Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][C:9]([CH3:16])([CH3:15])[CH2:8][C:7]=2[N:6]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:15][C:9]1([CH3:16])[CH2:8][C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc2c(n1)CC(C)(C)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCc2ccc(C(=O)O)nc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
7,7-Dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid methyl ester (1.88 g, 8.57 mmol) was dissolved in THF (30 mL) and water (10 mL). Lithium hydroxide monohydrate (616 mg, 25.7 mmol) was added with stirring at room temperature and the reaction mixture was stirred at reflux temperature for 1 h. The mixture was cooled, acidified with 2 N HCl to pH=5 and extracted with ethyl acetate. The organic phases were combined, dried with Na2SO4, and concentrated in vacuo. The residue was stirred with ethyl acetate (5 mL) at 40° C.; n-heptane (10 mL) was added and stirring at room temperature continued for 30 min. The precipitate was filtered and dried to give 1.7 g (96%) of the title compound as white solid; MS (ISP): m/e 206.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](O)=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21].C1C=[C:26]2[N:28]=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:28][CH3:26])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1c(-c2ccc(F)cc2)oc2ccc(O)c(F)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)c(F)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-fluoro-2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylic acid (73 mg, 0.252 mmol), methylamine, HCl (25.5 mg, 0.377 mmol), HOBT hydrate (65.5 mg, 0.428 mmol) and EDC hydrochloride (87 mg, 0.453 mmol) at r.t. under N2 was added N,N-diisopropylethylamine (0.220 mL, 1.258 mmol). The mixture was stirred at r.t. for 16 hours. After concentration, the mixture was added with 5 ml 1N HCl, and then 14 ml H2O. The white solid was filtered and washed with 3×5 ml H2O and dried (64 mg). 1H NMR (500 MHz, CD3OD) δ 7.89 (dd, J=8.09, 5.34, 2H), 7.25 (t overlapping with dd, 2H), 7.23 (dd, 1H), 6.99 (t, J=8.55, 1H), 2.96 (s, 3H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH—90% H2O—0.1% TFA, Solvent B=90% MeOH—10% H2O—0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=304.06, HPLC Rt=1.262 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:14].[OH-:15].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:14][C:6]([CH3:7])([CH3:5])[C:9]([OH:13])=[O:15]
Reactant: [OH-]
Reactant: CCCC(=O)c1ccc(O)c(Cl)c1Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCC(=O)c1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A mixture of 2,3-dichloro-4-butyrylphenol (15 g, 0.064 mole), acetone (140 ml) and sodium hydroxide (14.5 g, 0.36 mole) was stirred and heated to reflux. Chloroform (12 g, 0.1 mole) was added to the mixture dropwise over a period of 15 minutes. Refluxing was continued for 3 hours and the acetone was evaporated in vacuo. The residue was treated with ice water containing hydrochloric acid. The product was extracted with ether. The ether extract was washed with water, then with brine and finally dried over MgSO4. The ether was evaporated in vacuo and the residue chromatographed on a column containing silica gel (320 g) and eluted with methylene chloride/tetrahydrofuran/acetic acid 50/1/1. The appropriate fractions were combined and evaporated in vacuo to give 10 g of 2-(2,3-dichloro-4-butyrylphenoxy)-2-methylpropionic acid which was identified by NMR and the purity confirmed by thin layer chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:18])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br:19]Br.O>C(Cl)Cl>[Br:19][CH2:17][C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)=[O:18]
Reactant: BrBr
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O

Procedure:
20.6 g (83 mmol) of 1-(3,5-di-tert.-butyl-4-hydroxy-phenyl)ethanone were dissolved in 50 ml of methylene chloride with stirring and heated to boiling, and 14.4 g (90 mmol) of bromine were added dropwise in the course of 15 minutes. The mixture was then heated under reflux for a further 2 hours and cooled, 50 ml of water were added, and the organic phase was separated and dried over sodium sulfate. After removing the solvent under reduced pressure, the solid residue was recrystallized from methylcyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[Li+].CC([N-]C(C)C)C.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1([CH2:26][C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH3:29])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6][CH2:5]1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccccc1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-t-butoxycarbonyl isonipecotic acid methyl ester (10.1 g 41.8 mmol) in 140 ml of dry THF at -78° C. was added LDA (59 ml of a 1.0M solution in THF, 59 mmol) over 15 min. The resulting orange solution was stirred at -78° C. for 1 hr and then treated dropwise with 2-methylbenzyl bromide (6.80 ml, 50.7 mmol) and then allowed to warm slowly to room temperature over 16 hrs. The reaction was quenched with saturated aqueous NH4Cl, diluted with H2O, and extracted with EtOAc. The combined organic extracts were washed with brine, and concentrated in vacuo to an orange gum. Chromatography (SiO2, eluting with 20 to 30% EtOAc in hexanes) and evaporation of solvent in vacuo, afforded the product as a white solid.
Reaction SMILES: Cl.NO.C(O)C.CC[N:9](C(C)C)C(C)C.[Cl:16][C:17]1[C:18]([NH:23][C:24]([NH:26]CCOC(=O)C)=O)=[N:19][CH:20]=[CH:21][N:22]=1>CO>[Cl:16][C:17]1[C:18]2[N:19]([N:9]=[C:24]([NH2:26])[N:23]=2)[CH:20]=[CH:21][N:22]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)OCCNC(=O)Nc1nccnc1Cl
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2c(Cl)nccn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.6 g (23.2 mmol) hydroxylamine hydrochloride are suspended in 20 ml of a 1:1 mixture of ethanol and methanol. Then 2.4 ml (13.9 mmol) DIPEA are added and the mixture is stirred at ambient temperature for 1 h. At that time, the reaction suspension is added to 2 g (4.6 mmol, 62% content) 1-(3-chloro-pyrazin-2-yl)-3-acetoxyethyl-urea and refluxed for 2 h. The reaction is cooled to room temperature filtered and washed with water. The product is isolated after drying in a vacuum oven (60° C.) (790 mg, 4.65 mmol, 100%); LCMS (method C): mass found (M+H+, 170), HPLC (method D) Rt (min): 2.14 area % 100 (220 nm); 1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.83 (d, J=4.3, 1H), 7.92 (d, J=4.3, 1H), 6.77 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:12][CH2:11][C:5]2([O:9][CH2:8][C:7](=O)[CH2:6]2)[CH2:4][CH2:3]1.Cl.[NH2:14][OH:15]>CO>[CH3:1][N:2]1[CH2:12][CH2:11][C:5]2([O:9][CH2:8][C:7](=[N:14][OH:15])[CH2:6]2)[CH2:4][CH2:3]1
Reactant: CN1CCC2(CC1)CC(=O)CO2
Reactant: NO
Agent: Cl
Solvent: CO
Product: CN1CCC2(CC1)CC(=NO)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 2 (0.6 g, 3.5 mmol) was dissolved in methanol (50 ml) and placed under nitrogen. Hydroxylamine hydrochloride was added and the reaction was stirred at room temperature overnight.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6]Cl.C(=O)([O-])[O-].[K+].[K+].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1.O>CC(C)=O>[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:27]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:45])([CH3:46])[C:35]=2[CH:34]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCN(C)C)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reaction time: 48 h
Yield: 81.9 %

Procedure:
440 mg (2.78 mmol) of 3-dimethylaminopropyl chloride hydrochloride and 970 mg (7 mmol) of potassium carbonate are added to a solution of 1 g (2.33 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate in 50 ml of acetone. The reaction mixture is stirred for 48 hours at reflux. The reaction is stopped by adding water, and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (eluent: 90/10 ethyl acetate/methanol). 980 mg of ethyl 4′-(3-dimethylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a yellow oil (yield=82%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][N:32]1[C:36]([C:37](Cl)=[O:38])=[CH:35][C:34]([CH3:40])=[N:33]1>O1CCCC1>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:37]([C:36]5[N:32]([CH3:31])[N:33]=[C:34]([CH3:40])[CH:35]=5)=[O:38])=[CH:3][CH:4]=4)=[N:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)cc2)n(C)n1
Yield: 27.4 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (220 mg, 0.71 mmol), triethylamine (0.30 mL, 2.13 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (230 mg, 1.42 mmol) and tetrahydrofuran (6.6 mL) as starting materials and in the same manner as in Example 96, the title compound (84 mg, 27%) was obtained as a white powder.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH:4]1([C:10]2[S:14][C:13]([N:15]=[C:16]=[O:17])=[N:12][N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.NN>C(Cl)Cl>[CH3:1][N:2]([C:16]([NH:15][C:13]1[S:14][C:10]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[N:11][N:12]=1)=[O:17])[NH2:3]
Reactant: O=C=Nc1nnc(C2CCCCC2)s1
Reactant: CNN
Agent: NN
Solvent: ClCCl
Product: CN(N)C(=O)Nc1nnc(C2CCCCC2)s1
Temperature: 25 °C

Procedure:
A solution of methylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-methyl-4-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)semicarbazide as the residue.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][O:31][C:32](Cl)=[O:33].CCN(C(C)C)C(C)C>>[CH3:30][O:31][C:32]([N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)=[O:33]
Reactant: COC(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@H]3CCNC3)cnc21
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CC[C@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
(S)-3-{3-[5-(2-Trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid methyl ester was prepared from (S)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and methylchloroformate, using DIPEA as base and following the general synthetic procedures described in the above Examples.
Reaction SMILES: C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F:13][C:14]1[NH:15][C:16]([NH2:23])=[C:17]2[C:21]([N:22]=1)=[N:20][CH:19]=[N:18]2.C(O[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C>[F:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[C:16]([NH2:23])[N:15]=1
Reactant: CC(=O)OC1CCCCO1
Reactant: Nc1[nH]c(F)nc2ncnc1-2
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: Nc1nc(F)nc2c1ncn2C1CCCCO1
Temperature: 0 °C

Procedure:
N,O-bis(trimethylsilyl)acetamide (975 ml, 3.988 mol) was added to a stirred suspension of 2-fluoro-1H-purin-6-amine (200 g, 1.306 mmol) (available from, for example, AlliedSignal, US) in anhydrous acetonitrile (4 L) in a 10 L controlled lab reactor and the resulting mixture heated to reflux and maintained at that temperature for 2 hours. The circulator was then re-programmed and the reaction mixture cooled to 0° C. A solution of tetrahydropyranyl acetate (preparation described in Tetrahedron Letters 2006, 47(27), 4741) (282 g, 1.959 mol) in anhydrous acetonitrile (500 ml) was then added slowly via a dropping funnel followed by trimethylsilyl trifluoromethanesulfonate (283 ml, 1.567 mol) dropwise via a dropping funnel. No sigificant exotherm was observed. The circulator temperature was re-adjusted to 10° C. and stirring maintained for a further 1 hour. The mixture was then quenched by additon of 1M sodium carbonate (4 L). A solid precipitate was observed and the pH checked to be basic. Additional water was added to the suspension (1 L) and on standing the layers separated with the aqueous layer containing significant solid inorganics. The majority of the aqueous and inorganic solid was separated. The organic layer still contained significant solid and was cooled to 0° C. with stirring to encourage further precipitation. The solid was the collected by filtration and the pad was washed very well with water then dried in vacuo at 40° C. overnight to give the title compound as a cream coloured solid (152.8 g).
Reaction SMILES: [CH3:1][N:2]([CH3:57])[C:3]1[N:4]=[C:5]([O:15][C@H:16]2[CH2:56][N:19]3[C:20](=[O:55])[C@@H:21]([NH:47]C(=O)OC(C)(C)C)[C@H:22]([CH3:46])[CH2:23][CH:24]([CH3:45])[CH2:25][CH2:26][CH:27]=[CH:28][C@@H:29]4[CH2:34][C@@:30]4([C:35](=[O:44])[NH:36][S:37]([C:40]4([CH3:43])[CH2:42][CH2:41]4)(=[O:39])=[O:38])[NH:31][C:32](=[O:33])[C@@H:18]3[CH2:17]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61]>C(Cl)Cl>[OH:62][C:60]([C:59]([F:64])([F:63])[F:58])=[O:61].[NH2:47][C@@H:21]1[C:20](=[O:55])[N:19]2[CH2:56][C@H:16]([O:15][C:5]3[C:6]4[C:11](=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=4)[CH:12]=[C:3]([N:2]([CH3:1])[CH3:57])[N:4]=3)[CH2:17][C@H:18]2[C:32](=[O:33])[NH:31][C@:30]2([C:35]([NH:36][S:37]([C:40]3([CH3:43])[CH2:41][CH2:42]3)(=[O:38])=[O:39])=[O:44])[CH2:34][C@H:29]2[CH:28]=[CH:27][CH2:26][CH2:25][CH:24]([CH3:45])[CH2:23][C@H:22]1[CH3:46]
Reactant: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(C)CC6)C[C@H]5C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)nc(N(C)C)cc2c1
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(C)CC6)C[C@H]5/C=C\CCC(C)C[C@@H](C)[C@H](N)C(=O)N4C3)nc(N(C)C)cc2c1
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(C)CC6)C[C@H]5/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)nc(N(C)C)cc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(C)CC6)C[C@H]5C=CCCC(C)C[C@@H](C)[C@H](N)C(=O)N4C3)nc(N(C)C)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((3-(dimethylamino)-6-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (50 mg, 0.062 mmol) was dissolved in DCM (4 mL) and trifluoroacetic acid (TFA, 1 ml, 12.98 mmol) was added. The reaction was stirred for 1 h at room temperature. The volatiles were removed under vacuum to give (2R,6S,7R,13aS,14aR,16aS,Z)-6-amino-2-((3-(dimethylamino)-6-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-N-((1-methylcyclopropyl)sulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide TFA (51 mg) which was used in the next step as is. MS: MS m/z 711.1 (M++1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].CO.Cl>O1CCCC1>[NH2:6][CH2:5][C:4]1[C:3]([NH:2][CH3:1])=[N:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNc1ncccc1C#N
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNc1ncccc1CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
Borane/THF complex (1.44 mol) as a 1M solution in tetrahydrofuran was added, dropwise, to a solution of 2-(methylamino)-nicotinonitrile (63.9 g, 480 mmol) in tetrahydrofuran (480 mL). This mixture was stirred at room temperature for 1 hour then heated to reflux for 3 hours. The reaction mixture was quenched by dropwise addition of methanol (136 mL, 3.36 mol) followed by 6M HCl (80 mol, 480 mmol) and 10% HCl (400 mL). The phases were separated and the organic phase washed with brine (2×480 mL). The aqueous phase was made alkaline with 50% aqueous NaOH (250 g). The aqueous phase was extracted with dichloromethane (2×480 mL) and the organic extracts dried over Na2SO4. Concentration in vacuo gave 44.85 g of 3-(aminomethyl)-2-methylaminopyridine as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][S:31]([OH:34])(=[O:33])=[O:32])=C[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(#[N:48])C.O>>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][S:31]([OH:34])(=[O:33])=[O:32])=[N:48][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CC#N
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CS(=O)(=O)O)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](CS(=O)(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F

Procedure:
Sulfonic acid, 11, was synthesized in a manner similar to Compound 25 described below, using compound, 57a, as the starting material: 1H NMR (400 MHz, MeOD) δ 8.44 (s, 1H), 8.34 (dd, J=9.2, 2.6 Hz, 1H), 8.22 (d, J=5.7 Hz, 1H), 8.13 (s, 1H), 5.16 (d, J=4.1 Hz, 1H), 3.46-3.33 (m, 2H), 1.10 (d, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z 412.19 (M+H) retention time=1.91 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][NH2:12].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][NH:12][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1CN
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])ccc1CNS(C)(=O)=O
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a stirred solution of (2-methyl-4-nitrophenyl)methanamine (178 mg, 1.071 mmol) in pyridine, cooled to 0° C., were added methane sulfonylchloride (0.16 mL, 2.0349 mmol). The resulting reaction mixture was stirred for 2 h. The mixture dissolved in dichloromethane and washed with 1N HCl. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to obtain N-(2-methyl-4-nitrobenzyl)methanesulfonamide (100 mg, 38%).
Reaction SMILES: [C:1]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([Br:15])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].IC>CN(C)C=O>[C:1]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([Br:15])[CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c2c(Br)cccc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)c1cn(C)c2c(Br)cccc2c1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A mixture of 3-acetyl-8-bromoquinolin-4(1H)-one (5.35 g, 20.11 mmol) and K2CO3 (9.17 g, 66.3 mmol) in dry N,N-dimethylformamide (100 mL) was heated at 90° C. for 30 min. After cooling to room temperature, iodomethane (3.77 mL, 60.3 mmol) was added and the mixture was stirred again at 90° C. for 2 h. Then the reaction mixture was concentrated and diluted with water (50 mL), extracted with dichloromethane (4×50 mL), dried over sodium sulfate and absorbed onto silica gel. Purification by automatic silica gel column chromatography (Combiflash RF) eluting with ethyl acetate/hexanes (10-100%) afforded 3-acetyl-8-bromo-1-methylquinolin-4(1H)-one (3.4 g, 12.14 mmol, 60.4% yield) as a brown solid. LCMS: (M+H)+: 279.9.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)[CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Oc1cccc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-tert-Butylphenol (7.52 g, 50 mmol) in anhydrous DMF (40 mL) was added dropwise to NaH (2.2 g, 55 mmol, 60% w/w in mineral oil) at 0° C. under an atmosphere of nitrogen. After five min, ethyl 2-bromopropionate (6.49 mL, 50 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir for 18 h, gradually warming to ambient temperature. The reaction mixture was diluted with ethyl acetate (300 mL) and extracted twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[O:18][CH3:19]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[C:12]([O:18][CH3:19])[CH:13]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1cc(Cl)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1Cn1ccnc1C
Temperature: 25 °C
Yield: 39.7 %

Procedure:
2-Methyl imidazole (45 mg, 0.55 mmol) was dissolved in DMF. Sodium hydride (60 mg, 1.5 mmol) was added slowly. The mixture was stirred at room temperature until bubbling ceased. 1-Bromomethyl-4-chloro-2-methoxy-benzene (117 mg, 0.5 mmol) was added and the mixture was heated to 100° C. for 16 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and with brine. The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (1:1 hexanes/ethyl acetate) to provide 47 mg (40%) of the title compound. MS (ESI) m/e 237 (M+H)+.