Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[C:5]1([C:11]([OH:15])([C:13]#[CH:14])[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>CCCCCC.O>[CH2:1]([O:15][C:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([C:13]#[CH:14])[CH3:12])[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: C#CC(C)(O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: C#CCOC(C)(C#C)c1ccccc1
Temperature: 25 °C
Yield: 65 %

Procedure:
Propargyl bromide (22 g, 0.15 mol) was dissolved in 140 ml of n-hexane. This solution, 2-phenyl-3-butyne-2-ol (14.6 g, 0.1 mol), NaOH (60 g, 1.5 mol) and a catalytic amount of tetrabutyl ammonium hydrogen sulfate/water (120 ml) were mixed, reacted for 24 hours at an ambient temperature and refluxed for 30 minutes. After completion of the reaction, the mixture was cooled to an ambient temperature and water (100 ml) was added. The organic phase was extracted with 30 ml of n-hexane, three times. The extracted organic solvent was dried with anhydrous magnesium sulfate, filtered and evaporated to separate. b.p.: 61° C./0.5 mmHg; yield: 65%; MS: m/e 184 (parent), 129 (base).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34]5[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=5)[N:33]=[C:29]4[N:28]=[C:27]([CH3:42])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:45][O:46][C:47]([CH3:63])([CH3:62])[C:48]([NH:50][NH:51][C:52](=[O:61])[C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([OH:60])[CH:54]=1)=[O:49]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:45]/[O:46][C:47]([C:48](=[O:49])[NH:50][NH:51][C:52](=[O:61])[C:53]2[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([OH:60])[CH:54]=2)([CH3:62])[CH3:63])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34]5[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=5)[N:33]=[C:29]4[N:28]=[C:27]([CH3:42])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(-c3ccc(O)c(O)c3)nc2n1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)NNC(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)n2nc(-c3ccc(O)c(O)c3)nc2n1
Reaction time: 8 h
Yield: 93.9 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(3,4-dihydroxyphenyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (1.3 g) and 0.79 g of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 10 ml of dimethylacetamide. After standing overnight the mixture is evaporated in a vacuum. The residue is digested with 25 ml of water and the precipitate formed is filtered off under suction and dried. There are obtained 1.7 g of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[2-(3,4-dihydroxyphenyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a colourless powder.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([OH:19])([C:15]([F:18])([F:17])[F:16])/[CH:4]=[CH:5]\[CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][CH2:10][CH:11]=[O:12].C(N(CC)CC)C.[CH2:29]([Si:31](Cl)([CH2:34][CH3:35])[CH2:32][CH3:33])[CH3:30]>C1COCC1.CN(C)C1C=CN=CC=1>[F:1][C:2]([F:20])([F:21])[C:3]([O:19][Si:31]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:29][CH3:30])([C:15]([F:17])([F:18])[F:16])/[CH:4]=[CH:5]\[CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][CH2:10][CH:11]=[O:12]
Reactant: CC(C)(C/C=C\C(O)(C(F)(F)F)C(F)(F)F)CCCC=O
Reactant: CC[Si](Cl)(CC)CC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCCC=O)(C(F)(F)F)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of 6.73 g of (Z)-10,10,10-trifluoro-9-hydroxy-5,5-dimethyl-9-trifluoromethyl-dec-7-enal in 67 ml of THF was added at 22° subsequently 2.55 g of triethylamine, 0.128 g of 4-dimethylamino pyridine and 3.92 g of triethylsilyl chloride and the solution was stirred at 22° for 1.5 h after which time g.l.c. indicated completion of the reaction. The suspension was evaporated, the residue dissolved in dichloromethane and washed with 0.1 N of aqueous hydrochloric acid and with sat. aqueous NaCl. The organic layer was dried over MgSO4, evaporated and the residue was chromatographed over silica with hexane/AcOEt 15:1 to give 7.50 g of the pure (99%, g.l.c.) title compound as a colorless liquid. IR (neat): 1729s (C═O), 1661w (C═C). MS (EI): 405/10 M−C2H5).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][C:11]=3CN2CCOCC2)[N:7]([C:28]#[N:29])[CH2:6]1)=[O:4].C(N(CC)CC)C.Cl[O:38][C:39](C)(C)C.C(=O)(O)[O-]>O1CCCC1.C(OCC)(=O)C>[C:28]([N:7]1[C@H:8]2[C@@H:18]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:20]=3[C:10]([CH2:9]2)=[C:11]([CH:39]=[O:38])[NH:12]4)[CH2:19][C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)#[N:29]
Reactant: CC(C)(C)OCl
Reactant: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(CN5CCOCC5)c(c34)C[C@H]2N(C#N)C1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(C=O)c(c34)C[C@H]2N(C#N)C1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
7.89 g of 6-cyano-2-morpholinomethyl-8beta-ergoline-carboxylic acid methyl ester (20 mmol) is dissolved in 400 ml of anhydrous tetrahydrofuran, the solution is cooled to -40° C., mixed with 4 ml of triethylamine and then the solution of 3.0 ml of tert-butyl hypochloride (25 mmol) in 60 ml of anhydrous tetrahydrofuran is instilled. After 10 minutes of stirring, another 1 ml of tert-butylhypochlorite is added, stirred for 5 minutes and the solution is poured on ice. The mixture is made alkaline with bicarbonate solution and shaken with ethyl acetate. The organic phases are dried, the solvent is evaporated and the residue is crystallized from the diisopropylether, the yield is quantitative [α]D =+42.7° (0.5% in chloroform).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Yield: 47.2 %

Procedure:
Using a method similar to Intermediate 1, using 5-hydroxy-1-indanone (2.44 g, 16.5 mmol), 6-chloronicotinamide (2.34 g, 15.0 mmol) and K2CO3 (3.11 g, 22.5 mmol) gives the title compound (1.90 g) as a yellow solid. Mass spectrum (ion spray): m/z=269 (M+1); 1HNMR (DMSO-d6): 8.63 (s, 1H), 8.30 (d, 1H), 8.06 (s, 1H), 7.68 (d, 1H), 7.52 (s, 1H), 7.33 (s, 1H), 7.19 (d, 1H), 7.17 (d, 1H), 3.07 (t, 2H), 2.64 (t, 2H).
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH:20]([OH:23])CO)[N:19]=2)[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.I([O-])(=O)(=O)=O.[Na+].O>CO>[C:8]1([CH:7]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH:20]=[O:23])[N:19]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCC(O)c1csc(NC(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: O=Cc1csc(NC(c2ccccc2)c2ccccc2)n1

Procedure:
Following a procedure similar to that described in Preparation 50, the desired compound was prepared from 2.11 g of 1-(2-diphenylmethylaminothiazol-4-yl)ethane-1,2-diol, 3.15 g of sodium metaperiodate, 40 ml of water and 20 ml of methanol. The resulting product was a pale brown foam having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[NH:8]3.[H-].[Na+].Br[CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.O>CN(C=O)C>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][N:8]2[C:9]3[N:5]4[C:4](=[N:3][C:2]([CH3:1])=[C:6]4[C:7]2=[O:13])[CH:12]=[CH:11][CH:10]=3)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: Cc1nc2cccc3[nH]c(=O)c1n23
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cccc3n(CC4CCN(C(=O)OC(C)(C)C)CC4)c(=O)c1n23
Yield: 62.9 %

Procedure:
To a suspension of 735 mg (4.24 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 15 ml of DMF was added, while stirring under ice-cooling, 187 mg (4.68 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 20 minutes at the same temperature. To the mixture was added a solution of 1.18 g (4.24 mmol) of 4-bromomethyl-1-tert-butoxycarbonylpiperidine in 5 ml of DMF. The mixture was stirred for one hour at 100° C. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 988 mg of the desired compound (62.8%, pale yellow solid).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([N+]([O-])=O)[C:3]=1[C:4]#[N:5].[Cl-:14].[Li+].[Cl-].[Al+3].[Cl-].[Cl-]>CN1CCCC1=O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:14])[C:3]=1[C:4]#[N:5]
Reactant: [Cl-]
Reactant: N#Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: N#Cc1c(Cl)ccc(Cl)c1Cl
Yield: 91.9 %

Procedure:
10.9 parts of 2,3-dichloro-6-nitrobenzonitrile, 0.84 parts of lithium chloride, 2.22 parts of anhydrous aluminum chloride and 15 parts of N-methyl-2-pyrrolidone were reacted at 180° C. for one hour, and the reaction solution was treated similarly to EXAMPLE B12 to obtain 9.4 parts of 2,3,6-trichlorobenzonitrile with purity of almost 100%. Yield: 91.9%.
Reaction SMILES: C[O:2][C:3]([CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]([N:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])=[O:27])[CH:21]=3)[CH2:16]2)=[O:14])[CH2:8][CH2:7]1)=[O:4].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCOCC1>[C:3]([CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]([N:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])=[O:27])[CH:21]=3)[CH2:16]2)=[O:14])[CH2:8][CH2:7]1)([OH:4])=[O:2]
Reactant: COC(=O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1
Reaction time: 22 h

Procedure:
To a 1,4-dioxane (20 mL) mixture of trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-methoxycarbonylmethyl-cyclohexyl ester (1.48 g) obtained in Example 1, tetrabutylammonium hydroxide (1.0 mol/L aqueous solution, 4.0 mL) was added at room temperature. The reaction mixture was stirred for 22 hours and concentrated. The residue was acidified with a 1N aqueous hydrochloric acid solution (30 mL), then diluted with ethyl acetate, and vigorously stirred until complete dissolution. The separated organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated. The residue was purified by chromatography (dichloromethane/methanol). The obtained solid was recrystallized (isopropyl alcohol) to obtain the title compound (1.04 g, 72%) as a white solid.
Reaction SMILES: N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[C:25]([OH:28])(=O)[CH3:26].C(N(CC)C(C)C)(C)C.C(O)=O.[NH2:41][CH2:42][C:43]1[CH:44]=[C:45]([CH2:49][N:50]2[C:58]3[C:53](=[C:54]([OH:59])[CH:55]=[CH:56][CH:57]=3)[C:52]([NH:60][S:61]([C:64]3[S:65][C:66]([Cl:69])=[CH:67][CH:68]=3)(=[O:63])=[O:62])=[N:51]2)[CH:46]=[CH:47][CH:48]=1>CN(C=O)C>[Cl:69][C:66]1[S:65][C:64]([S:61]([NH:60][C:52]2[C:53]3[C:58](=[CH:57][CH:56]=[CH:55][C:54]=3[OH:59])[N:50]([CH2:49][C:45]3[CH:44]=[C:43]([CH2:42][NH:41][C:25](=[O:28])[CH3:26])[CH:48]=[CH:47][CH:46]=3)[N:51]=2)(=[O:62])=[O:63])=[CH:68][CH:67]=1
Reactant: NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(O)cccc32)c1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(O)cccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (39.7 mg, 0.064 mmol) in anhydrous DMF (1 mL) was added at room temperature acetic acid (3.36 μL, 0.059 mmol), followed by N,N-diisopropylethylamine (0.031 mL, 0.18 mmol) and finally a solution of N-(1-{[3-(aminomethyl)phenyl]methyl}-4-hydroxy-1H-indazol-3-yl)-5-chloro-2-thiophenesulfonamide formate salt (for a preparation see Intermediate 15) (29 mg, 0.059 mmol) in anhydrous DMF (1 mL) and the reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with brine:water (1:1), passed through a hydrophobic frit and evaporated in-vacuo to yield a colourless oil (23 mg). This was dissolved in MeOH:DMSO (1 mL) and purified by MDAP Sunfire C18 column eluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile) (25 min run). The appropriate fraction was evaporated in-vacuo to yield the title compound as a colourless oil (20 mg, 69%). LCMS (System B) RT=2.41 min, ES+ve m/z 491/493 (M+H)+.
Reaction SMILES: C[O-].[Na+].C([O:8][C:9]([CH:11]1[C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:14][CH:13]=[CH:12]1)=O)CCC.C(OC(C1C2C=CC(Cl)=CC=2C(C2C=CC=CC=2)=NCC=1)=O)CCC.Cl.[C:55]([NH2:58])(=[NH:57])[CH3:56]>C(O)C.O.CO>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]2[CH:11]3[C:9](=[O:8])[NH:58][C:55]([CH3:56])=[N:57][CH:12]3[CH2:13][N:14]=[C:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:16]=2[CH:21]=1
Reactant: CCCCOC(=O)C1C=CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CC(=N)N
Agent: CCCCOC(=O)C1=CCN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: C[O-]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCO
Product: CC1=NC2CN=C(c3ccccc3)c3cc(Cl)ccc3C2C(=O)N1

Procedure:
In one portion, 11.5 mL (49 mmol) of a 4.34 M methanol solution of sodium methoxide was added to a solution of 11.0 g (31 mmol) of a mixture of 8-chloro-1-phenyl-5H-2-benzazepine-5-carboxylic acid butyl ester and 8-chloro-1-phenyl-3H-2-benzazepine-5-carboxylic acid butyl ester and 5.7 g (60 mmol) of acetamidine hydrochloride in 200 mL of ethanol. The mixture was refluxed for 18 hr, cooled and poured into 800 mL of water. The resulting precipitate was collected by filtration and washed with ether to yield a yellow solid. Recrystallization from tetrahydrofuran gave off-white prisms, mp 155°-160°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][CH2:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][CH2:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCC[C@H](N)C(=O)OC
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Product: CCC[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)OC

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-aminopentanoate hydrochloride (prepared from (S)-2-aminopentanoic acid (Novabiochem) using General Procedure H), the title compound was prepared as a solid (mp=154-155° C.).
Reaction SMILES: Cl.C[C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11](=[O:19])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:17]1([CH2:18][CH:9]([NH:10][C:11](=[O:19])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][N:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(-c2cc3ccccc3c(=O)[nH]2)n1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NC(Cc1ccccc1)c1ccccn1)c1ccccc1

Procedure:
The amine prepared as described in (a) was dissolved in chloroform and equivalent amounts of benzoyl chloride and triethylamine were added. The reaction mixture was refluxed for two hours and then washed with water and dried with sodium sulphate. The solvent was distilled off and the residue crystallised from ethanol to yield N-[2-phenyl-1-(2-pyridyl)ethyl]benzamide.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=O)[CH2:3][CH2:2]1.[CH3:17][NH:18][NH2:19]>CN(C)C=O.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)[N:18]([CH3:17])[N:19]=2)[CH2:3][CH2:2]1
Reactant: CNN
Reactant: O=C(C#CC1CC1)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C2CC2)cc1-c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Cyclopropyl-1-(4-nitrophenyl)prop-2-yn-1-one (500 mg, 2.323 mmol) was dissolved in N,N-dimethylformamide (7.75 mL), and the solution was chilled to 0° C. Methylhydrazine (118 mg, 2.56 mmol) was added dropwise. The mixture was stirred overnight at room temperature then diluted with water (25 mL) and stirred for 45 minutes. The resulting precipitate was collected by filtration to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH:16]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[I-:37].[Na+]>C(C(C)=O)C>[I:37][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH:16]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [I-]
Reactant: CCOC(=O)C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(=NOCCI)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
A mixture of 6 g of the syn isomer of ethyl 2-(2-bromoethoxyimino)-2-(2-tritylamino-4-thiazolyl)-acetate, 60 ml of methyl ethyl ketone and 2.141 g of sodium iodide was refluxed for 70 minutes and was then evaporated to dryness under reduced pressure. The residue was taken up in 120 ml of methylene chloride and the solution was washed 5 times with 40 ml of water. Each of the wash waters were reextracted with 2 ml of methylene chloride and the combined organic phase were dried and evaporated to dryness. The resin residue was added to ether and the solution was evaporated to dryness under reduced pressure to obtain 6.22 g of the syn isomer of ethyl 2-(2-iodoethoxyimino)-2-(2-tritylamino-4-thiazolyl)acetate melting at 110° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13]C(N)=O>P(O)(O)O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(N)=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: OP(O)O
Product: NC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 94.3 %

Procedure:
334 g (2.0 mol) of 4-nitrobenzoic acid, 120 g (2.0 mol) of urea and 2.0 g of phosphorous acid are heated in 1000 ml of the organic mother liquor from the preceding experiment, with stirring, at from 158° to 163° C. The mixture is worked up as described above. 313.4 g of 4-nitrobenzamide are obtained having a melting point of from 192° to 195° C. This corresponds to a yield of 94.4% of theory. By acidification of the aqueous mother liquor to pH 2, 8.8 g of 4-nitrobenzoic acid (2.6% of theory) are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:27])[NH:23][CH2:24][CH2:25][NH2:26])([CH3:20])([CH3:19])[CH3:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][C:14]([NH:26][CH2:25][CH2:24][NH:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:27])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.20 g (0.90 mmol) of N-[(benzyloxy)carbonyl]-beta-alanine and 0.187 g (1.17 mmol) of tert-butyl(2-aminoethyl)carbamate are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.223 g (1.17 mmol) of EDC and 0.036 g (0.27 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:13][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:15](=[O:16])[C:11]=2[C:10]([O:28]CC2C=CC(OC)=CC=2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:28][C:10]1[C:11]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:13][C:12]=2[C:3]([O:2][CH3:1])=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: COc1ccc(COc2c3c(c(OC)c4cccnc24)CN(Cc2ccc(C(F)(F)F)cc2)C3=O)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(C(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
To 5-methoxy-9-(4-methoxy-benzyloxy)-7-(4-trifluoromethyl-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 305 (13 mg, 0.026 mmol) dissolved in dichloromethane (0.200 ml) was added triethylsilane (TES, 0.05 ml) and trifluoroacetic acid (TFA, 0.100 ml). After stirring at room temperature for 15 minutes, the reaction mixture was concentrated in vacuo and azeotroped three times with a (1:1) tetrahydrofuran to toluene mixture. The resulting residue was then triturated three times with a (3:1) hexane to ether mixture to afford 9-hydroxy-5-methoxy-7-(4-trifluoromethyl-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 306 (7 mg, 0.014 mmol, 54%). 1H NMR (CD3OD) δ 9.0 (dd, 1H), 8.58 (dd, 1H), 7.60 (d, 2H), 7.40 (d, 2H), 4.80 (s, 2H), 4.50 (s, 2H), 3.95 (s, 3H). 19F NMR δ −63, −76.2. MS: 389.1 (M+1).