Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2)=[CH2:2].Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>CO>[CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:15][OH:16])[CH2:8][CH2:7][CH2:6]2)=[CH2:2]
Reactant: C=Cc1ccc2c(c1)CCCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=Cc1ccc2c(c1)CCCC2=NO
Temperature: 80 °C
Yield: 69 %

Procedure:
To 6-vinyl-3,4-dihydronaphthalen-1(2H)-one (Intermediate I-1B, 1.6 g, 9.29 mmol) in methanol (10 mL) was sequentially added hydroxylamine hydrochloride (0.775 g, 11.15 mmol) and sodium acetate (0.915 g, 11.15 mmol). The reaction mixture was heated at 80° C. (oil bath temp.) for 1.5 h. The reaction mixture was concentrated under reduced pressure and to the residue was added water (30 mL). The contents were triturated and filtered. The solid material was washed with water (2×20 mL) and dried overnight to yield 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (1.2 g, 6.41 mmol, 69.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.81-1.94 (m, 2H) 2.71-2.87 (m, 4H) 5.23-5.32 (m, 1H) 5.78 (dd, J=17.61, 0.88 Hz, 1H) 6.69 (dd, J=17.61, 10.78 Hz, 1H) 7.18 (s, 1H) 7.28 (s, 1H) 7.85 (d, J=8.14 Hz, 1H) 8.23 (br. s., 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][OH:19])[CH2:16][CH2:17][C@H:10]2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].[OH-].[Na+]>C(Cl)Cl.O>[C:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][O:19][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:16][CH2:17][C@H:10]2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](CO)CC[C@H]2C1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2C[C@H](COS(C)(=O)=O)CC[C@H]2C1
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A solution of 6.0 g (22 mmol) of (7R,9aS)-2-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (WO 93/25552) and 3.41 mL (24.4 mmol) of triethylamine in 225 mL of dry methylene chloride was chilled to 0° C., and treated with 1.80 mL (23.3 mmol) of methansulfonyl chloride in 75 mL of methylene chloride. After stirring 1 h, water was added and the pH adjusted to 12 with 15% sodium hydroxide. The layers were separated and the aqueous phase extracted with methylene chloride. The combined organic phase was dried (magnesium sulfate), filtered and evaporated to give 7.73 g (100%) of (7R,9aS)-2-BOC-7-(methanesulfonyloxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:29])([F:28])[C:4]([F:27])([F:26])[C:5]([F:25])([F:24])[C:6]([F:23])([F:22])[CH2:7][O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([N+:17]([O-])=O)=[C:11]([F:20])[C:10]=1[F:21].O.O.[Sn](Cl)Cl.[OH-].[K+]>C(O)C.O>[OH:1][CH2:2][C:3]([F:28])([F:29])[C:4]([F:27])([F:26])[C:5]([F:24])([F:25])[C:6]([F:22])([F:23])[CH2:7][O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([NH2:17])=[C:11]([F:20])[C:10]=1[F:21]
Reactant: O=[N+]([O-])c1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)c(F)c1F
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)c(F)c1F
Temperature: 0 °C
Yield: 94.7 %

Procedure:
A solution of the 4-(6-hydroxy-2,2,3,3,4,4,5,5-octafluorohexyloxy)-2,3,5,6-tetrafluoronitrobenzene (2.0 g) in ethanol (50 mL) was treated with tin (II) chloride dihydrate (9.9 g) at 60° C. for 18 hrs. under a nitrogen atmosphere. The mixture was diluted with ice water, basified with potassium hydroxide (10.1 g) in water (80 mL) and extracted with ethyl ether. The extracts were washed with water and brine, dried (K2CO3), and concentrated to an oil. The oil was purified by chromatography to give 4-(6-Hydroxy-2,2,3,3,4,4,5,5-octafluorohexyloxy)-2,3,5,6-tetrafluorobenzeneamine as an oil (1.77 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:31][CH2:32][CH2:33]O)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:31][CH2:32][CH2:33][NH:44][S:41]([CH3:40])(=[O:43])=[O:42])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: CS(N)(=O)=O
Agent: CS(=O)(=O)Cl
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one by treatment with (i) MeSO2Cl and (ii) MeSO2NH2. LC-MS Method 2 tR=1.02 min, m/z=542.3; 1H NMR (CDCl3) 1.35 (m, 1H), 1.53 (d, 3H), 1.69 (m, 1H), 1.89 (m, 1H), 2.00 (m, 1H), 2.17-2.33 (m, 3H), 2.89 (s, 3H), 2.97 (m, 1H), 3.06 (m, 2H), 3.66 (s, 3H), 4.38 (s, 1H), 5.67 (m, 1H), 6.82 (d, 1H), 6.99 (m, 4H), 7.15 (m, 2H), 7.22 (m, 2H), 7.47 (s, 1H), 7.63 (d, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][C@H:8]1[C@@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]3[S:22][C:23]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:24]=4[N:25]=3)[CH:15]=2)[O:10][CH2:9]1)([OH:3])=[O:2].[N+](=[CH2:36])=[N-].C(O)(=O)C.O>C(OCC)C.O1CCCC1>[CH3:36][O:2][C:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][C@H:8]1[C@@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]3[S:22][C:23]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:24]=4[N:25]=3)[CH:15]=2)[O:10][CH2:9]1)=[O:3]
Reactant: O=C(O)c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1
Reactant: C=[N+]=[N-]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of 500 mg of (+)-cis-3-(3-carboxybenzyl)-4-hydroxy-6-(5-fluorobenzothiazol-2-ylmethoxy)chroman (EPO Application 313295-A; published Oct. 17, 1988) in 10 ml of diethyl ether and 30 ml of tetrahydrofuran was added an excess of diazomethane and the reaction stirred at 0° C. for 2 hours. The reaction was allowed to warm to room temperature and 0.5 ml of acetic acid was added followed after 30 minutes by 100 ml of water and 100 ml of diethyl ether. The organic phase was washed with a brine solution, dried over sodium sulfate and concentrated to give 550 mg of a foam.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[S:15][N:14]=[C:13]([CH3:16])[CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[S:15][N:14]=[C:13]([CH3:16])[CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: Cc1cc(Nc2nc(Br)cn(C)c2=O)sn1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3cc(C)ns3)n2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 69.7 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 331a (150 mg, 0.50 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (400 mg, 1.0 mmol), Pd(dppf)Cl2 (25 mg, 0.025 mmol), K3PO4 (220 mg, 1.0 mmol), sodium acetate trihydrate (136 mg, 1.0 mmol), acetonitrile (10 mL), and water (0.5 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (100/1 to 25/1) to afford 331b (200 mg, 70%) as a yellow solid. MS-ESI: [M+H]+ 574.2.
Reaction SMILES: C([O:8][C:9]1[C:18]([Br:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][C:13]([O:20][CH:21]([CH3:23])[CH3:22])=[N:14]2)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CS(O)(=O)=O.C(O)(=O)C.O>[Br:19][C:18]1[C:9]([OH:8])=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([O:20][CH:21]([CH3:23])[CH3:22])[CH:12]=[C:11]2[C:24]([F:27])([F:26])[F:25]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c(OCc3ccccc3)c(Br)ccc2n1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Oc1cc(C(F)(F)F)c2c(O)c(Br)ccc2n1
Yield: 91.8 %

Procedure:
A solution of 5-benzyloxy-6-bromo-2-isopropoxy-4-(trifluoromethyl)quinoline (13.5 g, 30.8 mmol) in 31 mL methanesulfonic acid and 31 mL acetic acid was stirred at rt for 10 h, whereupon it was poured in water (500 mL), neutralized with K2CO3 (ca. 75 g) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (2%–5% EtOAc:hexanes, gradient elution) afforded 9.9 g (92%) of 6-bromo-5-hydroxy-2-isopropoxy-4-(trifluoromethyl)quinoline, a yellow-brown oil. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, 1H, J=9.1), 7.38 (d, 1H, J=9.1), 6.23 (s, 1H), 5.53 (sept, 1H, J=6.2), 1.41 (d, 6H, J=6.2).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C[O-].[Na+].[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>CN(C=O)C>[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCCCCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 4-hydroxybenzoate (13.4 kg, 88 mol) in DMF (52 L) was added dropwise to a mixture of NaOMe (4.8 kg, 89 mol) and DMF (50 L) at room temperature under a gentle stream of nitrogen. The reaction mixture was heated at 60°-70° for 1 hr with stirring and then cooled to room temperature. To this mixture was added dropwise a solution of 4-phenylbutyl bromide (16.92 kg, 79.4 mol) in DMF (5 L). The resulting mixture was heated at 60°-70° for 1 hr with constant stirring and cooled to room temperature. After an addition of 1N-NaOH (110 L) was added, and the product was extracted twice with ethyl acetate (50 L and 80 L). The extracts were washed with 1N-NaOH (110 L) and saturated brine (20 L) successively, and then concentrated to dryness in vacuo to give the title compound in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](N)[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].Cl.N([O-])=O.[Na+].[I-:18].[K+].S(=O)(=O)(O)O>O>[I:18][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(C(=O)O)c(I)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 G. of 4-methoxy-anthranilic acid are suspended at 0° C. in 2 liters of water and 80 ml. of concentrated hydrochloric acid. To this solution is added dropwise with stirring at 0°-5° C. over a period of 30 minutes a solution of 62 g. of sodium nitrite in 130 ml. of water. The resulting diazonium salt solution is stirred for an additional 15 minutes at 0°-5° C. A solution of 164 g. of potassium iodide in 700 ml. of 5-N sulfuric acid is subsequently added dropwise at 3°-6° C. over a period of 45 minutes. Then, the mixture is stirred at room temperature for 30 minutes and heated slowly to reflux. After boiling at reflux for 2 hours, the mixture is cooled to room temperature. The precipitated brown crystals are removed by filtration and washed neutral with water. The filter cake is dried under reduced pressure, and there is obtained 2-iodo-4-methoxy-benzoic acid as brown crystals having a melting point of 174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12](N3CCCCC3)[CH:11]([CH3:19])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH3:19])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC1N=NN(c2ccc(F)cc2)C1N1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cn(-c2ccc(F)cc2)nn1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
Prepared in analogy to EP 0 433 842 A2. A mixture of 1-[3-(4-fluoro-phenyl)-5-methyl-4,5-dihydro-3H-[1,2,3]triazol-4-yl]-piperidine (1.15 g, 0.004 mol) and potassium hydroxide in MeOH (2 N, 29.2 mL, 58 mmol) was heated under reflux for 6 h then cooled to room temperature. The mixture was then poured into water and extracted with diethyl ether and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated to give the title product (555 mg) as a white solid. The filtrate was evaporated and purification by chromatography (silica, 10 to 60% ethyl acetate in heptane) afforded the title compound (41 mg, 79%) as an off white solid. Total yield (596 mg, 77%). MS: m/e=178.1 [M+H]+.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1)C>Cl>[CH3:14][N:12]([CH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=1)[CH3:13]
Reactant: CCOC(OCC)c1ccc(CN(C)C)cc1
Agent: Cl
Product: CN(C)Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To the mixture of 1-(4-(diethoxymethyl)phenyl)-N,N-dimethylmethanamine (7.0 g, 29.5 mmol) in hydrogen chloride (3M in water 30 mL) was stirred at room temperature for 5 hr. Then the mixture was extracted with ethyl acetate (50 ml×3). The aqueous layer was basified with sodium carbonate to pH=10, extracted with ethyl acetate (50 ml×3), dried with anhydrous sodium sulfate, and concentrated to give crude product (3.95 g, yield 82%). LC-MS (ESI) m/z: 164 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[N:30]1([C:36]2[S:37][C:38]3[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=3[N:40]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:33]3[CH2:34][CH2:35][N:30]([C:36]4[S:37][C:38]5[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=5[N:40]=4)[CH2:31][CH2:32]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2sc(N3CCNCC3)nc2c1
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCN(c3nc4ccccc4s3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-piperazin-1-yl-benzothiazole.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[O:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=1.[F:19][C:20]1[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=1[CH2:31][NH2:32].CCN(C(C)C)C(C)C>C(#N)C>[F:19][C:20]1[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=1[CH2:31][NH:32][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: Cn1ccc(COc2ccc([N+](=O)[O-])c(F)c2)n1
Reactant: NCc1ccc(OC(F)(F)F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(OC(F)(F)F)cc3F)c2)n1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A solution of 3-((3-fluoro-4-nitrophenoxy)methyl)-1-methyl-1H-pyrazole (70.0 g, 0.28 mol), (2-fluoro-4-(trifluoromethoxy)phenyl)methanamine (58.3 g, 0.28 mol), DIPEA (63.1 mL, 0.36 mol) and acetonitrile (350 mL) was stirred at 80° Celsius for 16 h. The reaction was cooled to RT, concentrated to dryness, and the resulting residue was recrystallized from ethanol (350 mL) and H2O (350 mL). The solid was collected by filtration and rinsed with a mixture of H2O/ethanol (3:1, 200 mL) followed by hexanes (2×300 mL) yielding the title compound as a yellow solid (116.3 g, 94.7%). MS (ESI): mass calcd. for C19H16F4N4O4, 440.1; m/z found, 441.0 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.68-8.52 (m, 1H), 8.20-8.14 (d, J=9.5, 1H), 7.39-7.34 (m, 1H), 7.34-7.31 (d, J=2.2, 1H), 7.06-6.97 (d, J=9.8, 2H), 6.42-6.33 (dd, J=9.5, 2.5, 1H), 6.33-6.24 (m, 2H), 5.09-5.01 (s, 2H), 4.60-4.52 (d, J=5.9, 2H), 3.93-3.85 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:39][CH2:38][C:11]2[N:12]=[C:13]([NH:15][C:16](=[O:37])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH:28]=[C:27]([C:29]5[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=5)[CH:26]=[N:25]4)[CH:18]=3)[S:14][C:10]=2[CH2:9]1)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C@H:8]1[CH2:39][CH2:38][C:11]2[N:12]=[C:13]([NH:15][C:16](=[O:37])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH:28]=[C:27]([C:29]5[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[CH:33][CH:34]=5)[CH:26]=[N:25]4)[CH:18]=3)[S:14][C:10]=2[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)cn4)c3)sc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@@H](N)CC5)c3)c2)cc1
Yield: 73.3 %

Procedure:
Stir ((S)-2-{3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzoylamino}-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (0.38 g, 0.69 mmol) in 2 mL CH2Cl2 and 2 mL TFA for 3 h in a capped flask. Concentrate the reaction and bring to alkaline pH with aq. Na2CO3. Triturate the residue with CH2Cl2 and filter the product to give 0.23 g 75% yield of N—((S)-6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzamide as a beige solid. MS, ES+ 455.73 (M+H), rt 1.39 min.
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:17])[CH2:15][Cl:16])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>C(Cl)(Cl)Cl.[Fe]>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:17])[CH2:15][Cl:16])=[C:11]([Br:1])[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: BrBr
Reactant: CC(CCl)Cc1ccc(C(C)(C)C)cc1
Agent: [Fe]
Solvent: ClC(Cl)Cl
Product: CC(CCl)Cc1ccc(C(C)(C)C)cc1Br
Reaction time: 17 h

Procedure:
16 parts by weight of bromine are added dropwise to a mixture of 23 parts by weight of 3-(p-tert.-butyl-phenyl)-2-methyl-propyl chloride and 0.5 part by weight of iron powder. The reaction temperature rises to 35° C. Stirring is continued for 17 hours, the product is dissolved in chloroform, the solution is washed with water, with aqueous NaHCO3 solution and again with water and is dried over Na2SO4, the solvent is evaporated and the residue is distilled.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH:9]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)[N:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH:9]2[CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12]2)[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CC(n2ccc([N+](=O)[O-])n2)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(n2ccc(N)n2)C1
Reaction time: 4 h
Yield: 102.2 %

Procedure:
A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 100 mg dry weight) and a solution of 105a (1.91 g, 7.23 mmol) in ethanol (25 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 4 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (5 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×25 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 100% yield of 105b (1.76 g) as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.22 (d, 1H, J=2.5 Hz), 5.61 (d, 1H, J=2.5 Hz), 4.80 (quant, 1H, J=7.0 Hz), 4.25 (d, 4H, J=7.0 Hz), 3.77 (br s, 2H), 1.41 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25]>>[F:17][C:18]1[CH:19]=[C:20]([C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]=3[CH:5]=[N:6][CH:7]=2)[CH:21]=[CH:22][C:23]=1[C:24]([F:25])([F:26])[F:27]
Reactant: CCS(=O)(=O)NC1CCc2c(Br)cncc21
Reactant: OB(O)c1ccc(C(F)(F)F)c(F)c1
Product: CCS(=O)(=O)NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Yield: 72 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)ethanesulfonamide (intermediate A-7) was reacted with 3-fluoro-4-(trifluoromethyl)phenylboronic acid to give the title compound as off-white solid in 72% yield. MS: 389.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[Cl:16][C:17]1[C:18]([C:23](O)=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=1.CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>C1C=CC2N(O)N=NC=2C=1.N1C=CC=CC=1>[Cl:16][C:17]1[C:18]([C:23]([NH:6][C:5]2[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=2)=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A mixture of 1.15 g of 3,5-bistrifluoromethylaniline, 0.78 g of 3-chloropicolinic acid, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting solid was washed with hexane and dried to obtain 1.67 g of 3-chloro-N-(3,5-bistrifluoromethylphenyl)picolinamide.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].C(N(CC)CC)C.[CH2:21]([O:23][P:24]([O-:28])[O:25][CH2:26][CH3:27])[CH3:22]>O1CCCC1>[CH2:21]([O:23][P:24]([CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Br:1])[OH:13])(=[O:28])[O:25][CH2:26][CH3:27])[CH3:22]
Reactant: CCOP([O-])OCC
Reactant: O=Cc1ccc2ccccc2c1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(O)c1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 250.6 %

Procedure:
To a solution of 1-bromo-2-naphthaldehyde (0.740 g, 0.001 mole) in tetrahydofuran (10 mL) was added triethylamine (0.150 mL, 0.001 mole) followed by diethylphosphite (0.330 mL, 0.002 mole). The reaction mixture was then stirred at room temperature under nitrogen gas for 18 hours. The volatiles then evaporated in vacuo and further dried under vacuum. The resulting solid was triturated with ether and the solid that separated out was collected and dried under vaccum to get 0.935 g of [(1-bromonaphthalene-2-yl)-hydroxymethyl]phosphonic acid diethyl ester