Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[NH:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[C:22]([O:26][C:27]([NH:29][C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:22]([O:26][C:27](=[O:28])[NH:29][C:30]1([C:33]([NH:2][C:3](=[O:21])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][CH:6]=2)=[O:34])[CH2:31][CH2:32]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(Cc1ccc(CCCCc2ccccc2)cc1)NO
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(=O)Cc2ccc(CCCCc3ccccc3)cc2)CC1
Reaction time: 8 h

Procedure:
N-hydroxy-2-(4-(4-phenylbutyl)phenyl)acetamide 174 (1 equiv, 156 mg, 0.55 mmol) was dissolved in DMF (3 mL). 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (1.5 equiv, 166 mg, 0.83 mmol) was then added followed by the sequential addition of HOBt (1 equiv, 74 mg, 0.55 mmol) and EDC (1.5 equiv, 158 mg, 0.83 mmol). The reaction was then stirred overnight. The reaction was then partitioned between EtOAc (5 mL) and H2O (5 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by trituration with Et2O to afford tert-butyl-1-((2-(4-(4-phenylbutyl)phenyl)acetamidooxy)carbonyl)cyclopropylcarbamate in 166 mg (65%). LRMS: 466.5 (calc) 489.3 (MNa)+.
Reaction SMILES: [CH3:1][NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([C:50]([O:52]C)=O)=[CH:48][C:47]([CH3:54])=[N:46]2)=[CH:31][CH:30]=1.CN>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([C:50]([NH:2][CH3:1])=[O:52])=[CH:48][C:47]([CH3:54])=[N:46]2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1cc(C)nn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: CN
Product: CNC(=O)c1cc(C)nn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from 3 methyl 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-3-methyl-1H-pyrazole-5-carboxylate and methylamine. M/e+ 380 for C20H19ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.29 (d, J=6.6 Hz, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.23 (m, 1H), 6.82 (t, J=6.9 Hz, 1H), 6.66 (s, 1H), 6.05 (s, 2H), 3.84 (s, 3H), 2.19 (s, 3H) 1.57 (s, 1H), ppm;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:15]=[CH:19][CH:18]=[CH:17]1)[CH3:2]
Reactant: CCOC(=O)c1ccccc1N
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccccc1-n1cccc1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-amino benzoic acid ethyl ester (20 g; 121 mmol) in acetic acid (35 mL) was added 2,5-dimethoxytetrahydrofuran (19 g; 174 mmol). The reaction mixture was stirred for two hours at reflux. After evaporation of the solvent, the crude product was purified by flash column chromatography (methylene chloride) to give compound 2-pyrrol-1-yl-benzoic acid ethyl ester as a yellow oil.
Reaction SMILES: ClC1C=CC=CC=1C([NH:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:10]=[C:9]([CH3:21])[C:8]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])=O.Br.O>C(O)(=O)C>[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:10]=[C:9]([CH3:21])[C:8]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29]
Reactant: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(NC(=O)c2ccccc2Cl)c1C(=O)c1ccccc1Cl
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(=O)c1ccccc1Cl

Procedure:
A solution of 1.94 g (3.50 mmol of the product of Step B in 20 mL of glacial acetic acid was treated with 20 mL of 48% hydrogen bromide and stirred at reflux for 8 hours. The cooled reaction mixture was treated with water to crystallize the product which was separated by filtration, washed with water and air dried to give the title product, 1.45 g (100%), m.p. softens about 210° C. and melts at 220° C. Anal. Calcd. for C17H11ON3Cl4 : 412.9656. Found: 412.9722.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:37]2[CH:36]=[N:35][C:34]([N:31]3[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]3)=[CH:39][CH:38]=2)[CH:3]=1)=[O:15]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C)CC4)nc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv), 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired compound (30% yield). LCMS: 515.20 (M+1)+; HPLC: 98.36% (@ 254 nm), (Rt; 4.876); 1H NMR (DMSO-d6, 400 MHz) δ 11.53 (s, 1H), 9.01 (s, 1H), 8.85 (t, 1H), 8.36 (d, 1H, J=8.8 Hz), 8.31 (s, 1H), 8.07 (s, 1H), 6.97 (d, 1H, J=8.4 Hz), 5.89 (s, 1H), 5.32-5.25 (m, 1H), 4.40 (d, 2H, J=4.4 Hz), 3.61 (t, 4H), 2.41 (t, 4H), 2.22 (s, 6H), 2.12 (s, 3H), 1.53 (d, 6H, J=6.8 Hz).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])=[CH2:2].[Cl:8][CH2:9][C:10](Cl)=[O:11].CN1CCOCC1.O>COC(C)(C)C>[Cl:8][CH:9]1[CH:1]([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][C:10]1=[O:11]
Reactant: C=COCC(C)C
Reactant: O=C(Cl)CCl
Solvent: CN1CCOCC1
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)COC1CC(=O)C1Cl
Yield: 75.8 %

Procedure:
A solution formed by dissolving 30.0 g of isobutyl vinyl ether (0.3 mol) as the compound (V) and 34.9 g of chloroacetyl chloride (0.3 mol) as the compound (VI) in 135 ml of tert-butyl methyl ether was heated to 50˜55° C. with stirring. Subsequently, a solution formed by dissolving 30.3 g of N-methylmorpholine (with a pKa value of 7.4) (0.3 mol) in 45 ml of tert-butyl methyl ether was added dropwise to the aforementioned solution over two hours. Four hours after the completion of the dropwise addition, 40 ml of water was added thereto in order to separate the solution, followed by removal of the water layer. Analysis of the organic layer using gas chromatography under the following analysis conditions, revealed a yield of 75.8% for the compound (IV), 2-chloro-3-isobutoxycyclobutanone. Furthermore, after concentration of the aforementioned organic layer, a sample for analysis was obtained by means of distillation, and analyzed by means of elemental analysis and nuclear magnetic resonance analysis (NMR).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])(=O)C.[Na+].[Br:20]Br.O>C(O)(=O)C>[Br:20][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:11][CH2:12][C:13]#[N:14]
Reactant: COc1ccc(CCC#N)cc1OC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c(CCC#N)cc1OC
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a mixture of 21 g of 3-(3,4-dimethoxyphenyl)propanenitrile, 10.3 g of sodium acetate and 400 mL of acetic acid there are added 20 g of dibromine in 50 mL of acetic acid. The resulting reaction mixture is stirred overnight and then poured into water and extracted with benzene. The organic phase is washed with aqueous sodium thiosulphate solution and then with water, dried over sodium sulphate and concentrated under reduced pressure. The crude reaction product is purified on a silica column (eluant: benzene), and the product obtained is recrystallised from ethanol to yield 19.3 g of the expected product.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.C(N(CC)C(C)C)(C)C.Cl.[NH2:44][C:45]([CH3:51])([CH3:50])[C:46]([O:48][CH3:49])=[O:47]>CN(C=O)C>[CH3:49][O:48][C:46](=[O:47])[C:45]([NH:44][C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1])=[O:14])([CH3:51])[CH3:50]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1O
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a solution of 4.70 g 1-hydroxy-2-naphthalene carboxylic acid in 40 ml abs. DMF under inert atmosphere 3.72 g 1-hydroxybenzotriazole and 8.89 g N,N′-diisopropyl carbodiimide and 7 ml of N,N-diisopropylethylamine were added at 0° C. After 30 minutes at 0° C. 4.22 g of methyl 2-aminoisobutyrate hydrochloride, followed by 5 ml of N,N-diisopropylethylamine were added. After 16 h at room temperature the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl and brine. The organic layer was dried over magnesium sulphate, and concentrated and the resulting residue was crystallized from toluene to yield 4.18 g of 2-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester. C16H17NO4 (287.12), LCMS (ESI): 287.97 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[NH:4][CH2:5][C:6]1[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][CH:16]=2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1.C(N(CC)CC)C.[C:40](Cl)(Cl)=[O:41]>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[N:4]1[CH2:5][C:6]2[C:7](=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=2)[N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:19][CH:20]=2)[C:40]1=[O:41]
Reactant: CSc1ncc(CNc2ccccc2Br)c(Nc2ccc(COC3CCCCO3)cc2)n1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N(c1ccc(COC3CCCCO3)cc1)C(=O)N(c1ccccc1Br)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution containing 0.93 g (1.8 mmol) of 5-(2-bromoanilino)methyl-4-[4-(tetrahydropyran-2-yloxymethyl)phenyl]amino-2-methylthiopyrimidine and 0.5 ml (3.61 mmol) of triethylamine in 5 ml of anhydrous tetrahydrofuran was added dropwise to 1.9 ml (3.61 mmol) of a 20% solution of phosgene in toluene dissolved in 5 ml of tetrahydrofuran at 0° C. under an atmosphere of nitrogen. The reaction was stirred at 0° C. for a further 60 minutes then evaporated. The residue was partitioned between ethyl acetate (10 ml) and 2M hydrochloric acid (10 ml), the ethyl acetate layer was separated then washed with saturated aqueous sodium bicarbonate (10 ml), dried over magnesium sulfate, filtered and evaporated to give 0.945 g (97%) of 3-(2-bromophenyl)-3,4-dihydro-1-[4-(tetrahydropyran-2-yloxymethyl)phenyl]-7-methylthio-pyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow gum. [Mass spectrum (ESI) MH+ =541].
Reaction SMILES: [C:1]([CH:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C@H:6]([CH2:15][OH:16])[CH2:5]1)(=[O:3])[CH3:2].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>ClCCl>[C:1]([CH:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C@H:6]([CH2:15][O:16][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCOC(=O)N1CC(C(C)=O)C[C@H]1CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=CCOC(=O)N1CC(C(C)=O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of (2S)-4-acetyl-1-allyloxycarbonyl-2-hydroxymethylpyrrolidine (2.14 g) and imidazole (770 mg) in dichloromethane (20 ml) was added dropwise a solution of tert-butyldimethylsilyl chloride (1.7 g) in dichloromethane (5 ml) at 0° C. After one hour, the reaction mixture was washed in turn with 1N-hydrochloric acid and brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (2:1, V/V) to give (2S)-4-acetyl-1-allyloxycarbonyl-2-(tert-butyldimethylsilyloxy)methylpyrrolidine (2.725 g).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[C:26]([Cl:28])[CH:27]=1)=[O:9])([CH3:6])[CH3:5].[O-:31][CH2:32][CH3:33].[Na+].O.Cl>CCO>[Cl:28][C:26]1[CH:27]=[C:22]([CH2:21][O:20][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:2])=[O:30])=[O:9])[CH:23]=[N:24][C:25]=1[O:31][CH2:32][CH3:33]
Reactant: CC[O-]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ncc(COc2c(C(=O)NC(C)(C)C(=O)O)ccc3ccccc23)cc1Cl
Yield: 80.8 %

Procedure:
A solution of 50 mg 2-{[1-(5,6-dichloro-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester and 30 mg sodium ethoxide in 3 ml EtOH containing 5% of water was heated to 120° C. for 2 min using a microwave reactor. The reaction mixture was acidified to pH 4 with 2 M HCl and the precipitated solid was collected by filtration and purified by RP-HPLC to yield 40 mg 2-{[1-(5-chloro-6-ethoxy-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]([Cl:10])=[CH:8][CH:9]=1)=O.[N:11]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[S:22])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39]>C(O)C>[Cl:10][C:7]1[S:6][C:5]([C:3]2[N:23]=[C:21]([N:20]([CH2:19][CH2:18][CH2:17][N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[C:38]([C:34]3[S:33][CH:37]=[CH:36][CH:35]=3)=[O:39])[S:22][CH:2]=2)=[CH:9][CH:8]=1
Reactant: NC(=S)NCCCN1CCOCC1
Reactant: O=C(Cl)c1cccs1
Reactant: O=C(CBr)c1ccc(Cl)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(c1cccs1)N(CCCN1CCOCC1)c1nc(-c2ccc(Cl)s2)cs1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
A mixture of 2-bromo-1-(5-chloro-thiophen-2-yl)-ethanone (72 mg, 0.3 mmol) and (3-morpholin-4-yl-propyl)-thiourea (61 mg, 0.3 mmol) in dry ethanol (3 ml) was heated at reflux for 10 min, cooled to room temperature, and concentrated in vacuo. The resulting residue was suspended in dichloromethane (3 mL) followed by the addition of N,N-diisopropylethylamine (105 μL, 0.6 mmol) and thiophene-2-carbonyl chloride (34 μL, 0.32 mmol). The reaction mixture was maintained at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in DMSO (1.5 mL) and subjected to HPLC purification (Method Y). The resulting free amine was dissolved in MeOH (1 mL) and 1M HCl/ether (50 mL) was added. The precipitate was filtered and dried in vacuo to provide the title compound (61 mg) as an yellow solid as the hydrochloride salt. LC/MS (ESI) m/z 453.9 [M+H]. HPLC retention time (Method A)=2.93 min.
Reaction SMILES: C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C=CC(C[Cl:26])=CC=1.C(Cl)Cl.[CH2:30]([P:38]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C>[Cl-:26].[CH2:47]([PH+:38]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: ClCc1ccccc1
Reactant: CCCCCCCCP(CCCCCCCC)CCCCCCCC
Agent: C=Cc1ccc(C=C)cc1
Solvent: CN(C)C=O
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCC[PH+](CCCCCCCC)CCCCCCCC
Product: [Cl-]

Procedure:
Merrifield's peptide resin (Aldrich, 1.1 meq/g of Cl), 20.0 g was stirred in a solution of 100 mL of CH2Cl2 and 100 mL of dry DMF with 92.4 g of tri-n-octylphosphine under argon. The slurry was filtered and the beads washed with 3×200 mL of CH2Cl2. The product was dried in the air and then under vacuum to produce 21.2 g of trioctylphosphonium chloride substituted polymer.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].CCN(C(C)C)C(C)C.Cl[C:49]([O:51][CH3:52])=[O:50]>C(Cl)Cl>[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([C:35]([F:38])([F:36])[F:37])(=[O:33])=[O:34])=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][N:19]([C:49]([O:51][CH3:52])=[O:50])[CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9]
Reactant: COC(=O)Cl
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)n2)CC[NH2+]CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[4-Carbamoyl-3-({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-7) (30 mg, 0.053 mmol) was dissolved in DCM (1.0 mL). DIPEA (0.055 mL, 0.32 mmol) was added, followed by methyl chloroformate (0.024 mL, 0.32 mmol). The resulting mixture was allowed to stir at ambient temperature for 30 minutes. The solvent was removed in vacuo and the crude residue was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #27-1, as a solid.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].O>CS(C)=O>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COc1nc2cc(C)ccc2nc1Cl
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CNc2nc3ccc(C)cc3nc2OC)c(OC)c1
Temperature: 60 °C
Reaction time: 45 h
Yield: 90.4 %

Procedure:
To 2-chloro-3-methoxy-6-methylquinoxaline (3.05 g, 14.6 mmol) dissolved in dimethylsulfoxide (40 ml), 2,4-dimethoxybenzylamine (9.77 g, 58.4 mmol) was added at room temperature. The mixture was stirred at 60° C. for 45 hours and then water was added thereto. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (13:1) mixture and concentration gave 4.48 g of the titled compound (yield, 90%).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([N+:37]([O-])=O)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]([NH2:37])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])cc1OCCCCCCCCCCCCCC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(N)cc1OCCCCCCCCCCCCCC
Yield: 87.7 %

Procedure:
A mixture of 3.5 g of 3,4-bis(tetradecyloxy)nitrobenzene and 0.5 g of 10% palladium on carbon in 80 ml of THF and 40 ml of ethyl acetate was stirred in a hydrogen atmosphere for 4 hours when uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was recrystallized from ethyl acetate-hexane to give 2.9 g (88% yield, mp 55°-58°) of 3,4-bis(tetradecyloxy)benzenamine.
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([CH3:20])=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH3:3].[C:21]([O:25][C:26](=[O:40])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]C(=O)C)=[CH:31][C:30]=1[CH3:39])([CH3:24])([CH3:23])[CH3:22].C(OC(=O)COC1C=CC(S)=CC=1C)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.CO>[C:21]([O:25][C:26](=[O:40])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35][CH:2]([C:4]2[C:5]([CH3:20])=[N:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)[CH3:3])=[CH:31][C:30]=1[CH3:39])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Reactant: CC(=O)Sc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Agent: Cc1cc(S)ccc1OCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC#N
Product: Cc1cc(SC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)OC(C)(C)C
Yield: 54.1 %

Procedure:
0.224 g (0.75 mmol) of [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine and 0.222 g (0.75 mmol) of (4-acetylsulfanyl-2-methyl-phenoxy)-acetic acid tert-butyl ester (prepared by standard acetylation of (4-mercapto-2-methyl-phenoxy)-acetic acid tert-butyl ester, described below in example 28A)-C]) were dissolved in 3.9 ml of acetonitrile and 0.2 ml of MeOH and treated with 0.292 g (1.2 eq.) of Cs2CO3. The reaction was then allowed to proceed over night. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9/1), afforded in the less polar fractions 0.210 g of pure title compound and in the more polar fractions 0.112 g of the corresponding methyl ester as waxy solid.