Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][CH2:18][CH2:19][CH2:20][NH:21][CH3:22])=[C:13]([Cl:23])[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][S:25]([NH:28][C:29]1[CH:38]=[CH:37][C:32]([O:33][CH2:34][CH2:35]Cl)=[CH:31][CH:30]=1)(=[O:27])=[O:26].C(N(CC)CC)C.N>CO.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:35][CH2:34][O:33][C:32]2[CH:31]=[CH:30][C:29]([NH:28][S:25]([CH3:24])(=[O:26])=[O:27])=[CH:38][CH:37]=2)[CH3:22])=[C:13]([Cl:23])[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCCNc1c(Cl)cnn(COCc2ccccc2)c1=O
Reactant: CS(=O)(=O)Nc1ccc(OCCCl)cc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCCNc1c(Cl)cnn(COCc2ccccc2)c1=O)CCOc1ccc(NS(C)(=O)=O)cc1
Reaction time: 16 h
Yield: 34.4 %

Procedure:
A mixture of 3.2 g (9.5 mmoles) of 2-benzyloxymethyl-5-chloro-4-[3-(N-methylamino)-propylamino]-3(2H)-pyridazinone, 3.56 g (14.25 mmoles) of 4-[(methylsulfonyl)-amino]-phenoxyethyl chloride and 2 ml (14.25 mmoles) of triethylamine is melted at a temperature of 80° C. for 16 hours. Then it is subjected to column chromatography using first ethyl acetate, then a 9:1:0.5 mixture of ethyl acetate--methanol--cc. ammonia. Thus 1.8 g (69%) of the aimed compound are obtained. Rf =0.7.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:24][O:25][C:26](=[O:53])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]#[C:45][C:46]2[CH:51]=[CH:50][C:49](Br)=[CH:48][CH:47]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[C:22][C:49]2[CH:50]=[CH:51][C:46]([C:45]#[C:44][C:41]3[NH:40][C:39]([CH:35]4[CH2:36][CH2:37][CH2:38][N:34]4[C:32](=[O:33])[CH:28]([NH:27][C:26]([O:25][CH3:24])=[O:53])[CH:29]([CH3:31])[CH3:30])=[N:43][CH:42]=3)=[CH:47][CH:48]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(Br)cc2)[nH]1)C(C)C
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(C#Cc3cnc(C4CCCN4C(=O)C(NC(=O)OC)C(C)C)[nH]3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (49 mg, 0.154 mmol), (1-{2-[5-(4-bromo-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (43 mg, 0.0908 mmol), Pd(PPh3)4 (10 mg, 0.00908 mmol), CuI (2 mg, 0.00908 mmol) and triethylamine (0.127 mL, 0.908 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80° C. for 4 hours then cooled to RT. Formic acid (0.1 mL) and water (1 mL) were added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (11 mg, 17%). 1H NMR (MeOH-d4, 400 MHz) 7.46 (d, J=3.9 Hz, 4H), 7.25 (s, 2H), 6.96 (d, J=8.4 Hz, 2H), 5.10 (m, 2H), 4.20 (m, 2H), 3.97 (m, 2H), 3.83 (m, 2H), 3.64 (s, 6H), 2.32-2.00 (m, 10H), 0.98-0.88 (m, 12H); MS (ESI) m/z 711 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]([C:13]([OH:15])=O)[CH:6]=[N:5]2.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]([C:13]([NH:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1)=[O:15])[CH:6]=[N:5]2
Reactant: Cc1cc2ncc(C(=O)O)nc2cc1C
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: Cc1cc2ncc(C(=O)Nc3nnn[nH]3)nc2cc1C

Procedure:
6,7-Dimethyl-2-quinoxalinecarboxylic acid (0.7 g) and N,N'-carbonyldiimidazole (0.84 g) in dimethylformamide (10 ml) were stirred and heated at 60° for 6 hours. 5Amino-1H-tetrazole (0.66 g) was added and the mixture was stirred and heated at 60° for a further 30 minutes. The solid was collected and dissolved in aqueous dimethylaminoethanol. Aqueous acetic acid was added and the solid was collected and dried. It had m.p. 304° (d) (46%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[C:29]=1[OH:30])[CH:25]=O)[CH3:20].[NH2:34][C:35]([NH2:37])=[O:36].Cl>CCO>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:25]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[NH:37][C:35](=[O:36])[NH:34]2)[CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[C:29]=1[OH:30])[CH3:20]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1F
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(OC)c(F)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 47.8 %

Procedure:
A mixture of 1-(3-fluoro-4-methoxyphenyl)-2-phenylethanone (100 mg, 0.41 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (72 mg, 0.34 mmol), urea (61 mg, 1.02 mmol), and concentrated HCl solution (0.03 mL, 0.34 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo, and the residue was purified by preparative HPLC to give Compound 39 (78 mg, yield 48%). 1H NMR (DMSO-d6 400 MHz): δ 10.28 (s, 1H), 8.71 (s, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 7.17 (s, 1H), 7.10-7.01 (m, 5H), 6.95 (d, J=9.2 Hz, 1H), 6.85 (d, J=6.8 Hz, 2H), 5.18 (s, 1H), 4.08-4.01 (m, 2H), 3.79 (s, 3H), 1.33 (t, J=7.2 Hz, 3H); MS (ESI): m/z 480.0 [M+1]+.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[CH:5].[CH3:12][C:13]1([CH3:29])[CH2:18][O:17][P:16](=[O:20])([OH:19])[O:15][CH:14]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28]>C(O)C>[CH3:12][C:13]1([CH3:29])[CH2:18][O:17][P:16](=[O:19])([OH:20])[O:15][CH:14]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28].[NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(N)c1ccccc1
Agent: COc1ccccc1C1OP(=O)(O)OCC1(C)C
Solvent: CCO
Product: C#CC[C@@H](N)c1ccccc1
Temperature: 25 °C

Procedure:
Dissolve (RS)-1-amino-1-phenyl-but-3-yne [Zh. Org. Khim. 18(4), 980-983 (1982) A. Mostamandi, L. A. Remizova, A. L. Pavienkova, I. A. Favorskayal] (20.0 g, 138 mmol) and (-)-5,5-dimethyl-2-hydroxy-4-(2-methoxyphenyl)-1,3,2,-dioxaphosphorinane 2-oxide (35.0 g, 129 mmol) in refluxing ethanol (300 mL). Cool the solution to ambient temperature and collect the precipitate by filtration. Rinse the precipitate with a small amount of isopropanol/ethanol (1/1). Two recrystallizations from ethanol gives (R)-1-amino-1-phenyl-but-3-yne 5,5-dimethyl-2-hydroxy-4-(2-methoxyphenyl)-1,3,2-dioxaphosphorinane 2-oxide salt (21 g). Combine (R)-1-amino-1-phenyl-but-3-yne 5,5-dimethyl-2-hydroxy-4-(2-methoxyphenyl)-1,3,2-dioxaphosphorinane 2-oxide salt (21 g, 50.4 mmol) with a mixture of aqueous 1M potassium hydroxide solution (100 mL) and toluene (50 mL) and stir or 0.75 hour. Separate the layers and extract the aqueous layer with toluene (50 mL), combine the organic layers, dry over (Na2SO4), and filter to obtain a solution. Pass hydrogen chloride gas through the solution until it is saturated and then remove the precipitate by filtration and rinse with toluene. Recrystallize from butanone (120 mL) to give 7.0 g the title compound. Specific rotation [α]2D0 =11.0° (c=0.500, MeOH).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:24].[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[CH2:8]1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccsc1Br)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccsc1Br)C2
Temperature: 90 °C
Reaction time: 13 h
Yield: 90.6 %

Procedure:
To a mixture of 7-(2-bromothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.12 g) and aminoguanidine hydrochloride (45 mg) were added ethanol (2 ml) and concentrated hydrochloric acid (0.05 ml), and the mixture was stirred at 90° C. for 13 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 7-(2-bromothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 123) (0.14 g) as pale yellow crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:24]=[N:23][C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[NH:18][C:13]=2[N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][CH2:29]Cl>O1CCCC1>[O:8]([CH2:9][CH2:10][C:11]1[CH:24]=[N:23][C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]([CH2:27][O:28][CH3:29])[C:13]=2[N:12]=1)[Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cnc2c(n1)Nc1ccccc1S2
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN1c2ccccc2Sc2ncc(CCO[Si](C)(C)C(C)(C)C)nc21

Procedure:
603 mg of 8-[(2-(tert-butyldimethylsilyloxy)ethyl]-10H-pyrazino[2,3-b][1,4]benzothiazine was dissolved in 6 ml of tetrahydrofuran. After adding 63 mg of 70% sodium hydride, the resulting mixture was stirred under ice-cooling for 15 minutes. Then 0.14 ml of chloromethyl methyl ether was added thereto and the resulting mixture was stirred for 1 hour and for additional 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 463 mg of the title compound as a brown oily substance.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:29][C@H:30]1[C@@H:34]([CH3:35])[CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:29][C@H:30]1[C@@H:34]([CH3:35])[CH2:33][N:32]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:31]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1c(N2C[C@@H](N)[C@@H](C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (150 mg), DBU (110 mg) and anhydrous acetonitrile (3 ml) was refluxed for 5 hours. After cooling, the resulting precipitate was collected by filtration. This precipitate was added to the mixture of concentrated hydrochloric acid-methanol (1:1, 6 ml) and stirred for 1.5 hours at room temperature. The reaction mixture was neutralized by concentrated aqueous ammonia and allowed to stand in the refrigerator. The resulting crystals were collected by filtration and washed with cold water to give the title compound (90 mg) as colorless prisms, mp 185°-188° C. (decompd.).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[CH:38]=[C:37]3[C:33]([CH2:34][CH2:35][N:36]3[C:39](=[O:41])[CH3:40])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[C:39]([N:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([N:29]([CH:26]3[CH2:25][CH2:24][N:23]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:28][CH2:27]3)[C:9](=[O:11])[C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:38]=2)[CH2:34][CH2:35]1)(=[O:41])[CH3:40]
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Reactant: O=C(O)C#Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)N1CCc2ccc(N(C(=O)C#Cc3ccccc3)C3CCN(Cc4ccccc4)CC3)cc21
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A mixture of phenyl-propynoic acid (220 mg, 1.5 mmol) and thionyl chloride (3.0 mL) in toluene (3.0 mL) was heated at reflux for 4 h. The reaction mixture was cooled to rt and the excess thionyl chloride and toluene were removed under reduced pressure. The resulting crude acid chloride was dissolved in CH2Cl2 (5 mL) and treated with 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (349 mg, 1.0 mmol) and TEA (0.28 mL, 2.0 mmol) at rt for 20 h. The reaction mixture was concentrated, and the residue was purified on silica gel (60-70% EtOAc/hexanes) to afford the title compound (402 mg, 84%). 1H NMR (500 MHz, CDCl3): 8.12 (s, 1H), 7.28-7.18 (m, 9H), 7.09 (d, J=7.8 Hz, 2H), 6.86 (dd, J=8.0, 1.7 Hz, 1H), 4.65-4.59 (m, 1H), 4.13 (t, J=8.5 Hz, 2H) 3.44 (s, 2H), 3.24 (t, J=8.5 Hz, 2H), 2.89 (d, J=10.7 Hz, 2H), 2.22 (s, 3H), 2.10 (t, J=10.8 Hz, 2H), 1.90-1.78 (m, 2H), 1.63-1.58 (m, 2H). MS: exact mass calculated for C31H31N3O2, 477.24; m/z found, 478.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][N:6]=1.Cl[C:10]1C(CCl)=CC=C(Cl)[N:11]=1>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:11][CH3:10])=[CH:5][N:6]=1
Reactant: ClCc1ccc(Cl)nc1Cl
Reactant: ClCc1cnc(Cl)s1
Solvent: ClCCl
Product: CNCc1cnc(Cl)s1

Procedure:
The reaction procedure of Reference Example 11 was repeated except that crude 2-chloro-5-chloromethylthiazole was used in lieu of 2,6-dichloro-3-pyridylmethyl chloride and that CH2Cl2 was used as the extractant. The procedure gave the title compound as a crude oil.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11]N2C=CC=CC2)=[O:9])=[C:6]([CH3:20])[CH:5]=1)(=[O:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1.C([N:39]([CH2:44][CH2:45][CH2:46][CH3:47])[CH2:40]CCC)CCC>C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([C:29]([OH:34])([C:30]([F:31])([F:32])[F:33])[CH2:2][C:1]([C:4]2[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][C:44]3[CH:45]=[CH:46][CH:47]=[CH:40][N:39]=3)=[O:9])=[C:6]([CH3:20])[CH:5]=2)=[O:3])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: CCCCN(CCCC)CCCC
Reactant: CC(=O)c1ccc(C(=O)NCN2C=CC=CC2)c(C)c1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCc1ccccn1
Temperature: 60 °C
Reaction time: 10 h
Yield: 150.6 %

Procedure:
1.52 g of 4-acetyl-2-methyl-N-(pyridin-1-ylmethyl)benzoic acid amide, 1.51 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.51 g of toluene and 0.52 g of tri-n-butylamine were fed and the mixture was stirred for 10 hours at 60° C. The mixture was left to cool to room temperature and 1 ml of toluene was added to the slurry-state reaction solution. The slurry was filtered under reduced pressure, and the solid was washed with a small amount of toluene. 2.16 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methyl-N-(pyridin-2-ylmethyl)benzoic acid amide as a flesh color solid was obtained by drying under reduced pressure.
Reaction SMILES: [ClH:1].C(S[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[NH:11])C1C=CC=CC=1.[NH2:18][CH:19]([C:25]#[N:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(OCC)C>C(Cl)(Cl)Cl>[ClH:1].[NH2:26][C:25]1[NH:11][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: N=C(SCc1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(N)C#N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)c1nc(-c2ccccc2)[nH]c1N
Reaction time: 8 h

Procedure:
Phenylformimino benzyl thioether hydrochloride (28.5gm) was refluxed in chloroform (200 ml) with ethyl aminocyanoacetate (17.0gm) for 1 hour. On standing for 8 hours the addition of dry diethyl ether (250 ml) caused the precipitation of the 5-amino-4-carbethoxy-2-phenylimidazole hydrochloride (24.5gm) m.p. 228° C after recrystallisation from ethanol.
Reaction SMILES: [OH:1][C@@:2]1([CH2:20][OH:21])[CH2:11][C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[C:4]2([S:19][CH2:18][CH2:17][S:16]2)[CH2:3]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:21][CH2:20][C@:2]1([OH:1])[CH2:11][C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[C:4]2([S:16][CH2:17][CH2:18][S:19]2)[CH2:3]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(OC)c2c1C[C@@](O)(CO)CC21SCCS1
Solvent: c1ccncc1
Product: COc1ccc(OC)c2c1C[C@@](O)(COC(C)=O)CC21SCCS1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
1.6 g of (S)-1',2',3',4'-tetrahydro-3'-hydoxy-3'-hydroxymethyl-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] were dissolved in 30 ml of dry pyridine and 1.5 g of acetic anhydride were added to the solution. The mixture was left to stand at room temperature for 20 hours and then poured into ice-cold 5-M sulphuric acid. The resulting mixture was extracted with ethyl acetate, the extracts were washed with water and sodium hydrogen carbonate solution, dried and evaporated to give (S)-3'-acetoxymethyl-1',2',3',4'-tetrahydro-3'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in the form of a colourless oil which was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:7]2[CH2:8][N:9]([CH:12]3[CH2:15][O:14][CH2:13]3)[CH2:10][CH2:11][N:6]2[N:5]=1)([O-])=O>[Pd].CCO>[O:14]1[CH2:15][CH:12]([N:9]2[CH2:10][CH2:11][N:6]3[N:5]=[C:4]([NH2:1])[CH:16]=[C:7]3[CH2:8]2)[CH2:13]1
Reactant: O=[N+]([O-])c1cc2n(n1)CCN(C1COC1)C2
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2n(n1)CCN(C1COC1)C2
Reaction time: 8 h
Yield: 95.6 %

Procedure:
In a 250 mL round-bottomed flask, 2-nitro-5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (674 mg, 2.99 mmol, Eq: 1.00) was combined with EtOH (50 ml) to give a light yellow suspension. The reaction mixture was vacuum flushed three times with argon then 10% Pd/C (159 mg, 1.5 mmol, Eq: 0.5) was added and the reaction mixture was stirred under hydrogen balloon overnight. The reaction was filtered through a pad of celite. The celite pad was washed with ethanol. The combined filtrate and washes were concentrated in vacuo to afford the desired product (555 mg). (M+H)+=195 m/e.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].C(N(CC)CC)C>CO>[F:12][C:13]([F:20])([F:19])[C:14]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:15]
Reactant: COC(=O)CCCCCN
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNC(=O)C(F)(F)F
Reaction time: 19 h
Yield: 87 %

Procedure:
To a 2 liter round bottom flask, charged with 100.2 g is (0.552 mol) of amine hydrochloride 2 and 1 liter of methanol was added 100 g (0.703 mol) of ethyl trifluoroacetate followed by 120 mL (0.861 mol) of triethylamine. The mixture was stirred at 20–30° C. for 19 h and then concentrated via rotary evaporation. The residue was diluted with 500 mL of diethyl ether and then filtered. The filtrate was washed with 3×300 mL aliquots of 1N aqueous HCl, 200 mL of de-ionized water, 2×200 mL aliquots of saturated aqueous sodium bicarbonate and finally with 200 mL of de-ionized water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was distilled under vacuum to afford 115.8 g of the product (3) as a colorless oil: b.p.=113–116° C. at 120 mm Hg: 1H NMR (d6-DMSO) d 3.57 (3H, s), 2.75 (2H, m), 2.29 (2H, t), 1.60–1.40 (4H, m) and 1.37–1.19 (2H, m) ppm.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:35])[CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH:22]([CH3:35])[CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CC(CCOc1ccccc1[N+](=O)[O-])N1CCC(O)CC1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: CC(CCOc1ccccc1[N+](=O)[O-])N1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[CH:14][C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH:7]=[CH:6]2)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:21]1[C:22]2[C:17](=[CH:16][C:15]([CH:14]=[CH:13][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[CH:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11]4)=[CH:24][CH:23]=2)[CH2:18][CH2:19][NH:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C=Cc3ccc4cc(C#N)ccc4c3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2cc(C=Cc3ccc4c(c3)CCNC4)ccc2c1

Procedure:
A solution of Example 42I (2.28 g, 0.55 mmol) in 1:1 dichloromethane:TFA (10 mL) at room temperature was stirred for 1 hour, then concentrated to provide the desired product.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][S:5](=[O:10])(=[O:9])[NH:4]1)=[CH2:2].[CH2:11]([O:18][C:19]1[CH:24]=[C:23](I)[CH:22]=[CH:21][C:20]=1[N:26]1[S:30](=[O:32])(=[O:31])[N:29](CC[Si](C)(C)C)[C:28](=[O:39])[CH2:27]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:11]([O:18][C:19]1[CH:24]=[C:23](/[CH:2]=[CH:1]/[CH:3]2[CH2:8][CH2:7][CH2:6][S:5](=[O:10])(=[O:9])[NH:4]2)[CH:22]=[CH:21][C:20]=1[N:26]1[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:39])[CH2:27]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CC1CCCS(=O)(=O)N1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CN(c2ccc(/C=C/C3CCCS(=O)(=O)N3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 120 °C

Procedure:
A mixture of 3-vinyl-[1,2]thiazinane 1,1-dioxide (107 mg, 0.664 mmol) (J. Org. Chem. 69, 6377 (2004)), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (250 mg, 0.563 mmol), Pd(OAc)2 (13 mg, 0.058 mmol) and triethylamine (0.768 mL, 5.51 mmol) in MeCN (4 mL) is heated at 120° C. for 1.5 h in a microwave apparatus. The reaction mixture is concentrated and the residue purified by preparative HPLC to afford the title compound.