Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](N(OC)C)=[O:19])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]([Mg]Br)=[CH2:26]>C1COCC1>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](=[O:19])[CH:25]=[CH2:26])[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Solvent: C1CCOC1
Product: C=CC(=O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 15 g (45.7 mmol) of benzyl(3-{2-[methoxy(methyl)amino]-2-oxoethyl}phenyl)carbamate (from Step C) in 1000 mL anhydrous THF under nitrogen atmosphere cooled to 0° C. via ice/water bath was added dropwise via cannula a 1.0 M solution of vinyl magnesium bromide (100 mL in THF, 100 mmol) and the resulting solution stirred for 1 h at 0° C. The reaction was quenched by a slow addition of 500 mL 1 M HCl keeping the temperature below 5° C. and stirred for 30 min. The mixture was then extracted with ethyl acetate and the combined organics washed with water followed by brine. The organics were then dried over sodium sulfate, filtered, and concentrate under vacuum. The residue was purified by Biotage 75M flash eluting with 30% ethyl acetate in hexane to afford the title compound (11 g, 78%) as a light yellow solid. LC-MS: m/z (ES) 310 (MH)+, 332 (MNa)+. 1HNMR (500 MHz, CDCl3) δ: 7.44-7.36 (m, 7H), 7.18 (d, J=8.4 Hz, 2H), 6.70 (br s, 1H), 6.44 (dd, J=10.5, 17.6 Hz, 1H), 6.32 (dd, J=1.1, 17.6 Hz, 1H), 5.85 (dd, J=1.1, 10.5 Hz, 1H), 5.22 (s, 2H), 3.86 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[Br:12]Br.OS([O-])=O.[Na+]>C(Cl)Cl>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=1
Reactant: BrBr
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A round-bottom flask with stirbar was charged with 2-(trifluoromethyl)phenol (1.7 g, 10.49 mmol) in 10 mL CH2Cl2 was cooled to 0° C. Bromine (0.540 ml, 10.49 mmol) in 2 mL CH2Cl2 was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour, then allowed to warm to ambient temperature over 1 hour. Aqueous NaHSO3 solution was added, and the mixture extracted with CH2Cl2. The organic phase was washed with aqueous NaHCO3 and brine, dried (MgSO4), filtered, and concentrated. The residues were purified by flash chromatography eluting with 100% CH2Cl2, to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 10.90 (s, 1H), 7.63 (m, 1H), 6.98 (d, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:5])#[N:2].C(O/[CH:17]=[CH:18]/[C:19](=O)[C:20]([F:23])([F:22])[F:21])C.N12CCN(CC1)CC2>COCCO.Cl.C(OCC)(=O)C>[F:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])=[CH:12][CH:11]=1
Reactant: N#CCC(=O)Nc1ccc(F)cc1
Reactant: CCO/C=C/C(=O)C(F)(F)F
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: COCCO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(F)(F)F)n(-c2ccc(F)cc2)c1=O
Temperature: 120 °C
Reaction time: 6 h
Yield: 7.3 %

Procedure:
To a solution of 2-cyano-N-(4-fluorophenyl)acetamide (2 g, 11.2 mmol) and (3E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.26 g, 13.4 mmol) in dimethyleneglycol monomethylether (20 mL) was added 1,4-diazabicyclo[2.2.2]octane (1.26 g, 11.2 mmol), and the mixture was stirred at 120° C. for 6 hr. The reaction mixture was diluted with 1N hydrochloric acid and ethyl acetate, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=1/2→1/1) to give a white solid. The white solid was washed with ethyl acetate and collected by filtration to give the title compound (230 mg, 7.2%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O>C1COCC1.CN(C=O)C>[Br:1][C:2]1[O:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)o1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-bromo-2-furoic acid (2.1 g, 6.856 mmol) in THF (20 mL) was added oxalyl chloride (0.66 mL, 7.541 mmol). 2 drops of DMF were then added to the reaction mixture, with bubbles of CO observed to come out vigorously. Oxalyl chloride ((COCl)2) (0.1 mL) was then added. The reaction mixture was stirred at room temperature for 10 min and at 90° C. for 10 min. Solvent and excess (COCl)2 were taken off under vacuum to yield 5-bromo-furan-2-carbonyl chloride as a pale yellow crystalline solid.
Reaction SMILES: I[CH:2]([CH2:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[Br:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:16]=[N+:17]=[N-:18].[Na+].C(O)C.N(C(CC(F)(F)C(F)(F)Br)C([O-])=O)=[N+]=[N-]>O>[N:16]([CH:2]([CH2:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[Br:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:17]=[N-:18]
Reactant: CCOC(=O)C(I)CC(F)(F)C(F)(F)Br
Reactant: [N-]=[N+]=[N-]
Agent: [N-]=[N+]=NC(CC(F)(F)C(F)(F)Br)C(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC(F)(F)C(F)(F)Br)N=[N+]=[N-]
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Subsequently, 9.7 g (0.024 mol) of ethyl 2-iodo-4,4,5,5-tetrafluoro-5-bromopentanoate and 2.73 g (0.042 mol) of sodium azide were added to 40 ml of 80% ethanol and were refluxed while under stirring at an elevated temperature for one hour. Then water was added to the resultant mixture and 2-azido-4,4,5,5-tetrafluoro-5-bromopentanoate was extracted with ether, whereafter the ether was removed by drying. The residual liquid was vacuum distilled to afford 4.54 g (0.014 mol, yield of 60%) of ethyl 2-azido-4,4,5,5-tetrafluoro-5-bromopentanoate having b.p. 78° to 79° C./4 mm, nD20 1.4291, d420 1.564, νN3 2120 cm-1 and νC=O 1746 cm-1.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:19])=[CH:9][N:8]=1.Cl[C:21]1[N:26]=[N:25][C:24]([N:27]([CH2:35][C:36]2([C:40]3[C:45]([F:46])=[CH:44][CH:43]=[CH:42][N:41]=3)[CH2:39][CH2:38][CH2:37]2)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][CH:22]=1>[Cl-].[Zn+2].[Cl-].C1COCC1>[CH3:19][C:14]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([C:21]3[N:26]=[N:25][C:24]([N:27]([CH2:35][C:36]4([C:40]5[C:45]([F:46])=[CH:44][CH:43]=[CH:42][N:41]=5)[CH2:39][CH2:38][CH2:37]4)[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:23][CH:22]=3)=[N:8][CH:9]=2)[C:17]([CH3:18])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C)n1-c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(Cl)nn1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ccc(-c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)nc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 463.5 %

Procedure:
THF (8.5 mL) was cooled to −78° C. under a nitrogen atmosphere. tBuLi (1.7 mL, 2.9 mmol, 2.0 equiv) was added, followed by the addition of 2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (370 mg, 1.47 mmol, 1.0 equiv dissolved in 2 mL THF) over 2 min. The reaction as stirred for 45 min at −78° C. Zinc chloride (510 mg, 3.75 mmol, 2.5 equiv dissolved in 5 mL of THF) was added and the reaction was allowed to warm to rt and stirred for 3 h. (t-Bu3P)2Pd (41 mg, 0.015 mmol, 0.10 equiv dissolved in 5 mL of THF) and t-butyl 6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (393 mg, 0.1 mmol, 0.07 equiv dissolved in 5 mL of THF) were added and the reaction was refluxed for 4 h followed by dilution with sodium bicarbonate (20 mL), and extraction with ethyl acetate (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (35% EtOAc/hexanes) to give 245 mg (46%) of tert-butyl 6-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.
Reaction SMILES: Cl.C(OC(=O)NC[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:32])[NH:17][CH2:18][C:19]2[S:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[CH:22][CH:23]=2)=[CH:12][N:11]=1)(C)(C)C.[NH2:34][C:35]1C(C(O)=O)=NC=C(N)N=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(O)C>[F:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[O:24][C:21]1[S:20][C:19]([CH2:18][NH:17][C:16](=[O:32])[C:13]2[CH:14]=[CH:15][C:10]([NH:34][CH3:35])=[N:11][CH:12]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)NCc2ccc(Oc3cccc(F)c3)s2)cn1
Reactant: Nc1cnc(C(=O)O)c(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ccc(C(=O)NCc2ccc(Oc3cccc(F)c3)s2)cn1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 85.5 %

Procedure:
Ethanol (20 mL) and 5N hydrochloric acid (0.8 mL) were added to (5-((5-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)carbamoyl)pyridin-2-yl)methyl-carbamic acid tert-butyl ester described in Preparation Example A+-3 (87 mg, 0.19 mmol), and the solution was stirred for 25 minutes at 80° C. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with water twice, washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the title compound (58 mg, 0.162 mmol, 85.5%) was obtained as a white solid.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[F:50][C@@H:51]1[CH2:55][NH:54][C@H:53]([C:56]#[N:57])[CH2:52]1>>[C:28]([C:32]1[N:33]=[C:34]([N:54]2[CH2:55][C@@H:51]([F:50])[CH2:52][C@H:53]2[C:56]#[N:57])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: N#C[C@@H]1C[C@H](F)CN1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2C[C@@H](F)C[C@H]2C#N)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2S,4S)-4-fluoropyrrolidine-2-carbonitrile and isolated as light-yellow gum (10.6 mg, 54%). MS(m/e): 414.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Br:7])[S:5][CH:6]=1.[Cl:8][CH2:9][C:10](Cl)=[O:11].N1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[Br:7][C:4]1[S:5][CH:6]=[C:2]([NH:1][C:10](=[O:11])[CH2:9][Cl:8])[N:3]=1
Reactant: Nc1csc(Br)n1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1csc(Br)n1
Yield: 29.7 %

Procedure:
The starting material was prepared as follows. 4-Amino-2-bromothiazole (15.6 g) and chloroacetyl chloride (7.6 g) were suspended in methylene chloride (100 ml) with stirring and treated with pyridine (16 ml) over 15 min., maintaining reaction temperature at 0° C. with an ice bath. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours, then poured onto 20% aqueous sodium acetate (500 ml) and stirred for 30 minutes. The mixture was separated and the organic layer washed with 2 N hydrochloric acid, water, sodium carbonate solution and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo and the residue recrystallised twice from carbon tetrachloride to give 2-bromo-4-chloroacetamidothiazole (5.1 g). m.p. 146°-8° C. (Found: C, 24.1; H, 1.7; N, 11.2. C5H4ClBrN2OS requires C, 23.5; H, 1.6; N, 11.0%).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]CC=C)[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[CH:20]1[C:25](Cl)=CC=C(Cl)[CH:21]=1>>[C:1]([NH:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([CH2:25][CH:20]=[CH2:21])=[C:12]([OH:16])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: Clc1ccc(Cl)cc1
Reactant: C=CCOc1cccc(C(NC(C)=O)C(=O)OC)c1
Product: C=CCc1ccc(C(NC(C)=O)C(=O)OC)cc1O
Temperature: 350 °C

Procedure:
A solution of methyl α-(acetylamino)-3-(2-propenoxy)benzeneacetate from Preparation 5 above (8.0 g, 32 mmol) in 15 g of p-dichlorobenzene is heated at 350° C. for 16 hours in a sealed tube. The reaction mixture is cooled and the contents of the tube are purified by silica gel chromatography, eluting with CHCl3 to remove the p-dichlorobenzene and then with 5% MeOH-CHCl2 to remove the rearrangement products (methyl α-(acetylamino)-3-hydroxy-2-(2-propenyl) benzeneacetate, methyl α-(acetylamino)-3-hydroxy-4-(2-propenyl)benzeneacetate). The rearrangement products (a 1:1 mixture of methyl α-(acetylamino)-3-hydroxy-2-(2-propenyl)-benzeneacetate, methyl α-(acetylamino)-3-hydroxy-4-(2propenyl)benzeneacetate) are separated by silica gel chromatography (Chromatotron/EtOAc). Recrystallization from diisopropylether/THF gives the compound of methyl α-(acetylamino)-3-hydroxy-4-(2-propenyl)benzeneacetate above (2.60 g, 33%) as a white solid, mp 143°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([N:43]2[CH:47]=[N:46][CH:45]=[N:44]2)=[CH:38][C:37]=1[CH3:48].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:48][C:37]1[CH:38]=[C:39]([N:43]2[CH:47]=[N:46][CH:45]=[N:44]2)[CH:40]=[C:41]([CH3:42])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-n2cncn2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-n6cncn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydro-benzofuran-3-yl)acetate and 1-(4-bromo-3,5-dimethylphenyl)-1H-1,2,4-triazole following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.16 min; Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[OH:20])([CH3:9])([CH3:8])[CH3:7].CCN(CC)CC>CN(C1C=CN=CC=1)C.ClCCl>[CH3:5][O:4][C:2](=[O:3])[O:20][C:11]1[CH:12]=[CH:13][C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:15][C:10]=1[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl chloroformate (58 mL, 750 mmol) was added dropwise to a solution of 2,4-di-tert-butyl-phenol (103.2 g, 500 mmol), Et3N (139 mL, 1000 mmol) and DMAP (3.05 g, 25 mmol) in dichloromethane (400 mL) cooled in an ice-water bath to 0° C. The mixture was allowed to warm to room temperature while stirring overnight, then filtered through silica gel (approx. 1 L) using 10% ethyl acetate-hexanes (˜4 L) as the eluent. The combined filtrates were concentrated to yield carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester as a yellow oil (132 g, quant.). 1H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J=2.4 Hz, 1H), 7.29 (dd, J=8.5, 2.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 1.30 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18](O)=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[CH:31][CH:30]=1>>[N:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:18]([C:17]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9](=[O:28])[C:10]3[C:15]([C:16]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=3)=[O:19])=[CH:31][CH:30]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reactant: NCc1ccncc1
Product: O=C(NCc1ccncc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (250 mg) and 4-picolylamine. Colorless crystals (17 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:43])([CH3:42])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[CH:21]1[C@:12]([CH3:41])([C@@:13]3([CH3:40])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([C:32](=[O:39])[NH:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[CH3:46][O:47][C:48]([C:50]1[S:54][C:53](B(O)O)=[CH:52][CH:51]=1)=[O:49].C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[CH3:38][N:36]([CH3:37])[CH2:35][CH2:34][NH:33][C:32]([C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:40])([CH2:14][CH2:15]2)[C@@:12]2([CH3:41])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:42])([CH3:43])[C:7]([C:53]2[S:54][C:50]([C:48]([O:47][CH3:46])=[O:49])=[CH:51][CH:52]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)=[O:39]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)c1ccc(B(O)O)s1
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: COCCOC
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)s6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 90 °C
Yield: 60.8 %

Procedure:
A mixture of (1R,3aS,5aR,5bR,7aR,11aR,13aR,13bR)-3a-(2-(dimethylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (100 mg, 0.152 mmol), 5-(methoxycarbonyl)thiophen-2-ylboronic acid (36 mg, 0.228 mmol), tetrakis(triphenylphosphine)palladium(0) (5.2 mg, 0.0045 mmol) and sodium carbonate (48 mg, 0.456 mmol) in water (1 mL) and DME (1 mL) was heated up at 90° C. for 2 hours. The reaction mixture was quenched with distilled water, extracted with ethyl acetate (3×5 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a brown oil (60 mg, 32%). LCMS: m/e 647.63 (M−H)−, 2.67 min (method 1).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH2:10]Br.[F:12][C:13]1[CH:14]=[C:15]([OH:29])[CH:16]=[C:17]([C:19]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)([O:22][CH3:23])[CH2:20][CH3:21])[CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([O:29][CH2:10][C:9]#[C:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:16]=[C:17]([C:19]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)([O:22][CH3:23])[CH2:20][CH3:21])[CH:18]=1
Reactant: CCC(OC)(c1cc(O)cc(F)c1)c1nccs1
Reactant: BrCC#Cc1ccccn1
Agent: Br
Product: CCC(OC)(c1cc(F)cc(OCC#Cc2ccccn2)c1)c1nccs1
Yield: 54 %

Procedure:
Using a similar procedure to that described in Example 8, 3-(2-pyridyl)prop-2-yn-1-yl bromide hydrobromide was reacted with 2-[1(5-fluoro-3-hydroxyphenyl)-1-methoxypropyl]thiazole to give 2-[1-[5-fluoro-3-(3 (2-pyridyl)prop-2-yn-1-yloxy)phenyl]-1-methoxypropyl]-thiazole in 54% yield, as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[Br-:15].[Na+].[CH3:17][C:18]1[C:26]([CH3:28])([CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:29]([OH:32])(=[O:31])=[O:30])[CH:24]=2)[N:19]=1.[K]>S1(CCCC1)(=O)=O.CC(C)=O>[Br-:15].[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][N+:19]1[C:20]2[C:25](=[CH:24][C:23]([S:29]([OH:32])(=[O:30])=[O:31])=[CH:22][CH:21]=2)[C:26]([CH3:28])([CH3:27])[C:18]=1[CH3:17])([O-:3])=[O:2]
Reactant: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)C
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Agent: [Br-]
Agent: [K]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CC(C)=O
Product: CC1=[N+](Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c2ccc(S(=O)(=O)O)cc2C1(C)C
Temperature: 100 °C
Reaction time: 5 h

Procedure:
3,5-Dinitrobenzyl chloride (22.1g, 102 mmol) and sodium bromide (10.5 g, 102 mmol) were added to 2,3,3-trimethyl-5-sulpho-indole, potassium salt (5.0 g, 20.4 mmol) in sulpholane (25 ml). The reaction mixture was stirred at 100° C. for 5 hours. The solution was then cooled to room temperature and acetone (300 ml) was added to the reaction flask. A brown precipitate was formed which was collected by filtration and then purified by reverse phase HPLC. This gave a beige solid which was dried in vacuo. UV (water/acetonitrile): λmax=283 nm. MS: m/z=420 (C18H18N3O7S=420.4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.O.[NH2:19][NH2:20]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH2:11][NH:19][NH2:20]
Reactant: Fc1ccc([C@@]2(Cn3cncn3)CO2)c(F)c1
Reactant: NN
Solvent: O
Product: NNCC(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A process according to claim 1 which comprises reacting (R)-1-[2-(2,4-difluorophenyl)oxiran-2-ylmethyl]-1H-1,2,4-triazole with hydrazine hydrate to form 2-(2,4-difluorophenyl)-1-hydrazino-3-(1H-1,2,4-triazol-1-yl)propan-2-ol, reacting this product with methyl (E)-4-(2,2,3,3)-tetrafluoropropoxy)cinnamimidate, and subsequently reacting the (E)-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-(2,2,3,3-tetrafluoropropoxy)cinnamamidrazone product with ethyl orthoformate to form (R)-2-(2,4-difluorophenyl)-1-(3-[(E)-4-(2,2,3,3-tetrafluoropropoxy)styryl]-1H-1,2,4-triazol-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.[OH:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[N:18]([OH:23])[C:17]([CH3:25])([CH3:24])[CH2:16]1.I[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>ClC1C=CC=CC=1>[OH:14][CH:15]1[CH2:20][C:19]([CH3:21])([CH3:22])[N:18]([O:23][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:17]([CH3:25])([CH3:24])[CH2:16]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CCCCCCCCI
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Clc1ccccc1
Product: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C

Procedure:
The title compound is prepared by the dropwise addition of tributyltin hydride to a solution of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine and 1-iodooctane in chlorobenzene under a nitrogen atmosphere.