Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:14](=O)[C:15]([F:18])([F:17])[F:16])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:20][NH2:21].[OH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C1C=CC=CC=1.C(O)(=O)C>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:11]3[C:14]([C:15]([F:18])([F:17])[F:16])=[N:21][NH:20][C:12]=3[N:13]=[C:27]([C:26]3[CH:29]=[CH:30][C:23]([OH:22])=[CH:24][CH:25]=3)[C:6]=2[CH:7]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NN
Reactant: COc1ccc(C(C#N)C(=O)C(F)(F)F)cc1OC
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COc1cc2c(-c3ccc(O)cc3)nc3[nH]nc(C(F)(F)F)c3c2cc1OC
Temperature: 70 °C
Yield: 30 %

Procedure:
2-[3,4-bis(methyloxy)phenyl]4,4,4-trifluoro-3-oxobutanenitrile (100 mg, 0.37 mmol) was dissolved in benzene (10 mL), acetic acid (1 mL), and anhydrous hydrazine (98%, 12 μL, 0.44 mmol). The resulting mixture was heated at reflux for 3 hours. It was cooled, concentrated, and the residue was basified with solid sodium bicarbonate, diluted with ethyl acetate (50 mL), washed with water and brine (50 mL each), dried over sodium sulfate, filtered, concentrated, and the residue was dried in vacuum to give an oily residue. To this residue was added of 4-hydroxybenzaldehyde (67 mg, 0.55 mmol) and trifluoroacetic acid (1 mL), and the mixture was heated at 70° C. for 18 hours. Then the reaction mixture was concentrated, dissolved in 10 mL of N,N-dimethylformamide and purified by preparatory HPLC (Shimadzu LC-8A HPLC, Waters Xterra C18 30 mm×100 mm column, acetonitrile-water-trifluoroacetic eluent). After concentration then then lyophillization of the pure fractions 4-[7,8-bis(methyloxy)-1-(trifluoromethyl)-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol trifluoroacetic acid salt (56 mg, 0.11 mmol, 30% yield) was obtained. 1H NMR (400 MHz, d6-DMSO): 7.63-7.61 (d, 2H), 7.59 (s, 1H), 7.58 (s, 1H), 6.99-6.97 (d, 2H), 4.00 (s, 3H), 3.80 (s, 3H); MS (EI) for C19H14N3O3F3: 340 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([C:9]#[C:10][CH:11]([CH3:13])[CH3:12])=[CH:4][N:3]=1.CC([O-])(C)C.[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN1C(=O)CCC1.C1COCC1.CN(C=O)C>[CH2:20]([N:8]1[C:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[CH:9]=[C:10]1[CH:11]([CH3:13])[CH3:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C#Cc1cnc(Cl)cc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CC(C)c1cc2cnc(Cl)cc2n1Cc1ccccc1
Temperature: 160 °C
Reaction time: 6 h

Procedure:
To a solution of 2-chloro-5-(3-methylbut-1-ynyl)pyridin-4-amine (Compound 12, 0.82 g, 4.2 mmol) in NMP (10 ml) was added KOtBu (2.40 g, 21 mmol). The mixture was stirred at 160° C. for 6 h and was cooled to room temperature, diluted with THF (10 ml) and DMF (15 ml). Benzyl bromide (0.50 ml, 4.2 mmol) was added. The mixture was stirred at room temperature for 16 h and was quenched with H2O, extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[Cl:10]C1C=CC=CC=1O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:10])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: Oc1ccccc1Cl
Product: Oc1c(Cl)cc(Cl)cc1Cl

Procedure:
The selectivity was 0.73 mol of 2,6-dichlorophenol mol of ortho-chlorophenol introduced.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O.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>[CH3:21][C:20]1[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:16][CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cnc1-c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 79 %

Procedure:
To a mixture of 4-(trifluoromethyl)phenylboronic acid (285 mg, 1.5 mmol), 2-bromo-3-methyl-5-nitropyridine (216 mg, 1.0 mmol), and potassium carbonate (345 mg, 2.5 mmol) in water (1.5 mL) and dioxane (6 mL) was added tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.035 mmol). The resulting mixture was stirred at 80° C. for 4.5 hours. The mixture was cooled to room temperature. Ethyl acetate was added and the mixture was washed with water, then brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 3-methyl-5-nitro-2-(4-(trifluoromethyl)phenyl)pyridine (223 mg, 79%). 1H NMR (400 MHz, CDCl3, δ): 9.35 (s, 1H), 8.42 (s, 1H), 7.77 (d, 2H), 7.69 (d, 2H), 2.51 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][NH:6]2.Cl.CN(C)CCCN=C=NCC.[CH3:25][N:26]1[C:31](=[O:32])[CH:30]=[C:29]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:28]=[C:27]1[CH2:39][C:40]([O-])=[O:41].[Na+].O>CN(C)C=O.N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][N:6]2[C:40](=[O:41])[CH2:39][C:27]1[N:26]([CH3:25])[C:31](=[O:32])[CH:30]=[C:29]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:28]=1
Reactant: CC1(C)CNc2cccc(F)c21
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CC(C)(C)c3c(F)cccc32)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
150 mg of 4-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole [reference example 2c] and 279 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 300 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2c of example 4c) in 5 ml of N,N-dimethylformamide and 5 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours and then 30 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by trituration from a mixture of ethyl acetate and diisopropyl ether, so as to give 260 mg of 2-[2-(4-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one, the characteristics of which are the following:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O-:21])=[O:20])=[C:8]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[CH:13][N:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[K+].[C:25]([O:31][CH2:32]I)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C.ClCCl>[OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O:21][CH2:32][O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20])=[C:8]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[CH:13][N:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ncc4sccn34)[C@H](C)[C@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ncc4sccn34)[C@H](C)[C@H]12
Temperature: 25 °C
Yield: 112.1 %

Procedure:
To a solution of 40 mg of potassium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.8 ml of DMF was added at −30° C. 30 mg of pivaloyloxymethyl iodide, and the mixture was stirred for 1 hour during which the temperature was raised up to room temperature. The reaction mixture was diluted with 30 ml of dichloromethane, washed with semi-saturated aqueous saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue thus obtained was purified by column chromatography on silica gel (ethyl acetate:methanol=4:1) to give 54 mg of the title compound.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[C:2]#[C:3][CH2:4][CH3:5].I[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][O:19][CH3:20])[CH:12]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.O>[CH3:20][O:19][CH2:18][O:17][C:13]1[CH:12]=[C:11](/[C:2](=[C:3](\[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[CH2:4][CH3:5])/[C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH:16]=[CH:15][CH:14]=1
Reactant: CCC#CC(=O)OCC
Reactant: OB(O)c1ccccc1
Reactant: COCOc1cccc(I)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: N#Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C(\CC)c1ccccc1)c1cccc(OCOC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
A mixture of Ethyl 2-pentynoate (350 mg, 2.77 mmol), 1-iodo-3-(methoxymethoxy)benzene (1.46 g, 5.53 mmol), Phenylboronic acid (675 mg, 5.54 mmol) and K2CO3 (766 mg, 5.54 mmol) in DMF (8 ml)-H2O (2 ml) was stirred at room temperature for 10 min. Then PdCl2(PhCN)2 (10.6 mg, 0.0276 mmol) was added under Ar atmosphere, and the mixture was stirred at room temperature for 24 h. The reaction was quenched with H2O under ice cooling, and the whole was extracted with Et2O. The organic layer was washed with H2O, brine, dried over Na2SO4, then concentrated. Purification by Biotage HPFC (eluent: hexane to hexane/AcOEt, 10:1) gave 2a (25%). 2a: colorless oil; 1H-NMR (CDCl3) δ 1.02 (3H, t, J=7.4 Hz), 1.31 (3H, t, J=7.2 Hz), 2.65 (2H, t, J=7.4 Hz), 3.33 (3H, s), 4.29 (2H, t, J=7.2 Hz), 4.91 (2H, s), 6.65 (1H, m), 6.68 (1H, m), 6.74 (1H, ddd, J=1.0, 2.5, 8.3 Hz), 7.00-7.05 (3H, m), 7.10-7.19 (3H, m).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](OC(C)(C)C)=O)[CH:12]=[N:13][C:14]=1[Cl:15])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C=O>C(O)=O>[ClH:15].[ClH:15].[C:1]([C:9]1[CH:10]=[C:11]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[CH3:23])[CH:12]=[N:13][C:14]=1[Cl:15])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Agent: C=O
Solvent: O=CO
Product: CCCCCCC#Cc1cc(OC[C@H]2CCCN2C)cnc1Cl
Product: Cl
Temperature: 70 °C
Yield: 157 %

Procedure:
To 5-(1-octynyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 79a (330 mg, 0.78 mmol) was added formalin (37%, 9 mL) and formic acid (4.5 mL), and the mixture was heated at 70° C. for 2 hours. The solvent was concentrated, and solid NaHCO3 was added to the residue. At pH 8 the mixture was extracted with CH2Cl2, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with CH2Cl2:MeOH 100:1-100:3 to afford to give the free base of the title compound (166.5 mg, 64% yield). MS (CI/NH3) m/z 335 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 0.92 (m, 3H), 1.32 (m, 4H), 1.48 (m, 2H), 1.62 (m, 2H), 1.80 (m, 4H), 2.02 (m, 1H), 2.30 (m, 1H), 2.45 (m, 1H), 2.47 (s, 3H), 2.66 (m, 1H), 3.12 (m, 1H), 3.93 (m, 2H), 7.27 (m, 1H), 7.98 (m, 1H). The base was converted to the salt by treatment with HCl in Et2O to give the title compound. mp 114-116° C. (dec). MS (CI/NH3) m/z 335 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 1.02 (t, J=6.7 Hz, 3H), 1.43 (m, 4H), 1.58 (m, 2H), 1.71 (m, 2H), 2.06 (m, 1H), 2.21 (m, 2H), 2.42 (m, 1H), 2.56 (t, J=6.7 Hz, 2H), 3.06 (s, 3H), 3.28 (m, 1H), 3.77 (m, 1H), 3.87 (m, 1H), 4.41 (m, 2H), 7.50 (m, 1H), 8.12 (d, J=2.4 Hz, 1H). Anal. Calcd for C19H27N2OCl.1.5 HCl: C, 58.58; H, 7.37; N, 7.19. Found: C, 58.64; H, 7.39; N, 7.20. [α]25D=+8.99° (c 0.64, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: O
Solvent: COCCOC
Product: N#Cc1ccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1
Yield: 48.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.034 g (48%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.N1CCCCC1>CO>[CH:15](=[C:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:14])[CH3:13])[CH:6]=2)[C:2]1=[O:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)Nc1ccc2c(c1)CCC2=O
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(=O)Nc1ccc2c(c1)CC(=Cc1ccccc1)C2=O

Procedure:
A mixture of N-(1-oxoindan-5-yl)acetamide (10.0 g, obtained from the Maybridge Chemical Co. Ltd), benzaldehyde (6.73 g), glacial acetic acid (1.06 g) and piperidine (10.8 g) was heated to 90° C. under nitrogen. Methanol (200 ml) was added and the mixture was cooled and then filtered to give N-(2-benzylidene-1-oxo-indan-5-yl)acetamide (13.47 g).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]([NH:12][CH3:13])[CH2:10][CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1)[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O.N1C=CC=C[CH:27]=1>>[CH2:1]([C:3]1[C:8]([CH:9]([N:12]([CH3:13])[S:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH:10]([CH3:27])[CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncncc1C(CC)NC
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: O
Product: CCc1ncncc1C(C(C)C)N(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 56 %

Procedure:
0.4 g (0.2 mmol) of [1-(4-ethyl-pyrimidin-5-yl)-propyl]-methyl-amine was dissolved in 20 ml of pyridine, and 0.43 g (0.22 mmol) of p-fluorobenzenesulfonyl chloride was dropwise added, followed by stirring at room temperature for 10 hours. To the reaction solution, 50 ml of water was added, followed by extraction with diethyl ether. The obtained organic phase was washed twice with 30 ml of a dilute citric acid aqueous solution and then dried over anhydrous magnesium sulfate. Diethyl ether was distilled off under reduced pressure, and the obtained crude product was purified by silica gel chromatography (developing solvent/n-hexane:ethyl acetate 4:1 to 1:1) to obtain 0.4 g (yield: 56%) of (N-[1-(4-ethyl-pyrimidin-5-yl)-2-methylpropyl]-4-fluoro-N-methyl-benzenesulfonamide as a colorless oil (nD20=1.5399).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>CN(C1C=CN=CC=1)C.CC#N>[C:25]([NH:29][S:21]([C:19]1[CH:18]=[CH:17][C:8]2[N:9]([CH2:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][C:7]=2[CH:20]=1)(=[O:23])=[O:22])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (82 mg, 0.22 mmol), tert-butylamine (32 mg, 0.44 mmol) and DMAP (54 mg, 0.44 mmol) in MeCN (4 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 40 mg (41% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.17 (s, 9 H), 1.49-1.64 (m, 4 H), 1.66 (s, 9 H), 2.29-2.44 (m, 1 H), 3.29-3.38 (m, 2 H), 3.87-3.97 (m, 2 H), 4.52 (d, J=7.62 Hz, 2 H), 7.97-8.05 (m, 2 H), 8.21 (dd, J=1.46, 0.68 Hz, 1 H); MS (ESI) (M+H)+=408.0; Anal. Calcd for C21H33N3O3S+1.200 TFA+0.20 EtOAc+0.1H2O (563.83): C, 51.55; H, 6.44; N, 7.45. Found: C, 51.59; H, 6.28; N, 7.41.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([S:21](Cl)(=[O:23])=[O:22])[CH2:19][CH3:20].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:16][CH2:15][N:14]2[S:21]([CH2:18][CH2:19][CH3:20])(=[O:23])=[O:22])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2)no1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CC[C@H]1C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-Azetidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (100 mg; 0.385 mmol) in DMF (1 mL) is added n-propylsulfonyl chloride (0.043 mL; 0.385 mmol) and N,N-diisopropylethylamine (0.201 mL; 1.155 mmol). The reaction mixture is left stirring at room temperature for 18 hours. After this time, the reaction mixture is diluted with ethyl acetate and washed with water twice then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/hexanes provides the title compound, m/z 330 [M+H+].
Reaction SMILES: [CH2:1]([C:19]1([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[O:24][CH2:23][CH:22]([CH2:25]S(C)(=O)=O)[CH2:21][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:48][NH:49][CH3:50]>C1COCC1.CO.C(Cl)(Cl)Cl>[CH2:1]([C:19]1([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[O:24][CH2:23][CH:22]([CH2:25][N:49]([CH3:50])[CH3:48])[CH2:21][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCC(CS(C)(=O)=O)CO1
Reactant: CNC
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCC(CN(C)C)CO1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To the above crude material (VII, 1.0 g) under nitrogen was added 20 mL of dimethylamine in THF (2.0 M). The resulting mixture was stirred at room temperature for 7 days. An oily residual was obtained upon evaporation of the solvent. Column chromatography on silica gel (230-400 mesh, 100 mL) with 0-3% methanol gradient in chloroform as eluent resulted in 150 mg of the product DLin-K6S-C1-DMA as pale oil. 1H NMR (400 MHz, CDCl3) δ: 5.24-5.51 (8, m, 4×CH═CH), 4.04 (2H, dd, 2×OCH)), 3.75 (2H, dd OCH), 2.7-2.9 (2H, br, NCH2), 2.78 (4H, t, 2×C═C—CH2—C═C), 2.57 (6H, s, 2×NCH3), 1.95-2.17 (9H, q, 4× allylic CH2 and CH), 1.67-1.95 (2H, m, CH2), 1.54-1.65 (4H, m, 2×CH2), 1.22-1.45 (32H, m), 0.90 (6H, t, 2×CH3) ppm.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Br.Br.[NH:16]1[CH2:22][CH:21]([OH:23])[CH2:20][NH:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>CCO>[F:9][CH:8]([F:10])[CH2:7][N:6]1[C:2]([N:16]2[CH2:22][CH:21]([OH:23])[CH2:20][NH:19][CH2:18][CH2:17]2)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]1
Reactant: OC1CNCCNC1
Reactant: O=[N+]([O-])c1cnn(CC(F)F)c1Cl
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1cnn(CC(F)F)c1N1CCNCC(O)C1
Temperature: 130 °C
Yield: 90.8 %

Procedure:
A mixture of 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (800 mg, 3.78 mmol), 1,4-diazepan-6-ol dihydrobromide (1.58 g, 5.67 mmol) and DIPEA (2.5 mL, 14.35 mmol) in EtOH (6 mL) was heated at 130° C. in a microwave for 3 hr. The solvent was removed under reduced pressure and the residue was passed through an SCX column washing with DCM and 1:1 MeOH:DCM and MeOH and eluting with 1N ammonia in MeOH to give 1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)-1,4-diazepan-6-ol as a pale yellow gum (1.0 g). This gum (1.0 g, 3.44 mmol) was dissolved in DCM (100 mL) and treated with di-tert-butyl dicarbonate (2.25 g, 10.31 mmol) and DIPEA (2.4 mL, 13.75 mmol). The reaction mixture was stirred at room temperature for 1.5 hr and washed with saturated aqueous NaHCO3 solution (100 mL). The organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100%) EtOAc/isohexane gave tert-butyl 4-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)-6-hydroxy-1,4-diazepane-1-carboxylate as a pale green gum (46% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 6.18 (tdd, J=55.6, 5.6, 3.2 Hz, 1H), 4.49-4.31 (m, 2H), 4.19-2.95 (m, 10H), 1.60-1.40 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].C[CH:9](CO)[CH2:10][OH:11]>C1COCC1>[CH3:4][C:3]1([CH3:5])[O:6][CH2:7][CH:9]([CH2:10][OH:11])[CH2:1][O:2]1
Reactant: COC(C)(C)OC
Reactant: CC(CO)CO
Solvent: C1CCOC1
Product: CC1(C)OCC(CO)CO1

Procedure:
A solution of 2,2-dimethoxypropane (5.88 g, 56.5 mmol), 2-methyl-propane-1,3-diol (5.0 g, 47 mmol), and PTSA monohydrate (0.48 g, 2.3 mmol) in THF (100 mL) was stirred O/N at rt. The mixture was concentrated in vacuo to give the title compound as a colorless liquid: yield 6.87 g (99%).
Reaction SMILES: [CH2:1]1[CH2:31][O:30][C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:4][O:5][CH2:6][CH2:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17]C4CCCCO4)[C:11]=3[O:10][CH:9]=2)[O:2]1.Cl.O>C1COCC1>[CH2:1]1[CH2:31][O:30][C:3]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([CH2:4][O:5][CH2:6][CH2:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[O:10][CH:9]=2)[O:2]1
Reactant: c1ccc(C2(COCCc3coc4c(OC5CCCCO5)cccc34)OCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Oc1cccc2c(CCOCC3(c4ccccc4)OCCO3)coc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
3-(2-(2,2-ethylenedioxy-2-phenylethoxy)ethyl)-7-tetrahydropyranyloxybenzofuran (239 mg) was dissolved in THF (3 ml). To this solution, 6N hydrochloric acid (1 ml) was added and the resulting solution was stirred at room temperature for 30 minutes. The reaction solution was poured into water layer (30 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (189 mg, yield: 98%).