Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.FC(F)(F)S(O[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=O)=O.O>C(OCC)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)c1ccc(Br)nc1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a reaction container equipped with a dropping funnel, 21.6 g of 2,5-dibromopyridine and 243 mL of diethyl ether were added. The obtained solution was cooled at −70° C. and then, 55.26 mL of butyl lithium (1.65 M/hexane solution) was added dropwise thereto. The obtained mixture was stirred for 3 hours and 10 minutes and then, a solution obtained by dissolving 20.96 mL of tert-butyldimethylsilyl trifluoromethanesulfonate in 16.7 mL of diethyl ether was added dropwise thereto. The obtained mixture was stirred for 17 hours and 55 minutes and then, 162 mL of water was added dropwise thereto at 0° C. The obtained mixture was stirred at room temperature for 30 minutes and then, 81 mL of ethyl acetate was added thereto. The obtained solution was extracted three times with 81 mL of ethyl acetate. The obtained organic layers were mixed and dried with magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated to obtain a crude product. The crude product was purified with silica gel column chromatography followed by further recrystallization with hexane to obtain 2.57 g of 2-bromo-5-tert-butyldimethylsilylpyridine. Purity: 98% (area percentage value obtained by gas chromatography analysis).
Reaction SMILES: [C:1]([C:8]1[N:9]=[C:10]([C:15](=O)[NH2:16])[S:11][C:12]=1[CH2:13][NH2:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O>[C:1]([C:8]1[N:9]=[C:10]([C:15]#[N:16])[S:11][C:12]=1[CH2:13][NH2:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)c1nc(C(N)=O)sc1CN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1nc(C#N)sc1CN
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.95 g (19.24 mmol) of 4-Boc-aminomethyl-2-carbamoylthiazole were introduced into 90 ml of methylene chloride and 16.7 ml (97.44 mmol) of diisopropylethylamine, the mixture was cooled to 0° C., a solution of 6.35 ml of trifluoroacetic anhydride in 10 ml of methylene chloride was added dropwise at 0 to 5° C., and the mixture was subsequently warmed to room temperature (TLC check). Then, 25 ml of water were added, the mixture was stirred for 30 minutes at room temperature and brought to pH 2.5 with 10% strength citric acid solution, and the organic phase was washed repeatedly, dried using magnesium sulfate and concentrated in vacuo. 5.4 g of viscous, pale brown crude product resulted, which were employed in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH:8]1([CH2:14][CH:15]([OH:18])[CH:16]=[CH2:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOCC>[CH:8]1([CH2:14][CH:15]([O:18][C:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4])[CH:16]=[CH2:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)CC(=O)Cl
Reactant: C=CC(O)CC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: C=CC(CC1CCCCC1)OC(=O)CC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.4 ml (19.5 mmol) of isovaleric acid chloride are added dropwise at 0° C. to a solution of 2.75 g (17.76 mmol) of 1-cyclohexyl-3-buten-2-ol, 3 ml (21.3 mmol) of triethylamine and 430 mg (3.5 mmol) of 4-dimethylaminopyridine in 20 ml of methylene chloride. When the addition is complete, the mixture is stirred for a further 3 hours at room temperature. After diluting with ether, the mixture is washed twice with 2N HCl, twice with saturated NaHCO3 solution and twice with brine and dried over MgSO4. After concentration by evaporation, the residue is distilled in a bulb tube at 150°/0.007 mbar.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: FC(F)(F)c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)=[CH:26][CH:25]=1>>[O:36]=[C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:37])([F:22])[F:38])=[CH:25][CH:26]=2)[CH:35]=[CH:34][N:33]1[C:2]1[CH:21]=[CH:20][C:5]2[N:6]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3cc(Br)ccc32)C1
Product: CC(C)(C)OC(=O)N1CCn2c(nc3cc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)ccc32)C1
Yield: 6.9 %

Procedure:
tert-Butyl 8-bromo-3,4-dihydropyrazino[1,2-a]benzimidazole-2(1H)-carboxylate (150 mg, 0.426 mmol) and 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (112 mg, 0.469 mmol) were reacted according to Example 18 (step g) to provide the title compound (15 mg, 7%) as a white solid: ESI MS m/z 511 [M+H]+.
Reaction SMILES: Br[CH:2]([CH:8](Br)[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:19][CH3:20])[CH:10]=1)[C:3]([O:5]CC)=[O:4].[OH-].[K+]>>[CH3:20][O:19][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH:17]=[CH:18][C:9]([C:8]#[C:2][C:3]([OH:5])=[O:4])=[CH:10]2
Reactant: CCOC(=O)C(Br)C(Br)c1ccc2c(OC)cccc2c1
Agent: [K+]
Agent: [OH-]
Product: COc1cccc2cc(C#CC(=O)O)ccc12

Procedure:
Powdered ethyl α,β-dibromo-β-(5-methoxynaphth-2-yl)propionate (27.4 g) is added portion-wise to 20% ethanolic potassium hydroxide (135 ml) at room temperature. The mixture is refluxed on a steam bath for 6 hours. The alcohol is evaporated and the residue is dissolved in water and covered with ether and is acidified with cold, dilute hydrochloric acid. The ether layer is washed with water, saline, and dried over sodium sulfate. The ether is removed to give a residue which is triturated with carbon tetrachloride. Recrystallization is carried out from acetic acid-water. This material is digested and triturated with boiling carbon tetrachloride to give 5-methoxynaphth-2-yl propiolic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>O1CCCC1>[C:16]1([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13](=[O:14])[CH2:12][NH:11][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:10])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCC(=O)N(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
3-Methylphenyl isocyanate (0.59 g) is added at a temperature in the region of 25° C. to a solution of 2-amino-N,N-diphenylacetamide (1 g) in anhydrous tetrahydrofuran (20 cc). The suspension obtained is stirred for 4 hours at a temperature in the region of 25° C. and the insoluble product is separated by filtration. After recrystallization in acetonitrile, N,N-diphenyl-2-[3-(3-methylphenyl)ureido]acetamide (0.8 g), m.p. 240° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][C:12]#[N:13])[C:9]=1[Cl:10])=[O:4]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][CH2:12][NH2:13])[C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1scc(CC#N)c1Cl
Solvent: C1CCOC1
Product: COC(=O)c1scc(CCN)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Methoxycarbonyl-3-chloro-4-cyanomethylthiophene (2 g, 9.27 mmol) was dissolved in THF (100 mL) and BH3 -THF (18.6 mL of a 1 M solution in THF, 18.6 mmol) was added. After stirring for 16 hours at ambient temperature, the reaction was quenched with water followed by 1 M NaOH. Potassium carbonate was added to afford two layers. The organic layer was separated and concentrated in vacuo to afford 2-methoxycarbonyl-3-chloro-4-(2-aminoethyl)thiophene.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[OH:19][NH3+:20]>N1C=CC=CC=1>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[N:20][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2CCC1c1ccccc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Product: ON=C1c2ccccc2CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
A mixture of 2-phenyl-1-tetralone (1.1 g, 5 mmol, J. Am. Chem. Soc. 1949, 71, 1092), hydroxylammonium chloride (0.7 g, 10 mmol) and dry pyridine (30 ml) was heated at reflux for 4 h and then stirred at ambient temperature overnight. The solvent was evaporated in vacuo and the residue was stirred in a mixture of ethyl acetate (50 ml) and 10% citric acid (50 ml). The phases were separated and the organic phase was washed with water and dried (MgSO4). The solvent was evaporated in vacuo to give 1.2 g of 2-phenyl-1-tetralone oxime as a solid. M.p. 156°-157° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:1][CH2:2][CH2:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cn1cccc1CCN
Product: Cn1cccc1CCNS(=O)(=O)c1ccc(F)cc1

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrol and p-fluorobenzenesulphonylchloride analogously to Example A.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:30])[C:11]2[C:16]([C:17](=[O:27])[C:18]=1[O:19]CC1C=CC=CC=1)=[C:15]([C:28]#[N:29])[CH:14]=[CH:13][CH:12]=2)C1C=CC=CC=1.B(Cl)(Cl)Cl>>[OH:8][C:9]1[C:10](=[O:30])[C:11]2[C:16]([C:17](=[O:27])[C:18]=1[OH:19])=[C:15]([C:28]#[N:29])[CH:14]=[CH:13][CH:12]=2
Reactant: N#Cc1cccc2c1C(=O)C(OCc1ccccc1)=C(OCc1ccccc1)C2=O
Agent: ClB(Cl)Cl
Product: N#Cc1cccc2c1C(=O)C(O)=C(O)C2=O

Procedure:
Treatment of 2,3-dibenzyloxy-5-cyano-1,4-naphthoquinone with boron trichloride as in Preparation 15 above gives 2,3-dihydroxy-5-cyano-1,4-naphthoquinone, mp 305°-312°.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]1)[CH2:7][CH2:6]2.[CH3:21][O:22]C1C=C2C(C=CN2)=CC=1>>[CH3:21][O:22][C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: COc1ccc2c(c1)CCN2CCCn1cc(N)cn1
Product: COc1ccc2c(c1)N(CCCn1cc(N)cn1)CC2

Procedure:
The title compound was synthesized according to above mentioned procedure for 1-[3-(5-methoxy-2,3-dihydro-indol-1-yl)-propyl]-1H-pyrazol-4-ylamine, starting form 6-methoxyindole. LC-MS conditions B: tR=0.46 min, [M+H]+=273.23.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17](=[O:29])[CH2:18][CH:19]1[C:23]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=2[O:21][CH2:20]1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:26]3[CH:25]=[CH:24][C:23]4[CH:19]([CH2:18][C:17]([OH:29])=[O:16])[CH2:20][O:21][C:22]=4[CH:27]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)CC1COc2cc(O)ccc21
Reactant: ClCc1cccnc1SC1CCCC1
Product: O=C(O)CC1COc2cc(OCc3cccnc3SC3CCCC3)ccc21
Yield: 70.5 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.21 g, 0.92 mmol) obtained in Step C of Preparation Example 8 and (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (0.19 g, 0.92 mmol) obtained in Preparation Example 52 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.25 g, 70%).
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19]CC)=[O:18])[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:38]>O1CCOCC1.O>[ClH:38].[NH2:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([OH:19])=[O:18])[CH2:11][CH2:10]1
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NC(C)(C)C
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A solution of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (324b) (1.1 g, 2.16 mmol) in 8 mL of dioxane and 8 mL of water was added LiOH monohydrate (0.45 g, 10.83 mmol) and heated in an oil bath at 110° C. for 18 h. It was concentrated under reduced pressure to half of its volume. The remaining mixture was lyophilized for 24 h to give a yellow solid. m/z (ESI, +ve) 480.2 (M+H)+. To the yellow solid suspended in 5 mL of dioxane at 0° C. was treated with 10 mL of 4 N HCl in dioxane. The resulting orange mixture was stirred at RT for 3 h. The mixture was concentrated to half of its volume. The insoluble solid was filtered, rinsed with 2×5 mL of ether. The filtrate was discarded. The orange solid was dried in a vacuum oven at 40° C. for 1 h to give 2-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (324c), which was used as crude material and based on theoretical yield. m/z (ESI, +ve) 380.2 (M+H)+. A suspension of the above obtained 2-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (324c) in 12 mL of DMF and 12 mL of DCM was treated with DIEA (2.25 mL, 12.93 mmol) followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.40 g, 2.70 mmol). The resulting homogeneous solution was stirred at RT for 2 h. It was diluted with 200 mL of DCM, washed sequentially with 25 mL of water, 25 mL of 1 N NaOH and 25 mL of brine. The organic solution was concentrated and the residue was purified on a silica gel column (50% EtOAc in hexanes followed by 1-3% MeOH in EtOAc) to give 2′-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (324) (540 mg, 1.494 mmol, 69% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.64 (1H, br.), 7.78 (1H, d, J=6.5 Hz), 7.67 (1H, s), 7.60 (1H, m), 7.35 (1H, t, J=7.8 Hz), 6.90 (1H, m), 6.00 (1H, s), 2.56 (3H, s), 1.52 (9H, s), 1.42 (2H, m), 1.33 (2H, m). m/z (ESI, +ve) 362.1 (M+H)+.
Reaction SMILES: [N:1]1([C:15]([O:17][CH2:18][CH:19]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])CC[CH:6]([C:9]2[CH:14]=[CH:13]C=CC=2)[C@H:2]1C(O)=O.C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C.CO>C(Cl)Cl>[C:15]([N:1]1[CH2:13][CH2:14][CH2:9][CH2:6][CH2:2]1)([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16]
Reactant: O=C(O)[C@@H]1C(c2ccccc2)CCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCCC1
Reaction time: 0.17 h

Procedure:
A solution of 7.4 g Fmoc-βPhPro-OH in 120 ml dry DCM was added to 12.0 g 2-chlorotrityl chloride resin (0.83 mmol/g, Novabiochem). DIPEA (3.0 ml) was added and the mixture was shaken for 10 min. Additional 4.5 ml DIPEA were added and shaking was continued for 145 min. Methanol (10 ml) was added the mixture was shaken for another 25 min. The resin was filtered off, washed with DCM (5×100 ml), methanol (2×100 ml) and DCM (4×100 ml). A small sample was dried carefully and deprotected with DCM/piperidine (1:1) for 30 min. Photometric determination of the resulting Fmoc-piperidine adduct (absorption at 301 nm) gave a resin loading of 0.54 mmol/g. The remaining resin was treated with 100 ml DCM and 80 ml piperidine at r.t. for 160 min, washed with DCM (10×100 ml) and diethyl ether (4×80 ml) and dried in vacuo to give 14.37 g HβPhPro-2-chlorotrityl resin.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C:9]2[N:13]([C@@H:14]3[CH2:19][CH2:18][C@H:17]([C:20]([O:22]C)=[O:21])[CH2:16][CH2:15]3)[C:12]3[CH:24]=[C:25]([CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:26]=[CH:27][C:11]=3[N:10]=2)=[O:7])=[CH:4][CH:3]=1.CO.[OH-].[Na+].[ClH:41]>CCOCC>[ClH:41].[F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C:9]2[N:13]([C@@H:14]3[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]3)[C:12]3[CH:24]=[C:25]([CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:26]=[CH:27][C:11]=3[N:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccc(F)cc3)nc3ccc(CN4CCCCC4)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: O=C(Nc1nc2ccc(CN3CCCCC3)cc2n1[C@H]1CC[C@@H](C(=O)O)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask under nitrogen atmosphere was charged with cis-methyl 4-(2-(4-fluorobenzamido)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (0.10 g, 0.203 mmol), MeOH (2.90 mL) and 1N aqueous NaOH (3.05 mL, 3.05 mmol) and stirred at RT overnight. The reaction mixture was adjusted to a pH of approximately 2 by treatment with 6N HCl and was extracted with DCM (3×50 mL). The organic layers were combined, dried over sodium sulfate and concentrated under vacuum to afford an off-white solid. Trituration with ether afforded cis-4-(2-(4-fluorobenzamido)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid hydrochloride as a white solid (0.095 g, 91% yield). MS m/z=479.2 [M+H]. Calc'd for C27H31N4O3: 478.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]([CH2:11][S:12][C:13](=O)[CH3:14])=[CH:8][C:6]=2[N:7]=1.C[O-].[Na+].[CH3:25][O:26][CH2:27]CCOS(C1C=CC(C)=CC=1)(=O)=O>CO>[CH3:25][O:26][CH2:27][CH2:14][CH2:13][S:12][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:3][C:2]([CH3:1])=[N:7][C:6]=2[CH:8]=1
Reactant: CC(=O)SCc1cc2nc(C)nc(N3CCOCC3)c2s1
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCCSCc1cc2nc(C)nc(N3CCOCC3)c2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a solution of thioacetic acid S-(2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl) ester (200 mg) in methanol (10 mL) at 0° C. was added a solution of sodium methoxide (35 mg) in methanol (2 mL). The reaction mixture was stirred at 0° C. for 30 min and then a solution of toluene-4-sulfonic acid 3-methoxy-propyl ester (156 mg) in methanol (3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 h and then quenched with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4), concentrated and purified using column chromatography to give 6-(3-methoxy-propylsulfanylmethyl)-2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a white solid (170 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][N:13]1[C:17]([C:18]#[N:19])=[CH:16][CH:15]=[C:14]1B(O)O.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CCCCCC.C(OC(=O)C)C.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.[Pd].[Pd].C1COCC1>[C:18]([C:17]1[N:13]([CH3:12])[C:14]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[C:4]([CH3:11])[CH:3]=2)=[CH:15][CH:16]=1)#[N:19]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: Cc1cc(Br)ccc1NC#N
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C#N)n2C)ccc1NC#N
Yield: 7.9 %

Procedure:
(4-bromo-2-methylphenyl)cyanamide (0.698 g, 3.34 mmol), tris(dibenzylideneacetone)dipalladium (76 mg, 0.083 mmol), N-methyl-5-cyanopyrroleboronic acid (1.1 g, 7.3 mmol), and potassium fluoride (0.776 g, 13.2 mmol) were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous flow of nitrogen and THF (10 mL) was added with stirring. Then tri-tert-butylphoshine (10 wt % in hexane) (0.486 mL, 0.083 mmol) was added to the mixture and allowed to stir 3 hours. The mixture was then diluted with 1/1 hexane/ethylacetate and filtered through a plug of silica gel, the reaction was concentrated and the residue was flash chromatographed using 4/1 Hexane/THF to give (0.062 g, 7%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([CH2:18][OH:19])=[CH:16][C:15]([C:20]([OH:22])=O)=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C:31]2=[O:36])=[CH:26][CH:25]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[O:36]=[C:31]1[CH2:32][O:33][CH2:34][CH2:35][N:30]1[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:20]([C:15]2[CH:16]=[C:17]([CH2:18][OH:19])[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[N:14]=2)=[O:22])=[CH:29][CH:28]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C(O)c1cc(CO)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)c1cc(CO)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reaction time: 16 h

Procedure:
To 100 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-hydroxymethyl-1H-pyrazole-3-carboxylic acid in 2 ml DCM and 0.1 ml NEt3, 67 mg 4-(4-Amino-phenyl)-morpholin-3-one and 74 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. The mixture was concentrated under reduced pressure and triturated in a mixture of water/DMF. The precipitate was collected by filtration and washed with water containing 0.5% TFA. The product was obtained as a white solid which was dried under reduced pressure.