Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:13][C:14](O)=[O:15].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:40]([NH:42][NH2:43])=[O:41]>O1CCCC1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:13][C:14]([NH:43][N:42]=[C:40]=[O:41])=[O:15]
Reactant: NNC=O
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NN=C=O)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
A mixture of 3-(1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (3.0 g, 8.1 mmol) and carbonyidiimidazole (1.45 g, 8.94 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 2 hours. To the solution was added formic hydrazide (644 mg, 10.7 mmol). The mixture was stirred for 18 hours. The resulting suspension was filtered and washed with ether. The isolated solid was stirred in a mixture of ethyl acetate (40 mL) and water (10 mL) for 1 hour. The suspension was filtered and washed with water and ether to give crude 3-(1,3-dioxoisoindolin-2-yl)-N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)propanamide (1.3 g, 39% yield). A solution of 3-(1,3-dioxoisoindolin-2-yl)-N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)propanamide (600 mg, 1.46 mmol) and phosphorus oxychloride (POCl3, 0.54 mL, 5.8 mmol) in acetonitrile (20 mL) was heated to reflux for 2 hours. This solution was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography gave an oil. The oil was slurried in ether (10 mL). The resulting suspension was filtered to yield 2-[1-(3-ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]isoindoline-1,3-dione as a white solid (250 mg, 43% yield): mp, 132.0-134.0° C.; 1H NMR (CDCl3); δ 1.46 (t, J=6.9 Hz, 3H, CH3), 2.82 (dd, J=6.0, 15.6 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.11 (q, J=7.0 Hz, 2H, CH2), 4.37 (dd, J=10.3, 15.7 Hz, 1H, CHH), 5.81 (dd, J=6.0, 10.3 Hz, 1H, NCH), 6.62 (d, J=7.9 Hz, 1H, Ar), 7.13-7.17 (m, 2H, Ar), 7.67-7.72 (m, 2H, Ar), 7.75-7.62 (m, 2H, Ar), 8.29 (s, 1H, Ar); 13C NMR (CDCl3)δ 14.69, 27.70, 51.85, 55.90, 64.42, 111.32, 112.51, 120.32, 123.44, 130.14, 13163, 134.13, 148.39, 143.43, 153.03, 163.99, 167.93; Anal Calcd for C21H29N3O5: C, 64.12; H, 4.87; N, 10.68. Found: C, 63.84; H, 4.90; N, 10.48.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][CH:56]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)[F:57])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][N:54]([CH2:55][CH:56]([C:58]2[CH:59]=[CH:60][C:61]([Cl:64])=[CH:62][CH:63]=2)[F:57])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNCC(F)c2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CC(F)c2ccc(Cl)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
To a solution of 15 mg (0.08 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 24 mg of TBTU (0.08 mmol) in 1.5 ml DMF, were added 0.066 ml (0.38 mmol) of N,N-diisopropylethyl amine in 1 ml DMF. After stirring for 5 min at rt, 25 mg (0.08 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-2-fluoro-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 40 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 4:1) to give 9 mg (21%) of a light yellow solid. MS (ISP): 497.3 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](O)=[O:29].Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:6][CH2:5]1)=[O:29]
Reactant: c1ccc(-c2cc(N3CCNCC3)nc3c2CCCC3)cc1
Reactant: O=C(O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccco1)N1CCN(c2cc(-c3ccccc3)c3c(n2)CCCC3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
A mixture of 2-(1-piperazinyl)-4-phenyl-5,6,7,8-tetrahydroquinoline (1.2 g), 2-furancarboxylic acid (0.46 g), chloroform (40 ml) and 1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (0.79 g) is stirred at 25° C. for 2 hours. The reaction mixture is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in toluene and subjected to silica gel column chromatography. The fractions eluted with toluene and toluene-ethyl acetate (9:1) are collected and recrystallized from ethanol to give the desired product (0.4 g), m.p. 128°-130° C.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccncc3)c(C(=O)O)c2)=C(C)C1=O
Yield: 92.5 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridylmethyloxy)benzoic acid (0.425 g, 0.938 mmol) was dissolved in a mixed solution of acetonitrile (18 ml) and water (6 ml) and after adding thereto CAN (1.29 g, 2.35 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) and then recrystallized from ether to obtain the titled compound (0.376 g, 0.868 mmol, 93%).
Reaction SMILES: C([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=O.[NH2:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1>N1C=CC=CC=1>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[NH:16][S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:3][CH2:4][CH2:5]2)(=[O:13])=[O:14]
Reactant: Nc1nccs1
Reactant: O=CN1CCc2cc(S(=O)(=O)Cl)ccc21
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CCN2
Temperature: 60 °C
Yield: 53.3 %

Procedure:
A mixture of N-formyl-5-(chlorosulfonyl)indoline (60 g, 0.26 mol) and 2-amino thiazole (25 g, 0.26 mol) in pyridine (250 mL) was heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature and poured into ice/water. The solid was filtered, co-evaporated with toluene until completely dry and used in the next step without further purification. The crude material was brought to reflux in EtOH/KOH (600 mL, 15-20% KOH). After 2 hours a part of the ethanol was removed in vacuo and the light brown precipitate was filtered and crystallized from ethanol. The sulfonamide (39 g, 62% yield) was isolated with a purity of 90% according to HPLC-MS. 1H-NMR (DMSO-d6) δ 7.33-7.30 (m, 2H), 6.87 (d, J=3.8 Hz, 1H), 6.36-6.34 (m, 2H), 5.80 (s, 1H), 3.42 (dt, J=12.0, 4.3 Hz, 2H), 2.88 (t, J=8.5 Hz, 2H).
Reaction SMILES: [N:1]1([C:7]([NH:9][CH:10]([C:16]([CH3:24])([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([O:13]CC)=[O:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1.O>[N:1]1([C:7]([NH:9][CH:10]([C:16]([CH3:24])([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([OH:13])=[O:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(NC(=O)N1CCOCC1)C(C)(C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(c1ccccc1)C(NC(=O)N1CCOCC1)C(=O)O
Temperature: 35 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of the product from Example 115 (2 g, 5.99 mmol) in dioxane (10 ml) was treated with 0.26 g (6.5 mmol) of sodium hydroxide in 5 ml of water. After stirring for 16 h at 35° C., the reaction was worked up as described in Example 114 to give a 93% yield of product.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.O[CH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[CH2:13][CH2:12]1.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([NH:28][CH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[CH2:13][CH2:12]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)c1ccc2c(c1)C(O)CC2
Reactant: CC(C)(C)N
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(NC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of methanesulfonic acid anhydride (6.79 g, 39.062 mmol, 2.5 eq.) in DCM (20 ml) was added dropwise at −78° C. to a solution of methyl 3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (3.0 g, 15.625 mmol, 1.0 eq.) and TEA (11.0 ml, 78.125 mmol, 5.0 eq.) in DCM (60 ml) and stirred for 2 hours at the same temperature. tert-Butylamine (16 ml, 156.5 mmol, 10.0 eq.) was slowly added dropwise at −78° C., and the mixture was heated to RT and stirred for 14 hours. The reaction solution was diluted with DCM (100 ml), washed with water (2×50 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 13% ethyl acetate in hexane). Yield: 32% (1.2 g, 4.858 mmol)
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]([NH:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].FC(F)(F)C(O)=O.[ClH:31]>>[ClH:31].[NH2:16][CH2:15][CH2:14][NH:13][C:11]([C:3]1[C:2]([CH3:1])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:5][N:4]=1)=[O:12]
Reactant: Cc1c([N+](=O)[O-])ccnc1C(=O)NCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([N+](=O)[O-])ccnc1C(=O)NCCN

Procedure:
14.6 g of t-butyl [2-(3-methyl-4-nitropyridine-2-carboxamido)ethyl]carbamate were reacted with trifluoroacetic acid in an analogous manner to that described in Example 2, paragraph 2. The residue was converted into the hydrochloride which was recrystallized from methanol/ether, whereby there was obtained N-(2-aminoethyl)-3-methyl-4-nitropyridine-2-carboxamide hydrochloride as white crystals, m.p. 204°-205°.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:50]([OH:52])=[O:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:58]O>>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:50]([O:52][CH3:58])=[O:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(=O)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: O=S(=O)(O)O
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(=O)OC)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 41.4 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid 2a (0.38 g, 0.53 mmol) in methanol (8 mL) was added concentrated sulphuric acid (56.9 mg, 0.58 mmol) at room temperature. The mixture was stirred at 40° C. for 12 hours and quenched with 0.5 mL of saturated aqueous sodium hydrogen carbonate. Most of the solvent of the mixture was removed in vacuo. To the residue was added water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 2b as colorless oil (155 mg, 41.4%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.48 (m, 1H), 7.39 (m, 2H), 7.38-7.29 (m, 7H), 7.28-7.23 (m, 3H), 7.19 (m, 3H), 7.08 (m, 2H), 6.91-6.86 (m, 2H), 6.80-6.73 (m, 2H), 4.82 (m, 3H), 4.63 (d, 1H), 4.53 (d, 1H), 4.26 (d, 1H), 4.24-4.16 (m, 2H), 4.09 (d, 1H), 4.05-3.94 (m, 4H), 3.87 (d, 1H), 3.75 (d, 1H), 3.71 (s, 3H), 1.41 (t, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.Cl.[NH:22]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:23]([C:27](O)=[O:28])[CH:24]([CH3:26])[CH3:25]>CO>[NH:22]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:23]([C:27]([NH:1][C@H:2]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:8][CH:9]=1)=[O:28])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CO
Product: CC(C)OC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C

Procedure:
7.9 g (25 mmoles) of H-Tyr(But)-O-CH(CH3)2 hydrochloride and 6.27 g (25 mmoles) of Z-Val-OH are subjected to a condensation reaction analogously to Example 30 C. Yield 11.8 g (92%), melting point 133°-134°, [α]D26 =-25.2° (c=1, methanol).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([NH2:13])=[NH:12])[CH:6]=[CH:7][C:8]=1[NH2:9].Cl.[CH2:15]([O:17][C:18](=[O:25])[CH2:19][C:20](OCC)=N)[CH3:16]>C(O)(=O)C>[ClH:1].[NH:10]([C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:20]([CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:25])=[N:2][C:3]=2[CH:4]=1)[C:11]([NH2:13])=[NH:12]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: N=C(N)Nc1ccc(N)c(N)c1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc2cc(NC(=N)N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.6 %

Procedure:
A mixture comprising N-(3,4-diaminophenyl)guanidine hydrochloride (9.9 g, 49 mmol), ethoxycarbonimidoylacetic acid ethyl ester hydrochloride (12.4 g, 59 mmol) and acetic acid (20 mL) was heated in an oil bath at 110° C. and stirred for 1.5 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethanol (15 mL) and then ethyl acetate (10 mL) was added to the solution to give a precipitate in suspension. The suspension was filtered and an excess of ethyl ether was added to the filtrate to give a second precipitate. The precipitate was collected by filtration, washed with additional ethyl ether and dried in vacuo to provide ethyl 5-guanidino-1H-benzoimidazol-2-ylacetate hydrochloride (14.1 g, 94% yield) as an off white solid; 1H-NMR (300 MHz, DMSO-d6): 10.2 (s), 7.8 (d), 7.7 (m), 7.3 (d), 4.5 (s), 4.2 (q), 1.2 (t).
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:19])=[C:12]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)[CH:13]=2)OC1.Br[C:22]1[N:26]2[CH:27]=[CH:28][C:29]([C:31]([OH:34])([CH3:33])[CH3:32])=[N:30][C:25]2=[N:24][CH:23]=1>>[F:19][C:11]1[CH:10]=[CH:9][C:8]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([C:31]([OH:34])([CH3:32])[CH3:33])=[N:30][C:25]3=[N:24][CH:23]=2)=[CH:13][C:12]=1[N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: CC1(C)COB(c2ccc(F)c(-n3cccn3)c2)OC1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-n4cccn4)c3)cnc2n1

Procedure:
1-[5-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]-1H-pyrazole (300 mg, 1.0 mmol) was coupled to 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (256 mg, 1.0 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 5% methanol then trituration with diethyl ether gave 2-[3-(4-fluoro-3-(pyrazol-1-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid: δH (400 MHz, CDCl3) 1.63 (6H, s), 4.40 (1H, br s), 6.54 (1H, t, J 2), 7.09 (1H, d, J 7), 7.40-7.44 (2H, m), 7.77 (1H, d, J 2), 7.89 (1H, s), 8.13 (1H, t, J 3), 8.16-8.19 (1H, m), 8.65 (1H, d, J 7); m/z (ES+) 338 (M++H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:11][CH2:10][C@H:9]([OH:12])[C:6]2[CH:7]=[N:8][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:4][CH:5]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: OC[C@H](O)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)c2ccc(C(F)(F)F)nc2)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred solution of (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethane-1,2-diol (6.4 g, 31 mmol) and pyridine (20 mL) in CH2Cl2 (200 mL) at 0° C. was added p-toluenesulfonyl chloride (7.0 g, 37 mmol) in small portions. The mixture was slowly warmed to rt and stirred for 40 hours, and then diluted with CH2Cl2 (100 mL). The organic phase was washed with aq. NaHCO3, brine, and dried (Na2SO4), and concentrated to yield the crude title compound.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[CH3:14][O:15][C:16]1[C:17]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:19]/[C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[C:17]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Cc1nc2ccccn2c(=O)c1Br
Reactant: CCCCCCOc1c(C=O)cccc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCOc1c(/C=C/c2nc3ccccn3c(=O)c2Br)cccc1OC

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.501 g, 6.271 mmol) and 3-methoxy-2-(hexyloxy)benzaldehyde (1.642 g, 6.942 mmol) in the presence of sodium ethoxide (0.642 g, 9.401 mmol) in absolute ethanol (30 ml) as described in Intermediate 1 to give 986 mg of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 0.84-0.90 (m, 3H), 1.30-1.38 (m, 4H), 1.52-1.58 (m, 2H), 1.88 (t, J=6.9 Hz, 2H) 3.87 (s, 3H), 4.01 (t, J=6.9 Hz, 2H), 6.90 (d, J=8.1 Hz, 1H), 7.04-7.10 (m, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.59-7.70 (m, 3H), 8.38 (d, J=15.6 Hz, 1H), 8.94 (d, J=7.5 Hz, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([CH:8]=O)=[CH:6][CH:7]=1.[S:10]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]#[N:20])(=[O:17])=[O:16])=[CH:11]1>>[CH3:1][S:2][C:3]1[S:4][C:5](/[CH:8]=[C:18](/[S:15]([C:12]2[CH:13]=[CH:14][S:10][CH:11]=2)(=[O:17])=[O:16])\[C:19]#[N:20])=[CH:6][CH:7]=1
Reactant: CSc1ccc(C=O)s1
Reactant: N#CCS(=O)(=O)c1ccsc1
Product: CSc1ccc(/C=C(\C#N)S(=O)(=O)c2ccsc2)s1

Procedure:
Reaction of 2-methylmercaptothiophen-5-carboxaldehyde and thien-3-ylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-methylmercaptothien-5-yl)-2-(thien-3-ylsulfonyl)acrylonitrile
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[N:10]1([C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(F)nc1
Solvent: C1CCOC1
Product: O=Cc1ccc(N2CCCC2)nc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
6-Fluoro-3-pyridinecarboxaldehyde (152 mg, 1.22=01) was dissolved in tetrahydrofuran (3.0 mL). To this, pyrrolidine (507 μL, 6.08 mmol) was added under a nitrogen atmosphere at room temperature and the mixture was stirred at the same temperature for 2 hours and successively at 60° C. for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give 6-(pyrrolidin-1-yl)-3-pyridinecarboxaldehyde (181 mg, yield: 84%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9]([CH2:11][N:12]1[C:17]([CH3:18])=[CH:16][N:15]=[C:14](O)[C:13]1=[O:20])=[O:10])[CH3:7].O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:3][C:14]1[C:13](=[O:20])[N:12]([CH2:11][C:9]([O:8][CH2:6][CH3:7])=[O:10])[C:17]([CH3:18])=[CH:16][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cn1c(C)cnc(O)c1=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1c(C)cnc(Cl)c1=O
Temperature: 60 °C

Procedure:
PHOSPHOROUS OXYCHLORIDE (2.8 ML, 30 MMOL) WAS ADDED TO A STIRRED MIXTURE OF 1-ETHOXYCARBONYLMETHYL-3-HYDROXY-6-METHYLPYRAZINONE (5.3 G, 25 MMOL) IN DRY TOLUENE (50 ML) UNDER ARGON. THE RESULTING MIXTURE WAS HEATED TO 60° C. AFTER 64 H, THE MIXTURE WAS COOLED AND WATER AND ETHYL ACETATE WERE ADDED. THE ORGANIC LAYER WAS DRIED (NA2SO4) AND EVAPORATED IN VACUO. THE RESIDUE WAS PURIFIED BY FLASH COLUMN CHROMATOGRAPHY ON SILICA GEL (50% ETOAC/HEXANES) TO GIVE THE TITLE COMPOUND AS A CRYSTALLINE SOLID:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][S-:12].[Na+].C(OCC)(=O)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:12][CH3:11])[CH:5]=[O:6]
Reactant: C[S-]
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
The 3,4-diflourobenzaldehyde (52.1 g, 0.36 mol) was dissolved in acetonitrile (500 mL). Sodium thiomethoxide (25.6 g, 0.36 mol) was added in four equal portions at 15 minute intervals. The slightly exothermic reaction was stirred at room temperature for 4 hours. The reaction mixture was poured into ethyl acetate (500 mL) and extracted with saturated sodium bicarbonate (2×200 mL) followed by saturated ammounium chloride (2×100 mL). The solution was dried over sodium sulfate and solvent removed at reduced pressure. The 3-flouro-4-(methylthio)-benzaldehyde (38.5 g, 0.22 mol) was isolated by vacuum distillation (135-145° C. at 25 mm Hg) as clear liquid. (61% yield) ESHRMS m/z 171.0302 (calcd for M+H, 171.0280).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:24]([S:27](Cl)(=[O:29])=[O:28])([CH3:26])[CH3:25]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:27]([CH:24]([CH3:26])[CH3:25])(=[O:29])=[O:28])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 22 %

Procedure:
Following procedures essentially as described in Example 90, 3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine and isopropylsulfonyl chloride gives the title compound in 22% yield as a white solid, mp 187.7° C. 1H NMR (CDCl3) δ 1.28 (d, 6H), 2.80-3.60 (br m, 5H), 6.47 (s, 1H), 6.75-7.50 (m, 13H); MS (ES) 426 (M+Na), 402 (M−H). HPLC shows 94% purity.