Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([NH2:30])([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])[CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH:32]([CH2:40][CH2:41]Br)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([N:30]4[CH2:41][CH2:40][CH:32]4[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])[CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)C(Br)CCBr
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(C)(N)C(=O)N3CCCC3)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(C)(C(=O)N3CCCC3)N3CCC3C(=O)OC(C)(C)C)ccc21
Temperature: 55 °C
Reaction time: 30 h

Procedure:
0.8 g (1.86 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole and 1.65 g ((5.5 mmol) of tert.butyl 2,4-dibromobutyrate are dissolved in 5 ml of ethanol, mixed with 0.2 g (1.86 mmol) of sodium carbonate and stirred under nitrogen for 30 hours at 55° C. After cooling, the white precipitate is filtered off and washed with ethanol. The filtrate is concentrated by evaporation, the residue is chromatographed on silica gel, eluting with ethyl acetate and ethyl acetate/ethanol/ammonia (20:1:0.01). The desired fractions are combined and concentrated by evaporation.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH:4]=[CH2:5].C(OC(Cl)=O)C.C(N(CC)CC)C.Cl.[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[CH2:22]([O:29][NH:30][C:1](=[O:7])[CH2:2][CH2:3][CH:4]=[CH2:5])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NOCc1ccccc1
Reactant: C=CCCC(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCCC(=O)NOCc1ccccc1

Procedure:
This compound was prepared in several steps. 4-pentenoic acid (1.2.6.4) was reacted with ethylchloroformate in the usual way to obtain the active mixed anhydride. To a solution of the mixed anhydride in chloroform was added triethylamine and O-benzylhydroxylamine hydrochloride to obtain O-benzyl-4-pentenohydroxamic acid (1.2.6.5). The double bond was oxidized using osmium tetroxide/N-methylmorpholine oxide to give the diol (1.2.6.6). The terminal hydroxyl group was then protected with t-butyldimethylsilylchloride in the usual way to yield (1.2.6.7). The secondary hydroxyl group was tosylated using pyridine/p-toluenesulfonyl chloride. Cyclization of (1.2.6.8) to the corresponding pyrrolidone (1.2.6.9) was effected by using sodium carbonate in methanol. The protecting silyl group was removed by treatment with tetraethylammonium fluoride. The title compound (1.2.6.3) was prepared by reacting the latter compound (1.2.6.10) with pyridinelp-toluenesulfonyl chloride in the usual way.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/S(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[N+:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])#[C-:23].CCO>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:23][NH:22][C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)/C=C/c2ccc(Cl)cc2)cc1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1[nH]ccc1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Under N2, at 0° C. 60% NaH in mineral oil (3.11 g, 78 mmol) was added to a solution of (E)-1-chloro-4-(2-tosylvinyl)benzene (19 g, 64.9 mmol) in dry THF (300 mL). After 5 minutes ethyl 2-isocyanoacetate (7.76 mL, 71.4 mmol) was added and the reaction mixture stirred at room temperature. After 18 h EtOH (50 mL) was added and the solvents were evaporated under reduced pressure. The residue was partitioned between EtOAc (400 mL) and H2O (400 mL). The organic phase was washed with (100 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product (16.55 g, “102%”) was used in the next step.
Reaction SMILES: [OH:1][C@@:2]([CH3:64])([C:16](=[O:63])[C@@H:17]([NH:22][C:23](=[O:62])[C@@H:24]([NH:32][C:33](=[O:61])[C@@H:34]([NH:39][C:40](=[O:60])[C@@H:41]([NH:50][C:51](=[O:59])[CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:3][O:4][S:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])(=[O:7])=[O:6].[CH3:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][NH2:90]>>[O:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][S:5]([O:4][CH2:3][C:2]([OH:1])([CH3:64])[C:16](=[O:63])[C@H:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[NH:22][C:23](=[O:62])[C@H:24]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH:32][C:33](=[O:61])[C@H:34]([CH2:35][CH:36]([CH3:37])[CH3:38])[NH:39][C:40](=[O:60])[C@H:41]([CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH:50][C:51](=[O:59])[CH2:52][N:53]1[CH2:54][CH2:55][O:56][CH2:57][CH2:58]1)(=[O:7])=[O:6])[NH:90][CH2:89][CH2:88][O:87][CH2:86][CH2:85][O:84][CH2:83][CH2:82][O:81][CH2:80][CH2:79][O:78][CH2:77][CH2:76][O:75][CH2:74][CH2:73][O:72][CH2:71][CH2:70][O:69][CH2:68][CH2:67][O:66][CH3:65]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)COS(=O)(=O)CCCCCC(=O)O
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCN
Product: COCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCCCCS(=O)(=O)OCC(C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1

Procedure:
6-({[(2R,4S)-2-Hydroxy-2,6-dimethyl-4-[(2S)-2-[(2S)-4-methyl-2-[(2S)-2-[2-(morpholin-4-yl)acetamido]-4-phenylbutanamido]pentanamido]-3-phenylpropanamido]-3-oxoheptyl]oxy}sulfonyl)hexanoic acid and 2,5,8,11,14,17,20,23-octaoxapentacosan-25-amine (Quanta Biodesign) were reacted following General PEGylation Conditions, Method D.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH:20][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)COC(=O)C(C)N
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Product: CC(C)COC(=O)C(C)NC(=O)CCc1ccccc1

Procedure:
Following General Procedure BA above and using 3-phenylpropionyl chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of from 51°-54° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:25][C@H:26](C)[CH2:27]O)[S:23][CH:24]=2)=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([N:25]3[C@H:26]([CH3:27])[CH2:2][O:4][C:5]3=[O:11])[S:23][CH:24]=2)=[CH:18][CH:19]=1
Reactant: C[C@H](CO)Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Reaction time: 3.5 h
Yield: 113 %

Procedure:
Triphosgene (2.62 g, 8.82 mmol) in 60 mL of methylene chloride was added under nitrogen dropwise over 1.75 h to a solution of (2R)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}propan-1-ol (2.30 g, 7.33 mmol), prepared in the previous step, and N,N-diisopropylethylamine in 125 mL of methylene chloride at ice-bath temperature. After the addition, the reaction was stirred at ice-bath temperature for 3.5 h. The ice bath was removed and the stirring continued for 15 h. The reaction was extracted with 2 N HCl, dried (anhydrous MgSO4), filtered and the solvent removed under reduced pressure to give 2.81 g of a yellow solid. Purification of the solid on 500 g of silica gel (230-400 mesh) using 30% methylene chloride-hexane to methylene chloride as the eluents gave the title compound (2.07 g, 83%) as a white solid, mp 197-199° C.; MS (ES) m/z 339.0 [M+H]+; Anal. Calcd for C13H11BrN2O2S: C, 46.03; H, 3.27; N, 8.26. Found: C, 45.80; H, 3.13; N, 8.16.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:20]([CH3:22])[CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:4][N:3]=1.[OH-:23].[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:20]([CH3:22])[CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=2)[C:15]([NH2:16])=[O:23])=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#N
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(N)=O
Temperature: 110 °C

Procedure:
To 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (49 mg, 0.16 mmol, from Example 15) suspended in ethanol (1 mL) was added sodium hydroxide (64 mg, 1.60 mmol, dissolved in 1 mL water). The reaction was heated at 110° C. for 5 hours, cooled, and washed with dichloromethane (25 mL). The dichloromethane layer was concentrated and purified by preparatory TLC plates (92/8/0.5 dichloromethane/methanol/ammonium hydroxide) to yield 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzamide as white solid (9 mg, 17%, MS (M+H)=318), which was converted to the hydrochloride salt.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1>C(OCC)(=O)C>[CH2:5]([O:4][C:2]([NH:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1cccc(S)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1cccc(S)c1

Procedure:
12 ml of ethyl chloroformate are added dropwise to a solution of 25 g of 3-aminothiophenol in 150 ml of ethyl acetate at 50°, under gentle reflux. 50 ml of ethyl acetate are added and the reaction mixture is boiled under reflux for 5 minutes, cooled to 40° and filtered with suction. The filtrate is evaporated to dryness and the oily evaporation residue is chromatographed on silica gel using toluene as the solvent. 3-Ethoxycarbonylaminothiophenol is obtained by evaporating the eluate. 10 g of this product are mixed with 8 g of ethyl acetoacetate and the mixture is added dropwise to 153 g of polyphosphoric acid at 90°. The mixture is warmed for 2 hours at an internal temperature of 95° and the hot reaction mixture is poured into 2 liters of ice-water, the resulting mixture is stirred for 30 minutes and the precipitate which has separated out is filtered off with suction. 2-Methyl-7-ethoxycarbonylamino-4-oxo-4H- 1-benzothiopyran is thus obtained and after recrystallisation from 70 ml of ethanol this melts at 216°-218°. 15.6 g of this product are refluxed with 28.7 ml of sulfuric acid and 52 ml of acetic acid for 5 hours. The reaction mixture is poured into 500 ml of ice-water and the resulting mixture is neutralised with sodium hydroxide solution. 2-Methyl-7-amino-4-oxo-4H-1-benzothiopyran with a melting point of 165°-169° is obtained and this can be purified via the hydrochloride and then melts at 172°-175°.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][CH:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12]([F:15])([F:14])[F:13])=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12]([F:13])([F:14])[F:15])=[O:9])=[CH:22][CH:23]=1
Reactant: CCCCCCC(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(OC(=O)c1ccc(N)cc1)C(F)(F)F
Reaction time: 8 h

Procedure:
The reaction liquid was poured into water, and extracted with methylene chloride, then, the organic layer was washed with a diluted hydrochloric acid and water in this order. The organic layer thus recovered was distilled under a reduced pressure to remove the solvent, and subjected to purification by a silica gel chromatography (n-hexane:ethyl acetate=10:2) to obtain 1.9 g of 1,1,1-trifluoro-2-octyl p-nitrobenzoate. The ester was dissolved in 30 ml of ethanol, to which 0.19 g of 5 % Pd-C catalyst was added. After the solution was stirred overnight under hydrogen atmosphere, the Pd-C catalyst was separated by filtration, and then the ethanol was distilled off under a reduced pressure to obtain 1.8 g of 1,1,1-trifluoro-2-octyl p-aminobenzoate which was the desired compound of the reaction [1].
Reaction SMILES: [NH2:1][C:2]1[C:18]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:17][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[N:8][C:4]=2[CH:3]=1.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[CH2:22]([N:19]([CH2:20][CH3:21])[C:18]1[C:2]([NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=2)=[CH:3][C:4]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])[NH:6][C:5]=2[CH:17]=1)[CH3:23]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCN(CC)c1cc2[nH]c(-c3ccccc3OC)nc2cc1N
Product: CCN(CC)c1cc2[nH]c(-c3ccccc3OC)nc2cc1NC(=O)c1ccc(Cl)cc1
Yield: 80.2 %

Procedure:
5-Amino-6-diethylamino-2-(2-methoxyphenyl)-1H-benzo[d]-imidazole (187 mg, 0.6 mmol) was reacted with 4-chlorobenzoyl chloride (105 mg, 0.6 mmol) in the same manner as that described above to give the desired product (216 mg, 80% yield) as pale yellow powder: 1H-NMR (300 MHz, CDCl3) δ 0.99 (t, 6H, J=7.2 Hz), 3.05 (q, 4H, J=7.2 Hz), 4.07 (s, 3H), 7.05 (d, 1H, J=8.4 Hz), 7.11 (t, 1H, J=7.8 Hz), 7.41 (t, 1H, J=7.8 Hz), 7.47 (d, 2H, J=8.4 Hz), 7.67 (s, 1H), 7.88 (d, 2H, J=8.4 Hz), 8.55 (d, 1H, J=6.9 Hz), 8.86 (s, 1H); 13C NMR (75 MHz, CDCl3) δ13.1, 50.6, 55.9, 111.5, 117.7, 121.7, 128.3, 129.0, 129.8, 131.1, 132.5, 133.9, 136.0, 137.7, 150.2, 156.7, 163.4; ESI MS m/z 449.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[N:15][CH:16]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:29]=1.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN.CN1CCOCC1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([NH:31][CH3:30])=[O:20])=[N:15][CH:16]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:29]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cn1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.7 %

Procedure:
To a solution of (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylic acid (0.057 g, 0.14 mmol) in DMF (1.406 mL) was added HATU (0.064 g, 0.17 mmol), methylamine hydrochloride (10.45 mg, 0.16 mmol) and NMM (0.077 mL, 0.70 mmol). The resulting mixture was stirred at room temperature for 48 h after which time the reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated in vacuo to afford the crude product which was purified by reverse phase HPLC (acidic condition, 3% TFA in 10-100% CH3CN/H2O) to afford (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)-N-methylacrylamide (30 mg, 0.05 mmol 37% yield). 1H NMR (400 MHz, (CD3)2SO) δ ppm=2.67-2.72 (m, 3 H), 6.77-6.90 (m, 4 H), 7.14-7.23 (m, 2 H), 7.30 (d, J=2.02 Hz, 1 H), 7.36 (d, J=15.16 Hz, 1 H), 7.44-7.51 (m, 3 H), 8.42 (d, J=3.03 Hz, 1 H), LC/MS (m/z, MH+): 419.3.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:13])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:14][C@@H:15]([CH2:19][CH3:20])[C:16](O)=[O:17].C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:6]([O:5][CH2:4][C@H:3]([OH:13])[CH2:2][NH:1][C:16](=[O:17])[C@@H:15]([Cl:14])[CH2:19][CH3:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC[C@@H](O)COCc1ccccc1
Reactant: CC[C@H](Cl)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](Cl)C(=O)NC[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 5.9 %

Procedure:
Preparation of 886355 using modifications to Scheme 7 and Scheme 4: To a stirred solution of (R)-1-amino-3-(benzyloxy)propan-2-ol, Compound 22 in Scheme 7 (8.0 g, 44.1 mmol) in DMF (60 mL) was added (S)-2-chlorobutanoic acid (5.0 g, 40.8 mmol) followed by TEA (10.5 g. 103.8 mmol), DMAP (0.4 g, 3.3 mmol) and finally EDC (9.52 g, 49.7 mmol). The reaction mixture was stirred at rt for 5 d after which time the completed reaction was concentrated to a crude syrup. Purification over silica gel (Biotage, eluting with a gradient of 20-100% EtOAc in heptanes) followed by collection of the desired fractions, concentration and drying in vacuo provided (S)—N—((R)-3-(benzyloxy)-2-hydroxypropyl)-2-chlorobutanamide (683.5 mg, 2.392 mmol, 5.9% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1)=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: C1CSCCN1
Product: O=C(c1ccc2cc(O)ccc2c1)N1CCSCC1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and thiomorpholine (commercially available) according to the procedure described for Example A. MS (m/e): 272.0 (MH−, 100%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=1[NH2:26].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:18])[NH:19][C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[NH2:26])=[CH:13][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cn1c(N)c(NC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (4-tert-butoxycarbonylamino-phenyl)-acetic acid (0.825 mmol) and crude 5,6-diamino-1,3-dimethyl-1H-pyrimidine-2,4-dione (0.75 mmol) in N,N-dimethylformamide (3 mL) under argon at 25° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.825 mmol) and 4-dimethylaminopyridine (0.15 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was triturated with water and the resulting solid collected by filtration, washed well with water and dried in vacuo to afford crude {4-[(6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-methyl]-phenyl}-carbamic acid tert-butyl ester as a light beige solid which was of sufficient purity for subsequent use without additional purification (87%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:27])=[C:5]2[C:9](=[C:10]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=1[CH2:12][CH:13]=[C:14]([CH2:17]O)[CH2:15][CH3:16])[C:8](=[O:26])[O:7][CH2:6]2)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl>[Br:48][CH2:17][C:14]([CH2:15][CH3:16])=[CH:13][CH2:12][C:11]1[C:10]([O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:26])=[C:4]([CH3:27])[C:3]=1[CH2:1][CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
5-Ethyl-6-(3-hydroxymethyl-pent-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (35.4 mg, 0.090 mmol) was dissolved in DCM (3.0 mL). Polymer-bound triphenylphosphine (3 mmol/g, 90.7 mg) was added, and the mixture was mechanically stirred at room temperature. Carbon tetrabromide (90.2 mg, 0.272 mmol) was added and the solution was stirred at room temperature. After 2 hours, the reaction was filtered and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography to provide 32.0 mg (78%) of the desired product. The material was used in the next step without further characterization.
Reaction SMILES: N1(CCN2C=C(C3C=NC=C(C(F)(F)F)C=3)N=C2C2CCN([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])CC2)CCC1.[N:37]1([CH2:41][CH2:42][N:43]2[CH:47]=[C:46]([C:48]3[CH:49]=[CH:50][C:51]([F:57])=[C:52]([CH:56]=3)[C:53]([NH2:55])=[O:54])[N:45]=[C:44]2[CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:40][CH2:39][CH2:38]1>>[NH2:34][C:30]1[N:31]=[CH:32][N:33]=[C:28]([N:61]2[CH2:60][CH2:59][CH:58]([C:44]3[N:43]([CH2:42][CH2:41][N:37]4[CH2:38][CH2:39][CH2:40]4)[CH:47]=[C:46]([C:48]4[CH:49]=[CH:50][C:51]([F:57])=[C:52]([CH:56]=4)[C:53]([NH2:55])=[O:54])[N:45]=3)[CH2:63][CH2:62]2)[C:29]=1[CH2:35][CH3:36]
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Reactant: NC(=O)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(N)=O)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 5-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-fluorobenzamide instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=493, obsd.=493).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.CCN(CC)CC.[C:23](Cl)(=[O:25])[CH3:24].Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:23]([N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:7]=2)[C:10]2([CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[CH2:9]1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Brc1ccc2c(c1)NCC21CCSCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2(CCSCC2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred ice-cooled solution of 6-bromo-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran] (0.7 g, 2.46 mmol), 4-dimethylaminopyridine (0.03 g, 0.25 mmol) and Et3N (0.37 g, 3.69 mmol) in DCM (25 mL) was added acetyl chloride (0.21 mL, 2.96 mmol) via syringe. The resulting mixture was stirred at 0° C. for 5 min and at rt for 1.5 h. After this time the mixture was poured into ice and 2N aqueous HCl and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, saturated aqueous NaHCO3, brine, and dried over anhydrous Na2SO4. Purification by column chromatography (EtOAc:hexanes) gave 1-acetyl-6-bromo-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran] as an off-white solid. Mass Spectrum (ESI) m/e=326.0 [(M+1) (79Br)] and 328.0 [(M+1) (81Br)].
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[O:3]1.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl>[Br:25][C:5]1[C:6](=[O:7])[C:2]([CH3:17])([CH3:1])[O:3][C:4]=1[C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=CC1=O
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=C(Br)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a 0° C. stirred solution of crude 2,2-dimethyl-5-(4-nitrophenyl)furan-3(2H)-one (170 mg, 0.73 mmol, 1 eq) in CHCl3 (10 mL) was added NBS (259 mg, 1.45 mmol, 2 eq), and the reaction mixture was then stirred at RT for 2 h. The chloroform was removed and the crude material was then purified via silica gel column chromatography eluting with 10% EtOAc in hexanes to afford 4-bromo-2,2-dimethyl-5-(4-nitrophenyl)furan-3(2H)-one (100 mg, 44%) as a yellow solid.