (2.94 L), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (722 g, 2.18 mol, 1.4 equiv), and N,N-diisopropylethylamine (869 mL, 4.98 mol, 3.2 equiv). Heat the resulting suspension to an internal temperature of 80° C. for 18 hours. Cool the reaction mixture to 10° C., pour the mixture into ice water (14 L), and stir for 90 min. Collect the solids by filtration, dry the material in air for 24 h, and in a vacuum oven at 50° C. for 24 h. Slurry the solid material in isopropanol (7 L), heat to an internal temperature of 73° C. for 3 h, and cool to 10° C. Filter the suspension to isolate the solid material. Dry the material in air for 24 h and in a vacuum oven at 55° C. for 48 h to give the title compound as an off-white solid (435 g, 83.4%). 1H NMR (DMSO-d6, 400 MHz): δ 11.84 (s, 2H), 8.13 (t, 1H, J=6.0 Hz), 7.47 (d, 1H, J=8.3 Hz), 7.40 (d, 1H, J=1.7 Hz), 7.31 (dd, 1H, J=8.3, 2.0 Hz), 6.73 (s, 2H), 4.27 (d, 2H, J=5.9 Hz), 1.12 (s, 9H). MS (m/z) (35Cl/37Cl) 335/337 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8](C([C@@H](NC(=O)CC3C4C=CC=CC=4C4C3=CC=CC=4)CC(C)C)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+].C([O:50][C:51](=[O:67])[CH2:52][N:53]1[CH:57]=[C:56](B2OC(C)(C)C(C)(C)O2)[CH:55]=[N:54]1)C.[F-].[K+].[Li+].[OH-].Cl>C1COCC1.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.O1CCOCC1.O>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:56]3[CH:55]=[N:54][N:53]([CH2:52][C:51]([OH:67])=[O:50])[CH:57]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)C[C@H](NC(=O)CC1c2ccccc2-c2ccccc21)C(=O)n1cc([C@H](C)c2c(Cl)ccc(F)c2Cl)c2cc(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(CC(=O)O)c3)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of N—((S)-1-{5-bromo-3-[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methylbutyl)-2-(9H-fluoren-9-yl)-acetamide (150.0 mg, 0.212 mmol) and aq 5M NaOH (0.42 mL, 1.1 mmol) in THF (5 mL) was cooled to 0° C. and stirred for 1 h. The organic solvent was removed in vacuo, and the material was transferred to a separatory funnel, extracting with DCM and water. The organic layer was concentrated in vacuo, and [4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)pyrazol-1-yl]-acetic acid ethyl ester (89.1 mg, 0.318 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol), potassium fluoride (61.6 mg, 1.06 mmol) and 4:1 dioxane/H2O were added, and the mixture was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was transferred to a separatory funnel and extracted with DCM and water. The organic layer was dry-loaded onto silica gel, and purified via column chromatography, eluting with 2% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo, redissolved in EtOH/H2O (8 mL), and LiOH (44.5 mg, 1.06 mmol) was added at 0° C. and stirred for 20 min. The pH of the solution was lowered to pH 5 by addition of 2M HCl, and the organic solvent was removed in vacuo. The material was transferred to a separatory funnel and extracted with DCM and brine. The organic layer was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.88 (d, J=7.1 Hz, 3 H), 4.83 (s, 2 H), 5.29 (q, J=7.1 Hz, 1 H), 7.19 (t, J=8.6 Hz, 1 H), 7.36 (d, J=1.5 Hz, 1 H), 7.39-7.53 (m, 2 H), 7.57 (s, 1 H), 7.82 (s, 1H), 8.34 (d, J=2.0 Hz, 1 H). MS (ES+): m/z 433.00 (100) [MH+]. HPLC: tR=3.53 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C.O>[NH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:11](=[O:13])[C@@H:9]([N:8]([CH3:14])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH3:10]
Reactant: NCc1ccccc1N
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)NCc1ccccc1N)N(C)C(=O)OC(C)(C)C
Reaction time: 9 h
Yield: 15.5 %

Procedure:
To a solution of N-Boc-N-methyl-L-alanine (200 mg), 2-aminobenzylamine (240 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (755 mg) and 1-hydroxybenzotriazole monohydrate (603 mg) in N,N-dimethylformamide (4 mL), N,N-diisopropylethylamine (355 μL) was added at room temperature, and the mixture was stirred at the same temperature for 9 hours. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 75 to 50% hexane in ethyl acetate) to obtain oily (S)-tert-butyl (1-((2-aminobenzyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (C9, 47 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[CH:4]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[CH2:12]([O:11][P:10]([CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[CH:4]=1)(=[O:17])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: CCc1cc(CCl)on1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(CC)no1)OCC
Reaction time: 2 h
Yield: 71.5 %

Procedure:
15 g of 5-chloromethyl-3-ethyl-isoxazole and 18 g of triethyl phosphite are slowly heated to 150° C. and left at this temperature for 21/2 hours. After the mixture has cooled, it is distilled under reduced pressure. 18.2 g of (3-ethylisoxazol-5-yl)-methanephosphonic acid diethyl ester of boiling point 120°-121° C./0.2 mm Hg are obtained. Yield: 71.2%. 1H-NMR spectrum (CDCl3, with TMS as internal standard): τ=3.85 (d, J=3 Hz, 1H), 4.17 (m, J=Hz, 4H), 6.60 (d, H=20 Hz, 2H), 7.35 (q, J=Hz, 2H), 8.50-8.93 (m, 9H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=2[C:6]=1I)=[O:4].[CH2:15]([OH:18])[C:16]#[CH:17].C(N(CC)CC)C>C(#N)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=2[C:6]=1[C:17]#[C:16][CH2:15][OH:18])=[O:4]
Reactant: C#CCO
Reactant: COC(=O)c1sc2c(c1I)CCCC2
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1sc2c(c1C#CCO)CCCC2
Temperature: 85 °C
Yield: 72.9 %

Procedure:
To a solution of 3-Iodo-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid methyl ester (15 g, 46.6 mmol) and prop-2-yn-1-ol (5.22 g, 93 mmol) in Acetonitrile (100 mL) was added Pd(PPh3)2Cl (3.27 g, 4.66 mmol), copper(I) iodide (0.89 g, 4.66 mmol) and triethylamine (14 g, 140 mmol). The mixture was heated at 85° C. reflux under N2 for 3 hrs. The reaction was cooled to room temperature, and concentrated to dryness, which was diluted with H2O (50 mL), extracted with ethyl acetate (200 mL×3), The organic phase was washed with saturated aqueous NaHCO3 150 mL, dried over Na2SO4, After concentration, the crude product was purified by silica gel chromatography eluted with PE:EtOAc=10:1-4:1 to give afford title product (8.5 g, 73% yield) as yellow oil. LCMS (m/z) ES+=233 (M+1).