Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH:16]1[CH2:18][CH2:17]1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH:16]1[CH2:17][CH2:18]1)[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([C:20]([F:19])([F:34])[F:35])[CH:22]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ccccc1-c1ccncc1NCC1CC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CC1CC1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-cyclopropylmethyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 40:60) for the chromatographic purification. Light yellow oil (27%). MS (ESI): m/z=499.1005 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH2:18][SH:19].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:13])[C:14](=[O:16])[S:19][CH2:18][CH3:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCS
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCSC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A 250 mL round bottom flask was charged with benzyloxy-carbonyl-L alanine (15.0 g, 67.2 mmol) and 67.2 mL of dichloromethane. To this mixture was added DMAP (0.82 g, 6.72 mmol) and chilled EtSH (0° C., 5.46 mL, 73.9 mmol) followed by the addition of DCC (15.2 g, 73.9 mmol) in one portion. The addition of the DCC is highly exothermic so the reaction will bubble upon addition, and the reaction should be kept well vented. The resulting mixture was stirred for 30 minutes at 22° C. The resulting white solid was then removed by vacuum filtration, and the filtrate was concentrated. Silica Gel chromatography using hexanes with polarization to 8:1 hexanes/ethyl acetate afforded 93% yield (18.0g, 62.5 mmol) of the desired product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[OH:8].[CH2:23]=O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([CH3:23])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[OH:8]
Reactant: COc1ccc(C(O)CNCc2ccccc2Cl)cc1OC
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(O)CN(C)Cc2ccccc2Cl)cc1OC
Yield: 93 %

Procedure:
A reaction mixture of 0.96 g (0.003 m) of N-(2-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-2-aminoethanol from Example 5, 3 ml (0.037 m) of formaldehyde and 0.4 g of sodium borohydride in methanol was reacted to give 0.94 g (93%) of N-(2-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-2-methylaminoethanol as an oil. This material (0.6 g., 0.0018 m) and 0.95 g (0.007 m) of aluminum chloride were reacted as described to give 0.42 g (66%) of 8-chloro-4-(3,4-dimethoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, m.p. 212°-217°. This material (0.68 g., 0.002 m) and 1.2 ml (0.013 m) of boron tribromide were reacted to give 0.70 g. (94%) of 8-chloro-4-(3,4-dihydroxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 266°-269°.
Reaction SMILES: Cl[C:2]1C=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CCO>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([O:45][CH2:2][CH3:7])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Reactant: Cc1cccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1[nH]c2cccc(C)c2c1Sc1ccc(Cl)cc1
Yield: 62 %

Procedure:
Following the method used to prepare 24a, the use of 1a (0.19 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with EtOH (3 mL) provided 41 mg (62%) of product 11 as a white solid, mp 186-188° C. 1H NMR (300 MHz, DMSO-d6) δ 1.25 (t, J=7 Hz, 3H), 2.59 (s, 3H), 4.31 (q, J=7 Hz, 2H), 6.88 (d, J=7 Hz, 1H), 6.94-6.98 (m, 2H), 7.23 (t, J=8 Hz, 1H), 7.25-7.30 (m, 2H), 7.42 (d, J=8 Hz, 1H), 12.48 (s, 1H). LC-MS (CI): m/z 346.1 [(M+H)+ C18H16ClNO2S requires 345.06]. Purity (100%). Calcd for C18H16ClNO2S: C, 62.51; H, 4.66; N, 4.05; S, 9.27; Cl, 10.25. Found: C, 62.53; H, 4.59; N, 4.08; S, 9.27; Cl, 10.35.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:18])=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=2)[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O.[CH3:26][O:27][C:28](=[O:46])[C@@H:29]([NH2:45])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1>>[C:22]([O:21][C:19]([N:6]1[C@H:5]([C:3](=[O:2])[NH:45][C@H:29]([C:28]([O:27][CH3:26])=[O:46])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:18])=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=2)[CH2:7]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)[C@@H]1Cc2cc([N+](=O)[O-])c(O)cc2CN1C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc([N+](=O)[O-])c(O)cc2CN1C(=O)OC(C)(C)C
Yield: 78.4 %

Procedure:
(S)-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (5.1 mmol) was hydrolyzed and coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (5.85 mmol) according to general procedures B and A to provide (S)-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2.4 g). (S)-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.1 g) was dissolved in MeOH, Pd/C was added and the mixture stirred under balloon pressure of hydrogen for 1 h. Mixture was filtered through celite, washed with MeOH and EtOAc and concentrated to provide (S)-6-amino-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.06 g) which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([O:14][CH:15]=[CH:16][Sn])[CH3:13]>CN(C)C=O>[CH2:15]([O:14][C:12]([C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)=[CH2:13])[CH3:16]
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: CCOC=C[Sn]
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc(C(=O)OC)nn1
Temperature: 80 °C
Yield: 71.8 %

Procedure:
A solution of methyl 6-chloropyridazine-3-carboxylate (1.5 g, 8.7 mmol), ethoxyvinyl tin (3.2 g, 8.7 mmol), trans-bis(triphenyl-phosphine)palladium (200 mg) and N,N-dimethylformamide (50 mL) were combined. The mixture solution was heated to 80° C. for 10 hours under nitrogen gas protected. N,N-dimethylformamide was concentrated to dry in vacuo. The residue was purified by column chromatography (silica-gel, petroleum/ethyl acetate=4:1) to give methyl 6-(1-ethoxyvinyl)pyridazine-3-carboxylate as a white solid (1.3 g, 72%). 1H NMR (300 MHz, CDCl3): δ 8.22 (d, J=9 Hz, 1H), 7.98 (d, J=9 Hz, 1H), 4.98 (d, J=2.4 Hz, 1H), 4.68 (d, J=Methyl 6-acetylpyridazine-3-carboxylate. A solution of methyl 6-(1-ethoxyvinyl)pyridazine-3-carboxylate (1.3 g, 7.2 mmol) in hydrochloric acid (6 mol/L, 20 mL) was stirred at room temperature for 4 hours. The mixture solution was neutralized with potassium carbonate, extracted with ethyl acetate (100 mL). The organic layer was concentrated to dry to give methyl 6-acetylpyridazine-3-carboxylate as a white solid (0.9, 81%). 1H NMR (300 MHz, CDCl3): δ 8.36-8.40 (m, 1H), 8.36-8.40 (m, 1H), 4.00 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[CH:6][C:5]=1[OH:24].[I-].[Na+].Cl[CH:28]([S:32][CH3:33])[C:29]([NH2:31])=[O:30]>O.C(COC)OC>[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[CH:6][C:5]=1[O:24][CH:28]([S:32][CH3:33])[C:29]([NH2:31])=[O:30]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: CSC(Cl)C(N)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSC(Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(N)=O
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a mixture of 1.3 g of sodium hydride and 100 ml of dimethoxyethane, 10 g of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenol were added at room temperature and stirred for 30 minutes. Then, 2.2 g of sodium iodide and 6.7 g of crude 2-chloro-2-(methylthio)acetamide were added thereto and stirred at room temperature for 3 hours, and water was poured into the reaction mixture. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to give 10.2 g of 2-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-(methylthio)acetamide.
Reaction SMILES: [Na].[NH:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2([CH2:18][C:19]#[CH:20])[CH2:17][O:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]>C(O)CCC>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]([OH:16])([CH2:17][N:2]2[CH:6]=[N:5][CH:4]=[N:3]2)[CH2:18][C:19]#[CH:20])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: C#CCC1(c2ccc(Cl)c(Cl)c2)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCCCO
Product: C#CCC(O)(Cn1cncn1)c1ccc(Cl)c(Cl)c1
Yield: 59.3 %

Procedure:
0.275 g (0.011 mol) of sodium is introduced into a boiling solution of 8.05 g (0.116 mol) of 1,2,4-triazole in 400 ml of n-butanol. 24 g (0.105 mol) of 2-(3,4-dichlorophenyl)-2-propargyl-oxirane, dissolved in 50 ml of n-butanol, are then added. The solution is heated at the boil for 12 hours, the solvent is distilled off in vacuo, the residue is taken up in 200 ml of trichloromethane, the solution is washed with twice 50 ml of water, and the organic phase is dried over anhydrous sodium sulphate and then filtered over 200 g of silica gel. 18.45 g (53.6% of theory) of 4-(3,4-dichlorophenyl)-5-(1,2,4-triazol-1-yl)-pent-1-in-4-ol are obtained as colorless crystals of melting point 114° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([O:12][C:13](Cl)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:23][CH2:24][CH2:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([O:12][C:13](=[O:14])[N:26]([CH2:25][CH2:24][Cl:23])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: ClCCNc1ccccc1
Reactant: COC(=O)Nc1cccc(OC(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)Nc1cccc(OC(=O)N(CCCl)c2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of 22.9 g of chloroformic acid-3-methoxycarbonylaminophenylester in 50 ml acetic acid ester is added dropwise together with a solution of 30.5 g potassium carbonate in 150 ml water at a temperature of 10° to 15° C. into a solution of 23 g N-(2-chloroethyl)-aniline hydrochloride in 50 ml water and 50 ml acetic acid ester. During the addition the solutions are stirred. The stirring is then continued for 30 minutes at 15° C. whereupon the organic phase is separated, diluted with about 100 ml acetic acid ester and washed at 0° C. successively with dilute sodium hydroxide, water, dilute hydrochloric acid and again water. After drying on magnesium sulfate the mass is concentrated by evaporation under a reduced pressure. The residue obtained is at first oily but soon crystallizes throughout and is then recrystallized from acetic acid ester/pentane.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: Cc1ccnc(Br)c1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
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: COCCOC
Product: Cc1ccnc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)c1
Temperature: 25 °C
Yield: 20 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromo-4-picoline (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (104 mg, 20%) as a light yellow oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[NH2:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:39]([CH2:46][C:47](Cl)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([NH:22][C:47](=[O:48])[CH2:46][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:30])[CH3:31])=[CH:26][CH:27]=2)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: CN(C)Cc1ccc(C(N)Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(C(Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)NC(=O)COc2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 26.2 %

Procedure:
To a stirring solution of 2-[8-(benzyloxy)-5-chloroquinolin-7-yl]-1-{5-[(dimethylamino)methyl]-2-furyl}ethanamine (0.431 mmol) and triethylamine (0.474 mmol, 1.1 eq.) in tetrahydrofuran (4 mL) at 0° C. was added phenoxyacetyl chloride (0.474 mmol, 1.1 eq.) and the resulting solution was stirred 5 min at 0° C. then warmed to room temperature and stirred 15 min. The reaction was quenched with saturated aqueous sodium bicarbonate solution (15 mL) and the resulting aqueous solution was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to a white foam that was purified by column chromatography using 10% methanol/dichloromethane to give the final product as a clear oil (0.113 mmol, 26%). MS (ESI) m/z 570.3; HRMS: calcd for C33H32ClN3O4+H+, 570.21541; found (ESI, [M+H]+ Obs'd), 570.2155.
Reaction SMILES: [S:1]1[C:5]2=[C:6]3[C:10](=[CH:11][CH:12]=[C:4]2[N:3]=[CH:2]1)[NH:9][C:8](=[O:13])[C:7]13[C:25]2[C:16](=[CH:17][C:18]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[CH:24]=2)[O:15][CH2:14]1.[NH:26]1[C:34]2[C:29](=CC=C[CH:33]=2)[C@@:28]2([C:46]3[C:37](=CC4OCCOC=4C=3)OC2)C1=O.Br.BrCC1C=CC=CN=1.BrCCOCCOC>>[N:26]1[CH:37]=[CH:46][CH:28]=[CH:29][C:34]=1[CH2:33][N:9]1[C:10]2[C:6](=[C:5]3[S:1][CH:2]=[N:3][C:4]3=[CH:12][CH:11]=2)[C:7]2([C:25]3[C:16](=[CH:17][C:18]4[O:23][CH2:22][CH2:21][O:20][C:19]=4[CH:24]=3)[O:15][CH2:14]2)[C:8]1=[O:13]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccc3ncsc3c2C12COc1cc3c(cc12)OCCO3
Agent: Br
Agent: BrCc1ccccn1
Agent: COCCOCCBr
Product: O=C1N(Cc2ccccn2)c2ccc3ncsc3c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 1-bromo-2-(2-methoxyethoxy)ethane, 6′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one was obtained (41%) as a colorless solid: mp 156-158° C.; 1H NMR (300 MHz, CDCl3) δ8.75 (s, 1H), 8.60-8.53 (m, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.69-7.61 (m, 1H), 7.32-7.26 (m, 1H), 7.23-7.17 (m, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.56 (s, 1H), 6.30 (s, 1H), 5.17 (ABq, 2H), 4.87 (ABq, 2H), 4.24-4.03 (m, 4H); MS (ES+) m/z 444.1 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1.[C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)#[N:17].C1C(O)=CC=CC=1C>>[CH3:15][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[NH:17])[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(-c2ccccc2N)c1
Reactant: N#CN1CCCCC1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: Cc1cccc(-c2ccccc2NC(=N)N2CCCCC2)c1
Temperature: 100 °C

Procedure:
A mixture of 2-amino-3'-methylbiphenyl hydrochloride (1.09 g), N-cyanopiperidine (0.6 g) and m-cresol (0.5 ml) was heated at 100° C. for 3 hours to give N-(3'-methyl-2-biphenylyl)piperidine-1-carboxamidine (m.p. 131° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:5]=1)([O-:3])=[O:2].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1NS(=O)(=O)c1ccccc1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccc([N+](=O)[O-])cc1NS(=O)(=O)c1ccccc1

Procedure:
N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N′-phenylurea was prepared from 4-nitro 2-(phenylsulfonylamino)aniline(82 mg) and phenyl isocyanate(33 mg) by method A. The reaction was cooled and then partitioned between saturated ammonium chloride and 9:1 methylene chloride and methanol. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacua. The residue was purified by column chromatography (ethyl acetate/hexanes) to afford desired(30.8 mg, 26%). EI-MS m/z 413(M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:11]([C:14]1[O:15][CH2:16][C@@H:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=1)[CH2:12][CH3:13])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1>ClCCl.[Cu](Br)Br>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:11]([C:14]1[O:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=1)[CH2:12][CH3:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H](C1=N[C@H](C(=O)OC)CO1)[C@@H](C)NC(=O)OC(C)(C)C
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC[C@@H](c1nc(C(=O)OC)co1)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.4 %

Procedure:
A solution of (S)-methyl 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)-4,5-dihydrooxazole-4-carboxylate (1.62 g, 5.14 mmol) in anhydrous dichloromethane (15 mL+15 mL+6 mL washing) was added via a glass Pasteur pipette to a stirred suspension of copper(II) bromide (4.60 g, 20.61 mmol), hexamethylenetetramine (2.89 g, 20.61 mmol) and DBU (3.11 ml, 20.61 mmol) in anhydrous dichloromethane (20 mL). The thick suspension was stirred at room temperature for 1.5 hours-HPLC analysis (at 220 nm) indicated complete consumption of starting material and desired product formation. The reaction was partitioned between dichloromethane (20 mL) and a mixture of 10% NH4OH solution and saturated aqueous ammonium chloride solution (1:1, 30 mL). The aqueous phase was extracted with dichloromethane (3×25 mL). The combined organic phase was then washed with 10% NH4OH solution and saturated aqueous ammonium chloride solution (1:1, 30 mL), and a mixture of 1N HCl:brine (1:1, 30 mL). The organic layer was then dried (MgSO4) and evaporated in vacuo to give the crude product which was purified by column chromatography using ethyl acetate-hexane as eluent to give methyl 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylate (711 mg, 2.28 mmol, 44.2% yield) as an oil. 1H NMR (400 MHz, CCl3D) δ 8.20 (s, 1H), 5.00 (d, J=9.0 Hz, 1H), 4.17-3.99 (m, 1H), 3.92 (s, 3H), 2.94 (dt, J=9.6, 5.4 Hz, 1H), 1.95-1.70 (m, 2H), 1.42 (s, 9H), 1.10 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.4 Hz, 3H). LC/MS: M+H+313.08, ret. time=0.93 min. Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=O)[NH:6][C:5]1=[O:14])[CH2:2][CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>N1C=CC=CC=1>[CH2:1]([N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[S:16])[NH:6][C:5]1=[O:14])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCCn1c(=O)[nH]c(=S)c2[nH]cnc21

Procedure:
A suspension of 9.32 g. (48 mM.) of 3-propylxanthine in 80 ml. of pyridine, was treated with 17.33 g. (78 mM.) of phosphorus pentasulfide in 80 ml. of pyridine, and worked up analogously to Example I. 8.9 g. of 3-propyl-6-thioxanthine was obtained. Recrystallization from methanol-acetone gave 7.4 g. (59% yield) of needles with a melting point of 249°-250° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[N:4][CH:3]=1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[Cl:41][C:42]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:43]=1[C:44](Cl)=[O:45]>ClCCl>[Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:44]([C:43]3[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:42]=3[Cl:41])=[O:45])[CH2:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1cnc2n1CCNC2
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1Cl)N1CCn2c(Cl)cnc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Chloro-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I20) (450 mg, 2.86 mmol) and diethylaminomethyl polystyrene (2855 mg, 9.14 mmol) were slurried in dichloromethane (DCM) (10 mL) and treated with 2,4-dichlorobenzoyl chloride (0.439 mL, 3.14 mmol). The slurry was stirred at RT for 24 h, whereupon the resin was filtered and washed with dichloromethane (20 mL). The filtrate was concentrated in vacuo to afford crude product. The product was purified by flash chromatography (Isolera, 10 g, 0-100% ethyl acetate/iso-hexane) to afford product then by MDAP (High pH method) to afford clean desired product in 350 mg.