Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7].C(N(CC)CC)C.[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[C:23]=[O:24])[CH:17]=1.CCCCCC>C1COCC1>[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([O:7][CH2:6][CH3:5])=[O:24])[CH:17]=1.[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([O:7][CH2:6][CH3:5])=[O:24])[CH:17]=1.[CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7]
Reactant: Cc1cccc(N=C=O)c1
Agent: OCC#CC#CCO
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 500 ml 3-necked round bottom flask was fitted with a magnetic stirrer, an addition funnel and a thermometer. To the flask was added 11.0 grams (0.1 mole) of 2,4-hexadiyn-1,6-diol in 300 ml of THF, 0.5 g of di-t-butyltin-di-2-ethoxyhexanoate and 2 ml. of triethylamine. The resultant solution was stirred and 39.9 g (0.3 mole) of m-tolyl isocyanate was added dropwise over a period of half an hour. The reaction temperature was maintained at about 25° C. by a cold water bath. The reaction was allowed to proceed for 2 hours. Into the resultant solution about 1500 ml of hexane was poured. The precipitate was collected and dried under vacuum. The yield of the crude material was quantitative. Elemental and infrared analysis was conducted on a sample recrystallized from acetone-hexane, which was in the inactive form. The m.p. was 133° C. Analytical: Calculated for C,H,N,O: 70.21; 5.32; 7.45; 17.02. Found for C,H,N,O: 70.17; 5.20; 7.12; 17.21. Infrared spectrum (KBr Pellet):
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C@@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:13]([O:15][CH3:16])[CH3:14])=O.O1CCOCC1>CC(O)=O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:9][C:10]([C@@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:13]([O:15][CH3:16])[CH3:14])=[N:1][C:2]=2[CH:7]=1
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)cc1N
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Br)ccc2[nH]1
Reaction time: 18 h
Yield: 29 %

Procedure:
A solution of tert-butyl {(1S,2R)-1-[(2-amino-4-bromophenyl)carbamoyl]-2-methoxypropyl}carbamate (Preparation 23, 6.5 g, 16.17 mmol) in AcOH (5 mL) was stirred at room temperature for 3 days followed by 40° C. for 18 hours. The reaction was diluted by the addition of dioxane and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-40% acetonitrile in 0.1% formic acid in water to afford the title compound as a white solid (1.8 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C(OC([NH:19][CH2:20][CH2:21][SH:22])=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:1].[NH2:19][CH2:20][CH2:21][S:22][C:2]1[C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Fc1ccc2onc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)NCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cl
Product: NCCSc1noc2ccc(F)cc12
Temperature: 0 °C
Yield: 100.6 %

Procedure:
To a solution of 3-chloro-5-fluoro-1,2-benzisoxazole (0.83 g) in dimethylformamide (8 ml) was added 2-t-butoxycarbonylaminoethanethiol (0.86 g) and potassium carbonate (0.67 g) with stirring under nitrogen atmosphere, and the mixture was then stirred at 80° C. for 3 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate and the combined extracts were washed with brine and dried over anhydrous magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography, to give the title compound (1.21 g, 80%) as a colorless powder.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1.Cl.[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1>CN(C)C1C=CN=CC=1>[CH:16]1([C:19]([N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=2)[C:25]([CH:24]2[CH2:23][CH2:27]2)=[O:26])=[O:20])[CH2:18][CH2:17]1
Reactant: C1CCOC1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cccc(I)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N(C(=O)C1CC1)c1cccc(I)c1
Temperature: 0 °C
Yield: 69 %

Procedure:
13ay) A mixture of 1.53 g of 3-iodoaniline, 2.02 g of triethylamine and 0.1 g of 4-dimethylaminopyridine in 25 ml of THF is treated dropwise with 1.83 g of cyclopropanecarbonyl chloride and subsequently held at reflux for 4 hrs. The mixture is poured into 50 ml of ice-water, made weakly acid (pH about 4) with dil. HCl and extracted three times with ethyl acetate. Chromatography on silica gel with petroleum ether/ethyl acetate 4:1 gives 1.73 g (69%) of crude cyclopropanecarboxylic acid cyclopropanecarbonyl-(3-iodo-phenyl)-amide as a colourless oil with solidifies after a few days. Yield: 69%.
Reaction SMILES: [CH3:1][SiH:2]([CH3:4])[Cl:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:9][C:10]([CH3:14])=[C:11]([CH3:13])[CH3:12]>>[CH3:9][C:10]([Si:2]([CH3:4])([CH3:1])[Cl:3])([CH3:14])[CH:11]([CH3:13])[CH3:12]
Reactant: C[SiH](C)Cl
Reactant: CC(C)=C(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)C(C)(C)[Si](C)(C)Cl
Reaction time: 1 h

Procedure:
100 ml (0.92 mol) of dimethylchlorosilane and 3.8 g (0.028 mol) of aluminium chloride are introduced into a 500 ml three-necked flask with a reflux condenser and dropping funnel. Within 1 hour, 109.5 ml (0.92 mol) of tetramethylethylene are added dropwise. The reaction temperature is maintained in the range from 25° to 30° C. by external cooling. After 4 hours, undissolved aluminium chloride is filtered off from the reaction solution which is then distilled.
Reaction SMILES: CN(C)C=O.[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(=O)([O-])N.[CH2:16]([NH:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38](N4CCC(N5CCCC5)CC4)=[O:39])[CH:32]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20])[CH3:17]>C(OCC)C>[CH2:16]([NH:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38]([N:6]4[CH2:11][CH2:10][O:9][CH2:8][CH2:7]4)=[O:39])[CH:32]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20])[CH3:17]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Reactant: C1COCCN1
Agent: NC(=O)[O-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCOCC4)c3)ccc21
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (5 ml) and morpholine (0.326 ml, 3.73 mmol) were added to a mixture (0.401 g) of phenyl N-(4-(1-(ethylamino)carbonyl)-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate obtained in Example 77; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the obtained solid was washed with a solvent mixture of hexane:diethyl ether=1:1 to yield the title compound (255 mg, 0.62 mmol).
Reaction SMILES: [F:1][C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12]C1C=CC=C(C(OO)=O)C=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:12][C:9]1[CH:8]=[C:3]([C:2]([F:1])=[CH:11][N:10]=1)[C:4]([O:6][CH3:7])=[O:5].[Cl:25][C:11]1[C:2]([F:1])=[C:3]([CH:8]=[CH:9][N:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccncc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COC(=O)c1cc(Cl)ncc1F
Product: COC(=O)c1ccnc(Cl)c1F

Procedure:
Methyl 3-fluoroisonicotinate was oxidized with 3-chloroperbenzoic acid, followed by heating in the presence of phosphoryl chloride. The product was separated by silica gel column chromatography to obtain methyl 2-chloro-5-fluoroisonicotinate (EI: 189) and methyl 2-chloro-3-fluoroisonicotinate (EI: 189).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][NH:34][CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44](O)(=[O:47])[CH2:45][OH:46].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[O:32][CH2:31][CH:30]4[CH2:33][N:34]([C:45](=[O:46])[CH2:44][OH:47])[CH2:35][CH2:36][N:29]4[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: O=C(O)CO
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(C3CN4CCN(C(=O)CO)CC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.10 mmol), triethylamine (43 μL, 0.31 mmol), and glycolic acid (8 mg, 0.10 mmol) in DMF (1 mL), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (51 mg, 0.11 mmol) was added at 0° C. The reaction was allowed to stir for 30 minutes while warming to rt. The mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous K2CO3 solution (10 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 20 mg (36%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.35 to 7.27 (m, 5H), 7.11 (dd, 1H), 6.71 (s, 1H), 5.64 (s, 2H), 5.16-5.12 (m, 1H), 4.35-3.96 (m, 3H), 3.88-3.85 (m, 1H), 3.67-3.55 (m, 1H), 3.36-3.27 (m, 1H), 3.12-3.01 (m, 1H), 2.79-2.64 (m, 2H), 2.55-2.41 (m, 3H), 2.19-2.10 (m, 2H); LC-MS [M+H]+=539, RT=2.19 min.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.N1C=CC=CC=1>ClCCl>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][C:10]([CH2:9][NH:8][C:1](=[O:3])[CH3:2])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:21])([CH3:22])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
Acetic anhydride (2.59 mL, 2.81 g, 27.5 mmol) was added dropwise to a stirred, cooled (0° C.) solution of 4-aminomethyl-1-t-butoxycarbonyl-4-phenylpiperidine (7.96 g) and pyridine (3.03 mL, 2.97 g, 37.5 mmol) in dichloromethane (100 mL) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure, aqueous sodium hydrogen carbonate (saturated, 100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×100 mL), aqueous sodium hydrogen carbonate (saturated, 100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (50:50 increasing to 100:0) to give the title compound as an off-white solid (5.96 g, 72% from 4-cyano-4-phenylpiperidine hydrochloride), δH (250 MHz, CDCl3) 7.45-7.26 (5H, m), 5.00 (1H, br m), 3.67 (2H, m), 3.45 (2H, br m), 3.21 (2H, m), 2.08 (2H, m), 1.88 (3H, s), 1.78 (2H, m), and 1.43 (9H, s).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Br)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1
Reaction time: 6 h

Procedure:
A mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine (480 mg, 2.09 mmol), (4-bromo-phenyl)-acetic acid (449 mg, 2.09 mmol), ethyldimethylpropylcarbodiimide hydrochloride (470 mg, 2.23 mmol), N-hydroxybenzotriazole (330 mg, 2.44 mmol), N-methyl morpholine (500 mg, 5.00 mmol) in 20 mL of DMF was shaken for 6 hours, concentrated under reduced pressure and the residue purified by preparative reverse-phase HPLC. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.82 (m, 2 H), 1.98 (m, 2 H), 3.01 (m, 2 H), 3.50 (m, 2 H), 3.79 (m, 4 H), 4.66 (t, J=6.24 Hz, 2 H), 7.12 (m, 1 H), 7.32 (m, 2 H), 7.54 (m, 2 H), 7.72 (m, 1 H), 8.08 (s, 1 H), 8.25 (s, 1 H), 10.44 (s, 1 H); MS (DCI/NH3) m/z 429 [M+H]+.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][C:6](N2CCCC2)=[C:5]1[C:14]([C:16]1[C:17]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15])(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)(C)(C)C>[Cl:29][C:25]1[CH:24]=[C:23]([N:22]2[C:17]3[N:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:14](=[O:15])[C:5]3[NH:4][CH:8]=[CH:7][C:6]2=3)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)n1ccc(N2CCCC2)c1C(=O)c1cccnc1Nc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Product: O=c1c2cccnc2n(-c2cccc(Cl)c2)c2cc[nH]c12

Procedure:
Reflux a mixture of 1-acetyl-2-[2-[(3-chlorophenyl)amino]-3-pyridinylcarbonyl]-3-(1-pyrrolidinyl)-1H-pyrrole (0.45 g), p-toluenesulfonic acid monohydrate (0.21 g) in a solvent of benzene (20 ml), and tert-butanol for 12 hours. Evaporate solvent and partition the residue between CHCl3 and 1M NaHCO3. Wash the CHCl3 solution with water, dry and filter the solution. Evaporate the solvent, and triturate the residue with CHCl3 to give 4-(3-chlorophenyl)-1,4-dihydro-9H-pyrrolo[3,2-b][1,8]-naphthyridin-9-one, m.p. 300°-301° C.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)#[CH:2].[NH2:11][C@H:12]([CH2:30][O:31][CH3:32])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C:23]2=[O:28])=[C:18]([CH3:29])[CH:17]=1)=[O:14].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([C:3]1[S:7][C:6]([C:8]([NH:11][C@@H:12]([C:13](=[O:14])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C:23]3=[O:28])=[C:18]([CH3:29])[CH:17]=2)[CH2:30][O:31][CH3:32])=[O:10])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(C(=O)O)s1
Reactant: COC[C@@H](N)C(=O)Nc1ccc(N2CCOCC2=O)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C#Cc1ccc(C(=O)N[C@H](COC)C(=O)Nc2ccc(N3CCOCC3=O)c(C)c2)s1

Procedure:
Prepared analogously to Example 1a from 5-ethynylthiophene-2-carboxylic acid and 2-(R)-amino-3-methoxy-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]propionamide with TBTU and NMM in DMF.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Br:11][C:12]1[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1>>[Br:11][C:12]1[S:16][C:15]([S:17]([NH:8][C:5]2[C:4]([O:9][CH3:10])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)(=[O:19])=[O:18])=[CH:14][CH:13]=1
Reactant: COc1nc(Cl)cnc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1ccc(Br)s1

Procedure:
Prepared by the method of Example 1 from 5-chloro-3-methoxy-2-pyrazinamine and 5-bromothiophenesulphonyl chloride.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[C:16](#[N:26])[C:17]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][O:20][C:19]=2[CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:21]1[O:22][C:23]2[CH:24]=[CH:25][C:17]([C:16](=[NH:26])[NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)=[CH:18][C:19]=2[O:20]1
Reactant: N#Cc1ccc2c(c1)OCO2
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of (4-methylsulfonyl)aniline (2.82 g, 16.5 mmol) in toluene (150 mL), trimethylaluminum (2M solution in toluene, 12.5 mL, 24.7 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of piperonylonitrile (4.85 g, 33 mmol) in toluene (100 mL) was added over 10 minutes and the reaction mixture was heated to 90°-95° C. After 20 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol (2/1).The combined filtrates were concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane/ether (2/1, 1000 mL). The product was filtered and washed with more of hexane/ether (2/1). The pale yellow solid 3,4-methylenedioxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (4.8g, 91%) was used in the next reaction without further purification: mp (DSC) 214° C. Anal. Calc'd. for C15H14N2SO4 : C, 56.59, H, 4.43, N, 8.80. Found: C, 56.33, H, 4.28, N, 8.66.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.CC1(C)O[C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1>O>[OH:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[O:1][C:17](=[O:18])[C:16]([C:14]([OH:15])=[O:13])=[CH:4]2
Reactant: O=Cc1cccc(O)c1O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: O=C(O)c1cc2cccc(O)c2oc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
2,3-dihydroxybenzaldehyde (0.096 g, 0.69 mmol) and Meldrum's acid (0.100 g, 0.69 mmol) were combined in H2O (1 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 0.123 g of 8-hydroxy-3-carboxy-coumarin in an 85% yield: LCMS (ESI) m/z 207 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[C:6](=[O:7])[CH2:5][CH2:4][O:3]1.[H-].[Na+].[CH2:11]([OH:13])C.C(OCC)=O>CCOCC.O>[OH:13][CH:11]=[C:5]1[CH2:4][O:3][C:2]([CH3:8])([CH3:1])[C:6]1=[O:7]
Reactant: CCO
Reactant: CC1(C)OCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCOCC
Solvent: O
Product: CC1(C)OCC(=CO)C1=O
Temperature: 0 °C
Yield: 43 %

Procedure:
An ether solution of dihydro-2,2-dimethyl-3-(2H)-furanone; (4.55 g, 39.9 mmol) in -30 mL of ether was added dropwise to a suspension of sodium hydride (3.2 g of 60%, 80 mmol) in 150 mL of ether containing three drops of ethanol and 6.5 mL (80 mmol) of ethyl formate stirred at 0° C. After stirring overnight at room temperature, the reaction mixture was taken up into water, the ether layer separated, washed with additional ether, acidified with 6N HCl and extracted into ether. The combined ether layers were washed with water and brine, dried over MgSO4, decolorized with charcoal, filtered and evaporated to leave 2.4 g of 4-hydroxymethylene-dihydro-2,2-dimethyl-3(2H)furanone as a colorless oil (43%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[C:21](=[O:33])[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH:19][C:20]1[C:21](=[O:33])[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1)=[O:6]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: Nc1cccn(-c2ccc(F)cc2)c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1cccn(-c2ccc(F)cc2)c1=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a solution of 2,4,5-trifluorobenzoic acid (Aldrich, 704 mg, 4.0 mmol) in dichloromethane (20 mL), was added oxalyl chloride (Aldrich, 0.70 mL, 8.0 mmol) dropwise, followed by two drops of DMF. The reaction mixture was stirred at room temperature for 2 h, and concentrated in vacuo. Toluene (20 mL) was added and the reaction mixture was evaporated in vacuo to remove the excess oxalyl chloride. The residue was dissolved in dichloromethane (20 mL). Half of this acid chloride solution was added to a mixture of 3-amino-1-(4-fluorophenyl)pyridin-2(1H)-one (306 mg, 1.5 mmol) in dichloromethane (5 mL) and TEA (0.5 mL, Aldrich) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The precipitate that formed was collected by filtration, and washed with methanol, to afford the desired product (363 mg, 67% yield) as a solid. MS(ESI+) m/z 363.25 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:35])[C:5]([O:10][CH2:11][C:12]([C:27]1[C:32]([F:33])=[CH:31][N:30]=[C:29]([Br:34])[CH:28]=1)([NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH3:13])([CH2:8][F:9])[CH2:6][F:7])C.[NH3:36].N.CO>CO>[Br:34][C:29]1[CH:28]=[C:27]([C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:16])=[O:17])([CH3:13])[CH2:11][O:10][C:5]([CH2:6][F:7])([CH2:8][F:9])[C:4]([NH2:36])=[O:35])[C:32]([F:33])=[CH:31][N:30]=1
Reactant: N
Reactant: CCOC(=O)C(CF)(CF)OCC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F
Solvent: CO
Product: CC(COC(CF)(CF)C(N)=O)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F
Reaction time: 16 h

Procedure:
A solution of 2-[2-(2-bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3-fluoro-2-fluoromethyl-propionic acid ethyl ester (970 mg, 1.660 mmol) and 7M NH3 in MeOH (10 ml) was stirred in a in a sealed glass vial at 55° C. for 20 h. Another 3 ml of 7N NH3/MeOH were added and stirring was continued for 16 h at 55° C. The reaction mixture was concentrated and yielded the title compound as a yellow solid that was used in the next step without further purification.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[O:11].[OH-].[K+]>CO>[O:11]=[C:10](/[CH:12]=[CH:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([OH:14])=[O:13]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)/C=C/c1ccccc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
In a 2 L 3-necked flask equipped with a mechanical stirrer, dropping funnel and thermometer was placed benzaldehyde (119.8 g, 1.13 mol) and pyruvic acid (99.44 g, 1.13 mol) in methanol (100 mL) under argon. The reaction mixture was cooled to 10° C. A freshly prepared solution of potassium hydroxide (95.2 g, 1.7 mol) in methanol (350 mL) was added over 30 min. During the addition, the solution turned yellow and eventually a precipitate was formed. The reaction was allowed to warm to room temperature and was placed in a refrigerator overnight. The granular solid in the flask was collected, and was suspended over a cold mixture of methanol (500 mL) and ether (500 mL). After stirring for 1 hr, the solid was collected and dried in a desiccator under high vacuum to give 185 g of a solid. This solid was dissolved in water (1500 mL) and extracted with ethyl acetate (2×200 mL). The aqueous layer was acidified with 3M HCl to pH 2 and extracted with dichloromethane (5×250 mL). The combined organic layers were washed with brine (2×250 mL), dried over magnesium sulfate (30 g) and concentrated under reduced pressure to give 84 g of intermediate 1 as an oil which solidified (32%).