Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1c(F)cccc1Br
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
2-Bromo-6-fluoroaniline (8.2 g, 43.2 mmol) was dissolved in pyridine (10 mL) and treated with pivaloyl chloride (7.0 mL, 57.2 mmol). The reaction was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and treated with ethyl acetate (50 mL). Mixture was washed 1 N hydrochloric acid (2×), then brine. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was triturated with hexanes to give a solid which was filtered, washed with hexanes, and dried in vacuo. The title compound was obtained as white solid in 76% yield. 1H NMR (300 MHz, CDCl3): δ 7.39-7.31 (m, 1H), 7.14-7.03 (m, 2H), 6.98 (bs, 1H), 1.34 (s, 9H). Mass spec.: 274.1 (MH)+, 276.1 (MNa)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[C:24]1([S:30]([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([S:30]([N:33]2[CH:37]=[C:36]([C:2]3[CH:3]=[CH:4][C:5]4[O:14][CH2:13][CH2:12][C:11]5[S:10][C:9]([C:15]6[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=6)=[N:8][C:7]=5[C:6]=4[CH:23]=3)[CH:35]=[N:34]2)(=[O:32])=[O:31])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC1(C)OB(c2cnn(S(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cnn(S(=O)(=O)c4ccccc4)c3)cc1-2
Yield: 39 %

Procedure:
9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted under palladium Suzuki conditions to give 301 (39% yield). LC/MS(ESI+): m/z 519 (M+H). 1H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.62 (d, J=2.1, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 8.03 (d, J=7.6, 2H), 7.81 (t, J=7.5, 1H), 7.75-7.60 (m, 3H), 7.12 (d, J=8.4, 1H), 5.82 (dt, J=13.0, 6.6, 1H), 4.39 (t, J=4.8, 2H), 3.46 (t, J=4.9, 2H), 1.59 (d, J=6.6, 6H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[NH:14])[NH:12][OH:13])=[CH:7][CH:6]=1)[CH3:2].[CH2:16]([N:18]([CH2:21][C:22]1[S:26][C:25]([C:27]([OH:29])=O)=[CH:24][C:23]=1[CH3:30])[CH2:19][CH3:20])[CH3:17].Cl>[Li+].[OH-].CO>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:14]=[C:27]([C:25]3[S:26][C:22]([CH2:21][N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])=[C:23]([CH3:30])[CH:24]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH3:2].[CH2:19]([N:18]([CH2:21][C:22]1[S:26][C:25]([C:27]2[O:29][N:14]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:15])=[O:3])=[CH:6][CH:7]=3)[N:12]=2)=[CH:24][C:23]=1[CH3:30])[CH2:16][CH3:17])[CH3:20]
Reactant: CCOC(=O)c1ccc(C(=N)NO)cc1
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(C(=O)O)cc3)no2)cc1C
Product: CCOC(=O)c1ccc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid ethyl ester (1.42 g) is prepared starting from 4-(N-hydroxycarbamimidoyl)-benzoic acid ethyl ester (1.01 g, 4.84 mmol) and 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (1.00 g, 4.40 mmol) according to Method A; LC-MS: tR=0.63 min; [M+1]+=400.12; 1H NMR (CDCl3): δ 1.11 (t, J=7.0 Hz, 6H), 1.45 (t, J=7.0 Hz, 3H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.73 (s, 2H), 4.44 (q, J=7.3 Hz, 2H), 7.69 (s, 1H), 8.16-8.20 (m, 2H), 8.22-8.25 (m, 2H). This material (1.42 g, 3.58 mmol) is dissolved in 2 M LiOH in methanol (50 mL) and the mixture is stirred at rt for 20 h before it is acidified by adding aq. HCl. The mixture is extracted twice with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (710 mg) as a white solid; LC-MS: tR=0.52 min; [M+1]+=372.14. b) To a solution of 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (400 mg, 1.08 mmol) in DMF (5 mL), HOBt (160 mg, 1.19 mmol) followed by EDC HCl (227 mg, 1.19 mmol) is added. The mixture is stirred at rt for 5 min before ethanolamine (72 mg, 1.19 mmol) is added. The reaction mixture is stirred at rt for 1 h. The mixture is diluted with EA and washed with sat. aq. NaHCO3. The washing is extracted back twice with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with DCM containing 4% of methanol to give the title compound (290 mg) as a white solid; LC-MS: tR=0.47 min; [M+1]+=415.14; 1H NMR (CDCl3): δ1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.67-3.72 (m, 2H), 3.73 (s, 2H), 3.90 (t, J=4.8 Hz, 2H), 6.69 (t br, J=5.3 Hz, 1H), 7.68 (s, 1H), 7.91-7.95 (m, 2H), 8.22-8.26 (m, 2H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH:5]=[O:6].C(C(O)=O)[C:9]([CH2:11][C:12](O)=O)=O.[CH:18]1([NH2:21])[CH2:20][CH2:19]1.Cl>O>[CH:18]1([N:21]2[CH:3]3[CH2:2][CH2:1][CH2:9][CH:11]2[CH2:12][C:5](=[O:6])[CH2:4]3)[CH2:20][CH2:19]1
Reactant: O=CCCCC=O
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: NC1CC1
Agent: Cl
Solvent: O
Product: O=C1CC2CCCC(C1)N2C1CC1
Reaction time: 0.5 h
Yield: 10.5 %

Procedure:
Glutaraldehyde (36.5 mL, 95 mmol) and 1,3-acetonedicarboxylic acid (10 g, 65 mmol) were suspended in water (100 mL) and stirred by a mechanical stirrer under argon for 30 min. To the yellow solution cyclopropylamine (3.5 mL, 50 mmol) were added in one portion whereby a slightly exothermic reaction occurred and a gas evolved. The reaction mixture was stirred at 23° C. overnight. The reaction mixture was acidified with 3 N Hydrochloride solution until pH<2, then extracted with dichloromethane. The water layer was now adjusted with 3 N NaOH to pH 8 and extracted three times with dichloromethane, the organic layers were combined, dried over MgSO4, filtered and the solvents were evaporated. Purification of the crude product by flash chromatography with n-heptane and ethyl acetate gave the title compound as a white solid (940 mg, 11%); MS: m/e=180.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 79 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12].S(Cl)([Cl:16])=O.[CH3:18]O>>[ClH:16].[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH3:18])=[O:12]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: NCc1ccccc1CC(=O)O
Agent: Cl
Product: COC(=O)Cc1ccccc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(Aminomethyl)-benzeneacetate hydrochloride was stirred in dry methanol. Thionyl chloride (1.1 eq.) was added dropwise and the mixture was stirred at room temperature overnight to provide for (methyl 2-(aminomethyl)-benzeneacetate hydrochloride as a white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23]CO)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:26]O>C1(C)C=CC=CC=1>[CH3:26][CH:22]([CH2:21][CH2:20][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:23][CH2:11][O:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([NH2:3])=[CH:13][CH:12]=1
Reactant: OCCCCCc1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(CCOC(=O)c1ccc(N)cc1)CCc1ccccc1
Yield: 25 %

Procedure:
Sodium hydride (600 mg, cat. 60% disp in oil) was added to a suspension of methyl 4-aminobenzoate (30 g, 19 mmol), 3-methyl, 5-phenyl pentanol (36 g, 20 mmol) in PhMe (100 mL). The suspension was heated under reflux for 24 hours with the azeotropic removal of MeOH. The mixture was cooled and filtered through a plug of silica (400 mL) with cyclohexane:isopropanol (95:5) as eluant to give the ester as a pale yellow oil (15 g, 25%) which slowly crystallized.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([C:15]2[C:16]3[C:21]([C:22]([C:29]4[C:34]5=[CH:35][CH:36]=[C:37]6[C:46]([CH:45]=[C:44]7[C:39]([CH:40]=[CH:41][CH:42]=[CH:43]7)=[CH:38]6)=[C:33]5[CH:32]=[CH:31][CH:30]=4)=[C:23]4[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]4)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>CN(C=O)C>[Br:1][C:38]1[C:37]2[C:46]([CH:45]=[C:44]3[C:39]=1[CH:40]=[CH:41][CH:42]=[CH:43]3)=[C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[CH:27]4)[C:34]1=[CH:35][CH:36]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2c3ccccc3c(-c3cccc4c3ccc3cc5ccccc5cc34)c3ccccc23)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1c2ccccc2cc2c1ccc1c(-c3c4ccccc4c(-c4ccccc4)c4ccccc34)cccc12
Reaction time: 3 h

Procedure:
20 g (116 mmol) of N-bromosuccinimide are added at 100° C. to a suspension of 55 g (116 mmol) of 4-(9-phenylanthracen-10-yl)benz[a]anthracene in 500 ml of DMF. After 3 h, 500 ml of ethanol are added at room temperature, and the solid is filtered off with suction, washed with ethanol and dried. Yield: 63 g (113 mmol), 65%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[C:15](Cl)=[N:14][C:13](Cl)=[C:12]([C:20]#[N:21])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CO.ClCCl.[Pd]>[CH2:1]([N:8]1[CH2:17][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([C:20]#[N:21])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(Cl)nc(Cl)c2c1CCN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1cncc2c1CCN(Cc1ccccc1)C2
Yield: 88.4 %

Procedure:
A mixture of 7-benzyl-1,3-dichloro-5,6,7,8-tetrahydro-[2,7]-naphthyridine-4-carbonitrile (70 g, 0.22 mol) and triethylamine (70 mL) in methanol (1 L) was placed in a 2.5 L hydrogenation bottle and hydrogenated over 10% Pd/C (15 g) for 3 hr. The reaction mixture was filtered to remove catalyst. The catalyst on filter paper was washed with methanol (100 mL). The filtrate was concentrated under reduced pressure to give an oil. The oil was dissolved in dichloromethane (500 mL), washed with water (2×200 mL), brine (200 mL), dried over anhydrous magnesium sulfate (10 g), filtered and concentrated under reduced pressure to give an oil. The oil was placed under high vacuum line overnight to give the title compound (48.5 g, 88%). 1H NMR 60 MHz, (CDCl3), δ 8.5 (s, 1H), 8.3 (s, 1H), 7.3 (s, 5H), 3.7 (s, 2H), 3.6 (s, 2H), 2.8 (m, 4H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1)=[O:4].[CH2:11]1[N:16]2[CH2:17][N:18]3[CH2:20][N:14]([CH2:15]2)[CH2:13][N:12]1[CH2:19]3.C(OCC)C>C(Cl)(Cl)Cl.C(Cl)Cl>[Br-:1].[O:4]=[C:3]([C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1)[CH2:2][N+:12]12[CH2:13][N:14]3[CH2:20][N:18]([CH2:17][N:16]([CH2:15]3)[CH2:11]1)[CH2:19]2
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: Cc1ccc(C(=O)CBr)s1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(C(=O)C[N+]23CN4CN(CN(C4)C2)C3)s1
Product: [Br-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-bromo-1-(5-methylthien-2-yl)ethanone (30.0 g of the aforesaid dark liquid) and hexamethylene tetramine (21.0 g, 0.15 mole) in chloroform (500 ml) was stirred at room temperature for three days. The solvent was removed from the reaction mixture by evaporation under reduced pressure, leaving a dark residue. This residue was stirred in warm methylene chloride. Diethyl ether was added slowly to the mixture, causing a solid to precipitate. After being cooled for several hours, the solid was collected by filtration. The filter cake was rinsed with diethyl ether and was dried under reduced pressure yielding 43.1 g of 1-[2-oxo-2-(5-methylthienyl)ethyl]-3,5,7-triaza-1-azoniatricyclo-[3,3,1,13,7 ]decane bromide (mp 141° C. dec).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Li+].[Cl-]>C1(C)C=CC=CC=1>[CH2:14]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11])[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(C#N)ccc1Br
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C#N)cc1OC

Procedure:
A mixture of 4-bromo-3-methoxybenzonitrile (1.4 g, 6.7 mmol), allyl-tributyl-stannane (2.7 g, 8.1 mmol), LiCl (0.86 mg, 20 mmol) and Pd(PPh)4 (0.2 g) in 25 mL of anhydrous toluene was refluxed under N2 overnight. Checked the reaction with TLC and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product 4-allyl-3-methoxybenzonitrile. MS m/z: 174 (M+1)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[CH2:11]([Br:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br-:18].[CH2:11]([N+:10]1[CH:9]=[CH:8][S:7][C:6]=1[CH:2]1[O:3][CH2:4][CH2:5][O:1]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1csc(C2OCCO2)n1
Reactant: BrCc1ccccc1
Product: [Br-]
Product: c1ccc(C[n+]2ccsc2C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
A reaction mixture of 3.1 g (19.74 mmol) of 2-(1,3-dioxolan-2-yl)thiazole and 3.38 g (19.74 mmol) of benzyl bromide was heated on a steam-bath with stirring for 6 h. The mixture was cooled to room temperature, triturated with ethyl acetate and decanted to afford 5.5 g (84.9%) of 3-benzyl-2-(1,3-dioxolan-2-yl)thiazolium bromide (Formula VI: A=2-thiazolyl; Y=1,3-dioxolan-2-yl; R1 =R6 =H; Z- =Br-).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH3:23])[CH:16]=3)[CH2:13][O:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.[NH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C1(C)C=CC=CC=1>[F:8][C:6]1[CH:5]=[C:4]([C:9]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH3:23])[CH:16]=3)[CH2:13][O:12][C:11]([NH2:14])=[N:10]2)[CH:3]=[C:2]([NH:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:7]=1
Reactant: COc1ccc(C2(c3cc(F)cc(Br)c3)COC(N)=N2)cc1C
Reactant: Nc1ccccc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1ccc(C2(c3cc(F)cc(Nc4ccccc4)c3)COC(N)=N2)cc1C
Temperature: 105 °C
Yield: 41.7 %

Procedure:
A dried pressure tube was charged consecutively with (RS)-4-(3-bromo-5-fluoro-phenyl)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (Building Block AH, 100 mg, 0.3 mmol), toluene (1.5 mL), sodium tert-butylate (52 mg, 0.5 mmol), and tert-butyl x-phos [di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine] (12 mg, 0.03 mmol). The mixture was purged with argon before [tris(dibenzylidenacetone)dipalladium chloroform complex] (8 mg, 0.008 mmol) and aniline (49 mg, 0.5 mmol) were added. The sealed tube was heated at 105° C. for 15 hours. For the working-up, the reaction mixture was cooled and evaporated under reduced pressure. The residue was directly chromatographed on an Isolute Flash NH2 column using a gradient of heptane/ethyl acetate=100/0 to 100/0 as the eluent. There were obtained 49 mg (47% of theory) of (RS)-4-(3-fluoro-5-phenylamino-phenyl)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine as a white foam; Mass (calculated) C23H22FN3O2 [391]; (found) [M+H]+=392.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCCO)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCNC(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.6 ml of methanesulfonyl chloride in 3 ml of methylene chloride is added dropwise at 0° to a solution of 1.5 g (0.0075 mol) of N-(2-hydroxyethyl)-4-chlorobenzamide and 1 ml of triethylamine in 15 ml of methylene chloride. After 15 minutes, the mixture is poured on to ice/water and extracted. There are obtained 2.1 g of N-(2-methylsulfonyloxyethyl)-4-chlorobenzamide in crystalline form which is used in the next step without further purification.
Reaction SMILES: C(OP(C[N+]#[C-])(=O)[O:5][CH2:6][CH3:7])C.[CH2:12]([Li])CCC.C([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=O)C.Cl>C(OCC)C>[S:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[CH:7]([CH3:12])[CH:6]=[O:5]
Reactant: [C-]#[N+]CP(=O)(OCC)OCC
Reactant: [Li]CCCC
Reactant: CC(=O)c1cccs1
Agent: Cl
Solvent: CCOCC
Product: CC(C=O)c1cccs1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of diethylisocyanomethylphosphonate in diethyl ether (40 ml) was added butyl lithium (6.9 ml, 1.6M in hexane) dropwise at −60° C. After the reaction mixture was stirred at −60° C. for additional 15 min a solution of 2-acetylthiophene (1.26 g, 10 mmol) in diethyl ether (10 ml) was added at the same temperature. The reaction mixture was warmed up to 0° C. and was stirred for 1.5 h. Concentrated HCl (15 ml) was added at 0° C. and then ice bath was removed. After the resulting mixture was stirred at room temperature overnight it was poured to cold water (20 ml). The organic layer was washed with water, sat. sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without purification.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([CH3:43])[C:24]1=[O:44])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:45](Br)[CH:46]=C.[CH3:49][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:43]([C:25]1([CH3:49])[CH2:26][C@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)[N:23]([C@@H:20]([CH2:21][CH3:22])[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:24]1=[O:44])[CH:45]=[CH2:46]
Reactant: C=CCBr
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.95 g (4.57 mmol) of (5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one (Example 121, Step J) and 7.91 mL (91.0 mmol) of allyl bromide in dry, degassed THF (22 mL) was added 68.6 mL (68.6 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF slowly via syringe over 6 min at room temperature. After 10 min, the orange solution was warmed to 50° C. and stirred for 24 h. At this time, 11.4 mL (11.4 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF and 790 μL (0.79 mmol) of allyl bromide were added. The reaction was stirred for an additional 6.25 h at 50° C., and then was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The mixture was extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2 to 25% EtOAc/hexanes, gradient elution) provided the title compound (mixture of C-3 epimers) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10](=N)[O:11]C)=[N:6][C:7]=1[O:8]C.[H-].[Na+].C[OH:17].Br[C:19]1[CH:20]=[CH:21][C:22]([C:26]#N)=[N:23][C:24]=1[Cl:25]>O1CCCC1>[ClH:25].[CH3:26][C:22]1[CH:21]=[C:20]([C:2]2[C:7](=[O:8])[NH:6][C:5]([C:10]([OH:11])=[O:17])=[CH:4][CH:3]=2)[CH:19]=[CH:24][N:23]=1
Reactant: COC(=N)c1ccc(Br)c(OC)n1
Reactant: CO
Reactant: N#Cc1ccc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(=O)O)[nH]c2=O)ccn1
Product: Cl
Reaction time: 0.92 h

Procedure:
Synthesis of methyl 5-bromo-6-methoxypyridine-2-carboximidoate (C29). Sodium hydride (60% dispersion in mineral oil, 3.57 g, 93.8 mmol) was added portion-wise over a 20 minute period to a stirred solution of methanol (7.1 mL) in tetrahydrofuran (123 mL) under argon; the reaction was then stirred for an additional 55 minutes. A solution of 5-bromo-6-chloropyridine-2-carbonitrile (C28) (8.16 g, 37.5 mmol) in tetrahydrofuran (71 mL) was then added drop-wise and the reaction mixture was stirred for 18 hours. After being quenched with saturated aqueous ammonium chloride solution (200 mL), the mixture was extracted with ethyl acetate (2×400 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (200 mL), dried over magnesium sulfate and concentrated in vacuo to give the crude title compound (9.42 g, quantitative) as an orange solid, which was used in the next step without further purification, as it was found to be unstable on silica gel. LCMS m/z 247.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 3.99 (s, 3H), 4.09 (s, 3H), 7.32 (d, J=7.8 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][P:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19](I)[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[CH:7]([P:8]([O:10][CH2:11][CH3:12])([O:13][CH2:14][CH3:15])=[O:9])[CH2:19][CH3:20])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCI
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Diethylphosphonoacetic acid tert-butyl ester (1.0 g, 4.0 mmol) was dissolved in N,N-dimethylformamide (1.4 mL), and 60% sodium hydride (0.17 g, 4.4 mmol) was added at 0° C. After stirring at room temperature for 30 minutes, the reaction mixture was cooled again to 0° C., ethyl iodide (0.33 mL, 4.1 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 0.5N hydrochloric acid, water and saturated brine, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=57/43) to give the title compound (0.92 g, 3.3 mmol, 83%).