Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@@:10]([C:26]#[C:27][CH2:28][OH:29])([OH:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:17])=[O:18])[CH2:15][C@@:9]1([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@@:10](/[CH:26]=[CH:27]\[CH2:28][OH:29])([OH:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]2(O)C#CCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]2(O)/C=C\CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Lindlar catalyst (200 mg) was added to a solution of (1R*,2R*,5S*,6R*)-8-benzyl-2-(3-hydroxypropynyl)-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 13; 2.1 g, 4.3 mmol) in ethyl acetate (100 ml). The mixture was stirred at room temperature for 8 hours then filtered through Celite™ and the filtrate concentrated in vacuo to yield the title compound (1.88 g, 90%).
Reaction SMILES: [C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:43])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:41])[N:34]([CH2:36][CH2:37][CH2:38][CH2:39]O)[CH3:35])=[CH:29][CH:28]=2)[CH3:19])[CH2:12][CH2:11]1.[CH2:50]([N:52](CC)CC)C.CS(Cl)(=O)=O.CN.CO>ClCCl>[C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:43])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:41])[N:34]([CH3:35])[CH2:36][CH2:37][CH2:38][CH2:39][NH:52][CH3:50])=[CH:29][CH:28]=2)[CH2:14][CH2:15]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)N(C)CCCCO)cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: CNCCCCN(C)C(=O)c1ccc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Reaction time: 0.17 h
Yield: 77.1 %

Procedure:
The compound (107 mg, 0.159 mmol) obtained in Example 80a was dissolved in dichloromethane (6 mL), triethylamine (0.044 mL, 0.32 mmol) and methanesulfonyl chloride (0.018 mL, 0.24 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. Triethylamine (0.044 mL, 0.32 mmol) and methanesulfonyl chloride (0.018 mL, 0.24 mmol) were further added under ice cooling, then a 40% methyl amine-methanol solution (6 mL) was added, and the mixture was stirred at room temperature for 14 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (elution solvents, n-hexane:ethyl acetate:methanol=1:1:0→0:1:0→0:9:1, v/v/v) to give the title compound (84 mg; yield, 77%) as a colorless oily substance.
Reaction SMILES: N#N.C(OC([NH:10][C@@H:11]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18])[CH2:12][CH2:13][C:14]([NH2:16])=[O:15])=O)(C)(C)C.O.[ClH:30].O1CCOCC1>>[ClH:30].[C:23]1([CH2:22][CH2:21][CH2:20][NH:19][C:17](=[O:18])[C@@H:11]([CH2:12][CH2:13][C:14]([NH2:16])=[O:15])[NH2:10])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(N)=O)C(=O)NCCCc1ccccc1
Agent: Cl
Agent: N#N
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)CC[C@@H](N)C(=O)NCCCc1ccccc1

Procedure:
A solution of N2 -(tert-butyloxycarbonyl)-N1 -(3-phenylpropyl)-D-glutamamide (1.5 g.) in hydrogen chloride-dioxane (4.5 N, 10 ml.) was stirred at room temperature for 15 minutes. Water (50 ml.) was added and the mixture was concentrated to about 5 ml. Ethanol (50 ml.) was added and the mixture was concentrated to less than 5 ml. Dimethylformamide (20 ml.) was added and the mixture was stripped of the remaining ethanol, affording N1 -(3-phenylpropyl)-D-glutamamide hydrochloride as a solution in the dimethylformamide. N-(tert-Butyloxycarbonyl)-O-(tert-butyl)-L-tyrosine pentafluorophenyl ester (2.08 g.) and diisopropylethylamine (0.72 ml.) were added and the mixture was stirred at room temperature for two hours. More diisopropylethylamine was added to neutralize the mixture. The reaction was complete in one half hour. The mixture was stripped of volatiles under vacuum. A solution of the residue in ethyl acetate was washed twice with water, twice with saturated aqueous sodium bicarbonate, once again with water, twice with aqueous citric acid and once with saturated aqueous sodium chloride, dried and stripped of ethyl acetate. Methanol was added to the residue and the mixture was stripped again. The product (1.80 g.) was purified by high pressure liquid chromatography using ethyl acetate-ethanol (96:4) as the eluant, affording [N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosyl]-N1 -(3-phenylpropyl)-D-glutamamide as a gel in two crops (711 mg., 427 mg.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[N:11]=[C:10]([NH2:15])[C:9]3[N:16]=[C:17]([CH2:22][O:23][CH2:24][CH3:25])[N:18]([CH2:19][CH2:20][CH3:21])[C:8]=3[C:7]=2[CH:6]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:53]1[CH2:57][CH2:56][CH2:55][CH:54]1[C:58](O)=[O:59].C(N(CC)CC)C>ClCCl.O>[NH2:15][C:10]1[C:9]2[N:16]=[C:17]([CH2:22][O:23][CH2:24][CH3:25])[N:18]([CH2:19][CH2:20][CH3:21])[C:8]=2[C:7]2[CH:6]=[C:5]([O:4][CH2:3][CH2:2][NH:1][C:58]([CH:54]3[CH2:55][CH2:56][CH2:57][O:53]3)=[O:59])[CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OCCN)cc3c21
Reactant: O=C(O)C1CCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCCNC(=O)C4CCCO4)cc3c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.46 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.282 g, 2.90 mmol) in dichloromethane (15 mL) was cooled to 0° C. A solution of tetrahydro-2-furoic acid (0.168 g, 1.45 mmol) in dichloromethane (5 mL) and triethylamine (0.811 mL, 5.82 mmol) were sequentially added. The reaction was stirred at 0° C. for 30 minutes, allowed to warm to ambient temperature, stirred for two hours, and poured into water. The aqueous layer was extracted with dichloromethane. The combined organic fractions were washed sequentially with water (2×) and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 99:1 to 96:4) to provide the desired product and a bis amide by-product. The bis amide by-product was treated with 1N aqueous hydrochloric acid, heated at reflux for 1.5 hours, and cooled to 0° C. The mixture was adjusted to pH 13 with the addition of 10% aqueous sodium hydroxide and extracted with dichloromethane. The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a yellow oil. The oil and the previously recovered amide were combined and recrystallized from acetonitrile to provide 0.220 g of N-(2-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}ethyl)tetrahydrofuran-2-carboxamide as a tan, crystalline solid, mp 202.5-204.5° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[C:4]([Br:11])[CH:3]=1.[F:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][NH:18][CH3:19])=[CH:15][CH:14]=1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>O.CCOC(C)=O>[Br:11][C:4]1[CH:3]=[C:2]([N:18]([CH2:17][C:16]2[CH:20]=[CH:21][C:13]([F:12])=[CH:14][CH:15]=2)[CH3:19])[C:10]2[C:6]([CH:5]=1)=[N:7][O:8][N:9]=2
Reactant: CNCc1ccc(F)cc1
Reactant: Brc1cc(Br)c2nonc2c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CN(Cc1ccc(F)cc1)c1cc(Br)cc2nonc12
Temperature: 100 °C
Yield: 47 %

Procedure:
4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3688 g, 1.33 mmol), 4-fluoro-N-methylbenzylamine (0.18 mL, 1.39 mmol), NMP (3 mL) and DIPEA (0.26 mL, 1.5 mmol) were sealed in a tube and heated to 100° C. overnight. Upon cooling to room temperature, the mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was then back-extracted. The combined organic extracts were then washed with H2O, 1 N HCl (aq), saturated NaHCO3 (aq), H2O (3×), brine and then dried (Na2SO4), filtered and concentrated to give 6-bromo-N-(4-fluorobenzyl)-N-methylbenzo[c][1,2,5]oxadiazol-4-amine. The crude aniline and 3-formylbenzeneboronic acid (0.2593 g, 1.73 mmol) were sealed in a tube. The tube was evacuated and purged with argon (3 cycles). 2M Na2CO3 (2.0 mL, aq solution) was added along with DME (3.0 mL). The solution was degassed for 10 minutes and then Pd(PPh3)4 (0.0768 g, 0.066 mmol) was added all at once. The tube was re-sealed and heated to 100° C. overnight. After cooling to room temperature, the mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was then back-extracted. The combined organic extracts were then washed with H2O (3×), brine and then dried (Na2SO4), filtered and concentrated. This crude material was then dissolved in THF (4.0 mL) and cooled in an ice bath. To this solution was added CF3TMS (0.39 mL, 2.66 mmol) and then TBAF (0.1 mL, 1.0 M solution in THF). After 5 minutes, the ice bath was removed and the mixture was stirred for an additional 2 hours. The solution was then re-cooled to 0° C. and TBAF (4.7 mL, 4.7 mmol) was added, the mixture was allowed to warm to room temperature overnight. The mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was then back-extracted. The combined organic extracts were then washed with H2O (3×), brine and then dried (Na2SO4), filtered and concentrated. The crude material was purified via chromatography (15% EtOAc/hexane) to afford 0.2675 g (47% yield, 4 steps) of TRV-1390. 1H NMR (500 MHz, CDCl3) δ=7.70 (s, 1H), 7.64 (dt, J=7.0, 2.0 Hz, 1H), 7.55-7.50 (m, 2H), 7.27-7.24 (m, 3H), 7.04-7.00 (m, 2H), 6.34 (s, 1H), 5.12-5.10 (m, 3H), 3.19 (s, 3H), 2.71 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.Cl.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[CH3:8][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][NH2:10])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(CN)cc2)ccn1
Temperature: 96 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-2-methylpyridine 13-1 (516 mg, 3.00 mmol), (4-(aminomethyl)phenyl)boronic acid hydrochloride 13-2 (422 mg, 2.25 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol) and K3PO4 (1.7 g, 8 mmol) in anhydrous dioxane (10 mL) was stirred at 96° C. under argon overnight. After cooling to room temperature, the mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated by rotavap and the residue subjected to silica gel column chromatography with 7% ammonia-saturated methanol in dichloromethane as eluent to give (4-(2-methylpyridin-4-yl)phenyl)methanamine 13-3 as an oil.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[ClH:11].Cl.[C:13]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]([NH2:29])=[NH:28])=[NH:25])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(O)C>[ClH:11].[CH2:2]([CH:1]1[N:23]([C:20]2[CH:21]=[CH:22][C:17]([C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:18][CH:19]=2)[C:24]([NH2:25])=[N:26][C:27]([NH2:29])=[N:28]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC=O
Reactant: CC(C)(C)c1ccc(NC(=N)NC(=N)N)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCC1N=C(N)N=C(N)N1c1ccc(C(C)(C)C)cc1

Procedure:
100 ml of ethanol, 4.8 ml (27.9 mmol) of 1-nonanal and 0.8 ml of concentrated hydrochloric acid were added to 5.0 g (18.5 mmol) of N1-(4-tert-butylphenyl)-biguanide hydrochloride, and the mixture was refluxed for 15 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)), and recrystallized from 70% aqueous acetonitrile to obtain 16 g of colorless crystals having a melting point of 231 to 234° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:23]([CH3:29])=[CH:24][CH:25]=[CH:26][C:27]=2[CH3:28])[C:15]2[O:14][CH:13]([CH2:12][N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CN1CCNCC1)C2

Procedure:
The title compound was prepared (0.118 g, 81%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and piperazine (0.58 g, 6.76 mmol). mp 190-192° C.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[S:8][CH:9]=[C:10](Br)[CH:11]=1.[CH3:13][C:14]1[S:15][CH:16]=[C:17]([CH:19]=[O:20])[CH:18]=1.[NH4+].[Cl-]>CCOCC>[CH3:6][C:7]1[S:8][CH:9]=[C:10]([CH:19]([C:17]2[CH:18]=[C:14]([CH3:13])[S:15][CH:16]=2)[OH:20])[CH:11]=1
Reactant: Cc1cc(Br)cs1
Reactant: Cc1cc(C=O)cs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cc(C(O)c2csc(C)c2)cs1
Temperature: 25 °C

Procedure:
113 mL of 1.6 M n-BuLi solution (0.18 mol) was added to a solution of 31.3 g of 2-methyl-4-bromo-thiophene (0.177 mol) in 150 mL of ether at −70° C. under stirring. The resulting solution was kept under stirring at −60 to −70° C. for 30 min and then was added of 22.3 g of 2-methyl-4-formyl-thiophene (0.177 mol) in 100 mL of ether. The mixture was allowed to warm to room temperature, then neutralized with 10% aqueous solution of NH4Cl and washed with water. The organic phase was separated and evaporated. The crude bis(2-methyl-4-thienyl)methanol (or 2,2′-dimethyl-4,4′-dithienyl carbinol) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1)[CH3:3].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17].CN(CCOC1C=CC(C(=O)C(F)(F)F)=CC=1)C>>[CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])[CH:10]=[CH:11][CH:12]=1)[CH3:3]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CN(C)CCOc1cccc(Br)c1
Agent: CN(C)CCOc1ccc(C(=O)C(F)(F)F)cc1
Product: CN(C)CCOc1cccc(C(=O)C(F)(F)F)c1
Yield: 43.8 %

Procedure:
N,N-Dimethyl-2-(3-bromophenoxy)ethylamine (2.87 g, 11.7 mmol) and ethyl trifluoroacetate (2.5 g, 17.6 mmol) were reacted by the general procedure as described in the preparation of [4-[2-(N,N-dimethylamino)ethoxy]phenyl]-2,2,2-trifluoroethanone. The residue was distilled under reduced pressure to afford the title compound (1.34 g, 44%) as a pale yellow liquid. Analytically pure sample was obtained by a second distillation under reduced pressure. Analysis for C12H14F3NO2.0.8H2O calcd. C 52.29%, H 5.70%, N 5.08%; Found: C 52.61%, H 5.53%, N 4.96%.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>ClCCl.C1CCN2C(=NCCC2)CC1>[OH:13][N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: O=Nc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 96.8 %

Procedure:
Scale up: DBU (3.8 mg, 0.025 mmol) was added under argon to a solution of 4-nitrobenzaldehyde (3 g, 20 mmol), nitrosobenzene (2.14 g, 20 mmol) and catalyst (9 mg, 0.025 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature for 2 min. The product precipitated as a yellow solid. The solvent was removed under vacuum, and the solid was washed with hexane and ether to yield a pure product (5 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)O1.Br[C:27]1[C:28]([CH3:34])=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O.C(=O)(O)[O-].[Na+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:33][C:29]1[C:28]([CH3:34])=[C:27]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)[CH:32]=[N:31][CH:30]=1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)C4CC4)ncc3c2)OC1(C)C
Reactant: Cc1c(N)cncc1Br
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(N)cncc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
To a mixture of N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide (119.4 mg, 0.3530 mmol), 5-bromo-4-methylpyridin-3-amine (83.7 mg, 0.448 mmol), cesium carbonate (286.6 mg, 0.8796 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (19.2 mg, 0.0271 mmol) was added 1,4-dioxane (4 mL, 50 mmol) and water (0.4 mL, 20 mmol). The reaction was then stirred in a sealed vial at 100° C. for two hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and extracted four times with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude residue was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-15% MeOH in dichloromethane) followed by reverse phase HPLC purification and lyophilization to yield 41.3 mg (37%) of N-(7-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT(min)=2.42, M+H=319.2, method=H; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.18 (s, 1H), 8.49 (s, 1H), 7.98 (s, 2H), 7.91 (d, J=8.5 Hz, 1H), 7.72 (s, 1H), 7.68-7.57 (m, 1H), 5.22 (s, 2H), 2.14-2.03 (m, 1H), 2.01 (s, 3H), 0.85 (dd, J=11.6, 6.1 Hz, 4H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH:5]1[CH3:18])(=[O:3])[CH3:2].[NH2:19][C:20]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:21]=1[C:22]([NH2:24])=[O:23].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]3[NH:24][C:22](=[O:23])[C:21]4[C:20](=[CH:28][C:27]([O:29][CH3:30])=[CH:26][C:25]=4[O:31][CH3:32])[N:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(C)=O)C(C)C4)cc3)nc2c1
Temperature: 155 °C
Yield: 21.9 %

Procedure:
To a solution of 4-(4-acetyl-3-methylpiperazin-1-yl)benzaldehyde (0.400 g, 1.62 mmol) in DMA (15 mL) was added 2-amino-4,6-dimethoxybenzamide (0.349 g, 1.78 mmol), NaHSO3 (0.201 g, 1.94 mmol) and p-TsOH (0.030 g, 0.16 mmol). The resulting solution was heated to 155° C. for 5 hours. The mixture was cooled to room temperature, diluted with water, extracted with CH2Cl2, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 50% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.150 g, 21%). 1H NMR (300 MHz, DMSO-d6): mixture of rotamers δ 11.57 (s, 1H), 8.10 (d, J=8.9 Hz, 2H), 6.90-7.14 (m, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 4.42-4.75 (m, 0.5H), 4.03-4.42 (m, 1H), 3.61-4.02 (m, 8H), 3.41-3.60 (m, 1H), 2.85-3.13 (m, 2H), 2.63-2.85 (m, 0.5H), 1.88-2.13 (m, 3H), 1.04-1.31 (m, 3H). ESI MS m/z 423 [M+H]+.
Reaction SMILES: [C:1]([NH:9][C:10]1([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:13][CH:12]([C:14]([OH:16])=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:34][NH:35][O:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:10]2([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH:12]([C:14](=[O:16])[N:35]([O:36][CH3:37])[CH3:34])[CH2:11]2)=[CH:18][CH:19]=1
Reactant: CNOC
Reactant: O=C(NC1(c2ccc(Cl)cc2)CC(C(=O)O)C1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CC(NC(=O)c2ccccc2)(c2ccc(Cl)cc2)C1
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A solution of 3-benzamido-3-(4-chlorophenyl)cyclobutanecarboxylic acid (1.16 g, 3.52 mmol), diisopropylethylamine (1.57 mL, 9.14 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.446 g, 4.572 mmol) in dichloromethane (45 mL) was treated with HATU (1.61 g, 4.22 mmol). After stirring overnight, the solution was diluted with dichloromethane (50 mL), washed successively with 1 M HCl (3×), 5% aqueous NaHCO3 and saturated aqueous sodium chloride. The organic phase dried over MgSO4, filtered and concentrated to give a colorless gum. Crystallization from diethyl ether gave the subject compound as a white crystalline solid (1.13 g 86%). 1H NMR (CDCl3, 600 MHz) δ 7.79 (d, J=7.5 Hz, 2H), 7.49-7.52 (m, 3H), 7.42-7.45 (m, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.08 (bs, 1H), 3.68 (s, 3H), 3.43-3.47 (m, 1H), 3.22 (s, 3H), 2.98-3.01 (m, 2H), 2.87-2.91 (m, 2H). ESI MS found for C20H21ClN2O3 m/z [395.4/397.3 (M+NO, 373.3/375.3 (M+1), 371.3/373.3 (M−1)].
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:26]O>>[CH:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:23])([CH3:24])[C:17]=3[CH:25]=2)=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSC3CCCCC3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)C3CCCCC3)cc21

Procedure:
Prepared analogously to Example 2 from 6-(4-cyclohexylmercaptobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[CH:17][CH:18]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)COc1ccc(CCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1ccc(CCOS(C)(=O)=O)cc1
Temperature: -10 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
Tert-butyl [4-(2-hydroxyethyl)phenoxy]acetate (6.000 g, 23.781 mmol) and triethylamine (9.9 ml, 71.341 mmol) were dissolved in DCM. The mixture was cooled to −10° C. and methanesulfonyl chloride (2.8 ml, 35.671 mmol) was added dropwise to the mixture. The reaction mixture was allowed to reach room temperature and was stirred for 16 hours. The mixture was diluted with DCM. The organic layer was washed with water, brine and 0.3M KHSO4, dried with MgSO4, and evaporated under reduced pressure. Obtained 7.5 g of light-yellow crystals (yield 95.5%).