Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH:8]=[O:9])[CH2:6][CH3:7])[CH3:2].[Cl:11][CH2:12][CH2:13]O>C1C=CC=CC=1.S(=O)(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4](=[O:10])[C:5]([CH2:6][CH3:7])=[CH:8][O:9][CH2:13][CH2:12][Cl:11])[CH3:2]
Reactant: OCCCl
Reactant: CCOC(=O)C(C=O)CC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C(=COCCCl)CC
Yield: 83.6 %

Procedure:
28.8 g 2-Formyl-butyric acid ethyl ester was refluxed in 250 ml benzene with 54 g 2-chloroethanol in the presence of 250 mg sodium bisulfate, and the water of reaction formed thereby was withdrawn continuously. Conditions analogous to those in Example 1 were maintained to produce 34.5 g 3-(2-chloroethoxy)-2-ethyl-acrylic acid ethyl ester (84% yield) boiling at 104°-107° C./2 torr. nD23 =1.4719. The compound was hydrogenated as in Example 1, and 3-(2-chloroethoxy)-2-ethylpropionic acid ethyl ester was obtained in a yield of 81.5%. It boiled at 120°-122° C./14 torr, nD27 =1.4352.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[O:26])=[CH:21][C:20]=4[Cl:34])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:35]=1.[C:36]([Cu])#[N:37]>>[Cl:34][C:20]1[CH:21]=[C:22]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])[CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:36]#[N:37])=[CH:35][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN1CCN(C(=O)c2ccc(N(C)C(=O)c3cc4c(s3)-c3ccc(Br)cc3OCC4)c(Cl)c2)CC1
Reactant: N#C[Cu]
Product: CN1CCN(C(=O)c2ccc(N(C)C(=O)c3cc4c(s3)-c3ccc(C#N)cc3OCC4)c(Cl)c2)CC1

Procedure:
Following Examples 53 and 91, 8-bromo-N-(2-chloro-4-(4-methylpiperazine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide and CuCN gave 182. MS: (ESI+) 521.2
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:18])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[N:8]=1.C(O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C.[Fe]>[CH3:17][O:16][C:9]1[CH:10]=[CH:11][C:12]2[NH:13][C:3](=[O:2])[CH:4]([CH3:18])[CH2:5][NH:6][C:7]=2[N:8]=1
Reactant: COC(=O)C(C)CNc1nc(OC)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(n1)NCC(C)C(=O)N2
Temperature: 90 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
To a solution of methyl-3-((6-methoxy-3-nitropyridin-2-yl)amino)-2-methylpropanoate (4.0 g, 14.86 mmol) in anhydrous ethanol (50 mL) was added iron powder reduced (8.30 g, 148.56 mmol) and acetic acid (17.84 g, 297.12 mmol). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was neutralized to pH 8 with solid sodium hydrogencarbonate, concentrated in vacuo and washed with water (20 mL), filtered. The filtrate was extracted with acetic ester (200 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph silica gel (elute: dichloromethane/Methanol: 80:1→50:1) to give 7-methoxy-3-methyl-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-one (3 g, 96%) as a yellow solid.
Reaction SMILES: C(P(CCCC)CCCC)CCC.Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:21][SiH:22]([Cl:24])[Cl:23]>>[Cl:23][Si:22]([Cl:24])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:21]
Reactant: CCCCCCCl
Reactant: C[SiH](Cl)Cl
Agent: CCCCP(CCCC)CCCC
Product: CCCCCC[Si](C)(Cl)Cl
Yield: 16.7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 0.90 g (7.5 mmol) of 1-chlorohexane, and 3.90 ml (37.5 mmol) of methyldichlorosilane were reacted at 150° C. for 12 hrs. The resulting mixture was distilled to give 0.25 g of 2,2-dichloro-2-silaoctane (yield:16%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:14]=[CH:15][C:16]([N+:26]([O-:28])=[O:27])=[C:17]([CH:25]=1)[O:18][C@H:19]1[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20]1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N+:26]([O-:28])=[O:27])=[C:17]([CH:25]=1)[O:18][C@H:19]1[CH2:23][CH2:22][C@H:21]([NH:24][C:1](=[O:3])[CH3:2])[CH2:20]1
Reactant: CC(=O)Cl
Reactant: N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (360 μl) was added at 0° C. to a mixture of (1S,3S)-3-(5-fluoro-2-nitrophenoxy)-cyclopentylamine trifluoroacetate (1.80 g) and DIPEA (4.4 ml) in methylene chloride (150 ml) and stirred at rt for 1 hour. The reaction mixture was diluted with water and the organic layer was dried and concentrated. The crude was triturated with diisopropyl ether to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16]OS(C)(=O)=O)=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)=[N:10]2)=[CH:4][CH:3]=1.[N:33]1([CH2:39][CH2:40][OH:41])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][N:36]3[CH2:37][CH2:38][N:33]([CH2:39][CH2:40][OH:41])[CH2:34][CH2:35]3)=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)=[N:10]2)=[CH:31][CH:32]=1
Reactant: OCCN1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(CCO)CC3)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Yield: 65.1 %

Procedure:
Following the procedure of Example 1(10), 2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-piperazineethanol were reacted to yield the title compound as slightly-yellow needles (yield: 65.1%).
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[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][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]([O:48][CH2:49][CH3:50])(=[O:47])[CH:45]=[CH2:46].[O-]CC.[Na+]>C(O)C>[CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH2:46][CH2:45][C:44]([O:48][CH2:49][CH3:50])=[O:47])[CH2:21]1)[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][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CC(=O)OCC
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CCC(=O)OCC)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Reaction time: 5.5 h
Yield: 91.5 %

Procedure:
Compound 1 (100 mg, 0.167 mmol) obtained in Example 1 was dissolved in ethanol (2 mL), and stirred for 5.5 hours under heat and reflux after adding ethyl acrylate (0.181 mL, 1.67 mmol) and sodium ethoxide (5.7 mg, 0.083 mmol). After cooling the reaction solution, the solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3) to give ethyl 3-((3R,4R)-3,4-bis((9Z,12Z)-octadec-9,12-dienyloxy)pyrrolidin-1-yl)propanoate (107 mg, 91.2%).
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][CH:5]=1)[CH2:2][CH3:3].Br[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1>>[CH2:1]([C:4]1[S:8][C:7](=[NH:9])[N:6]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cnc(N)s1
Reactant: BrCC1CCCO1
Product: CCCc1cn(CC2CCCO2)c(=N)s1

Procedure:
A mixture of 5-propylthiazol-2-amine and 2-(bromomethyl)tetrahydrofuran were processed using the method described in Example 2A to afford the title compound. MS (ESI) m/z 227 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[N+](=[CH2:15])=[N-]>C(OCC)C>[CH3:15][O:11][C:10]([CH:7]1[CH2:8][CH2:9][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6]1)=[O:12]
Reactant: C=[N+]=[N-]
Reactant: CCCC[C@H]1CCC(C(=O)O)C1
Solvent: CCOCC
Product: CCCC[C@H]1CCC(C(=O)OC)C1

Procedure:
A mixture of 84 mg of (1RS,3S)-3-butylcyclopentanecarboxylic acid (prepared in Reference Example 14) and 1.0 ml of a 1M solution of diazomethane in diethyl ether was stirred with cooling. The mixture was concentrated under ambient pressure to give 72 mg of the title compound having the following physical characteristic.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]2[CH2:9][C@H:3]1[C:4](=[O:17])[N:5]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[C:18]([NH:28][C@H:29]([C:34](O)=[O:35])[CH2:30][CH2:31][S:32][CH3:33])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:21]([O:20][C:18]([NH:28][C@@H:29]([CH2:30][CH2:31][S:32][CH3:33])[C:34]([NH:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]2[CH2:9][C@H:3]1[C:4](=[O:17])[N:5]2[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:35])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H]2C[C@H]1C(=O)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Preparation A3, Step 2: A solution of (1R,2S,5R)-tert-butyl 2-amino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.5 g) was dissolved in DMF (34 mL) and cooled to 0° C. prior to the addition of N-Cbz methionine (5.3 g), 4-methyl morpholine (3.7 g), and BOP (8.3 g). The reaction was stirred for 12 h at RT and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford (1R,2S,5R)-tert-butyl 2-((S)-2-(benzyloxycarbonylamino)-4-(methylthio)butanamido)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (5.1 g). MS found: (M+H)+=506.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.C([O-])([O-])=O.[Na+].[Na+]>CCO.CC(O)=O.O.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[C:18]([F:19])([F:20])[F:21])[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(OCc2ccccc2)c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)c(OCc2ccccc2)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
Add 14.1 g (252 mmol) of iron filings to a mixture of 15 g (50.3 mmol) of 2-(benzyloxy)-4-nitro-1-(trifluoromethyl)benzene in 200 mL of EtOH, 10 mL of AcOH and 100 mL of water, then stir the reaction mixture vigorously at 70° C. for 20 minutes. After cooling to RT, slowly add the reaction mixture to a mixture of 300 mL of ether and 1 L of a saturated aqueous solution of Na2CO3. After neutralizing, extract the aqueous phase again with 2×100 mL of ether. Combine the organic phases, wash with 100 mL of water, dry over calcium chloride and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a pentane/EtOAc gradient from 0 to 50% of EtOAc. After concentration under reduced pressure, we obtain 8.1 g of 3-(benzyloxy)-4-(trifluoromethyl)aniline in the form of oil.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1.[C:17]1([CH2:23][CH2:24][NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C(O)CO.N>O.[Cu]I.C(O)(C)C>[CH3:16][C:12]1[CH:11]=[C:10]([NH:25][CH2:24][CH2:23][C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(I)c1
Reactant: NCCC1=CCCCC1
Agent: [Cu]I
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: O
Solvent: OCCO
Product: Cc1cccc(NCCC2=CCCCC2)c1
Temperature: 80 °C
Reaction time: 22 h
Yield: 86.9 %

Procedure:
An oven-dried resealable 15 mL Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), K3PO4 (440 mg, 2.07 mmol), evacuated and backfilled with argon. 3-Iodotoluene (130 μL, 1.01 mmol), 2-(1-cyclohexenyl)ethylamine (170 μL, 1.22 mmol), ethylene glycol (115 μL, 1.97 mmol), and isopropyl alcohol (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred magnetically at 80° C. for 22 h. The resulting thick, green-brown suspension was allowed to reach room temperature, poured into a solution of 30% aq ammonia (1 mL) in water (20 mL), and extracted with 3×15 mL of CH2Cl2. The organic phase was dried (Na2SO4), concentrated, and the residue was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 50:1; 15 mL fractions). Fractions 12–17 provided 189 mg (87% yield) of the product as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.06 (t, J=7.4 Hz, 1H), 6.52 (d, J=7.4 Hz, 1H), 6.46–6.39 (m, 2H), 5.53 (m, 1H), 3.57 (br s, 1H), 3.14 (t, J=6.8 Hz, 2H), 2.30–2.22 (m, 5H), 2.07–1.98 (m, 2H), 1.97–1.90 (m, 2H), 1.67–1.52 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 148.5, 138.9, 134.9, 129.1, 123.5, 118.1, 113.6, 109.9, 41.4, 37.6, 27.8, 25.2, 22.8, 22.4, 21.6. IR (neat, cm−1): 3406, 1603, 1590, 1509, 1492, 1478, 1328, 766, 691. Anal. Calcd. for C15H21N: C, 83.67; H, 9.83. Found: C, 83.82; H, 9.84.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18](=[O:24])[CH:19](Br)[CH2:20][CH2:21][Br:22]>CN(C=O)C>[CH3:16][O:17][C:18](=[O:24])[CH:19]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH2:20][CH2:21][Br:22]
Reactant: COC(=O)C(Br)CCBr
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCBr)Oc1ccc(F)cc1F
Temperature: 60 °C
Yield: 61.6 %

Procedure:
To a solution of 2,4-difluoro phenol (0.35 g, 2.73 mmol) in DMF (5 ml), added potassium carbonate (0.38 g, 2.73 mmol) and 2,4-Dibromo-butyric acid methyl ester (0.71 g, 2.74 mmol) and heated at 60° C. for 3 h. Reaction mixture was cooled to r.t. It was then extracted in EtOAc (30 ml) and washed with brine (2×10 ml), dried over Na2SO4 and concentrated under reduced pressure to obtain crude product, purification on silica gel to yield 4-Bromo-2-(2,4-difluoro-phenoxy)-butyric acid methyl ester (0.52 g, 61%). 1H NMR (400 MHz, CDCl3): δ 12.42-2.56 (m, 2H), 3.53-3.71 (m, 2H), 3.77 (s, 3H), 4.81 (dd, J=3.6 and 8.8 Hz, 1H), 6.72-6.80 (m, 1H), 6.85-6.90 (m, 1H), 6.95-7.02 (m, 1H).
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[C:11]([O:10][C:9](=[O:15])[NH:8][C@H:3]([C:2](=[S:26])[NH2:1])[CH2:4][CH:5]([CH3:7])[CH3:6])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(N)=S
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 140 %

Procedure:
A mixture of (S)-tert-butyl 1-amino-4-methyl-1-oxopentan-2-ylcarbamate (1.8 g, 8 mmol) and Lawesson's reagent (1.58 g, 4 mmol) in toluene (20 mL) was stirred at 90° C. for 2.5 h. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, 30 g, ethyl acetate/MeOH, 20/1) to yield the title compound (1.38 g, 72%) as yellow solid; MS: m/e 269.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1.[Br:22][C:23]1[N:28]=[C:27]([C:29](O)=[O:30])[C:26]([F:32])=[CH:25][CH:24]=1>>[Br:22][C:23]1[N:28]=[C:27]([C:29]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]2)=[O:30])[C:26]([F:32])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Reactant: O=C(O)c1nc(Br)ccc1F
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc(Br)ccc2F)C1

Procedure:
Following Method 11 (Example 305), (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate was coupled to 6-bromo-3-fluoropicolinic acid yielding (S)-tert-butyl 1-(3-(6-bromo-3-fluoropicolinamido)pyridin-4-yl)piperidin-3-ylcarbamate which was used directly as is. LCMS (m/z): 496.2 (MH+); LC Rt=2.71 min.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+].[Br:21][C:22]([F:31])([F:30])[C:23](Br)([F:28])[C:24]([F:27])([F:26])[F:25].C(=O)([O-])[O-].[Na+].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C.O>[Br:21][C:22]([F:31])([F:30])[C:23]([C:13]1[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=1)([F:28])[C:24]([F:27])([F:26])[F:25]
Reactant: FC(F)(F)C(F)(Br)C(F)(F)Br
Reactant: Nc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COC(C)(C)C
Solvent: O
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
First 476.74 g (2.74 mol) of sodium dithionite and then 250 g (2.68 mol) of aniline were added at room temperature to a mixture of 4000 ml of water, 1200 ml of tert-butyl methyl ether, 270.61 g (3.22 mol) of sodium hydrogencarbonate and 10.94 g of tetra-n-butylammonium hydrogensulphate. Subsequently, a solution of 998.07 g of 1,2-dibromo-1,1,2,3,3,3-hexafluoropropane in 300 ml of tert-butyl methyl ether was added dropwise at 35–40° C. and, on completion of addition, the mixture was stirred at RT for a further 18 h. If necessary, sodium carbonate was used to adjust to a pH of 5 and the organic phase was removed, dried and concentrated. The remaining residue is incipiently distilled under reduced pressure at 0.3 mbar up to an internal temperature of 100° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].C(N(C(C)C)CC)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)CC>[F:10][C:4]1[CH:3]=[C:2](/[CH:35]=[CH:34]/[C:33]([O:37][CH2:38][CH3:39])=[O:36])[CH:7]=[C:6]([OH:8])[C:5]=1[F:9]
Reactant: C=CC(=O)OCC
Reactant: Oc1cc(Br)cc(F)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCOC(=O)/C=C/c1cc(O)c(F)c(F)c1
Temperature: 25 °C

Procedure:
A second 1 L round-bottomed flask was charged with a stir bar, 5-bromo-2,3-difluorophenol (50.2 g, 240 mmol) and propionitrile (460 mL). The solution was deoxygenated by bubbling nitrogen for 15 minutes. To this solution was added Pd(OAc)2 (5.42 g, 24.1 mmol), P(O-tol)3 (29.3 g, 96.1 mmol), ethyl acrylate (52 mL, 480 mmol) and diisopropylethylamine (167 mL, 959 mmol) sequentially. The flask was immersed into a preheated (120° C.) oil bath. The reaction was heated at this temperature for 22 h. Upon cooling to room temperature, the reaction mixture was filtered through a Celite-plugged filter frit, washed with CH2Cl2, and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9]C#N)=[CH:5][CH:4]=1.Cl.O.[C:16](=[O:19])([O-])[O-:17].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][C:16]([OH:17])=[O:19])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(OCCC#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(OCCC(=O)O)cc1
Temperature: 100 °C
Yield: 86.04 %

Procedure:
A 945 g (5.34 mol, 1 eq.) sample of 1 (3-(4-methoxyphenoxy)propionitrile (1)) was charged to a 22 L round bottom flask equipped with an overhead stirrer under N2. To the stirred solids, 4 L of concentrated HCl was slowly added, followed by 2 L of H2O. The reaction mixture was heated to 100° C. for 3.5 h, at which point the reaction was complete by HPLC analysis. The reaction was cooled to 10° C. by the addition of ice to the reaction mixture, and was filtered. The dried solids gave 920 g of crude 2. The crude material was dissolved in 5 L of 6 wt. % sodium carbonate (such that pH=9), and 2 L of DCM (dichloromethane) was added to the reaction vessel. After stirring thoroughly, the organic layer was separated and discarded via a separatory funnel, and the aqueous layer charged back into the 22 L flask. The pH of the aqueous layer was carefully adjusted to 4.0, by slow addition of 6 M HCl. The precipitated solids were filtered, and dried in a vacuum oven to give 900 g of 2 as a white solid (Yield: 86.04%). 1H NMR (450 MHz, CDCl3); δ=2.78 (t, 2H; CH2COOH); 3.70 (s, 3H; OCH3); 4.18 (t, 2H; OCH2); 6.78 (m, 4H; Ar—H); 13C NMR (112.5 MHz, CDCl3): δ=34.703 (CH2COOH); 55.925 (OCH3); 64.088 (OCH2); 114.855 (CH3OCCH); 115.984 (CH2OCCH); 152.723 (CH3OC); 154.302 (CH2OC); 177.386 (COOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([F:26])([F:25])[F:24])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[C:15](O)=[O:16])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([F:26])([F:24])[F:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][CH:19]3[CH2:20][CH2:21]3)[C:15]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=3)=[O:16])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: O=C(O)C(CC1CC1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(NC(=O)C(CC2CC2)n2ccc(-c3cc(Cl)ccc3C(F)(F)F)cc2=O)cc1

Procedure:
105 mg (purity 94%, 0.26 mmol) of 2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoic acid (racemate) and 1.1 eq. of methyl 4-aminobenzoate were reacted according to General Method 5A. After aqueous work-up, the crude product was reacted further without further purification. Yield: 200 mg (purity 48%, 72% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([CH3:19])=[C:17]3[C:12]([C:13]([CH3:21])=[N:14][N:15]=[C:16]3[CH3:20])=[C:11]2[CH3:22])=[CH:6][C:5]=1[CH2:23][OH:24])[CH3:2]>O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11]([CH3:22])=[C:12]3[C:17]([C:16]([CH3:20])=[N:15][N:14]=[C:13]3[CH3:21])=[C:18]2[CH3:19])=[CH:6][C:5]=1[CH:23]=[O:24])[CH3:2]
Reactant: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)cc1CO
Agent: O=[Mn]=O
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)cc1C=O

Procedure:
Utilizing the general procedure outlined in Example 82, [5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenyl]-methanol (prepared as described in Example 81; 100 mg, 0.3 mmol) reacted with MnO2 (200 mg, excess) to afford 2-ethoxy-5-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-benzaldehyde as a yellow solid: 1H NMR (CDCl3, 500 MHz) δ 9.20 (s, 1H), 7.57 (s, 1H), 7.34 (d, 1H), 7.24 (d, 1H), 4.20 (q, 2H), 2.90 (s, 6H), 2.42 (s, 6H), 1.51 (t, 3H); MS (ESI) 324 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].C(O)C.Cl[C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:12]1[CH:13]=[CH:14][N:15]=[CH:16][C:11]=1[C:22]1[CH:23]=[CH:24][C:19]([CH:17]=[O:18])=[CH:20][CH:21]=1
Reactant: Clc1cnccn1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2cnccn2)cc1
Yield: 42.2 %

Procedure:
1 M aq. Na2CO3 (20 mL) and ethanol (10 mL) were added to a solution 15 of 2-chloropyrazine (2.30 g, 20.06 mmol), 4-formylphenylboronic acid (3.90 g, 26.01 mmol) and [1,4-bis(diphenylphosphino)butane]palladium(II) dichloride (0.60 g, 0.99 mmol) in toluene (40 mL) and the mixture was heated to reflux for 18 h. The cooled reaction mixture was diluted with ethyl acetate, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 1.56 g (42%) of 4-pyrazinylbenzaldehyde.