Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([OH:19])=[C:14]([N+:20]([O-:22])=[O:21])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(C)=O.O>[Cl:1][C:2]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([O:19][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:14]([N+:20]([O-:22])=[O:21])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:8])[F:9]
Reactant: CCOC(=O)CBr
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(O)cc2F)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)COc1cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
At 25° C., 6.11 g (0.018 mole) 4-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-nitrophenol, 2.5 g (0.019 mole) K2CO3, and 2.0 mL (0.019 mole) ethyl bromoacetate were slurried in 100 mL acetone. The reaction mixture was stirred at 40° C. for 4 hours. The mixture was cooled, diluted with 100 mL cold water, and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and stripped in vacuo. The residue was recrystallized from methylcyclohexane to give 7.5 g (99%) of (4-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-nitrophenoxy)acetic acid, ethyl ester as a light yellow solid, mp 95°-96° C.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14]([O:16]CC)=O)=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:21])[NH:3]1.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1>C(OCC)(=O)C>[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][C:14](=[O:16])[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([C:7]3[CH:2]([CH3:1])[NH:3][C:4](=[O:21])[NH:5][N:6]=3)=[CH:20][CH:19]=2)[CH2:24][CH2:23]1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1
Solvent: CCOC(C)=O
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NCCN2CCOCC2)cc1
Reaction time: 1 h
Yield: 69.8 %

Procedure:
0.4 g of ethyl α-[4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetate (prepared as described in Example 18) was mixed with 0.36 g of 2-morpholinoethylamine, and the mixture was stirred at 115° to 120° C. for 1 hour. The mixture was then cooled, and ethyl acetate was added. The crystals which precipitated were collected by filtration and washed with ethyl acetate to give a pale yellow powder. Recrystallization of this powder from ethyl acetate gave 0.36 g of the title compound as pale brown, fine crystals melting at 147°-149° C.
Reaction SMILES: N1(CCN2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)CCCCCC1.NC1C=C[C:37]([CH2:38][N:39]([CH3:46])[CH:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=CC=1>>[CH3:46][N:39]([CH2:38][C:37]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[C:25]([O:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23][CH:22]=3)=[O:18])=[CH:14][CH:15]=1)[CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Product: CC(C)COc1cccc2[nH]c(C(=O)Nc3ccc(CN(C)C4CCOCC4)cc3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8) and (4-Amino-benzyl)-methyl-(tetrahydro-pyran-4-yl)-amine (WO9932468).
Reaction SMILES: OO.[CH3:3][C:4]1[C:12]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:22].C([O-])([O-])=[O:24].[K+].[K+].CS(C)=O>O>[CH3:3][C:4]1[C:12]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]([NH2:19])=[O:24])=[CH:16][N:15]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:22]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Oc2ccc(C#N)cn2)ccc2c1CCC2=O
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(Oc2ccc(C(N)=O)cn2)ccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 164.1 %

Procedure:
Add 30% aqueous H2O2 (3.6 ml) to a suspension of 6-(4-Methyl-1-oxo-indan-5-yloxy)-nicotinonitrile (1.22 mg, 4.61 mmol), K2CO3 (319 mg, 2.31 mmol) and DMSO (20 ml) stirring under nitrogen at ambient temperature. After 2.5 hours, dilute the reaction mixture with water (100 ml) and extract with EtOAc (2×). Wash the extract with water and brine, dry (MgSO4) and concentrate on rotary evaporator to yield 1.07 g of the title compound as a yellow solid. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d6): 8.55 (s, 1H), 8.27 (d, 1H), 8.01 (s, 1H), 7.51 (d, 1H), 7.47 (s, 1H), 7.17 (d, 1H), 7.12 (d, 1H), 3.03 (t, 2H), 2.66 (t, 2H), 2.07 (s, 3H).
Reaction SMILES: [SH:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH-].[Na+].Br[CH2:13][N+:14]([O-:16])=[O:15]>CN(C=O)C.O>[N+:14]([C:13]1[S:1][C:2]2=[N:9][CH:8]=[CH:7][CH:6]=[C:3]2[C:4]=1[NH2:5])([O-:16])=[O:15]
Reactant: O=[N+]([O-])CBr
Reactant: N#Cc1cccnc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c([N+](=O)[O-])sc2ncccc12
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
To a solution of 2-mercaptonicotinonitrile (1 g, 7.4 mmol) in DMF (20 mL) was added a solution of NaOH (0.88 g, 22 mmol) in water (5 mL) at 0° C. The mixture was stirred for 20 min, then bromonitromethane (2 g, 14.7 mmol) was added dropwise. The resulting mixture was stirred for 1 h at 0° C., diluted with water (100 mL), and filtered. The filter cake was washed with water (20 mL×3) to give a yellow solid (1.1 g, yield 78%), which was used in the next step without further purification. ESI MS: m/z 196 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[C:18](B(O)O)[CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:18]1[CH:17]=[C:16]([CH3:25])[CH:21]=[CH:20][CH:19]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cccc(-c2c(C(C)O)oc(=O)c3ccccc23)c1
Yield: 55.5 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1 using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.52 g, 1.93 mmol), m-tolylboronic acid (0.45 g, 3.28 mmol), Pd(PPh3)4 (0.11 g, 0.096 mmol) and Cs2CO3 (0.81 g, 2.5 mmol) to afford the title compound (0.3 g, 55%).
Reaction SMILES: [CH2:1](Br)[CH2:2][C@H:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:4].[Li+].[Cl-].[CH3:14][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[CH3:9][C:8](=[CH:7][CH2:6][CH2:5][C@H:3]([CH3:4])[CH2:2][CH2:1][CH3:14])[CH3:10]
Reactant: C[Mg]Cl
Reactant: CC(C)=CCC[C@H](C)CCBr
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@@H](C)CCC=C(C)C
Temperature: 25 °C

Procedure:
To (S)-citronellyl bromide (50 g, 0.228 mol) in THF (800 mL) at 0° C. was added LiCl (4.3 g) followed by CuCl2 (6.8 g). After 30 minutes methylmagnesium chloride (152 mL of a 3 M solution in THF, Aldrich) was added and the solution warmed to room temperature. After 10 hours the solution was cooled to 0° C. and a saturated aqueous solution of ammonium chloride carefully added. The resultant two layers were separated and the aqueous phase extracted with ether. The combined organic phases were dried (MgSO4) and concentrated to give (R)-2,6-dimethyl-non-2-ene. 32.6 g; 93%. Used without further purification. 1H NMR (400 MHz; CDCl3) δ 5.1 (m, 1H), 1.95 (m, 2H), 1.62 (s, 3H), 1.6 (s, 3H), 1.3 (m, 4H), 1.2 (m, 2H), 0.8 (s, 6H); 13C NMR (100 MHz; CDCl3) δ 131.13, 125.28, 39.50, 37.35, 32.35, 25.92, 25.77, 20.31, 19.74, 17.81, 14.60.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:16]=[CH:15][C:9]([O:10][CH:11]3[CH2:14][NH:13][CH2:12]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:16]=[CH:15][C:9]([O:10][CH:11]3[CH2:12][N:13]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])=[CH:20][CH:19]=4)[CH2:14]3)=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)NC(C)(C)c1ccc(Br)cc1
Reactant: c1cc(OC2CNC2)ccc1OCC1CC1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NC(C)(C)c1ccc(N2CC(Oc3ccc(OCC4CC4)cc3)C2)cc1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
To 35 mg (0.16 mmol) 3-(4-cyclopropylmethoxy-phenoxy)-azetidine (IX.1) in THF (2.0 mL) are added under an argon atmosphere 41 mg (0.16 mmol) N-[1-(4-bromo-phenyl)-1-methyl-ethyl]-acetamide, 63 mg (0.64 mmol) NaOtBu, 19 mg (0.064 mmol) 2-(di-tert-butylphosphino)biphenyl and 15 mg (0.016 mmol) tris-(dibenzylidene-acetone)-dipalladium(0). The mixture is stirred for 12 h at 45° C. The mixture is filtered and concentrated in vacuo. The residue is purified by HPLC (Zorbax, acetronitrile/H2O (+0.15% HCOOH)) to yield the desired product.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.CN(C=O)C>O>[Br:14][C:9]1[C:10](=[O:13])[NH:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: O=c1cnc(-c2ccccc2)c[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cc(-c2ccccc2)nc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
A mixture of 5-phenylpyrazin-2(1H)-one (0.86 g), N-bromosuccinimide (0.89 g) and DMF (16 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give the title compound (0.18 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:23])[NH2:22])[NH:6]2.Br[CH:25]([CH:28]=O)[CH:26]=[O:27].CN(C)C(=O)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:23][C:25]([CH2:26][OH:27])=[CH:28][N:22]=1)[NH:6]2
Reactant: O=CC(Br)C=O
Reactant: CN(c1ccc(Cl)c2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(c1ccc(Cl)c2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 90 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
A mixture of 4-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.51 g), bromomalonaldehyde (0.30 g) and N,N-dimethylacetamide (15 ml) was stirred at 90° C. for 4 hr. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried. To a mixture of the obtained crystals, tetrahydrofuran (5 ml) and methanol (5 ml) was added sodium borohydride (55 mg) at 0° C., and the mixture was stirred at the same temperature for 1 hr. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.30 g, yield 52%) as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). melting point 225-226° C.
Reaction SMILES: [F:1][C:2]1[C:23]([F:24])=[CH:22][C:5]2[NH:6][C:7]([NH:9][CH:10]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]3)=[N:8][C:4]=2[CH:3]=1.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:1][C:2]1[C:23]([F:24])=[CH:22][C:5]2[N:6]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:7]([NH:9][CH:10]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCCC(Nc2nc3cc(F)c(F)cc3[nH]2)CC1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCCC(Nc2nc3cc(F)c(F)cc3n2Cc2ccc(F)cc2)CC1
Temperature: 80 °C
Yield: 40.6 %

Procedure:
A mixture of 11 parts of ethyl 4-[[5,6-difluoro-1H-benzimidazol-2-yl]amino]hexahydro-1H-azepine-1-carboxylate, 7.2 parts of 1-(chloromethyl)-4-fluorobenzene, 3.2 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred and heated for 24 hours at 80° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 6 parts (40.6%) of ethyl 4-[[5,6-difluoro-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]hexahydro-1H-azepine-1-carboxylate as a residue; (compound 35).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](Cl)=[CH:4][C:5]([F:8])([F:7])[F:6].FF.[H][H].[OH-].[K+]>C(O)C.[Ni]>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Agent: FF
Agent: [K+]
Solvent: CCO
Product: FC(F)(F)CCC(F)(F)F
Yield: 47.8 %

Procedure:
1,1,1,4,4,4-Hexafluoro-2-chloro-2-butene (40 g) (prepared according to the method described by J. H. Babcock et al in Preparation, Properties, and Technology of Fluorine and Organic Flyoro Compounds, eds. C. Slesser and S. R. Schram (New York , Toronto, London: McGraw-Hill Book Company, Inc., 1951) at p. 817) in 300 ml ethanol was hydrogenated in a stainless steel autoclave with hydrogen for 3 hours at 20° C. and for 1 hour at 100° C. in the presence of potassium hydroxide (12 g) and Raney nickel (25 g). The pressure was in the range from 30 to 40 bar. The solid constituents were separated from the reaction mixture by filtration and the filtrate was distilled to give 16 g of 1,1,1,4,4,4-hexafluorobutane, boiling point 25°-30° C. at 1013 mbar. The mass spectrum showed an m+ /e of 166.
Reaction SMILES: [ClH:1].[CH2:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:10]#[C:11][NH2:12]>>[ClH:1].[CH2:2]([NH:9][C:11]([NH2:12])=[NH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCc1ccccc1
Reactant: N#CN
Agent: Cl
Product: N=C(N)NCc1ccccc1
Yield: 42.7 %

Procedure:
A mixture of benzylamine hydrochloride (4.3 g, 0.03 mol) and cyanamide (1.3 g, 0.031 mol) in xylenes (15 ml) was heated to reflux for 6 hours. After concentration, the reaction mixture was triturated with ether and the solid separated was filtered and crystallized from methanol to provide a colorless solid (2.38 g); purity: 96.8% (HPLC); 1H-NMR (CD3OD) δ 4.41 (s, 2H, CH2), 7.32–7.37 (m, 5H, Ar).
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[CH:15][C:9]([C:10](OCC)=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:17]1[C:22]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:21][C:20]([NH2:27])=[C:19]([OH:28])[CH:18]=1>>[N:1]1([C:6]2[CH:16]=[CH:15][C:9]([C:10]3[O:28][C:19]4[CH:18]=[CH:17][C:22]([S:23]([OH:26])(=[O:24])=[O:25])=[CH:21][C:20]=4[N:27]=3)=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1ccc(N2CCCC2)cc1
Reactant: Nc1cc(S(=O)(=O)O)ccc1O
Product: O=S(=O)(O)c1ccc2oc(-c3ccc(N4CCCC4)cc3)nc2c1

Procedure:
In accordance with the procedure of Example 1, 10.0 g of ethyl 4-pyrrolidinobenzoate were reacted with 8.7 g of 2-aminophenol-4-sulfonic acid to yield 2-(p-pyrrolidinophenyl)-benzoxazole-5-sulfonic acid, melting point 310° (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[NH2:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[S:22])=[CH:11][C:6]=2[N:7]=1
Reactant: Nc1ccc2sc(N)nc2c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: Nc1nc2cc(NC(=S)NC(=O)c3ccccc3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of anhydrous THF (6.7 mL) was added 5-amino-benzothiazol-2-ylamine (Example 16, 100 mg, 0.61 mmol) and benzoyl isothiocyanate (0.08 mL, 1 equiv). The resulting mixture was stirred at room temperature for 2 hours, after which the solvent was evaporated and the residue was washed with a 1:1 mixture of ether/hexanes (0.164 g, 83%). 1H NMR (DMSO d6) δ: 12.61 (s, 1H), 11.53 (s, 1H), 7.99 (d, 1H, J=3.9 Hz), 7.76 (s, 1H), 7.69–7.65 (m, 2H), 7.59–7.53 (m, 4H), 7.25–7.23 (d, 1H, J=3.9 Hz); MS (ESI) 328.8 (M+1, 100%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Cl:11][CH2:12][C:13]([C:8]1[S:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:10][CH:9]=1)=[O:14]
Reactant: ClCCCCc1cccs1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)c1ccc(CCCCCl)s1
Yield: 90.7 %

Procedure:
To a solution of 23 g of 2-(4-chlorobutyl)thiophene and 17.9 g of chloroacetyl chloride in 250 ml of dichloromethane is added a small portion of 21 g of aluminum chloride under cooling at 0°-5° C. and with stirring. After stirring under cooling with ice for 2 hours, the resultant mixture is poured into water and the organic layer is separated. The water layer is extracted with chloroform and the extract is combined with the organic layer. The combined organic layer is washed with water and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give 30 g of 2-chloroacetyl-5-(4-chlorobutyl)thiophene as a brown oil. To a solution of the oil in 300 ml of ethanol is added 11 g of thiourea, and refluxed on a water bath for 2 hours. After the solvent is concentrated under reduced pressure, water is added to the residue and the precipitated crystalline hydrochloride is collected by filtration. To a suspension of the crystals in a mixture of water and ethyl acetate is added sodium hydrogencarbonate until the mixture is made alkaline. The organic layer is separated, washed with water and dried over magnesium sulfate. After the is distilled off under reduced pressure, the residue is recrystallized from ethanol to give 2-amino-4-[5-(4-chlorobutyl)-2-thienyl] thiazole as pale yellow crystals, melting at 99°-100° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.Cl.CN.[CH3:16][N:17](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:17][CH3:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(Br)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.2 %

Procedure:
To a solution of (4-bromophenoxy)acetic acid (500 mg, 2.10 mmol) in N,N-dimethylformamide (15 mL) was added methylamine hydrochloride (320 mg, 5.10 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (570 mg, 3.00 mmol), 1-hydroxybenzotriazole (400 mg, 3.00 mmol) and N-methyl-morpholine (600 mg, 6.00 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL), and then washed three times with ethyl acetate (20 mL). The combined organics was dried and concentrated to give the title compound (580 mg, 90% yield) that was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 2H), 6.79 (d, 2H), 6.56 (s, 1H), 4.46 (s, 2H), 2.91 (d, 3H).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[F:14][C:15]([F:30])([F:29])[C:16]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>CN(C1C=CN=CC=1)C>[F:14][C:15]([F:29])([F:30])[C:16]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:17]=1[C:18](=[O:19])/[CH:13]=[C:7]1\[S:8][C:9]([CH3:12])=[C:10]([CH3:11])[N:6]\1[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(C(F)(F)F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2,5-bis(trifluoromethyl)benzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.28-1.38 (m, 2 H) 1.56-1.64 (m, 2 H) 2.19 (s, 3 H) 2.23 (s, 3 H) 3.92-3.98 (m, 2 H) 6.02 (s, 1 H) 7.82-7.84 (m, 1 H) 7.93-7.97 (m, 1 H) 7.98-8.02 (m, 1 H); MS (ESI) m/z 424 (M+H)+.
Reaction SMILES: C[Si](OP(=O)=O)(C)C.[NH2:9][C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][N:11]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:22](O)=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:22]2[O:16][C:15]3[C:10]([N:9]=2)=[N:11][CH:12]=[CH:13][CH:14]=3)[CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Reactant: Nc1ncccc1O
Agent: C[Si](C)(C)OP(=O)=O
Product: COc1cc(-c2nc3ncccc3o2)ccc1-c1ccccn1
Temperature: 200 °C

Procedure:
To 5 mL of trimethylsilyl polyphosphate was added 2-aminopyridin-3-ol (175 mg, 1.59 mmol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (344 mg, 1.50 mmol). The mixture was heated at 200° C. for 2 h, quenched over ice, and made basic (pH 14) with 1N NaOH. The aqueous phase was extracted with MTBE (3×200 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 2-(3-methoxy-4-pyridin-2-ylphenyl)[1,3]oxazolo[4,5-b]pyridine as a light yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.72 (d, 1H), 8.58 (d, 1H), 8.30 (d, 1H), 8.05–7.91 (m, 4H), 7.88 (t, 1H), 7.51 (dd, 1H), 7.40 (dd, 1H), 4.02 (s, 3H); MS (ESI) 304 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=[CH2:8].C>N1C=CC=CC=1.Cl>[C:6]([CH:7]([CH3:9])[CH2:8][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)([OH:11])=[O:10]
Reactant: C=C(C)C(=O)O
Reactant: c1nc[nH]n1
Agent: Cl
Solvent: c1ccncc1
Product: CC(Cn1cncn1)C(=O)O
Temperature: 140 °C

Procedure:
A mixture of 1,2,4-triazole (27.6 g) and methacrylic acid (34.4 g) in pyridine (40 ml) was heated at 140° C. for 6 hours. The precipitate was dissolved in hot hydrochloric acid (1%, 400 ml). Charcoal was added and the mixture was filtered hot. The solution was concentrated in vacuo and the colourless solid collected by filtration and washed with cold water. NMR (90 MHz): 8.48 (s, 1H), 7.98 (s, 1H), 4.32 (m, 2H), 2.94 (m, 1H), 1.01 (d, 3H).