Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([Br:11])=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:17]=[N+:18]=[O:19]>C(#N)C.[Cl-].[Na+].O>[NH2:1][C:2]1[C:3]([N+:18]([O-:19])=[O:17])=[CH:4][C:5]([Br:11])=[C:6]([F:10])[C:7]=1[C:8]#[N:9]
Reactant: O=[N+]=O
Reactant: N#Cc1c(N)ccc(Br)c1F
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1c(N)c([N+](=O)[O-])cc(Br)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a cooled (0° C.) solution of 6-amino-3-bromo-2-fluoro-benzonitrile (8.0 g, 37 mmol) in acetonitrile (40 mL) under nitrogen was added dropwise a solution of nitronium tetrafluoroborate in acetonitrile. The reaction mixture and stirred for 16 h at RT. The reaction mixture was treated with brine and extracted with ethyl acetate. The organic fraction was washed with water followed by brine and dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (10 to 20% ethyl acetate:hexanes) afforded 5.0 g (52%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.6 (d, J=6.9 Hz, 1H), 6.8-7.1 (br. s, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=O)[CH2:17][CH2:16][CH2:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([CH2:25]P(=O)(OCC)OCC)#[N:24].[H-].[Na+].O>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[CH:25][C:23]#[N:24])[CH2:17][CH2:16][CH2:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCCc2cc(OCCCCc3ccccc3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC=C1CCCc2cc(OCCCCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of 6-(4-phenylbutoxy)-3,4-dihydronaphthalen-1(2H)-one (300 mg) in tetrahydrofuran (10 mL), diethyl cyanomethylphosphonate (199 mg) and sodium hydride (60%, 97.8 mg) were added, followed by stirring at room temperature for 24 hours. After adding water, the reaction, mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, concentrated and then purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to thereby give the title compound (E/Z mixture, 207 mg) having the following physical properties.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:15][C:16]([CH3:19])=[N:17][CH:18]=1.[ClH:44]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:44][C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:15][C:16]([CH3:19])=[N:17][CH:18]=1
Reactant: COC(=O)COc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
60 mg of isoamyl nitrite was added to a mixture of 0.17 g of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxy-2-methylpyrimidine, 67 mg of copper(I) chloride, 137 mg of copper(II) chloride and 2 ml of acetonitrile dropwise at room temperature, and the mixture was stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 20 mg of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxy-2-methylpyrimidine [present compound 4-85].
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=2)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10].S(Cl)([Cl:31])=O>>[Cl:31][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:13]([NH:12][S:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:28])([F:27])[F:1])(=[O:11])=[O:10])=[N:14][CH:15]=[CH:16][N:17]=2)=[CH:20][CH:21]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CO)cc1)c1ccccc1C(F)(F)F
Product: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Yield: 96 %

Procedure:
Following the general method as outlined for Intermediate 8, starting from 2-trifluoromethyl-N-{3-[4-(hydroxymethyl)phenyl]pyrazin-2-yl}benzene sulfonamide and thionyl chloride, the title compound was isolated, after evaporation and recrystallization, as a white solid in 96% yield (97% purity by HPLC).
Reaction SMILES: [F-:1].[K+].I([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:9]([NH:11][CH2:12][C:13]([O-:15])=[O:14])=[O:10])(=O)=O.[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10]
Reactant: O=C([O-])CNC(=O)c1ccc([N+](=O)[O-])c(I(=O)=O)c1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)CNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 105 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
A mixture of spray-dried KF (138 mg, 2.3 mmol), intermediate 9 (100 mg, 0.23 mmol), catalytic amount of 18-crown-6 in dry DMSO (4 mL) was stirred at 100-110° C. for 15 min. Work-up of the reaction mixture as described in example 1 gave the product as a colorless solid (40 mg, 69%), mp 136-138° C. 1H NMR (400 MHz, DMSO-d6): δ 8.76 (1H, br s), 8.25 (1H, t, J=7.8 Hz), 8.00 (1H, d, J=12.0 Hz), 7.90 (1H, d, J=8.4 Hz), 3.75 (2H, d, J=4.4 Hz).
Reaction SMILES: N[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH2:16][CH3:17])=[CH:11][C:10]=2[OH:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:19][B-](F)(F)F.[H+].N([O-])=O.[Na+]>C(O)(=O)C>[CH2:16]([C:12]1[C:13]([F:15])=[CH:14][C:9]([O:8][C:7]2[C:2]([F:19])=[N:3][CH:4]=[CH:5][CH:6]=2)=[C:10]([OH:18])[CH:11]=1)[CH3:17]
Reactant: CCc1cc(O)c(Oc2cccnc2N)cc1F
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cc(O)c(Oc2cccnc2F)cc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 17.6 %

Procedure:
To a stirred solution of 2-(2-aminopyridin-3yloxy)-5-ethyl-4-fluorophenol (45 mg, 0.18 mmol) in glacial acetic acid (2.5 ml) was added 0.36 ml of tetrafluoroboric acid (48% in water). The reaction mixture was cooled to 0° C. and sodium nitrite (18 mg, 0.27 mmol) was added at 0° C. and stirred at 0° C. for 1.5 hours until reaction was complete on TLC. The reaction mixture was quenched by adding ice and sodium bicarbonate solution and stirred for 10 minutes before extracting the aqueous solution with ethylacetate. The combined ethyl acetate fraction was washed with saturated sodium bicarbonate solution, water, followed by brine, dried over anhydrous sodium sulfate and concentrated in vacuo to get the crude compound. The crude material was column purified over silica gel using Petroleum ether/ethyl acetate 9:1 as eluant and then further purified by preparative HPLC using 0.1% TFA in water and acetonitrile as solvent system to get 8 mg (17.6%) of 5-Ethyl-4-fluoro-2-(2-fluoropyridin-3yloxy)phenol as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH2:51])[CH2:48][CH2:49][CH3:50]>>[CH2:47]([NH:51][C:41](=[O:43])[CH2:40][CH:37]1[CH2:38][CH2:39][N:34]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][C:7]=2[O:44][CH2:45][CH3:46])=[O:33])[CH2:35][CH2:36]1)[CH2:48][CH2:49][CH3:50]
Reactant: CCCCN
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCCCNC(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with n-butylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H52Cl2N5O3 [(M+H)+] 720.3442, observed 720.3438.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:6][CH:5]=1.P(Br)(Br)[Br:24]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:24][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCO)cc1
Reactant: BrP(Br)Br
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCBr)cc1
Temperature: 25 °C

Procedure:
A solution of 2-{2-[4-(2-Hydroxy-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione (Preparation 10, 22.37 g) and phosphorus tribromide (8.20 g) in toluene (500 mL) was refluxed for 4 hours. The mixture was allowed to cool to room temperature, diluted with ethyl acetate (300 mL) and carefully quenched with sodium bisulphite/sodium bicarbonate (1:1) in water (100 mL). The organic layer was separated and washed with further sodium bisulphite/sodium bicarbonate (1:1) in water (100 mL), dried over sodium sulphate and concentrated in vacuo. The resulting solid (24.26 g) was triturated with heptane:tert-butyl methyl ether (100 mL; 9:1, by volume) to give the title compound as a pale green solid, 17.94 g.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([C:13]2([NH2:16])[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:17][CH:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[C:7]1([C:13]2([NH:16][C:19](=[O:20])[CH:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[Br:17])[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC1(c2ccccc2)CC1
Reactant: CC(C)(C)C(Br)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(Br)C(=O)NC1(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (100 ml), 1-phenylcyclopropylamine (8.9 g) and triethylamine (7.4 g), and α-bromo-tert-butylacetyl chloride (14.5 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. The benzene layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 14.8 g of N-(1-phenylcyclopropyl)-α-bromo-tert-butylacetamide. M.P., 161°-162.5° C.
Reaction SMILES: Cl.Cl.[N:3]1([CH:9]([CH3:12])[CH2:10][OH:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(C(C)C)C(C)C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH:39][C:40](=[O:48])[C:41]3[CH:46]=[CH:45][C:44](F)=[CH:43][CH:42]=3)[NH:37][N:38]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>CS(C)=O>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH:39][C:40](=[O:48])[C:41]3[CH:42]=[CH:43][C:44]([N:6]4[CH2:7][CH2:8][N:3]([CH:9]([CH3:12])[CH2:10][OH:11])[CH2:4][CH2:5]4)=[CH:45][CH:46]=3)[NH:37][N:38]=2)[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3ccc(F)cc3)[nH]n2)cc(OC)c1
Reactant: CC(CO)N1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C(C)CO)CC4)cc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.4 %

Procedure:
2-(Piperazin-1-yl)propan-1-ol 2HCl (0.274 g, 1.26 mmol) was added to N-ethyl-N-propan-2-ylpropan-2-amine (0.330 mL, 1.89 mmol) in DMSO (5 mL). The reaction mixture was stirred at room temperature for 10 mins. N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-fluorobenzamide (0.233 g, 0.63 mmol) was added and the mixture heated at 110° C. for 18 h under nitrogen. Heating was continued for 12 additional days. The reaction was cooled and the crude mixture was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.048 g, 15.44%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](O)=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:46][C:47]([F:53])([F:52])[S:48]([NH2:51])(=[O:50])=[O:49]>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([NH:51][S:48]([C:47]([F:53])([F:52])[F:46])(=[O:50])=[O:49])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: NS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCC(CC)N1C(=O)[C@@](C)(CC(=O)NS(=O)(=O)C(F)(F)F)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 47 mg (0.10 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic acid (Example 71, Step F) in DMF (4 mL) was added 64 mg (0.34 mmol) of EDC, 48 mg (0.36 mmol) of HOBt, and a catalytic amount of DMAP. After 30 min, 45.5 mg (0.30 mmol) of trifluoromethanesulfonamide was added. The resulting light yellow solution was stirred at room temperature for 3 h, and then was concentrated under reduced pressure. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 50% MeCN in water to 90% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:15])[CH2:13][O:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1>CCO.CCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:15])[CH2:13][O:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(c2cc(F)cc(Cl)c2)COC(N)=N1
Solvent: CCCCCCC
Solvent: CCO
Product: C[C@]1(c2cc(F)cc(Cl)c2)COC(N)=N1

Procedure:
(RS)-4-(3-Chloro-5-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was sepa-rated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:850) to give (S)-4-(3-chloro-5-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:5]=1[O:6][CH:7]([OH:10])[CH2:8][CH3:9])([O-])=O.[H][H]>>[NH2:1][C:4]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:5]=1[O:6][CH:7]([OH:10])[CH2:8][CH3:9]
Reactant: CCC(O)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Product: CCC(O)Oc1ccc(N)cc1N

Procedure:
0.039 mol (9.5 g) of (2,4-dinitro) phenoxypropanol in 30 cm3 of absolute alcohol are reduced on Pd/C at 10% in a bomb under 25 kg of pressure of hydrogen at 70° C. for 1 hour.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][OH:12]>>[Cl:6][C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][O:12][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1ccc(Cl)cc1Cl
Product: NS(=O)(=O)OCCOc1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by the procedures of Example 16 from sulfamoyl chloride and 2-(2,4-dichlorophenoxy)ethanol. The viscous oil obtained solidified and was recrystallized from isopropyl ether to give the solid title compound, mp 75°-77° C., in 35% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[CH2:8][C:7]=2[CH:15]=1)#[N:2].CC(C)([O-])C.[K+].CN(C)C=O.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(=O)C>[C:27]1([NH:33][C:34]([C:8]2[C:7]3[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][C:10]([CH3:13])([CH3:12])[C:9]=2[OH:14])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2CC1=O
Reactant: O=C=Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2C(C(=O)Nc2ccccc2)=C1O
Temperature: 0 °C
Yield: 21.4 %

Procedure:
To a mixture of 0.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 0.39 g of potassium t-butoxide, and 5 ml of dried N,N-dimethylformamide was added dropwise a mixture of 0.42 g of phenyl isocyanate and 1.5 ml of dried N,N-dimethylformamide while stirring under cooling with ice. After stirring for 4 hours under ice-cooling, ice-water was added thereto, and the mixture was made acidic with acetic acid and extracted with diethyl ether. The ether layer was washed with water and dried over sodium sulfate. Diethyl ether was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH2Cl2) to obtain 0.17 g of N-phenyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[CH3:13][C:14]1[S:18][C:17]([C:19](Cl)=[O:20])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:19]([C:17]3[S:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[O:20])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: COc1cccc2sc(N)nc12
Solvent: c1ccncc1
Product: COc1cccc2sc(NC(=O)c3ccc(C)s3)nc12

Procedure:
Using 2-amino-4-methoxy-benzothiazole and 5-methyl-thiophene-2-carboxylic acid chloride in pyridine the title compound was obtained as a beige solid (95% yield), MS: m/e=304.1 (M+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]#[CH:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N:28]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[N+:29]=[N-:30]>O1CCCC1.[Cu]I>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[N:30]=[N:29][N:28]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:17]=2)=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NCCc1ccc(F)cc1
Reactant: C#Cc1nc(C)c(C(=O)NCc2ccccc2)s1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2cn(CCc3ccc(F)cc3)nn2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 54.8 %

Procedure:
To a solution of N-benzyl-2-ethynyl-4-methylthiazole-5-carboxamide (0.10 g, 0.39 mmol) in tetrahydrofuran (5 mL) was added copper(I) iodide (0.002 g, 0.008 mmol), N,N-diisopropylethylamine (0.082 mL, 0.47 mmol) and 1-(2-azidoethyl)-4-fluorobenzene (0.077 g, 0.47 mmol). The reaction mixture was stirred at ambient temperature for 17 hours then concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexanes, 1:1) to afford the title compound as a white solid (0.090 g, 55%): mp 181-182° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.38-7.24 (m, 5H), 7.09-6.99 (m, 2H), 6.95-6.85 (m, 2H), 6.23 (t, J=5.6 Hz, 1H), 4.61-4.56 (m, 4H), 3.20 (t, J=7.1 Hz, 2H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.9, 161.6, 157.9, 156.7, 142.5, 137.8, 132.2, 130.1, 128.8, 127.8, 127.7, 124.8, 121.8, 115.9, 52.0, 44.2, 35.7, 17.3; MS (ES+) m/z 422.3 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([O:4][C:5]([NH:7][CH:8]([CH:23]([CH3:25])[CH3:24])[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1)=[O:10])=[O:6])[CH3:3].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][CH2:36]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:30][CH:29]=1.C[O-].[Na+]>CO>[CH3:3][C:2]([CH3:26])([O:4][C:5]([NH:7][CH:8]([CH:23]([CH3:24])[CH3:25])[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:36][C:35]#[C:34][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[C:16]([O:21][CH3:22])[CH:15]=1)=[O:10])=[O:6])[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)OCC#Cc2ccc(Cl)cc2)cc1
Reactant: COc1cc(CCNC(=O)C(NC(=O)OC(C)(C)C)C(C)C)ccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCNC(=O)C(NC(=O)OC(C)(C)C)C(C)C)ccc1OCC#Cc1ccc(Cl)cc1

Procedure:
A mixture 2-(1,1-dimethylethoxycarbonylamino)-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-3-methylbutyramide (4.0 g), toluene-4-sulfonic acid 3-(4-chloro-phenyl)-prop-2-ynyl ester (5.3 g) and 1M sodium methoxide solution in methanol (18 ml) in methanol (100 ml) is heated to reflux for 3 hours . Then the solvent is removed by distillation. Water (300 ml) is added. The mixture is extracted with ethyl acetate (2×200 ml) and washed with brine (100 ml). The organic layers are collected, dried (MgSO4) and evaporated. 2-(1,1-dimethylethoxycarbonylamino)-N-{2-[3-methoxy-4-(4-chlorophenyl-prop-2-ynyloxy)-phenyl]-ethyl}-3-methylbutyramide is obtained which is purified by flash column chromatography on silica gel (ethyl acetate/hexane 1:1) and recrystallisation (ethyl acetate/hexane), m.p. 141-142° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)=O)C.C1(C)C=CC=CC=1>ClCCl.CC(C[AlH]CC(C)C)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]=[O:3])=[N:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(F)cn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1ccc(F)cn1
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To 5-fluoro-pyridine-2-carboxylic acid ethyl ester (94 mg, 0.556 mmol) in dichloromethane (4.0 mL), 1 M DIBAL in toluene (1.23 mL, 1.23 mmol) was added at room temperature and the mixture was stirred for 30 min. The reaction mixture was quenched with 2 M sodium carbonate and extracted with dichloromethane. The dichloromethane was dried and concentrated to give 39 mg (54.7%) of crude 5-fluoro-pyridine-2-carbaldehyde which could be used for the next step reaction without further purification. GC-MS (M+): 125
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1CO>CC(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH2:22][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[O:34][CH3:33])[CH2:16][CH2:17]1
Reactant: COc1ccccc1CO
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Solvent: CC(C)O
Product: COc1ccccc1COCC(O)CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1

Procedure:
Compound 18 was prepared in a similar manner to compound 7, substituting the commercially available 2-methoxy-benzylalcohol for 2-propanol in part C. MS (M+1)=442.41