Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.O1CCCC1.[CH3:7][O:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=O)[N:18]([CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CO>[CH3:7][O:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CCCCCCCC(=O)N(C)c1ccccc1
Agent: B
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCCCCCCCN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
Borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 3.09 mL, 3.09 mmol) was added at 0° C. to a solution of 8-(methyl-phenyl-carbamoyl)-octanoic acid methyl ester (300 mg, 1.03 mmol) in tetrahydrofuran (20 mL) The reaction mixture was stirred at room temperature overnight. A further aliquot of borane-tetrahydrofuran complex (2.1 mL, 2.1 mmol) was added and the reaction mixture was stirred at room temperature for 3.5 hours. Methanol (60 mL) was added followed by concentrated sulfuric acid. The reaction mixture was refluxed at 80° C. for 2 hours. After cooling to room temperature, saturated sodium carbonate was added and the reaction mixture was extracted 3 times with dichloromethane. The combined organic layers were dried over sodium sulfphate, filtered and the solvent was removed in vacuo. The crude product was purified by chromatography (SiO2; heptane-ethyl acetate gradient) to afford 9-(methyl-phenyl-amino)-nonanoic acid methyl ester (89 mg, 31%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])[CH3:6].[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>C(=S)=S>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[CH:10][CH:11]=1)(=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)Cl
Reactant: CC(=O)Nc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1290 g of aluminium chloride (9.6 mole) were suspended with stirring in 1500 ml of carbon disulphide. 405 g of acetanilide (3 moles) were added slowly to this suspension, while the temperature was kept at 25° C. The reaction mixture was heated until reflux and was cooled immediately to 25° C. 565 ml of propionyl chloride (6.5 moles) were added dropwise in such a way that the temperature was kept at 25° C. The reaction mixture was heated until reflux for 5 hours and kept overnight at ambient temperature (20° C.). The supernatant carbon disulphide layer was decanted and the remaining viscous mixture was poured in a mixture of ice and hydrochloric acid. The residue formed was filtered off and further recrystallized from a mixture of 1500 ml of ethanol and 75 ml of water. Drying was applied under vacuum at 100° C. A light yellow powder was obtained.
Reaction SMILES: [C:1]([N:4]([C:40]1[C:45]([I:46])=[C:44]([C:47](=[O:57])[NH:48][CH2:49][CH:50]2[CH2:54][O:53]C(C)(C)[O:51]2)[C:43]([I:58])=[C:42]([C:59](=[O:69])[NH:60][CH2:61][CH:62]2[CH2:66][O:65]C(C)(C)[O:63]2)[C:41]=1[I:70])[CH2:5][CH:6]([OH:39])[CH2:7][NH:8][C:9]([C:11]1[C:12]([I:38])=[C:13]([NH:30][C:31](COC(=O)C)=[O:32])[C:14]([I:29])=[C:15]([C:18](=[O:28])[NH:19][CH2:20][CH:21]2[CH2:25][O:24]C(C)(C)[O:22]2)[C:16]=1[I:17])=[O:10])(=[O:3])[CH3:2]>CO>[OH:32][CH2:31][NH:30][C:13]1[C:12]([I:38])=[C:11]([C:16]([I:17])=[C:15]([C:18]([NH:19][CH2:20][CH:21]([OH:22])[CH2:25][OH:24])=[O:28])[C:14]=1[I:29])[C:9]([NH:8][CH2:7][CH:6]([OH:39])[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[C:40]1[C:45]([I:46])=[C:44]([C:47]([NH:48][CH2:49][CH:50]([OH:51])[CH2:54][OH:53])=[O:57])[C:43]([I:58])=[C:42]([C:41]=1[I:70])[C:59]([NH:60][CH2:61][CH:62]([OH:63])[CH2:66][OH:65])=[O:69])=[O:10]
Reactant: CC(=O)OCC(=O)Nc1c(I)c(C(=O)NCC(O)CN(C(C)=O)c2c(I)c(C(=O)NCC3COC(C)(C)O3)c(I)c(C(=O)NCC3COC(C)(C)O3)c2I)c(I)c(C(=O)NCC2COC(C)(C)O2)c1I
Solvent: CO
Product: CC(=O)N(CC(O)CNC(=O)c1c(I)c(NCO)c(I)c(C(=O)NCC(O)CO)c1I)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I

Procedure:
Acetic acid {3-[3-(acetyl-{3,5-bis-[(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-carbamoyl]-2,4,6-triiodo-phenyl}-amino)-2-hydroxy-propylcarbamoyl]-5-[(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-carbamoyl]-2,4,6-triiodo-phenylcarbamoyl}-methyl ester (1.2 g, 725 μmol) was refluxed in MeOH/2M HCl (1:1, 5 mL:5 mL) for 1 hour. The reaction was then concentrated to dryness and the crude material purified by R-HPLC to give the desired product.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1([CH3:20])[O:13][C:12]2=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:11]2[CH2:10]1)(=O)=O.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C.[I-].[K+]>CN(C=O)C>[CH3:20][C:9]1([CH2:8][CH2:7][CH2:6][N:24]2[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]2)[O:13][C:12]2=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:11]2[CH2:10]1
Reactant: CC1(CCCOS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)propyl methane-sulfonate (2 g, 6.6 mmol), tert-butyl piperazine-1-carboxylate (1.4 g, 7.5 mmol), triethylamine (1.3 g, 12.85 mmol), potassium iodide (1.8 g, 10.8 mmol) and DMF (15 ml) was stirred at 60° C. overnight. The reaction mixture was allowed to return to room temperature and then added water, and the resulting solution was extracted with ethyl acetate three times. The organic phases were combined, washed with water twice and then with a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford tert-butyl 4-[3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)propyl]piperazine-1-carboxylate (1.9 g, yield 73%) as a white powder.
Reaction SMILES: [S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[F:6][C@@H:7]1[CH2:11][N:10]([C:12](=[O:26])[CH2:13][NH:14][C@@H:15]2[CH2:19][CH2:18][C@H:17]([CH2:20][N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)[CH2:16]2)[C@H:9]([C:27]#[N:28])[CH2:8]1.CO>C(OCC)(=O)C>[S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[F:6][CH:7]1[CH2:11][N:10]2[C:12](=[O:26])[CH2:13][N:14]([CH:15]3[CH2:19][CH2:18][CH:17]([CH2:20][N:21]4[CH:25]=[N:24][CH:23]=[N:22]4)[CH2:16]3)[C:27](=[NH:28])[CH:9]2[CH2:8]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN[C@@H]1CC[C@H](Cn2cncn2)C1
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: N=C1C2CC(F)CN2C(=O)CN1C1CCC(Cn2cncn2)C1
Temperature: 27.5 °C

Procedure:
(2S,4S)-4-fluoro-1-({[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)-cyclopentyl]amino}acetyl)pyrrolidine-2-carbonitrile mesylate salt was melted at 150-160° C. for 3 to 4 h and the residue was cooled to 25-30° C. To this, a mixture of methanol (100 ml, 2 vol.) and ethyl acetate (250 ml, 5 vol.) was added and heated at 50-55° C. The reaction mixture on cooling to 25-30° C. precipitates 7-fluoro-1-imino-2-[(3S,1R)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentyl]-perhydroazolo[1,2-a]pyrazin-4-one mesylate. 1H NMR (300 MHz, DMSO-d6) δ 1.52-1.88 (m, 6H), 2.21-2.40 (m, 5H), 2.77-2.80 (m, 1H), 3.52-3.83 (m, 2H), 3.95-4.00 (d, 1H), 4.18-4.25 (m, 3H), 4.42 (m, 1H), 4.85 (m, 1H), 5.39-5.56 (d, 1H), 7.98 (s, 1H), 8.54 (s, 1H), 9.17 (s, 2H); ESI-MS (m/z) 321 (100%); 13C NMR (300 MHz, DMSO-d6) δ 27.00, 26.71, 32.04, 35.81, 32.54, 37.74, 39.97, 47.06, 51.85, 51.54, 52.80, 56.02, 57.73, 92.12, 89.82, 144.14, 151.43, 161.74, 162.12.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cccc(F)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, grey solid (61 mg, 76%), MS (ISP) m/z=320.5 [(M+H)+], mp 226° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: O[C:2]1([CH3:29])[CH:26]=[C:25]2[C@:20]([CH3:27])([CH2:21][CH2:22][CH2:23][CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1.CC(C)[O-:32].[Al+3].CC(C)[O-].CC(C)[O-].CC(=O)CC.N#N>C1(C)C=CC=CC=1>[CH3:29][C:2]1[C@@H:3]2[C@@H:19]([C@:20]3([CH3:27])[C:25]([CH:26]=1)=[CH:24][C:23](=[O:32])[CH2:22][CH2:21]3)[CH2:18][CH2:17][C@@:16]1([CH3:28])[C@H:4]2[CH2:5][CH2:6][C@@H:7]1[C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CCCCC1=CC3(C)O
Reactant: CC(C)[O-]
Agent: N#N
Agent: [Al+3]
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(C)=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 89.2 %

Procedure:
A mixture of methyl 7-hydroxy-7-methylchol-5-en-24-oate (8) (2.0 g, 4.78 mmoles), aluminum isopropoxide (1.17 g, 5.72 mmoles), 2-butanone (8.6 ml, 96 mmoles) in toluene (40 ml) was heated at 80° in a N2 atmosphere for 6 hrs. About 15 ml of solvent was distilled from the reaction mixture at atmospheric pressure. Toluene (30 ml) was added, and the mixture was extracted with 3N HCl (2 times), H2O (3 times) and dried with MgSO4. Evaporation in vacuo gave 1.7 g of an orange oil that was purified by flash chromatography on silica gel with hexane-EtOAc (7:2 and 2:1 ) to give 0.62 g of pure 9 as a colorless syrup. NMR (CDCl3): δ0.76 (s, 3H, 18-Me); 0.94 (d, 3H, 20-Me); 1.08 (s, 3H, 19-Me); 3.67 (s, 3H, CO2Me); 5.59 (s, 1H, 4H); 5.95 (s, 1H, 6-H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5](=[O:37])[C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C(OCC)(=O)C.O>CC(C)=O.OS(O)(=O)=O>[CH:2]([C:3]1[CH2:4][S:5](=[O:37])[C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[O:1]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS(=O)[C@H]12
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S(=O)C1
Yield: 39.4 %

Procedure:
As described in Belgian Patent 770,531, to a solution of 1.80 g (3.4 mmole) of benzhydryl 3-hydroxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide in 100 ml of acetone at 0° was added over the period of 2 min. 0.90 ml of 8N CrO3 in H2SO4 and the mixture was stirred at 0° for 5 min., then poured into a mixture of 300 ml ethyl acetate and 300 ml of water and the ethyl acetate layer was washed with water, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica with CHCl3 to yield 0.716 g of benzhydryl 3-formyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide after crystallization from methanol; uv max (C2H5OH): 269 nm (4600), 292 nm (4300), and 355 nm (1760); nmr (dmso-d6): 3.75 and 4.32 (AB, 2 (JAB = 19 Hz), C2 -CH2), 3.88 (s, 2, α-thienyl CH2), 5.08 (d, 1 (J = 5 Hz), C6 -H), 6.18 (dd, 1 (J = 5 Hz, J' = 8.5 Hz), C -H), 7.17 (1, s, -CO2CH Ph2), 7.02 (d, 2 (J = 3.0 Hz), thiophene 3- and 5-H), 7.44 (10, s, phenyl-H), 8.72 (d, 1 (J = 8.5 Hz), amide N-H), and 9.85 (s, 1, aldehyde-H).
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]=[C:13]=[S:14]>C(O)C>[C:2]([NH:3][C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[Cl:5])=[S:14])#[N:1]
Reactant: S=C=Nc1ccccc1Cl
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
The suspension of monosodium cyanamide (1.9 g, 29.4 mmol) in absolute ethanol (50 mL) was slowly treated with 2-chlorophenylisothiocyanate (5.0 g, 29.4 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (6.0 g), m.p. 253°-255° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:25](=[O:26])[N:24]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[N:23]=[CH:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:25](=[O:26])[N:24]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[N:23]=[CH:22]4)=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CCC(CC)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Agent: Br
Product: CCC(CC)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Yield: 98 %

Procedure:
This compound was synthesized as a white amorphous solid from 4j (41.5 mg, 0.099 mmol) in 48% aqueous HBr (1.0 mL) in 98% yield by following general procedure 1.4: 1H NMR (400 MHz, CDCl3, δH) 7.64 (s, 1H), 7.40 (d, J=8.9 Hz, 2H), 7.04-6.92 (m, 4H), 6.72 (d, J=8.5 Hz, 2H), 4.15-3.97 (m, 1H), 3.42-3.31 (m, 4H), 3.29-3.18 (m, 4H), 1.95-1.62 (m, 4H), 0.89 (t, J=7.4 Hz, 6H); 13C NMR (100 MHz, CDCl3, δC) 153.31, 151.93, 150.78, 143.66, 134.54, 125.92, 124.36, 119.46, 116.94, 116.36, 59.27, 51.82, 49.09, 26.99, 10.97. MALDI-MS: 408.2 (M+H+), 430.2 (M+Na+).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=1
Reactant: CCOc1cc(Cl)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CCOc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-ethoxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, DMSO-d6): δ 1.42 (3H, t, J=6.8 Hz), 4.09 (2H, q, J=6.8 Hz), 5.23 (2H, s), 5.79 (1H, d, J=1.6 Hz), 6.90 (1H, dd, J=2.0 Hz, 8.0 Hz), 6.95 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.34 (1H, d, J=8.0 Hz), 7.39 (1H, m), 7.57 (1H, d, J=2.0 Hz), 8.05 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd for C18H15ClN4O2, 355; Found, 355.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(Cl)Cl.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>[NH2:31][C:30]1[CH:32]=[CH:33][C:27]([C:2]2[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])[N:3]=2)=[CH:28][CH:29]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)O)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: C[C@H]1COCCN1c1cc(C(C)(C)O)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 60.4 %

Procedure:
Dichlorobis(triphenylphosphine)palladium(II) (0.492 g, 0.70 mmol) was added to 2-[2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]propan-2-ol (3.81 g, 14.02 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.38 g, 15.42 mmol) and sodium carbonate (4.46 g, 42.06 mmol) in DME (80 mL) and water (20.00 mL) under nitrogen. The resulting solution was stirred at 80° C. for 6 hours. The reaction mixture was diluted with DCM (200 mL), and washed with water (400 mL) twice. The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% ethyl acetate in isohexane, to give a material which was further purified by ion exchange chromatography using an SCX column, eluting with 2M ammonia in methanol, to give the desired material as a pink gum (2.78 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(O)[CH3:7])[CH3:2].[I-].[K+].P(=O)(O)(O)O>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: O=P(O)(O)O
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)CC(C)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A mixture of 32 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester, 8.7 g. of potassium iodide, 5.2 of red phosphorus and 45 ml. of 85% phosphoric acid is stirred and heated to 130° for 7 hours. It is worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].C([O-])=O.[NH4+]>CCOC(C)=O.CO.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:28])=[O:29]
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccncn2)c1Cl)c1c(F)cccc1F
Temperature: 60 °C
Yield: 40.6 %

Procedure:
To a solution of N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.15 g, 0.26 mmol) and ammonium formate (0.17 g, 2.6 mmol) in EtOAc (7 mL) and MeOH (7 mL) was added 20% palladium hydroxide on carbon (0.17 g, 0.24 mmol). The reaction mixture was heated to 60° C. for 2 h. The palladium was filtered off using a nylon membrane. The filtrate was concentrated under vacuum to a crude yellow solid. The residue was purified by silica gel chromatography eluting 0-100% EtOAC/hexanes. The resulting solid was dissolved in DCM (5 mL) and hexanes added to afford the title compound as a pale yellow solid (58 mg, 38.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, 1H), 9.11 (d, J=1.3 Hz, 1H), 8.57 (d, J=5.4 Hz, 1H), 7.60-7.73 (m, 1H), 7.52-7.55 (m, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.41-7.45 (m, 1H), 7.20 (t, J=9.1 Hz, 2H), 6.56 (dd, J=5.4, 1.3 Hz, 1H), 3.92 (ddd, J=9.6, 2.0, 1.9 Hz, 2H), 3.46 (td, J=11.6, 1.9 Hz, 2H), 2.00 (dd, J=12.8, 1.9 Hz, 2H), 1.68-1.80 (m, 2H), Note: The methine (—H) peak of the THP (tetrahydro-2H-pyran-4-yl) group is submerged under the water peak at 3.33 ppm causing broadening. MS (ESI) 549.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.BrC[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C.O>[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:5][CH2:4][C:3]([OH:11])=[O:10])([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1ccccc1[N+](=O)[O-]
Reaction time: 0.05 h
Yield: 56.9 %

Procedure:
Sodium hydride (60% in paraffin oil, 1.0 g, 25 mmol) was added to a solution of diethyl malonate (3.2 g, 20 mmol) in DMF (20 ml) and the mixture was stirred for 3 min. 1-Bromomethyl-2-nitrobenzene (4.3 g, 20 mmol) was then added in portions during 5 min. The reaction mixture was stirred for 3 h, diluted with water, and extracted twice with ethyl acetate. The combined organic phases was washed with water and evaporated. The residue was suspended in acetic acid (40 ml) and 7.5 M HCl (10 ml) was added. The mixture was refluxed for 19 h, cooled and partitioned between diethyl ether and saturated aqueous NaHCO3. The organic phase was washed with saturated aqueous NaHCO3 and then acidified with 2M HCl. The precipitate was collected by filtration and dried to give the title compound (2.22 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:32][S:33]([O:22][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:35])=[O:34]
Reactant: OC(c1ccc(F)cc1)C(c1cccnc1)c1cccnc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OC(c1ccc(F)cc1)C(c1cccnc1)c1cccnc1
Reaction time: 10 h

Procedure:
To the solution of 1-(4-fluorophenyl)-2,2-dipyridin-3-ylethanol (0.2 g, 0.68 mmol) in THF (4 mL) was added i-Pr2NEt (0.4 mL, 2.3 mmol) at 0° C. followed by methanesulfonyl chloride (0.1 mL, 1.3 mmol). The reaction mixture was stirred for 10 h. Diluted with saturated NaHCO3 and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give 1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl methanesulfonate. LRMS m/z (M+H) Calcd: 373.4. found: 373.0.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([CH:19]([CH3:21])[CH3:20])[NH:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[S:13][CH:14]=1)=[O:7].O.[OH-].[Li+].C1COCC1.Cl>O>[CH3:18][N:8]([C:6]([NH:5][C@H:4]([C:3]([OH:22])=[O:2])[CH:19]([CH3:20])[CH3:21])=[O:7])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[S:13][CH:14]=1
Reactant: COC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reaction time: 2 h

Procedure:
To a one liter three neck flask was charged the product of Example 73C (50 g, 0.153 mol), lithium hydroxide monohydrate (13 g, 0.310 mol), 200 ml THF and 190 ml water. This hazy solution was stirred for 2 hours. The reaction was quenched with a solution of conc. HCl (32.4 g, 0.329 mol) in 65 mL water, the THF was removed under vacuum and the product extracted into methylene chloride (3×210 ml). (NOTE: If necessary, the pH of the aqueous layer should be adjusted to maintain pH 1-4 during the extractions.) The combined organics were then dried with 50 g sodium sulfate, filtered with a 150 ml methylene chloride rinse of the sodium sulfate, and the solvent was removed under vacuum. The product was dissolved in 450 ml THF and again the solvent was removed. Next the product was dissolved in 475 ml THF containing 0.12 g butylated hydroxytoluene (BHT) for storage. If desired, the solvent can be removed under vacuum and the residual syrup added in a vacuum oven at 55° C. to provide a glassy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]=[C:10]([O:16]C)[CH:9]=2)[CH:7]=1.Cl.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][NH:11][C:10](=[O:16])[CH:9]=2)[CH:7]=1
Reactant: COc1cc(-c2cc(Cl)ccc2[N+](=O)[O-])c(OC)cn1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
124 mg (purity 93%, 0.39 mmol) of 4-(5-chloro-2-nitrophenyl)-2,5-dimethoxypyridine and pyridinium hydrochloride were reacted according to General Method 3A. Yield: 115 mg (purity 85%, 89% of theory)