Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:10]([C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:17]=3)=[CH:11][NH:12][C:13]=2[CH3:14])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(O)CO.COC>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:16]2[C:15](=[O:25])[C:10]3=[CH:11][NH:12][C:13]([CH3:14])=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:7]=[CH:6][CH:5]=4)[C:9]3=[N:17]2)=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(N)c1
Agent: COC
Solvent: OCCO
Solvent: c1ccncc1
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(NS(C)(=O)=O)c1
Yield: 91.5 %

Procedure:
To a stirred solution of 7-(3-aminophenyl)-2-(4-chlorophenyl)-2,5-dihydro-6-methylpyrazolo[4,3-c]pyridin-3-one (0.100 g, 0.285 mmol) in anhydrous ethylene glycol, dimethyl ether (5 ml) was added portionwise, over a few hours, pyridine (0.228 ml, 2.82 mmol) and methanesulphonyl chloride (0.174 ml, 2.25 mmol), and the mixture was heated at 50° C. for 1.5 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 5-10% MeOH/CH2Cl2) to leave 0.1119 g (92%) of the title compound as a yellow solid; mp 332-341° C. (CH2Cl2-MeOH-EtOAc); 1H NMR (360 MHz, DMSO-d6) δ2.28 (3H, s), 3.06 (3H, s), 7.24 (2H, dd, J 7.9, J′1.8 Hz), 7.40 (1H, m), 7.43 (2H, d, J 9.0 Hz), 7.46 (1H, t, J 8.0 Hz), 8.13 (2H, d, J 9.0 Hz), 8.56 (1H, s); MS (ES+) m/z 429/431[MH]+. Anal. found: C, 55.89; H, 4.06; N, 12.60. C20H17CLN4O3S.0.2H2O requires: C, 55.54; H, 4.06; N, 12.95%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:54])[C:34]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41](B4OC(C)(C)C(C)(C)O4)[CH:40]=3)=[CH:35][NH:36]2)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[C:25]([C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:54])[C:34]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:2]4[CH:3]=[C:4]([NH:10][C:11]5[CH:16]=[CH:15][C:14]([C:17]([N:19]6[CH2:24][CH2:23][O:22][CH2:21][CH2:20]6)=[O:18])=[CH:13][N:12]=5)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=4)[CH:40]=3)=[CH:35][NH:36]2)=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(C)(C)c1ccc2c(=O)c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)c[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2cccc(-c3c[nH]c4cc(C(C)(C)C)ccc4c3=O)c2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 17 %

Procedure:
A solution of 5-Bromo-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (19 mg, 0.050 mmol), 7-tert-Butyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-quinolin-4-one (20 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium(0) (6.0 mg, 0.0052 mmol), and sodium carbonate (16 mg, 0.15 mmol) in 2 mL 1,2-dimethoxyethane and 1 mL water was microwaved at 170° C. for 12.5 minutes. The resulting mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by preparative TLC (5% methanol/dichloromethane) to yield 7-tert-Butyl-3-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1H-quinolin-4-one (5.7 mg, 0.0085 mmol). MS (ESI) 590.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CN1CCOCC1.[Cl:26][C:27]1[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1>C(#N)C>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:32]([C:30]2[S:31][C:27]([Cl:26])=[CH:28][CH:29]=2)=[O:33])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:18]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
N-Boc-cis-4-Amino-L-proline methylester hydrochlorid (5 g) was dissolved in acetonitrile (25 ml) and suspended with NMM (1.2 g) for 15 min at 25° C. (Suspension A). 5-Chlorothiophene-2-carboxylic acid (5.184 g) was dissolved in acetonitrile (25 ml), NMM (2.4 g) and IBCF (4.865 g) were added to the solution. This solution was stirred for 30 min at 25° C. and then added to the above mentioned suspension A. The whole mixture was stirred for 24 h at 25° C. The mixture was then evaporated to dryness and purified by chromatography (silica gel; gradient: CH2Cl2->methanol 2N NH3) to yield (2S,4S)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.5 g) as a light yellow gum. MH+=289.1 (Cl-isotopes, loss of Boc-group).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1.C(O)(=O)C1C=CC=CC=1>ClC1C=CC(Cl)=CC=1Cl.CCCCCC>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Agent: O=C(O)c1ccccc1
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: CCCCCC
Product: Brc1cn2cncc2s1
Temperature: 180 °C
Reaction time: 24 h
Yield: 49.2 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (32 mg, 0.13 mmol) and benzoic acid (16 mg, 0.13 mmol) dissolved in 1,2,4-trichlorobenzene (1 ml) was stirred at 180° C. for 24 hr. The reaction solution was allowed to cool to room temperature, was diluted with hexane, and was extracted with 2 M hydrochloric acid (3 ml×3). The aqueous layer was neutralized with a 2 M aqueous solution of sodium hydroxide and was extracted with ethyl acetate (5 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under the reduced pressure, and the residue was thoroughly dried to give 2-bromoimidazo[5,1-b]thiazole (13 mg, 49%) as a white solid.
Reaction SMILES: [I-].C[N+]1C=CN([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])C=1.C(NC(C)C)(C)C.[CH2:34]([NH:41][CH2:42][CH3:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[CH2:34]([N:41]([CH2:42][CH3:43])[C:8](/[N:10]=[C:11]1\[S:12][C:13]([CH3:26])=[CH:14][N:15]\1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=1)=[O:9])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: CCNCc1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: CCN(Cc1ccccc1)C(=O)/N=c1\sc(C)cn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (45 mg, 0.09 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) was added followed by the addition of diisopropylamine (21 μL, 0.12 mmol) dissolved in acetonitrile (0.6 mL). Then to the solution was added N-benzylethanamine (14 mg, 0.1 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:11][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9]
Reactant: BrCCOCCBr
Reactant: CC(=O)c1cc(N)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(N2CCOCC2)ccc1F
Yield: 73.3 %

Procedure:
A mixture of 1-(5-amino-2-fluoro-phenyl)-ethanone (3.5 g), bromoethyl ether (5.929 g), and i-Pr2NEt (7.121 g) in toluene (20 mL) was refluxed for 16 hours. After cooling, the reaction mixture was quenched with water. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (25% ethyl acetate in hexane) to give 3.74 g of the title compound as an oil.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[C:4]2[CH:3]=[CH:2]1.C([Li])(C)(C)C.[I:18]I.C(Cl)Cl.CO>C(OCC)C>[I:18][C:2]1[O:1][C:5]2[C:4](=[C:9]([C:10]([OH:12])=[O:11])[CH:8]=[CH:7][CH:6]=2)[CH:3]=1
Reactant: O=C(O)c1cccc2occc12
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1cccc2oc(I)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To a cold (−78° C.) solution of benzofuran-4-carboxylic acid (100 mg) in dry diethyl ether (1.2 mL), was added dropwise tert-butyl lithium (1.7 M in pentane, 0.8 mL, 2.2 eq). The reaction mixture was stirred at −78° C. for 30 min. under nitrogen, then a solution of iodine (172.2 mg, 1.2 eq) in ether (1.9 mL) was added dropwise. The reaction was stirred at −78° C. for 30 min. and allowed to warm to rt. The reaction mixture was partitioned between sat. NH4Cl and diethyl ether, the aqueous phase was extracted once again with diethyl ether. The combined organic extracts were washed with sat. sodium thiosulfate, water, dried (Na2SO4), filtered and concentrated to yield a crude brown solid. FC (DCM/MeOH: 99/1 to 97/3) afforded the title compound as a pink solid (40 mg, 23%). LC-MS: tR=0.89 min; [m+H]+=288.99. b) 2-Iodo-benzofuran-4-carboxylic acid [3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-thiazolidin-4-ylmethyl]-amide A solution of 2-iodo-benzofuran-4-carboxylic acid (29.5 mg), TBTU (34 mg 1 eq), DIPEA (0.087 mL, 5 eq) in dry DMF (0.325 mL) was stirred at rt for 15 min. Then, was added (4-Aminomethyl-thiazolidin-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone (34 mg, 1.0 eq.) in dry DMF (0.325 mL). Stirring was continued over night. The reaction mixture was partitioned between sat. aq. NaHCO3 solution/EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to give 2-iodo-benzofuran-4-carboxylic acid [3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-thiazolidin-4-ylmethyl]-amide (57 mg, 93%) which was used for the next step without further purification. LC-MS: tR=0.89 min; [m+H]+=288.99. c) 2-Trifluoromethyl-benzofuran-4-carboxylic acid [3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-thiazolidin-4-ylmethyl]-amide
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.Cl[Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:40][C:37]([Si:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5]2)([CH3:38])[CH3:39]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cccc2cc(O)ccc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-hydroxy-1-naphthalenecarboxylic acid, methyl ester (1.01 g, 5 mmol), triethylamine (1.55 mL, 6 mmol) and N,N-dimethyl-4-pyridineamine (0.30 g, 2.5 mmol) in CH2Cl2 (25 mL) is treated with a solution of chloro(1,1-dimethylethyl)diphenylsilane (1.55 mL, 6 mmol) in CH2Cl2 (10 mL) and stirred at room temperature overnight. The mixture is washed with saturated aqueous NaHCO3, dried (Na2SO4) and solvent is evaporated off under reduced pressure to give a residue, which is purified by column chromatography (SiO2; hexane/CH2Cl2 1:1) to afford the title compound as an oil.
Reaction SMILES: [ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=2)[C:16]([C:31]([OH:33])=[O:32])=[C:15]3[CH2:34][N:35]([CH2:37][C:38]([O:40]CC)=[O:39])[CH3:36])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]>O1CCOCC1>[Cl-:1].[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=2)[C:16]([C:31]([OH:33])=[O:32])=[C:15]3[CH2:34][NH+:35]([CH2:37][C:38]([OH:40])=[O:39])[CH3:36])=[CH:10][CH:11]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: CCOC(=O)CN(C)Cc1c(C(=O)O)n(-c2ccc(OC(C)C)cc2)c2ccc(-c3ccc(C(C)(C)C)cc3)cc12
Reactant: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-n2c(C(=O)O)c(C[NH+](C)CC(=O)O)c3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1
Product: [Cl-]

Procedure:
An excess of HCl (4 M in dioxane) was added to a suspension of 5-(4-tert-butylphenyl)-3-[(ethoxycarbonylmethylmethyl-amino)methyl]-1-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (189 mg, 0.35 mmol; see step (e) above) in dioxane (4 mL). After 10 min the mixture was concentrated and the residue treated with Et2O and filtered to give the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[(2-methoxy-2-oxoethyl)(methyl)amino]carbonyl)-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 38) (315 mg, 0.70 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene. The residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium citrate and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as an oil (273 mg)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:21])[NH:8][CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)=[C:5]([C:22]([O:24]CC)=[O:23])[CH:4]=[N:3]1.[Li+].[OH-].Cl>C1COCC1.C(O)C>[CH3:1][N:2]1[C:6]([C:7](=[O:21])[NH:8][CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)=[C:5]([C:22]([OH:24])=[O:23])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)NCCc1nc2ccccc2n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ncc(C(=O)O)c1C(=O)NCCc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a solution of ethyl 1-methyl-5-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethylcarbamoyl)-1H-pyrazole-4-carboxylate (76 mg, 214 μmol) in THF (0.9 mL) and ethanol (0.3 mL) was added LiOH (1M aqueous solution, 428 μL, 428 μmol) at 0-5° C. The mixture was stirred at RT for 2 h. HCl (1M aqueous solution, 0.43 mL, 0.43 mmol) was added and the precipitating product was filtered, washed with THF/water 4:1 and dried in vacuo to give the product as colorless solid (52 mg, 159 μmol, 74.3%).
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][C:41]([NH2:43])=[S:42])[CH2:4][CH2:3]2.C(N(CC)C(C)C)(C)C.Br[CH:54]([CH3:58])[C:55](=O)[CH3:56].O>CN(C=O)C>[CH3:58][C:54]1[N:43]=[C:41]([NH:40][C@:5]23[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]2[C@@H:7]2[C@@:2]([CH3:1])([CH2:3][CH2:4]3)[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[S:42][C:55]=1[CH3:56]
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(N)=S)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(=O)C(C)Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(Nc3nc(C)c(C)s3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-thioureido-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (150 mg, 0.249 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (0.173 mL, 0.995 mmol) and 3-bromobutan-2-one (56.4 mg, 0.373 mmol). The reaction mixture was stirred at rt. After 18 h, the reaction mixture was poured into a separatory funnel containing H2O (10 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to white solid. The material was redissolved in DCM (5 mL) and MeOH was added to effect precipitation. The mixture was concentrated to remove most of DCM and the resulting white precipitate was filtered, washed with cold MeOH, and dried in a vacuum oven to give methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4,5-dimethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (121 mg, 0.175 mmol, 70.5% yield) as a white solid. LCMS: m/e 655.3 (M+H)+, 2.72 min (method 2). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.95 (d, J=8.2 Hz, 2H), 7.21 (d, J=8.2 Hz, 2H), 5.31 (d, J=4.6 Hz, 1H), 4.76 (br. s., 1H), 4.65 (s, 1H), 3.93 (s, 3H), 2.43 (d, J=10.4 Hz, 1H), 2.21 (s, 3H), 2.15 (s, 3H), 2.11 (d, J=6.7 Hz, 1H), 2.07-1.96 (m, 1H), 1.80-1.65 (m, 6H), 1.57-1.36 (m, 8H), 1.35-1.27 (m, 2H), 1.23 (d, J=10.1 Hz, 1H), 1.17-1.11 (m, 1H), 1.09 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H), 0.94 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:6]=[CH:7][CH:8]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:19]>CO.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:19])=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCCCCCC(=O)O)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCc1cccc(OC)c1
Temperature: 0 °C

Procedure:
An anhydrous solution of methanol:toluene (2:5) (10.5 mL) was used to solubilize 7-(3-methoxyphenyl)heptanoic acid (0.159 g, 0.673 mmol) under an atmosphere of argon and the solution was then cooled to 0° C. Stirring was initiated and a 2 M solution of TMSCHN2 (in hexanes) (0.740 mL, 1.48 mmol) was added dropwise to the reaction solution. The yellow solution was allowed to stir for 30 minutes at room temperature before again being cooled to 0° C. The reaction was quenched with the dropwise addition of acetic acid until the characteristic yellow color of diazomethane dissipated. The solvent was removed under vacuum and the resultant suspension taken in ethyl acetate. The organic phase was washed with saturated sodium bicarbonate then brine and dried over sodium sulfate. The solvent was removed under vacuum and the target product was purified as a light yellow oil (92%, 0.139 g) using flash column chromatography (silica) with a 10% ethyl acetate:hexanes mobile phase: 1H NMR (500 MHz, CDCl3) δ 7.19 (t, 1H), 6.74 (q, 3H), 3.80 (s, 3H), 3.67 (s, 3H), 2.59 (t, 2H), 2.31 (t, 2H), 1.63 (m, 4H), 1.36 (m, 4H); 13C NMR (500 MHz, CDCl3) δ 174.17, 159.60, 144.31, 129.17, 120.82, 114.17, 110.86, 55.06, 51.41, 35.93, 34.05, 31.17, 29.01, 28.91, 24.89.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.CC[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1CCCCC1.C1(O)CCCC1>[C:10]1([CH3:20])[CH:11]=[CH:12][C:13]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[CH:23]1([O:8][C:7](=[O:9])[C@@H:2]([NH2:1])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCCCCCC
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OC1CCCC1
Solvent: C1CCCCC1
Product: CC(C)C[C@H](N)C(=O)OC1CCCC1
Yield: 85 %

Procedure:
To a suspension of (S)-leucine (15 g, 0.11 mol) in cyclohexane (400 ml) was added cyclopentanol (103.78 ml, 1.14 mmol) and p-toluene sulfonic acid (23.93 g, 0.13 mol). The suspension was heated at reflux to effect solvation. After refluxing the solution for 16 hours it was cooled to give a white suspension. Heptane (500 ml) was added to the mixture and the suspension was filtered to give the product as a white solid (35 g, 85% yield). 1H NMR (300 MHz, MeOD), δ: 1.01 (6H, t, CH3×2, J=5.8 Hz), 1.54-2.03 (11H, m, 11×CH), 2.39 (3H, s, CH3), 3.96 (1H, t, CH, J=6.5 Hz), 5.26-5.36 (1H, m, CH), 7.25 (2H, d, ArH×2, J=7.9 Hz), 7.72 (2H, d, ArH×2, J=8.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:10]([NH:17][C:18]3[CH:19]=[C:20]([NH:25]C(=O)OC(C)(C)C)[C:21]([Cl:24])=[N:22][CH:23]=3)=[N:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=2)[N:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:10]([NH:17][C:18]3[CH:19]=[C:20]([NH2:25])[C:21]([Cl:24])=[N:22][CH:23]=3)=[N:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=2)[N:3]=1
Reactant: COc1cnc(Nc2cnc(Cl)c(NC(=O)OC(C)(C)C)c2)c(-c2nc(C)nc(N)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc(Nc2cnc(Cl)c(N)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a 20 mL scintillation vial which contained tert-butyl 5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-methoxypyridin-2-ylamino)-2-chloropyridin-3-ylcarbamate (0.210 g, 0.458 mmol) in DCM (5 mL) was added trifluoroacetic acid (Aldrich) (0.170 mL, 2.288 mmol). The resulting mixture was capped and stirred at rt in closed system for 1 h. The reaction mixture was first neutralized with sat. NaHCO3 then extracted with CHCl3 (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified using the column chromatography (40 g, 3% to 5% MeOH in DCM) to afford the desired product as a yellow solid (135 mg). MS (ESI pos. ion) m/z: 359.0. Calc'd exact mass for C15H15Cl N8O: 358.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H) 3.84 (s, 3H) 5.43 (s, 2H) 7.78 (br. s., 1H) 7.86 (br. s., 1H) 7.89 (d, J=2.35 Hz, 1H) 7.94 (d, J=2.15Hz, 1H) 8.16 (d, J=3.13 Hz, 1H) 8.40 (d, J=3.13 Hz, 1H) 11.75 (s, 1H).