Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:10]=3[NH:11][C:12](=O)[C@@:13]3([CH2:16][C@H:15]3[CH3:17])[N:14]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.[NH2:53][NH2:54]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:10]=3[NH:11][C:12](=[N:53][NH2:54])[C@@:13]3([CH2:16][C@H:15]3[CH3:17])[N:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C)C(=O)N2
Reactant: NN
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C)C(=NN)N2
Temperature: 110 °C
Yield: 82.8 %

Procedure:
A round bottomed flask was charged with (1S,2R)-5′-(4-chlorophenyl)-2,6′,7′-trimethylspiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one (289 mg, 0.838 mmol) and a stir bar. Toluene (8.5 mL, 0.1 M) added, followed by Lawesson's Reagent (186 mg, 0.461 mmol), and the reaction was stirred at 110° C. After conversion to the thioamide intermediate, as determined by LC/MS, the reaction was cooled and diluted with THF (20 mL) for the addition of hydrazine (263 μl, 8.38 mmol). The reaction was stirred at room temperature before being concentrated and purified by column chromatography to give (1S,2R)-5′-(4-chlorophenyl)-2′-hydrazono-2,6′,7′-trimethyl-1′,2′-dihydrospiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepine] (249 mg). LRMS (M+H)+: 359 m/z
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6]2.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6]2
Reactant: CCOC(=O)CC1CCCc2cc(OC)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CC1CCCc2cc(O)ccc21
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of ethyl 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetate (513) (0.708 g, 2.85 mmol) in dichloromethane (28 mL) at 0° C. was added boron tribromide (0.809 mL, 8.56 mmol). The solution was stirred for 2 hours and quenched with ethanol (5 mL) followed by a saturated solution of sodium bicarbonate (5 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to obtain the intermediate ethyl 2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetate (514) (0.600 g, 90.0%) as an oil residue.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH2:33]1[O:35][C@H:34]1[CH2:36][OH:37]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:33][C@H:34]([OH:35])[CH2:36][OH:37])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: OC[C@H]1CO1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C[C@H](O)CO)CC4)cn3)nc2n1C1CCCC1
Yield: 51.3 %

Procedure:
Following General Procedure E, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and (S)-(+)glycidol (51 mg, 0.691 mmol) gave 7-cyclopentyl-2-{5-[4-((S)-2,3-dihydroxy-propyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (60 mg, 50%). MS (ESI) m/z 509.3 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2ccc(N3CCC(c4c[nH]c5ccccc45)CC3)nn12
Yield: 30.8 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.223 g, 1.0 mmol), 3-(piperidin-4-yl)-1H-indole (0.240 g, 1.20 mmol) and DIPEA (0.257 mL, 1.50 mmol) in DMF (3 mL) was heated at 70° C. for 1 hour. The reaction mixture was run onto an SCX cartridge, which was washed with MeOH and eluted with 2M ammonia in methanol. The crude product was purified by MPLC silica chromatography, eluting with ethyl acetate. Pure fractions were evaporated to a gum which crystallised on trituration with ether to afford 6-[4-(1H-indol-3-yl)piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (0.119 g, 31%) as a colourless crystalline solid.
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32]3=[N:33][CH:34]=[C:35](O)[CH:36]=[C:31]3[N:30]([CH2:38][CH3:39])[C:29]2=[O:40])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Cl-].[Ca+2]>CN(C=O)C>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]3=[N:33][CH:34]=[C:35]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])[CH:36]=[C:31]3[N:30]([CH2:38][CH3:39])[C:29]2=[O:40])=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(OCC(F)(F)F)cc21

Procedure:
2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.144 mL) was added to a solution of 3-[4-(benzyloxy)phenyl]-1-ethyl-6-hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) and potassium carbonate (229 mg) in DMF (5 mL) at room temperature. The mixture was stirred at ambient temperature under a dry atmosphere (CaCl2 tube) for 3 h. The mixture was quenched with water at room temperature and extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15%-50% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-1-ethyl-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (308 mg) as colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>CC(C)=O.CCCCCC>[N+:13]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:5]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(-c2cccnc2)cc1
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Temperature: 70 °C
Reaction time: 96 h

Procedure:
3-Phenylpyridine (25.0 g, 0.161 mole) is added carefully and with cooling (ice-bath) to 70% nitric acid (140 ml). The resulting solution is stirred and, when TLC (1:1 acetone-hexane) shows no reaction after 24 hr, it is heated in a 70° C. oil bath. Some reaction is observed by TLC but it is very slow and so, after 4 days, concentrated sulfuric acid (50 ml) is added. The mixture is stirred over several days at room temperature after which the starting material is entirely consumed. The solution is poured onto ice and the mixture is made alkaline by the cautious addition of 50% aqueous NaOH. The mixture is extracted 3 times with ethyl acetate. (650 ml), the combined organic layers are washed with brine, dried over MgSO4, filtered, and reduced in volume to 400 ml. Crystallization occurred, giving a first crop of 13.139 g of tilted product, melting point of 145°-148° C. and, from the concentrated filtrate, a second crop of 4.16 g (total 17.299 g, 0.0865 mole, 53%) of product, melting point 143°-147° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[CH:21]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:36]=1)[CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[CH:21]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:40]=1)[CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1
Reactant: BrCCCBr
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCBr)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
0.27 g (1.35 mmol) of 1,3-dibromopropane, 29 mg (0.089 mmol) of tetrabutylammonium bromide and 0.62 g (4.5 mmol) of anhydrous potassium carbonate are added to a solution of 0.2 g (0.45 mmol) of methyl 4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (racemate, Example 18A) in 4 ml of dry toluene, and the mixture is then stirred at 110° C. for a further 24 h. Another 0.27 g (1.35 mmol) of 1,3-dibromopropane are then added, and the mixture is stirred at 110° C. for a further 24 h. The mixture is then filtered through kieselguhr, and the filtrate is evaporated to dryness. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: dichloromethane). This gives 0.155 g (0.274 mmol, 60.9% of theory) of a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[C:25]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:26]=[CH:27][CH:28]=[O:29])=[CH:20][CH:19]=1>O1CCCC1>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[C:25]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:26]=[CH:27][CH:28]([OH:29])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])=[CH:22][CH:23]=1
Reactant: Cn1nnnc1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a chilled suspension (0° C., ice-water bath) of NaH (0.64 g, 16.0 mmoles) (60% in mineral oil) in 20 mL of dry tetrahydrofuran under argon was added ethyl acetoacetate 2.04 mL (16.0 mmoles) in 4 equal portions. The homogeneous clear solution was stirred at 0° C. for 30 minutes followed by the dropwise addition of 6.4 mL of 2.5 Molar n-BuLi (16.0 mmoles) over a period of 15 minutes. The orange dianion solution was stirred at 0° C. for an additional hour. The ice-water bath was replaced by an acetone-dry ice bath at -78° C. and the dianion was transferred via a cannula into a tetrahydrofuran (20 mL) solution containing 5,5-bis(4-fluorophenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal (2.82 g, 8.01 mmoles). Analytical TLC showed the major desired product at Rf =0.15 (50% EtOAc in hexanes) and a minor product at Rf =0.2. The crude reaction mixture was diluted with 40 mL of 1N HCl and the aqueous layer was extracted with ethyl acetate (50 mL×2). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. The desired product was purified by flash silica gel column chromatography eluted with 20% EtOAc in hexanes (v/v) to give 2.26 g (58.5%) of the title compound. MS (CI): m/e=483 for (M+H)+.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(OC([N:31]1[C@H:38]2[C@H:34]([CH2:35][N:36]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:37]2)OS1(=O)=O)=O)(C)(C)C.O.[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55]([OH:58])(=[O:57])=[O:56])=[CH:51][CH:50]=1>CCOC(C)=O>[S:55]([C:52]1[CH:53]=[CH:54][C:49]([CH3:59])=[CH:50][CH:51]=1)([OH:58])(=[O:57])=[O:56].[S:55]([C:52]1[CH:53]=[CH:54][C:49]([CH3:59])=[CH:50][CH:51]=1)([OH:58])(=[O:57])=[O:56].[CH2:39]([N:36]1[CH2:35][C@@H:34]([F:1])[C@H:38]([NH2:31])[CH2:37]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CN(Cc3ccccc3)C[C@@H]2OS1(=O)=O
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@@H]1CN(Cc2ccccc2)C[C@H]1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A solution of 1M tetrabutylammonium fluoride in THF (1.27 L, 1.27 mol, 2.5 eq) and (3aR,6aS)-5-benzyl-2,2-dioxo-tetrahydro-1-oxa-2λ6-thia-3-5-diaza-pentalene-3-carboxylic acid t-butyl ester (180 g, 0.508 mol, 1.0 eq) were heated at 60° C. (jacket temperature) for 2 hr. Upon reaction completion, the mixture was partially distilled under vacuum to remove the THF. After concentration to a low stir volume, THF was displaced with EtOAc (2×500 mL). After again reducing to a low stir volume, EtOAc (3.6 L) and p-toluenesulfonic acid monohydrate (396 g, 2.10 mol, 4.1 eq) were charged and heated at 80° C. for 2 hr. The mixture was cooled to 10° C. over 1.5 hr and then granulated at 10° C. for 2 hr. The solid product was filtered and washed with EtOAc (2×900 mL) and dried at 50° C. in a vacuum oven for 12 hr. The title compound was isolated as an air stable crystalline solid in 83% yield (231 g, 419 mmol). 1H NMR (400 MHz, D2O) δ ppm 7.69-7.61 (m, 4 H) 7.56-7.42 (m, 5 H) 7.36-7.29 (m, 4 H) 5.65-5.49 (m, 1 H) 4.47 (br. s., 2H) 4.37-4.23 (m, H) 4.15 (ddd, J=12.8, 8.2, 1.4 Hz, 1 H) 3.88 (dd, J=19.1, 1.2 Hz, 1 H), 3.74 (ddd, J=33.2, 14.0, 5.5 Hz, 1 H) 3.44 (dd, J=12.8, 8.2 Hz, 1 H) 2.34 (s, 6 H). m/z (EI+) for C11H15FN2 194.8 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45]>>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:32][CH2:31][N:30]([CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45])[CH2:29][CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CN1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 60 °C
Yield: 43.3 %

Procedure:
The suspension of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (500 mg, 1.81 mmol) was treated with N,N-diisopropylethylamine (411 uL, 2.36 mmol) followed by 2-chloro-N,N-dimethylacetamide (192 uL, 1.42 mmol). The mixture was heated at 60° C. for 3 h then cooled to rt. The white solid was filtered then purified by ISCO® using 0-10% 2N NH3 in MeOH/EtOAc. 313 mg (52.1%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.42 (s, 1H), 8.04 (s, 1H), 8.19-8.12 (m, 2H), 7.82-7.70 (m, 5H), 7.62-7.60 (d, 1H), 6.99 (s, 1H), 6.02 (s, 2H), 5.96 (s, 2H), 3.70-3.59 (m, 3H), 3.50 (s, 3H), 3.48-3.40 (m, 2H), 3.36 (s, 3H), 2.79-2.50 (m, 2H), 2.59-2.48 (m, 2H), 2.36-2.24 (m, 2H); LC-MS m/z[M+H]+ 509.2, RT 2.09 min.
Reaction SMILES: C(Cl)CCl.ClC(Cl)C(O)=O.[CH:11]1([NH:14][C:15](=[O:46])[CH:16]([OH:45])[CH:17]([NH:25][C:26](=[O:44])[C:27]2[CH:32]=[CH:31][CH:30]=[N:29][C:28]=2[C:33]2[N:34]=[C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[S:36][CH:37]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1.C([O-])(O)=O.[Na+]>CS(C)=O>[CH:11]1([NH:14][C:15](=[O:46])[C:16](=[O:45])[CH:17]([NH:25][C:26](=[O:44])[C:27]2[CH:32]=[CH:31][CH:30]=[N:29][C:28]=2[C:33]2[N:34]=[C:35]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[S:36][CH:37]=2)[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:12][CH2:13]1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-c1csc(-c2ccccc2)n1
Agent: O=C(O)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCCl
Product: O=C(NC1CC1)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
EDC (700 mg, 3.65 mmol) and 2,2-dichloroacetic acid (12411, 1.46 mmol) were added to a solution of N-(4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide (217 mg, 0.435 mmol) in dimethyl sulfoxide (DMSO) (4 ml), and the reaction mixture stirred for 10 min at room temperature. For work up the reaction mixture was mixed with 80 ml of sat. NaHCO3-solution for 10 minutes. The resulting solid was filtered off with suction, washed with water and dried in vacuo to give 193 mg of the title product as white amorphous solid;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)C(=Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
(+)-1,2-bis((2S,5S)-2,5-Diethylphospholano) benzene (cyclooctadiene) rhodium(I) trifluoromethanesulfonate (0.22 g) was dissolved in 2 mL of DCM and added to a solution of 2-tert-butoxycarbonylamino-3-{(S)-2-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]-dioxin-6-yl}-acrylic acid methyl ester (1.8 g) in 20 mL EtOAc. The mixture was then degassed and flushed with hydrogen and stirred under hydrogen atmosphere (balloon) for 1 hour. The solvent was then evaporated and the residue was purified by silica gel flash chromatography (DCM to 5% EtOAC in DCM) to get pure product 1.7 g. 1H NMR (400 MHz, CDCl3): 7.55 (d, 1H), 7.46 (d, 1H), 7.24-7.37 (m, 2H), 7.00-7.06 (m, 2H), 6.92-6.97 (m, 1H), 6.90 (d, 1H), 6.70 (d, 1H), 6.61-6.70 (m, 1H), 5.08 (m, 1H), 5.03 (d, 2H), 4.99 (d, 1H), 4.50-4.60 (m, 1H) 4.34 (m, 1H), 3.98 (m, 1H) 3.74 (s, 3H), 2.80-3.20 (m, 2H), 1.44 (s, 9H). LCMS (m/z): 589.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[C:6]([F:15])[C:3]=1[C:4]#[N:5].O[C@H:17]([CH3:27])[CH2:18][NH:19]C(=O)OC(C)(C)C>>[NH2:19][CH2:18][C@@H:17]([N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[C:6]([F:15])[C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1)[CH3:27]
Reactant: N#Cc1c(F)cc(-c2cc[nH]n2)cc1Cl
Reactant: C[C@@H](O)CNC(=O)OC(C)(C)C
Product: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared using the procedure described in Example 3(g) starting from 2-chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (13.5 mmol, 3 g) and (R)-tert-butyl (2-hydroxypropyl)carbamate (27 mmol, 4.72 g). Yield 1.3 g. 1H-NMR (400 MHz; CDCl3): δ 1.47 (d, 3H), 3.02-3.19 (m, 2H), 4.30-4.38 (m, 1H), 6.60 (d, 1H), 7.52-7.59 (m, 2H), 7.75 (s, 1H). LC-MS: [M+1]=279.17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.C([Cu])#N.[Li+].[Cl-].[C:24](Cl)(=[O:26])[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[C:12]=2[C:24](=[O:26])[CH3:25])=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2ccc(F)cc2)nn1
Reactant: CC(=O)Cl
Agent: N#C[Cu]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccc(F)cc2)nnn1C
Temperature: -35 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
To a suspension of 4-(4-fluoro-phenyl)-1-methyl-1H-[1,2,3]triazole (3.54 g, 20.0 mmol) in DME (52 mL) was added n-BuLi (1.6 M in hexane, 15.0 mL, 24.0 mmol) dropwise at −75° C. The mixture was allowed to warm up to −35° C. and was stirred at −35° C. for 1 h. The reaction mixture was cooled again to −78° C. and a light green suspension of CuCN (1.79 g, 20.0 mmol) and LiCl (1.70 g, 40.0 mmol) in THF (26 ml) was added rapidly while stirring at −78° C. After 1 h the mixture was allowed to warm up to −35° C. and acetyl chloride (7.10 mL, 100.0 mmol) was added dropwise at this temperature. Then the reaction mixture was stirred at room temperature for 2 h and then poured carefully into aqueous saturated sodium carbonate solution (150 mL) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (2.2 g, 50%) as a yellow oil. MS: m/e=220.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1>>[CH3:20][C:21]1[C:25]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[C:24]([CH3:29])[O:23][N:22]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Product: Cc1noc(C)c1-c1ccc(OCc2cccc(C(=O)O)c2)cc1

Procedure:
3-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenoxymethyl]-benzoic acid was prepared using general procedure 1 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 3,5-dimethylisoxazole-4-boronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=324.
Reaction SMILES: O=[C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][C:4]#[N:5].Cl.[NH:13]([CH2:15][C:16]([O:18][CH2:19]C)=[O:17])[NH2:14]>CO>[NH2:5][C:4]1[N:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:14]=[C:2]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=1
Reactant: N#CCC(=O)c1cccnc1
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CO
Product: COC(=O)Cn1nc(-c2cccnc2)cc1N
Temperature: 120 °C
Yield: 24.4 %

Procedure:
A mixture of 3-oxo-3-pyridin-3-ylpropane nitrile (1.31 g, 9 mmol), ethyl hydrazinoacetate hydrochloride (1.39 g, 9 mmol) in methanol (9 mL) was heated under microwave irradiation at 120° C. for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel, ethyl acetate) yielding the title compound as a solid (510 mg).