Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])[CH3:34]>O1CCCC1>[C:33]([N:36]1[CH2:41][CH2:40][N:39]([C:18](=[O:20])[CH2:17][N:16]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:38][CH2:37]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)N1CCN(C(=O)Cn2c(-c3ccc(Cl)cc3)nc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole), 1,1'-carbonyldiimidazole (2.26 g, 0.014 mole) and dry tetrahydrofuran (80 ml) was stirred at room temperature for 3 hr with a stream of nitrogen bubbling through it. A solution of 1-acetylpiperazine (4.49 g, 0.035 mole) in tetrahydrofuran (10 ml) was added and the resulting suspension was heated at 60° C. overnight. The solvent was evaporated under reduced pressure and the residue was triturated in water (100 ml), filtered, and the filter cake rinsed with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, and allowed to cool to room temperature. The resulting solid was collected by filtration and dried under high vacuum at 50° C. to yield 3.18 g (57%) of title compound, mp 217°-219° C.
Reaction SMILES: N.[CH3:2][C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:5][N:6]([CH:8]([CH2:12][CH2:13][CH3:14])[C:9](O)=[O:10])[CH:7]=1.C[CH:22]([N:26]1[CH:30]=C(C)C(C2C=CC=CC=2)=N1)C(O)=O>>[CH3:22][N:26]([CH3:30])[C:9](=[O:10])[CH:8]([CH2:12][CH2:13][CH3:14])[N:6]1[CH:7]=[C:3]([CH3:2])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:5]1
Reactant: CCCC(C(=O)O)n1cc(C)c(-c2ccccc2)n1
Reactant: Cc1cn(C(C)C(=O)O)nc1-c1ccccc1
Agent: N
Product: CCCC(C(=O)N(C)C)n1cc(C)c(-c2ccccc2)n1

Procedure:
Following the procedure of Example 68, but substituting dimethylamine for aqueous ammonia and 4-methyl-3-phenyl-α-propylpyrazole-1-acetic acid for α,4-dimethyl-3-phenylpyrazole-1-acetic acid, there was obtained N,N,4-trimethyl-3-phenyl-α-propylpyrazole-1-acetamide having a melting point of 84°-86° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]2[CH2:11][C:12](=[CH:20][CH2:21][CH2:22][Br:23])[C:13]3[C:14]([O:19][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[N:15][CH:16]=[CH:17][CH:18]=3)=O.[NH2:24][C:25]([NH2:27])=[S:26].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:27][C:25]1[S:26][CH:2]=[C:3]([C:5]2[C:10]3[CH2:11][C:12](=[CH:20][CH2:21][CH2:22][Br:23])[C:13]4[C:14]([O:19][C:9]=3[CH:8]=[CH:7][CH:6]=2)=[N:15][CH:16]=[CH:17][CH:18]=4)[N:24]=1
Reactant: O=C(CBr)c1cccc2c1CC(=CCCBr)c1cccnc1O2
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(-c2cccc3c2CC(=CCCBr)c2cccnc2O3)cs1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of the product of step 1 (1.1 g) in ethanol (11 ml) was added thiourea (193 mg) at room temperature, and the mixture stirred at 70° C. for 30 minutes. The reaction mixture was cooled to room temperature and poured into saturated aqueous sodiumbicarbonate. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give 7-(2-aminothiazol-4-yl)-5-(3-bromopropylidene)-5,11-dihydro[1]benzoxepino[2,3-b]pyridine (749 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15](=[O:30])[CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[NH2:41][CH2:42][C:43]([NH2:45])=[O:44]>>[NH2:45][C:43](=[O:44])[CH2:42][NH:41][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15](=[O:30])[CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[CH:3]=1
Reactant: NCC(N)=O
Reactant: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CNc1cc(NC(=O)CN2CCC(Cc3ccccc3)CC2)nc(-c2ccccc2)n1
Temperature: 100 °C
Yield: 39.9 %

Procedure:
To a crude sample of N-(6-chloro-2-phenylpyrimidin-4-yl)-2-(4-benzylpiperidin-1-yl)acetamide (22.55) (0.75 g in 60 ml DMSO) were added glycinamide hydrochloride (1.85 g in 10 ml DMSO) and N,N-diisopropylethylamine (2.96 ml) and the mixture heated to 100° C. for 16 hrs. The solvent was then removed in vacuo and the residue purified by flash chromatography on silica gel using mixtures of dichloromethane and methanol (97:3, 95:5 then 93:7 v/v/v). Further purification by recrystallization from methanol furnished the title compound (326 mg over 2 steps).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][CH2:20]Br.[OH-].[Na+]>CO>[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][CH2:20][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: Fc1ccccc1CCBr
Reactant: COC(=O)c1ccnc(-c2c[nH]cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccnc(-c2cn(CCc3ccccc3F)cn2)c1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield from methyl 2-(1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 5) and 2-fluorophenethyl bromide according to the procedure for the preparation of Example 44, followed by saponification using NaOH in MeOH. 1HNMR (400 MHz, DMSO): δ 3.14 (2H, t, J=6.9 Hz), 4.29 (2H, t, J=7.0 Hz), 7.13 (2H, m), 7.27 (2H, m), 7.58 (1H, d, J=4.0 Hz), 7.63 (1H, s), 7.80 (1H, s), 8.25 (1H, s), 8.62 (1H, d, J=4.9 Hz). [M+H] Calc'd for C17H14FN3O2, 312. Found, 312.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[C:8]([Cl:16])[C:6]=2[N:7]=1.C(N(C(C)C)C(C)C)C.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:5]2[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[C:8]([Cl:16])[C:6]=2[N:7]=1
Reactant: COC(=O)c1cc(Cl)c2nc(Cl)nc(Cl)c2n1
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Cl)c2nc(Cl)nc(N3CCCCC3)c2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
To a solution of methyl 2,4,8-trichloropyrido[3,2-d]pyrimidine-6-carboxylate (4.65 g; 15.9 mmol; 1 eq.) (Intermediate 1.3) in acetonitrile (140 mL) was added N-ethyldiisopropyl amine (4 mL; 23.8 mmol; 1.5 eq.). The mixture was cooled down to 0° C. A solution of piperidine (1.57 mL; 15.9 mmol; 1 eq.) in acetonitrile (20 mL) was added dropwise. The mixture was stirred 15 min at 0° C. The mixture was partly concentrated and the precipitate was filtered, washed with MeOH and dried under vacuum to afford methyl 2,8-dichloro-4-(1-piperidinyl)pyrido[3,2-d]pyrimidine-6-carboxylate (Intermediate 1.4) (3.98 g; 73%) as a pink solid in 98.8% HPLC purity; Amount: 3.98 g; Yield: 73%; Formula: C14H14O2Cl2N4; 1H NMR (DMSO-d6) δ 1.71 (sl, 6H), 3.92 (s, 3H), 4.01 (sl, 2H), 4.82 (sl, 2H), 8.42 (s, 1H); LC-MS: M/Z ESI: Rt (min) 2.02; 341.02, 342.89 (M+1); HPLC (H2O TFA 0.1%-ACN TFA 0.05%): Rt (min); Area %=4.27; 98.84.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:25]=[C:26]([O:28][C@@H:29]([CH3:39])[CH2:30][O:31][Si](C(C)(C)C)(C)C)[CH:27]=3)[C:15]([NH:17][C:18]3[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[O:16])=[C:9]([F:42])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1>CO.Cl>[N:1]1([C:5]([C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:25]=[C:26]([O:28][C@@H:29]([CH3:39])[CH2:30][OH:31])[CH:27]=3)[C:15]([NH:17][C:18]3[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[O:16])=[C:9]([F:42])[CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Agent: Cl
Solvent: CO
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-(5-methylpyrazin-2-yl)benzamide (3.6 g, 5.96 mmol) in methanol (60 mL) and 1M hydrochloric acid (60 mL) was stirred for 30 mins at RT. The volatiles were removed in vacuo and the residue adjusted to pH6 with saturated aqueous sodium bicarbonate solution then extracted into ethyl acetate (3×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and the solvents removed in vacuo. 10% Methanol in ethyl acetate was added and a white solid filtered off. This was crystallised from ethyl acetate/methanol to give the desired compound. (1.24 g), mpt 172° C. The data was in agreement with samples prepared through alternative routes.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:4]#[N:5].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1>[CH3:18][S:19]([O:1][N:2]=[C:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:4]#[N:5])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(=NO)c1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON=C(C#N)c1cccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
In general analogy to the reaction described under 3.2, 38 g (0.25 mol) of α-hydroxyiminothiophene-2-acetonitrile and 37.95 g (0.375 mol) of triethylamine are dissolved in 350 ml of tetrahydrofuran and to this solution is then added dropwise a solution of 31.5 g (0.275 mol) of methanesulfonyl chloride at 0-5° C. After the addition is complete, the mixture is stirred for 30 minutes at 0° C. and then overnight at room temperature. The reaction mixture is filtered, the filtrate is washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off on a rotary evaporator, giving a grey solid which is then recrystallised from toluene. 52.4 g (91%) of α-(methylsulfonyloxyimino)thiophene-2-acetonitrile are obtained in the form of beige crystals having an m.p. of 108-111° C. The 1H-NMR spectrum shows it to be a 55:45 mixture of the cis- and trans-isomers.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[C:4](=[O:25])[CH2:5][CH2:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1)[CH3:2].[OH-].[K+]>CCO>[CH2:1]([N:3]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[C:4](=[O:25])[CH2:5][CH2:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCN(Cc1ccccc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 18.1 %

Procedure:
Methyl 2-[(4-{3-[ethyl(2-fluorobenzyl)amino]-3-oxopropyl}phenoxy)methyl]-benzoate (0.454 g, 1.001 mmol) was dissolved in EtOH (5 ml) and potassium hydroxide (0.085 g, 1.514 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). Workup was by removing the solvent by evaporation, addition of HCl (20 ml, 1 M) and the water phase was washed with two portions of EtOAc (20 ml). The organic phases were pooled and the solvent was removed by evaporation. The crude was purified by preparative HPLC (starting with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product-containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation to give 0.079 g of 2-[(4-{3-[ethyl(2-fluorobenzyl)amino]-3-oxopropyl}phenoxy)methyl]benzoic acid (18.0%).
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)([Cl:8])=O.[CH3:11][O:12][C:13]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]([CH3:35])[C:14]=1[C:15]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][N+:20]([O-])=[CH:19][C:18]=1[Cl:26])=[O:16]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]([CH3:35])[C:14]=1[C:15]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][N:20]=[C:19]([Cl:8])[C:18]=1[Cl:26])=[O:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(C)c(C(=O)c2c(Cl)c[n+]([O-])cc2OC)c(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(C)c(C(=O)c2c(OC)cnc(Cl)c2Cl)c(OC)c1OC
Yield: 739.8 %

Procedure:
5 ml of dimethylformamide was added to 2.5 ml of toluene, the mixture was cooled with ice, and 1.3 ml (1.4 mmol) of phosphorus oxychloride was dropwise added thereto. After the mixture was stirred under cooling with ice for 10 minutes, 2.5 g (0.7 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-methoxypyridine-N-oxide was added thereto. After the mixture was stirred under cooling with ice for 30 minutes, the temperature was recovered to room temperature, followed by stirring for 2 hours. 30 ml of water was added to the mixture to terminate the reaction, and ethyl acetate was added thereto for extraction. The organic layer was dried over anhydrous sodium sulfate, subjected to filtration and purified by silica gel column chromatography to obtain 2.0 g (yield 76%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-2,3-dichloro-5-methoxypyridine (compound No. 193; m.p. 98-99° C.).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([OH:11])[CH:5]=1)([O-:3])=[O:2].[CH2:12](Br)[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][O:11][C:6]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(OCCC(C)C)cc1[N+](=O)[O-]

Procedure:
A mixture of 50 parts of 3-nitro-p-cresol, 94 parts of isoamyl bromide and 94.2 parts of anhydrous potassium carbonate in 650 parts of acetone was stirred and heated under reflux for 18 hours. Insoluble material was filtered off and washed with acetone and the total acetone solution was evaporated. An oil remained which was partitioned between 250 parts of ether and 500 parts of water. The ethereal layer was isolated dried over anhydrous magnesium sulphate then evaporated to leave 66.6 parts of 4-(3-methylbutoxy)-2-nitrotoluene as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>O1CCCC1>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)(=[O:22])[CH:20]=[CH2:21]
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2oc(C)nc2c1
Temperature: 0 °C

Procedure:
About 150 parts of (2) are dissolved in about 1200 ml of warm tetrahydrofuran in a 3 liter three-necked flask equipped with a mechanical stirrer and dropping funnel. About 113 parts of triethylamine are added to the flask and then cooled to 0° C. using an ice bath. About 100 parts of acryloyl chloride are combined with about 300 ml of tetrahydrofuran in a dropping funnel and added dropwise to the flask while stirring under dry nitrogen. The mixture in the flask is allowed to return to room temperature while being stirred overnight and then filtered. The filter is stirred in about 1 liter of warm tetrahydrofuran for about thirty minutes and filtered again. Both filtrates are combined and about 10 ml of nitrobenzene are added to inhibit polymerization. Solvent is removed using a rotary evaporator and ethyl ether is added to solidify the product. The dark brown solid obtained after filtering is washed with methylene chloride, then ethyl ether to provide 5-acrylamido-2-methyl benzoxazole (3) as a tan solid after drying under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:25]=4)[C:17]4[S:22][CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:37]O.N>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:15]=[C:16]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[CH:25]=4)[C:17]4[S:22](=[O:37])[CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCN(c3nc4c(c(Nc5cccc(CN6CCOCC6)c5)n3)SCC4)CC2)cc1
Reactant: OO
Agent: N
Solvent: CC(=O)O
Product: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Nc3cccc(CN4CCOCC4)c3)c21
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
313.80 mg {2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidin-4-yl}-(3-morpholin-4-ylmethyl-phenyl)-amine are placed in 2.70 ml glacial acetic acid and cooled to 10° C. 57 μl hydrogen peroxide (35%) are added dropwise, then the mixture is stirred for 0.25 hours. Then the reaction mixture is stirred in 30 ml ice water and made basic with cold ammonia solution. The precipitate formed is suction filtered, washed with water and dried. The crude product is extracted with petroleum ether and diethyl ether, suction filtered and dried. The product is purified by chromatography (10 g Chromabond SiOH-cartridge). 140.0 mg of the product are obtained as a powder (m.p 244°-248° C.).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Br:19][C:20]1[CH:46]=[CH:45][C:23]2[N:24]([C:32]([C:34]3[CH:35]=[CH:36][C:37]4[O:42][CH2:41][C:40](=[O:43])[NH:39][C:38]=4[CH:44]=3)=[O:33])[CH:25]([CH2:28][C:29](O)=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1.[CH3:47][NH2:48].C1COCC1>CCOC(C)=O>[Br:19][C:20]1[CH:46]=[CH:45][C:23]2[N:24]([C:32]([C:34]3[CH:35]=[CH:36][C:37]4[O:42][CH2:41][C:40](=[O:43])[NH:39][C:38]=4[CH:44]=3)=[O:33])[CH:25]([CH2:28][C:29]([NH:48][CH3:47])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1
Reactant: CN
Reactant: O=C(O)CC1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)CC1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Reaction time: 0.08 h
Yield: 56 %

Procedure:
TEA (0.461 mL, 3.33 mmol) and T3P (50 wt. % in EtOAc, 0.989 mL, 1.66 mmol) were added to a solution of {7-bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetic acid (Intermediate 29, 372 mg, 0.83 mmol) in EtOAc (5 mL). The mixture was stirred for 5 min. Methanamine in THF (1.248 mL, 2.50 mmol) was added and the mixture was stirred at rt for 2 h. EtOAc (50 mL) was added and the mixture washed with Na2CO3 (40 mL), HCl (1 M, 30 mL) and brine (30 mL), dried through a phase separator and evaporated. The compound was purified by preparative HPLC (Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% ACN in H2O/ACN/FA 95/5/0.2 buffer over 20 min with a flow of 100 mL/min, UV detection at 254/280 nm) to give the title compound (215 mg, 56%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([F:16])[CH:3]=1.C([Li])CCC.CN(C)[C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[F:16][C:4]1[CH:3]=[C:2]([C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CCCCCC(=O)N(C)C
Reactant: Cc1cc(Br)cc(F)c1NC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC(=O)c1cc(C)c(NC(=O)C(C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
A solution of N-(4-bromo-2-fluoro-6-methylphenyl)-2,2-dimethylpropanamide (21.7 g, 79.2 mmol) in anhydrous tetrahydrofuran (500 mL) was placed under a nitrogen atmosphere, cooled in a dry ice-acetone bath, and stirred while butyllithium (124 mL of a 1.6M solution in hexanes, 198 mmol) was added dropwise. The resulting mixture was aged at −78° C. for 30 minutes and then treated with N,N-dirnethylhexanamide (28.3 g, 198 mmol). After warming up to 0° C. over 2 hours, the mixture was removed from the cooling bath and treated with aqueous saturated NH4Cl (20 mL). The resulting slurry was diluted with CH2Cl2 (1000 mL), dried over MgSO4, filtered through a pad of silica, and concentrated under vacuum. The residue was purified by flash chromatography on a Biotage 40M KP-Sil column, eluting with 19:1 to 9:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to provide N-(2-fluoro-4-hexanoyl-6-methylphenyl)-2,2-dimethylpropanamide (12.7 g, 55%) as a yellow foam.
Reaction SMILES: [CH:1]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH:1]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C(c1ccc(O)cc1)C1CCCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1

Procedure:
In analogy to the procedure of Example III, the title compound is prepared from 10 g (45.8 mmol) of the compound from Example XII, 10.3 g (48.1 mmol) of 2-chloromethylquinoline hydrochloride and 13.8 g (0.10 mol) of potassium carbonate.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[C:28](O)[CH:27]=[CH:26]3)=[CH:19][CH:18]=1>ClCCl.N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)[CH:24]=2)[CH:29]=1)(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2cc(-c3ccc(F)cc3)ccc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2cc(-c3ccc(F)cc3)ccc2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Trifluoromethanesulfonic anhydride (1.3 mL, 7.74 mmol) was added over 5 minutes to a stirred solution of 6-(4-fluorophenyl)-2-naphthol (Step 1, 1.75 g, 7.35 mmol) in dichloromethane (25 mL) and pyridine (15 mL) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 1 hour then allowed to warm to room temperature. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated in vacuo to give 6-(4-fluorophenyl)-2-naphthyl trifluoromethanesulfonate (2.34 g, 86%). 1H NMR (500 MHz, CDCl3) δ 8.03 (1H, s), 7.96 (2H, dd, J=9.1, 13.1 Hz), 7.81-7.77 (2H, m), 7.67-7.65 (2H, m), 7.41 (1H, dd, J=2.4, 9.0 Hz), 7.21-7.17 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:16]=1[N+:25]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:25][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([F:22])([F:23])[F:24])[C:15]=1[O:14][CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1c([N+](=O)[O-])cccc1C(F)(F)F)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](COc1c(N)cccc1C(F)(F)F)C(=O)O
Yield: 88.8 %

Procedure:
10% Pd/C (150 mg) was added to a solution of (S)-2-(tert-butoxycarbonylamino)-3-(2-nitro-6-(trifluoromethyl)phenoxy)propanoic acid (1.5 g, 3.8 mmol) in MeOH and the mixture stirred under H2. After 4 h the mixture was filtered through Celite, the filter cake washed with MeOH and the filtrate concentrated to afford (S)-3-(2-amino-6-(trifluoromethyl)phenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (1.23 g, 89%) which was used without purification.