Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CCOCC>[CH2:9]([OH:8])[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Reaction time: 1 h
Yield: 93 %

Procedure:
To a magnetically stirred solution of 0.5 ml (0.5 mmol) of LiAlH4 in Et2O, 100 mg (0.314 mmol) of arachidonic acid methyl ester in 2 mL of Et2O was added dropwise at 0° C. The reaction mixture was stirred for 1 h and then quenched by addition of 1 mL of EtOAC. 2 mL of saturated NH4Cl solution was added and the organic layer was separated, dried with MgSO4, filtered and evaporated. Chromatography on silica gel (eluents: CH2Cl2/petroleum ether up to 70% CH2Cl2), evaporation, followed by Millipore filtration of a CH2Cl2 solution of the product gave 99.3 mg (0.292 mmol, 93% yield) of arachidonyl alcohol as a colorless oil: TLC (CHCl3) Rf 0.28; 1H NMR (200 MHz, CDCl3) δ 5.37 (m, 8 H ), 3.61 (t, 2 H, J=6 Hz), 2.79 (m, 6H), 2.08 (m, 4 H), 1.66-1.17 (m, 8 H), 0.92 (t, 3 H, J=7 Hz).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[C:10]([CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)#[N:11]>O.C(O)C>[N:22]1[C:23]2[C:18](=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][CH2:12][C:10](=[N:2][OH:3])[NH2:11])[CH:19]=[CH:20][CH:21]=1
Reactant: N#CCOc1cccc2cccnc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(COc1cccc2cccnc12)=NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6.4 g of hydroxylamine hydrochloride in 10 ml of water and 6.4 g of potassium carbonate in 10 ml of water is added dropwise at room temperature, within 15 minutes, to 15.8 g of 8-(cyanomethoxy)-quinoline in 100 ml of ethanol, in the course of which the reaction mixture warms up to 30° C. After 3 hours' stirring at room temperature, the reaction mixture is diluted with 250 ml of water; it is subsequently filtered, and the residue is washed with water and dried. There is thus obtained 2-(8-quinolinoxy)-acetamide oxime in the form of light-brown powder, m.p. 201°-204° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][N:10]=1.[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49]Cl)=[CH:47][CH:46]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:49][C:48]2[CH:51]=[CH:52][C:45]([Cl:44])=[CH:46][CH:47]=2)=[CH:11][N:10]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Cc1ccc(OCCc2ccc(CN3CCN(C(=O)/C=C/c4cc(C)c(Oc5ccc(O)cn5)c(Cl)c4)CC3)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCCc2ccc(CN3CCN(C(=O)/C=C/c4cc(C)c(Oc5ccc(OCc6ccc(Cl)cc6)cn5)c(Cl)c4)CC3)cc2)cc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a solution of (E)-3-{3-chloro-4-[(5-hydroxypyridin-2-yl)oxy]-5-methylphenyl}-1-(4-{4-[2-(4-methylphenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one (479 mg) and p-chlorobenzyl chloride (129 mg) in DMF (5.0 mL) was added NaH (41.6 mg, 60% in mineral oil) at 0° C. Then the reaction mixture was stirred over night at room temperature. The reaction mixture was quenched by addition of saturated aqueous NH4Cl, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/0 to 9/1) to afford (E)-3-[3-chloro-4-({5-[(4-chlorobenzyl)oxy]pyridin-2-yl}oxy)-5-methylphenyl]-1-(4-{4-[2-(4-methylphenoxy)-ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one (507 mg) as a colorless amorphous. To a solution of that amorphous (507 mg) in EtOH (10 mL) was added 6 M aqueous HCl (0.129 mL) at room temperature, then the reaction mixture was stirred for 3 hours. The reaction mixture was filtered off, and the precipitate was dried at 50° C. under reduced pressure to afford (E)-3-[3-chloro-4-({5-[(4-chlorobenzyl)oxy]pyridin-2-yl}oxy)-5-methylphenyl]-1-(4-{4-[2-(4-methylphenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one hydrochloride (486 mg) as a colorless crystal.
Reaction SMILES: C(OC([C:8]1[N:9]([CH3:44])[C:10]([NH:13][C:14]([C@@H:16]2[NH:20][C@@H:19]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@:18]3([C:33]4[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[C@H:17]2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=2[F:43])=[O:15])=[CH:11][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:44][N:9]1[CH:8]=[CH:12][CH:11]=[C:10]1[NH:13][C:14]([CH:16]1[NH:20][CH:19]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]2([C:33]3[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH:17]1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1[F:43])=[O:15]
Reactant: Cn1c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 109.3 %

Procedure:
A solution of rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-1-methyl-1H-pyrrole-2-carboxylic acid tert-butyl ester (0.1 g, 0.16 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 20 h, then concentrated. To the residue was added aqueous saturated NaHCO3 solution until “pH” became 7-8, and the mixture was extracted with ethyl acetate several times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (1-methyl-1H-pyrrol-2-yl)-amide as a light brown solid (95 mg, 93%).
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][C@@H:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH3:44])[CH:41]=3)[CH2:36][C@@H:35]2[CH2:45][CH3:46])=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][C@@H:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH3:44])[CH:41]=3)[CH2:36][C@@H:35]2[CH2:45][CH3:46])=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(N[C@@H]2c3cc(OC)ccc3C[C@@H]2CC)n1
Product: CCc1nc(N[C@@H]2c3cc(OC)ccc3C[C@@H]2CC)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-[(cis)-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 0.93, 1.21-1.34, 2.57, 2.73, 2.82, 3.00, 3.79, 4.41, 5.76, 6.82, 7.17; HRMS (FAB) calcd for C20H26BrN3O+H 404.1338, found 404.1317. Anal. Calcd for C20H26BrN3O: C, 59.41; H, 6.48; N, 10.39; Br, 19.76. Found: C, 59.05; H, 6.42; N, 10.13.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][C@H:11]([CH3:16])/[C:12](/[NH2:15])=[N:13]/[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](N1C=CN=C1)(=O)[CH3:19]>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:17])[NH:10][C@@H:11]([C:12]1[N:15]=[C:18]([CH3:19])[O:14][N:13]=1)[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)/C(N)=N/O
Reactant: CC(=O)n1ccnc1
Solvent: C1COCCO1
Product: Cc1nc([C@@H](C)NC(=O)OCc2ccccc2)no1
Temperature: 90 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
To a solution of benzyl[(1R,2Z)-2-amino-2-(hydroxyimino)-1-methylethyl]carbamate (2.25 g, 9.48 mmol) in dioxane (80 ml) was added 1-acetyl-1H-imidazole (3.13 g, 28.5 mmol) and the mixture heated to 90° C. After 16 h, the solution was concentrated and the residue was dissolved in 200 mL of dichloromethane. The mixture was washed with 100 mL of aquous saturated sodium bicarbonate (2×) and saturated aqueous sodium chloride (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) to give the title compound (1.1 g). MS 262.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][N:5]([CH3:8])[N:4]=1.[Br-:9].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>CO.O>[Br:9][C:7]1[C:3]([O:2][CH3:1])=[N:4][N:5]([CH3:8])[CH:6]=1
Reactant: COc1ccn(C)n1
Reactant: [Br-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: COc1nn(C)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-methoxy-1-methyl-1H-pyrazole (0.500 g, 4.46 mmol) in MeOH (50.0 mL) was cooled to 0° C. and charged with pyridinium tribromide (1.43 g, 4.46 mmol) in portions. The solution was stirred for 1 h at 0° C. then for an additional 16 h at rt. The reaction mixture was charged with sat. NaHCO3 (2.5 mL) and diluted with H2O and extracted with CHCl3 (3×). The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo resulting in the title compound as a red oil. This material was used in the next step without further purification. 1H NMR (400 MHz, CD3OD): δ=3.66 (s, 3H), 4.07 (s, 3H), 7.30 (s, 1H). MS (ES+): m/z 190.98, 192.99 (49.5/50.5) [MH+]. HPLC: tR=2.29 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[C:33](=[O:34])[O:32][C:14]4=[N:15][C:16]([N:19]5[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]5)=[CH:17][CH:18]=[C:13]4[CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:35].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[C:33](=[O:34])[O:32][C:14]4=[N:15][C:16]([N:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]5)=[CH:17][CH:18]=[C:13]4[CH:12]=3)[N:10]=[C:4]2[CH:3]=1
Reactant: Cc1ccn2cc(-c3cc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4oc3=O)nc2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccn2cc(-c3cc4ccc(N5CCNCC5)nc4oc3=O)nc2c1
Reaction time: 16 h

Procedure:
To a suspension of t-butyl 4-(3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate (112 mg, 0.24 mmol) in CH2Cl2 (3 mL) was added 4N HCl in dioxane (1.5 mL). The mixture was stirred for 16 hours, and filtered. The solid was washed with ether and dried under nitrogen. 3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-pyrano[2,3-b]pyridin-2-one hydrochloride was obtained quantitatively and used in the next step without further purification. MS m/z 362.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]=[N:4][N:3]=1.C([Li])CCC.[C:18]1([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:29]2([OH:32])[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:27][CH2:28]2)=[N:4][N:3]=1
Reactant: Cc1nncn1-c1ccccc1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnc(C2(O)CCN(CCc3ccccc3)CC2)n1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.6 g of 3-methyl-4-phenyl-4H-1,2,4-triazole (10 mmol) in 15 ml of THF at -78° C. is added 7.0 ml of n-butyllithium (1.6N in hexane). The mixture is stirred for 50 minutes before a solution of 2.44 g of N-(2-phenylethyl)-4-piperidinone in 12 ml of THF is charged into the flask. After stirring for 30 minutes at -78° C. and then 1 hour at -20° C. the mixture is poured into cold water and is extracted three times with chloroform. The combined chloroform extracts are washed twice with water, brine, dried over sodium sulfate and concentrated in vacuo to yield an amber oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([C:20]4[CH:21]=[C:22]([CH2:26]O)[CH:23]=[CH:24][CH:25]=4)=[N:18][CH:19]=3)[CH:11]=[N:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:28]([C:31]1[CH:32]=[CH:33][C:34](=[O:37])[NH:35][N:36]=1)([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:28]([C:31]1[CH:32]=[CH:33][C:34](=[O:37])[N:35]([CH2:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:17]3[N:16]=[CH:15][C:14]([C:12]4[CH:11]=[N:10][N:9]([CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:13]=4)=[CH:19][N:18]=3)[CH:21]=2)[N:36]=1)([CH3:30])[CH3:29]
Reactant: OCc1cccc(-c2ncc(-c3cnn(CCN4CCOCC4)c3)cn2)c1
Reactant: CC(C)c1ccc(=O)[nH]n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(=O)n(Cc2cccc(-c3ncc(-c4cnn(CCN5CCOCC5)c4)cn3)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.3 A solution, kept under nitrogen, of 324 mg (0.70 mmol) of (3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}phenyl)methanol, 131 mg (0.91 mmol) of 6-isopropyl-2H-pyridazin-3-one and 278 mg (1.05 mmol) of triphenylphosphine in 1.4 ml of THF is cooled in an ice bath, and 217 μl (1.056 mmol) of diisopropyl azodicarboxylate are added dropwise. After the reaction mixture has been stirred at room temperature for 2 hours, it is evaporated. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent, giving 6-isopropyl-2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one (“A13”) as yellowish crystals; ESI 486;
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[Cl:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[C:9]=1[C:10]([NH2:12])=[O:11]>C(Cl)Cl>[Cl:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[C:9]=1[C:10]([N:12]=[C:2]=[O:3])=[O:11]
Reactant: NC(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl

Procedure:
3.5 ml of oxalyl chloride are added dropwise at room temperature over a period of 30 minutes to a suspension of 7.68 g of 2,6-dichloro-3-nitrobenzoic acid amide in 570 ml of methylene chloride. The batch is then heated at reflux temperature for 18 hours and the solvent is subsequently distilled off in vacuo, affording 8.6 g of crude 2,6-dichloro-3-nitrobenzoyl isocyanate which can be used directly in the subsequent reactions.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:10]=[N:11][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[N:13][CH:14]=2)=[C:4]([F:19])[C:3]=1[CH:20]1[CH2:24][CH2:23][CH2:22][O:21]1.O1CCOCC1.[CH2:31]([NH:33][C:34]([NH:36][C:37](SC)=NC(=O)NCC)=[O:35])[CH3:32].C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[CH2:31]([NH:33][C:34]([NH:36][C:37]1[NH:1][C:2]2[C:3]([CH:20]3[CH2:24][CH2:23][CH2:22][O:21]3)=[C:4]([F:19])[C:5]([C:9]3[CH:10]=[N:11][C:12]([C:15]([OH:18])([CH3:16])[CH3:17])=[N:13][CH:14]=3)=[CH:6][C:7]=2[N:8]=1)=[O:35])[CH3:32]
Reactant: CC(C)(O)c1ncc(-c2cc(N)c(N)c(C3CCCO3)c2F)cn1
Reactant: CCNC(=O)N=C(NC(=O)NCC)SC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c(C3CCCO3)c2[nH]1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a stirring suspension of 2-[5-(4,5-diamino-2-fluoro-3-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol (21) (111.3 g, 334.9 mmol) and 1,4-dioxane (556.5 mL, Sigma-Aldrich 360481) was added 1-ethyl-3-(N-(ethylcarbamoyl)-C-methylsulfanyl-carbonimidoyl)urea (10) (93.36 g, 401.9 mmol, CB Research and Development) followed by a pH 3.5 buffer (1.113 L), prepared by dissolving NaOAc trihydrate (158.1 g) in 1N aqueous H2SO4 (1.100 L). The reaction mixture was stirred at reflux overnight (HPLC showed complete conversion), cooled to room temperature, and poured portion-wise (to minimize frothing) into a stirring solution of aqueous saturated NaHCO3 (2.23 L) giving pH 8-9. The resulting mixture was stirred for 30 minutes, the solid was collected by filtration, washed copiously with water to neutral pH, and then more sparingly with EtOH. The solid was dried under reduced pressure giving 22 as an off-white yellowish solid (135.2 g, 94% yield; 99% HPLC purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 429.58 (2.03 min). 1H NMR (300 MHz, MeOD) δ 8.95 (d, J=1.6 Hz, 2H), 7.45 (d, J=6.5 Hz, 1H), 5.38 (br.s, 1H), 4.27 (dd, J=14.9, 7.1 Hz, 1H), 4.01 (dd, J=15.1, 7.0 Hz, 1H), 3.37-3.29 (m, 2H), 2.55 (br.s, 1H), 2.19-2.07 (m, 2H), 2.02-1.82 (br.s, 1H), 1.63 (s, 6H), 1.21 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=3)[C:18]2=[O:34])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:33][O:32][C:30]([CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([N:19]2[CH2:20][CH2:21][N:17]([CH:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)[C:18]2=[O:34])=[CH:23][CH:24]=1)=[O:31]
Reactant: [H][H]
Reactant: COC(=O)CCc1ccc(N2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(N2CCN(C3CCNCC3)C2=O)cc1

Procedure:
Prepared by treating 1-(1-benzyloxycarbonyl-4-piperidinyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one with hydrogen at 3 bars in the presence of 5% palladium/charcoal in methanol.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:8](Cl)([Cl:11])([Cl:10])=[S:9]>>[C:1]1([P:8]([Cl:11])([Cl:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: S=P(Cl)(Cl)Cl
Product: S=P(Cl)(Cl)c1ccccc1

Procedure:
Phenol is treated with an excess of thiophosphoryl chloride (at reflux) to yield phenyl thiophosphoryl dichloride ##STR16## and this product was condensed with p-nitroaniline and hydrogenated as set out in Example 1. The corresponding polymer is obtained by polycondensation with isophthaloyl chloride as in Example 2. The inherent viscosity was 0.9 dl/g.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25]O)[C:5]1=[O:30])[CH:2]=[CH2:3].[CH2:32]([SH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(#N)C>>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25][S:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: SCc1ccccc1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Solvent: CC#N
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CSCc2ccccc2)C2CC2)C1=O
Temperature: 100 °C

Procedure:
A mixture of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one (1.35 g, 2.94 mmol; Example 252, Step A), benzyl mercaptan (0.691 ml, 5.89 mmol) and 2-(tributylphosphoranylidene) in acetonitrile (1.579 ml, 5.89 mmol) was heated to 100° C. for 2 h. The reaction mixture was cooled to RT, and extracted with 80 mL of EtOAc. The combined organics were washed with sat. aq. NH4Cl solution and brine, dried over Na2SO4, filtered and the filtrate was concentrated. The crude product was purified by chromatography on silica gel eluting with 0 to 50% EtOAc/hexane to give the title compound.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39]([C:35]3[O:34][CH:38]=[CH:37][CH:36]=3)=[O:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccco4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 72.3 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.650 g, 2.22 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 2-furoyl chloride (0.290 g, 2.22 mmol) was added and the mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-furylcarboxamide (0.51 g, 73%) as a white solid: mp 121-123° C.; 1H NMR (DMSO-d6) δ d 11.13 (s, 1H), 9.01 (t, J=5.7 Hz, 1H), 7.88-7.68 (m, 4H), 7.18 (d, J=3.3 Hz, 1H), 6.66 (m, 1H), 5.20-5.13 (dd, J=5.4 and 12.5 Hz, 1H), 4.90 (d, J=5.6 Hz, 2H), 2.97-2.84 (m, 1H), 2.65-2.49 (m, 2H), 2.10-1.98 (m, 1H); 13C NMR (DMSO-d6) δ d 172.73, 169.80, 167.52, 166.94, 158.09, 147.49, 145.27, 139.06, 134.80, 132.98, 131.52, 127.09, 121.88, 113.86, 111.91, 48.86, 37.64, 30.92, 21.97; Anal. Calcd. For C19H15N3O6+0.18H2O: C, 59.34; H, 4.03; N, 10.93. Found: C, 59.47; H, 4.16; N, 10.49.
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([C:20]1[CH2:21][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24][CH:25]=1)=[N:8][C:9]=2[NH:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)([CH3:3])[CH3:2].C([O-])=O.[NH4+].C(OCC)(=O)C>C(O)C.[Pd]>[CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:21]1)=[N:8][C:9]=2[NH:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)([CH3:2])[CH3:3]
Reactant: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(C3=CCCN(C(=O)OC(C)(C)C)C3)nc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(C3CCCN(C(=O)OC(C)(C)C)C3)nc21
Temperature: 60 °C
Yield: 75.3 %

Procedure:
A solution of tert-butyl 3-(9-isopropyl-6-((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (821 mg, 1.87 mmol) in ethanol (35 mL) was degassed with nitrogen and to this was added 10%-Pd/C (150 mg), and ammonium formate (650 mg, 10 mmol). The resulting mixture was stirred and heated at 60° C. for 3 hr. The reaction was cooled to ambient temperature and the catalyst was removed by filtration. The filtrate was evaporated to give a residue, which was taken into ethyl acetate (100 mL) and the solution washed with water (30 mL), brine (30 mL), dried over Na2SO4 and evaporated to give a residue that was purified via flash chromatography with a gradient from 100% heptane to 100% ethyl acetate to afford the title compound (620 mg), which was used in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[C:13]([F:19])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][C:13]=2[F:19])=[C:4]([I:9])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1I
Reactant: Fc1cc(Cl)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cc(Cl)ccc1COc1ccc(Cl)cc1I

Procedure:
As for Reaction 1, using 84.87 g 4-chloro-2-iodophenol, 76 g 4-chloro-2-fluorobenzyl bromide and 92 g potassium carbonate in 900 ml acetone. Yield 129.36 g. Identical by TLC with product of Reaction 1.