Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].Cl[C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1>>[OH:11][C:4]1[CH:5]=[CH:6][C:7]([CH:8]([CH3:9])[CH3:10])=[C:2]([NH:1][C:13]2[N:18]=[C:17]([NH:1][C:2]3[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=3[CH:8]([CH3:10])[CH3:9])[C:16]([F:20])=[CH:15][N:14]=2)[CH:3]=1
Reactant: CC(C)c1ccc(O)cc1N
Reactant: Fc1cnc(Cl)nc1Cl
Product: CC(C)c1ccc(O)cc1Nc1ncc(F)c(Nc2cc(O)ccc2C(C)C)n1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 3-amino-4-isopropylphenol and 2,4-dichloro-5-fluoropyrimidine were reacted to produce N2,N4-bis(5-hydroxy-2-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.93 (d, 1H, J=3.5 Hz), 7.79 (br s, 1H), 7.64 (br s, 1H), 7.13 (d, 1H, J=8.7 Hz), 7.06 (d, 1H, J=2.3 Hz), 7.05 (d, 1H, J=8.7 Hz), 6.89 (d, 1H, J=2.3 Hz), 6.66 (d, 1H, J=2.3 and 8.7 Hz), 6.57 (d, 1H, J=2.3 and 8.7 Hz), 2.96 (m, 2H), 1.25 (d, 6H, J=7.0 Hz), 1.13 (dd, 6H, J=7.0 Hz); LCMS: ret. time: 24.27 min.; purity: 97%; MS (m/e): 397 (MH+).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].FC(F)(F)C(O)=O.N[C:13]1[CH:14]=[C:15]([C:19]([NH:21][CH2:22][C:23]([NH:25][CH:26]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])=[O:20])[CH:16]=[CH:17][CH:18]=1.[OH-].[K+].C(O)(C(F)(F)F)=O.[ClH:48]>>[ClH:48].[NH2:1][C:2]([NH:4][C:17]1[CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]([NH:25][CH:26]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[O:20])[CH:14]=[CH:13][CH:18]=1)=[O:3]
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(N)c1)c1cccnc1
Reactant: NC(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Nc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2cccnc2)c1

Procedure:
Urea (4 g) and ethyl β-[[2-[[(3-aminophenyl)-carbony]amino]acetyl]amino]pyridine-3-propanoate trifluoroacetate salt (4 g) were dissolved in 20% aqueous HCl (50 ml) and refluxed for 6 hours. The reaction was made basic with KOH (pH>12). After 4 hours the reaction was acidified with TFA and purified by HPLC (RP--CH3CN/H2O). The white solid was dissolved in 1:1 CH3CN:H2O (100 ml) and subjected to the resin exchange described in Example 43, Step C. Lyophilization gave the desired product (3.2 g). MS, 1H-NMR and CHNCl were consistent with the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[Cl:10][CH2:11][CH2:12][CH2:13]I.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH:5][CH2:13][CH2:12][CH2:11][Cl:10]
Reactant: ClCCCI
Reactant: Cc1ccc(N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NCCCCl)cc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 60 %

Procedure:
A mixture of 3-chloro-4-methylaniline (7.79 g, 55 mmol), 1-chloro-3-iodopropane (5.91 ml, 55 mmol), cesium carbonate (35.84 g, 110 mmol) and DMF (15 ml) was stirred at room temperature for 19 hours. To the mixture was added water (75 ml), and the mixture was extracted with hexane (60 ml, 30 ml×2). The organic layer was washed with water (10 ml), dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 200 g, hexane/ethyl acetate=1/0 to 19/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (7.30 g, 33 mmol, Yield 61%) as a pale brown oily substance.
Reaction SMILES: [CH3:1][C@@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:3][CH2:4][CH3:5].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClCCl>[Br:23][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][C@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=2
Reactant: CCC[C@@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCC[C@@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
2-{[(1R)-1-methylbutyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (5.05 g, 16.54 mmol) was dissolved in chloroform (30 ml) and cooled to 0° C. To this solution N-bromosuccinimide (3.24 g, 18.19 mmol) was added portionwise keeping the temperature below 2° C. This gave a dark green solution which was stirred at 0° C. for 30 minutes before allowing to warm to room temperature and stirring for 6 hours. The reaction mixture was washed with water (2×50 ml) and the layers separated using hydrophobic frit. The organic layer was concentrated to give a dark brown gum which was dissolved in dichloromethane and purified by chromatography silica (100 g) using a 0-50% gradient of ethyl acetate-cyclohexane over 60 mins on a Flashmaster II. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow foam (5.23 g).
Reaction SMILES: Cl.N([O-])=O.[Na+].[CH2:6]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1N)[CH3:7].[OH:16]S(O)(=O)=O>O.CCO>[CH2:6]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[OH:16])[CH3:7]
Reactant: CCc1cccc(C)c1N
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1cccc(C)c1O
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
19.4 mL (0.23 mmol) concentrated HCl and a solution of 16.1 g (0.23 mmol) sodium nitrite in water (approx. 70 mL) were added at 0° C. to a solution of 30 g (222 mmol) 2-ethyl-6-methyl-aniline in 135 mL EtOH and stirred for 15 min. This mixture was added at 45° C. to a solution of 10.5 mL of concentrated H2SO4 in 300 mL water and at the end of the addition heated to 70° C. The aqueous phase was cooled to RT and exhaustively extracted with EtOAc. The combined organic phases were extracted with 1 M NaOH solution. The aqueous phase was washed with DCM, acidified to pH 1 with 4 N HCl solution and extracted with DCM. The organic phase was washed with saturated NaCl solution, dried on Na2SO4 and concentrated by evaporation i. vac. The crude product was used in the subsequent reaction step without any further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[SH:13].O.[CH3:15]I>[OH-].[Na+].CCO>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[S:13][CH3:15]
Reactant: Cn1c(S)nnc1-c1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nnc(-c2ccccc2)n1C
Reaction time: 0.25 h

Procedure:
To a solution of 4-methyl-5-phenyl-4H-1,2,4-triazole-3-thiol (2.00 g, 10 mmol) in NaOH 1.0 M in H2O (21 ml, 21 mmol) was added a solution of CH3I (0.98 mL, 16 mmol) in 6 mL EtOH. The reaction became cloudy and then clear. After 15 min, a white solid precipitated out of the reaction. The reaction was filtered, rinsing with water. The solid was collected and dried in vacuo to give 4-methyl-3-(methylthio)-5-phenyl-4H-1,2,4-triazole as a white solid. MS m/z=206 [M+H]+. Calc'd for C10H11N3S: 205.3.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])([CH3:26])[C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH:18]=[CH2:19])[C:13]2[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:12]=2[O:11][C@@H:10]1[CH3:25])=[O:7])C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:17]([N:14]1[C:13]2[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:12]=2[O:11][C@H:10]([CH3:25])[C@H:9]([NH:8][C:6](=[O:7])[C:5]([CH3:27])([CH3:26])[C:4]([OH:28])=[O:3])[C:15]1=[O:16])[CH:18]=[CH2:19]
Reactant: C=CCN1C(=O)[C@@H](NC(=O)C(C)(C)C(=O)OCC)[C@@H](C)Oc2ccc(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCN1C(=O)[C@@H](NC(=O)C(C)(C)C(=O)O)[C@@H](C)Oc2ccc(F)cc21
Yield: 71.9 %

Procedure:
0.72 g (1.84 mmol) N-((6R,7S)-9-Allyl-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-2,2-dimethyl-malonamic acid ethyl ester in 10 ml tetrahydrofurane were treated with 0.08 g (1.84 mmol) lithium hydroxide monohydrate in 3 ml water for 5 hours at room temperature. The tetrahydrofurane was distilled off and the aqueous phase was extracted with diethylether. The water phase was acidified with 1.84 ml 1 N aqueous hydrochloric acid and extracted with ethylacetate to yield 482 mg (72%) N-((6R,7S)-9-allyl-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-2,2-dimethyl-malonamic acid as white solid, MS m/e (%): 365.0 (M+H+, 100).
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C(OC(C)(C)C)=O)[CH:14]=[C:13]3[C:26]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:29]=[CH:28][N:27]=2)=[N:7][N:6]=1)(=O)=O.[NH3:38].O>CS(C)=O>[O:35]1[CH2:34][CH2:33][N:32]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:8]5[S:9][C:5]([NH2:38])=[N:6][N:7]=5)[CH:11]=4)[NH:15][CH:14]=3)[N:31]=2)[CH2:37][CH2:36]1
Reactant: N
Reactant: CC(C)(C)OC(=O)n1cc(-c2nccc(N3CCOCC3)n2)c2cc(-c3nnc(S(C)(=O)=O)s3)ccc21
Solvent: CS(C)=O
Solvent: O
Product: Nc1nnc(-c2ccc3[nH]cc(-c4nccc(N5CCOCC5)n4)c3c2)s1
Temperature: 110 °C
Yield: 5 %

Procedure:
A sealed tube was charged with tert-butyl 5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-3-(4-morpholinopyrimidin-2-yl)-1H-indole-1-carboxylate (1.7 g, 3.3 mmol) in DMSO (17 mL) saturated with NH3. The reaction was heated at 110° C. for 7 h, then the mixture was poured into H2O. The mixture was extracted with EtOAc and the combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography to give 5-(3-(4-morpholinopyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (65 mg, 5%). MS (ESI, pos. ion) m/z: 380.1 (M+1). 1H-NMR (DMSO-d6, 300 MHz) δ: 11.89 (1H, s), 8.79 (1H, s), 8.28 (1H, d, J=6.3 Hz), 8.24 (1H, d, J=2.4 Hz), 7.75 (1H, dd, J=8.4, 1.5 Hz), 7.52 (1H, d, J=8.7 Hz), 7.32 (2H, s), 6.66 (1H, d, J=6.3 Hz), 3.81 (8H, brs).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[F:15].[Cl:16][C:17]1[N:18]=[C:19]([C:24](O)=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>>[Cl:16][C:17]1[N:18]=[C:19]([C:24]([NH:1][C@@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]2[F:15])=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](F)C1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)nc1Cl
Yield: 72.1 %

Procedure:
The same operation as in Example (196d) was performed using tert-butyl trans(±)-4-amino-3-fluoropiperidine-1-carboxylate obtained in Example (197a) (30.0 mg, 0.137 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (28.8 mg, 0.165 mmol), 1-hydroxybenzotriazole hydrate (27.9 mg, 0.206 mmol), WSC hydrochloride (39.5 mg, 0.206 mmol) and triethylamine (28.7 μL, 0.206 mmol), to obtain 37.0 mg of the title compound (72%) as a pale yellow foamy substance.
Reaction SMILES: F[C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5].[F:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH3:30])[CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)=[O:5])=[C:25]([CH3:30])[CH:24]=1
Reactant: Cc1cc(F)ccc1O
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
A mixture of 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)-benzamide (13.6 g, 45.30 mmol), 4-fluoro-2-methyl-phenol (17.1 g, 135.9 mmol), Cs2CO3 (44.28 g, 135.9 mmol) and DMF (340.0 mL) was heated at 100° C. for 1.5 hours. The mixture was cooled to room temperature and was poured into water (500 mL). The mixture was stirred vigorously for 30 min before it was filtered. The solid was washed with water (250 mL) and was slurried with methyl tert-buthyl ether (200 mL). The mixture was filtered and the solid was slurried with hexanes (2×400 mL) and the filtrate was dried under vacuum to give 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (9a) (13.1 g, 70%) as a solid. ESI-MS m/z calc. 406.09, found 407.5 (M+1)+; Retention time: 1.73 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 10.63 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.60 (d, J=7.1 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.26-7.20 (m, 1H), 7.14-7.06 (m, 2H), 7.00-6.95 (m, 1H), 6.75 (d, J=1.8 Hz, 1H), 6.38 (dd, J=7.2, 2.1 Hz, 1H), 2.16 (s, 3H) ppm.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.C(N(CC)CC)C.[CH3:37][C@H:38]1[CH2:40][O:39]1>C(O)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([CH2:37][C@@H:38]([OH:39])[CH3:40])[CH2:6]4)[C:12]([F:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C[C@H](C)O)C1
Temperature: 90 °C

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (15 mg, 0.032 mmol, from Example 67, Step 1) and triethylamine (18 μL, 0.13 mmol) in ethanol (0.53 mL) was added (S)-(−)-methyloxirane (6.8 μL, 0.097 mmol). The resulting mixture was heated at 90° C. for 3 h, then purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The enantiomers were separated on a Phenomenex Lux Cellulose C-4 column (5 μM, 21.2×250 mm), eluting with 20% ethanol in hexanes, at flow rate of 18 mL/min, to give two enantiomers. First peak (2.7 mg, 18%) retention time 8.9 min; LCMS calculated for C21H27ClFN6O2 (M+H)+: m/z=449.2; Found: 449.1. 1H NMR (DMSO-d6, 500 MHz) δ 8.11 (1H, s), 7.42 (1H, d, J=8.5 Hz), 7.25 (2H, br s), 6.21 (1H, q, J=7.5 Hz), 4.28 (1H, d, J=4.0 Hz), 3.82 (3H, m), 3.62 (3H, s), 3.55 (1H, m), 3.05 (1H, m), 2.97 (1H, m), 2.55 (3H, s), 2.28 (2H, m), 1.70 (2H, d, J=7.5 Hz), 1.00 (3H, d, J=6.0 Hz) ppm. Second peak retention time 10.0 min.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[CH:36]([O:35][C:32]1[CH:31]=[N:30][C:29]([N:23]2[CH2:22][CH2:21][C:20]3([CH2:19][C:18]4([O:17][C:14]5=[CH:15][N:16]=[C:11]([C:8]6[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=6)[CH:12]=[C:13]5[CH2:27]4)[CH2:26]3)[CH2:25][CH2:24]2)=[N:34][CH:33]=1)([CH3:38])[CH3:37]
Reactant: CC(C)Oc1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)Oc1cnc(N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)nc1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 60 mg), 2-chloro-5-isopropoxy-pyrimidine (25 mg), potassium carbonate (45 mg), and N-methyl-pyrrolidinone (2 ml) is stirred in a microwave oven at 150° C. for 20 min. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate/methanol 5:5:0→5:5:1) to give the title compound. LC (method 3): tR=0.93 min; Mass spectrum (ESI+): m/z=526 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15](Cl)(=[O:17])=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>N1C=CC=CC=1>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][S:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:17])=[O:16]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)c2ccccc12
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nccs2)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.1 %

Procedure:
To a solution of 4-acetamidonaphthalene-1-sulfonyl chloride (3.69 g, 2.42 mmol) and pyridine (2 ml) was added 2-aminothiazole (0.24 g, 2.42 mmol). This mixture was stirred at RT for 72 h. Purification via silica gel chromatography (first using 2% MeOH in CH2Cl2 to wash out remaining amine, then using 8% MeOH in CH2Cl2) gave N-[4-(thiazol-2-ylsulfamoyl)-naphthalen-1-yl]-acetamide (0.48 g, 57%). LC/MS (10-99% CH3CN), M/Z: M+1 obs=348.10; tR=1.78 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:6][CH2:5]1.[C:7]([CH2:10][N:11]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][N:17]([CH2:23][C:24]([OH:26])=[O:25])[CH2:16][CH2:15][N:14]([CH2:27][C:28]([OH:30])=[O:29])[CH2:13][CH2:12]1)([OH:9])=[O:8].[OH-].[K+]>O1CCOCC1.O>[OH:6][CH:4]([CH2:3][O:2][CH3:1])[CH2:5][N:20]1[CH2:21][CH2:22][N:11]([CH2:10][C:7]([OH:9])=[O:8])[CH2:12][CH2:13][N:14]([CH2:27][C:28]([OH:30])=[O:29])[CH2:15][CH2:16][N:17]([CH2:23][C:24]([OH:26])=[O:25])[CH2:18][CH2:19]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: COCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COCC(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
7.63 g (86.58 mmol) of glycidyl methyl ether and 10 g (28.86 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane are dissolved in a mixture of 50 ml of dioxane/80 ml of water, and the pH is brought to 10 with 6 N potassium hydroxide solution. It is stirred for 24 hours at 50° C. It is evaporated to dryness, the residue is taken up with 300 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 1 with 5 N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and precipitated potassium chloride is filtered out. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then put on a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent =gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 10.38 g (77% of theory) of a greatly hygroscopic, vitreous solid is obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)=[O:8])[CH2:2][CH3:3]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Propoxy-6-pentadecyl-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Propoxy-N-(4-nitro-3-trifluoromethyl-phenyl)-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [H-].[Na+].C1COCC1.CC1C=CC(S(O[CH2:19][CH2:20][N:21]2[CH:25]=[C:24]([I:26])[CH:23]=[C:22]2[CH2:27][OH:28])(=O)=O)=CC=1>O>[I:26][C:24]1[CH:23]=[C:22]2[N:21]([CH:25]=1)[CH2:20][CH2:19][O:28][CH2:27]2
Reactant: Cc1ccc(S(=O)(=O)OCCn2cc(I)cc2CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Ic1cc2n(c1)CCOC2
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a stirred mixture of sodium hydride (0.261 g, 6.53 mmol) and THF (10 mL) was slowly added a solution of 2-(2-(hydroxymethyl)-4-iodo-1H-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate (2.75 g, 6.53 mmol) and THF (25 mL). The reaction mixture was stirred at room temperature for 30 hours, then diluted with water (20 mL) and extracted with EtOAc (2×60 mL). The organic phase was dried over sodium sulfate, evaporated, and purified using silica gel column (80 g) chromatography, eluting with a gradient of 0-100% hexane and EtOAc. The pure compound fractions were combined and evaporated to give the title compound as a tan solid, which turned green on standing (1.02 g, 63%). ESI-MS m/z [M+H]+ calc'd for C7H8INO, 250. found, 250.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][CH2:26][CH3:27])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][CH2:26][CH3:27])[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCCOc1cc(Cl)ccc1CO
Product: CCCOc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-propoxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.01 (3H, t, J=7.2 Hz), 1.77-1.86 (2H, m), 3.98 (2H, t, J=2.4 Hz), 5.24 (2H, s), 5.78 (1H, d, J=1.6 Hz), 6.90 (1H, d, J=1.6 Hz), 6.95 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.34 (1H, d, J=8.4 Hz), 7.39 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.58 (1H, d, J=1.6 Hz), 8.05 (1H, d, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H17ClN4O2, 369; Found, 369.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C@:16]3([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=O)[NH:17]3)[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C@:16]3([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=[S:38])[NH:17]3)[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3cc(Cl)cc(Cl)c3)ccc2F)C1(F)F
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3cc(Cl)cc(Cl)c3)ccc2F)C1(F)F
Yield: 97.3 %

Procedure:
The reaction of (R)-5-(3′,5′-dichloro-4-fluoro-biphenyl-3-yl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (250 mg, 578 μmol) with Lawesson's reagent (187 mg, 463 μmol) in 1,4-dioxane (19 ml) yielded the (R)-5-(3′,5′-dichloro-4-fluoro-biphenyl-3-yl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (202 mg, 78% yield) as a white foam. MS (ISN): m/z=446.0 [M−H]− and 447.9 [M+2-H]−.