Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[Cl-].[NH4+].[Br:5][C:6]1[CH:7]=[CH:8][N:9]2[C:14]=1[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=1[F:25])=[CH:12][CH:11]=[N:10]2>O1CCCC1.[Zn]>[Br:5][C:6]1[CH:7]=[CH:8][N:9]2[C:14]=1[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:25])=[CH:12][CH:11]=[N:10]2
Reactant: O=[N+]([O-])c1ccc(Oc2ccnn3ccc(Br)c23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnn3ccc(Br)c23)c(F)c1
Temperature: 70 °C
Yield: 93.7 %

Procedure:
Methanol (1.2 mL), zinc powder (300 mg, 4.57=1) and ammonium chloride (130 mg, 2.47 mmol) were sequentially added to a solution of 5-bromo-4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-b]pyridazine (67 mg, 0.19 mmol) in tetrahydrofuran (4.7 mL) and heated at 70° C. for 1.5 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature and filtered by passing through a celite pad. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (1-6% ethyl acetate in dichloromethane) to give the target compound (57 mg, 0.178 mmol, 93% yield).
Reaction SMILES: [CH2:1]([C:12]1[N:13]=[C:14]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[S:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:14]3[S:15][CH:16]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:13]=3)=[CH:18][CH:19]=2)=[CH:29][CH:28]=1
Reactant: CCCCCCCCCCCc1csc(-c2ccc(C=O)cc2)n1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: CCCCCCCCCCCc1csc(-c2ccc(CNCc3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 90 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(4-undecyl-1,3-thiazol-2-yl)benzaldehyde and 4-(trifluoromethyl)benzylamine gave the title compound as a colorless oil (90%). 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, 2H, J=8.3 Hz), 7.45 (d, 2H, J=8.1 Hz), 7.35 (d, 2H, J=8.1 Hz), 7.25 (d, 2H, J=8.3 Hz), 6.72 (s, 1H), 3.689 (s, 2H, J=7.3 Hz), 3.74 (s, 2H), 2.67 (t, J=2H, 7.7 Hz), 1.95-1.72 (m, 1H), 1.62-1.55 (m, 2H), 1.37-1.05 (m, 16H), 0.74 (t, 3H, J=6.7 Hz). M+(LC/MS(ESI)): 503.4. HPLC (Condition A), Rt: 4.99 min (HPLC purity: 91.2%).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][C:21]=3[C:28]3[CH:29]=[C:30]([C:36]4[CH2:41][CH2:40][CH:39]([C:42]([O:44]C)=[O:43])[CH2:38][CH:37]=4)[CH:31]=[CH:32][C:33]=3[O:34][CH3:35])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Li+].Cl>O1CCOCC1.O.CCOC(C)=O>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][C:21]=3[C:28]3[CH:29]=[C:30]([C:36]4[CH2:41][CH2:40][CH:39]([C:42]([OH:44])=[O:43])[CH2:38][CH:37]=4)[CH:31]=[CH:32][C:33]=3[O:34][CH3:35])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: COC(=O)C1CC=C(c2ccc(OC)c(C3=C(CN4C(=O)O[C@H](c5cc(C(F)(F)F)cc(C(F)(F)F)c5)[C@@H]4C)CC(C)(C)CC3)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C2=CCC(C(=O)O)CC2)cc1C1=C(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC(C)(C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
According to the same method as the synthesis of Compound 354, the obtained methyl 4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)cyclohex-3-enecarboxylate was dissolved in dioxan/water (5 mL, v/v 2:1). Lithium hydroxide (10 mg) was added dropwise to the obtained solution at room temperature, and stirred at room temperature for 5 hours. After the completion of the reaction, the reaction mixture was acidified with 2 M HCl solution. The reaction mixture was diluted with EtOAc, was washed with water and brine. The organic layers were collected, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was separated by MPLC (3:1 hexane:EtOAc), thus obtaining Compound 362 (30 mg, 24%) as white solid foam.
Reaction SMILES: C(Br)C1C=CC=CC=1.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]>>[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][N:31]([CH2:10][C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([O:16][CH3:17])=[O:15])[C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCc1ccccc1
Product: COC(=O)c1cccc(CN2CCN(c3nc(C)c(C(C)=O)s3)C2=O)c1
Yield: 64 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with methyl 3-(bromomethyl)benzoate to react with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one, the title compound was obtained as a white solid in 64% yield: mp 122-124° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.99-7.93 (m, 2H), 7.52-7.40 (m, 2H), 4.53 (s, 2H), 4.11-4.05 (m, 2H), 3.96 (s, 3H), 3.49-3.43 (m, 2H), 2.59 (s, 3H), 2.49 (s, 3H); MS (ES+) m/z 374.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:4][CH:5]=[C:6]([C:8](O)=[O:9])[CH:7]=1.[CH2:32]([NH2:34])[CH3:33]>O1CCCC1.CN(C)C=O>[CH2:32]([NH:34][C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:4][CH:5]=1)=[O:9])[CH3:33]
Reactant: O=C(O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Reactant: CCN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
0.43 g of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphine (1.12 mmol) was added to 0.49 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3]bipyridinyl-5-carboxylic acid (79) (1.12 mmol) prepared in Example 66 dissolved in 1.0 mL of tetrahydrofuran and 1.0 mL of dimethylformamide, and stirred at room temperature for 10 minutes. 0.56 mL of ethylamine (1.12 mmol) in 2.0 M tetrahydrofuran solution was added thereto, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure. Then, the mixture was dissolved in ethyl acetate, and washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/1) to obtain 0.35 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3]bipyridinyl-5-carboxylic acid ethyl amide (yield 68%).
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[F:9][C:10]([F:25])([S:21](F)(=[O:23])=[O:22])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[OH-].[K+]>O>[F:25][C:10]([F:9])([S:21]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])(=[O:23])=[O:22])[C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OCC(F)(F)C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2,3,3-tetrafluoropropan-1-ol (202 g, 1.52 mol, obtained from Sinochem Corp.), 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (465 g, 1.52 mol, obtained from 3M Company) and water (500 g) were combined in a 3-liter, 3-necked round bottom flask. The flask was equipped with a magnetic stirrer, cold water condenser, thermocouple and an addition funnel. Aqueous potassium hydroxide (45 percent by weight, 211.5 g, 1.7 mol, obtained from Aldrich Chemical Co., Milwaukee, Wis.) was added dropwise via the addition funnel at such a rate that the temperature did not exceed 35° C. Once the addition of the potassium hydroxide was complete, the mixture was stirred for 16 hours at room temperature. Precipitated salts were then filtered from the mixture and the lower liquid fluorochemical product phase was separated from the upper aqueous phase. Unreacted 2,2,3,3-tetrafluoropropan-1-ol and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride were removed from the liquid fluorochemical product phase by atmospheric distillation.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[O:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:7]1[N:1]1[CH2:6][CH2:5][N:4]([C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:20]3[N:19]=[C:18]([C:17]([F:32])([F:16])[F:33])[O:22][N:21]=3)[CH:24]=2)=[O:27])[CH2:3][CH2:2]1
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2nc3ccccc3o2)CC1
Yield: 12 %

Procedure:
This compound was synthesized from 2-(piperazin-1-yl)benzo[d]oxazole and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (20 mg, yield 12%). 1H NMR (400 MHz, CDCl3) δ 8.26-8.22 (m, 2H), 7.69-7.63 (m, 2H), 7.40-7.39 (m, 1H), 7.31-7.29 (m, 1H), 7.23-7.19 (td, J=7.7 Hz, 1.1 Hz, 1H), 7.10-7.06 (m, 1H), 3.96-3.63 (m, 8H). MS (ESI) m/z: Calculated for C21H16F3N5O3: 443.12. found: 444.2 (M+H)+
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]1[NH:31][C:30](=[O:32])[N:29]2[CH2:33][CH2:34][CH2:35][C@@H:28]12>>[CH3:26][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:4]3[CH:3]=[C:2]([N:31]4[CH2:27][C@@H:28]5[CH2:35][CH2:34][CH2:33][N:29]5[C:30]4=[O:32])[CH:7]=[CH:6][CH:5]=3)[CH2:11][CH2:12]2)[N:21]=1
Reactant: O=C1NC[C@@H]2CCCN12
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(I)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C[C@@H]6CCCN6C5=O)c4)CC3)cccc2n1
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and (S)-hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:34](Cl)(=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1>>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:34]([C:35]5[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=5)=[O:43])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)N2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)cc1

Procedure:
{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-(4-methoxy-phenyl)-methanone was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 25) with p-anisoyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 2.04-2.13 (m, 4H), 3.30 (methyl sulfonyl and water peak), 3.80 (m, 3H), 5.10-5.15 (m, 1H), 7.00-7.02 (m, 2H), 7.41-7.43 (m, 2H), 7.62-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.41 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=508.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]([F:17])=[C:8]2[C:3]=1[C:4](=[O:18])[CH2:5][CH2:6][S:7]2.[Cl-].[Na+].[BH4-].[Na+].Cl>ClCCl.CO>[OH:18][CH:4]1[C:3]2[C:8](=[C:9]([F:17])[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]=2[Cl:1])[S:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)c1cc(F)c2c(c1Cl)C(=O)CCS2
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1cc(F)c2c(c1Cl)C(O)CCS2
Yield: 39 %

Procedure:
30 ml of methanol and 20 ml of dichloromethane were added to 7.4 g (25.6 mmol) of 5-chloro-6-ethoxycarbonyl-8-fluorothiochroman-4-one (corresponding to compound of the formula (VIII)). While the mixture was maintained at a temperature not exceeding 0° C. with a sodium chloride aqueous solution and an ice bath, 0.97 g (25.6 mmol) of sodium borohydride as a reducing agent was gradually added. The mixture was allowed to react at room temperature for 3 hours, and then the reaction mixture was poured into a 5% hydrochloric acid aqueous solution and extracted with dichloromethane. The resultant organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel; hexane:ethyl acetate=2:1) to give 2.9 g (yield 40%) of 4-hydroxy-5-chloro-6-ethoxycarbonyl-8-flurothiochroman (corresponding to compound of the formula (IX)).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6](I)[CH:5]=[CH:4][C:3]=1[F:10].[CH2:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=1)[CH2:12][CH3:13].Cl>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:21]#[C:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:11][CH2:12][CH3:13])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[F:10]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: Fc1ccc(I)c(F)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: CCCc1ccc(C#Cc2cc(F)c(Br)c(F)c2)cc1
Temperature: 5 °C
Yield: 57.1 %

Procedure:
2-Bromo-1,3-difluoro-4-iodobenzene (20 g) was dissolved in diethylamine (30 ml) under nitrogen atmosphere, and then bis(triphenylphosphine)palladium(II) chloride (0.06 g) and copper(I) iodide (0.06 g) were added thereto, followed by stirring. The flask was cooled to 5° C. or lower, and then 4-propylphenylacetylene (10 g) was added dropwise thereto. After stirring at room temperature for 5 hours, the reaction solution was poured into a mixture of concentrated hydrochloric acid (15 ml) and ice (30 g). After extraction with chloroform, the resultant was washed with water twice, followed by distilling off chloroform. The residue was distilled under reduced pressure (b.p. 185° to 192° C./4 mmHg), and then recrystallized from a mixed solvent of acetone and methanol to give 4-bromo-3,5-difluoro-4'-propyltolane (12 g).
Reaction SMILES: [CH2:1](B(O)O)[CH:2]([CH3:4])[CH3:3].Br[C:9]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=1[C:11]#[N:12].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:3][CH:2]([CH3:4])[CH2:1][C:9]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Br
Reactant: CC(C)CB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1ccc([N+](=O)[O-])cc1C#N
Temperature: 100 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a solution of isobutylboronic acid (5.89 g), 2-bromo-5-nitrobenzo nitrile (12.5 g) and Cs2CO3 (35.9 g) in toluene (150 mL) and water (5 mL) stirred under nitrogen at room temperature was added solid PdCl2(dppf)-CH2Cl2 adduct (2.248 g) in one charge. The reaction mixture was stirred at 100° C. for 16 h. After cooling the reaction, the solvent was removed in vacuo. The residue was purified by column chromatography to give 2-(2-methylpropyl)-5-nitrobenzonitrile (D56) (11 g) as a light yellow oil. δH (CDCl3, 400 MHz): 1.00 (6H, d), 2.06 (1H, m), 2.86 (2H, d), 7.52 (1H, d), 8.37 (1H, dd), 8.51 (1H, d).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:3][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: OCCC1CCN(CCCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CC1(c2ccc(OCCCN3CCC(CCO)CC3)cc2)CCOCC1
Yield: 36.5 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (288 mg, 1.22 mmol), 2-[1-(3-chloro-propyl)-piperidin-4-yl]-ethanol (252 mg, 1.22 mmol), DMF (8 ml) and K2CO3 (674 mg, 4.88 mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:4:1) provided the title compound (180 mg, 36%) as an off white solid. 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 3.99 (t, 2H), 3.75 (dt, 2H), 3.70 (t, 2H), 3.55 (td, 2H), 2.98-2.88 (m, 2H), 2.49 (t, 2H), 2.40 (s, 2H), 2.14-1.82 (m, 6H), 1.97 (s, 6H), 1.75-1.15 (m, 10H).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH3:9][C:10]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:11]=1[CH2:12][NH2:13]>C1(C)C=CC=CC=1>[CH3:9][C:10]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:11]=1[CH2:12][N:13]=[C:4]=[O:3]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2ccccc2)cc1CN
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2)cc1CN=C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
2.5 g (12.6 mmol) of diphosgene, 0.40 g of activated carbon and 30 ml of toluene were mixed, and allowed to left overnight, and to this solution was slowly dropped at room temperature a solution prepared by dissolving 1.00 g (5.07 mmol) of 2-methyl-5-phenylbenzylamine (produced in the same manner as in Intermediate Production Example 6) in 5 ml of toluene. The reaction mixture turned to white suspension directly after the dropping. The white suspension was stirred at room temperature for 1 hour, further stirred for 5 hours under reflux with heating, then, concentrated under reduced pressure to obtain 1.13 g of 2-methyl-5-phenybenzyl isocyanate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)[CH:3]=1.[OH-:34].[Na+]>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C@:19]2([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[N:5]=[CH:6][NH:7][C:2](=[O:34])[CH:3]=4)=[CH:9][CH:10]=3)[CH3:15])[CH2:21][CH2:20]2)=[CH:27][CH:28]=1
Reactant: C[C@@H](c1ccc(-c2cc(Cl)ncn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: [OH-]
Agent: [Na+]
Product: C[C@@H](c1ccc(-c2cc(=O)[nH]cn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 110 °C
Yield: 78 %

Procedure:
A mixture of (R)-3-((S)-1-(4-(6-chloropyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (20 mg, 0.0426 mmol) in 15% aq NaOH (5 mL) was heated to 110° C. overnight. Then the solvent was evaporated, and the residue was washed with EtOAc. The solid was filted off and the filtrate was dried, and condensed in vacuum to give the crude product, which was purified by preparative HPLC to afford (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one (15 mg, 78%). LC-MS Method 2 tR=0.91 min, m/z=452, 408. 1H NMR (CD3OD): δ=1.31 (m, 1H), 1.59 (m, 3H), 1.95 (m, 2H), 2.25 (m, 1H), 2.35 (m, 1H), 2.46 (m, 1H), 3.15 (m, 1H), 3.48 (m, 2H), 5.59 (m, 1H), 6.81 (s, 1H), 7.12 (m, 4H), 7.33 (m, 2H), 7.79 (m, 2H), 8.25 (s, 1H).
Reaction SMILES: [CH:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]([O:6][CH3:7])=[O:5])=[O:2].[O:24]=O>>[C:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]([O:6][CH3:7])=[O:5])([OH:24])=[O:2].[CH:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]([O:6][CH3:7])=[O:5])=[O:2]
Reactant: O=O
Agent: CCCCCCCCCCCCCCCCC(C=O)C(=O)OC
Product: CCCCCCCCCCCCCCCCC(C(=O)O)C(=O)OC

Procedure:
Friedrich, in an article entitled "Oxidation of Methyl Formylstearate with Molecular Oxygen" at J. Am. Oil Chemists' Soc. 53, pp. 125-129 (1976) reports the use of air or oxygen to form methyl carboxystearate from methyl formylstearate in an emulsion with a soluble rhodium complex. The reuse of catalyst in hydroformylation reactions is described by Awl in an article entitled "Hydroformylation with Recycled Rhodium Catalyst and One-Step Esterification-Acetalation: A Process for Methyl 9(10)-Methoxymethylenestearate from Oleic Acid," which is printed in J. Am. Oil Chemists' Soc. 53, pp. 190-195 (1976).
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH3:20])[CH3:17])=[CH:14][C:8]=2[O:7]1)=O)C.[NH3:28]>CO>[C:24]([O:23][C:21](=[O:22])[N:18]([CH:16]([CH3:17])[CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[O:10][CH:6]([C:4](=[O:3])[NH2:28])[O:7][C:8]=2[CH:14]=1)[CH2:19][CH3:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)C1Oc2ccc(CC(C)N(CC)C(=O)OC(C)(C)C)cc2O1
Reactant: N
Solvent: CO
Product: CCN(C(=O)OC(C)(C)C)C(C)Cc1ccc2c(c1)OC(C(N)=O)O2
Reaction time: 1 h
Yield: 96 %

Procedure:
To 2.04 g (5.37 mmol) of 2D was added 30 mL of anhydrous methanol, and ammonia gas was passed through the solution for 1 hour at room temperature. The mixture was concentrated to dryness and the residue purified by silica gel column chromatography using 30% hexane in ethyl acetate to give 1.8 g (5.13 mmol, 96%) of 2E as a colorless gum (M+Na, 373).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([OH:32])=[C:26]([CH:31]=1)[C:27]([O:29]C)=[O:28].Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[OH:32][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18])=[CH:31][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1cc(N)ccc1O
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)Nc1ccc(O)c(C(=O)O)c1
Reaction time: 14 h
Yield: 80.9 %

Procedure:
To a solution of (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid (1.66 g, 5.98 mmol) and methyl 5-amino-2-hydroxybenzoate (1.0 g, 5.98 mmol) in methylene chloride (100 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.16 g, 6.0 mmol) and dimethylaminopyridine (100 mg). The mixture was stirred under N2 (14 h) and then diluted with methylene chloride (100 mL) and washed successively with 3N HCl, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the corresponding amide (2.0 g).