Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([O:20][C:21]1[CH:22]=[C:23]([N+:65]([O-:67])=[O:66])[CH:24]=[C:25]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:68](Cl)([CH:70]=[CH2:71])=[O:69]>N1C=CC=CC=1>[C:68]([O:1][CH:2]([O:20][C:21]1[CH:22]=[C:23]([N+:65]([O-:67])=[O:66])[CH:24]=[C:25]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:69])[CH:70]=[CH2:71]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc([N+](=O)[O-])cc(OC(O)CCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Reactant: C=CC(=O)Cl
Solvent: c1ccncc1
Product: C=CC(=O)OC(CCCCCCCCCCCCCCCCC)Oc1cc([N+](=O)[O-])cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Subsequently, into pyridine controlled at 0° C., dissolved was 4.0 g of 3-(1′-hydroxyoctadecyloxy)-4,5-dioctadecyloxy nitrobenzene and added 0.50 g of acryl chloride for 30 minutes, followed by stirring 1 hour at room temperature. After finishing the reaction, resulting solution was purified via silica gel chromatography (mix solvent of hexane and ethyl acetate) to obtain 3.9 g of 3-(1′-acryloyloxyoctadecyloxy)-4,5-dioctadecyloxy nitrobenzene (yield: 92%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])C(O)=O)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(Cl)(=O)C(Cl)=O.[C:36]([O:42][CH2:43][CH3:44])(=[O:41])[CH2:37][C:38]([O-])=[O:39].C([Mg]Cl)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([C:38](=[O:39])[CH2:37][C:36]([O:42][CH2:43][CH3:44])=[O:41])[CH:25]=[CH:26][C:27]=2[CH3:28])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CC(C)[Mg]Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In an oven-dried round bottom flask, 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (see Example 487) (0.75 g, 1.62 mmol), DCM (2.00 mL), and oxalyl chloride (0.97 mL, 1.94 mmol) were combined under argon. DMF (3-5 drops) was added to aid in dissolution. Stirred at RT overnight. Solvent was removed and the crude acid chloride was coevaporated with DCM (3-5 mL×3) and dried in vacuo to give an orange solid. In a separate oven-dried flask, in an argon atmosphere, a solution of monoethyl malonate (0.38 mL, 3.23 mmol) in THF (3.00 mL) was cooled to −78° C. Isopropyl magnesium chloride (3.23 mL, 6.46 mmol) was added dropwise. The solution was stirred for 30 min at −78° C. The acid chloride prepared as described above was added dropwise as a solution in THF. The reaction was warmed to RT. After 30 min, the reaction was cooled (0° C.) and 10% citric acid (5.0 mL) added. The crude product was extracted in EtOAc, washed with 5% NaHCO3, dried over Na2SO4, filtered, and concentrated to a crude brown oil. Recrystallization from DCM and hexane. Filtered a beige solid, dried in vacuo (0.41 g, 47%). 1H NMR (CD3OD/400 MHz) δ 8.02 (m, 1H), 7.79 (s, 1H), 7.65 (m, 2H), 7.05 (t, 2H, J=9.2 Hz), 6.66 (s, 1H), 5.36 (s, 2H), 4.16 (q, 2H, J=7.2 Hz), 2.11 (s, 3H), 2.07 (s, 2H), 1.99 (s, 3H), 1.23 (t, 3H, J=7.2 Hz). ES HRMS m/z 534.0744 and 536.0746 (M+H calculated for C25H23BrF2NO5 requires 534.0722 and 536.0706).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([CH:15]1O[CH2:16]1)[Cl:14].FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Cl:14][CH2:13][C@H:15]1[O:11][CH2:10][C@H:9]([CH3:12])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16]1
Reactant: C[C@@H](CO)NCc1ccccc1
Reactant: ClCC1CO1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CO[C@H](CCl)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2S)-2-[benzylamino]propan-1-ol (1 equivalent) and epichlorohydrin (1 equivalent) was stirred at room temperature overnight. The mixture was cooled down to 0° C. and cold trifluoromethanesulfonic acid (4 equivalents) was added. The flask was equipped with a reflux condenser and the mixture was stirred at 160° C. overnight. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 and quenched with ice water. The mixture was then made basic (pH=12) with a 30% NaOH solution. The two phases were separated, and the aqueous phase was extracted with CH2Cl2. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to afford a dark brown oil. The crude product contained an equimolar mixture of (2R,5S)-2-(chloromethyl)-5-methyl-4-benzylmorpholine(cis diastereoisomer) and (2S,5S)-2-(chloromethyl)-5-methyl-4-benzylmorpholine(trans diastereoisomer), which were separated by chromatography on silica gel (ethyl acetate/hexanes 1:20 to 1:8). (2S,5S)-2-(chloromethyl)-5-methyl-4-benzyl morpholine was obtained as the isomer with the lower Rf. GC/MS: 239 (15%, M+), Rt=15.08 minutes; LC/MS (m/z): 240.0 (MH+), Rt 1.56 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH2:34]([O:36][CH2:37][CH2:38][NH2:39])[CH3:35].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:25])[NH:39][CH2:38][CH2:37][O:36][CH2:34][CH3:35])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOCCN
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOCCNC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)sc1C(=O)OCC
Yield: 76 %

Procedure:
The same operation as in Example (247a) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (250 mg, 0.50 mmol), 2-ethoxyethylamine (0.11 mL, 1.00 mmol), WSC hydrochloride (288 mg, 1.50 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol), to obtain 217 mg of the title compound as a white solid (76%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:12](=[NH:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C([O:25][CH:26]=[C:27]([C:33](OCC)=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])C>CO>[CH2:31]([O:30][C:28]([C:27]1[C:26](=[O:25])[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12]([CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:22])[CH:9]([CH3:11])[CH3:10])=[N:21][CH:33]=1)=[O:29])[CH3:32]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CO
Product: CCOC(=O)c1cnc(C(NC(=O)OC(C)(C)C)C(C)C)n(Cc2ccccc2)c1=O
Temperature: 100 °C

Procedure:
Following the procedure of Veale, J. Org. Chem., 58,4490 (1993), to [1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester (10.86 g, 35.6 mmol) in methanol (160 mL) was added diethyl ethoxymethylenemalonate (7.7 g, 35.6 mmol). The reaction is equipped with a Dean-Stark trap. The reaction was heated at 100° C. until all solvent was removed. The residue was dissolved in methylene chloride, washed with 1 N HCl and water, dried (Na2SO4), and concentrated. The resulting pale yellow syrup was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)=[O:27])#[N:2].C1COCC1>[C].[Pd].CO>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1[CH2:24][CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)=[O:27])#[N:2]
Reactant: COc1ccc(NC(=O)/C=C/c2c(C#N)c3c(C)cc(C)nc3n2[C@H]2CCCc3ccccc32)cc1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(NC(=O)CCc2c(C#N)c3c(C)cc(C)nc3n2[C@H]2CCCc3ccccc32)cc1OC

Procedure:
A mixed solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(3,4-dimethoxyphenyl)prop-2-enamide (170 mg, 0.336 mmol), 10% palladium carbon (20 mg), THF (3 ml) and methanol (3 ml) was stirred under hydrogen atmosphere for 4 hours. Insolubles were filtrated off and the filtrate was concentrated to give the objective product as a solid material.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([CH:20]3[CH2:23][N:22]([C:24](=O)[CH2:25][CH3:26])[CH2:21]3)=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([CH:20]3[CH2:23][N:22]([CH2:24][CH2:25][CH3:26])[CH2:21]3)=[CH:18][CH:19]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)C1
Solvent: C1CCOC1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)C1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a solution of 4-isopropyl-N-[6-(1-propionyl-azetidin-3-yl)-pyridin-3-yl]-benzenesulfonamide (150 mg, 0.38 mmol) in THF (15 ml) was added dropwise 1M BH3. THF (3.8 ml) and the mixture was stirred at room temperature for 12 h. It was then quenched by careful addition of 1N aqueous HCl (10 ml) and the resulting solution was heated at reflux for 4 h. The solution was next cooled to room temperature, adjusted to pH˜8 with 2 N NaOH solution and diluted with CH2Cl2. Separation of the layers, drying (Na2SO4) of the organic phase, filtration and evaporation in vacuo provided the crude material, which was purified by flash column chromatography (CH2Cl2:methanol, 95:5) to give the title compound (95 mg, 66%) as a light yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br.O>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCCCCCc1ccc(-c2ccc(OC)cc2)nc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCc1ccc(-c2ccc(O)cc2)nc1

Procedure:
The 2-(p-methoxyphenyl)-5-octylpyridine was dissolved in 100 ml of acetic acid. 8 ml of 48% hydrobromic acid was added to the reaction solution and the solution was heated for 15 hours under reflux. 100 ml of water was added to the reaction solution and the organic layer was extracted with chloroform. After washing the extract three times with water, the chloroform was removed by distillation. The residue was recrystallized from a mixture of acetone and hexane to yield 8.3 g (0.029 mol) of 2-(p-hydroxyphenyl)-5-octylpyridine.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].C1C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:27]4[C:28]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:24]=[CH:25][CH:26]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1cccc2ccccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc5ccccc45)cc3CC[C@@H]12
Yield: 50.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 1-naphthylboronic acid 134 mg, 0.78 mmol), 0.65 mL of 1M sodium hydroxide solution and 2 mL of benzene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), followed by recrystallization from ethyl acetate to give 116 mg (50%) of the title compound as a white solid. mp 159°. FDMS: m/e=355. α[D]589 =+60.00 (c=0.50, chloroform).
Reaction SMILES: C(OC([NH:7][C@@H:8]([CH:72]([CH3:74])[CH3:73])[C:9]([NH:11][C@@H:12]([CH3:71])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:23][C@H:24]3[CH:30]=[N:29][C:28]4[CH:31]=[C:32]([O:37][CH2:38][CH2:39][CH2:40][O:41][C:42]5[C:43]([O:67][CH3:68])=[CH:44][C:45]6[C:51](=[O:52])[N:50]7[CH:53]=[C:54]([C:56]8[CH:65]=[CH:64][C:59]([C:60]([O:62][CH3:63])=[O:61])=[CH:58][CH:57]=8)[CH2:55][C@H:49]7[CH:48]=[N:47][C:46]=6[CH:66]=5)[C:33]([O:35][CH3:36])=[CH:34][C:27]=4[C:26](=[O:69])[N:25]3[CH:70]=2)=[CH:18][CH:17]=1)=[O:14])=[O:10])=O)C=C.N1CCCC1>ClCCl.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.[Pd].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C@@H:8]([CH:72]([CH3:74])[CH3:73])[C:9]([NH:11][C@@H:12]([CH3:71])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH2:23][C@H:24]3[CH:30]=[N:29][C:28]4[CH:31]=[C:32]([O:37][CH2:38][CH2:39][CH2:40][O:41][C:42]5[C:43]([O:67][CH3:68])=[CH:44][C:45]6[C:51](=[O:52])[N:50]7[CH:53]=[C:54]([C:56]8[CH:57]=[CH:58][C:59]([C:60]([O:62][CH3:63])=[O:61])=[CH:64][CH:65]=8)[CH2:55][C@H:49]7[CH:48]=[N:47][C:46]=6[CH:66]=5)[C:33]([O:35][CH3:36])=[CH:34][C:27]=4[C:26](=[O:69])[N:25]3[CH:70]=2)=[CH:20][CH:21]=1)=[O:14])=[O:10]
Reactant: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(C(=O)OC)cc7)C[C@H]5C=N6)cc4N=C[C@@H]3C2)cc1)C(C)C
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: COC(=O)c1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)cc7)C[C@H]5C=N6)cc4N=C[C@@H]3C2)cc1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of 8 (43 mg) in anhydrous dichloromethane (3 mL) was added Ph3P (0.5 mg, 0.002 mmol), pyrolidine (7 μL, 0.082 mmol) and tetrakis palladium (1.1 mg, 0.001 mmol). After approximately 30 minutes, the reaction mixture was aspirated onto a 1 mm radial chromatotron plate and eluted with 5% and then 10% methanol in dichloromethane. The major band was collected and concentrated under reduced pressure to give 22 mg (56%) of 9: MS (ES+) m/z 952.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])[C:3]=1[CH3:13].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C(N)CCC.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([N+:10]([O-:12])=[O:11])=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]=1[CH3:13]
Reactant: O=Cc1ccccc1
Reactant: Cc1c(F)cccc1CC[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCN
Solvent: CC(=O)O
Product: Cc1c(F)cccc1CC(=Cc1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Yield: 81.1 %

Procedure:
The compound of step 2 (17.951 g, 98 mmol), benzaldehyde (10.43 ml, 102.90 mmol), n-butylamine (0.49 ml, 4.90 mmol) and acetic acid (0.28 ml, 4.90 mmol) in 49 ml of toluene were heated at 180° C. in a Dean-Stark apparatus for 6 h. After cooling to room temperature, the mixture was evaporated to dryness under reduced pressure. The residue was taken up in 49 ml of toluene, benzaldehyde (10.43 ml, 102.90 mmol), n-butylamine (0.49 ml, 4.90 mmol) and acetic acid (0.28 ml, 4.90 mmol) were added, and the mixture was heated at 180° C. in a Dean-Stark apparatus for 3 h. After cooling to room temperature, the mixture was evaporated to dryness under reduced pressure. The residue was triturated with 25 ml of diethyl ether/pentane (1:1). The solid was filtered off, rinsed with cyclohexane, and dissolved in 75 ml of DCM. The solution was dried with magnesium sulfate and evaporated to dryness to give 21.57 g of the title compound as a yellow solid melting at 111-112° C.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[Sn](Cl)(Cl)(Cl)Cl.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:17][C:16](=[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COC(=O)CC(=O)C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
1.50 g of methyl isobutyrylacetate (10.0 mmol, concentration 96%) and 1.24 g of 4-fluorobenzonitrile (10 mmol, concentration 98%) were dissolved in 10 ml of toluene and treated with 2.63 g of tin tetrachloride (10 mmol, concentration 99%) at room temperature over the course of 6 min. After 3 h at room temperature, the mixture was heated to 80° C. After 2.5 h, the suspension was again cooled to room temperature and treated with 10 ml of water. It was diluted with 5 ml of ethyl acetate and the phases were separated. After extraction of the aqueous phase with ethyl acetate (2×5 ml), the combined organic phases were dried over magnesium sulphate. After concentration in vacuo, 3.50 g of crude product were obtained in the form of a pale yellow, tacky solid. The solid was dissolved in ethyl acetate and purified by flash chromatography (n-hexane/ethyl acetate 5:1 to 1:1). After concentration in vacuo, 1.44 g of methyl 2-[1-amino-1-(4-fluorophenyl)-methylene]-4-methyl-3-oxopentanoate were obtained.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([C:25]2[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>>[N:19]1([C:25]2[N:30]=[CH:29][C:28]([NH:31][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:27][CH:26]=2)[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(N2CCSCC2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(N2CCSCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-thiomorpholin-4-yl-pyridin-3-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-thiomorpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C20H17F3N4O2S (m/e) 434, obsd 435 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[Na].[CH2:14]1[O:16][CH2:15]1.Cl>[OH-].[Na+].O>[OH:16][CH2:15][CH2:14][O:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Reactant: C1CO1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=C(O)C(O)c1ccc(OCCO)cc1
Temperature: 95 °C
Yield: 89.3 %

Procedure:
1040.8 g (5.00 mol) of 4-hydroxymandelic acid, sodium salt monohydrate, 10.0 g (0.25 mol) of sodium hydroxide and 1000 ml of water are placed in an autoclave of 6.3 liter capacity. The autoclave is flushed with nitrogen and 330.4 g (7.50 mol) of ethylene oxide are then injected. The contents are slowly heated to 95° C. over a period of 2 hours with stirring and stirred at this temperature for another 2 hours. The still hot reaction mixture is poured into another vessel, acidified at 95° C. with 540 ml (about 5.5 mol) of 32% hydrochloric acid and crystallized by slow cooling to about +10° C. The precipitated product is filtered with 1000 ml of cold water and dried to give 948 g (89%) of 4-(2-hydroxyethoxy)mandelic acid, m.p. 162°-164° C. (compound (201), Table 2).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:30])[C:16]([C:20]1[N:21]=[C:22]([NH:25]C(=O)CCl)[S:23][CH:24]=1)=[N:17][O:18][CH3:19])(=[O:3])[CH3:2].[Na+:31].CSC(=S)N.[Na]>O>[C:1]([O:4][C@@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:30])[C:16]([C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1)=[N:17][O:18][CH3:19])(=[O:3])[CH3:2].[Na+:31]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1OC(C)=O)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1OC(C)=O)c1csc(N)n1
Yield: 64.6 %

Procedure:
To a solution of 0.101 g of the above sodium (3S,4S)-4-acetoxy-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate (syn-isomer) in 4 ml of water is added 28.4 mg of sodium monomethyldithiocarbamate under ice-cooling with stirring, and the mixture is stirred at room temperature for one hour. The insolubles are filtered off and the filtrate is purified on a column of XAD-II. The above procedure gives 55.4 mg of sodium (3S,4S)-4-acetoxy-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate (syn-isomer).
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=O)[CH2:4][CH2:3][CH2:2]1.O.NN.C([O-])([O-])=O.[K+].[K+]>C(O)COCCO>[CH:1]1([CH2:5][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1ccc(C(=O)C2CCC2)cc1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccc(CC2CCC2)cc1
Yield: 95 %

Procedure:
A mixture of compound (G) (5.00 g), hydrazine hydrate (4.12 g), K2CO3 (7.00 g) and diethylene glycol (16 ml) were heated to reflux temperature for 1 hour. The condenser was exchanged by a distillation device and the mixture was distilled at 220-230° C. The distillate was extracted with MTBE and the organic phase washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography to yield a colorless oil (4.4 g).