Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]1)[CH3:2].[H][H]>C(O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCN(C(C)(C)C)CC1
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)CC1CCN(C(C)(C)C)CC1
Yield: 78 %

Procedure:
To a solution of (1-tert-butyl-piperidin-4-ylidene)-acetic acid ethyl ester (5.1 g, 22.7 mmol) in ethanol (50 mL) 10% Pd/C (0.6 g) was added and the mixture was stirred under the hydrogen atmosphere (42 psi) at ambient temperature for 14 hours. The catalyst was removed by filtration, and the filtrate was concentrated to give the title (4.03 g, yield 78%), which was used in the next step directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[NH:57][C:56](=[O:58])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49]2)=[CH:44][C:43]=1[O:59][CH3:60]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)[O:11][N:10]=2)[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[O:28][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[NH:57][C:56](=[O:58])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49]2)=[CH:44][C:43]=1[O:59][CH3:60]
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Reactant: COc1cc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)on2)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1c(OC)cc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)on2)cc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 75.2 %

Procedure:
2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenol (20b) (387.38 mg, 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (25d) (546 mg, 80% yield).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].FC(F)(F)C(O)=O.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCC
Reactant: CCO[SiH](OCC)OCC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 87.4 %

Procedure:
224 mg Of octene-1, 328 mg of triethoxysilane and 56 mg of toluene were placed in a glass reaction tube and 0.002 ml of trifluoroacetic acid then added. Then, 0.001 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of octene-1 was 95.2% and n-octyltriethoxysilane was produced at a yield of 87.4%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC2C=CC=C(N(C)C)C=2)[CH:5]=[C:4]([F:18])[C:3]=1/[CH:19]=[C:20](\[CH3:24])/[C:21]([OH:23])=[O:22].F[C:26]1C=C(F)C=C(OC2C=CC=C(N(C)C)C=2)[C:27]=1/C=C(\C)/C(O)=O.[F:49]C1C=C(F)C=C(F)C=1C=O>>[F:18][C:4]1[CH:5]=[C:6]([F:49])[CH:7]=[C:2]([F:1])[C:3]=1/[CH:19]=[C:20](\[CH3:24])/[C:21]([O:23][CH2:26][CH3:27])=[O:22]
Reactant: C/C(=C\c1c(F)cc(Oc2cccc(N(C)C)c2)cc1F)C(=O)O
Reactant: O=Cc1c(F)cc(F)cc1F
Reactant: C/C(=C\c1c(F)cc(F)cc1Oc1cccc(N(C)C)c1)C(=O)O
Product: CCOC(=O)/C(C)=C/c1c(F)cc(F)cc1F

Procedure:
E-3-[2,6-Difluoro-4-(3-dimethylaminophenoxy)phenyl]-2-methyl-propenoic acid guanidide and E-3-[2,4-difluoro-6-(3-dimethylaminophenoxy)-phenyl]-2-methyl-propenoic acid guanidide ##STR16## 11 a/12 a) Ethyl E-3-[2,4,6-trifluorophenyl]-2-methyl-propenoate was synthesized analogously to 8 a starting from 2,4,6-trifluorobenzaldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:28]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:29])[CH:25]=[CH:26][CH:27]=1.[Cl:36]C1C=C(C(C2C=NC=CC=2)=O)C=CC=1>>[Cl:36][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[OH:29])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1cccnc1)c1cccc(Cl)c1
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1
Reactant: COc1cccc(C(=O)c2cccnc2)c1
Product: COc1cccc(C(O)(c2cccnc2)c2ccc3ncc(-c4ccccc4)c(Cl)c3c2)c1

Procedure:
The title compound was prepared using 6-bromo-4-chloro-3-phenylquinoline (Intermediate 3, step c) and (3-methoxyphenyl)(pyridin-3-yl)methanone in place of 6-bromo-2,4-dichloro-3-phenylquinoline and (3-chlorophenyl)(pyridin-3-yl)methanone, respectively, according to the procedure described in Example 25. 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.61-8.65 (m, 1H), 8.53-8.57 (m, 1H), 8.37 (d, J=1.96 Hz, 1H), 8.09 (d, J=9.05 Hz, 1H), 7.68-7.75 (m, 2H), 7.50-7.55 (m, 5H), 7.26-7.30 (m, 2H), 6.83-6.91 (m, 3H), 3.75 (s, 3H); MS m/e 452.9 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+]>C1COCC1>[CH2:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ClCCCCCCOCc1ccccc1
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a stirred solution of 6-chloro-1-hexanol (15.0 g, 0.110 mol) and benzyl bromide (18.8 g, 0.110 mol) in dry THF (200 ml) at room temperature under argon was slowly added (over 30 min.) sodium hydride powder (2.899 g, 0.121 mol). The solution was left overnight and the solids filtered off. The solvent was removed under reduced pressure, the residues taken up into dichloromethane (100 ml) and washed (2×20 ml water). The solution was dried over MgSO4 and the solvent removed to yield an orange oil which was subsequently distilled (160° C., 0.5 mBar) to yield the title compound (17.5 g, 70%) as a colourless oil. C13H19OCl requires 226. Found DCl: MNH4+, 244. δH (CDCl3) 1.49 (4H, m, (CH2)2(CH2)2Cl), 1.70 (2H, p, CH2CH2O), 1.83 (2H, t, CH2CH2Cl), 3.54 3.56 (4H, 2×t, CH2CH2O, CH2Cl), 4.56 (2H, s, CH2Ph), 7.40 (5H, m, Ph). δC (CDCl3) 25.3 (1C, CH2(CH2)2Cl), 26.4 (1C, CH2(CH2)3Cl), 29.3 (1C, CH2(CH2)2O), 32.3 (1C, CH2CH2Cl), 44.8 (1 C, CH2Cl), 69.9, 72.6 (2C, CH2O), 127.2 (1C, CH(CH2)2C), 127.3 (2C, CHC), 128.1 (2C, CHCHC), 138.4 (1C, CCH2O).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](/[CH:18]=[C:19]3/[C:20](=[O:28])[NH:21][C:22]4[C:27]/3=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:16]=2)[CH:11]=[N:10]1>CN(C=O)C>[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C@H:18]3[C@@:19]4([C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][C:20]4=[O:28])[CH2:2]3)[CH:16]=2)[CH:11]=[N:10]1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2cn[nH]c2c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
To a solution of trimethylsulfoxonium iodide (264 mg, 1.2 mmol) in anhydrous DMF (40 mL) was added sodium hydride (60% dispersion in oil) (140 mg, 3.48 mmol) at 0° C. The mixture was stirred for 15 min after which time (E)-3-((1H-indazol-6-yl)methylene)indolin-2-one (151 mg, 0.58 mmol) was added. The solution was stirred overnight at rt. The reaction was quenched with sat. NH4Cl solution (10 mL), extracted with EtOAc (4×50 mL), dried over MgSO4 and concentrated to dryness. The major diastereomer was isolated by silica gel chromatography (EtOAc/Hex 1:1) as a beige solid (44 mg, 28%). 1H NMR (400 MHz, d6-DMSO) δ 13.01 (s, 1H), 10.61 (d, 1H J=8.3 Hz), 8.01 (s, 1H), 7.63 (d, 1H, J=8.3 Hz), 7.44 (s, 1H), 6.99 (t, 1H, J=7.5 Hz), 6.92 (d, 1H, J=8.0 Hz), 6.84 (d, 1H, J=8.0 Hz), 6.51 (t, 1H, J=7.0 Hz), 5.98 (d, 1H, 8.0 Hz), 3.20-3.17 (m, 1H), 2.30-2.26 (m, 1H), 2.00-1.95 (m, 1H); MS ESI 276.1 [M+H]+, calcd for [C17H13N3O+H]+ 276.3.
Reaction SMILES: [OH:1][C:2]1[CH:25]=[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:11]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:37](I)[CH2:38][CH:39]([CH3:41])[CH3:40].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:27]([O:26][C:24]1[CH:23]=[CH:22][C:3]([C:4]([C:6]2[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)=[O:5])=[C:2]([O:1][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH:25]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2O)ccc1OCC(C)C
Reactant: CC(C)CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2OCCC(C)C)ccc1OCC(C)C
Temperature: 120 °C
Reaction time: 2 h

Procedure:
In 3 ml of N,N-dimethylformamide are suspended 0.28 g of methyl 2-[5-(2-hydroxy-4-isobutoxybenzoyl)-2-isobutoxyphenyl]acetate, 0.32 g of potassium carbonate and 0.23 ml of isopentyl iodide. The suspension is stirred at 120° C. for 2 hours. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 0.17 g of methyl 2-[5-(4-isobutoxy-2-isopentyloxybenzoyl)-2-isobutoxyphenyl]-acetate as a colorless oily product.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=O)=O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10](S)=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:1][Cl:5]
Reactant: Cc1ccc(S)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccccc1SCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
A solution of 27.2 g of sulfuryl chloride in 50 ml of dry carbon tetrachloride was added dropwise to a cold (ice-salt bath) solution of 25 g of 4-methylbenzenethiol in 50 ml of carbon tetrachloride containing a few drops of pyridine. The solution was stirred for 0.5 hour at ice-salt bath temperature, allowed to warm to room temperature, then heated under gentle reflux for 0.5 hour. The solution was filtered through a layer of anhydrous sodium sulfate and the filtrate concentrated under reduced pressure. The red liquid residue was distilled to give 24.1 g of 2-methylbenzenesulfenyl chloride, b.p. 67°-69° at 2 mm, nD25 1.6015.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([N:21]=[C:22]=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:15]([NH:21][C:22]([N:11]1[CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:14])[NH:9][C:10]1=[O:13])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=c1[nH]cc(-c2ccccc2)c(=O)[nH]1
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)n1cc(-c2ccccc2)c(=O)[nH]c1=O
Yield: 44 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 1, starting from 5-phenyluracil (0.05 g, 0.26 mmol); 1.8 equivalents of hexyl isocyanate were used herein. The crude was purified by silica gel column chromatography (cyclohexane:EtOAc 70:30) to afford the title compound (0.04 g, 44%) as white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (t, J=6.5 Hz, 3H), 1.16-1.37 (m, 6H), 1.43-1.61 (m, 2H), 3.23-3.32 (m, 2H), 7.30-7.46 (m, 3H), 7.48-7.57 (m, 2H), 8.28 (s, 1H), 9.19 (t, J=5.6, 1H), 11.94 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 14.14, 22.67, 26.66, 29.31, 31.53, 41.50, 116.87, 128.53, 128.76, 131.49, 136.05, 149.92, 151.03, 161.31. MS (ESI) m/z: 333 [M-NH4]+. MS (ESI) m/z: 314 [M-H]−.
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[Br:35][CH2:36][CH2:37][CH2:38][C:39](Cl)=[O:40].C(N(CC)CC)C.ClCC(NC1N=C2C(C3C=CC=C(C(F)(F)F)C=3)=C(C)C(C3N(C4C=CC(C#N)=CC=4)N=CC=3)=CN2N=1)=O>>[Br:35][CH2:36][CH2:37][CH2:38][C:39]([NH:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1)=[O:40]
Reactant: O=C(Cl)CCCBr
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Agent: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCCBr)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 400 mg, 1.0 mmol), 4-bromo-butyryl chloride (0.5 mL, 4.32 mmol) and triethylamine (0.84 mL, 6.02 mmol) instead of DIPEA using a similar method to that employed for Intermediate 17 (362 mg).
Reaction SMILES: C([Cl:4])(=O)C.[CH2:5]([C:9]1[S:18][C:17]2[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]=[C:12]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[C@@H:25]([CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:24]3)[C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8].CO>C(O)C>[ClH:4].[ClH:4].[CH2:5]([C:9]1[S:18][C:17]2[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]=[C:12]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[C@@H:25]([CH2:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:24]3)[C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)Cl
Agent: CCCCc1nc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccccc2)C1
Solvent: CO
Solvent: CCO
Product: Cl

Procedure:
Add a solution of acetyl chloride (0.15 mL, 2.1 mmol) in absolute ethanol at ambient temperature to (S)-2-Butyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.19 g, 0.41 mmol) in absolute ethanol, with added drops of methanol to solubilize the freebase, and concentrate under reduced pressure gives the title compound (0.18 g). Mass spectrum (APCI+, m/e): 460 (M+1−2HCl); exact mass spectrum (ES+, m/e, C27H33N5S.2HCl): calc. 460.2535 (M+1−2HCl), found 460.2556.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[NH:8][N:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:6])[CH3:3].[CH2:17](I)[CH3:18]>C(O)C.C([O-])C.[Na+]>[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:17][CH3:18])[N:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cn[nH]c1C(=O)OCC
Reactant: CCI
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnn(CC)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.9 %

Procedure:
Sodium ethanolate solution was freshly prepared by dissolving sodium (240 mg) in ethanol (30 ml). 2H-Pyrazole-3,4-dicarboxylic acid diethyl ester (800 mg, 3.77 mmol) was dissolved in this sodium ethanolate solution (11 ml) and stirred for 10 min (r.t.), before ethyl iodide (1.4 g, 9 mmol) was added dropwise. After the completion of the addition, the mixture was heated to reflux until all starting material was consumed (1 h). The solvent was then evaporated, the residue was taken up in ethyl acetate and washed (water). The organic layer was dried (Na2SO4), evaporated, and the title compound (280 mg, 31%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). (The regioisomeric 1-ethyl-1H-pyrazole-3,4-dicarboxylic acid diethyl ester can also be isolated, and can be distinguished from the desired product by NOE-1H-NMR.) MS (m/e)=241.1 [M+H+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][CH2:7][C:8]([C@@H:10]([C@H:12]([C@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[O:13][CH2:14][C:15]([OH:17])=[O:16])[OH:11])=[O:9].[C:24](ON1C(=O)CCC1=O)(=[O:27])[CH:25]=[CH2:26]>O.CO.C(N(CC)CC)C>[C:24]([NH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][CH2:7][C:8]([C@@H:10]([C@H:12]([C@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[O:13][CH2:14][C:15]([OH:17])=[O:16])[OH:11])=[O:9])(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)ON1C(=O)CCC1=O
Reactant: NCCSCCCC(=O)[C@H](O)[C@@H](OCC(=O)O)[C@@H](O)[C@H](O)CO
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: C=CC(=O)NCCSCCCC(=O)[C@H](O)[C@@H](OCC(=O)O)[C@@H](O)[C@H](O)CO
Reaction time: 2 h
Yield: 63.7 %

Procedure:
Compound 9 (1.5 g) was dissolved in water/methanol (1:1, 10 mL) to which triethylamine was added to obtain pH 10. N-acryloyloxy succinimide (2.0 g) was added and the mixture was stirred for 2 hr. After TLC analysis indicated the complete disappearance of starting material 9, the volatiles were removed from the reaction mixture. The residue was chromatographed on a silica gel column using 20% methanol in dichloromethane. The appropriate fractions were pooled and solvent was removed to give the derivative 10 as a white foam (1.1 g). 1H NMR (D2O): δ, 1.62-1.95, mm, 6H; 2.64-2.80, m, 2H; 3.05-3.14, m, 2H; 3.28-3.35, m, 1H; 3.68-3.72, dd, 1H; 4.11-4.15, m, 2H; 4.24-4.29, m, 1H; 4.38-4.41, m, 2H; 5.82-5.86,dd, 2H, acryloyl CH2; 6.26-6.36,m, 1H, acryloyl CH: 13C NMR (D2O): 176.92, 175.14, 168.12, 129.42, 78.76, 74.44, 71.47, 66.38, 66.41, 65.70, 60.72, 38.21, 30.11, 27.62, 24.49, 22.31.
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.N[C@@H:29]([CH2:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[C@@H:30]([OH:40])[CH:31]([OH:39])[CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(N(CC)CC)C>CN(C=O)C>[NH2:2][CH:32]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[CH:31]([OH:39])[CH:30]([OH:40])[CH2:29][CH2:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CN1CCOCC1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(C(O)C(O)CCC1CCCCC1)N1CCOCC1
Temperature: 0 °C

Procedure:
50 mg of L-N-[(2S or-R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucine was dissolved in 0.2 ml of dry DMF, and 28.2 mg of 1-hydroxybenzotriazole and 33.2 mg of DCC were added thereto at 0° C. under stirring. Then, 55.2 mg of (2RS,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol dihydrochloride was dissolved in 0.2 ml of dry DMF, and 31.1 mg of triethylamine was added thereto for neutralization. This mixture was added to the previous reaction solution, and the mixture was stirred at 0° C. for two hours and at room temperature overnight. The precipitated dicyclohexyl urea was removed by filtration, and the filtrate was diluted with 10 ml of ethyl acetate. The ethyl acetate layer was washed sequentially with a 4% sodium hydrogencarbonate aqueous solution, with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue was purified by silica gel column chromatography (chlorofrom/methanol= 20/1) to obtain 20.1 mg of (2S,3R,4S)-4-{L-N-[(2S or R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucyl}amino-5-cyclohexyl-1-morpholino-2,3-pentanediol as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([NH2:10])=[C:8]([Cl:11])[C:7]([NH2:12])=[CH:6][C:3]=1[C:4]#[N:5].CN(C)[CH:15]=[O:16].C(N(CC)CC)C.[C:25]([O:28][CH2:29][CH3:30])(=[O:27])C>>[NH2:10][C:9]1[C:8]([Cl:11])=[C:7]([NH:12][C:15](=[O:16])[C:25]([O:28][CH2:29][CH3:30])=[O:27])[CH:6]=[C:3]([C:4]#[N:5])[C:2]=1[Cl:1]
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Reactant: N#Cc1cc(N)c(Cl)c(N)c1Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cc(C#N)c(Cl)c(N)c1Cl
Temperature: 25 °C

Procedure:
A solution of 32.3 g. (0.16 mole) of 2,4-dichloro-3,5-diaminobenzonitrile in 100 ml. of dimethyl-formamide, 250 ml. of ethyl acetate and 38.4 g. (0.38 mole) of triethylamine is cooled to 0° in an ice bath. To the solution is added 51.87 g. (0.38 mole) of ethyl oxalyl chloride and the temperature is kept below 18°. The reaction mixture is stirred in the ice-bath for 1 hour and allowed to warm to room temperature overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.[F:24][C:25]1[CH:31]=[C:30]([F:32])[C:29]([OH:33])=[CH:28][C:26]=1[NH2:27].S(Cl)([Cl:36])=O>>[ClH:36].[F:24][C:25]1[CH:31]=[C:30]([F:32])[C:29]([OH:33])=[CH:28][C:26]=1[NH:27][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COCCOc1cc2nc[nH]c(=O)c2cc1OC
Reactant: Nc1cc(O)c(F)cc1F
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Nc3cc(O)c(F)cc3F)c2cc1OC
Product: Cl
Yield: 28 %

Procedure:
6-Methoxy-7-(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one (200 mg, 0.8 mmol), (prepared as described for the starting material in Example 9), and DMF (0.1 ml) in thionyl chloride (20 ml) were heated at reflux for 2 hours. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene. The residue was dissolved in isopropranol (15 ml), 2,4-difluoro-5-hydroxyaniline (128 mg, 0.88 mmol), (prepared as described for the starting material in Example 11), added, and the mixture heated at reflux for 2 hours. The reaction mixture was then allowed to cool, the precipitated product collected by filtration, washed with isopropanol and dried to give 4-(2,4-difluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline hydrochloride (83 mg, 28%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][C:11]2[C:12]3[C:19]4[CH2:20][CH2:21][NH:22][CH2:23][C:18]=4[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][C:4]=1[OH:24].Br[CH2:26]/[CH:27]=[CH:28]/[C:29]([OH:31])=O.[CH:32]12[CH2:39][CH:36]([CH2:37][CH2:38]1)[CH2:35][NH:34][CH2:33]2>>[CH:32]12[CH2:39][CH:36]([CH2:37][CH2:38]1)[CH2:35][N:34]([CH2:26]/[CH:27]=[CH:28]/[C:29]([N:22]1[CH2:21][CH2:20][C:19]3[C:12]4[C:11]([NH:10][C:6]5[CH:7]=[C:8]([Cl:9])[C:3]([Cl:2])=[C:4]([OH:24])[CH:5]=5)=[N:16][CH:15]=[N:14][C:13]=4[S:17][C:18]=3[CH2:23]1)=[O:31])[CH2:33]2
Reactant: C1CC2CNCC1C2
Reactant: O=C(O)/C=C/CBr
Reactant: Oc1cc(Nc2ncnc3sc4c(c23)CCNC4)cc(Cl)c1Cl
Agent: Cl
Product: O=C(/C=C/CN1CC2CCC(C2)C1)N1CCc2c(sc3ncnc(Nc4cc(O)c(Cl)c(Cl)c4)c23)C1

Procedure:
The compound was synthesized in analogy to Example 147 from 2,3-dichloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 69A (100 mg, 0.25 mmol), (2E)-4-bromobut-2-enoic acid (61 mg, 0.37 mmol) and 3-azabicyclo[3.2.1]-octane (44 mg, 0.40 mmol) to yield 25 mg (19%).