Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][O:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28]C)=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O.CO>C1COCC1.Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NOCc4ccc(Cl)cc4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NOCc3ccc(Cl)cc3)cc1)OCCC2C(=O)O
Reaction time: 2 h
Yield: 82.7 %

Procedure:
Methyl 7-(4-((4-chlorobenzyloxy) carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate (5 mg, 0.0101 mmol) was diluted with THF (500 μL) followed by the addition of NaOH (0.0203 mL, 0.101 mmol), water (200 μl) and methanol (200 μL). After stirring for 2 hours, the reaction was diluted with 2N HCl and ethyl acetate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the title compound (4.0 mg, 82.3% yield). 1H NMR (400 MHz, CD3OD) δ 7.80 (d, 2H), 7.70 (s, 1H), 7.48 (d, 2H), 7.40 (d, 2H), 7.15 (d, 2H), 6.41 (s, 1H), 4.95 (s, 2H), 4.2-4.35 (m, 2H), 3.82 (bt, 1H), 2.35-2.40 (m, 1H), 2.10-2.15 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:27][CH3:28])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:23][CH:22]([C:24]#[N:25])[CH2:21]3)=[O:19])=[C:14]([F:26])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+]>CO.C(#N)C>[NH2:35][CH:1]([C:4]1[C:5]([O:27][CH3:28])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:23][CH:22]([C:24]#[N:25])[CH2:21]3)=[O:19])=[C:14]([F:26])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(=O)N2CC(C#N)C2)c(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1ccc(C(=O)N2CC(C#N)C2)c(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[(3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-yl)carbonyl]azetidine-3-carbonitrile (25 mg, 0.062 mmol), ammonium acetate (48 mg, 0.62 mmol) and sodium cyanoborohydride (8 mg, 0.1 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The resulting crude product was used directly in next step (21 mg, 84%). LCMS calculated for C21H19ClFN2O2 (M−NH2)+: m/z=385.1. found: 385.1.
Reaction SMILES: Cl.Cl.[C:3]1([N:9]2[CH2:15][CH2:14][NH:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].C(N(CC)C(C)C)(C)C>CN(C)C=O>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:13]1[CH2:14][CH2:15][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][CH2:11][NH:12]1)([O-:25])=[O:24]
Reactant: c1ccc(N2CCNNCC2)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1N1CCN(c2ccccc2)CCN1

Procedure:
A mixture of hexahydro-5-phenyl-1H-1,2,5-triazepine dihydrochloride (15.0 g), 1-fluoro-2-nitrobenzene (9.84 ml), N,N-diisopropylethylamine (36.5 ml) in N,N-dimethylformamide (150 ml) was magnetically stirred and heated at 75°-80° for 5 hours under nitrogen. The solution was evaporated under oil pump vacuum and the residual syrup was mixed with chloroform and dilute sodium hydroxide. The aqueous phase was extracted once more with chloroform and the combined chloroform extracts were dried (MgSO4). The solution was evaporated to a syrup which was subjected to an oil pump vacuum. This material in benzene was applied to a column (80×4.0 cm) of dry column grade neutral alumina (Woelm) prepacked in benzene. Elution was with benzene and monitoring of fractions was by t.l.c. on Alox 25 uv254 plates (Brinkmann) with benzene as developer. The fractions containing the major component were evaporated to a syrup which was crystallized from benzeneheptane; wt. 13.82 g (78%), mp=118°-120°. Recrystallization from benzeneheptane gave pure titled product, mp=119° -121°.
Reaction SMILES: [NH2:1][C:2]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:15][CH2:16][CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28]CC3C=CC=CC=3)=[CH:24][CH:23]=2)[O:18][CH2:19][CH2:20][OH:21])[CH3:14])=[CH:8][CH:7]=1)=[O:3].[H][H]>C(O)(=O)C.[Pd]>[NH2:1][C:2]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:15][CH2:16][CH:17]([O:18][CH2:19][CH2:20][OH:21])[C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)[CH3:14])=[CH:8][CH:7]=1)=[O:3]
Reactant: CC(Cc1ccc(OCC(N)=O)cc1)NCC(OCCO)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(Cc1ccc(OCC(N)=O)cc1)NCC(OCCO)c1ccc(O)cc1

Procedure:
N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanamine (3.5 g) in glacial acetic acid (30 ml) was hydrogenated in the presence of 10% Palladium on carbon at atmospheric pressure and room temperature until hydrogen uptake was complete. The solution was filtered through diatomaceous earth and the solvent removed under vacuum. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, the organic layer separated, dried (MgSO4) and evaporated to give an oil. The oil was crystallised from ethyl acetate to give the title compound, m.p. 145°-160° C. as a 40:60 mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[C:31](=[O:32])[C:30](=[O:33])[C:29]=3[O:34]C(C)C)=[CH:18][CH:17]=2)[C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C>O>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[C:29](=[O:34])[C:30](=[O:33])[C:31]=3[OH:32])=[CH:20][CH:21]=2)[C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2c(O)c(=O)c2=O)cc1

Procedure:
Methyl 2-butyl-4-chloro-1-[2'-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylate (0.26 g; preparable as described in Example 27(c)) was heated in a mixture of glacial acetic acid (5 ml) and water (5 ml) at 95°-100° C. for 5 hours. The solvents were evaporated in vacuo and the residue obtained was purified by flash chromatography on silica gel (eluting with 10% rising to 30% industrial methylated spirit in ethyl acetate) to give methyl 2-butyl-4-chloro-1-[2'-(2-hydroxy-3,4-dioxo-cyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylate, an active compound of the present invention, as a yellow oil (0.1 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)[CH:19]=2)[O:14]1.C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)[CH:19]=2)[O:14]1)=[O:11]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CO)O3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](C=O)O3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of dimethyl sulfoxide (33 mg, 0.425 mmol) in methylene chloride (2 mL) at −78° C., was added 0.14 mL of 2 M oxalyl chloride (0.272 mmol). After the solution had stirred at this temperature for 10 minutes, a solution of methyl 4-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (50 mg, 0.17 mmol) in methylene chloride (2 mL) was added dropwise and the resulting mixture was stirred at −78° C. for an additional 1.6 hours. At this time, triethylamine (0.14 mL, 1.02 mmol) was added to the mixture slowly, and then it was allowed to warm to room temperature over 15 minutes. The solution of desired product was used directly in following steps.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1.CCN(C(C)C)C(C)C.[F:19][C:20]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[C:21]=1[C:22](Cl)=[O:23]>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[C:21]=1[C:22]([NH:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1)=[O:23]
Reactant: O=C(Cl)c1c(F)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: COc1cc(N)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)c2c(F)cc(C(F)(F)F)cc2C(F)(F)F)ccn1
Reaction time: 2 h
Yield: 61.7 %

Procedure:
2-Methoxypyridin-4-amine (632.1 mg, 5.09 mmol) and DIEA (1.8 mL, 10.18 mmol) were dissolved in DMF (15 mL) and treated dropwise with a solution of 2-fluoro-4,6-bis(trifluoromethyl)benzoyl chloride (1500 mg, 5.09 mmol) in DMF (2 mL). After 2 hours, the reaction was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The solution was dried over anhydrous Na2SO4, filtered, and dried down to a purple residue. Silica gel chromatography using a gradient of ethyl acetate/hexane (10-99%) provided 2-fluoro-N-(2-methoxypyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide (1.2 g, 67%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.42 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.13 (dd, J=5.4, 0.9 Hz, 1H), 7.14-7.10 (m, 2H), 3.85 (s, 3H) ppm. ESI-MS m/z calc. 382.05. found 383.1 (M+1)+; Retention time: 1.48 minutes (3 minutes run).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][O:2]1.[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH2:11])[CH3:8]>>[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH:11][C:1](=[O:6])[O:2][CH2:3][CH2:4][OH:5])[CH3:8]
Reactant: O=C1OCCO1
Reactant: CCCCC(CC)CN
Product: CCCCC(CC)CNC(=O)OCCO
Temperature: 50 °C

Procedure:
135 grams (1.5 moles, 98% pure) of ethylene carbonate were charged to a flask and heated to approximately 50° C. to melt it. 198 grams (1.5 moles, 98% pure) of 2-ethyl-1-hexylamine were charged to a dropping funnel and fed drop-wise to the stirred flask contents at a rate sufficient to maintain the reaction mixture at 70° C. during the addition. The resulting mixture was heated at 95° C. for an additional 10 hours. Infrared analysis of the resultant product was consistent with the proposed structure.
Reaction SMILES: CC(C)[N:3]=C=NC(C)C.[CH3:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[S:24][C:23]([NH:25][C:26]3[CH:27]=[C:28]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][OH:41])[CH2:35][CH2:34]4)[N:29]=[C:30]([CH3:32])[N:31]=3)=[N:22][CH:21]=2)=[O:19])=[C:15]([Cl:42])[CH:14]=[CH:13][CH:12]=1.[NH:43](C(OC(C)(C)C)=O)[C@H:44]([C:49]([OH:51])=O)[CH2:45][CH:46]([CH3:48])[CH3:47].C1(C)C=CC(S([O-])(=O)=O)=CC=1.CN(C)C1C=C[NH+]=CC=1>C(Cl)Cl.CN(C=O)C>[CH3:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[S:24][C:23]([NH:25][C:26]3[CH:27]=[C:28]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][OH:41])[CH2:35][CH2:34]4)[N:29]=[C:30]([CH3:32])[N:31]=3)=[N:22][CH:21]=2)=[O:19])=[C:15]([Cl:42])[CH:14]=[CH:13][CH:12]=1.[NH2:43][C@H:44]([C:49]([NH2:3])=[O:51])[CH2:45][CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)N=C=NC(C)C
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1cc[nH+]cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cc1nc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)cc(N2CCN(CCO)CC2)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N)C(N)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
DIC (302 mg, 2.4 mmol) was added with stirring to a DMF (4 mL) solution of dasatinib (196 mg, 0.4 mmol), Boc-Leu-OH (111 mg, 0.48 mmol), and DPTS (124 mg, 0.4 mmol). The resulting mixture was stirred at room temperature for five hours. After this period, DCM (100 mL) was added to the reaction mixture which was allowed to stir for an additional 20 minutes. The resulting mixture was transferred into a separatory funnel and washed with 5% NaCl (100 mL×3). The organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. The resulting residue was purified by column chromatography (biotage: DCM/CH3OH, CH3OH, 5-10%, 25 CV). The obtained solid was dissolved in 5.0 mL of TFA/DCM (2:3) and the solution was stirred at room temperature for one hour. TFA and DCM were removed under reduced pressure. The residue was dissolved in 150 mL of DCM and the resulting solution was washed with 5% Na2CO3 and 5% NaCl. The desired product was obtained (146 mg, yield: 61%) as a white solid; 1H NMR (500 MHz, CD3OD). δ 0.98 (m, 6H), 1.46 (m, 1H), 1.60 (m, 1H), 1.80 (m, 1H), 2.33 (s, 3H), 2.48 (s, 3H), 2.62 (t, 4H), 2.74 (t, 2H), 3.50 (m, 1H), 3.65 (t, 4H), 4.33 (m, 2H), 6.02 (s, 1H), 7.25 (m, 2H), 7.36 (d, 1H), 8.15 (s, 1H); LC-MS (m/z) calcd., 600.2, found 601.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH3:9].[Br:10]Br>[W]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: BrBr
Reactant: Cc1cc(Br)ccc1Br
Agent: [W]
Product: BrCc1cc(Br)ccc1Br
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
33 g (0.1 mole) 2,5-dibromo toluene is placed in a 100 ml three-necked flask, fitted with a reflux condenser, a sealed mechanical stirrer, and a separatory funnel with the stem reaching nearly to the bottom of the flask. The flask is illuminated with two 300-watt tungsten lamps during the reaction. The flask is heated in an oil bath to 150° C., and 18.4 g (5.9 ml, 0.115 mole) bromine is added over two hours. The mixture is stirred for an additional 10 minutes, and the contents, while still liquid, are poured into a 500 ml round-bottom flask containing 300 ml of hot light petroleum ether and 2 g decolorizing carbon. A reflux condenser is attached, and the mixture is heated to reflux until the material dissolves, then rapidly filtered through a pre-heated Buchner funnel. The filtrate is cooled and washed with cold light petroleum.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[NH:4][N:5]=[C:6]([N+:22]([O-:24])=[O:23])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=1.[CH2:26](I)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:26]([N:4]1[C:3](=[O:25])[C:2]([Cl:1])=[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=2)[C:6]([N+:22]([O-:24])=[O:23])=[N:5]1)[CH3:27]
Reactant: CCI
Reactant: CCCOc1cc(CNc2c([N+](=O)[O-])n[nH]c(=O)c2Cl)ccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1cc(CNc2c([N+](=O)[O-])nn(CC)c(=O)c2Cl)ccc1OC
Reaction time: 1.5 h

Procedure:
A mixture comprising 500 mg of 4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 22) prepared in Example 2, 634 mg of ethyl iodide, 562 mg of anhydrous potassium carbonate and 25 ml of methyl ethyl ketone, was refluxed under stirring for 1.5 hours. The solvent was distilled off under reduced pressure, and water was added to the residue thereby obtained and the mixture was extracted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off, and the residual oily substance thereby obtained was crystallized from a solvent mixture of diethyl ether-n-hexane, to obtain 473 mg of the above identified compound having a melting point of from 76° to 77° C. as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14](OCC)[CH2:15][CH3:16])[S:10][C:9]2=[S:20])=[CH:4][CH:3]=1.C(O)C.[S-2:24].[Na+].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([SH:24])[CH2:15][CH3:16])[S:10][C:9]2=[S:20])=[CH:4][CH:3]=1
Reactant: CCOC(CC)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O
Reactant: [S-2]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(S)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O
Reaction time: 0.25 h

Procedure:
To a suspension of 3 g. (0.091 m.) of 3-(4'-chlorophenyl)-5-(1'-ethoxypropylidene)-rhodanine in 15 ml. of ethanol is added a solution of sodium sulfide in 10 ml. of water and the mixture is stirred at room temperature until solution is complete (15-20 minutes). This solution is added to 100 ml. of water, allowed to stand for 15 minutes, filtered and the filtrate is acidified with 2N hydrochloric acid to give 3-(4'-chlorophenyl)-5-(1'-mercaptopropylidene)-rhodanine, m.p. 163°-165°C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][CH:12]([C:14]1([CH2:18][CH2:19][CH3:20])[CH2:17][O:16][CH2:15]1)[CH3:13].N1C=CC=CC=1>CCOCC>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:11][CH:12]([C:14]2([CH2:18][CH2:19][CH3:20])[CH2:17][O:16][CH2:15]2)[CH3:13])=[O:7])=[CH:4][CH:3]=1
Reactant: CCCC1(C(C)O)COC1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCC1(C(C)OC(=O)c2ccc(I)cc2)COC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-iodobenzoyl chloride (3.5 g) in dry ether (25 ml) was added to a stirred solution of 3-(1-hydroxyethyl)-3-n-propyloxetane (1.7 g) and pyridine (1.8 ml) in ether (50 ml) at 0° C. The resulting mixture was stirred for 24 hours at room temperature. After this time the mixture was washed with water and brine. The organic extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was purified by column chromatography on silica (pre-eluted with 1% triethylamine in hexane) and eluted with hexane/ether mixtures. 3-[1-(4-Iodobenzoyloxy)ethyl]-3-n-propyloxetane was obtained as a colourless oil (1.8 g).
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19])(=O)C.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>CO>[N+:18]([C:9]1[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=1[CH2:7][OH:6])([O-:20])=[O:19]
Reactant: CC(=O)OCc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CO
Yield: 100.9 %

Procedure:
1.9 cm3 (1.9 mmol) of a 1M aqueous sodium hydroxide solution are added, at a temperature in the region of 20° C., to 0.5 g (1.9 mmol) of 2-nitro-4-trifluoromethylbenzyl acetate in solution in 50 cm3 of methanol. After stirring for 2 hours at a temperature in the region of 20° C., 20 cm3 of a saturated aqueous sodium phosphate solution are added and the mixture is then extracted with 3 times 50 cm3 of dichloromethane. The organic phases are combined, washed with 50 cm3 of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa), to give 0.424 g of (2-nitro-4-trifluoromethylphenyl)methanol in the form of an oil;
Reaction SMILES: [C:1]([NH:6][C:7](=[O:11])OCC)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([NH:19][C:7]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C(C)C(=O)NC(=O)OCC
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)NC(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 42.6 %

Procedure:
A reaction vessel was charged with 78.5 g of ethyl N-methacryloylcarbamate and 53.5 g of benzylamine to which 100 g of toluene were added and heated at 100° C. for 30 minutes, The resulting mixture was condensed under reduced pressure and isolated by column chromatography to obtain 46.4 g of N-benzyl-N'-methacryloyl urea having a melting point of 96°-98° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@H:35]4[CH2:40][CH2:39][C@H:38]([C:41]([O:43]CC)=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:46]([F:49])([F:48])[F:47])=[CH:19][N:18]=2)=[C:12]([O:50][CH2:51][CH3:52])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C1COCC1.CO.O.[OH-].[Li+].O>>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@H:35]4[CH2:40][CH2:39][C@H:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:46]([F:47])([F:49])[F:48])=[CH:19][N:18]=2)=[C:12]([O:50][CH2:51][CH3:52])[CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc([C@H]3CC[C@H](C(=O)OCC)CC3)c3c2C(=O)N(C)C3)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc([C@H]3CC[C@H](C(=O)O)CC3)c3c2C(=O)N(C)C3)n1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Ethyl trans-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-ethoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (Example 245, 23.4 mg, 0.031 mmol) was taken up in THF (0.042 mL, 0.52 mmol) and MeOH (0.042 mL, 1.0 mmol). This was treated with a solution of lithium hydroxide, monohydrate (6.57 mg, 0.16 mmol) in H2O (0.042 mL, 2.30 mmol) and allowed to stir at rt for 30 hrs. The reaction was concentrated in vacuo to a solid and was purified by CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dried loaded, elution gradient: 0>5% MeOH in DCM] to afford 22.3 mg (99%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 4.54 (s, 1 H), 4.05-4.21 (m, 6 H), 3.29 (s, 2 H), 3.20 (s, 3 H), 2.60-2.69 (m, 1 H), 2.38-2.48 (m, 1 H), 2.15 (d, J=11.87 Hz, 2H), 1.91-1.98 (m, 2 H), 1.56-1.77 (m, 4 H), 1.43 (t, J=6.95 Hz, 3 H), 1.30 (t, 6 H). MS (ES+): m/z 720.22/721.25 (100/98) [MH+]. HPLC: tR=1.54 min (Micromass TOF: polar—3 min).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:26])[O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](CC2C=CC=CC=2)[CH2:14][CH2:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C)C.[OH-].[Pd+2].[OH-]>[C:1]1([NH:7][C:8](=[O:26])[O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH2:14][CH2:13]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)Oc1ccc2c(c1)CCN2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(Nc1ccccc1)Oc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of 1-benzylindolin-5-yl phenylcarbamate (30 mg, 87 μmol) in 3.0 mL of isopropylalcohol was added palladium hydroxide 10% on carbon (60 mg) under nitrogen. After the vessel was purged with hydrogen, the reaction mixture was stirred under 1 atm of hydrogen at room temperature for 3 h. After the vessel was purged with nitrogen, the reaction mixture was filtered to remove palladium hydroxide 10% on carbon. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 40/60) to obtain the title compound as a white solid (11.5 mg, 52%).