Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24](O)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O:29][C:30]([C:32]1([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])C>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:15][C:14]=3[C:24]([NH:43][C:39]3[CH:38]=[C:37]([C:32]4([C:30]([OH:29])=[O:31])[CH2:33][CH2:34][CH2:35][CH2:36]4)[CH:42]=[CH:41][CH:40]=3)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCOC(=O)C1(c2cccc(N)c2)CCCC1
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Product: O=C(Nc1cccc(C2(C(=O)O)CCCC2)c1)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) was reacted with 1-(3-amino-phenyl)-1-cyclopentanecarboxylic acid ethyl ester (prepared from 1-(4-chloro-phenyl)-1-cyclopentanecarboxylic acid using Mutti's procedure (S. Mutti et al. Synth. Comm. 1997, 27, 425)) according to the procedure of Example 20, step d. The ethyl ester was hydrolysed using the same procedure as in Example 247, step b to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.00 (1H, br s), 9.29 (1H, br s), 7.63 (2H, m), 7.16 (1H, m), 7.02 (1H, d), 2.85 (2H, m), 2.49 (3H, m), 1.98-1.34 (33H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 62.88; H, 8.79; N, 7.07%. C41H62N4O8.2.5 mols H2O requires: C, 62.81; H, 8.61; N, 7.15%.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH2:10])=[O:4].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH:10][C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=1)=[O:24])=[O:4]
Reactant: CNC(=O)c1sc(C(C)(C)C)cc1N
Reactant: O=C=Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CNC(=O)c1sc(C(C)(C)C)cc1NC(=O)Nc1ccc(F)cc1
Reaction time: 3 h
Yield: 81.1 %

Procedure:
A slurry of N-methyl-3-amino-5-tert-butylthiophene-2carboxamide (7.63 g, 36 mmol) and 4-fluorophenyl isocyanate (4.93 g, 36 mmol, 1.0 equiv) in anh. toluene (100 mL) was heated at the reflux temp. for 3 h, during which the mixture clarified then generated a new precipitate, which was filtered while hot. The resulting solids were washed with hexane and dried under reduced pressure to afford N-(2-methylcarbamoyl-5-tert-butylthienyl)-N′-(4-fluorophenyl)urea (10.2 g, 81%): mp 203-4° C.; TLC (5% MeOH/CH2Cl2) Rf0.61; 1H NMR (CDCl3) δ1.34 (s, 9H), 2.73 (d, J=4.4 Hz, 3H), 7.07-7.13 (m, 2H), 7.49-7.54 (m, 2H), 7.80 (s, 1H), 7.96 (q, J=4.4 Hz, 1H), 9.88 (s, 1H), 10.46 (s, 1H); 13C NMR (CDCl3) δ25.8, 31.6 (3C), 34.5, 107.4, 115.2 (d, JC-F=22.0 Hz, 2C), 117.3, 120.1 (d, JC-F=7.3 Hz, 2C), 136.1 (d, JC-F=2.4 Hz, 2C), 143.1, 151.6, 157.4 (d, JC-F=238.1 Hz, 1C), 158.0, 164.3; EI-LRMS m/z (rel abundance) 349 (M+, 13%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:17]=[CH:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].Cl>C(Cl)Cl>[C:38]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:17]=[CH:16][C:15]4[N:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1)(=[O:40])[CH3:39]
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CNC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CN(C(C)=O)C1
Temperature: 0 °C

Procedure:
Dissolve 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (75 mg, 0.171 mmol) and triethylamine (52.5 μL, 0.376 mmol) in dry CH2Cl2 (700 μL). Chill to 0° C. and add acetylchloride (13.4 μL, 0.188 mmol). Allow to warm to room temperature overnight. Add 1 N HCl solution and extract with CH2Cl2 (3×5 mL). Combine the organic portions and wash with water (2×5 mL). Dry the organic layer with Na2SO4, filter, and concentrate in vacuo. Purify the resulting residue on HPLC with 5 μm 30×75 mm XBridge C18 column; eluent: 34% water (with 10 mM NH4HCO3 added to pH=10/acetonitrile (isocratic) to give 39 mg, (48%). ES/MS m/z (35Cl) 481.8 [M+1]+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[S:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[C:4]=2[N:3]=1.[Cl:20]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[Cl:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[S:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[C:4]=2[N:3]=1
Reactant: Oc1nc2c3ccc(F)cc3sc2c2ccccc12
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Product: Fc1ccc2c(c1)sc1c3ccccc3c(Cl)nc21

Procedure:
The procedure was similar to step S19C, while the starting material was 29B in stead of 19B.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].[CH3:13][S:14](Cl)(=[O:16])=[O:15].Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc([N+](=O)[O-])cc1NS(C)(=O)=O
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 2-methoxy-5-nitroaniline (5 g) in pyridine (25 ml) at 0° C. was added dropwise methanesulfonyl chloride (3.5 ml) then pyridine (0.5 ml). The mixture was left at 0° C. for 1 hour, then brought to RT for 2 h. The mixture was poured onto ice (100 g) and dilute hydrochloric acid (3M, 100 ml), the solid formed was filtered then washed with water to give 2-Methoxy-5-nitro-methanesulfonylaminobenzene (5.2 g, 71%) as an off-white crystalline solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)(=O)=O)=CC=1>>[F:37][C:33]1[CH:32]=[C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccc(F)c2)cc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Product: O=C(N[C@H]1CCN(CCc2cccc(F)c2)C1)C12CC3CC(CC(C3)C1)C2
Yield: 29.6 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.5 g) and 2-(3-fluorophenyl)ethyl p-toluenesulfonate (0.59 g) were reacted under the same conditions as in Example 6 to give (S)-N-(1-(2-(3-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.22 g), melting point 87-89° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1.[Cl:17][C:18]([Cl:23])([Cl:22])[C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[Cl:17][C:18]([Cl:23])([Cl:22])[C:19]([N:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]1)=[O:20]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)CNC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(N1Cc2ccccc2C1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Triethylamine (3.48 mL, 25.0 mmol) was added to a solution of isoindoline (4.98 g, 25.0 mmol) in chloroform (100 mL) at room temperature and the mixture was cooled in ice. Trichloroacetic acid chloride (2.79 mL, 25.0 mmol) was added dropwise thereto and the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to afford 2,2,2-trichloro-1-(1,3-dihydro-2 H-isoindol-2-yl)ethanone as a purple powder (6.59 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([O:25]C)=O)=[CH:14][C:12]=2[N:13]=1.[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[C:36]([F:39])([F:38])[F:37].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:27][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([F:28])=[C:30]([C:36]([F:39])([F:37])[F:38])[CH:31]=3)=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(F)c(C(F)(F)F)c3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 35.3 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.100 g, 0.245 mmol), 4-fluoro-3-(trifluoromethyl)aniline (0.064 g, 0.357 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) at room temperature to afford 0.048 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.06 (s, 2H), 7.24 (s, 1H), 7.51 (t, J=9.6 Hz, 1H), 7.84 (m, 1H), 8.30 (d, J=4.2 Hz, 1H), 8.45 (s, 2H), 9.84 (s, 1H), 11.99 (br s, 1H), 11.53 (br s, 1H); MS [M+H]+: 554.54.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:34])[N:6]2[C@H:21]1[CH2:26][CH2:25][C@H:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:23][CH2:22]1.[CH3:35]CN(P1(N(C)CCCN1)=NC(C)(C)C)CC.IC>CC#N>[Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:35])[C:5](=[O:34])[N:6]2[C@H:21]1[CH2:26][CH2:25][C@H:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:23][CH2:22]1
Reactant: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Reactant: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](OC2CCCCO2)CC1
Solvent: CC#N
Solvent: CI
Product: Cn1c(=O)n([C@H]2CC[C@H](OC3CCCCO3)CC2)c2nc(-n3cnc4ccc(F)cc43)nc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9-(trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl)-7H-purin-8(9H)-one (0.06 mmol) in anhydrous CH3CN (10 mL) were added BEMP on polystyrene (loading 2.2 mmol/g, 4 equiv.) and iodomethane (primary alkyl iodide/benzyl iodide or bromide to be used for alkylation) (6 equiv.) with stirring at room temperature. After 1 h, LCMS showed reaction to be complete. The reaction mixture was filtered under vacuum, the resin washed with CH3CN and methanol, and the combined filtrate and washings were concentrated in vacuo to give the desired product as a pale yellow solid, which was used in the next step without further purification. MS (EI) m/z 501.2 (MH)+.
Reaction SMILES: N1C=CC=[CH:3][C:2]=1[CH2:7][S@@:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9].N1C=CC=C[C:15]=1C[Li]>C1COCC1>[CH2:7]([S@:8]([C:10]([CH3:11])([CH3:12])[CH3:13])=[O:9])[CH:2]([CH3:3])[CH3:15]
Reactant: CC(C)(C)[S@@](=O)Cc1ccccn1
Reactant: [Li]Cc1ccccn1
Solvent: C1CCOC1
Product: CC(C)C[S@@](=O)C(C)(C)C
Temperature: 25 °C

Procedure:
Preparation of (S)-picolinyl t-butylsulfoxide from (S)-tert-Butyl (1R, 2S)-aminoindanol 4-toluene sulfonamide sulfinate: To a picolinyl lithium solution (2 mL, 0.6 M) in THF at −78° C. was added (S)-t-butyl-(1R, 2S)-aminoindanol tosylate sulfinate (130 mg, 0.30 mmol). The mixture was warmed to room temperature and stirred until the starting material was consumed as monitored by TLC. The reaction was quenched by aq. NaHCO3 (20 mL) and diluted with ethyl acetate (20 mL), and the organic phase was washed with water (20 mL) and brine (20 mL). The organic layer was concentrated in vacuo and the residue was purified by chromatography eluted with ethyl acetate to yield 32 mg of the desired product.
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]1[S:11][C:10]2=[CH:12][C:13]3[S:14][C:15]([CH3:18])=[CH:16][C:17]=3[C:9]2=[CH:8]1.[CH2:19]([O:22][C:23]1[C:28]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][C:26]([CH3:33])=[CH:25][C:24]=1[Si:34](Cl)([CH2:37][CH3:38])[CH2:35][CH3:36])[CH:20]=[CH2:21]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:19]([O:22][C:23]1[C:28]([C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:27][C:26]([CH3:33])=[CH:25][C:24]=1[Si:34]([C:12]1[C:13]2[S:14][C:15]([CH3:18])=[CH:16][C:17]=2[C:9]2[C:10]=1[S:11][CH:7]([CH3:6])[CH:8]=2)([CH2:35][CH3:36])[CH2:37][CH3:38])[CH:20]=[CH2:21]
Reactant: Cc1cc2c(s1)C=C1SC(C)C=C12
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](CC)(CC)C1=C2SC(C)C=C2c2cc(C)sc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
At −78° C., n-butyllithium (1.56 M, 1.69 mL, 2.64 mmol) was added dropwise to a solution of 2,5-dimethylcyclopenta[1,2-b:4,3-b′]dithiophen (0.50 g, 2.42 mmol) in tetrahydrofuran (10 mL) and the mixture was stirred at room temperature for 4 hours. After the reaction mixture was cooled to −78° C., a solution of (2-allyloxy-3-tert-buyl-5-methylphenyl)chlorodiethylsilane (0.72 g, 2.20 mmol) in toluene (3 mL) was added dropwise thereto. The resulting reaction mixture was warmed to room temperature and stirred for 2 hours. After the solvent was distilled off under reduced pressure, toluene was added and the mixture was filtered to remove insoluble substances. The filtrate was concentrated under reduced pressure to quantitatively obtain (2-allyloxy-3-tert-butyl-5-methylphenyl)(2,5-dimethylcyclopenta[1,2-b:4,3-b′]dithiophen-7-yl)diethylsilane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[C:7]([C:15]#[N:16])[C:6]2=O.O=P(Cl)(Cl)[Cl:20].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:20][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][C:7]=1[C:15]#[N:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2[nH]cc(C#N)c(=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Temperature: 70 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (from Step B, 20 g, 87 mmol) and POCl3 (87 mL) was heated to reflux and allowed to stir for 2 hours. The reaction mixture was cooled to 70° C. and concentrated in vacuo to provide a crude residue. The crude residue was diluted with methylene chloride and the resultant solution was cooled to 0° C. and to the resultant solution was added aqueous K2CO3 until the solution was at pH 8-9. The resultant solution was allowed to stir for 30 minutes at 25° C., then transferred to a separatory funnel. The organic layer was collected, washed with water, dried over sodium sulfate, filtered through celite, and concentrated in vacuo to provide 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile as an off-white solid (19.8 g, 92%). A sample recrystallized from methylene chloride was characterized as follows: mp 220-223° C.; 1H NMR (DMSO-d6)δ 8.98 (s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:5][N:4]=1.Cl[C:19]([O:21][CH2:22][CH2:23][Cl:24])=[O:20]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:19]([O:21][CH2:22][CH2:23][Cl:24])=[O:20])[CH2:12][CH2:11][N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:5][N:4]=1
Reactant: O=C(Cl)OCCCl
Reactant: CCN1CCC(O)N(c2nnc(OC)s2)C1=O
Solvent: c1ccncc1
Product: CCN1CCC(OC(=O)OCCCl)N(c2nnc(OC)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C. and chloroethyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-chloroethoxycarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[H-].[Na+].C1C=CC=CC=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:10]#[N:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: BrCCCCCBr
Reactant: COc1ccc(CC#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C2(C#N)CCCCC2)cc1
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
To a solution of 4-methoxyphenylacetonitrile (2) (1.002 g, 6.8 mmol) and 1,5-dibromopentane (1.886 g, 8.2 mmol) in dry dimethylformamide (15 ml) at ice bath temperature slowly (ca. 2-3 min.) a 60% suspension of NaH in mineral oil (0.579 g, 14.4 mmol) was added. The obtained reaction mixture was stirred for 15 minutes at ice bath temperature and for 1.5 hours at room temperature, then the content was poured into benzene (75 ml). The mixture was successively washed with water (3×75 ml), brine (25 ml), and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel (50 g) with petroleum ether-ethyl acetate (5:1) as eluent to give the title compound (0.924 g, 63%) as a white solid. 1H NMR (CDCl3, HMDSO) δ: 1.00-2.28 (10H, m); 3.81 (3H, s); 6.90 (2H, d, J=9.0 Hz); 7.40 (2H, d, J=9.0 Hz).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]([C:24](=[O:25])[NH:14][C:13]1[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)[CH:27]([CH3:28])[CH3:29])([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccnc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N2-phenylpyridine-2,3-diamine (556 mg, 3.0 mmol), (S)-2-tertbutoxycarbonylamino-3-methylbutyric acid (0.72 g, 3.3 mmol), HOAt (0.450 g, 3.3 mmol), 4-methylmorpholine (0.73 mL, 6.6 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.63 g, 3.3 mmol) in DCM (15 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-2-methyl-1-(2-phenylaminopyridin-3-ylcarbamoyl)propyl]carbamic acid tert-butyl ester as a white solid (1.13 g, quantitative).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40]>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:45]5[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: CS(=O)(=O)N1CCNCC1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Yield: 18.3 %

Procedure:
In the manner described in Example 30 (1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 27B (225 mg, 0.427 mmol) was reacted with 1-methanesulfonyl-piperazine (140.2 mg, 0.854 mmol) to yield 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-(methyl sulfonyl)piperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea (51 mg, 18%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.05 (s, 1H), 8.55 (s, 1H), 7.58 (d, 2H), 7.35 (m, 2H), 7.22 (d, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.25 (m, 2H), 3.98 (s, 3H), 3.15 (m, 5H), 2.88 (s, 4H), 2.55 (m, 4H), 2.00 (m, 2H), 1.25 (s, 9H); LC-MS (ESI) m/z 654 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[NH:32]1[CH2:36][CH:35]=[CH:34][CH2:33]1>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:32]1[CH2:36][CH:35]=[CH:34][CH2:33]1)=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: C1=CCNC1
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N1CC=CC1

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and 3-pyrroline.
Reaction SMILES: [CH:1]1([NH:7][C:8]([N:10](C2CCCCC2)[CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[NH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[P:30](=[O:34])([OH:33])([OH:32])[OH:31].CCO[CH2:38][CH3:39]>C(O)C>[P:30]([OH:34])([OH:33])([OH:32])=[O:31].[CH:1]1([NH:7][C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[N:9][CH:39]2[CH2:38][CH2:3][CH2:2][CH2:1][CH2:6]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(NC1CCCCC1)N(CCOc1ccc2ccccc2c1)C1CCCCC1
Reactant: CCOCC
Agent: O=P(O)(O)O
Solvent: CCO
Product: c1ccc2cc(OCCNC(=NC3CCCCC3)NC3CCCCC3)ccc2c1

Procedure:
10.0 g of 1,3-dicyclohexyl-3-[2-(2-naphthyloxy)ethyl]guanidine was dissolved in ethanol (100 ml) and 5.7 g 85% phosphoric acid in 100 ml ethanol was added to this solution. After 16 hours 1400 ml ether was added to the solution. The resulting precipitate was removed by filtration and dried under vacuum to afford the title compound (mp 132°-134°).