Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:4][C:3]=1[C@H:31]([NH:36][S@@](C(C)(C)C)=O)[C:32]([F:35])([F:34])[F:33]>CO.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:4][C:3]=1[C@H:31]([NH2:36])[C:32]([F:33])([F:35])[F:34]
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc([C@H](N[S@](=O)C(C)(C)C)C(F)(F)F)c(Cl)c5)nn34)ccnc2c1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc([C@H](N)C(F)(F)F)c(Cl)c5)nn34)ccnc2c1
Reaction time: 0.5 h

Procedure:
A solution of (R)—N—((S)-1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (135 mg, 218 μmol) in MeOH (2 mL) and 4M HCl (2 mL) was stirred for 30 min at 35° C. LCMS suggests full conversion. Solvents removed under reduced pressure with azeotroping from toluene. Residue dissolved in MeOH (10 mL) and Si-Carbonate (2 g; 1.4 mmol) added. Suspension stirred for 30 min, then filtrated collected by filtration. Solvents removed under reduced pressure and residue purified on silica (12 g) eluting product with 0>5% MeOH/DCM. MS (ESI pos. ion) m/z: 515 (MH+). Calc'd exact mass for C24H18ClF3N6O2: 514.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9](=[O:17])[C:10](=[O:16])[C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])=[O:4].CCOCC.[Li+].[OH-].Cl>O.CO>[O:17]=[C:9]([N:6]1[CH2:7][CH2:8][C@H:5]1[C:3]([OH:4])=[O:2])[C:10](=[O:16])[C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13]
Reactant: CCC(C)(C)C(=O)C(=O)N1CC[C@H]1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CCC(C)(C)C(=O)C(=O)N1CC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of (2S)-Methyl-1-(1,2-dioxo-3,3-dimethylpentyl)-azetidine-2-carboxylate from Reference Example 3 (0.64 g, 2.65 mmol) in a 1:1 mixture of ether:methanol (20.0 mL) was added LiOH in water (4.9 mL, 1N solution) at about 0° C. The mixture was stirred at about 0° C. for about 30 minutes and then at about room temperature overnight. The pH was adjusted to about pH 1 by adding 1N HCl, then the mixture was diluted with water and extracted with dichloromethane. The organic layers were washed with brine and dried over sodium sulfate and then concentrated to give 0.40 g (67% yield) of the product as a yellow semisolid. 1H NMR (DMSO) δ 0.77-0.83 (m, 3H); 1.20-1.29 (series of s, 6H); 1.49-2.84 (series of m, 4H); 4.02-4.43 (series of m, 2H); 5.01-5.31 (series of dd, 1H); 6.10-6.80 (br, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cesium carbonate (1.82 g), 1-iodo-2,2-dimethylpropane (0.74 mL) and N,N-dimethylacetamide (10 mL) was stirred at 130° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([Cl:13])[CH3:12].[O-:14][C:15]#[N:16].[K+].O>COCCOCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([Cl:13])[CH3:12].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15](=[O:14])[NH:16][C:11]([CH3:12])=[N:10]1
Reactant: N#C[O-]
Agent: CC(Cl)=NNc1ccc(Cl)cc1Cl
Agent: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: Cc1nn(-c2ccc(Cl)cc2Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 5.1 grams (0.0214 mole) of N-(2,4-dichlorophenyl)ethanehydrazonoyl chloride (A), prepared as in Example 1, 2.1 grams (0.0257 mole) potassium cyanate, and 3 mL of water in 51 mL of diglyme was stirred at ambient temperature for about 22 hours. After this time, the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in about 500 mL of ethyl acetate and washed with three 25 mL portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was triturated with hexane and the resultant solid was collected by filtration. The solid was dried, yielding 4.5 grams (85.2% yield from (A)) of subject compound (I).
Reaction SMILES: [C:1]([O:4][CH:5]([C@@H:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([N:14]2[C:18]3[N:19]=[C:20]([NH2:24])[NH:21][C:22](=[O:23])[C:17]=3[S:16][C:15]2=[O:25])[O:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1>[C:1]([O:4][CH:5]([C@@H:8]1[CH2:12][C:11](=[O:13])[C@H:10]([N:14]2[C:18]3[N:19]=[C:20]([NH2:24])[NH:21][C:22](=[O:23])[C:17]=3[S:16][C:15]2=[O:25])[O:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2]
Reactant: CCC(OC(C)=O)[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CCC(OC(C)=O)[C@@H]1CC(=O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl acetate (compound 22a, 2.8 g, 7.6 mmol) in THF (100 mL) was added Dess-Martine periodinane (4.8 g, 11.3 mmol). After being stirred at room temperature for 2 hours, the resulting solution was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:10 methanol in DCM) to afford 2.8 g crude product of 1-[(2S,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-oxo-tetrahydrofuran-2-yl]propyl acetate (compound 22b). MS obsd. (ESI−) [(M−H)−]: 367.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6]C)=[O:5].[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.Cl.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.C([Si](C)(C)Cl)(C)(C)C>[CH3:20][C:19]([Si:23]([CH3:26])([CH3:25])[O:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([OH:6])=[O:5])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 30 h
Yield: 103.5 %

Procedure:
50 g of methyl (R)-3-hydroxytetradecanoate, 35 g of t-butyldimethylchlorosilane, 6.1 g of 4-dimethylaminopyridine and 29.4 g of triethylamine were dissolved in 200 ml of methylene chloride and stirred at room temperature for 30 hours as well as under reflux for 16 hours. Thereupon, a further 2 g of t-butyldimethylchlorosilane were added. After a further 24 hours under reflux the precipitated triethylamine hydrochloride salt was filtered off, washed with ether and the filtrate was concentrated. The residue was dissolved in ether and washed in sequence with water, 0.5M citric acid, again with water and saturated sodium chloride solution, dried, concentrated and subsequently freed from volatile material at 5° C. in a high vacuum for 5 hours. There were obtained 71.8 g of (R)-3-[(1,1-dimethylethyl)dimethylsilyloxy]tetradecanoic acid, IR (cm-1): 1745, 1254, 895, 776.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[NH:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1.[I-].[Na+]>COCCOC>[NH:24]1[C:25]2[C:21](=[CH:20][CH:19]=[C:18]([NH:17][C:9]3[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:29]5[CH2:34][CH2:33][S:32][CH2:31][CH2:30]5)=[C:6]([O:27][CH3:28])[CH:7]=4)[N:12]=[CH:11][C:10]=3[C:15]#[N:16])[CH:26]=2)[CH:22]=[N:23]1
Reactant: C1CSCCN1
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN1CCSCC1
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 173.0 mg (0.44 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 454.0 mg (4.4 mmol) of thiomopholine and 66.0 mg (0.44 mmol) of sodium iodide in 4 mL of DME was heated at 135° C. for 16 hr. The work up gave 108.4 mg (53.5%) of the product as a light yellow solid, m.p. 213-215° C., mass (electrospray, m/e): M+H 461.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]([CH3:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31](C)[C:32](=O)OC(C)(C)C)=[C:19]([OH:41])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]([CH3:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][CH3:32])=[C:19]([OH:41])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CN(CCCCCCCCN(C)C(=O)OC(C)(C)C)Cc1c(O)ccc2c1O/C(=C\c1c[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCCCCCCCCN(C)Cc1c(O)ccc2c1O/C(=C\c1c[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A solution of tert-butyl (Z)-8-[({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)(methyl)amino]octyl(methyl)carbamate (0.020 g, 0.036 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and then the residue was added with triethylamine and thereby made basic. Then, the mixture was azeotroped with toluene, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxy-7-({methyl[8-(methylamino)octyl]amino}methyl)benzofuran-3(2H)-one (0.010 g, 60%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]1[S:10][C:9]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([NH2:22])=[O:21])[C:13]=3[N:12]=2)=[CH:8][CH:7]=1.C=O.[C:25]([BH3-])#N.[Na+]>CO.O>[CH3:25][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]1[S:10][C:9]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([NH2:22])=[O:21])[C:13]=3[N:12]=2)=[CH:8][CH:7]=1
Reactant: [BH3-]C#N
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc([C@H]4CCCN4)s3)nc12
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCC[C@@H]1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)s1
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 16D (50 mg) in methanol (20 mL) was treated with 37 wt % formaldehyde in water (114 μL) and stirred overnight. Sodium cyanoborohydride (315 mg) was added, and the solution was stirred for 3 hours and concentrated. The concentrate was dissolved in methanol and TFA, and purified by HPLC (Zorbax C-8, 0.1% TFA/acetonitrile/water). 1H NMR (CD3OD) δ 2.30 (m, 2H), 2.47 (m, 1H), 2.74 (m, 1H), 2.94 (s, 3H), 3.31-3.40 (m, 1H), 3.88 (m, 1H), 4.81 (m, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.51 (d, J=3.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.86 (d, J=4.0 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:19]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(OCCCCOc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1ccc(OCCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1

Procedure:
1,4-Diphenoxy-n-butane (24.2 g) and benzoyl chloride (29 g) are reacted in 250 ml of 1,2-dichloroethane in the presence of aluminum chloride (28 g) for 4 hours at 60° to yield 18.3 g (41% of theory) of colorless crystals mp 163°-4°. Calculated for C30H26O4 : C, 79.98% H, 5.82%. Found: C, 80.16%; H, 5.98%.
Reaction SMILES: [OH:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18].CI.[C:28](=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[OH:1][C:2]1[N:7]([CH3:28])[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18]
Reactant: CCOC(=O)CNC(=O)c1c(O)[nH]c(=O)n(Cc2ccccc2)c1=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 28.2 %

Procedure:
A mixture of ethyl N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate (295 mg, 0.85 mmoles), methyl iodide (62 uL, 1.0 mmoles) and sodium carbonate (320 mg, 3.0 mmoles) in dimethylformamide (5.0 mL) was stirred under argon at 100° C. for 2.5 hours. The mixture was cooled, poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The ester was hydrolysed by stirring in a mixture of ethanol (5 mL) and 1 molar sodium hydroxide solution (4 mL) for 4 hours. The mixture was acidified and extracted with ethyl acetate. Purification by preparative HPLC (acetonitrile-water-0.1% TFA, 20-100%) and crystallization from ether-hexane gave the title compound (80 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1 H), 10.09 (br. s., 1 H), 7.28-7.36 (m, 4 H), 7.19-7.29 (m, 1 H), 5.01 (s, 2 H), 4.14 (d, J=5.81 Hz, 2 H), 3.21 (s, 3 H).
Reaction SMILES: [CH:1]([O:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC3C=CC=CC=3)[C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:6]1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH2:6][C@H:7]2[CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[C:12]1=[O:27]
Reactant: [H][H]
Reactant: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Reaction time: 8 h

Procedure:
A sample of benzyl (S)-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate A (faster isomer, 0.41 g) and Pd/C (0.08 g) were taken in MeOH (20 mL) and stirred at rt under 50 psi hydrogen pressure. After stirring overnight, the reaction mixture was filtered through Celite using EtOAc. Upon concentration and drying in vacuo, (S)-3-amino-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one was obtained as a clear viscous oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([O:16]CC3C=CC=CC=3)[CH:13]=[C:12]([O:24][CH:25]([CH2:28][F:29])[CH2:26][F:27])[CH:11]=2)=[N:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([O:24][CH:25]([CH2:26][F:27])[CH2:28][F:29])[CH:11]=2)=[N:3]1
Reactant: Cc1cc(NC(=O)c2cc(OCc3ccccc3)cc(OC(CF)CF)c2)nn1C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(NC(=O)c2cc(O)cc(OC(CF)CF)c2)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of N-(1,5-dimethyl-1H-pyrazol-3-yl)-3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzamide (1.89 mmol) in ethanol (30 mL) was treated with 10% palladium on carbon (78 mg, wetted with 1 mL ethanol). The flask was evacuated and filled with hydrogen and this procedure repeated a further 4 times. The mixture was left to stir at RT overnight under an atmosphere of hydrogen then the mixture filtered through Celite® and the cake washed with ethanol (50 mL) and ethyl acetate (50 mL). The combined organics were evaporated in vacuo to give the desired compound as a white foam (613 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=O)=[N:6][C:7]=1[Cl:8].[NH2:12][C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([NH2:16])=[O:15]>>[C:14]([C@@H:13]([NH:12][C:9]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([Cl:8])[N:6]=1)=[O:11])[CH2:17][CH:18]([CH3:20])[CH3:19])(=[O:15])[NH2:16]
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(Br)c(Cl)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-bromo-6-chloropicolinic acid (CAN 959958-25-9) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=350.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH3:14])[N:3]=1.COCCOC.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:14])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]=1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1Cl
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccccc1
Yield: 66.1 %

Procedure:
To a suspension of methyl 2-(2,4-dichloro-6-methylpyrimidin-5-yl)acetate (4.42 g; 18.80 mmol) in a mixture of degassed DME (75 mL) and water (25 mL) was added phenyl boronic acid (5.73 g; 47 mmol), Tetrakis(triphenylphosphine) palladium(0) (2 g; 1.731 mmol) and diisopropyl ethylamine (12.96 mL; 75 mmol). The reaction was stirred under reflux for 3.5 h. The reaction mixture was partitioned between brine and ethyl acetate. The phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to give 3.44 g (65%) of the title compound as a white solid. ESI/APCI(+): 277 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12].C([O-])([O-])=O.[Na+].[Na+]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:12][CH2:11][C:10]([OH:14])=[O:13]
Reactant: Sc1cccc(Cl)c1Cl
Reactant: C=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CCSc1cccc(Cl)c1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
2,3-Dichlorothiophenol (4.94 g, 28 mmol) was placed in a flask with acrylic acid (2.11 g, 29 mmol) and stirred at 50° C. for 3 hours. The reaction mixture was poured into 10% Na2CO3 and extracted with ether. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give the 3-(2,3-dichlorophenylthio)propanoic acid (3.88 g), contaminated with some acrylic acid, as a clear oil which was used without further purification in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:44])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([CH3:43])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[O:44])=[CH:17][C:18]=4[CH3:43])=[N:42][C:27]2=3)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: Cc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 93 %

Procedure:
A solution of 0.071 g (0.115 mmole) of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-191) in 4 mL of dichloromethane was stirred with 2 mL of trifluoroacetic acid for 2 hours and concentrated under reduced pressure. The residue was dissolved in 80 mL of dichloromethane, washed with 15 mL of sodium carbonate solution, twice with 15 mL of brine and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 90:10-0:100) to give 0.0549 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-N-piperidin-4-yl-benzamide (I-192) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN(C)C=O>[Cl:23][CH2:22][CH2:21][CH2:20][N:8]1[C:2](=[O:1])[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]1=2
Reactant: ClCCCBr
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2Nc2ccccc2N1CCCCl
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine (12.1 g, 0.058 mol, prepared as described in Synthesis, 1985, 550) in dry N,N-dimethylformamide (150 ml) kept under an atmosphere of nitrogen, sodium hydride (2.8 g, 0.069 mol, 60% dispersion in oil) was added and the reaction mixture was stirred for 1 hour. 1-Bromo-3-chloropropane (10.9 g, 0.069 mol) was slowly added and the mixture was stirred overnight. The reaction mixture was quenched with water (200 ml) and extracted with diethyl ether (2×250 ml). The combined organic extracts were washed with water (3×300 ml), dried (MgSO4) and the solvent was evaporated in vacuo. The solid was washed with heptane (100 ml), filtered off and dried, affording 11.1 g (67%) of 10-(3-chloropropyl)-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one.
Reaction SMILES: NC(N)=O.[CH2:5]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=1[OH:19])(=[O:10])=[O:9])[CH3:6].[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:29]([NH:28][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=2[Cl:20])=[O:30])=[C:12]([OH:19])[C:11]=1[S:8]([NH:7][CH2:5][CH3:6])(=[O:9])=[O:10]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=O
Product: CCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 41.5 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-ethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (266 mg, 1.06 mmol) and 2,3-dichlorophenylisocyanate (200 mg, 1.06 mmol) were coupled to form the desired urea (193 mg, 41%). LC-MS (m/z) 440.0 (M+).