Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]2[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([CH3:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:36]=[C:37]=O)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([CH3:30])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:17]=3[CH:31]=2)=[CH:10][CH:11]=[C:12]1[C:37]#[N:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(c1ccccc1)OCC(=O)N2
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(c1ccccc1)OCC(=O)N2

Procedure:
tert-Butyl-2-cyano-5-(5-methyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate was prepared from tert-butyl-2-(5-methyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate and chlorosulfonyl isocyanate according to the cyanation procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.02 (s, 1H), 7.42-7.38 (m, 2H), 7.32-7.10 (m, 7H), 6.49 (d, J=3.80 Hz, 1H), 4.20 (d, J=14.63 Hz, 1H), 3.99, (d, J=14.41 Hz, 1H), 1.87 (s, 3H), 1.39 (s, 9H); MS (ES) m/z 442 ([M−H]−, 100%).
Reaction SMILES: [Cl:1]C1C(C(F)(F)F)=CC=CC=1CNCC(C1C=CC=CC=1Cl)C.Cl[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([CH3:61])[CH2:32][N:33]([CH2:46][CH2:47][CH2:48][O:49][C:50]1[CH2:51][C:52](=[CH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]=[CH:54][CH:55]=1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]=1[Cl:45]>>[Cl:1][C:30]1[CH:25]=[C:26]([CH:31]([CH3:61])[CH2:32][N:33]([CH2:46][CH2:47][CH2:48][O:49][C:50]2[CH2:51][C:52](=[CH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]=[CH:54][CH:55]=2)[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]=2[Cl:45])[CH:27]=[CH:28][CH:29]=1
Reactant: CC(CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccccc2Cl)C1
Product: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2cccc(Cl)c2)C1
Yield: 49 %

Procedure:
The titled compound was prepared from N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propylamine in 49% yield in the same manner as the preparation of N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in Example 184f. MS (ESI) 568 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(Cl)nc(Nc3ccccc3)c2c1

Procedure:
In a procedure analogous to that of Example 1a 2,4-dichloro-6-methoxy-quinazoline (1.53 g) (prepared as described in J. Chem. Soc. 1948, 1759), aniline (0.8 g) (0.184 g) and N,N-diisopropyl-ethylamine (1.72 g) are reacted together to give 2-chloro-6-methoxy-4-phenylamino-quinazoline as light yellow crystals melting at 177-179° C., Rf (A2) 0.59.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:46]1([CH2:49][O:50][C:51]2[CH:66]=[CH:65][C:54]3[CH2:55][CH:56]([C:58]4[N:63]=[CH:62][C:61](O)=[CH:60][CH:59]=4)[O:57][C:53]=3[CH:52]=2)[CH2:48][CH2:47]1>C1COCC1.C1(C)C=CC=CC=1>[CH:46]1([CH2:49][O:50][C:51]2[CH:66]=[CH:65][C:54]3[CH2:55][CH:56]([C:58]4[N:63]=[CH:62][C:61]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])=[CH:60][CH:59]=4)[O:57][C:53]=3[CH:52]=2)[CH2:47][CH2:48]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1ccc(C2Cc3ccc(OCC4CC4)cc3O2)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc(C2Cc3ccc(OCC4CC4)cc3O2)nc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.3 %

Procedure:
A toluene solution (1.9 M, 0.474 mL) of diisopropyl azodicarboxylate was added dropwise to a solution of tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (158 mg), triphenylphosphine (236 mg) and 6-[6-(cyclopropylmethoxy)-2,3-dihydro-1-benzofuran-2-yl]pyridin-3-ol (170 mg) in THF (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hr, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (80 mg).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]#[C:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[Br:22]>>[Br:22][C:17]1[C:18]([CH3:21])=[N:19][O:20][C:16]=1[NH:15][S:2]([C:5]1[S:6][C:7]([C:10]#[C:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: CCCC#Cc1ccc(S(=O)(=O)Cl)s1
Product: CCCC#Cc1ccc(S(=O)(=O)Nc2onc(C)c2Br)s1
Yield: 87.6 %

Procedure:
N-(bromo-3-methyl-5-isoxazolyl)-5-(1-pentynyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(1-pentynyl)thiophene (55 mg. 0.22 mmol) with 5-amino-4-bromo-3-methylisoxazole (43 mg, 0.22 mmol) yielded 75 mg of N-(bromo-3-methyl-5-isoxazolyl)-5-(1-pentynyl)thiophene-2-sulfonamide (87% yield). A portion of the product was further purified by preparative HPLC to give the pure sulfonamide as a light brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[C:33]1([CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 64 h
Yield: 22.3 %

Procedure:
A solution of 270 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester and 98 mg of 4-phenylbutyric acid in 10 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 81 mg of hydroxybenzotriazole, 69 mg of N-ethylmorpholine and 136 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 64 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using System G for the elution to give 79 mg of N-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(4-phenylbutyryl)-L-asparaginyl]amino]butyl]-L-proline tert.butyl ester as a white solid; MS: m/e 595 [M+H]+.
Reaction SMILES: [Na][C:2]([CH:4]([CH2:7][NH:8][CH:9]=[O:10])[C:5]#[N:6])=[O:3].S(OC)(O[CH3:15])(=O)=O>O1CCCC1>[CH3:15][O:3][CH:2]=[C:4]([CH2:7][NH:8][CH:9]=[O:10])[C:5]#[N:6]
Reactant: COS(=O)(=O)OC
Reactant: N#CC(CNC=O)C(=O)[Na]
Solvent: C1CCOC1
Product: COC=C(C#N)CNC=O
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To the residue of α-sodioformyl-β-formylaminopropionitrile is added 300 parts by volume of tetrahydrofuran and 138 parts of dimethyl sulfate. The mixture is reacted under stirring at 70°C for 5 hours. After completion of the reaction, the mixture is cooled at 25°C. The precipitated sodium methyl sulfate is removed and the filtrate is concentrated and kept standing overnight, whereby 135 parts of α-methoxymethylene-β-formylaminopropionitrile is obtained as crystals.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH2:3]1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:17]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)[C:10]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: CC1CCC(=O)C(CC(=O)c2nccs2)C1
Reactant: Nc1ccc(C(=O)O)cc1
Product: CC1CCc2c(cc(-c3nccs3)n2-c2ccc(C(=O)O)cc2)C1
Yield: 45 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]cyclohexanone and 4-aminobenzoic acid, the title compound was isolated in 45% yield (94% purity by HPLC). MS(ESI+): 339.5; MS(ESI−): 337.7.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:12]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][C:11]([O:10][CH3:9])=[O:12])=[CH:20][CH:19]=2)(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
4-Chloroaniline (957 mg, 7.5 mmol) was dissolved in pyridine (25 mL). The resulting mixture was cooled down to 0° C. Methyl 3-(4-chlorosulphonyl)phenylpropionate (1.314 g, 5.0 mmol) was added in portions. The mixture was stirred between 0° C. and room temperature overnight. Solvents were evaporated to dryness. The crude oil was dissolved in ethyl acetate (30 mL) and washed with 10% HCl (2×15 mL) and brine (1×15 mL). Organic phase was dried over magnesium sulfate before filtering and removal of solvent. The desired product, e.g. methyl 3-{4-[(4-chloroanilino)sulfonyl]phenyl}propanoate (1.458 g, 82.4%), was obtained as a colorless solid, in 98.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=[O:19].[NH4+].[OH-]>CCCCCC.CCOCC>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[OH:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C=O)cc1OC
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(C(O)c2ccccn2)cc1OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 187.5 ml of 1.6 M solution of butyllithium in hexane was cooled to -40° under nitrogen and 39.5 g (0.25 M) of 2-bromopyridine in 100 ml of ether added dropwise. The mixture was stirred 15 minutes at -40° and a solution of 41.5 g (0.25 M) of 3,4-dimethoxybenzaldehyde in 200 ml of ether added. After stirring at -15° for 45 minutes, the mixture was poured into 500 g ice/100 ml conc. HCl. The separated aqueous layer was made alkaline with conc. NH4OH, extracted with methylene chloride and the dried extract concentrated. The residual oil crystallized from benzene/hexane to give 3,4-dimethoxyphenyl-2-pyridyl carbinol, mp 92°-94°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:9][O:10][C:11]2[C:19]3[C:18]4[CH:20]=[C:21]([C:24]#[N:25])[N:22]=[CH:23][C:17]=4[NH:16][C:15]=3[N:14]=[CH:13][CH:12]=2)([CH3:8])[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].[Br:31]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:31][C:12]1[CH:13]=[N:14][C:15]2[NH:16][C:17]3[CH:23]=[N:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=3[C:19]=2[C:11]=1[O:10][CH2:9][C:5]1([CH3:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: BrBr
Reactant: CN1CCC(C)(COc2ccnc3[nH]c4cnc(C#N)cc4c23)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN1CCC(C)(COc2c(Br)cnc3[nH]c4cnc(C#N)cc4c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.7 %

Procedure:
A mixture of 4-((1,4-dimethylpiperidin-4-yl)methoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (50 mg, 0.16 mmol), sodium acetate (26 mg, 0.3 mmol), and bromine (32 L, 0.6 mmol) in acetic acid (1 mL) was stirred at ambient temperature for 10 minutes. The reaction mixture was diluted with water (1 mL) and basified to pH ˜8 by dropwise addition of 6N sodium hydroxide solution, producing a yellow precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (25 mg, 38%). 1H NMR (500 MHz, d6-DMSO) δ 9.02 (d, J=8.7, 1H), 8.70 (d, J=9.9, 1H), 8.43 (s, 1H), 4.21 (s, 2H), 2.81 (m, 2H), 2.62 (m, 2H), 2.45 (s, 3H), 1.97 (m, 2H), 1.68 (m, 2H), 1.30 (s, 3H), NH signal not observed. LCMS (Method D): RT=8.660 min, M+H+=414.0/416.0.
Reaction SMILES: [CH:1]([Si:5]([CH:9]([CH2:11][CH3:12])[CH3:10])([CH3:8])OC)([CH2:3][CH3:4])[CH3:2].[ClH:13]>>[CH:1]([Si:5]([CH:9]([CH2:11][CH3:12])[CH3:10])([CH3:8])[Cl:13])([CH2:3][CH3:4])[CH3:2]
Reactant: Cl
Reactant: CCC(C)[Si](C)(OC)C(C)CC
Product: CCC(C)[Si](C)(Cl)C(C)CC
Yield: 81 %

Procedure:
The resulting organic layer containing di-sec-butyl methylmethoxysilane was treated with 35% hydrochloric acid in the same manner as in Example 15(d). The organic layer was separated from the aqueous layer and was subjected to a fractional distillation under a reduced pressure to afford 32 g of di-sec-butylmethylchlorosilane as a fraction boiling at 78° C.-81° C./16 mm Hg (yield; 81%).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[C:6]([N:34]([CH3:36])[CH3:35])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].[OH-].[Na+]>O1CCCC1.CO>[CH3:36][N:34]([CH3:35])[C:6]1[C:5]([CH2:4][C:3]([OH:37])=[O:2])=[C:10]([N:11]([CH3:12])[CH3:13])[N:9]=[C:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:33])[C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=3)=[CH:19][CH:20]=2)[N:7]=1
Reactant: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc(N(C)C)c1CC(=O)O

Procedure:
A solution of methyl[4,6-bis(dimethylamino)-2-(4-{[4-(trifluoromethyl)benzoyl]amino}-benzyl)pyrimidin-5-yl]acetate (4.34 g, 8.42 mmol) in 20% tetrahydrofuran in methanol (100 mL) was treated with 1N sodium hydroxide solution (25 mL). The resulting mixture was heated at refluxing temperature for 5 hours and then the volatiles were removed by rotary evaporation under vacuum. The remaining aqueous solution was washed with diethyl ether and then neutralized with 1N hydrochloric acid at 0° C. The separated precipitate was collected by suction and rinsed with cold water. Recrystallization from methanol then gave [4,6-bis(dimethylamino)-2-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)pyrimidin-5-yl]acetic acid (3.86 g, 81%) as colorless needles.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:7]([O:14][NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:7]([O:14][NH:15][C:1](=[O:4])[CH:2]=[CH2:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NOCc1ccccc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NOCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A solution of acryloyl chloride (3 mL; 3.342 g; 36.9 mmole) dissolved in dry dichloromethane (25 mL) was cooled at 0° C. with an ice bath. A mixture of O-benzyl hydroxylamine hydrochloride (6.4902 g; 40.66 mmole) and N,N-diisopropylethylamine (15.6 mL; 11.575 g; 89.56 mmole) in dry dichloromethane (110 mL) was slowly added over a period of 1 hour to the cooled solution. Next, the ice bath was removed, and the reaction mixture was left stirring overnight while its temperature warmed up gradually to room temperature. Water (250 mL) was added to the reaction and the layers were separated. The organic solution was washed with diluted hydrochloric acid (0.2N; 3×300 mL), a saturated sodium bicarbonate solution (1×200 mL), water (3×250 mL), and finally brine (1×250 mL). The organic layer was then dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate (70:30) to elute the product. The purification gave 3.165 g (48.4%) of N-benzyloxyacrylamide (30) as a viscous colorless oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[CH3:14][C:15]1[C:16]([NH2:30])=[N:17][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH2:29])[CH:27]=3)[O:22][CH2:21][CH2:20]2)[N:19]=1>>[NH2:30][C:16]1[C:15]([CH3:14])=[N:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH:29][C:9](=[O:11])[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:8][N:7]=4)[CH:27]=3)[O:22][CH2:21][CH2:20]2)[N:17]=1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Product: CC1=NC2(CCOc3ccc(NC(=O)c4ccc(C(F)(F)F)cn4)cc32)N=C1N
Yield: 47.4 %

Procedure:
The title compound (44 mg, 46% yield) was prepared as described for Example 13a starting from 5-(trifluoromethyl)picolinic acid (45 mg, 0.23 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 54 mg, 0.23 mmol): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85-1.98 (m, 2 H), 2.24 (s, 3 H), 4.30-4.50 (m, 2 H), 6.56 (s, 2 H), 6.81 (d, 1 H), 7.02-7.10 (m, 1 H), 7.62-7.71 (m, 1 H), 8.28 (d, 1 H), 8.46 (dd, 1 H), 9.01-9.10 (m, 1 H), 10.57 (s, 1 H); MS (APCI+) m/z 404 [M+H]+.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.O.ON1C2C=CC=CC=2N=N1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C>[N:21]1([C:7]([C@H:2]2[NH:1][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:9])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C1CC[C@@H](C(=O)N2CCOCC2)N1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
The reaction vessel is charged with 30 g L-pyroglutamic acid and 4.71 g 1-hydroxybenzotriazole hydrate. The solids are then suspended in 190 ml anhydrous acetonitrile and the mixture is then heated to 45° C. Subsequently, 20.24 ml morpholine is added via a dropping funnel within 20 min, and the dropping funnel is then washed with 5 ml anhydrous acetonitrile. The resulting mixture is then heated to 65° C. and 29.32 g N—-N′-diisopropylcarbodiimide added within 1 h via a dropping funnel. After complete addition, the dropping funnel is washed with 5 ml anhydrous acetonitrile and the reaction mixture is stirred at 65° C. for an additional 30 min. The resulting suspension is then cooled to ambient temperature, filtered and the filter cake washed with 3×30 ml acetonitrile. The filtrate is concentrated under heating and reduced pressure to approx. ½ of its original volume and the residue is then seeded with 16 mg (S)-5-(morpholine-4-carbonyl)pyrrolidine-2-one. Concentration under reduced pressure is continued until approx ⅓ of the original volume of the filtrate is reached. While further concentrating the filtrate under reduced pressure and removing approx. 95 ml of distillate, simultaneously 210 ml 2-methyltetrahydrofuran is added. The suspension is then cooled to 0° C. and the solids are isolated by filtration. The filter cake is washed with 3×20 ml cooled 2-methyltetrahydrofuran and dried at 55° C. under vacuum to give 42.54 g of (S)-5-(morpholine-4-carbonyl)pyrrolidine-2-one as fine white crystals (98.0% purity by HPLC, ee (HPLC)>99.6% [4-a, R1=H; R4=morpholine]).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([NH2:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:1]1([N:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[CH:10][C:9]([NH:16][C:18](=[O:19])[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)F)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)n(-c2ccccc2)n1)Oc1ccccc1
Yield: 78.8 %

Procedure:
Using the procedure described in Example 161C, 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (0.665 g, 2.9 mmol) and phenyl chloroformate (0.548 g, 3.5 mmol) were reacted in the presence of K2CO3 (0.691 g, 5 mmol) in THF (20 mL) and purified by silica gel chromatography with 10-20% EtOAc/hexane as eluants to afford phenyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate as a solid (0.794 g, 79%). 1H NMR (300 MHz, CDCl3) δ 7.97 (br, 1H), 7.38-7.46 (m, 7H), 7.14-7.29 (m, 4H); LC-MS (ESI) m/z 348 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:23])[CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])CCC>C(Cl)Cl.O>[C:12]([O:11][C:9]([NH:8][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])[C:6]([OH:23])=[O:5])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1O

Procedure:
Similarly, N-t-butoxycarbonyl-2-(2-hydroxyphenyl)glycine n-butyl ester was hydrolyzed to give N-t-butoxycarbonyl-2-(2-hydroxyphenyl)glycine, m.p. 125° (methylene chloride-water).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[SH:23].CN(C=O)C>CS(C)=O>[Cl:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: Sc1ccc2ccccc2c1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1

Procedure:
2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-napthalene was synthesized (100%) from 3,4,5-trichloronitrobenzene (Acros) and napthalene-2-thiol (Avocado) in a similar manner as described in example 1 using DMSO as solvent instead of DMF.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:10][O:11][CH3:12])[N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=O)=[CH:17][CH:16]=1>>[I:1][C:2]1[N:3]=[C:4]([CH2:10][O:11][CH3:12])[N:5]2[CH2:7][CH2:8][NH:9][CH:23]([CH2:22][CH2:21][C:18]3[CH:19]=[CH:20][C:15]([C:14]([F:13])([F:25])[F:26])=[CH:16][CH:17]=3)[C:6]=12
Reactant: COCc1nc(I)cn1CCN
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Product: COCc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 95° C.; 9 bars; 10 min.) between 2-(4-iodo-2-methoxymethyl-imidazol-1-yl)-ethylamine (596 mg; 2.119 mmol) and 3-(4-trifluoromethyl-phenyl)-propionaldehyde (428 mg; 2.119 mmol) afforded 1-iodo-3-methoxymethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by FC (DCM/MeOH=30/1).