Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:19])[CH:17]=[CH2:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH2:23])[CH2:21][CH3:22]>C(#N)C>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:19])[CH2:17][CH2:18][N:23]([CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:19])[CH2:20][CH2:21][CH3:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reactant: CCCN
Solvent: CC#N
Product: CCCN(CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reaction time: 6 h
Yield: 19.4 %

Procedure:
A solution of 400 mg (1.5 mmol) (R)-1-acryloyl-pyrrolidine-2-carboxylic acid benzyl ester and 63 ml (0.75 mmol) propylamine in 5 ml acetonitrile was stirred for 16 h at room temperature, then for 6 h at 45° C., and finally for 16 h at 80° C. Concentration in vacuo and flash chromatography (20% H2O in acetone) afforded 84 mg (19%) of the title compound as a pale yellow oil. MS m/e (%): 578 (M+H+, 100).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:11]([O:10][P:9]([CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4])([O:13][CH2:14][CH3:15])=[O:16])[CH3:12]
Reactant: NC(=O)NC(=O)CCl
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC(=O)NC(N)=O)OCC

Procedure:
While stirring, 682 gm (5 mol) of chloroacetylurea were added portionwise to 831 gm (5 mol) of triethyl phosphite at a temperature of 135°C to 150°C. Each time, the addition of the next portion was delayed until the violent gas evolution had abated. After the last portion of chloracetylurea had been added, the stirring was continued at 150°C until the evolution of gas was terminated. Small quantities of a volatile substance distilled off when the reaction mixture was heated on the water bath under the vacuum generated by an oil pump. The reaction mixture solidified upon cooling. The pure diethylphosphonoacetylurea was obtained from the crude product by recrystallization from isopropanol or acetone and proved to be a water-soluble product having a melting point of 120°C. The yield of crude product was 1120 gm (94% of the theory).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].CCCCCC.C(O[CH:19]=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][C:3]=1[CH3:9]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cc(N)ccc1I
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccc(I)c(C)c1)C(=O)OCC
Temperature: 130 °C

Procedure:
4-iodo-3-methylaniline (5.75 g) was suspended in diethyl ethoxymethylenemalonate (5.5 mL). The mixture was heated at 130° C. for 2.5 h. After cooling to ˜90° C., hexane was added and the mixture stirred while cooling to room temperature. The product crystallized out, and was filtered off, washing well with more hexane. The solid was dried in vacuo to yield the title compound as a pale grey powder (7.947 g); 1H NMR δ (CDCl3) 1.33 (3H, t), 1.38 (3H, t), 2.43 (3H, s), 4.25 (2H, q), 4.3 (2H, q), 6.69 (1H, dd), 7.01 (1H, d), 7.75 (1H, d), 8.46 (1H, d), and 10.95 (1H, br d).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:17]=[C:16](I)[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]=2[CH:6]=1)=[O:4].[Br-].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([Zn+])=[N:25][CH:26]=1>C1COCC1.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>[CH3:1][O:2][C:3]([C:5]1[CH:17]=[C:16]([C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:26][N:25]=2)[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]=2[CH:6]=1)=[O:4]
Reactant: Cc1ccc([Zn+])nc1
Reactant: COC(=O)c1cc(I)c2ncn(CC(C)C)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(C)cn2)c2ncn(CC(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of 7-iodo-3-isobutyl-3H-benzoimidazole-5-carboxylic acid methyl ester (400 mg, 1.12 mmol) in THF (4 mL) was added Pd(PPh3)4 (65 mg, 0.056 mmol), followed by 5-methyl-pyridinyl zinc bromide (2.68 mL of 0.5M solution in THF, 1.34 mmol). The reaction mixture was stirred overnight at room temperature, then quenched by addition of saturated aqueous NH4Cl solution. The mixture was partitioned between water and ethyl acetate, and the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography gave 207 mg (57%) of 3-Isobutyl-7-(5-methyl-pyridin-2-yl)-3H-benzoimidazole-5-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].ClC1C(CC2SC(C3OC=CC=3)=NN=2)=CC([C@H]2[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O2)=C(OC)C=1.OS(C(F)(F)F)(=O)=O.C1C(=O)N([Br:57])C(=O)C1>C(#N)C>[Br:57][C:7]1[C:8]([OH:10])=[CH:9][C:2]([Cl:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(O)cc1Cl
Agent: COc1cc(Cl)c(Cc2nnc(-c3ccco3)s2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: N#Cc1cc(Br)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of 2-chloro-4-hydroxybenzonitrile (compound 86, 10.0 g, 65.1 mmol) in acetonitrile (200 mL) was added triflic acid (10.0 mL, 71.6 mmol) and NBS (16.2 g, 91.2 mmol) at −30° C. The solution was allowed to warm up to room temperature and stirred overnight prior to quenching with saturated sodium bisulfite. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (5-40% EtOAc/hexanes) to yield title compound (9.80 g, 65%) as a white solid.
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][C:10]1[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][CH:11]=1.[NH2:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:30]=[C:31]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:32]([Cl:35])=[N:33][CH:34]=2)[CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2[CH3:41].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:35][C:32]1[N:33]=[CH:34][C:29]([C:27]2[CH:26]=[C:25]3[C:21]([CH:22]=[N:23][N:24]3[CH3:41])=[C:20]([NH:19][C:16]([C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:9])[N:15]=3)=[O:18])[CH:28]=2)=[CH:30][C:31]=1[NH:36][S:37]([CH3:40])(=[O:39])=[O:38]
Reactant: Cn1ncc2c(N)cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc21
Reactant: Cc1cccc(C(=O)O)n1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc3c2cnn3C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propen-1-amine (0.042 ml) was added to 6-methyl-2-pyridinecarboxylic acid (44 mg) in DCM (1 ml). The reaction was stirred at RT for 20 mins. N-[5-(4-Amino-1-methyl-1H-indazol-6-yl)-2-chloro-3-pyridinyl]methanesulfonamide (75 mg) in DCM (2 ml) was added and the reaction stirred for 30 mins. Approximately 4 ml saturated sodium bicarbonate (aq) was added followed by DCM (3 ml). The reaction was stirred vigorously. The DCM was passed through a hydrophobic frit then evaporated to dryness. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method E). The pure fraction was evaporated to dryness to give title compound (6 mg)
Reaction SMILES: [CH3:1][C:2]1([N:10]2[C:18](=O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9]>C(O)(=O)C.[Zn]>[CH3:1][C:2]1([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9]
Reactant: CC1(N2C(=O)c3ccccc3C2=O)CCC(=O)NC1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: CC1(N2Cc3ccccc3C2=O)CCC(=O)NC1=O
Yield: 34.7 %

Procedure:
8.2 g of 2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione were dissolved in 470 ml of glacial acetic acid. When the solution was boiling under reflux, five 3.9 g portions of zinc dust were added at intervals of one hour. Then zinc was removed by filtration and washed with 1,4-dioxane. The filtrate was evaporated under vacuo yielding a crude product which was crystallized from ethyl alcohol. The residue obtained by evaporation of the mother liquor was purified by column chromatography (stationary phase: silica gel 60, MERCK, 40-63 mm; mobile phase: 4:1 acetone/dichloromethane). Thus 2.7 g (35%) of 3-methyl-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[C:22]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][CH:25]=1)=O>C(O)(=O)C>[CH3:30][N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:3]3[N:4]=[CH:5][C:6]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)[CH:21]=1)[C:27](=[O:29])[CH3:28]
Reactant: Nc1n[nH]cc1C(=O)c1cccs1
Reactant: CC(=O)N(C)c1cccc(C(=O)C=CN(C)C)c1
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cccc(-c2ccnc3c(C(=O)c4cccs4)cnn23)c1
Temperature: 25 °C

Procedure:
A fifty liter flask is charged with 1.936 kg of (3-amino-1H-pyrazol-4-yl)-2-thienylmethanone, 2.450 kg of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methylacetamide and 33.3 kg of acetic acid (Van Waters). The reaction mixture is heated at reflux for 6 hours. The reaction mixture is evaporated to a residue under reduced pressure while maintaining the temperature at approximately 45?C. The residue is dissolved in methylene chloride (8 L; Spectrum) then precipitated by the addition of 32 L of methyl-t-butyl ether. The solid is isolated by filtration and the cake washed with a small portion (3.6 L) of methyl-t-butyl ether (Van Waters). The solid is suspended in a mixture of hexanes (20 L) and ethyl acetate (20 L) and heated at reflux for 5 minutes. The mixture was allowed to cool to room temperature and the solid is isolated by filtration. The cake is washed with a small portion (6 L) of hexanes/ethyl acetate (1:1). The material is dissolved in hot methylene chloride (17 L) then the product is precipitated by the addition of hexanes (17 L). The mixture was allowed to cool to room temperature and the solid is collected by filtration. The solid may be further purified by crystallization from any one of a variety of known solvents and/or washing techniques.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[O:14][CH2:15][C:16]([OH:18])=[O:17].CC(C)([O-])C.[K+].CC(N(C)C)=O>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C(O)COc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)COc1ccccc1Oc1ccc([N+](=O)[O-])cc1

Procedure:
4-(fluoro)nitrobenzene was reacted with 2-(2-hydroxyphenoxy)acetic acid in the presence of potassium t-butoxide/DMA at 150° C. for 2 hrs to give 2-[(2-(4-nitrophenoxy)phenoxy] acetic acid. The product was purified by chromatography.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34]([OH:36])=[O:35])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:10]1)=O)(C)(C)C>CO.O1CCOCC1>[F:22][C:20]1[CH:19]=[CH:18][C:17]([NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34]([OH:36])=[O:35])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[C:16]([O:15][C@H:11]2[CH2:12][CH2:13][CH2:14][NH:9][CH2:10]2)[CH:21]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCNC3)c12

Procedure:
HCl in Methanol (4M; 0.250 ml) was added into a solution of 4-[2-((S)-1-tert-butoxycarbonyl-piperidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (50 mg) in dioxane (2.5 ml) at room temperature. The reaction was stirred over the weekend. The reaction mixture was purified by chromatography. The product was triturated from hot MeOH to give the intended product.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1.[CH3:20][O:21][CH2:22][CH2:23][CH:24]1[CH2:29]N[CH2:27][CH2:26][NH:25]1.CS(C)=O>C1(C)C=CC=CC=1>[F:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:27][CH2:26][NH:25][C@@H:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:29]3)[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1
Reactant: Cc1cc2c(s1)Nc1cc(F)c(F)cc1N=C2N
Reactant: COCCC1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sc(C)cc32)CCN1
Temperature: 115 °C
Yield: 66.4 %

Procedure:
Add 6,7-difluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (65.0 g, 215 mmol) and 2-(2-methoxy-ethyl)-piperazine (96.3 g, 668 mmol) to a solution of DMSO (650 mL) and toluene (1300 mL) with stirring under nitrogen. Heat at gentle reflux (115° C.) for 2 days, and then allow cooling to ambient temperature. Remove most of the organic portion under reduced pressure, and then partition the residue between ethyl acetate (450 mL) and aqueous saturated ammonium chloride solution (450 mL). Separate the layers, and then extract the aqueous layer with ethyl acetate (3×200 mL). Extract the combined organic layers with brine (3×200 mL). Concentrate the organic layer under reduced pressure. Purify the crude product by flash chromatography, eluting with 90:10/methylene chloride:MeOH to give 56 g (66%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 6.74 (m, 2H), 6.36 (s, 1H), 3.86 (bm, 2H), 3.39 (m, 2H), 3.23 (s, 3H), 2.88 (bd, 1H), 2.72 (bm, 3H), 2.44 (bt, 1H), 2.31 (s, 3H), 2.31 (bm, 1H), 1.53 (m, 2H). HRMS (ES) exact mass M+H calcd for C19H22F2N4OS 393.1561; found 393.1554.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Cl[CH2:12][C:13]([NH2:15])=[O:14]>O>[NH2:7][C:6]1[CH:5]=[C:4]([CH:10]=[CH:9][CH:8]=1)[O:3][CH2:12][C:13]([NH2:15])=[O:14]
Reactant: Nc1cccc(O)c1
Reactant: NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: NC(=O)COc1cccc(N)c1

Procedure:
A solution of 50% sodium hydride (5.76 g., 0.12 M), 3-hydroxyaniline (13.09 g., 0.12 M) and chloroacetamide (11.22 g., 0.12 M) is stirred at room temperature for 18 hours. The mixture is diluted with water to decompose residual sodium hydride and is then extracted with chloroform. The chloroform extract is dried (MgSO4) and concentrated to an oil under reduced pressure. The addition of chloroform causes it to crystallize. Yield = 10.0g. (50%); m.p. 107°-111° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[Cl:20].CN([CH:24]=[O:25])C.[Cl-].[NH4+]>C1COCC1>[Cl:20][C:19]1[C:14]([Cl:13])=[CH:15][N:16]=[CH:17][C:18]=1[CH:24]=[O:25]
Reactant: Clc1ccncc1Cl
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cncc(Cl)c1Cl
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (10.73 ml, 75.9 mmol) in THF (60 ml) at −40° C., was added n-butyllithium (47.45 ml, 75.9 mmol, 1.6M in hexanes) and the solution was stirred for 15 min at −40° C., before cooling to −70° C. A solution of 3,4-dichloropyridine (10.7 g, 72.3 mmol) in THF (30 ml) was added dropwise to maintain the temperature below −65° C. The reaction was stirred at −70° C. for 2 hours before the addition of DMF (6.74 ml, 86.8 mmol). The reaction was then stirred at −40° C. for 1 hours and then allowed to warm to −5° C. before the careful addition of saturated ammonium chloride solution (50 ml) with rapid stirring over 3 min. The mixture was then partitioned between saturated ammonium chloride (150 ml) and dichloromethane (150 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (2×100 ml) and the combined organic layers were dried over magnesium sulfate, then concentrated in vacuo. Purification of the resultant residue by flash chromatography (Si-PPC, dichloromethane:ethyl acetate gradient 100:0 to 94:6) afforded the title compound as white waxy solid (8.01 g, 63%).
Reaction SMILES: C([O:5][C:6](=[O:36])[C@@H:7]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[N:20]=[C:21]([NH2:24])[S:22][CH:23]=2)=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][C:21]1[S:22][CH:23]=[C:19]([CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:26][S:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)(=[O:29])=[O:28])[C:6]([OH:36])=[O:5])=[O:25])=[CH:16][CH:15]=2)[N:20]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCc2csc(N)n2)cc1)NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(CCc2ccc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2)cs1

Procedure:
Ester 21-5 (200 mg, 0.377 mmol) was dissolved in 2 mL CH2Cl2, and 2 ml TFA was added. After 4 h at RT the mixture was concentrated, azeotroped with toluene, and purified by flash chromatography (silica, 28:10:1:1 EtOAc/EtOH/NH4OH/H2O) providing 21-6 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccccc1Cl
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccccc4Cl)cc3c2C1
Yield: 72.7 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 5.7 mg (0.051 mMol) 2-chlorobenzoyl chloride, 12.3 mg (73%) of the title compound were recovered as a beige solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH:19]([NH2:22])([CH3:21])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][CH:19]([CH3:21])[CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC(C)C
Yield: 88.8 %

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (267 mg, 1.0 mmol) was treated with isopropylamine (1.5 mmol) following general procedure B to afford 4-isopropylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (256 mg). 3-Ethyl-1-isopropyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (14 mg) was prepared from 4-isopropylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and ethyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 314 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](Br)([CH3:14])[O:10][C:9]2=[O:16])=[CH:4][CH:3]=1.[I-:17].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([I:17])([CH3:14])[O:10][C:9]2=[O:16])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC1(Br)OC(=O)N(c2ccc(Cl)cc2)C1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CC1(I)OC(=O)N(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 168 h

Procedure:
6.1 g (0.02 mole) of the 3-(4-chlorophenyl)-5-bromo-5-methyl-oxazolidine-2,4-dione, produced in a manner analogous to that described in Example 1, and 33.2 g (0.2 mole) of potassium iodide are placed, together with a spatula tip of benzyltriethylammonium chloride, in 50 ml of water, and the mixture is stirred at 50° for 7 days. It is then cooled to room temperature, and the solid product is filtered off with suction. After washing with water, the crude product is taken up in methylene chloride, and extracted once with water. The organic phase is then dried over sodium sulphate, filtered, and concentrated in a vacuum evaporator. The substance remaining behind is digested with a small amount of ether/petroleum ether, then filtered off with suction and dried. There is obtained a yield of 3.3 g of substance having a melting point of 132°-142°.
Reaction SMILES: C1(S[C:8]2([O:11][C:12]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:13]=3[CH:14]=[O:15])[CH2:10][CH2:9]2)C=CC=CC=1.[C-]1C2C(=CC=CC=2)C=CC=1.[Li+].O>C1COCC1>[CH:8]1([O:11][C:12]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][C:13]=2[CH:14]=[O:15])[CH2:10][CH2:9]1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1OC1(Sc2ccccc2)CC1
Agent: [Li+]
Agent: [c-]1cccc2ccccc12
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 6 %

Procedure:
Freshly cut lithium metal (97 mg, 13.9 mmol) was added to a solution of naphthalene (1.77 g, 13.9 mmol) in THF (20 mL) and the mixture was sonicated at room temperature for 30 min. to produce a dark green solution of lithium naphthalenide. A solution of 2-(1-phenylthiocycloprop-1-yl)oxy-5-(trifluoromethoxy)benzaldehyde (Description 1, 96 mg, 0.27 mmol) in THF (2 mL) was cooled to −78° C. and the solution of lithium naphthalenide in THF (2 mL) was added dropwise until the intense green colour persisted. The reaction was then stirred for 5 min., water (6 mL) was added and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate, the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2O (80:20), to give to give the title compound as a colourless oil (4 mg, 6%). 1H NMR (360 MHz, CDCl3) δ 0.86 (4H, m), 3.82-3.9 (1H, m), 7.42 (2H, m), 7.62 (1H, d, J=2.5 Hz), and 10.36 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:4]=2[O:3]1.[Br:15][CH2:16][CH2:17]Br>C(O)(C)C>[CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:13][CH2:17][CH2:16][Br:15])=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C)NC(=O)c2ccc(O)cc2O1
Reactant: BrCCBr
Solvent: CC(C)O
Product: CC1(C)NC(=O)c2ccc(OCCBr)cc2O1

Procedure:
16.2 g of 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-1,3-benzoxazin-4-one are reacted analogously to Example (3a) with 84 ml of 1,2-dibromoethane and yield 2,3-dihydro-2,2-dimethyl-7-(2-bromoethoxy)-4H-1,3-benzoxazin-4-one having a melting point of 156°-158° (from isopropanol).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[Br-].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[C:22](=O)[CH3:23]>C1(C)C=CC=CC=1.C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[C:22]([CH3:23])=[CH2:1]
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(C)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
KHMDS(1 eq) in toluene is added dropwise over 5 minutes to a stirred suspension of triphenylphosphinemethyl bromide(1.2 eq) in THF at −78° C. under nitrogen. After complete addition solution is allowed to warm to room temperature for 5 minutes then cooled a second time to −78° C. 1-(2-fluoro-5-nitrophenyl)ethanone(1 eq) in THF is then added via cannulla into the cold suspension over 10 minutes. Resulting mixture is then allowed to warm to room temperature and stirred for 1 h. Solvent is then removed under reduced pressure, cyclohexane is then added and mixture heated briefly to reflux, cooled to room temperature, filtered and filtrate concentrated. Crude product is purified using flash chromatography(85% Hex:15% EtoAc) on silica to afford 1-fluoro-4-nitro-2-(prop-1-en-2-yl)benzene.