Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][CH3:52]>>[CH2:51]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1)[CH3:52]
Reactant: CCc1ccccc1OCCCCBr
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: CCc1ccccc1OCCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCCOC)C(=O)CC3)cc1

Procedure:
Analogously to Method I, 0.160 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.101 g of 1-(4-bromobutoxy)-2-ethylbenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.35 (2:1 EtOAc-heptane); Rt=6.48.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Cl.[C:21](Cl)(=[O:31])[O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(Cl)(=O)O[C@@H]1C2CCN(CC2)C1>N1C=CC=CC=1>[NH3:8].[CH3:16][O:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][CH:19]=[C:10]([CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:21]([O:22][C@@H:23]2[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:31])[CH:11]=1
Reactant: COC(=O)c1cccc(CNc2ccc(F)cc2)c1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccc(F)cc2)c1
Product: N
Temperature: 0 °C
Reaction time: 1 h
Yield: 197.4 %
Yield: 10 %

Procedure:
To a stirred solution of methyl 3-(((4-fluorophenyl)amino)methyl)benzoate (0.3 g, 1.157 mmol) in anhydrous pyridine (6 mL) at 0° C. under N2 was added (R)-quinuclidin-3-yl carbonochloridate hydrochloride (0.314 g, 1.39 mmol) in one portion. After stirring at 0° C. for 1 hour the reaction was allowed to warm to room temperature. After 25 minutes, further (R)-quinuclidin-3-yl carbonochloridate (0.314 g, 1.39 mmol) was added, and the reaction was stirred at room temperature for 18 hours. The reaction was quenched by addition of 10% aqueous potassium carbonate solution and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine and dried (sodium sulfate), filtered and the solvent was removed in vacuo to afford a red oil. The crude material was purified by silica gel column chromatography eluting sequentially with ethyl acetate, 10% methanol in ethyl acetate, 5% 7N methanolic ammonia in ethyl acetate and 10% 7N methanolic ammonia in ethyl acetate to afford the title compound as a yellow oil (0.471 g, 98%).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][N:12]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][N:12]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccsn1
Reactant: CCN
Product: CCNC(=C[N+](=O)[O-])NCCSCc1ccsn1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(3-isothiazolylmethylthio)ethylamino]ethylene (see Example 72(ii)) with ethylamine by the procedure of Example 8(ii) gives the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12]C(C)([O-])C.[K+].S(OC)(OC)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH:7][CH3:12]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CNc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution at 0° C. of 5-chloro-2-nitroaniline (100 g) in dimethylformamide (1.0 l) was added potassium t-butoxide (70.3 g) and the mixture was stirred at 0° C. for 1 hour. To the reaction mixture was added dropwise a solution of dimethyl sulfate (62 ml) in dimethylformamide (100 ml) and the resulting mixture was stirred at 25° C. for 1.5 hours to afford a solution of 5-chloro-N-methyl-2-nitroaniline in dimethylformamide. To the resulting mixture was added 24% sodium methoxide in methanol (230 ml) and the mixture was heated at 55° C. for 2 hours with stirring. At the end of this time the reaction mixture was cooled to 25° C. and water (1.5 l) was added. The precipitated crystals were collected by filtration and washed with water and methanol to give the desired compound (94.5 g, yield 90%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(COC)OC.C(O)C.Cl[Pd]Cl>[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]4[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]4)[C:9]4[C:4](=[N:5][CH:6]=[CH:7][N:8]=4)[CH:3]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CNc2nc(Cl)cc3nccnc23)C1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Temperature: 160 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
A mixture of (S)-tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)piperidine-1-carboxylate (0.15 mmol), 4-morpholinophenylboronic acid (0.23 mmol), PdCl2 (dppf) (0.015 mmol) and Cs2CO3 (0.30 mmol) in dimethoxyethane/ethanol was sealed in a microwave reaction and stirred at 160° C. for 45 minutes in a microwave reactor. The mixture was cooled to room temperature, concentrated, and purified by chromatography to afford the title compound (73% yield). MS (m/z): 505 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[C:11]([NH2:22])[N:10]([CH3:23])[N:9]=1)(=O)C.[Na].[Cl-].[NH4+]>C(O)C.O>[NH2:22][C:11]1[N:10]([CH3:23])[N:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:12]=1[C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1N
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a solution of 2-{[5-amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-yl]oxy}ethyl acetate (100 mg) (Preparation 33) in ethanol (6 ml) at room temperature, was added sodium hydroxyde (100 mg). After one hour, the reaction was diluted with water (5 ml) and an aqueous saturated solution of ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (3×6 ml). The organic fraction was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound as a white solid (85 mg).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH:12]1[CH2:16][CH2:15][O:14][CH2:13]1)=[O:10].Cl.[C:18]([C:20]1[CH:37]=[CH:36][C:23]([O:24][CH2:25][CH:26]([NH:28][C:29](=[O:35])[C@H:30]([CH:32]([CH3:34])[CH3:33])[NH2:31])[CH3:27])=[CH:22][CH:21]=1)#[N:19].O>C(Cl)Cl>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH:26]([NH:28][C:29](=[O:35])[C@H:30]([CH:32]([CH3:33])[CH3:34])[NH:31][C:9]([O:11][CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[O:10])[CH3:27])=[CH:36][CH:37]=1)#[N:19]
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Reactant: O=C(Cl)OC1CCOC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)OC1CCOC1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
1.0 g of N-methylmorpholine, and subsequently 0.7 g of 3-tetrahydrofuranyl chloroformate were added to a suspension containing 1.5 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide hydrochloride suspended in 100 ml of methylene chloride at -20° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 2 hours at room temperature. Water was subsequently added to the reaction mixture. After the dichloromethane layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of white powder (yield: 61%).
Reaction SMILES: [C:1]1([S:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Ca+2].[Cl-].[F:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][C@H:20]2[O:25][CH:24](O)[CH2:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]1([S:7]([CH:24]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH2:19][O:18][C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:28][CH:27]=3)[O:25]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCC[C@@H](COc2ccc(F)cc2)O1
Reactant: O=S(O)c1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCC[C@@H](COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
25% HCl was added dropwise to benzenesulfinic acid sodium salt (0.6 g), until the solid dissolved. This mixture was extracted with ethyl acetate (5 ml) dried (Na2SO4) and concentrated to give benzenesulfinic acid (0.4 g). To an ice-cooled mixture of benzenesulfinic acid (0.32 g, 2.23 mmol) and calcium chloride (0.25 g, 2.23 mmol) in dry CH2Cl2 a solution of (2RS, 6S)-6-(4-fluorophenoxymethyl)-2-hydroxy-tetrahydropyran (0.42 g, 1.86 mmol) in dry CH2Cl2 (5 ml) was added. The reaction mixture was stirred for 4 h, filtered through celite and washed with CH2Cl2. The combined organic layers were washed with saturated aqueous Na2CO3, water, brine and dried (Na2SO4). The solvent was removed under vacuum and the residue was purified on a silica gel column using light petroleum-ethyl acetate (4:1) as eluent to afford pure (2RS, 6S)-2-benzenesulfonyl-6-(4-fluorophenoxymethyl)-tetrahydropyran (0.5 g, 70%) as a viscous liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): δ 1.5 (m, 2H), 1.75-2.0 (m, 2H), 2.2-2.4 (m, 1H), 2.6-2.8 (m, 1H), 3.75-3.9 (m, 2H), 4.65 (d, 1H), 4.85-5.0 (m, 1H), 6.7-7.0 (m, 4H), 7.5-7.7 (m, 3H), 7.95 (d, J=5.4 Hz, 2H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:35]=[CH:34][N:33]([C:36]3[N:44]=[CH:43][CH:42]=[CH:41][C:37]=3[C:38]([OH:40])=O)[N:32]=2)[CH2:26][CH2:25]1.[NH2:45][CH:46]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH:47]([OH:51])[C:48]([NH2:50])=[O:49]>C(Cl)Cl.CCN(CC)CC>[NH2:50][C:48](=[O:49])[CH:47]([OH:51])[CH:46]([NH:45][C:38](=[O:40])[C:37]1[CH:41]=[CH:42][CH:43]=[N:44][C:36]=1[N:33]1[CH:34]=[CH:35][C:31]([CH2:30][N:27]2[CH2:26][CH2:25][O:24][CH2:29][CH2:28]2)=[N:32]1)[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: O=C(O)c1cccnc1-n1ccc(CN2CCOCC2)n1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCOCC2)n1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (280 mg, 1.461 mmol mmol), 1-hydroxybenzotriazole hydrate (220 mg, 1.437 mmol) and triethylamine (Et3N) (2204) were successively added to a suspension of 2-(3-(morpholinomethyl)-1H-pyrazol-1-yl)nicotinic acid (350 mg, 1.214 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (260 mg, 1.339 mmol) in CH2Cl2 (40 mL) at 5° C., and the mixture was stirred at 5° C. for about 5 minutes. A pH of 8 was adjusted by adding 50 μL of Et3N, the mixture stirred for 1 hour at 5° C. and then overnight at room temperature. Dichloromethane (50 mL) was added, washed subsequently with water and brine, dried (MgSO4) and concentrated in vacuo to give 430 mg of a yellow oil, which was purified by chromatography over silica gel (eluent CH2Cl2/methanol) to give 260 mg of an amorphous white solid; ESI-MS [M+H]+: 465.2
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][OH:5])[CH3:2].[C:8](Cl)([Cl:10])=[O:9].ClC([O-])=O>C1C=CC=CC=1>[Cl:10][C:8]([O:5][CH2:4][CH:3]([CH2:6][CH3:7])[CH2:1][CH3:2])=[O:9]
Reactant: O=C(Cl)Cl
Reactant: CCC(CC)CO
Agent: O=C([O-])Cl
Solvent: c1ccccc1
Product: CCC(CC)COC(=O)Cl
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
20.4 G. (0.2 moles) of 2-ethyl-1-butanol is added dropwise under anhydrous conditions to 250 ml. (0.4 moles) of 17.2% phosgene solution in benzene with stirring in an ice bath. The addition is complete in 70 minutes and the solution is allowed to gradually warm to room temperature and stirred for 16 hours. The excess phosgene and hydrogen chloride are removed with a stream of nitrogen and the residual solution evaporated to dryness in vacuo affording 17.9 g. (54%) of a light yellow oil which IR demonstrates having a strong chloroformate band and no hydroxy. The oil is used as is in further reactions.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH3:21])[C:11]2=[O:22])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:24][OH:25].N1C=CC=CC=1.CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH3:21])[C:11]2=[O:22])=[CH:6][C:3]=1[CH:4]=[N:24][OH:25]
Reactant: NO
Reactant: Cc1ccncc1N1CCN(c2ccc(F)c(C=O)c2)C1=O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccncc1N1CCN(c2ccc(F)c(C=NO)c2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde (I-113a: 230 mg, 0.769 mmol), hydroxylamine hydrochloride (160 mg, 2.307 mmol) and pyridine (5 mL) were taken in a reaction flask and the flask was stirred at room temperature for 18 hours under nitrogen atmosphere. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ice water and ethylacetate. The organic layer was dried over Na2SO4 and concentrated. The concentrate was washed with diethyl ether and decanted to afford 170 mg of 2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde oxime (70.8% yield).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH:5]=[C:6]([Cl:10])[C:7](=[O:9])[CH3:8].[CH3:11][OH:12]>>[Cl:10][CH:6]([C:7](=[O:9])[CH3:8])[CH:5]([O:12][CH3:11])[O:2][CH3:1]
Reactant: CC(=O)C(Cl)=CCl
Reactant: CO
Reactant: C[O-]
Agent: [Na+]
Product: COC(OC)C(Cl)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 297 g (5.5 mole) sodium methoxide in 5 liters of methanol at 0° C., is added in a slow stream 695 g (5.0 mole) 1,2-dichloro-1-buten-3-one. After the addition is complete, the mixture is stirred at 0° C. for one hour, an additional 54 g (1.0 mole) sodium methoxide is added, and stirring continued at 0° C. for one hour. The mixture is allowed to stir at room temperature overnight, another g mole of sodium methoxide added and stirring continued for an hour. The mixture is filtered (filter aid) to remove salts, washing with fresh methanol. The filtrate is concentrated in vacuo to a slurry which is taken up in isopropyl ether and washed in turn with water, saturated sodium bicarbonate solution and brine, then dried over anhydrous magnesium sulfate. The extract is concentrated in vacuo to provide a residual oil which is distilled in vacuo to afford a main fraction of 628 g (75%) of product, B.P. 66°-75° C. at 8 mm. 1H-NMR (CDCl3) ppm (delta): 2.33 (s, 3H), 3.43 (s, 3H), 3.47 (s, 3H), 4.23 (d, 1H), 4.63 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH:18]([CH3:19])[CH2:17][NH:16][CH:15]([CH2:20][O:21][CH3:22])[C:14]3=[O:23])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[S:29][C:28]([O:30][CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH:18]([CH3:19])[CH2:17][N:16]([C:32](=[O:33])[CH2:31][O:30][C:28]4[S:29][C:25]([Cl:24])=[CH:26][CH:27]=4)[C@@H:15]([CH2:20][O:21][CH3:22])[C:14]3=[O:23])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(O)COc1ccc(Cl)s1
Reactant: COCC1NCC(C)N(Cc2ccc3c(N)ncnc3c2)C1=O
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)C(C)CN1C(=O)COc1ccc(Cl)s1

Procedure:
The title compound is prepared as described in EXAMPLE 123 using 1-(4-amino-quinazoline-7-ylmethyl)-3-methoxymethyl-6-methyl-piperazine-2-one, EXAMPLE 87, and 5-chloro-2-thienyloxyacetic acid, EXAMPLE 24. 1H NMR (CD3OD300 MHz) δ8.68 (s, 1H), 8.27 (d, 1H), 7.62 (m, 2H), 6.54 (d, 1H), 6.18 (m, 1H), 7.39 (d, 1H), 4.94 (m, 4H), 4.15 (m, 2H), 3.76 (m, 2H), 3.44 (s, 3H), 3.10 (m, 2H), 1.28 (d, 3H).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[F:4][C:5]([F:12])([F:11])[C:6](=O)[CH2:7][C:8]#[N:9].Cl>CCO>[CH3:1][N:2]1[C:8]([NH2:9])=[CH:7][C:6]([C:5]([F:12])([F:11])[F:4])=[N:3]1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: CNN
Agent: Cl
Solvent: CCO
Product: Cn1nc(C(F)(F)F)cc1N
Yield: 20.9 %

Procedure:
A solution of methylhydrazine (5.0 g, 60 mmol) and 4,4,4-trifluoro-3-oxo-butyronitrile (9.8 g, 71 mmol) in EtOH (50 mL) was treated with conc. HCl (5 mL) and the resultant mixture was heated to reflux overnight. The solvent was removed in vacuo and the crude product was dissolved in EtOAc washed with saturated aq. Na2CO3 solution until the washings were pH 8. The organics were concentrated and purified by pre-HPLC to provide 2-methyl-5-trifluoromethyl-2H-pyrazol-3-ylamine (2.07 g, 21% yield). 1HNMR (300 MHz, DMSO-d6), δ 5.57 (s, 1 H), 5.54 (br s, 2 H), 3.55 (s, 3 H); MS (ESI) m/z: 166.1 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:15]([N:18]=[C:19]=O)(=[O:17])=[O:16]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[C:9]([O:13][S:15](=[O:17])(=[O:16])[NH2:18])[CH:10]=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([CH2:7][C:19]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1cccc(-c2ccccc2)c1
Solvent: Cc1ccccc1
Product: N#CCc1ccccc1
Product: NS(=O)(=O)Oc1cccc(-c2ccccc2)c1

Procedure:
Using the procedure described in Example 75, the title compound was prepared from 17.0 g (0.010 mole) of 3-phenylphenol and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 100 ml of toluene to obtain 19.0 g (77%) of white flakes, mp 197°-199° C. (benzene-acetonitrile).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH2:25])[O:5][CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:32]=[C:31]1[NH:25][C:24]2[CH:23]=[CH:22][C:4]([O:5][CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][C:2]=2[NH:1]1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccc(N)c(N)c1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccc2[nH]c(=O)[nH]c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl [(1R)-2-(3,4-diaminophenoxy)-1-phenylethyl]carbamate (Intermediate 6) (318 mg, 0.93 mmol) was placed in a 50-mL RBF under a nitrogen atmosphere and dissolved in DMF (5 mL). CDI (135 mg, 0.83 mmol) was added, and the reaction was stirred at room temperature for four hours. The reaction was added to a separatory funnel containing ethyl acetate (125 mL) and dilute aqueous NaHCO3 (75 mL); the phases were separated, and the organic layer was washed with brine (75 mL), dried over anhydrous Na2SO4 and then concentrated in vacuo. The crude product mixture was then purified by silica gel chromatography to afford tert-butyl {(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}carbamate as a white solid. 1H NMR (500 MHz, C2D6SO) δ 10.49 (s, 1H), 10.37 (s, 1H), 7.54 (d, 1H), 7.34 (m, 4H), 7.25 (t, 1H), 6.77 (d, 1H), 6.48 (s, 2H), 4.86 (q, 1H), 3.98 (m, 2H), 1.37 (s, 9H). LRMS (ESI) calc'd for (C16H16N3O4) [M−C4H8+H]+, 314.1; found 314.1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([C:36](=[O:38])[CH3:37])[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1
Reactant: Cc1nc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3noc(C)n3)CC2)C1
Reaction time: 16 h

Procedure:
To a solution of trans-8-chloro-1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.10 g, 0.24 mmol) and triethylamine (0.70 ml, 0.50 mmol) in dichloromethane (4.8 ml) was added acetyl chloride (0.019 ml, 0.26 mmol) at room temperature. After stirring for 16 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.003 g, 3%) as white solid. MS m/e: 427 ([M+H]+).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.[ClH:13].[C:14]1([CH:20]([NH2:31])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[ClH:13].[NH2:8][CH2:9][C:10]([NH:31][CH:20]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=1)=[O:11]
Reactant: NC(c1ccccc1)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Product: NCC(=O)NC(c1ccccc1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared in analogy to example 3.1, starting from N-tert.butyloxycarbonyl glycine and C-phenyl-C-(4-trifluoromethyl-phenyl)-methylamine hydrochloride (CA [49703-60-8]).
Reaction SMILES: C[O:2][C:3]1[C:4]([O:25]C)=[CH:5][C:6]2[C:7]([CH:24]=1)=[C:8]1[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15]2[C:10]([CH:11]=[C:12]([O:22]C)[C:13]([O:20]C)=[CH:14]2)=[CH:9]1.[K+].[Br-]>>[OH:2][C:3]1[C:4]([OH:25])=[CH:5][C:6]2[C:7]([CH:24]=1)=[C:8]1[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15]2[C:10]([CH:11]=[C:12]([OH:22])[C:13]([OH:20])=[CH:14]2)=[CH:9]1
Reactant: COc1cc2cc3c(ccc4cc(OC)c(OC)cc43)nc2cc1OC
Agent: [Br-]
Agent: [K+]
Product: Oc1cc2cc3c(ccc4cc(O)c(O)cc43)nc2cc1O

Procedure:
Prepared from 14a; mp>270° C.; IR (KBr): 3361,3164, 1620,1516; 1H NMR (CD3OD): δ7.26 (1H, s), 7.37 (1H, s), 7.56(1H, s), 7.61 (1H, d, J=9.2), 8.05 (2H, m), 9.61(1H, s),; 13C NMR (CD3OD): δ101.1, 108.7, 110.3, 114.3, 114.7, 122.9, 124.4, 124.8, 126.7, 137.6, 137.8, 138.3, 139.0, 149.4, 150.7, 150.8, 159.3; HRMS calcd for C17H11NO4 : 293.0688; found: 293.0685.
Reaction SMILES: [S:1]([C:5]1[C:6]([C:10]([O:12]C)=O)=[CH:7][S:8][CH:9]=1)(=[O:4])(=[O:3])[NH2:2]>C[O-].[Na+]>[O:12]=[C:10]1[C:6]2=[CH:7][S:8][CH:9]=[C:5]2[S:1](=[O:4])(=[O:3])[NH:2]1
Reactant: COC(=O)c1cscc1S(N)(=O)=O
Agent: C[O-]
Agent: [Na+]
Product: O=C1NS(=O)(=O)c2cscc21

Procedure:
31.6 g (0.143 mole) of methyl 4-sulfamoylthiophene-3-carboxylate (IX; R1 =H; R=CH3) is refluxed for 20 hours in 150 ml of 1N methanolic sodium methylate solution. The methanol is evaporated, the residue taken up in water, and the aqueous phase extracted with methylene chloride and acidified with concentrated hydrochloric acid; the product precipitates as crystals. It may be recrystallized from water or ethanol.