Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S:18](=[O:39])[CH2:19][C:20]([CH2:37]Cl)=[C:21]2[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I-:54].[Na+]>CC(C)=O>[C:1]([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S:18](=[O:39])[CH2:19][C:20]([CH2:37][I:54])=[C:21]2[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS(=O)[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS(=O)[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of (6R,7R)-4-methoxybenzyl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (10.00 g, 12.56 mmol) in Acetone (100 mL) at rt was added sodium iodide (2.82 g, 18.84 mmol). The mixture was stirred at the same temperature over 2 h. LCMS indicated completion of the reaction. The solid was filtered off, the filtrate was concentrated under vacuum, and the residue was purified by Combiflash automated silica gel chromatography (120 g Gold column), eluting with ethyl acetate/hexanes (0-50%) to afford (6R,7R)-4-methoxybenzyl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxy carbonyl)amino)thiazol-4-yl)acetamido)-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (10.86 g, 12.23 mmol, 97% yield) as a yellow solid. LCMS: (M+H)+: 887.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].[ClH:35]>ClCCl.O1CCOCC1>[ClH:35].[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:23](=[O:24])[N:10]([CH:11]3[CH2:12][CH2:13][N:14]([CH:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[CH2:15][CH2:16]3)[C:3]=2[CH:4]=1)[CH3:9]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCc1ccc(N)c(NC2CCN(C3CCOCC3)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1ccc2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a solution of (2-amino-5-ethylphenyl)[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]amine D26 (251 mg, 0.83 mmol) in dichloromethane (10 mL) was added 1,1′-carbonyldiimidazole (403 mg, 2.49 mmol). The mixture was stirred under room temperature for 1 hour and 2 mL of 4 M HCl in 1,4-dioxane was added. The resulting mixture was stirred for 5 min and concentrated in vacuo. The residue was dissolved in MeOH and purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 10% B to 90% B in 10 min, where A=H2O and B=CH3CN pumped at 150 mL/min to yield 89 mg of the title compound (29% yield). MS (ESI): 330 [M+H]+; 1H NMR (HCl salt) (400 MHz, CDCl3): δ 1.30 (3H, t), 1.99 (5H, m), 2.25 (2H, d), 2.75 (2H, q), 3.03 (2H, m), 3.44 (4H, d), 3.68 (2H, m), 4.14 (2H, d), 4.69 (1H, m), 6.91 (1H, d), 7.00 (1H, d), 7.84 (1H, s), 9.36 (1H, s), 12.91 (1H, br).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH:19]([CH2:21][CH3:22])[CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:23]([O-])=[O:24].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH:19]([CH2:21][CH3:22])[CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CCC(C)N(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Product: CCC(C)N(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 22.4 %

Procedure:
7.0 g of 1-(2-chloroethyl)-3-sec.butyl-3-D-galactopyranosylurea are dissolved in 20 ml of formic acid, and 5.0 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.7 g of 1-(2-chloroethyl)-1-nitroso-3-sec.butyl-3-D-galactopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]([CH3:28])([CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:27])=[C:20]([Cl:26])[CH:21]=[C:22]2[Cl:25])=[N:17]1)[C:13]#[N:14]>C1COCC1>[C:13]([C:12]([NH:11][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:28])[CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:27])=[C:20]([Cl:26])[CH:21]=[C:22]2[Cl:25])=[N:17]1)#[N:14]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(I)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-iodobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=533, RT=0.77 min.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=O)[CH2:7][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:20][CH2:21][CH3:22]>C(O)(=O)C.CO.[Pd]>[OH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:20][CH2:21][CH3:22]
Reactant: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OC)CC2=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OC)CC2
Yield: 45.9 %

Procedure:
A solution of 4.1 g (13.4 mmole) of ester product of Example 4 in 100 ml of acetic acid and 50 ml of methanol was hydrogenated for 21 hours at 4 psi and room temperature using palladium on carbon as catalyst. The catalyst was filtered and the filtrate was evaporated to dryness. Chromatography of the residue on silica gel using 20% ethyl acetate/hexane as eluent gave 1.8 g of the title compound as an oil. Structure assignment was confirmed by nmr and infrared spectra.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[Na+].Br[CH2:13][C:14]#[N:15]>O1CCOCC1>[C:14]([CH2:13][S:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[NH2:3])#[N:15]
Reactant: N[C@@H](CS)C(=O)O
Reactant: N#CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#CCSC[C@H](N)C(=O)O
Reaction time: 18 h

Procedure:
A 360 mL aqueous solution of commercially available (Aldrich) L-cysteine hydrochloride monohydrate (60.0 g, 341.7 mmole) and sodium hydroxide (27.33 g, 683.4 mmole), at room temperature, is treated with a solution of bromoacetonitrile (44.5 g, 370.6 mmole) in 130 mL of dioxane over 30 minutes. The reaction is stirred for 18 hours, during which time a thick precipitate will form. The solid is filtered off, washed with diethyl ether (100 mL) and dried under high vacuum at 40° C. to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[C:19]([CH2:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1O)[CH3:9].Cl.[CH3:26][N:27]([CH2:29][C:30]([OH:32])=[O:31])[CH3:28]>C(Cl)Cl>[CH3:26][N:27]([CH2:29][C:30]([O:32][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]([O:22][CH3:23])=[C:19]([CH2:20][CH3:21])[C:10]=1[CH2:8][CH3:9])=[O:31])[CH3:28]
Reactant: CCc1c(CC)c(OC)c2ccccc2c1O
Reactant: CN(C)CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1c(CC)c(OC(=O)CN(C)C)c2ccccc2c1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
Triethylamine (3 eq) and dry methylene chloride (150 ml) are introduced to a mixture of 2,3-diethyl-4-methoxynaphthol (1.59 g, 6.5 mmole), dimethylamino acetic acid hydrochloride (2 eq, 1.8 g, 13.0 mmole), dicyclohexylcarbadiimide (2 eq, 2.7 g, 13.0 mmole) and 4-dimethylaminpyridine (1 eq, 2.7 ml, 19.5 mmole), prepared under an argon atmosphere, at room temperature under argon. The resulting suspension is stirred at room temperature for 20 hours under argon, then diluted with 300 ml of methylene chloride. The methylene chloride extracts are washed thoroughly with saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is chromatographed through a silica gel (200 g) flash column and eluted by ether to give 1.48 g (72.2%) of N,N-dimethylamino acetic acid, 2,3-diethyl-4-methoxynaphth-1-yl ester as a yellowish brown oil.
Reaction SMILES: [OH-].[Na+].C(#N)C.[CH3:6][CH2:7][C@@H:8]([C:10]([O:12][C@@H:13]1[C@@H:18]2[C@@H:19]([CH2:24][CH2:25][C@@H:26]([OH:34])[CH2:27][C@@H:28]([OH:33])[CH2:29][C:30]([O-:32])=[O:31])[C@@H:20]([CH3:23])[CH:21]=[CH:22][C:17]2=[CH:16][C@@H:15]([OH:35])[CH2:14]1)=[O:11])[CH3:9].[Na+]>O>[CH3:6][CH2:7][C@@H:8]([C:10]([O:12][C@@H:13]1[C@@H:18]2[C@@H:19]([CH2:24][CH2:25][C@@H:26]([OH:34])[CH2:27][C@@H:28]([OH:33])[CH2:29][C:30]([OH:32])=[O:31])[C@@H:20]([CH3:23])[CH:21]=[CH:22][C:17]2=[CH:16][C@@H:15]([OH:35])[CH2:14]1)=[O:11])[CH3:9]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)[O-])[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Temperature: 50 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
The pH was raised to 8.5 by addition of 2M sodium hydroxide in water (1.2 ml) and the solution was heated to 50° C. Acetonitrile (90 ml) was added to the mixture and then the mixture was stirred at elevated temperature for one hour. The mixture was allowed to cool to 20–25° C. (“ambient temperature”), was held at ambient temperature for two hours and then cooled to 5° C. and maintained at 5° C. for 12 hours, whereupon pravastatin sodium crystallized. The crystals were then isolated by filtration and washed with acetonitrile (2×10 ml) and dried under vacuum at 50° C. X-ray diffraction analysis revealed the presence of Form A. Pravastatin Form A was obtained in 92% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][C:25]1[N:26]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]=2)[CH:27]=[CH:28][N:29]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:33]5[CH:32]=[N:31][C:30]([N:26]6[CH:27]=[CH:28][N:29]=[C:25]6[CH3:24])=[CH:35][CH:34]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nccn1-c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(-n5ccnc5C)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-(2-methyl-imidazol-1-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 78.1.1) to give the title compound as a white solid. (HPLC: tR 2.10 min (Method A); M+H=451 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.68-8.66 (m, 1H), 8.18-8.13 (m, 2H), 8.09-8.00 (m, 2H), 7.78-7.74 (m, 1H), 7.63-7.59 (m, 2H), 6.94-6.93 (m, 1H), 3.93 (s, 3H), 3.59 (s, 3H), 2.54 (s, 3H), 1.96 (s, 3H))
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.FC1C=C2C(C(C3CCNCC3)=NN2C2C=CC=CC=2)=CC=1.Cl[CH2:47][CH2:48][CH2:49][CH:50]([C:58]1[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=1)[C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC(C)CC(=O)C>[F:57][C:54]1[CH:53]=[CH:52][C:51]([CH:50]([C:58]2[CH:59]=[CH:60][C:61]([F:64])=[CH:62][CH:63]=2)[CH2:49][CH2:48][CH2:47][N:20]2[CH2:21][CH2:22][CH:17]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:7]=3)[CH2:18][CH2:19]2)=[CH:56][CH:55]=1
Reactant: Fc1ccc2c(C3CCNCC3)nn(-c3ccccc3)c2c1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Fc1ccc(C(CCCN2CCC(c3nn(-c4ccccc4)c4cc(F)ccc34)CC2)c2ccc(F)cc2)cc1
Yield: 23.7 %

Procedure:
A stirred mixture, under nitrogen, of 6-fluoro-1-phenyl-3-(4-piperidinyl)-1H-indazole (1.5 g, 0.005 mol), the free base of Example 98, 4-chloro-1,1-bis-(4-fluorophenyl)butane (1.6 g, 0.0056 mol), Na2CO3 (0.6 g), a few crystals of KI and 4-methyl-2-pentanone (70 ml) was refluxed for 16 hours. The reaction was poured into H2O, and the aqueous mixture extracted with ethyl acetate. The ethyl acetate was washed (H2O), dried (MgSO4) and the solvent was concentrated to a liquid. The liquid was dissolved in anhydrous ether and HCl (g) was added to precipitate a gum. The supernatant ether was decanted, H2O was added to the gum, and the mixture was made basic with NH4OH. The basic suspension was extracted with ether, the extract washed (H2O), dried (MgSO4), and the solvent was concentrated to yield 0.64 g (24%) of a solid. This material was combined with 2.9 g of a compound from another run and recrystallized from isopropyl ether to yield 2.1 g of 3-[1-[4,4-bis(4-fluorophenyl)butyl-4-piperidinyl]-6-fluoro-1-phenyl-1H-indazole, mp 113°-115° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH:49]([CH3:51])[CH3:50])=[CH:44][CH:43]=3)=[CH:38][C:37]=2[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:28][CH2:29]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:43]=[CH:44][C:45]([O:48][CH:49]([CH3:51])[CH3:50])=[CH:46][CH:47]=3)=[CH:38][C:37]=2[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:32]([F:34])([F:35])[F:33])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(OC(C)C)cc5)cc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(OC(C)C)cc5)cc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (130 mg, 0.164 mmol) in CH2Cl2 (4 mL) was added TFA (1 mL), and the reaction mixture was stirred at 25° C. for 12 h. The mixture was concentrated, and neutralized to pH 7-8 with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a light yellow solid that is used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][N:12]([C:29](=[O:31])[CH3:30])[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc(CNc2ccc(Cl)cc2)c[nH]1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(CN(C(C)=O)c2ccc(Cl)cc2)c[nH]1
Temperature: 0 °C
Yield: 81.8 %

Procedure:
4-[(4-chlorophenylamino)-methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (187) (0.2868 g, 1.03 mmol) was weighed out into a 10 mL flask. A stir bar and septum were added, and the flask was purged with nitrogen. The amine was dissolved in methylene chloride (2.6 mL, 0.4 M) and then the flask was cooled to 0° C. N,N-diisopropyl ethyl amine (0.1971 mL, 1.13 mmol) was added, then acetyl chloride (0.0805 mL, 1.13 mmol) was added slowly by syringe to the stirring 0° C. solution. The reaction was then allowed to warm to room temperature. When the reaction was judged complete by HPLC (90 min) the reaction was diluted with methylene chloride and quenched with water. The organic phase was removed, washed with brine, dried with Na2SO4, filtered and concentrated en vacuo. The crude product was purified by silica gel chromatography (Combiflash column, 2:1 Hexanes:Ethyl acetate) to obtain pure 4-[(acetyl-(4-chlorophenyl)-amino)-methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (189, 0.2701 g, 82%) as a sticky white solid. 1H (CD3OD, 400 MHz): δ 11.25 (1H, broad s), 7.35 (2H, d, J=8.4 Hz), 7.05 (2H, d, J=8.4 Hz), 6.76 (1H, s), 6.69 (1H, s), 4.68 (2H, s), 4.22 (2H, q, J=7.1 Hz), 1.81 (3H, s), 1.29 (3H, t, J=7.1 Hz) ppm. 13C (CD3OD, 100 MHz): δ 172.17, 162.50, 142.39, 134.87, 130.94, 130.70, 124.46 & 124.30, 123.94, 121.91 & 121.88, 116.64, 61.13, 46.43, 22.70, 14.75 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.70, 14.75; CH2 carbons: 61.13, 46.43; CH carbons: 130.94, 130.70, 124.46 & 124.30, 116.64 ppm. HPLC: 9.247 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:39][O:40][C:41]([C:43]1([NH2:52])[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42]>CN(C=O)C>[CH3:39][O:40][C:41]([C:43]1([NH:52][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([F:13])[C:10]([O:11][CH3:12])=[C:2]([Br:1])[CH:3]=2)[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42]
Reactant: COc1c(F)cc(C(=O)O)cc1Br
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2cc(F)c(OC)c(Br)c2)Cc2ccccc2C1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
2.4 g (9.64 mmol) of the compound of step 3 were dissolved in 40 ml of DMF and 2.49 g (19.27 mmol) of EDIA and 4.03 g (10.60 mmol) of 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate were added. Then a solution of 2.19 g (9.64 mmol) of 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in 10 ml of DMF was added. After stirring overnight, the mixture was evaporated to dryness and the residue purified by preparative RP HPLC (water/ACN gradient). 3.6 g of the title compound were obtained.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.C(N(CC)C(C)C)(C)C.[C:39]([N:43]=[C:44]=[O:45])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:39]([NH:43][C:44]([N:27]1[CH2:26][CH:25]=[C:24]([C:22]2[NH:21][C:17]3[N:18]=[CH:19][N:20]=[C:15]([NH:14][C:10]4[CH:9]=[C:8]5[C:13](=[CH:12][CH:11]=4)[N:5]([CH3:4])[N:6]=[CH:7]5)[C:16]=3[CH:23]=2)[CH2:29][CH2:28]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)N=C=O
Reactant: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)ccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCN(C(=O)NC(C)(C)C)CC5)cc34)ccc21
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suspension of (1-methyl-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (166.8 mg, 0.3631 mmol, 1 eq) in anhydrous DMF (17 mL), N,N-diisopropylethylamine (DiPEA) (260 μL, 4.1 eq) was added at rt. The solution was then cooled to −20° C., after which tert-butyl isocyanate (36.5 mg, 0.368 mmol, 1 eq in anhydrous DMF (2 mL) was added. The solution was stirred at rt for 1 h. The reaction was cooled to 0° C., after which additional tert-butyl isocyanate (11.4 mg, 0.115 mmol, 0.3 eq) in anhydrous DMF (1 mL) was added. The reaction was stirred again at rt for 4 h. The reaction was quenched with MeOH, concentrated in vacuo, and dried under vacuum pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH:DCM 1%→5%]. Fractions containing product were combined and concentrated in vacuo. The material was further purified by trituration in MeOH, yielding the title compound as an off-white solid. 1H NMR (400 MHz, DMSOd6): δ=1.28 (s, 9H), 2.44 (s, br, 2H), 3.52 (t, J=5.6 Hz, 2H), 3.99 (d, J=2.0 Hz, 2H), 4.03 (s, 3H), 5.77 (s, —NH), 6.40 (s, br, 1H), 6.75 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.69 (dd, J=8.8, 2.0 Hz, 1H), 8.01 (s, 1H), 8.26 (s, 1H), 8.39 (s, 1H), 9.32 (s, —NH), 11.89 (s, —NH). MS (ES+): m/z 445.07 (100) [MH+]. HPLC: tR=2.29 min (ZQ2000, polar—5 min).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:10][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[CH:9]=[CH:8][CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCc1cccc(OCc2ccccc2)c1
Reaction time: 17 h

Procedure:
To a solution of 3-(2-hydroxyethyl)phenol (1.0 g) and K2CO3 (1.5 g) in acetone (20 mL) was added (bromomethyl)benzene (1.49 g) at ambient temperature. The reaction mixture was stirred at the same temperature for 17 hours. The resulting mixture was evaporated in vacuo. The residue was diluted with EtOAc and washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=90:10-70:30) to give 2-[3-(benzyloxy)phenyl]ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:10](O)[C:11]#[CH:12]>>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:12][C:11]#[CH:10])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: C#CCO
Reactant: Cc1ccc(O)cc1C
Product: C#CCOc1ccc(C)c(C)c1

Procedure:
The title compound was synthesized using 3,4-dimethylphenol and propargyl alcohol by conducting a reaction similar to that mentioned in Reference example 35.