Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:15]=[C:16]([CH2:22][C:23]([CH3:31])([CH3:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:17]=[C:18]([F:21])[C:19]=1[OH:20].[C:32]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:37]=CC=C[CH:33]=1.Cl.O1CCOCC1>C1COCC1.C(O)C>[NH2:1][CH2:33][CH2:32][CH2:37][O:20][C:19]1[C:18]([F:21])=[CH:17][C:16]([CH2:22][C:23]([CH3:30])([CH3:31])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:15][C:14]=1[Br:13]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CC(C)(C)Cc1cc(F)c(O)c(Br)c1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)CC(C)(C)Cc1cc(F)c(OCCCN)c(Br)c1
Reaction time: 0.25 h

Procedure:
A solution of diethyl azodicarboxylate (0.488 g, 2.8 mmol) in 3 ml THF was added to a solution of the product of STEP 7 (0.72 g, 2.16 mmol) and triphenylphosphine (0.734 g, 2.8 mmol) in 13 ml THF at room temperature and stirred for 15 min. Tert-butyl N-(3-hydroxypropyl) carbamate (0.491 g, 2.8 mmol) was added. The reaction was stirred at room temperature for 18 h. THF was evaporated and the residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/4) to yield a golden oil in 0.87 g. This product was dissolved in 10 ml ethanol and 10 ml 4N HCl/dioxane and stirred at room temperature for 1 h. Solvents were evaporated to afford a light golden oil in 0.734 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8])(=[O:19])[CH3:18]
Reactant: Cc1csc(N)c1C(N)=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1scc(C)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-4-methyl-thiophene-3-carboxylic acid amide (5 g, 32 mmol) in DCM (100 mL) is cooled to 0° C. Dry pyridine (3.6 mL, 45 mmol) is added, followed by acetylchloride (11 mL, 156 mmol) which is added dropwise to the solution. The resulting mixture is stirred at room temperature overnight, then diluted with DCM and washed with aqueous NaHCO3. The organic phase is dried over MgSO4, filtered and concentrated. The obtained residue is triturated in di-isopropylether, filtered, and the cake is dried to afford the desired product.
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([C:66]3[CH:71]=[CH:70][CH:69]=[C:68]([Cl:72])[CH:67]=3)=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([C@:59]2([CH3:65])[CH2:63][O:62]C(=O)[NH:60]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:60][C@@:59]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([O:48][C@H:45]3[CH2:44][CH2:43][C@H:42]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:47][CH2:46]3)[C:50]=2[C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([Cl:72])[CH:67]=2)[CH:55]=1)([CH3:65])[CH2:63][OH:62]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2cccc(Cl)c2)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2cccc(Cl)c2)CC1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(3-chlorophenyl)naphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 82% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(3-chlorophenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=449.40 [M−16]+. 1H NMR (MeOD) δ: 7.93 (d, J=2.0 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.47-7.52 (m, 1H), 7.45 (d, J=7.3 Hz, 1H), 7.38-7.44 (m, 3H), 7.30 (d, J=1.5 Hz, 1H), 7.23 (dd, J=7.2, 1.4 Hz, 1H), 4.08-4.17 (m, 1H), 3.72 (d, J=10.8 Hz, 1H), 3.67 (d, J=10.8 Hz, 1H), 1.98-2.09 (m, 1.75-1.84 (m, 2H), 1.51 (s, 3H), 1.03-1.23 (m, 4H), 0.90-1.02 (m, 1H), 0.85 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:29]1[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 90.5 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate (28 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 36 mg of the titled compound (yield, 94%). 1H NMR (300 MHz, CDCl3): δ 3.30 (s, 4H), 3.77 (s, 4H), 4.15 (s, 3H), 6.90-6.97 (m, 3H), 7.28-7.45 (m, 4H), 7.75-7.76 (m, 1H).
Reaction SMILES: COC1C=CC(C(C2SC=NN=2)[N:10]2[C:18]3[C:13](=[N:14][CH2:15][NH:16][CH:17]=3)[CH:12]=[C:11]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=C(C(F)(F)F)C=1.FC1C=CC=CC=1C1NC2C=NC=NC=2C=1.[F:51][C:52]([F:72])([F:71])[C:53]1[CH:58]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:56]=[CH:55][C:54]=1[C:63]1[N:64]=[N:65][C:66]([CH2:69]Cl)=[CH:67][CH:68]=1>>[F:72][C:52]([F:51])([F:71])[C:53]1[CH:58]=[C:57]([C:59]([F:62])([F:60])[F:61])[CH:56]=[CH:55][C:54]=1[C:63]1[N:64]=[N:65][C:66]([CH2:69][N:16]2[CH:17]=[C:18]3[N:10]=[C:11]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH:12]=[C:13]3[N:14]=[CH:15]2)=[CH:67][CH:68]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)nn2)c(C(F)(F)F)c1
Reactant: COc1ccc(C(c2nncs2)n2c(-c3ccccc3F)cc3c2=CNCN=3)c(C(F)(F)F)c1
Agent: Fc1ccccc1-c1cc2ncncc2[nH]1
Product: Fc1ccccc1-c1cc2ncn(Cc3ccc(-c4ccc(C(F)(F)F)cc4C(F)(F)F)nn3)cc-2n1
Yield: 5 %

Procedure:
Prepared analogously to the method described for 3-[5[(4-methoxy-2-trifluoromethyl-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-6-(2-fluorophenyl)-3H-pyrrolo[3,2-d]pyrimidine beginning with 6-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine (200 mg, 0.93 mmol) and 3-(2,4-Bis-trifluoromethylphenyl)-6-chloromethylpyridazine (383 mg, 1.12 mmol) to obtained desired product (9 mg, 5%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][N:12]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[NH2:1][C:2]1[CH:9]=[C:8]([N:18]2[CH2:19][CH2:20][C:15]3([CH2:11][N:12]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:13][CH2:14]3)[CH2:16][CH2:17]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: N#Cc1cnc(N)cc1Cl
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3cc(N)ncc3C#N)CC2)C1

Procedure:
From intermediate 16 and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate, reacted in an analogous manner to the preparation of intermediate 42. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 6.66 (s, 2H), 5.90 (s, 1H), 3.10-3.32 (s, 8H), 1.69-1.79 (m, 2H), 1.52-1.66 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][C:4]2([CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[CH2:3]1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26]C(C(Cl)=O)=[CH:21][CH:20]=1.[C:28](OCC)(=O)C>C(=O)([O-])[O-].[K+].[K+]>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:1]([N:2]2[CH2:7][CH2:6][N:5]([CH3:28])[C:4]3([CH2:16][CH2:15][C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8]3)[CH2:3]2)=[CH:21][CH:20]=1
Reactant: CN1CCNC2(CCc3ccccc3C2)C1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(N2CCN(C)C3(CCc4ccccc4C3)C2)cc1
Yield: 74 %

Procedure:
1'-methylspiro[tetralin-2,3'-piperazine] (50 mg, 0.23 mmol) was dissolved in ethyl acetate (4 ml)-saturated aqueous potassium carbonate solution (4 ml). While the solution was vigorously stirred, p-methoxybenzoyl chloride (51 mg, 0.3 mmol) was added. After the organic layer was separated, the solvent was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography for elution with n-hexane-ethyl acetate (9:1) to yield 60 mg (74%) of the title compound as a crude crystal.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.C(O[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29]C=[CH:27][C:26]=1OC(=O)C)(=O)C.[C:35](=[O:38])([O-])[O-].[K+].[K+]>>[C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.[OH:6][C:21]1[CH:20]=[CH:19][C:18]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:35]([OH:38])=[CH:27][CH:26]=2)=[CH:17][CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Oc1ccccc1CCc1ccccc1OC(C)=O
Agent: O=C(O)c1cccc(C(=O)O)c1
Agent: [K+]
Product: Oc1ccc(CCc2ccc(O)cc2)cc1
Temperature: 245 °C

Procedure:
A charge consisting of 167 parts of isophthalic acid and 298 parts of 1,2-bis(acetoxyphenyl)ethane and 0.005 mols potassium carbonate per mol of 1,2-bis(acetoxyphenyl)ethane is placed in a reaction vessel equipped with a stirrer, condenser and receiver. The vessel is evacuated and purged with nitrogen three times. During the reaction a nitrogen blanket is maintained in the reactor. The temperature is raised to about 245° C. and acetic acid distills. The rate of distillation during the initial 67 percent of reaction is 1.82 ml mol-1 min.-1. The distillation rate tapers after 87 parts of acetic acid have distilled in 55 minutes. The temperature rises slowly to 270° C. during the initial stage. Thereupon the vessel is evacuated to a pressure of about 200 torr for about 5 minutes and the pressure is then slowly reduced to about 1 torr while the temperature is increased to about 290° C. When the amperage on the stirrer motor increases by 0.02 to 0.04 amps, the stirrer motor is switched off and the vacuum is released with nitrogen. A total of 112 parts of acetic acid (98 percent of theoretical) is collected. The rate of evolution of acetic acid during the vacuum stage is 1.67 ml mol-1 min.-1. The prepolymer is extruded from the vessel under slight nitrogen pressure and is reduced in a mill to a powder of particle size in the range of from 0.1 to 0.25 mm. The inherent viscosity of the prepolymer is 0.28. The prepolymer is off white in color.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([NH:10][C:11]([C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[O:12])[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([NH:10][C:11]([C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[O:12])[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CN
Temperature: 25 °C
Reaction time: 16 h

Procedure:
290.0 mg (0.75 mmol) tert. Butyl (2S,4R)-2-azidomethyl-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1-carboxylate are dissolved in a mixture of 4 ml THF and 0.4 ml of water and combined with 0.3 g (1.1 mmol) triphenylphosphine. The reaction mixture is stirred at RT for 16 hours. Then the mixture is concentrated i. vac., combined with water and dil. Sodium hydroxide solution and extracted three times with DCM. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The crude product is purified by flash chromatography on silica gel (eluant DCM/methanol 9:1→1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7](=[O:17])[C:8]([C:14]([NH2:16])=[O:15])=[C:9](OC(C)C)[C:5]=2[CH:4]=1.C1(C2CCCCCCCCCC=2)CC[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22]N=1>NC1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7](=[O:17])[C:8]([C:14]([NH2:16])=[O:15])=[C:9]([NH:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:5]=2[CH:4]=1
Reactant: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Reactant: COc1ccc2c(c1)C(OC(C)C)=C(C(N)=O)S2=O
Solvent: CCOC(C)=O
Solvent: Nc1ccccc1
Product: COc1ccc2c(c1)C(Nc1ccccc1)=C(C(N)=O)S2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 66 %

Procedure:
A mixture of 5-methoxy-(3-(1-methylethoxy))benzo[b]thiophene-2-carboxamide-1-oxide (250 mg, 0.89 mmol) and diazabicycloundecene (DBU) (664 μL, 4.4 mmol) in 5 mL of aniline is stirred at room temperature for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl, saturated NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. Recrystallization from ethyl acetate:methanol gives 5-methoxy-3-(phenylamino)benzo[b]thiophene-2-carboxamide-1-oxide in 66% yield; mp=191°-192° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:23][C:24]1[C:25]([F:32])=[C:26]([OH:31])[CH:27]=[CH:28][C:29]=1[F:30].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.CN(C=O)C>[F:32][C:25]1[C:26]([OH:31])=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[NH:23][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:9]=1
Reactant: Nc1c(F)ccc(O)c1F
Reactant: O=C(O)c1cccc(-c2cccc(F)c2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1c(F)ccc(O)c1F)c1cccc(-c2cccc(F)c2)c1
Reaction time: 2 h
Yield: 49.9 %

Procedure:
To a stirred solution of 3-(3-fluorophenyl)benzoic acid (430 mg, 1.99 mmol, 1.1 eq), in CH2Cl2 (10 mL) and DMF (0.15 mL) at 0° C. was added (COCl)2 (760 mg, 5.97 mmol, 3.3 eq) dropwise. The reaction was stirred for 2 h, then the solvent removed. The residue dissolved in THF (6 mL) and added to a mixture of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (262.5 mg, 1.81 mmol, 1.0 eq) and NaHCO3 (760 mg, 9.05 mmol, 5 eq) in THF (6 mL) at 0° C. The reaction was stirred for 3 h then quenched by addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with Na2CO3, water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was crystallised from petroleum ether:EtOAc 3:1 to give the title compound (310 mg, 50%). Evaporation of the filtrate provided a further 180 mg of impure material.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.CO[C:35]1[C:39](OC)=[N:38][S:37](=[O:42])[N:36]=1.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>CO>[N:47]1[CH:48]=[CH:49][CH:50]=[C:45]([CH2:44][NH:43][C:35]2[C:39]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]3[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:9]=3)=[N:38][S:37](=[O:42])[N:36]=2)[CH:46]=1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: NCc1cccnc1
Reactant: COC1=NS(=O)N=C1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: O=S1N=C(NCCCOc2cccc(CN3CCCCC3)c2)C(NCc2cccnc2)=N1
Reaction time: 3 h

Procedure:
A solution of 3-(3-piperidinomethylphenoxy)propylamine (from the dihydrochloride, 3.21 g; 10.0 mmoles) in 30 ml of methanol was added dropwise over a period of 60 minutes to a partial solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (1.62 g; 10.0 mmoles) that had been cooled to 5°-7° in an ice-water bath. After 3 hours at ambient temperature, a solution of 3-aminomethylpyridine (1.14 g; 10.5 mmoles) in 10 ml of methanol was added and the solution was then stirred for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue chromatographed by flash chromatography on 100 g of silica gel (230-400 mesh) using methylene chloride-methanol-ammonia. The appropriate fractions were combined, evaporated and triturated with acetonitrile to give 4.05 g of product. Recrystallization from isopropyl alcohol yielded the title compound, mp 139.5°-143°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20][CH2:19]1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([Cl:49])[C:35]=1[OH:50]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:22][CH2:23]2)=[CH:3][C:2]([C:38]2[CH:39]=[C:34]([Cl:33])[C:35]([OH:50])=[C:36]([Cl:49])[CH:37]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure F, tert-butyl {trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl}methylcarbamate (62 mg, 0.123 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (53 mg, 0.185 mmol) to afford the crude product (58 mg) as a yellow solid: ESI MS m/z 584 [C31H35Cl2N3O4+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]#[C:13][Si](C)(C)C)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]#[CH:13])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#CCCC#Cc1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CCCC#Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.7 %

Procedure:
To a solution of (6-(4-fluorophenyl)hexa-1,5-diynyl)trimethylsilane (1.90 g, 7.7 mmol) in THF (24 mL) cooled in a ice bath at 0° C., was added dropwise 7.7 mL of tetrabutylammonium fluoride 1M in THF solution (7.70 mmol). The reaction mixture was stirred 15 min at 0° C., and warmed to room temperature for 2h30. The reaction was quenched with water and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 500 mg of 1-fluoro-4-(hexa-1,5-diynyl)benzene (Yield: 45%) as a yellow oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][P+:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:11]=1
Reactant: Clc1ccc(-c2ccccc2CBr)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Clc1ccc(-c2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]

Procedure:
A mixture of Example 37B (8.05 g) and triphenylphosphine (7.5 g) in xylene (100 mL) was heated to 110° C. for one hour. The reaction was cooled and filtered, and the solid washed with toluene, and vacuum-dried to give the title compound.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:27])[CH2:21][S:22][CH2:23][CH2:24][CH2:25][OH:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:27])[CH2:21][S:22][CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:30])[CH3:29])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CSCCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: CC(=O)OCCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 87 %

Procedure:
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(3-hydroxypropylthio)acetamide [prepared as described in step (c) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 87% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13]([CH3:20])=[N:14][CH:15]=[N:16]3)=[CH:11][C:10]=2[C:21](O)=[O:22])=[C:4]([Cl:24])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH:42]([O:44][CH2:45][CH2:46][O:47][NH2:48])=[CH2:43].CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH:42]([O:44][CH2:45][CH2:46][O:47][NH:48][C:21]([C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([F:19])[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:24])[N:16]=[CH:15][N:14]=[C:13]2[CH3:20])=[O:22])=[CH2:43]
Reactant: Cc1ncnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc12
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1cc2c(C)ncnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 168 h
Yield: 44 %

Procedure:
To a solution of 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (47 mg, 0.11 mmol) in DMF (2 mL) was added HOBt (26.0 mg, 0.170 mmol), Et3N (0.060 mL, 0.044 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (15 mg, 0.15 mmol), and EDCI (30 mg, 0.16 mmol) at room temperature. The resulting solution was stirred for 7 days at room temperature. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (1.5 to 2% MeOH in CH2Cl2) to afford 24 mg (42%) of 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (2-vinyloxy-ethoxy)-amide. To a solution of the vinyl ether (24.0 mg, 0.048 mmol) in EtOH (2 mL) was added 1 N aqueous HCl (0.21 mL) at room temperature. After stirring for 3 hours at room temperature, pH of the reaction mixture was adjusted to 6 to 7 with 1 N aqueous NaOH, and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (5 to 10 to 20% MeOH in CH2Cl2 with 1% Et3N) to afford 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (2-hydroxyethoxy)-amide (5 mg, 22%). MS APCI (−) m/z 467, 469 (M-, Br, Cl pattern) detected; 1H NMR (400 MHz, CD3OD) δ 9.06 (s, 1H), 8.38 (s, 1H), 7.60 (d, 1H), 7.35 (dd, 1H), 6.86 (dd, 1H), 4.10 (t, 2H), 3.81 (t, 2H), 2.99 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[O:38][CH3:39]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([OH:29])=[C:31]([O:38][CH3:39])[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)ccc1O

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-hydroxy-3-methoxy-benzaldehyde. MS (ESI) m/z 515.