Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[CH:3]1[C:23]2(CC)[C:24]3=[N:25][C:4]1=[CH:5][C:6]1[NH:10][C:9]([CH:11]=[C:12]4[NH:39][C:15](=[CH:16][C:17]5[C:34](CC)=[C:33](CC)[C:19](=[C:20]3C=C2C(OCC)=O)[N:18]=5)[C:14](CC)=[C:13]4CC)=[C:8](CC)[C:7]=1CC>ClCCl>[C:6]12[CH:5]=[C:4]3[N:25]=[C:24]([CH:23]=[CH:3]3)[CH:20]=[C:19]3[NH:18][C:17]([CH:34]=[CH:33]3)=[CH:16][C:15]3=[N:39][C:12]([CH:13]=[CH:14]3)=[CH:11][C:9]([NH:10]1)=[CH:8][CH:7]=2
Reactant: CCOC(=O)C1=Cc2c3nc(cc4[nH]c(cc5[nH]c(cc6nc2C1(CC)C6CC)c(CC)c5CC)c(CC)c4CC)C(CC)=C3CC
Solvent: ClCCl
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
A 50 mg portion of Purpurin NT2 was dissolved in 20 ml dichloromethane, and the resulting solution was allowed to stand for a total of 16 hours in sunlight, in contact with air, and under ambient conditions (temperature about 22°). The dichloromethane was then removed by evaporation, leaving 50 mg porphyrin derivative (hereafter "Porphyrin NT2") which was found by nuclear magnetic resonance to have the formula of FIG. 7 of the attached drawings where R1 through R8 are ethyl, R10 through R12 are hydrogen, and R13 is CH2CH3. The production of Purpurin NT2 is described in Example i of PCT/U.S. Pat. No. 86/02824; it has the formula of FIG. 5 of the drawings of that application where R1 through R8 are ethyl, R9 is CO2CH2CH3, and R10 through R13 are hydrogen.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>CCO>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: NC=O
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: CCO
Product: O=c1[nH]cnc2ccc(Br)cc12
Temperature: 70 °C
Yield: 81 %

Procedure:
Briefly, 2-amino-5-bromobenzoic acid (A, 50.0 g, 0.233 mmol, 1.0 equiv) is added to formamide (50.0 mL, d=1.133, 56.7 g, 1.26 mmol). The reaction mixture is heated at reflux for 12 h. The solution is then cooled to 70° C., and EtOH (100 mL) is added to the reaction mixture. The resultant precipitates are collected by filtration, washed with EtOH (50 mL), and dried under vacuum to provide the desired 6-bromo-3H-quinazolin-4-one (B, 42.5 g, 0.189 mol) in 81% yield: ESI-MS m/z 225.0 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=O)[CH:28]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:10][C:9]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(4-Amino-2-phenylbenzoyl)methionine methyl ester hydrochloride (5.0 g, 12.7 mmol), prepared as in Example 192B, and 3-pyridinecarboxaldehyde (1.25 mL, 13.3 mmol) were dissolved in 100 mL 1% acetic acid in methanol. After 10 minutes, sodium cyanoborohydride (0.95 g, 15.9 mmol) was added. After stirring at room temperature 18 hours, the reaction mixture was evaporated and partitioned between 5% NaHCO3 and ethyl acetate. The organic layer was washed with 5% NaHCO3 and brine, dried over Na2SO4, and evaporated to provide [4-(3-pyridylmethylamino)-2-phenylbenzoyl]methionine methyl ester which was used without further purification. MS m/e 450 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.65 (m, 2H), 1.87 (m, 2H), 2.00 (s, 3H), 3.63 (s, 4H), 4.42 (s, 2H), 4.61 (m, 1H), 5.69 (d, J=7 Hz, 1H), 6.50 (d, J=3 Hz, 1H), 6.63 (m, 1H), 7.45 (m, 6H), 7.68 (m, 2H), 8.55 (m, 1H), 8.62 (d, J=3 Hz, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23]([OH:25])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[NH:22][CH:21]=2)=[O:25])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A75) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH:37]([OH:40])[CH2:38][OH:39]>>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32]([NH:35][CH2:36][CH:37]([OH:40])[CH2:38][OH:39])=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Reactant: NCC(O)CO
Product: O=C(NCC(O)CO)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 269 using 268 (30 mg, 0.07 mmol) and 3-amino-propane-1,2-diol to provide 272. LC-MS (M+H=524, obsd.=524).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[C:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:1][C:2]2[S:3][CH2:4][CH2:5][N:6]=2)=[O:23])=[CH:25][CH:26]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: Nc1nccs1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)NC2=NCCS2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Aminothiazole (38 mg, 0.37 mmole) was dissolved in dry tetrahydrofuran (6.5 ml) followed by addition of triethylamine (77 mg, 0.76 mmole) and 4-t-butylbenzoyl chloride (151 mg, 0.76 mmole). The reaction was stirred overnight at room temperature, and then the solvent removed under reduced pressure. The residue was purified by reverse phase HPLC (water/acetonitrile gradient), giving [4-(tert-butyl)phenyl]-N-(1,3-thiazolin-2-yl)carboxamide. The product was characterized by HPLC-MS.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)([CH:9]=[O:10])[CH2:5][CH2:4]1.[BH4-].[Na+].O>COCCOC>[CH3:26][O:25][C:3]1([O:2][CH3:1])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:12]=2)([CH2:9][OH:10])[CH2:5][CH2:4]1
Reactant: COc1ccc(C2(C=O)CCC(OC)(OC)CC2)cc1OC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C2(CO)CCC(OC)(OC)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one dimethyl ketal (0.24 g, 0.66 mmol) in 1,2-dimethoxy-ethane (5 mL) under an argon atmosphere was added sodium borohydride (0.05 g, 1.3 mmol) and the mixture was stirred at room temperature for 0.75 h. Water was added, the mixture was partitioned between ether and water, was extracted twice with ether, the organic exact was dried (,potassium carbonate) and evaporated to an oil (0.19 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15]Br)=[C:8]([O:17][CH3:18])[CH:7]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25]>>[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:15][CH2:14][CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([O:19][CH3:20])[C:3]([O:2][CH3:1])=[O:21])=[CH:7][C:8]=3[O:17][CH3:18])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: COC(=O)C(Cc1ccc(OCCCBr)c(OC)c1)OC
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Product: COC(=O)c1ccc(-c2ccc(OCCCOc3ccc(C[C@H](OC)C(=O)OC)cc3OC)cc2)cc1

Procedure:
3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid methyl ester (Step A) and 4′-hydroxy-biphenyl-4-carboxylic acid methyl ester (Example 197, Step A) were treated under Mitsunobu standard condition B. The crude was purified by chromatography on silica gel (hexanes/ethyl acetate 7:3) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[NH2:14][CH2:15][C:16]1([NH2:20])[CH2:19][O:18][CH2:17]1>CO>[NH2:20][C:16]1([CH2:15][NH:14][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=3)[N:3]=[C:2]([Cl:1])[N:11]=2)[CH2:19][O:18][CH2:17]1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCC1(N)COC1
Solvent: CO
Product: Cc1ccc2nc(Cl)nc(NCC3(N)COC3)c2c1

Procedure:
A solution of 2,4-dichloro-6-methylquinazoline (645 mg, 3 mmol) and 3-(aminomethyl)oxetan-3-amine (340 mg, 3.3 mmol) in methanol (15 mL) was stirred at room temperature overnight. After the resulting mixture was concentrated in vacuo, the residue was purified by column chromatography (eluting with 10% methanol in dichloromethane) to afford the desired product.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([N:7]([CH2:14][CH2:15][CH2:16][NH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6].C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([N:7]([CH2:14][CH2:15][CH2:16][N:17]=[C:1]=[S:2])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:6]
Reactant: S=C(Cl)Cl
Reactant: CCN(CCCN)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CCCN=C=S)c1ccccc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of thiophosgene (7.43 ml) in CH2Cl2 (300 ml) was added dropwise over 11/2 hours at 20° C. under a nitrogen atmosphere to a stirred solution of N-ethyl-N-(3-aminopropyl)aniline (17.8 g) and triethylamine (27.8 ml) in CH2Cl2 (500 ml). The mixture was stirred at 20° C. for a further 1/2 hours then heated under reflux for 11/2 hours. The mixture was allowed to cool, washed with water, dried over MgSO4, filtered and solvent removed from the filtrate in vacuo. The product was purified by chromatography on silica gel eluting with CH2Cl2 to give N-ethyl-N-(3-isothiocyanatopropyl)aniline (7.2 g) as a red oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>C(#N)C>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])=[CH:11][CH:12]=3)[CH2:6][CH2:5]2)=[CH:31][CH:30]=1
Reactant: CCCCOC(=O)CCc1ccc(N2CCNCC2)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOC(=O)CCc1ccc(N2CCN(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
A mixture of 20.0 g. (68.8 mmole) n-butyl 3-[4-(piperazin-1-yl)-phenyl]-propionate, 200 ml. acetonitrile, 10.4 g. (75.6 mmole) pulverised potassium carbonate and 12.2 g. (75.6 mmole) 4-chlorobenzyl chloride is heated for 36 hours at reflux temperature, filtered with suction and the filtrate evaporated. The residue is taken up in diethyl ether and the hydrochloride precipitated out by adding hydrogen chloride-containing diethyl ether. It is filtered off with suction, recrystallised from isopropanol and dried. Yield 29.0 g. (87% of theory) of hydrochloride; m.p. 222°-225° C.
Reaction SMILES: [C:1]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:28]([O:31][CH:32]([C:41]([CH3:48])([CH3:47])[CH2:42][O:43][C:44](=[O:46])[CH3:45])[C:33]([NH:35][CH2:36][CH2:37][C:38](O)=[O:39])=[O:34])(=[O:30])[CH3:29]>>[C:28]([O:31][CH:32]([C:41]([CH3:48])([CH3:47])[CH2:42][O:43][C:44](=[O:46])[CH3:45])[C:33]([NH:35][CH2:36][CH2:37][C:38]([O:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:22][CH:23]=1)=[O:39])=[O:34])(=[O:30])[CH3:29]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(O)cc1
Reactant: CC(=O)OCC(C)(C)C(OC(C)=O)C(=O)NCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(OC(=O)CCNC(=O)C(OC(C)=O)C(C)(C)COC(C)=O)cc1
Yield: 45.3 %

Procedure:
4-Oleoylaminophenol (372 mg) and 259 mg of 3-[N-(2,4-diacetoxy-3,3-dimethyl-1-oxobutyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 255 mg of the title compound (yield: 39%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:18]O>>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:18])=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N(C)C)cc1

Procedure:
p-Dimethylaminobenzoic acid (50 g.) and concentrated H2SO4 (25 ml.) in 350 ml. methanol were refluxed 18 hours. The reaction mixture was cooled, quenched with ice and water (350 ml.), neutralized portionwise with KHCO3 until foaming ceased, and extracted 3×200 ml. CHCl3. The organic layers were combined, washed 1×150 ml. brine, dried (MgSO4) and reduced in volume to yield crystalline title product, 52 g.; 1H-nmr: 3.02 (s, 6H), 3.87 (s, 3H), 6.66 (d, J=16 Hz, 2H), 7.95 (d, J=16 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12]2[N:18]([CH3:31])[C:19](=[O:30])[C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])=[CH:21][C:11]3=2)[N:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:20]1[C:19](=[O:30])[N:18]([CH3:31])[C:12]2[N:13]([CH3:17])[C:14]3[C:10]([C:11]=2[CH:21]=1)=[CH:9][C:8]([C:6]1[N:7]=[C:3]([CH2:2][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[S:4][CH:5]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CCl)n4)ccc3n(C)c21
Reactant: C1COCCN1
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CN5CCOCC5)n4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 122 above, with the compound from Example 128A 6-(2-chloromethylthiazol-4-yl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and morpholine.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3nccs3)c2c1
Yield: 56 %

Procedure:
This compound was prepared from 6b and 2-tributylstannylthiazole according to method J. Yellow powder; Yield: 56%; mp>280° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 7.10 (t, J=8.8 Hz, 1H), 7.38 (dd, J=9.1, 2.7 Hz, 1H), 7.95-8.00 (m, 2H), 8.07-8.12 (m, 3H), 8.21 (m, 2H), 10.18 (s, 1H), 10.26 (s, 1H); MS (ESI) m/z 337 ([M−H]−), 339 ([M+H]+); Anal. Calcd for C18H11FN2O2S: C, 63.90; H, 3.28; N, 8.28. Found: C, 62.6; H, 3.43; N, 7.59.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:9]=2[CH:18]=1)(=[NH:4])[NH2:3].[C:19](Cl)(=[O:22])[O:20][CH3:21].[OH-].[Na+]>C(Cl)Cl>[CH3:21][O:20][C:19]([NH:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:9]=2[CH:18]=1)=[NH:3])=[O:22]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)c1cc2cc(C(=N)N)ccc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(C(=N)NC(=O)OC)ccc2o1
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
Methylene chloride (2 ml) was added to ethyl 5-amidino-2-benzofurancarboxylate hydrochloride (100 mg, 0.372 mmol), and methyl chlorocarbonate (30 μl, 0.391 mmol) and then, a 0.2N aqueous sodium hydroxide solution (0.391 ml, 0.782 mmol) was added at room temperature, which was followed by vigorous stirring for 10 minutes. Methylene chloride (15 ml) was added to the reaction mixture. The mixture was washed with water and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 88.0 mg of ethyl 5-(methoxycarbonylamidino)-2-benzofurancaroxylate as a colorless solid (82%). Tetrahydrofuran (2 ml), water (2 ml) and a 1N aqueous sodium hydroxide solution (2 ml, 2 mmol) were added to the compound (73.0 mg, 0.252 mmol), and the mixture was stirred at room temperature for one hour. 1N Hydrochloric acid was added to the reaction mixture to adjust its pH to 2-3, and low boiling matters were distilled away under reduced pressure to give 183 mg of 5-(methoxycarbonylamidino)-2-benzofurancarboxylic acid as a yellow solid (inclusive of sodium chloride).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[C:4]([C:11]([NH2:13])=[O:12])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=1.[O:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29](=O)[O:30]C2C=CC([N+]([O-])=O)=CC=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:29]([NH:28][CH:25]3[CH2:26][CH2:27][O:22][CH2:23][CH2:24]3)=[O:30])[CH2:10][C:5]2=[C:4]([C:11]([NH2:13])=[O:12])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=1
Reactant: N#Cc1cccc(-c2c(C(N)=O)c3n(c2Cl)CCNC3)c1
Reactant: O=C(NC1CCOCC1)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cccc(-c2c(C(N)=O)c3n(c2Cl)CCN(C(=O)NC2CCOCC2)C3)c1
Temperature: 65 °C
Yield: 82.8 %

Procedure:
A suspension of 0.67 g (2.23 mmol) of 6-chloro-7-(3-cyanophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide, 0.712 g (2.67 mmol) of 4-nitrophenyl tetrahydro-2H-pyran-4-ylcarbamate and 0.616 g (1.12 mmol) of potassium carbonate in 10 ml of acetonitrile is heated at 65° C. for 1 hour 30 minutes. After cooling, the mixture is concentrated under reduced pressure, the residue is diluted with dichloromethane and the solution is washed with aqueous 1N sodium hydroxide solution. The organic phase is washed with water, dried over sodium sulfate and filtered, and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of 2 to 5% methanol in dichloromethane, to give 0.79 g of 6-chloro-7-(3-cyanophenyl)-N2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a whitish powder after recrystallizing from 100 ml of ethanol, filtering off and drying under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH:18]=1)[CH:16]=O>C1(C)C=CC=CC=1>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH:18]=1)[CH:16]=[N:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: N#Cc1ccccc1N
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(C=Nc2ccccc2C#N)c1
Yield: 62.1 %

Procedure:
Toluene (167 ml) and 2-aminobenzonitrile (19.7 g, 167 mmol) were added to 5-methyl-2-nitrobenzaldehyde (27.5 g, 167 mmol) as obtained in Reference Example 1, and the mixture was stirred and refluxed for 14 hours, followed by cooling. The resultant crystals were filtered off, washed with a mixed solvent of hexane/toluene (2:1, 150 ml) and hexane (150 ml) twice to give 27.5 g of 2-[N-(5-methyl-2-nitrobenzylidene)amino]benzonitrile. In addition, the solid precipitated from the filtrate was filtered off and washed with hexane (100 ml and 50 ml) to give 10.0 g of the compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccn(CCCO)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(Nc1ccn(CCCO)n1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
In a round bottom flask was placed 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 51 mg, 0.36 mmol), 2,6-lutidine (57 μL, 0.49 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride in methylene chloride (prepared as in Example 102, ˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 40% ethyl acetate/hexanes to 65% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (99 mg, 74%) as a white foam: [α]30589=−27.3° (c=0.11, methylene chloride); ES-HRMS m/e calcd for C20H25N3O2Cl2 (M+H)+ 410.1397, observed 410.1398; 1H NMR (400 MHz, DMSO-d6) δ 1.10 (m, 2H, CH2), 1.35-1.78 (m, 8H, 4×CH2), 1.85 (m, 2H, CH2), 2.04 (m, 1H, CH), 3.34 (t, J=6.4 Hz, 2H, OCH2), 3.79 (m, 1H, ArCHCO), 4.02 (t, J=6.8 Hz, 2H, NCH2), 4.56 (br, 1H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.35 (dd, Jm=2.0 Hz, Jo=8.4 Hz, 1H, Ar), 7.55 (d, J=2.2 Hz, 1H, Ar), 7.59 (d, Jo=8.4 Hz, 1H, Ar), 7.59 (s, 1H, Ar), 10.71 (s, 1H, NH).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO>O>[N:7]1[CH:8]=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccncc1
Solvent: O
Solvent: CO
Product: CC(O)c1ccncc1
Yield: 99.7 %

Procedure:
To a stirred solution of 4-acetylpyridine (2.50 g, 20.6 mmol) in methanol (25 ml) sodium borohydride (1.56 g, 41.2 mmol) was added in portions. After stirring overnight at RT water was added and the mixture was evaporated to dryness in vacuo. The product was taken into ethyl acetate. The solvent was evaporated to give 2.53 g of the title compound. 1H NMR (400 MHz, DMSO-d6): 1.32 (3H, d), 4.69-4.75 (1H, m), 5.38 (1H, d), 7.34 (2H, d), 8.49 (2H, d).