Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C1N2CN3CN(C2)CN1C3.O.S(=O)(=O)(O)[OH:23]>C(O)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:23])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=S(=O)(O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc(C=O)cc1
Yield: 78.5 %

Procedure:
56.2 g of p-cyanobenzylamine, 59.6 g of hexamethylenetetramine, 46 ml of water, 320 ml of acetic acid and 46.0 g of 98% sulfuric acid were mixed and reacted at 100° C. for 2 hours while stirring. The reaction solution was concentrated to about a half amount in an evaporator and 400 ml of water was added to precipitate crystals. The crystals precipitated were collected by filtration, washed with water and dried to obtain 43.8 g (yield: 78%) of p-cyanobenzaldehyde. The purity was 99.8% or more.
Reaction SMILES: [OH:1][CH:2]([CH3:10])[CH2:3][NH:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7].ClC(Cl)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(N(CC)CC)C>[Cl:15][CH2:16][C:17]([O:1][CH:2]([CH3:10])[CH2:3][NH:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: C=C(C)C(=O)NCC(C)O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCC(C)OC(=O)CCl

Procedure:
The compound was prepared by the method described in Example 7, using N-(2-hydroxypropyl)methacrylamide (14.3 g), dichloroethane (200 ml), chloroacetyl chloride (11.3 g) and triethylamine (10.1 g). The product distilled at 112° C./0.1 mm (12 g) and was obtained as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.Br[CH:10]1[C:15](=O)[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]1>C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][N:3]2[C:10]3[CH2:11][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:14][C:15]=3[N:1]=[C:2]2[CH:7]=1
Reactant: Nc1cc(Br)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2nc3cc(Br)ccn3c2C1
Temperature: 105 °C
Yield: 31.9 %

Procedure:
2-Amino-4-bromopyridine (786 mg, 4.55 mmol) and tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (1.39 g, 5.00 mmol) were combined in toluene (20 mL) and heated at 105° C. for 16 h. The mixture was concentrated and purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 40 mL/min) to provide the title compound (512 mg, 32%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.93 (s, 1H), 7.46 (d, J=9.1 Hz, 1H), 7.22 (d, J=9.1 Hz, 1H), 4.69 (br s, 2H), 3.85 (br s, 2H), 2.93 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]([NH:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:21])[C:10]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[C:10]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNC(=O)c1c(O)c2ccccc2n(OCc2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1c(O)c2ccccc2n(OCc2ccccc2)c1=O
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirring solution of ethyl 2-(1-(benzyloxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (500 mg, 1.261 mmol) in THF (5 mL) was added solution of sodium hydroxide (126 mg, 3.15 mmol) in water (5 mL) and stirred at 25-30° C. for 2 h. Organic solvent was distilled out followed by addition of ice cold water. Reaction mixture was then acidified using dil. HCl up to pH-2-3. Precipitated solid was filtered to get titled compound in 80% yield.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH:19]([C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=O.S([O-])(O)(=O)=O.[K+]>CN(C=O)C>[C:13]([O:12][C:10](/[CH:9]=[CH:19]/[C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:36][CH:37]=2)[CH2:23][CH2:22]1)=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: CCOC(=O)c1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([C@H]2CC[C@H](/C=C/C(=O)OC(C)(C)C)CC2)cc1

Procedure:
0.682 g of tert-butyl diethylphosphonoacetate (2.7 mmol, 1.1 eq.) is placed in 5 mL of DMF at 4° C. with stirring, 0.065 g of sodium hydride (2.7 mmol, 1.1 eq.) is added. After stirring for 1 hour, 0.64 g of ethyl trans-4-(4-formylcyclohexyl)benzoate (2.46 mmol, 1 eq.) dissolved in 5 mL of DMF is added dropwise. After stirring for 18 hours, 10% potassium hydrogen sulfate solution is added. The reaction medium is extracted twice with ethyl acetate. The organic phases are combined, washed twice with water, washed with brine, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel with a gradient of ethyl acetate in heptane ranging from 10% to 20%. 0.71 g of ethyl trans-4-[4-((E)-2-tert-butoxycarbonylvinyl)cyclohexyl]benzoate is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)Cl.CCOCC>[O:1]=[CH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CCCO)cc1
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CCC=O)cc1
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl 4′-(3-hydroxypropyl)biphenyl-2-carboxylate (7.00 g, 22.4 mmol) in CH2Cl2 (200 mL) at 0° C. was added trichloroisocyanuric acid (5.47 g, 23.5 mmol) and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (35 mg, 0.224 mmol). After stirring at it for 20 min, the reaction mixture was diluted with Et2O (200 mL) and filtered through a silica gel pad, rinsing with Et2O (400 mL). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (5-75% EtOAc in Hexanes) to afford the title compound.
Reaction SMILES: N1C=C[CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.Cl.BrC1C=C[N:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[N:20]1[CH:4]=[CH:3][C:2]([C:7]2[CH:8]=[CH:9][C:10]([CH:11]=[O:12])=[CH:13][CH:14]=2)=[CH:18][CH:19]=1
Reactant: Brc1ccncc1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2ccncc2)cc1

Procedure:
This aldehyde was prepared using the procedure for 4-pyridin-2-yl-benzaldehyde in Example 126 from 4-bromopyridine hydrochloride, triethylamine and 4-formylboronic acid to give a yellow crystalline solid (51%): mp=90-91° C.; Rf=0.08 (30% EtOAc/hexanes); IR (KBr) 1697, 1595, 1214, 1169, 801 cm−1; 1H NMR (CDCl3) δ 7.74 (d, 2H, J=5.8 Hz), 7.84 (d, 2H, J=8.3 Hz), 8.05 (d, 2H, J=8.1 Hz), 8.77-8.78 (m, 2H), 10.11 (s, 1H). LRMS 184 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[I:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:12]([CH3:13])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(I)cc1C(=O)O
Product: Cc1nc2ccc(I)cc2c(=O)o1
Yield: 90 %

Procedure:
2-Amino-5-iodobenzoic acid (25.4 g, 96.6 mmol) was added in portions to cold acetic anhydride (100 mL). The suspension was first stirred without cooling, then the resulting thick precipitate was heated at reflux for 1 h (red solution). The product crystallized spontaneously upon cooling. After stirring in ice for 30 min, the crystals were filtered off and washed twice with heptane. The crystals were thoroughly dried at 0.1 mbar/50° C. One obtained 25.1 g (90%) of beige crystals. MS: m/z=287 (M).
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:15](OCC)(OCC)OCC>>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:8]2[C:3]3[N:4]([CH:15]=[N:2][N:1]=3)[CH:5]=[CH:6][CH:7]=2)[CH:10]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1ncccc1-c1cccnc1
Product: c1cncc(-c2cccn3cnnc23)c1
Temperature: 100 °C

Procedure:
A mixture of 4.15 g of 2-hydrazino-3,3'-bipyridine and 30 ml of triethyl orthoformate was heated at 100° C. for 2 hours. The volatiles were removed under vacuum and the residue placed on a short pad of hydrous magnesium silicate and eluted with ethyl acetate. The product was eluted with methanol. The methanol was removed under vacuum, the residue dissolved in methylene chloride, dried and the methylene chloride boiled off while hexane was added. Chilling and filtration gave 2.67 g of off-white crystals of the desired product, mp 186°-189° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1)(=[O:12])=[O:11].[H-].[Na+].CS(O[CH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)(=O)=O>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:14]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cccc(CO)c2)c(C)c1
Reactant: CS(=O)(=O)OCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cccc(COCC3CCOCC3)c2)c(C)c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
N-(2,4-dimethylphenyl)-3-(hydroxymethyl)-N-isobutylbenzenesulfonamide (40 mg, 0.115 mmol) and sodium hydride (4.14 mg, 0.173 mmol) were dissolved in anhydrous N,N-dimethylformamide (DMF) (3 mL). The solution was stirred for 10 minutes under nitrogen at 20° C. (Tetrahydro-2H-pyran-4-yl)methyl methanesulfonate (49 mg, 0.252 mmol) was added to the solution, which was stirred overnight at 20° C. under nitrogen. The reaction was concentrated under vacuum (Biotage V10) to give the crude product. This was then partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with water (5×5 mL), passed through a hydrophobic frit and concentrated in vacuo. The crude product was then dissolved in a minimum of DCM and purified by silica (Si) chromatography using a 0-25% ethyl acetate-cyclohexane gradient. The relevant fractions were combined and condensed to provide the required product, 28 mg. LCMS [LCMS1] Rt 1.46 min, m/z (ES+) 446 (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]([C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][CH:35]=1)[CH2:15][S:16][CH2:17][C:18]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=1)(O)[C:19]([F:22])([F:21])[F:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CN=C1.C(=O)(O)[O-].[Na+]>C(#N)C>[O:5]([C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][CH:35]=1)[CH2:15][S:16][CH2:17][C:18]([Cl:3])([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=1)[C:19]([F:22])([F:21])[F:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOc1ccc(C(O)(CSCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CCOc1ccc(C(Cl)(CSCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
Thionyl chloride (0.2 g) was added to a cooled solution of 1,1,1-trifluoro-2-(4-ethoxyphenyl)-2-hydroxyprop-3-yl 3-phenoxybenzyl sulphide (0.165 g) and imidazole (0.123 g) in acetonitrile (5 cm3), the temperature of the mixture being maintained at 0° C. The reaction mixture was then allowed to warm to the ambient temperature (21° C.) and stirred for 30 minutes, before being added to a saturated aqueous solution of sodium bicarbonate (7 cm3). The product was extracted into diethyl ether (3×15 cm3), and the combined organic layers were dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on a silica gel support, eluting with petroleum ether containing 10% by volume diethy ether, to give 1,1,1-trifluoro-2-chloro-2-(4-ethoxyphenyl)prop-3-yl 3-phenoxybenzyl sulphide (0.12 g) as a colourless oil.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.Cl.[Cl:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][O:37][CH2:38][C:39]([NH2:41])=[NH:40])[CH:32]=[CH:33][CH:34]=1>C(Cl)Cl.CN(C=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][O:37][CH2:38][C:39]2[NH:41][C:8](=[O:10])[C:7]3[CH:6]=[C:5]([F:11])[CH:4]=[N:3][C:2]=3[N:40]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)c1cc(F)cnc1F
Reactant: N=C(N)COCCc1cccc(Cl)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1[nH]c(COCCc2cccc(Cl)c2)nc2ncc(F)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.3 %

Procedure:
To a solution of 2,5-difluoropyridine-3-carboxylic acid (150 mg, 0.94 mmol) in CH2Cl2 (5 ml) at 0° C. was added oxalylchloride (97 μl, 1.13 mmol) dropwise followed by 2 drops of DMF. The reaction mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was concentrated in vacuo and used in the next step without further purification. The crude acid chloride was dissolved in MeCN (5 ml) and N,N-diisopropyl ethyl amine (345 μl, 2.67 mmol) was added followed by 2-[2-(3-chlorophenyl)-ethoxy]-acetamidine hydrochloride salt (222 mg, 0.89 mmol) (prepared as described in example 79.2). The reaction mixture was stirred at room temperature for 16 h and then heated to reflux for an additional 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a residue which was partitioned between water and ethyl acetate. The organic phases were combined, washed with 1N HCl, sat. NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude residue which was triturated with ether (3×5 ml) to give the desired product 2-[2-(3-chlorophenyl)-ethoxymethyl]-6-fluoro-3H-pyrido[2,3-d]pyrimidin-4-one (65 mg, 0.19 mmol; 22%) as an off white solid. MS: m/e=334.1 [M+H+].
Reaction SMILES: Br[C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[C:9]([O-:17])(=[S:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cs+]>CN(C=O)C.CCOCC>[C:9]([S:16][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[C@H](Br)C(=O)O
Reactant: [O-]C(=S)c1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)[C@@H](SC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.5 %

Procedure:
To a solution of (S)-(−)-2-bromo-3-methylbutyric acid (4.20 g, 23.2 mmol) in DMF (41 mL) was added cesium thiobenzoate (6.08 g, 22.5 mmol). The mixture was stirred at rt for 20 h. The resulting solution was diluted with ether (200 mL) and washed with H2O (4×40 mL). The ethereal layer was dried (Na2SO4), and concentrated. The crude residue was recrystallized from hexanes to afford (R)-2-benzoylthio-3-methylbutanoic acid as a pale yellow solid (4.05 g, 75%); 1H NMR (300 MHz, CDCl3) δ 1.09 (d, J=7.4 Hz, 3H), 1.11 (d, J=7.4 Hz, 3H), 2.40 (m, 1H), 4.37 (d, J=5.9 Hz, 1H), 7.45 (t, J=7.4 Hz, 2H), 7.57 (t, J=7.4 Hz, 1H), 7.97 (d, J=7.4 Hz, 2H), 11.9 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ19.8, 20.6, 30.5, 53.1, 127.6, 128.8, 133.9, 136.3, 177.9, 190.3; IR (neat) 3100, 2967, 1709, 1669 cm−1; [α]D22=+95.6 (c 1, CH2Cl2). All spectral data was identical to that previously published (Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1986, 51, 3664).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][C:7](=[O:11])[CH2:6][C:5]=2[CH:4]=[N:3]1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH:17]=[C:6]1[C:7](=[O:11])[CH2:8][CH2:9][C:10]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]1=2)[CH3:16]
Reactant: Cn1ncc2c1CCC(=O)C2
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1C(=O)CCc2c1cnn2C

Procedure:
The above procedure was repeated using 1,4,6,7-tetrahydro-1-methyl-5H-indazol-5-one and N,N-dimethylformamide dimethyl acetal. The crude product was flash chromatographed (5% methanol in dichloromethane) on silica gel to give a thick amber oil which was triturated with etherhexane to give 4-(dimethylaminomethylene) 1,4,6,7-tetrahydro-1-methyl-5H-indazol-5-one as a tan powder melting at about 94°-100° C.
Reaction SMILES: O1CCCCC1O[C:8]1[CH:9]=[C:10]([CH:14](OC(=O)C)[C:15]([Cl:18])(Cl)[Cl:16])[CH:11]=[CH:12][CH:13]=1.C(O)(=[O:25])C>[Zn]>[Cl:16][C:15]([Cl:18])=[CH:14][C:10]1[CH:11]=[CH:12][C:13]([OH:25])=[CH:8][CH:9]=1
Reactant: CC(=O)OC(c1cccc(OC2CCCCO2)c1)C(Cl)(Cl)Cl
Reactant: CC(=O)O
Agent: [Zn]
Product: Oc1ccc(C=C(Cl)Cl)cc1

Procedure:
22 g (0.06 mole) of 3-(tetrahydropyranyloxy)-1-(2,2,2-trichloro-1-acetoxyethyl)-benzene were dissolved in 80 ml of glacial acetic acid, 4.6 g (0.07 mole) of zinc dust were added a little at a time, and the mixture was heated at 60°-70° C. for 3 hours. The mixture was cooled and filtered, after which it was introduced into 1.5 liters of water and extracted with ether. The extracts were combined, washed three times with NaHCO3 solution and water, dried end evaporated down, and the residue was taken up in toluene. The solution was filtered over silica gel, and 8.0 g of 4-dichlorovinylphenol were obtained as a wax-like product.
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C@@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: C[C@@H](CCl)COc1ccccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{[(2R)-3-chloro-2-methylpropyl]oxy}-2-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M+H)+.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[NH:18][C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:31]3[C:32](=[O:36])[N:33]([CH3:35])[CH2:34][C:30]=3[CH:29]=[CH:28][N+:27]=2[O-])[C:22]([C:38]([F:41])([F:40])[F:39])=[CH:21][N:20]=1)[CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].Cl.O>CCO.[Fe]>[CH3:35][N:33]1[CH2:34][C:30]2[CH:29]=[CH:28][N:27]=[C:26]([NH:25][C:23]3[C:22]([C:38]([F:41])([F:39])[F:40])=[CH:21][N:20]=[C:19]([NH:18][C:17]4[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=4)[N:24]=3)[C:31]=2[C:32]1=[O:36]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3c4c(cc[n+]3[O-])CN(C)C4=O)n2)c(OC)c1)OCC
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3nccc4c3C(=O)N(C)C4)n2)cc1)OCC
Yield: 52.6 %

Procedure:
A solution of diethyl [3-methoxy-4-({4-[(2-methyl-5-oxido-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (Example 310, 35.0 mg, 0.0587 mmol) in EtOH (2.0 mL) was charged with iron (6.9 mg, 0.12 mmol) and heated to reflux. The reaction mixture was charged with 1 M of HCl in H2O (0.07 mL, 0.07 mmol) and stirred at reflux for 10 minutes. Additional 1 M of HCl in H2O (0.03 mL, 0.03 mmol) was added to the reaction mixture and stirred at reflux for 10 minutes. The reaction mixture was filtered through a pad of celite. The filtrate was quenched with NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to a yellow solid. The crude material was purified by silica gel chromatography on an ISCO Combi-flash Rf system using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid (17.0 mg, 50%). The material was re-purified by HPLC. The fractions containing product were combined and concentrated to yield a white solid (4.3 mg, 13%). 1H NMR (DMSO-d6, 400 MHz): δ=8.71 (br. s., 1H), 8.60 (d, J=5.05 Hz, 1H), 8.54 (s, 1H), 8.47 (br. s., 1H), 8.32 (s, 1H), 7.41 (d, J=5.05 Hz, 1H), 6.95 (s, 1H), 6.85-6.92 (m, 1H), 4.57 (s, 2H), 3.90-4.01 (m, 4H), 3.84 (s, 3H), 3.21 (s, 1H), 3.06 (s, 3H), 1.19 (t, J=6.95 Hz, 6H). MS (ES+): m/z 581.10 [MH+] (TOF, polar).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][C:28]([NH2:30])=[O:29].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][C:28]([NH2:30])=[O:29])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: NC(=O)COCCOCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: c1ccccc1
Product: NC(=O)COCCOCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Temperature: 110 °C
Yield: 77 %

Procedure:
A mixture of 29.9 g of 4-(diphenylmethylene)-piperidine, 36.3 g of 2-[2-(2-chloroethoxy)ethoxy]-acetamide and 18 g of sodium carbonate in 80 ml of xylene is heated for 20 hours at a temperature of from 90°to 110° C. Thereafter, 80 ml of benzene are added thereto. The precipitate obtained is filtered off and the organic phase is extracted with a dilute solution of hydrochloric acid (20 ml of concentrated hydrochloride acid and 80 ml of water). After the addition of 30 ml of a concentrated solution of sodium hydroxide and extraction with benzene, the benzene solution obtained is washed, dried over anhydrous potassium carbonate and the benzene evaporated in vacuo. The 2-[2-[2-[4-(diphenylmethylene)-1-piperidinyl]ethoxy]ethoxy]-acetamide obtained is used as such for the preparation of the corresponding acid (see Example 3.4).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH3:13])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(O)(C)C.C(O)=O.[NH3:21]>C1(C)C=CC=CC=1>[NH2:21][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(=O)c1cccnc1
Reactant: N
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: CC(C)O
Product: COC(=O)C=C(N)c1cccnc1
Temperature: 65 °C

Procedure:
Methyl nicotinoylacetate (88 g, 0.5 mol) was dissolved in toluene (200 g), isopropyl alcohol (200 g), and formic acid (98-100%, 1.22 g, 0.03 mol) and heated to 60-65° C. Gaseous ammonia (23 g, 1.35 mol) was bubbled through the solution for 15 minutes. The white suspension was stirred at 65° C. until a homogeneous solution formed. The solution was stirred for two hours at 65° C. and then concentrated (ca. 200 g) at 65° C. The residue was cooled to −5° C. with stirring and methyl 3-amino-3-(3-pyridyl)-2-propenoate crystallized as colorless needles. The process of reducing the volume to 50% followed by cooling was repeated three times with the mother liquors. Filtration, washing with toluene, and drying at 30° C. resulted in 77.74 g (88.8%) of methyl 3-amino-3-(3-pyridyl)-2-propenoate as colorless crystals.