Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[C:34]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][CH:28]=2)[C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12](=[O:25])[NH:13][C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:24])=[CH2:23])[CH:17]=1)[CH3:15])=[CH:6][CH:5]=2>C(O)C.[Pd]>[CH:22]([C:18]1[CH:17]=[C:16]([C@@H:14]([NH:13][C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]4[C:34]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:31][CH:32]=2)[C:2]([CH3:1])=[C:10]3[CH3:11])=[O:25])[CH3:15])[CH:21]=[CH:20][CH:19]=1)([CH3:24])[CH3:23]
Reactant: C=C(C)c1cccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of (S)-tert-butyl 4′-((2,3-dimethyl-5-((1-(3-(prop-1-en-2-yl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (0.13 mmol, 1 equiv.) in ethanol (5 mL) was degassed with argon. A hint of Pd/C 10% was added to the solution. The suspension was stirred at rt for 5 h under H2 bubbling. The resulting mixture was then filtered and concentrated. The obtained oil was used without further purification. ESI-MS (m/z): 601 [M+H]+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]([NH:41][NH:42][C:43](=O)[CH2:44][CH:45]1[CH2:48][CH:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:46]1)=[O:40])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[O:40][C:43]([CH2:44][CH:45]2[CH2:46][CH:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:48]2)=[N:42][N:41]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(Cc2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)C1
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
To s solution of PPh3 (7.9 g, 30.0 mmol) in dry DCM (60 mL) was added I2 (7.8 g, 30.0 mmol). After I2 was dissolved completely, TEA (10.5 mL, 75.0 mmol) was added quickly at rt. The mixture was stirred for 15 mins. Tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclobutylcarbamate (4.9 g, 15.0 mmol) was added. The mixture was stirred at rt for 1 hr. The solvent was concentrated. EtOAc (300 mL) was added, and the solution was filtered to remove PPh3O. The filtrate was concentrated. The residue was purified by silica gel column chromatography (gradient elution 0˜50% EtOAc/petroleum ether) to afford tert-butyl 3-((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutyl-carbamate (6.2 g, 85%) as a white solid. ESI-MS (EI+, m/z): 484.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1([C:27](Cl)=[O:28])[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:27]([C:14]1([CH2:13][CH2:12][CH2:11][CH2:10][Br:9])[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:28]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: NCc1ccccn1
Product: O=C(NCc1ccccn1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 2-(aminomethyl)-pyridine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[Br:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>>[Br:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:9]1[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:21]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Reactant: BrCc1cccc(Br)c1
Product: O=c1c2sc3ccccc3c2n(Cc2cccc(Br)c2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with 3-bromobenzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 7.10-7.18 (m, 2H); 7.22 (ddd, J1=8 Hz, J2=1 Hz, 1H); 7.31 (ddd, J1=7 Hz, J2=2 Hz, 1H); 7.39 (dd, J=8 Hz, 1H); 7.44 (s, 1H); 7.71 (d, J=8 Hz, 1H); 7.97 (d, J1=8 Hz, 1H); Ret. time=2.82 min., m/z=403.0.
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2S(C1C=CC(C)=CC=1)(=O)=O>C(O)C>[CH3:2][O:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: COCc1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Na]
Solvent: CCO
Product: COCc1cccc2[nH]ccc12
Temperature: 0 °C
Yield: 77.9 %

Procedure:
4th stage: A solution of 2.84 g of sodium in 155 ml of ethanol is dripped within 10 minutes into a solution of 15.57 g of 4-methoxymethyl-1-tosylindole in 155 ml of ethanol, whereupon the mixture is heated with reflux for 11/2 h; next it is cooled, stirred into 1.5 liters of half-saturated ice-cold sodium-dihydrogen-phosphate solution, extracted with ethyl acetate; whereupon, the ethyl-acetate extracts are washed neutral with water. After the solvent has been distilled off, the raw product is chromatographed on silical gel with hexane/ethyl-acetate (0-20%). 6.2 g of 4-methoxymethyl-indole is obtained in the form of a colorless oil.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[Cl-].[K+].[CH2:28]([CH:30]([C:34](=[O:36])[CH3:35])[C:31]([NH2:33])=[O:32])[CH3:29].COC1C=CC(C=O)=CC=1>C(O)C>[CH2:28]([C@@H:30]([C@@H:34]([OH:36])[CH3:35])[C:31]([NH2:33])=[O:32])[CH3:29]
Reactant: CCC(C(C)=O)C(N)=O
Agent: COc1ccc(C=O)cc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Solvent: CCO
Product: CC[C@H](C(N)=O)[C@H](C)O
Reaction time: 60 h
Yield: 49.2 %

Procedure:
Geotrichum candidum (ATCC 34614) is cultured according to the method of Buisson and Azerad (Tet. Lett. 27, 2631-2634 (1986), herein incorporated by reference) in one liter of a medium of glucose (30 grams), KH2PO4 (1 gram), K2HPO4 (2 grams), corn steep liquor (10 grams) MgSO4.7H2O (0.5 gram), NaNO3 (2 grams), FeSO4.7H2O (0.02 gram), and KCl (0.5 gram) with rotary shaking at 25° C. Two grams of 2-ethyl-3-ketobutyramide is dissolved in 2 ml of 95% ethanol, the resulting solution is added to the culture, and shaking is resumed. The reaction is followed by TLC (staining with anisaldehyde) to monitor the consumption of starting material and the production of product alcohol. After 48-72 hours the reaction is judged complete, and the reaction is terminated by removing from the shaker and adding 20-30 grams of Celite. The resulting suspension is suction filtered through a pad of Celite and the clear yellow filtrate is extracted with ethyl acetate (4×200 ml). The extracts are combined, dried over MgSO4, filtered, and rotary evaporated to leave 1 gram of (2S,3S)-2 ethyl-3-hydroxybutyramide as a yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([CH3:15])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([CH3:15])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1ccc(-c2ccc(N)cc2)o1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(-c2ccc(C(C)=O)o2)cc1
Yield: 73 %

Procedure:
A mixture of 5.0 g (0.0248 mole) of methyl 5-(p-aminophenyl)-2-furyl ketone and 75 ml of acetic anhydride was heated at 70°-90° for 2 hours. The excess acetic anhydride was removed on a Calab evaporator, and the residual solid was recrystallized from ethyl acetate to yield 4.4 g (73%) of methyl 5-(p-acetamidophenyl)-2-furyl ketone. An analytical sample was prepared by drying a sample in the vacuum pistol at the temperature of refluxing chloroform, m.p. 214°-215°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:22])[CH:13]=2)[N:3]=1.[Cl:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][N:25]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[C:14]([CH3:22])[CH:13]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH:27]=[CH:26][N:25]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example A.38) (0.68 g, 2.0 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.35 g, 2.2 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.33 g, 39%). MS (ISP) 418.3 [(M+H)+]; mp 105.5° C.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:24][N:23](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:22][CH2:21][N:20](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:19][CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.[CH2:71](O)[CH3:72]>C(OCC)C>[NH:16]1[CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][NH:23][CH2:72][CH2:71][CH2:24][NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: C1CNCCNCCCNCCNCCNC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 36 %

Procedure:
A mixture-of 1,4,7,11,14-penta(p-toluenesulfonyl)-1,4,7,11,14-pentaazacyclopentadecane prepared as in Example 11C (26.3 g, 0.0258 mole) and concentrated H2SO4 (80 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 72 h. To the resulting brown solution, ethanol (160 mL) was added dropwise with stirring at 0° C. followed by ethyl ether (400 ml). The resulting tan solid was filtered and dried in vacuo over P2O5. The tarry solid was then dissolved by the addition of 10N NaOH and the salts were removed by filtration. The solution was then extracted with CHCl3 (6×200 ml). The extracts were combined, dried (Na2SO4) and the solvent was removed in vacuo to give an oil which crystallized on standing. The crude product was dissolved in hexane and insoluble impurities were removed by filtration. Upon cooling to -20° C., 2.28 g (36% yield) of the product was obtained as colorless needles: mp 49°-51° C.; 1H NMR (CDCl3) δ 1.69 (m, 4H), 1.78 (br s, 5H), 2.76 (m, 20H). Exact mass: (M+H)+ : calcd., 244. 2501; Found: 244.2557 (C12H30N5).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1Br)[N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:21]=[C:20]2[NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39]>O.O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][C:25]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:21]=[C:20]3[NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)c(Br)cc12
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccccc3)c(-c3ccccc3)cc12
Yield: 141.6 %

Procedure:
1.12 g of phenylboronic acid, 1.55 g of sodium carbonate in 40 cm3 of water and 463 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[5,6-dibromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 70, in 150 cm3 of dioxane, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 100 cm3 of ethyl acetate and with 100 cm3 of water and is then filtered through a sinter funnel packed with Celite. The organic phase is separated out after settling of the phases has taken place and washed with 75 cm3 of saturated sodium chloride solution, separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated under reduced pressure (2 kPa; 50° C.) to give 2.6 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined, evaporated under reduced pressure (2 kPa; 50° C.) and then dried (90 Pa; 45° C.) to give 1.4 g of N-[5,6-diphenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([O-])(O)=O.[Na+]>CCO>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:21][CH2:20]2)[N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
2,4-Dichloropyrimidine (5.0 g, 33.56 mmol) and 1-Boc-piperazine (6.25 g, 33.56 mmol) were dissolved in EtOH (40 mL). NaHCO3 (5.07 g, 60.41 mmol) was added and the reaction mixture was heated to reflux for 1.5 h, cooled to room temperature, and concentrated under reduced pressure. The mixture was diluted with CH2Cl2 and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 5% MeOH in CH2Cl2) to get tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate (3.5 g, yield 35%). 1H NMR (400 MHz, CDCl3) δ 8.07-8.05 (d, J=6.0 Hz, 1H), 6.40-6.39 (d, J=6.3 Hz, 1H), 3.65 (m, 4H), 3.54-3.51 (m, 4H), 1.48 (s, 9H). MS (ESI) m/z: Calculated for C13H19ClN4O2: 298.12. found: 299.2 (M+H)+
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][C:26](=[O:28])[CH3:27]>>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Reactant: CC(=O)CCCBr
Product: CC(=O)CCCN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
4-(5-dibenzo[a,d]cycloheptenylidene)piperidine is reacted in a manner analogous to that described in Example 7 with 5-bromo-2-pentanone. M.P. of the hydrochloride of the title compound 206°-207° after crystallization from isopropanol.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1.[O-:11][CH2:12][CH3:13].[Na+]>CN(C=O)C>[CH2:12]([O:11][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1)[CH3:13]
Reactant: CC[O-]
Reactant: COc1ccc(I)nc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1nc(I)ccc1OC
Temperature: 100 °C

Procedure:
In a microwave vial, 2-bromo-6-iodo-3-methoxypyridine (16-1 or 131-3, 150 mg, 0.48 mmol, 1 equiv) was dissolved in DMF (300 uL). Sodium ethoxide (268 uL, 21 wt % in EtOH, 0.72 mmol, 1.5 equiv) was added to the solution, and the reaction was heated in the microwave for 5 minutes at 100° C. The reaction mixture was partitioned between saturated NaHCO3 and DCM. The organic phase was washed once with brine, dried over Mg2SO4 and concentrated. The residue was purified by normal phase column chromatography (0-20% EtOAc in hexanes) to give the title compound (16-2). ESI+MS [M+H]+ C8H11INO2: 280.0 found, 280.1 required.
Reaction SMILES: [Na+].[Cl-].[Cl-].[K+].C([O-])(O)=O.[Na+].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C[C:23]1[N:31](C(C2C=CC(Cl)=CC=2)=O)[C:30]2[CH:29]=[CH:28][C:27]([O:41]C)=[CH:26][C:25]=2[C:24]=1[CH2:43][C:44](O)=O.C[N:48]1[C@@H]2C[C@@H](OC(C(C3C=CC=CC=3)CO)=O)C[C@H]1CC2.CC(NC[C@H](O)COC1C=CC=C2C=CC=CC=12)C.O=O.C(=O)=O>>[CH:28]1[C:27]([OH:41])=[CH:26][C:25]2[C:24]([CH2:43][CH2:44][NH2:48])=[CH:23][NH:31][C:30]=2[CH:29]=1
Reactant: CN1[C@@H]2CC[C@H]1C[C@@H](OC(=O)C(CO)c1ccccc1)C2
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CC(C)NC[C@H](O)COc1cccc2ccccc12
Agent: O=C([O-])O
Agent: O=C=O
Product: NCCc1c[nH]c2ccc(O)cc12

Procedure:
For the experiment, helical segments of the basilar artery of pigs were used which were isolated from pig brains supplied by a slaughterhouse. Each strip was fixed in an organ bath consisting of 10 ml of a modified Tyrode solution such that the tissue was under a tension of 10 mN. Tyrode solution is an aqueous solution containing per liter 150.0 mmol of NaCl, 4.0 mmol of KCl, 1.8 mmol of CaCl2.2H2O, 1.1 mmol of MgCl2.6H2O, 25.0 mmol NaHCO3, 0.3 mmol of NaH2PO4.H2O and 11.1 mmol of glucose. The solution was modified by adding 10-8 mol/l of indomethacin, 10-7 mol/l of atropine and 10-7 mol/l of propanolol and adjusted to pH=7.4. The bath was aerated with a mixture of 95% O2 and 5% CO2. After an equilibration phase of 1 hour a contraction of the tissue was produced twice, in each case by addition of serotonin at a concentration of 10-5 mol/l and the preparation was subsequently washed out. The contraction effect was then measured with increasing serotonin concentration and a cumulative concentration effect curve for serotonin was drawn up. A cumulative concentration effect curve was drawn up for the test substance on the same preparation (after washing out again).
Reaction SMILES: CS(O)(=O)=O.[Br:6][C:7]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:8]=1[CH2:9][NH2:10].[OH-].[Na+].ClC(Cl)=C.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH:30]=O.C(=O)([O-])[O-].[K+].[K+]>C(OC)(C)(C)C>[F:25][C:26]([F:39])([F:40])[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=1)[CH2:30][NH:10][CH2:9][C:8]1[CH:11]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:13]=[CH:14][C:7]=1[Br:6]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCc1cc(C(F)(F)F)ccc1Br
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=C(Cl)Cl
Solvent: COC(C)(C)C
Product: FC(F)(F)c1cc(CNCc2cc(C(F)(F)F)ccc2Br)cc(C(F)(F)F)c1
Yield: 95 %

Procedure:
To the product from step A (640 g) in methyl tert-butyl ether (4.3 L) was added 1N sodium hydroxide (3.4 L). The mixture was stirred until 2 clear layers formed. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to the free amine (460 g). The free amine (460 g, 1.81 mol) was taken into 1,1-dichloroethene (4.3 L) and 3,5-bis(trifluoromethyl)benzaldehyde (438 g, 1.81 mol) was added. The mixture was cooled in an ice-water bath and NaBH(CH3CO2)3 (767 g, 3.62 mol) was added. The mixture was stirred for 16 hours at which point LC analysis revealed complete reaction. Saturated aq potassium carbonate was added until pH 8 was reached. Added water (1 L) and filtered undissolved salts. The layers were separated and the aqueous layer was washed with 1,1-dichloroethene (2 L). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated (880 g product, >95% yield). 1H-NMR of HCl salt (CD3OD)8.23 (s, 2H), 8.09 (s, 1H), 7.98 (s, 1H), 7.93 (d, 8.3 Hz, 1H), 7.67 (d, 8.3 Hz, 1H), 4.61 (s, 2H), 4.56 (s, 2H). Mass Spec (ESI); M+1=480.1
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12][CH3:13].ClN1C(=O)CCC1=O.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[C:3]([NH2:4])=[C:5]([CH2:11][S:12][CH3:13])[C:6]([F:10])=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)c(F)cc1Br
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1c(N)c(Br)cc(F)c1F

Procedure:
To a solution of 2-bromo-4,5-difluoroaniline (100 g) and dimethyl sulfide (49 ml) in anhydrous dichloromethane (1.2 liter) is added gradually N-chlorosuccinimide (90 g) at below 15° C., and thereafter is further added in portions triethylamine (93 ml) at 15° C. After the addition, the mixture is refluxed for 7 hours. After cooling, 10% aqueous sodium hydroxide (one liter) is added to the reaction mixture, and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated, and the resulting residue is purified by silica gel column chromatography (solvent, dichloromethane: n-hexane=1:2). The product is recrystallized from n-hexane to give 6-bromo-3,4-difluoro-2-methylthiomethylaniline (52 g) as a white crystal, m.p. 60°-61° C.
Reaction SMILES: N#N.Br[C:4]1[S:5][CH:6]=[CH:7][N:8]=1.Br[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:22][C:23]2[C:28]([Cl:29])=[CH:27][N:26]=[CH:25][C:24]=2[Cl:30])=[N:12][N:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1.[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:30][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:29])[C:23]=1[CH2:22][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:10]([C:4]2[S:5][CH:6]=[CH:7][N:8]=2)=[N:11][N:12]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Br)c2c1
Reactant: Brc1nccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-c3nccs3)c2c1
Yield: 51.6 %

Procedure:
A suspension of zinc (0.18 g, 2.76 mmoles) in THF/toluene 2:1 (15 ml), under stirring and N2 under reflux, was added with 2-bromothiazole (0.23 ml, 2.5 mmoles). After 2½ hours 4-bromo-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.5 g, 1.25 mmoles), prepared as described in example 46, palladium acetate (14 mg, 0.0625 mmole) and triphenylphosphine (32 mg, 0.125 mmole) were added to the cold mixture. The mixture was refluxed for further 30 minutes. After 21 hours the same amounts of palladium acetate and triphenylphosphine were added. After 3 hours under reflux the mixture was cooled and poured into water/ice and NH4Cl, then extracted first with ethyl acetate, then with CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: hexane/ethyl acetate 7:8) to give 0.26 g of the title compound (yield: 51%). m.p.: 225-230° C.