Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[Br:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28](=[O:31])[CH2:29]Br>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:29]=1[C:28](=[O:31])[C:27]1[CH:32]=[CH:33][CH:34]=[C:25]([Br:24])[CH:26]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2cccc(Br)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 3-bromophenacyl bromide.
Reaction SMILES: C([O:5][C:6](=O)[C:7]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[CH:10]=[CH:9][C:8]=1[S:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])CCC.[H-].[Na+]>CN(C=O)C>[CH2:22]([O:21][C:19]([C:18]1[S:17][C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:14][O:15][CH3:16])=[CH:12][C:7]=2[C:6]=1[OH:5])=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOC(=O)CSc1ccc(OCOC)cc1C(=O)OCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1sc2ccc(OCOC)cc2c1O

Procedure:
6.20 g (16 mmol) IV and 0.80 g (20 mmol, 60%) NaH were stirred for 5 h at room temperature in 80 ml DMF. The solvent was removed and the residue was taken up in 250 ml CHCl3, washed three times with water and dried over Na2SO4. Recrystallization from n-hexane gave 4.22 g (13.6 mmol, 85%) V.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH2:12])[NH:8][C:5]2=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][C:53]=1[C:54]([N:56]1[CH2:60][CH:59]=[CH:58][CH2:57]1)=[O:55])[C:48](O)=[O:49]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][C:48](=[O:49])[C:47]3[CH:51]=[CH:52][C:53]([C:54]([N:56]4[CH2:57][CH:58]=[CH:59][CH2:60]4)=[O:55])=[C:45]([CH3:44])[CH:46]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NCc1nc2cc(Br)cnc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCc2nc3cc(Br)cnc3[nH]2)ccc1C(=O)N1CC=CC1

Procedure:
Prepared analogously to Example 1g from C-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)methylamine, TBTU, diisopropylethylamine, and 3-methyl-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid in tetrahydrofuran. Purification is effected by chromatography on silica gel (gradient: dichloromethane/ethanol=100:0□80:20). Yield: 240 mg (96%); Rf value: 0.68 (silica gel; dichloromethane/ethanol=8:2+2% ammonia solution); C20H18BrN5O2 (440.30); mass spectrum: (M+H)+=440/442 (bromine isotope).
Reaction SMILES: [OH:1][C@@H:2]1[O:10][CH2:9][C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C[O-].[Na+].[N+:14]([CH3:17])([O-:16])=[O:15]>CO>[N+:14]([CH2:17][C@H:2]([C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4])[OH:1])([O-:16])=[O:15]
Reactant: C[N+](=O)[O-]
Reactant: O[C@@H]1[C@@H](O)[C@@H](O)CO[C@H]1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])C[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Reaction time: 20 h

Procedure:
A suspension of commercial α-L-arabinose (100 g.) in absolute methanol (200 ml.) and dry nitromethane (360 ml.), in a 3-necked, 2-liter flask fitted with an efficient mechanical stirrer and a calcium chloride drying tube, was treated with a 1.3 N methanolic sodium methoxide solution (700 ml.). After 20 hr. of vigorous stirring, the precipitated sodium aci-nitro alcohols were collected by filtration and washed with a small volume of cold methanol followed by cold petroleum ether (60°-80°). The moist, highly hygroscopic salts were immediately dissolved in 800 ml. of iced water and the solution deionized either by passage over a column containing 800 ml. of Dowex® 50W-X8 (H+) resin or by three successive treatments with 300 ml. of fresh resin. The effluent and washings (total volume 2.5-3.0 liters for the column treatment and 1.5-2.0 liters for the batch treatment) were then evaporated at reduced pressure to a semi-crystalline mass which was further concentrated with several portions of absolute ethanol to remove residual water. The resulting crystalline mass was filtered with the aid of cold ethanol and the filtrate reprocessed to provide two additional crops of crystals. The crude product (70 g.) was separated by fractional crystallization from ethanol into the less soluble 1-deoxy-1-nitro-L-mannitol (30 g.) and the more soluble 1-deoxy-1-nitro-L-glucitol (25 g.). Two additional recrystallizations of samples of the nitro alcohols provided 1-deoxy-1-nitro-L-glucitol, m.p. 106°-107°, [α]D +7.44° (c 3.2, water), compared to m.p. 107°-108°, [α]D +9.5° (c 6.7, water); and 1-deoxy-1-nitro-L-mannitol, m.p. 133°-134°, [α]D +6.67° (c 5.4, water), compared to m.p. 133°-134°, [α]D +7.0° (c 6.2, water).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][N:10]2[CH2:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=1>CC#N>[Cl:8][C:6]1[N:7]=[C:2]([NH:32][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[N:3]=[C:4]([NH:9][N:10]2[CH2:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[N:5]=1
Reactant: O=C1CN(Nc2nc(Cl)nc(Cl)n2)C(=O)N1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CNc2nc(Cl)nc(NN3CC(=O)NC3=O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a mixture of 1-(4,6-dichloro-[1,3,5]-triazin-2-yl-amino)-imidazolidine-2,4-dione (Example 1.1, Part A) (3.84 g, 14.6 mmol) and K2CO3 (4.4 g, 31.8 mmol) in CH3CN (50 mL) was added (4-methoxyphenyl)-methanamine (2.0 g, 14.6 mmol) drop-wise at 0° C. The mixture was stirred at r.t. overnight. TLC showed the reaction was complete. The mixture was filtered and the cake was portioned between water and EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the expected compound (3.50 g, yield: 66%) as a white solid. It was used for the next step without further purification. δH (400 MHz, DMSO-d6): 11.30-11.23 (m, 1H), 10.06-9.83 (m, 1H), 8.67-8.60 (m, 1H), 7.24-7.13 (m, 2H), 6.90-6.83 (m, 2H), 4.40-4.35 (m, 2H), 4.26-4.05 (m, 214), 3.73 (s, 3H). Mass spectrum (ESI) m/z 364 (100%, MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]3)[N:5]=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)=[CH:26][CH:25]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: OCCN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Product: OCCN1CCN(c2cc(Sc3ccc(Cl)cc3)nc(-c3ccccc3)n2)CC1
Temperature: 160 °C

Procedure:
A well blended mixture of 3.8 g. of 4-(4-chloro-2-phenylpyrimidin-6-yl)-1-piperazineethanol and 7.0 g. of p-chlorothiophenol is heated in an oil bath maintaining the temperature at 160°C. for 3 hours. After being cooled to room temperature, the reaction mixture is triturated with 60 ml. of 30°/o sodium hydroxide. The product is collected on a sintered glass funnel and washed with water repeatedly. Upon recrystallization from 65°/o ethanol, there is obtained 4-[4-(4-chlorophenylthio)-2-phenyl-6-pyrimidinyl]-1-piperazine ethanol, m.p. 118°-120°C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](P(=O)(OC)OC)[O:3]1.[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[C:21]=12.CCN(CC)CC>C1COCC1>[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2](=[O:1])[O:3]3)[C:21]=12
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Reactant: O=Cc1cccn2ccnc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC(=Cc2cccn3ccnc23)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.5 %

Procedure:
To a solution of dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (610 mg, 2.4 mmol), imidazo[1,2-a]pyridine-8-carbaldehyde (350 mg, 2.4 mmol, 1 equiv.) in THF (5 mL) was added Et3N (0.33 mL 2.4 mmol). The mixture was stirred at rt for 48 h. The precipitation was filtered off and washed with EtOAc. The filtrate was concentrated to give 3-(imidazo[1,2-a]pyridin-8-ylmethylene)isobenzofuran-1(3H)-one (400 mg, 64%) as a yellow solid. Small crude sample (˜20 mg) was purified on RP-HPLC with CH3CN and water as eluent to separated the E/Z isomers (10 mg, 7 mg). 1H NMR (400 MHz, CD3OD) Z-form: δ=8.52 (d, 1H), 7.95-7.91 (m, 2H), 7.62-7.54 (m, 4H), 7.52-7.48 (m, 1H), 7.09 (s, 1H), 7.04 (t, 1H) E-form: δ=8.38 (d, 1H), 8.15 (d, H), 8.05 (d, 1H), 7.95 (d, 1H), 7.90-7.84 (m, 2H), 7.67 (t, 1H), 7.64 (s, 1H), 7.33 (s, 1H), δ 7.05 (t, 1H). LRMS (M+H+) m/z 263.1
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12](C)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:11][CH2:10]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 104 °C
Yield: 72 %

Procedure:
4-(Diphenylmethoxy)-1-(methyl)piperidine (prepared by neutralization of the commercial HCl salt; 4 g, 14.2 mmol, 1 equiv.) in anhydrous toluene (20 mL) was stirred at room temperature under nitrogen. Ethyl chloroformate (4.66 g, 43 mmol, 4.1 mL, 3 equiv.) was added dropwise over 5 minutes, whereupon significant effervescence was noted. The mixture was heated over the course of 1 h to reflux with an oil bath (bath temperature 104° C.). The mixture was then cooled to room temperature, whereupon more ethyl chloroformate (4 mL) was added. The mixture was heated at reflux (bath T=104° C.) for 7 h and again cooled to room temperature. The cooled mixture was concentrated and the residue purified by dry column chromatography (4×8.5 cm silica bed; 2:1 heptane:ethyl acetate) to yield 3.49 g (72%) of 4a as a slightly yellow oil. 1H NMR was consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:19][N:20]1[C:24]3=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]3[C:22](I)=[N:21]1)[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[N:7]2.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=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>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:19][N:20]1[C:24]3=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]3[C:22]([C:35]3[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=3)=[N:21]1)[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[N:7]2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncnc2c1c(I)nn2Cc1cc2c(Cl)cccc2nc1-c1ccccc1Cl
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: CN(C)C=O
Product: Cn1cc(-c2nn(Cc3cc4c(Cl)cccc4nc3-c3ccccc3Cl)c3ncnc(N)c23)cn1

Procedure:
Prepared according to Procedure J using 1-((5-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.060 g, 0.110 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.032 g, 0.164 mmol, 1.5 eq), tetrakis(triphenylphosphine)palladium (0.006 g, 10 mol %), and sodium carbonate (2M aq. Sol., 6 eq) in DMF (0.2M)). 1-((5-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.56 (s, 1H), 8.01-8.05 (m, 3H), 7.87 (d, 1H, J=5.0), 7.80-7.83 (m, 1H), 7.65 (s, 1H), 7.47 (d, 1H, J=5.0), 7.34 (t, 1H, J=5.0), 7.24 (t, 1H, J=5.0 Hz), 7.15 (d, 1H), 5.63 (s, 2H), 3.89 (s, 3H), Mass Spectrum (ESI) m/e=502 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C1C(=O)N([Cl:20])C(=O)C1.O>C(#N)C>[Cl:1][C:2]1[C:10]([Cl:20])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(Cl)ccc1C(=O)O
Solvent: O
Solvent: CC#N
Product: COc1cc(Cl)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 549 %

Procedure:
A mixture of 4-chloro-2-methoxybenzoic acid (10 g, 53.6 mmol) and NCS (35 g, 19.2 mmol) in acetonitrile (200 mL) was stirred at room temperature for 48 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to get the crude product (23.3 g).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:38])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20]([C:22]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[O:24][C:23]=3[C:34]([F:37])([F:36])[F:35])=[O:21])[CH:14]=2)[CH:9]=1.O.Cl>C1COCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[O:24][C:23]([C:34]([F:36])([F:35])[F:37])=[C:22]([C:20]([NH:19][CH2:18][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH:9]=[C:8]([O:7][CH2:6][C:5]([OH:38])=[O:4])[CH:17]=[CH:16]4)=[O:21])[CH:26]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)COc1ccc2cc(CNC(=O)c3cc(-c4ccc(Cl)cc4)oc3C(F)(F)F)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc2cc(CNC(=O)c3cc(-c4ccc(Cl)cc4)oc3C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 91.9 %

Procedure:
1 N NaOH (324 μL, 0.32 mmol) was added under nitrogen to a solution at room temperature of [6-({[5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester (140 mg, 0.27 mmol), prepared in the previous step, in 15 mL of THF plus 8 mL of water. After the addition the reaction was stirred at room temperature for 7 h. The reaction was acidified with 1 N HCl and then concentrated under reduced pressure to remove the THF. The solid present was collected by filtration and dried under reduced pressure to give the title compound (125 mg, 91%) as an off-white solid, mp 194-196° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>>[NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[CH3:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c(N)c1F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1F
Yield: 36 %

Procedure:
The sub-title compound is prepared from crude 3-amino-4-chloro-2-fluoro-benzylamine, 2,2-dimethyl-propionic acid chloride and TEA in analogy to step Ae.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[O:11][C:10]2=[O:17])=[CH:5][CH:4]=1.[OH-].[Na+].[C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)#[N:21].Cl>C1COCC1>[C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([N:9]3[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[O:11][C:10]3=[O:17])=[CH:7][CH:8]=2)=[O:27])=[CH:24][CH:23]=1)#[N:21]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: NCc1ccc(N2CC(C(=O)O)OC2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)NCc2ccc(N3CC(C(=O)O)OC3=O)cc2)cc1

Procedure:
5.4 g of 3-(4-aminomethylphenyl)-2-oxo-5-oxazolidinecarboxylic acid are suspended in 70 ml of THF. 35 ml of 1N NaOH are added dropwise with stirring. Subsequently, a solution of 6.6 g of 4-cyanobenzoyl chloride in 60 ml of THF is added dropwise. The pH of the solution is maintained at between 9 and 10.5 by addition of 1N NaOH. After reaction has taken place, the mixture is acidified at a pH of 1 with 2N HCl. The solvent is removed and the residue is filtered off with suction and washed with water. 3-[4-(4-cyanobenzamidomethyl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid is obtained, m.p. 234°.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH:3]=[O:4].[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]([CH3:8])([CH:3]([OH:4])[CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH:6]=[CH2:7]
Reactant: [Li]CCCC
Reactant: C=CCC(C)(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(C)(C)C(O)CCCC
Temperature: -60 °C
Yield: 100 %

Procedure:
15 g (133 mmol) of 2,2-dimethyl-4-pentenal was added to 600 mL of THF in a 2 L, 3-neck flask, flushed with N2, and sealed with rubber stoppers. The reaction mixture was cooled to −60° C. in a dry ice/acetone bath. Butyllithium solution (2.5 M in hexane, 64.4 mL, 160.7 mmol) was added 4-5 mL at a time from a 20 mL glass syringe. The reaction temperature, was kept at −65° C., during addition and afterwards was stirred for an additional hour. The reaction mixture was allowed to warm to −5° C. over 1 hour, cooled to −60° C. again, and slowly quenched with ammonium chloride solution (10.5 g/200 mL water, 200 mmol). THF was evaporated using a rotary evaporator, keeping the water bath temperature set at 30° C. The resultant aqueous solution was first extracted with CH2Cl2 (3×200 mL), and then with ether (1×200 mL). The organic extracts were combined, dried, and concentrated on a rotary evaporator (30° C. water bath) to yield 22.64 g of 4,4-dimethyl-non-1-en-5-ol, TLC Rf=0.67 (1:1 ethyl acetate:hexanes, visualization by I2). 1H NMR (CDCl3, 500 MHz) δ (ppm): 5.86 (m, 1H), 5.06 (m, 1H), 5.03 (s, 1H), 3.26 (d, 1H), 2.15 (m, 1H), 1.95 (m, 1H), 1.5 (m, 2H), 1.3 (m, 4H), 0.95, (t, 3H), 0.90 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.[OH:26][CH2:27][C:28]#[CH:29]>N1CCCC1.O.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>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:29]#[C:28][CH2:27][OH:26])[CH:20]=2)[N:3]=1
Reactant: C#CCO
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCNC1
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C#CCO)c2)N=C1N
Temperature: 70 °C
Yield: 45 %

Procedure:
A mixture of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (2.4 g, 5.85 mmol), 3-hydroxy-1-propyne (3.27 g, 58.5 mmol) and Pd(PPh3)4 (670 mg, 0.585 mmol) in pyrrolidine is heated at 70° C. under a nitrogen atmosphere for 16 h, diluted with water and extracted with CH2Cl2. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is purified by chromatography on a silica cartridge, to give 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one, 1 g (45% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:13][C:14](ON1C(=O)CCC1=O)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH2:6]([O:13][C:14](=[O:15])[NH:5][CH2:4][CH2:3][Br:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCBr
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Br
Solvent: ClCCl
Product: O=C(NCCBr)OCc1ccccc1

Procedure:
2-Bromoethylamine hydrobromide (15 g, 73 mmol) and N-(benzyloxycarbonyloxy)-succinimide (15.5 g, 62 mmol) are suspended in CH2Cl2 (150 mL) at 0° C. TEA (9 mL, 65 mmol) is added slowly keeping the temperature at 0° C. After 1 h the mixture is washed with 0.5M aq. KHSO4 (50 mL) and sat. aq. NaCl (50 mL), the organic phase is dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:12]([CH3:34])[CH2:13][CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1.[N:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37][CH:36]=1.[H-].[Na+]>CS(C)=O.O1CCCC1>[CH3:11][O:10][C:8]1[CH:7]=[C:6]([CH:12]([CH3:34])[CH2:13][CH:14]=[CH:41][C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)[CH:5]=[C:4]([O:3][CH3:2])[CH:9]=1
Reactant: COc1cc(OC)cc(C(C)CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cc(OC)cc(C(C)CC=Cc2ccncc2)c1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A mixture of 3-(3,5-dimethoxyphenyl)butyl triphenylphosphonium bromide (19.0 g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to 4-pyridinecarboxaldehyde (3.79 g., 35.4 mmoles) in tetrahydrofuran (40 ml.). The resulting mixture is then added dropwise to a slurry of 50% sodium hydride (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under a nitrogen atmosphere at 0°-5° C. Following completion of addition, the mixture is stirred for one hour at 0°-5° C. and then concentrated under reduced pressure. The concentrate is diluted with water (200 ml.) and then acidified with 6 N HCl. The aqueous acid solution is extracted with benzene (4×50 ml.). It is then made basic and extracted with ethyl acetate (3×50 ml.). Evaporation of the combined extracts after drying (MgSO4) affords 4-(3,5-dimethoxyphenyl)-1-(4-pyridyl)-1-pentene (7.1 g., 70%) as an oil.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:32])[CH2:14]/[CH:15]=[CH:16]/[CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[C:25]([O:27]C(C)(C)C)=[O:26])=[O:19])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:25]([C@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:18](=[O:19])[CH2:17]/[CH:16]=[CH:15]/[CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:32])([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)C/C=C/CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)C/C=C/CC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a stirred solution of 600 mg (1.33 mmol) (E)-(R)-1-[6-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl)-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 15 ml dichloromethane at 0° C. was added dropwise 4.4 ml (57.8 mmol) trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded 402 mg (90%) of the title compound as a white foam.