Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([SH:12])=[C:9]([OH:11])[CH:10]=1.CC(C)([O-])C.[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][C:23]=1[N+]([O-])=O>>[F:21][C:22]1[CH:23]=[CH:24][C:25]2[S:12][C:8]3[C:9]([O:11][C:26]=2[CH:27]=1)=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:13])[F:14])=[CH:6][CH:7]=3
Reactant: Oc1cc(OCC(F)(F)F)ccc1S
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Fc1ccc2c(c1)Oc1cc(OCC(F)(F)F)ccc1S2

Procedure:
3-Fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin can be prepared according to the teachings provided herein and the knowledge in the art. Briefly, treating 5-(2,2,2-trifluoroethoxy)-2-mercaptophenol with base followed by addition of 1,4-difluoro-2-nitrobenzene can afford 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin. For example, 5-(2,2,2-trifluoroethoxy)-2-mercaptophenol can be combined with potassium tert-butoxide followed by combination with 1,4-difluoro-2-nitrobenzene which upon heating can afford 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin. In an exemplary embodiment, the solvent used to dissolve potassium tert-butoxide and 1,4-difluoro-2-nitrobenzene can be anhydrous N,N-dimethylformamide. For example, 5-(2,2,2-trifluoroethoxy)-2-mercaptophenol dissolved in a THF/MTBE mixture can be added to potassium tert-butoxide in N,N-dimethylformamide; subsequent to their combination, under the conditions disclosed herein, the mixture can then be treated with 1,4-difluoro-2-nitrobenzene dissolved in N,N-dimethylformamide.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[O:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[N:7][N:8]=1>O.C1COCC1.[Zn]>[CH3:3][C:4]1[O:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:7][N:8]=1
Reactant: Cc1nnc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc(-c2ccc(N)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
Ammonium chloride (1.12 g, 21 mmol) in water (5 mL) was added to a stirred solution of 2-methyl-5-(4-nitro-phenyl)-[1,3,4]oxadiazole (530 mg, 2.6 mmol) in THF (10 mL). Zinc powder (1.4 g, 21 mmol) was added portion wise and the mixture was stirred at room temperature for 1 hour then heated to reflux at 65° C. for 5 hours. The mixture was then filtered over celite and the filtrate was concentrated. The residue was extracted with ethyl acetate and the organics were washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using basic alumina (4% methanol in chloroform) to afford 220 mg (48%) of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl amine. 1H NMR: (CDCl3): δ 7.8 (d, 2H), 6.7 (d, 2H), 4.0 (s, 2H), 2.6 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C@H:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:21]2)=[O:19])=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[OH:10][CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([C@H:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:21]2)=[O:19])=[CH:15][CH:16]=1
Reactant: O=C(c1ccccc1)c1ccc(NC(=O)[C@@H]2CC(c3cccnc3)=NO2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccc(C(O)c2ccccc2)cc1)[C@@H]1CC(c2cccnc2)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
) NaBH4 (0.054 mol) was added to a solution of compound (3) (0.054 mol) in methanol (300 ml). The reaction mixture was stirred overnight at RT. The precipitate was filtered off, washed with CH3OH and DIPE, then dried, yielding 18 g (89%) of (5S)4,5-dihydro-N-[4-(hydroxyphenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide (compound 499).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=O)[CH:9]=[CH:10][CH:11]=1>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([Cl:3])=[O:15])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
Thionyl chloride (2.035 mL, 27.90 mmol) was added to 2-(3-bromophenyl)acetic acid (1.500 g, 6.98 mmol) in DCM (30 mL). The resulting solution was stirred at room temperature for 18 hours. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford crude product (1.570 g, 96% yield), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:29][O:30][C:31]1[CH:54]=[CH:53][C:34]([CH2:35][O:36][C:37]([NH:39][C:40]2[N:48]=[CH:47][N:46]=[C:45]3[C:41]=2[N:42]=[CH:43][N:44]3[CH2:49][C:50](O)=[O:51])=[O:38])=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:50](=[O:51])[CH2:49][N:44]1[CH:43]=[N:42][C:41]2[C:45]1=[N:46][CH:47]=[N:48][C:40]=2[NH:39][C:37]([O:36][CH2:35][C:34]1[CH:53]=[CH:54][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)=[O:38])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Reactant: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)O)cc1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1cnc2c(NC(=O)OCc3ccc(OC)cc3)ncnc21

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [6-N-(4-methoxybenzyloxycarbonyl)-adenin-9-yl]-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 10.56 (s, 1H), 10.59 (s, 0.55H), 9.31 (brs, 0.55H), 9.11 (brs, 0.45H), 8.57 (s, 0.45H), 8.56 (s, 0.55H), 8.40 (d, 0.55H), 8.39 (d, 0.45H), 8.31 (s, 0.55H), 8.30 (s, 0.45H), 8.03–7.99 (m, 1H), 7.93 (d, 0.55H), 7.91 (d, 0.45H), 7.39 (d, 1H), 6.95 (d, 2H), 5.38 (s, 1.1H), 5.17 (s, 0.9H), 5.14 (s, 2H), 4.48 (s, 0.9H), 4.23 (q, 0.9H), 4.08 (s, 1.1H), 4.07 (q, 1.1H), 3.76 (s, 3H), 3.72 (t, 1.1H), 3.54 (t, 1.1H), 3.45 (t, 0.9H), 3.29 (t, 0.9H), 1.27 (t, 1.35H), 1.15 (t, 1.65H).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20](O)=[O:21])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[N:25]1([C:20]([C:15]2[CH:16]=[N:17][N:18]([CH3:19])[C:14]=2[C:12]([NH:11][C:8]2[CH:9]=[CH:10][N:5]3[N:4]=[C:3]([N:2]([CH3:1])[CH3:24])[N:23]=[C:6]3[CH:7]=2)=[O:13])=[O:21])[CH2:28][CH2:27][CH2:26]1
Reactant: C1CNC1
Reactant: CN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
A mixture of 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (150 mg, 455 μmol), azetidine (123 l, 1.82 mmol), propylphosphonic anhydride (50% in ethyl acetate, 671 μl, 1.14 mmol) and diisopropylethylamine (398 μl, 2.28 mmol) in tetrahydrofurane (8 ml) is stirred for 18 hours at room temperature under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed with water and dried affording 4-(azetidine-1-carbonyl)-N-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide (119 mg, 70.9%) as an off-white solid. Mp.: 240-1° C. MS: m/z=369.1 (M+H+).
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)C=CC=CC=1.[N:17]1([CH2:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:13]1[CH:14]=[CH:15][C:10]([NH:9][C:8]([N:20]2[CH2:21][CH2:22][N:17]([CH2:23][C:24]3[CH:25]=[N:26][C:27]4[C:32]([CH:33]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:18][CH2:19]2)=[O:16])=[N:11][CH:12]=1
Reactant: c1ccc2ncc(CN3CCNCC3)cc2c1
Reactant: O=C(Nc1ccncn1)Oc1ccccc1
Product: O=C(Nc1ccncn1)N1CCN(Cc2cnc3ccccc3c2)CC1

Procedure:
The title compound was prepared from pyrimidin-4-yl-carbamic acid phenyl ester and 3-piperazin-1-ylmethyl-quinoline in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 8.94 (d, J=2.0 Hz, 1H), 8.76 (s, 1H), 8.54 (d, J=6.1 Hz, 1H), 8.25 (s, 1H), 8.20 (d, J=8.8 Hz, 1H), 7.99 (d, J=5.8 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.79-7.75 (m, 1H), 7.64-7.60 (m, 1H), 7.38 (br s, 1H), 3.85 (s, 2H), 3.64 (br s, 4H), 2.66 (bs, 4H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22]([C:27](Cl)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>C1COCC1.C(N(CC)CC)C>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:27]([C:22]4[C:21]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:28])=[CH:18][CH:19]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccccc1
Yield: 1.6 %

Procedure:
A mixture of 4-[4-(phenylmethyl)-1-piperazinyl]-benzenamine (0.12 mole) in THF (300 ml) and triethylamine (50 ml) was stirred. [1,1′-Biphenyl]-2-carbonyl chloride (0.12 mole) was added dropwise. The mixture was stirred overnight. The solvent was evaporated. The residue was dissolved in DCM. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE/2-propanol. The precipitate was filtered off and dried. A part (1 g) of this fraction was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 0.84 g of N-[4-[4-(phenylmethyl)-1-piperazinyl]phenyl]-[1,1′-biphenyl]-2-carboxamide (intermediate 9, melting point 162° C.).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](C2N=CNN=2)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCOCC1>[C:1]([NH:4][C:5]1[N:6]=[C:7]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2nc(-c3ccc(F)cc3)ccc2n1
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(Nc2ccccc2)c2nc(-c3ccc(F)cc3)ccc2n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-acetamido-4-(1,2,4-triazolyl)-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (367 mg, 1 mmol) in dioxane (20 ml) was added aniline (186 mg, 2 mmol). The solution was stirred overnight at 60° C. The solvents were evaporated in vacuo yielding crude 2-acetamido-4-anilino-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine. The residue was redissolved in a mixture of dichloromethane and ethanol (in a ratio of 80/20, 10 ml). A sodium ethoxide solution (0.2 N solution) was added till pH 12 and the resulting mixture was stirred overnight at room temperature. The solvents were evaporated in vacuo. The crude residue was purified by preparative TLC on silica, using a methanol/dichloromethane mixture in a ratio of 10:90 as mobile phase, yielding the pure title compound (160 mg, 50%) which was characterised as follows:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.I[CH2:26][C@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:34]=[CH:35][C:36]3[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=3[CH:43]=2)[CH2:28]1.CCN(C(C)C)C(C)C.Cl>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:26][C@H:27]5[O:31][C:30](=[O:32])[N:29]([C:33]6[CH:34]=[CH:35][C:36]7[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=7[CH:43]=6)[CH2:28]5)[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C1CSc2ccc(N3C[C@@H](CI)OC3=O)cc2N1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C1CSc2ccc(N3C[C@@H](CN4CCN(c5cc6c(cc5F)c(=O)c(C(=O)O)cn6C5CC5)CC4)OC3=O)cc2N1
Temperature: 80 °C

Procedure:
A mixture of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinoline carboxylic acid (commercial; 331 mg), 6-((S)-5-iodomethyl-2-oxooxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one (prepared according to WO 2008/126034; 395 mg) and DIPEA (0.5 ml) in DMSO (6 ml) was heated at 80° C. for 24 h. The reaction mixture was allowed to reach rt, poured on 0.1N HCl (50 ml) and filtered. The resulting solid was purified by CC (DCM/MeOH 19:1 to 9:1 to 4:1, followed by DCM/MeOH 19:1+1% AcOH), affording after concentration under reduced pressure and subsequent stirring in MeOH/EA a beige solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:27]=[C:26](/[CH:28]=[CH:29]/[CH:30]([C:35]2[CH:40]=[C:39]([Cl:41])[C:38]([Cl:42])=[C:37]([Cl:43])[CH:36]=2)[C:31]([F:34])([F:33])[F:32])[CH:25]=[CH:24][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)=[O:12]>C(Cl)Cl>[NH2:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[C:10]1[CH:24]=[CH:25][C:26](/[CH:28]=[CH:29]/[CH:30]([C:35]2[CH:40]=[C:39]([Cl:41])[C:38]([Cl:42])=[C:37]([Cl:43])[CH:36]=2)[C:31]([F:34])([F:32])[F:33])=[CH:27][C:9]=1[Br:8]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.4 %

Procedure:
TFA (0.5 mL) was added to a stirred solution of (E)-tert-butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)ethylcarbamate (200 mg, 0.31 mmol) in CH2Cl2 (10 mL) at 0° C. and the reaction mixture was then stirred at ambient temperature for 18 h. The volatiles were evaporated under reduced pressure; water was added to the residue and the mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 1-5% MeOH in CH2Cl2 to afford the title compound as a brown solid (50 mg, 31%): 1H NMR (400 MHz, DMSO-d6) δ 8.56 (bs, 1H), 7.70 (bs, 2H), 7.94-7.91 (m, 3H), 7.62-7.59 (m, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.00 (dd, J=15.6, 9.2 Hz, 1H), 6.77 (d, J=15.6 Hz, 1H), 4.84-4.81 (m, 1H), 3.46-3.41 (m, 2H), 2.95-2.92 (m, 2H); ESIMS m/z 528.72 ([M+H]+); IR (thin film) 3435, 1671, 1113, 722, 555 cm−1.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH2:23][CH:24]3[CH2:26][O:25]3)[C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=3>CO>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH2:23][CH:24]([OH:25])[CH2:26][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=3
Reactant: Sc1ccccc1
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Solvent: CO
Product: OC(CSc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Benzenethiol (30 Tl, 0.29 mmol) was added to a solution of 3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (epoxide 2-A, 101.6 mg, 0.27 mmol) in 5.0 ml MeOH at r.t. The reaction mixture was heated to 80° C. and stirred overnight at the same temperature. The reaction was monitored by lc/ms for the consumption of SM. The reaction was cooled, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4, filtered and condensed.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[F:5][C:6]([F:23])([F:22])[C:7]1[O:8][C:9]([CH2:20]Br)=[CH:10][C:11]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.P([O-])(O)(O)=O.[Na+]>O1CCCC1.[Cu](Cl)Cl>[F:23][C:6]([F:5])([F:22])[C:7]1[O:8][C:9]([CH2:20][C:1]#[CH:2])=[CH:10][C:11]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1
Reactant: FC(F)(F)c1oc(CBr)cc1COC1CCCCO1
Reactant: C#C[Mg]Br
Agent: Cl[Cu]Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCc1cc(COC2CCCCO2)c(C(F)(F)F)o1
Temperature: 20 °C

Procedure:
90 ml of ethynyl magnesium bromide as a 1M solution in tetrahydrofuran and 1.8 g of copper chloride were added to 6.18 g of the product of Stage E in 15 ml of tetrahydrofuran and the mixture was refluxed for 18 hours, cooled to 20° C., poured into a saturated aqueous sodium dihydrogenphosphate solution, and extracted with isopropyl ether. The extract was dried and the solvent evaporated. The residue was chromatographed on silica (eluent: 9/1 hexane/isopropyl ether) to obtain 1.5 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CCCCCCC)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([O:15][C:13](=[O:14])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: CCCCCCCCCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.9 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-2,4-heptadecadienoic acid (7.5 g) and 4-nitrophenol (3.77 g) in 30 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (4.2 g). The mixture was stirred at room temperature for 3 days to give, after the usual work up, 8.5 crude ester. The material was purified by HPLC (ether-hexane; 1:7), then was crystallized from 2-propanol to furnish 5.88 g of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid 4-nitrophenyl ester, mp 46°-47° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:41])[CH:31]=[CH:32][C:33]=1[CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH:41][C:15]2[N:14]=[CH:13][C:12]3=[CH:11][CH:10]=[C:9]([C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:17]3[N:16]=2)[CH:31]=[CH:32][C:33]=1[CH:34]1[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]1
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Reactant: COc1cc(N)ccc1C1CCN(C)CC1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc(C5CCN(C)CC5)c(OC)c4)nn23)cn1

Procedure:
Trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.138 g, 0.369 mmol) and 3-Methoxy-4-(1-methyl-piperidin-4-yl)-phenylamine (0.102 g, 0.461 mmol) were reacted in an analogous manner to Example 908D at room temp for 72 h. The reaction mixture was concentrated, taken up in EtOAc, and washed with brine. The EtOAc layer was dried, filtered over MgSO4, and concentrated. The resulting residue was purified by Gilson RP-HPLC and lyophilized. HPLC rt=2.455 min, purity=98%, LCMS=445.0 (M+H). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.47 (s, 1H), 9.29 (bs, 1H), 9.02 (s, 1H), 8.99 (d, 1H), 7.47 (s, 1H0, 7.23 (d, J=7.5 Hz, 1H), 7.17 (d, J=4.8 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 7.17 (d, J=4.8 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.98 (s, 1H), 6.96 A (d, J=4.1 Hz, 1H), 3.93 (s, 3H), 3.71 (s, 3H), 3.49 (d, J=11.7 Hz, 2H), 3.11-3.05 (m, 3H), 2.80 (d, J=4.0 Hz, 3H), 1.95-1.76 (m, 4H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10]1.Cl.[CH3:18][NH:19][O:20][CH3:21].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:21][O:20][N:19]([CH3:18])[C:14]([C:13]1[N:9]([CH3:8])[CH:10]=[N:11][CH:12]=1)=[O:16]
Reactant: CNOC
Reactant: Cn1cncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cncn1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Triethylamine (5.51 mL, 39.646 mmol) was added slowly to a mixture of commercially available 1-methyl-1H-imidazole-5-carboxylic acid (2 g, 15.859 mmol), N,O-dimethylhydroxylamine hydrochloride (1.55 g, 15.859 mmol), and EDCI (3.65 g, 19.03 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 72 hours then quenched with saturated aqueous NaHCO3. Water (50 mL) was added followed by additional CH2Cl2. The mixture was stirred for 10 minutes and layers were separated. The CH2Cl2 layer was dried over Na2SO4, then filtered. The solvent was removed under reduced pressure and the residual oil chromatographed (CH2Cl2/EtOAc) to provide the product as a solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22]CC)=[CH2:21])CCC.Cl>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]([C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1)(=[O:22])[CH3:21]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)C(=O)Nc1cnc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A slurry of N-(5-bromo-pyrazin-2-yl)-2,2-dimethyl-propionamide (1.30 g, 5.04 mmol) and dichlorobis(triphenylphosphine)palladium(II) (35.3 mg, 0.05 mmol) in toluene (10 mL) was treated with tributyl(1-ethoxyvinyl)tin (2.00 g, 5.54 mmol). The reaction slurry was then heated under reflux, resulting in a homogeneous yellow solution. After heating under reflux for 15 h, the resulting black reaction mixture was allowed to cool to 25° C. and then was cooled to 0° C. with an ice-water bath. The cooled reaction mixture was treated slowly with a 5% aqueous hydrochloric acid solution (8.4 mL). The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to 25° C. where it was stirred for 24 h. The resulting two layers were separated, and the organic layer was further diluted with ethyl acetate (100 mL). The organic layer was then diluted with a 10% aqueous ammonium fluoride solution (100 mL), and the resulting mixture was stirred at 25° C. for 5 h. The solids were then filtered, and the filtrate layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 15% ethyl acetate/hexanes) afforded N-(5-acetyl-pyrazin-2-yl)-2,2-dimethyl-propionamide (1.07 g, 96%) as a white solid: mp 173–174° C.; (ES)+-HRMS m/e calcd for C11H15N3O2 (M+H)+ 222.1237, found 222.1240.