Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:53][O:54][C:55]1[CH:63]=[CH:62][C:58]([CH2:59][NH:60][CH3:61])=[CH:57][CH:56]=1>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:60]([CH2:59][C:58]4[CH:62]=[CH:63][C:55]([O:54][CH3:53])=[CH:56][CH:57]=4)[CH3:61])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1ccc(OC)cc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(C)CC(=O)Nc2cc(COc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c4ccccc34)ccn2)cc1
Temperature: 55 °C
Reaction time: 12 h
Yield: 12.3 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.2 mL) and DIPEA (17.5 μl, 0.10 mmol) was added N-(4-methoxybenzyl)-N-methylamine (15.5 μl, 0.09 mmol) The reaction mixture was stirred at 55° C. for 12 hr. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with a mixture of diethyl ether, DCM and iso-hexane (2:1:2, 5.0 mL) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-((4-methoxybenzyl)(methyl)amino) acetamide (Example 14) as a white solid (7 mg, 11%): m/z 713 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.25 (3H, s), 2.39 (3H, s), 3.22 (2H, s), 3.59 (2H, s), 3.72 (3H, s), 5.38 (2H, s), 6.35 (1H, s), 6.90 (2H, m), 7.01 (1H, m), 7.27 (3H, m), 7.35 (2H, m), 7.43 (2H, m), 7.64-7.55 (3H, m), 7.94 (1H, m), 8.37-8.28 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 9.97 (1H, s).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17]CC2C=CC=CC=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][CH3:34])=[O:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O.[Pd]>[CH2:32]([NH:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][C:10]1[C:9](=[O:8])[C:14]([CH3:15])=[C:13]([CH3:16])[C:12](=[O:17])[C:11]=1[CH3:25])[CH2:33][CH3:34]
Reactant: CCCNC(=O)CCCc1c(C)c(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)CCCC1=C(C)C(=O)C(C)=C(C)C1=O
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
A stirred solution of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-N-propylbutanamide (176.6 mg) in TFA (2 mL) was treated with Pd/C (40 mg, 5% Pd by wt), sparged with H2 and heated to 40° C. for 2.25 h. The reaction was cooled, diluted with CH2Cl2, (4 mL) filtered and the solids washed 2×3 mL CH2Cl2 before concentration to a brown oil which solidified upon standing. The crude hydroquinone was dissolved into 1 mL MeCN and 1.5 mL 1 M aqueous CAN added (1.5 mmol, 3.9 equiv.). After 0.25 h, 5 mL EtOAc was added and the organics washed with 4×3 mL saturated NaCl (aq). The combined aqueous layers were back-extracted 2×3 mL EtOAc, the combined organics dried over Na2SO4, concentrated and purified by flash chromatography (gradient elution, 10-50% EtOAc/heptane) yielding N-propyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid (78.0 mg), MS M++H 278; 1H NMR (400 MHz, CDCl3) δ=5.83 (m, 1H), 3.24 (q, 2H), 2.50 (t, 2H), 2.22 (t, 2H), 2.08 (s, 3H), 1.97 (s, 6H), 1.71 (pent, 2H), 1.54 (m, 2H), 0.92 (t, 3H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:23]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:24])[CH2:10][N:9]=2)=[C:18](I)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2].C([Mg]Cl)(C)C.[C:30]1(=[O:34])[CH2:33][CH2:32][CH2:31]1.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:23]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:24])[CH2:10][N:9]=2)=[C:18]([C:30]2([OH:34])[CH2:33][CH2:32][CH2:31]2)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2]
Reactant: CCc1cn(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)cn1
Reactant: O=C1CCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1cn(C2=NCC(=O)N3CCc4c(cccc4C4(O)CCC4)C3=C2)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
113-1. A solution of 2-(4-ethyl-1H-imidazol-1-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (250 mg, 0.58 mmol) in dry THF was cooled to −78° C. under Ar and a solution of iPrMgCl*LiCl (1.78 mL, 2.31 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min and cyclobutanone (0.22 mL, 2.90 mmol) was then added dropwise. The mixture was stirred at −78° C. for another 30 min and then at RT for 4 h. The mixture was poured onto a saturated aq. solution of NH4Cl and the mixture was extracted with AcOEt. The combined org. phases were then dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 9:1) gave the title compound (129 mg) as a red solid. UPLC-MS: MS 377.3 (M+H+); UPLC rt 0.76 min.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].N1C=CC=CC=1.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=1>C(Cl)(Cl)Cl>[Cl:19][C:15]1[CH:16]=[C:17]2[O:18][C:1](=[O:2])[NH:11][C:12]2=[N:13][CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ncc(Cl)cc1O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ncc(Cl)cc2o1
Temperature: 25 °C
Yield: 85 %

Procedure:
Phosgene is introduced at 40°-50° C., after the addition of 20 parts of pyridine, into a solution of 10 parts of 2-amino-3-hydroxy-5-chloropyridine in 200 parts of chloroform, and stirring is maintained for one hour at room temperature; the chloroform and the pyridine are evaporated off in a water-jet vacuum, and ice-water is added to the residue. The precipitate is filtered off and dried at 40°-50° C. in vacuo. There are obtained 10 parts of 6-chloro-oxazolo[4,5-b]pyridin-2-(3H)-one (85% of theory), m.p. 184°-186° C.
Reaction SMILES: [C:1]1([CH:7]([CH:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>ClCCl>[CH2:32]([O:31][C:29]([N:17]1[CH2:18][CH2:19][O:20][CH:15]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:16]1)=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc(CC(c2ccccc2)C2CNCCO2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCOC(C(Cc2ccccc2)c2ccccc2)C1
Reaction time: 24 h

Procedure:
To a solution of 2-(1,2-Diphenyl-ethyl)-morpholine (2 g, 7.49 mmol) in dry dichloromethane (15 ml) at 0° C. under nitrogen atmosphere is added neat triethylamine (2.2 ml, 15.5 mmol, 2.07 equiv.) followed by the addition of neat benzyl chloroformate (1.61 ml, 11.23 mmol, 1.5 equiv.). The reaction is left to reach room temperature over 24 hours and then quenched by addition of a saturated bicarbonate (NaHCO3) aqueous solution. The resulting mixture is extracted with dichloromethane and the resulting organic phases are mixed, dried (MgSO4) and concentrated under reduced pressure to give an oil containing the four possible diastereoisomers (2.3 g, 78%). The diastereoisomers are separated using preparative HPLC, followed by each single enantiomer being resolved by preparative chiral HPLC.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])=[CH:10][CH:9]=1.CC(C)=O.O>O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:12][CH:13]=1
Reactant: O=C(O)CCCc1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCCCCc1ccc(Br)cc1
Yield: 77.9 %

Procedure:
Lithium aluminum hydride (759 mg) was added to a solution of 4-(4-bromophenyl)butyric acid (3.12 g) in tetrahydrofuran (90 mL) under ice-cooling, and the mixture was stirred under ice-cooling for one hour. Acetone and water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1→10:1→7:1 5:1) to give 4-(4-bromophenyl)butan-1-ol (2.29 g, quant.).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18][C@@H:19]([C:21]2[CH2:25][CH2:24][CH2:23][CH:22]=2)O)=[C:16]([CH2:26][CH3:27])[C:15]([CH3:28])=[C:14]2[C:10]=1[C:11](=[O:29])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C(C)(C)C.[C:37](OCC)([O:42]CC)([O:39][CH2:40][CH3:41])[CH3:38]>>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:21]2/[C@H:22]([CH2:38][C:37]([O:39][CH2:40][CH3:41])=[O:42])[CH2:23][CH2:24][CH2:25]/2)=[C:16]([CH2:26][CH3:27])[C:15]([CH3:28])=[C:14]2[C:10]=1[C:11](=[O:29])[O:12][CH2:13]2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C[C@H](O)C1=CCCC1)C(=O)OC2
Reactant: CCOC(C)(OCC)OCC
Agent: CC(C)(C)C(=O)O
Product: CCOC(=O)C[C@@H]1CCC/C1=C\Cc1c(CC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Temperature: 138 °C
Reaction time: 2.5 h

Procedure:
A mixture of (S)-2-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-1-cyclopentenyl-1-hydroxyethane (2.8 g), pivalic acid (0.1 g) and triethyl orthoacetate (125 ml) was heated to 138° C. After 2.5 hours, more pivalic acid (65 mg) was added and the reaction was continued 1 hour more. The reaction mixture was cooled, the excess triethyl orthoacetate removed in vacuo, and the residue chromatographed on silica gel (20% ethyl acetate/hexane) to give ethyl (S)(E)-2-{2-[2-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene]cyclopent-1-yl}acetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH:26]1(O)[CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: OC1CCCC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCCC2)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from rac-[1-(4-chloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and cyclopentanol in analogy to Example 9c): MS (ISP): 466.1 and 468.3 (M+H)+, 366.0 and 368.0 ((M-Boc)+H)+ (100%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9]([CH:12](C#N)[C:13]#N)([CH3:11])[CH2:8][CH2:7]2.[OH-:19].[K+].Cl.[OH2:22]>C(O)CO>[F:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9]([CH2:12][C:13]([OH:22])=[O:19])([CH3:11])[CH2:8][CH2:7]2
Reactant: [OH-]
Reactant: O
Reactant: COc1ccc2c(c1F)C(C)(C(C#N)C#N)CC2
Agent: Cl
Agent: [K+]
Solvent: OCCO
Product: COc1ccc2c(c1F)C(C)(CC(=O)O)CC2
Temperature: 133 °C
Reaction time: 8 h

Procedure:
A solution of 38.3 (190 mg, 0.78 mmol) and potassium hydroxide (860 mg, 15 mmol) in water (0.5 mL) and ethylene glycol (1.0 mL) was heated in a sealed tube and stirred at 133° C. overnight. The reaction was cooled and then acidified with hydrochloric acid to pH ˜1. The mixture was extracted with EtOAc (5×), and the combined organic layers were dried over magnesium sulfate. The filtrate was concentrated to yield crude 38.4 and taken directly to the next step. MS ESI (neg.) m/e: 237.1 (M−H)−.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C1(C)C=CC(S([CH:22]([C:25]([CH3:30])([CH3:29])[CH:26]([CH3:28])[CH3:27])[C:23]#[N:24])(=O)=O)=CC=1.P(O)(O)([O-])=O.[Na+]>O1CCCC1.C1CCCCC1>[CH3:28][C:26]1([CH3:27])[C:25]([CH3:29])([CH3:30])[CH:22]1[C:23]#[N:24]
Reactant: Cc1ccc(S(=O)(=O)C(C#N)C(C)(C)C(C)C)cc1
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CC(C)NC(C)C
Product: CC1(C)C(C#N)C1(C)C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
9.15 ml of a cyclohexane solution of 1.75M of butyllithium were added with stirring under an inert atmosphere at -30° to -40° C. to a mixture of 2.49 ml of diisopropylamine and 5 ml of tetrahydrofuran and after 10 minutes of contact, the mixture was cooled to -60° to -70° C. A mixture of 4.068 g of 4-tolyl sulfonyl-4,3,3-trimethyl-pentanenitrile in 15 ml of tetrahydrofuran were added to the mixture over 5 minutes and the mixture was stirred at -60° to -70° C. for 10 minutes after which the temperature was allowed to rise to 20° to 25° C. The mixture was stirred for one hour and was then poured into an iced aqueous saturated monosodium phosphate solution. The mixture was extracted with n-pentane and the organic phase was dried and evaporated to dryness under reduced pressure. The residue was distilled under reduced pressure to obtain 1.064 g of pure 2,2,3,3-tetramethyl-cyclopropane-carbonitrile with a boiling point of 58°-60° C. at 12-14 mm Hg and a melting point of 17° C.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14](O)[CH3:15].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C1C=CC=CN=1)C>[CH2:14]([O:12][C:11](=[O:13])[C@@H:9]([CH3:10])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2])[CH3:15]
Reactant: CCO
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
Boc-D-alanine (5.0 g, 26.4 mmol), dimethylaminopyridine (161 mg, 1.3 mMol), and ethanol (1.34 g, 29.1 mMol) were dissolved in methylene chloride (300 ml), and the solution was cooled to 0° C. To this solution was added 1,3-dicyclohexylcarbodiimide (6.0 g, 29.1 mMol). The mixture was allowed to slowly come to room temperature, and stirred under nitrogen overnight, during which time a white solid precipitated. The precipitate was removed by filtration, rinsed with methylene chloride, and the filtrate was concentrated to a pale yellow oil. Flash chromatography in 10-30% EtOAc/Hexanes yielded 4.9 g of a colorless oil as product. NMR (300 MHz, CDCl3) δ 5.05 (b, 1H), 4.28 (q, 1H, J=7 Hz), 4.20 (q, 2H, J=7 Hz), 1.45 (s, 9H), 1.38 (d, 3H, J=7 Hz), 1.28 (t, 3H, J=7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.Cl.Cl.[N:52]1([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:55][CH2:54][CH2:53]1.C(N(CC)CC)C.O>CN(C)C=O>[N:52]1([CH:56]2[CH2:61][CH2:60][N:59]([C:13]([NH:12][C:8]3[CH:7]=[C:6]([O:5][C:4]4[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]5([C:40]([NH:41][C:42]6[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=6)=[O:49])[CH2:39][CH2:38]5)=[O:36])=[C:2]([F:1])[CH:3]=4)[CH:11]=[CH:10][N:9]=3)=[O:14])[CH2:58][CH2:57]2)[CH2:55][CH2:54][CH2:53]1
Reactant: C1CN(C2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCC(N2CCC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.5 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) were added 4-(azetidin-1-yl)piperidine dihydrochloride (79.9 mg), triethylamine (0.105 ml) and water (0.050 ml), followed by stirring at room temperature for 24 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (22.9 mg, 51.7%).
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CC(O)C.[C]=O.[C:16]([O:19][CH:20]([CH2:27][CH2:28][S:29][CH3:30])[C:21]([O:23][CH:24](C)C)=O)(=[O:18])[CH3:17]>O1CCCC1.C1(C)C=CC=CC=1>[C:16]([O:19][CH:20]([CH2:27][CH2:28][S:29][CH3:30])[C:21]([O:23][CH3:24])=[S:8])(=[O:18])[CH3:17]
Reactant: CSCCC(OC(C)=O)C(=O)OC(C)C
Reactant: CSCC=COC(C)=O
Agent: [C]=O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 100 °C

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene (Z:E ratio 43:57) and 2.5 mmoles 2-propanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. No catalyst was added. Toluene was included as an internal standard. Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 100° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that no 2-acetoxy-4-(methylthio)butanoic acid, 2-propyl ester was produced and that no 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced. 0.0515 mmoles of acrolein and 0.0456 mmoles of methyl acetate were the only products detectable.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:26]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:23])=[C:12]([CH:22]=1)[NH:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16](SC)[N:15]=1)=[O:6].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:26]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:23])=[C:12]([CH:22]=1)[NH:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:15]=1)=[O:6]
Reactant: C1COCCN1
Reactant: CSc1nccc(Nc2cc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)ccc2C)n1
Solvent: O
Product: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1Nc1ccnc(N2CCOCC2)n1
Temperature: 150 °C

Procedure:
A mixture of 4-[5-(3-fluoro-5-morpholinobenzamido)-2-methylanilino]2-methylthiopyrimidine (0.228 g) and morpholine (1 ml) was stirred and heated to 150° C. for 10 days. The reaction mixture was allowed to cool to ambient temperature and poured into water (10 ml). The resultant precipitate was collected by filtration and dried in a vacuum oven at 60° C. for 16 hours. There was thus obtained the title compound (0.175 g); NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 3.21 (m, 4H), 3.59 (m, 8H), 3.74 (m, 4H), 5.98 (d, 1H), 6.96 (m, 1H), 7.09 (m, 1H), 7.18 (m, 1H), 7.26 (m, 1H), 7.38 (m, 1H), 7.89 (d, 1H), 8.01 (m, 1H), 8.49 (s, 1H), 10.07 (s, 1H); Mass Spectrum: M+H+ 493.
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[OH2:16].Cl>>[CH:12]1[C:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[PH:2](=[O:16])[O:3][C:4]=2[CH:15]=[CH:14][CH:13]=1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Reactant: O
Agent: Cl
Product: O=[PH]1Oc2ccccc2-c2ccccc21
Temperature: 180 °C
Yield: 99.9 %

Procedure:
77.6 g (0.331 mol) of 6-chloro-(6H)-dibenzo[c,e][1,2]oxaphosphorin are heated to 110° C. 5.96 g (0.331 mol) of water are subsequently added over the course of 30 minutes with vigorous stirring, during which some of the hydrogen chloride gas produced departs. The temperature is subsequently raised in steps to 180° C. and is maintained until no further hydrogen chloride is evolved (a period of approximately 2 hours). The reaction product is subsequently cooled, solidifies, and is comminuted. 71.5 g of 6H-dibenzo[c,e][1,2]-oxaphosphorin-6-one (melting point: 117° C.) are obtained, corresponding to a yield of 100 % of theory. In accordance with 31P NMR spectroscopy the purity is 99%, and the content of hydrogen chloride is 0.08%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.Cl.[F:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[F:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:13]([C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[O:15])[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 4-(4-Fluorobenzoyl)piperidine hydrochloride (31.4 mg, 0.151 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.7 mg, 0.197 mmol) and triethylamine (59.8 mg, 0.591 mmol) were mixed in dichloromethane (2 ml) and stirred at room temperature over night. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C23H21FN2O3: 392.1536, found 392.1542.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([CH2:21][OH:22])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.[O-2].[Mn+2]>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([CH:21]=[O:22])=[CH:8][CH:7]=1
Reactant: CN(C)CCNc1ccc(CO)c2sc3ccccc3c(=O)c12
Agent: [Mn+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CN(C)CCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Temperature: 60 °C
Yield: 86.4 %

Procedure:
A mixture of 1-[[2-(dimethylamino)ethyl]amino]-4-(hydroxymethyl)thioxanthen-9-one (9.2 g, 0.028 mol) in toluene (322 mL) was heated to about 60 'C. and then manganese oxide (MnO2, 16 g) was added and the mixture was heated at 60° C. for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to afford 7.9 g (87%) of 1-[[2-(dimethylamino)ethyl]amino]-9-oxothioxanthen-4-carboxaldehyde (Formula II: R1 =R2 =Me; R8 =H; n=2).