Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9](Cl)(=[O:11])=[O:10]>O1CCCC1>[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([NH2:2])(=[O:11])=[O:10]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)CCCCCCl
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)CCCCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.5 ml of a 28% aqueous solution of ammonium hydroxide were added dropwise at 0° to +5° C. under an inert gas atmosphere to a solution of 2.5 g of 5-chloropentane sulfonyl chloride (preparation described in: Bull. Soc. Chim. Belg. (1965) Vol. 74., p. 21) in 30 ml of tetrahydrofuran. The temperature was allowed to rise from 3° C. to 16° C., and the mixture was stirred at ambient temperature for 2 hours. The tetrahydrofuran was evaporated under reduced pressure and the residue was taken up in water, extracted with methylene chloride, washed with water, then with an aqueous solution of sodium chloride, dried and evaporated under reduced pressure to obtain 2.01 g of the expected product melting at 62° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][N:43](C(OC(C)(C)C)=O)[CH:44]=2)O1>>[CH3:31][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[CH:22][C:14]=2[NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:40]4[CH:41]=[N:42][NH:43][CH:44]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[N:17]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(-c6cn[nH]c6)ccn45)cccc32)n1

Procedure:
Prepared according to procedure of Example 68 using 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate. MS (ES+APCI) m/z=463 (M+H) detected.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:17][C:16]=1[NH:25][C:26](=[O:42])[CH2:27][CH:28]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:35][C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(OCC)C.C(Cl)Cl>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=[O:24])=[CH:17][C:16]=1[NH:25][C:26](=[O:42])[CH2:27][CH:28]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:35][C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(CCCO)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CCC=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 87.9 %

Procedure:
2 ml of a methylene chloride solution containing 155 mg (1.98 mmol) of dimethyl sulfoxide were added dropwise over a period of 5 minutes to 2 ml of a methylene chloride solution containing 126 mg (0.99 mmol) of oxalyl chloride which had previously been cooled at -78° C. The mixture was then stirred for 5 minutes at this temperature, after which 15 ml of a methylene chloride solution containing 354 mg (0.825 mmol) of N-[2-t-butyl-5-(3-hydroxypropyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 18) were added, and the mixture was stirred for a further 15 minutes at this temperature. 501 mg (4.95 mmol) of triethylamine were then added to the reaction mixture, which was then stirred for 5 minutes at the same temperature. The reaction mixture was then allowed to return to room temperature, after which it was diluted with diethyl ether, and washed with dilute aqueous hydrochloric acid and then with water. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 20 g of silica gel. Elution with a 100:5 by volume mixture of methylene chloride and ethyl acetate afforded 310 mg (yield 88%) of the title compound as crystals, melting at 176°-177° C. (after recrystallization from a mixture of methylene chloride and diethyl ether).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1)[CH3:2].C([Li])(C)(C)C.[CH3:15][C:16]1([CH3:47])[CH:25]=[C:24](OS(C(F)(F)F)(=O)=O)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:35][C:36]3[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=3)[CH:22]=2)[S:17]1>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:35][C:36]4[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=4)[CH:22]=3)[S:17][C:16]([CH3:15])([CH3:47])[CH:25]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)S3)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)cc1
Temperature: 25 °C

Procedure:
A solution of 4-ethylbromobenzene (670.9 mg. 3.63 mmol) in 4.0 mL of THF was cooled to −78° C. and tert-butyllithium (464.5 mg. 7.25 mmol, 4.26 mL of a 1.7M solution in pentane) was added to give a yellow solution. After 30 min a solution of ZnCl2 (658.7 mg. 4.83 mmol) in 8.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 4-(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-thiochromen-6-ylethynyl)-benzoate (1.20 g. 2.42 mmol) and tetrakis (triphenylphosphine) palladium(0) (111.7 mg. 0.097 mmol) in 8.0 mL THF. This solution was heated to 50° C. for 1 h, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. This solution was extracted with EtOAc and the combined organic layers washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. Ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate was isolated by column chromatography (5% EtOAc/hexanes) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ7.99 (2h, D, j=8.2 Hz), 7.52 (2H, d, J=8.4 Hz), 7.40 (5H, m), 7.35 (2H, m), 5.85 (1H, s), 4.38 (2H, q, J=7.1 Hz), 2.72 (2H, q, J=7.6 Hz), 1.48 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.30 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[C:32]1(B(O)O)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:40]4[C:41]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:37]=[CH:38][CH:39]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccc5ccccc45)cc3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionic acid ethyl ester (0.907 mmol) (see Ex. 2, part B) and 1-naphthaleneboronic acid (0.998 mmol) in toluene:ethanol (18.2 mL of a 1:1 solution) was treated with Na2CO3(aq) (0.906 mL of a 2M solution). A nitrogen atmosphere was applied, Pd(PPh3)4 (52.5 mg) was added, and the orange mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The layers were separated, and the aqueous phase was back-extracted with ethyl acetate (2×10 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4 and concentrated. The product was purified by silica gel chromatography (20 g SiO2, 3:7 ethyl acetate:hexanes) to give the desired product in 87% as an orange oil; Rf=0.46 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ8.09 (d, J=8 Hz, 2H), 7.92-7.82 (m, 3H), 7.59-7.40 (m, 6H), 6.81-6.72 (m, 4H), 4.22-4.17 (m, 4H), 2.98 (t, 2H), 2.38 (s, 3H), 1.46 (s, 6H), 1.22 (t, 3H); MS (EI) 536.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([OH:27])=O)=[N:10]2)=[CH:5][CH:4]=1.[CH2:28]([NH2:31])[CH2:29][CH3:30].O>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([NH:31][CH2:28][CH2:29][CH3:30])=[O:27])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCCN
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(OC)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.3 %

Procedure:
N,N'-Carbonyldiimidazole (1.35 g) is added to a solution of [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (3 g) in anhydrous dimethylformamide (70 cc), and the mixture is stirred for 2 hours at a temperature in the region of 25° C. Propylamine (0.4 g) is then added and the mixture is stirred again for 16 hours at a temperature in the region of 25° C. The reaction mixture is then poured into water (150 cc) and the precipitate obtained is separated by filtration, washed with water, dried under reduced pressure (0.05 kPa) and recrystallized in ethanol. [2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]-N-propylacetamide (2.95 g), m.p. 174° C., is thereby obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][O:12][CH3:13])[CH2:6][CH2:5]1.[C:14]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:1][CH2:2][CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([O:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:9]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCCCCC1
Reactant: COCOC1CCN(CCN)CC1
Product: COCOC1CCN(CCNC2CCCCCCC2)CC1
Yield: 90.9 %

Procedure:
Using 3 g of 1-(2-aminoethyl)-4-methoxymethoxy-piperidine and 2 g of cyclooctanone, 4.3 g of 1-(2-cyclooctylaminoethyl)-4-methoxymethoxypiperidine was obtained in the same manner as in Reference Example 1.
Reaction SMILES: C(Cl)(C(Cl)=O)=O.CS(C)=O.[CH2:11]([N:18]([C@@H:26]([CH3:29])[CH2:27][OH:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[CH2:19]([N:18]([C@@H:26]([CH3:29])[CH:27]=[O:28])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To a cold (−78° C.) solution of (COCl)2 (2M in CH2Cl2, 2.47 mL, 4.94 mmol) in CH2Cl2 (8 mL), DMSO (0.70 mL, 9.89 mmol) was added dropwise. After stirring at −78° C. for 15 min, a solution of (S)-2-(N,N-dibenzylamino)-1-propanol (1.01 g, 3.96 mmol) in CH2Cl2 (10 mL) was added dropwise. The mixture was stirred at −78° C. for 1 h, and then Et3N (2.76 mL, 19.78 mmol) was added. The reaction was warmed up to 0° C. and stirred for 15 min, followed by the addition of NH4Cl (25 mL, sat. aq.). The crude was extracted with CH2Cl2 (3×25 mL), washed successively with NaHCO3 (50 mL, sat. aq.) and brine (50 mL), dried over Na2SO4 and concentrated in vacuo. Aldehyde 4 was obtained as a yellow oil and used without further purification (928 mg, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][CH:11]([C:17](=O)[CH3:18])[C:12](OCC)=[O:13]>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([CH3:9])[CH:3]=1)[N:6]=[C:17]([CH3:18])[C:11]([CH3:10])=[C:12]2[OH:13]
Reactant: Cc1cc(Cl)ccc1N
Reactant: CCOC(=O)C(C)C(C)=O
Product: Cc1nc2c(C)cc(Cl)cc2c(O)c1C
Temperature: 170 °C

Procedure:
Prepared according to procedure R using 4-chloro-2-methylaniline (2.22 g, 15.7 mmol), ethyl 2-methyl-3-oxobutanoate (4.08 g, 31.4 mmol) in PPA (6.3 g, 62.8 mmol) and heating at 170° C. for 2 h and at rt overnight. The crude mixture was neutralized to pH 7-8 and the precipitated was filtered. The solid was then dried under high vacuum to give 6-chloro-2,3,8-trimethylquinolin-4-ol as white solid. Mass Spectrum (ESI) m/e=222 (M+1).
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCc1ccccc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
Methyl iodide (51 g, 22.4 ml, 0.24 mole) was added to a stirred mixture of 3-(2-bromophenyl)propanoic acid (36.7 g, 0.16 mole, prepared as described by F. G. Holliman and F. G. Mann J Chem. Soc. 9, 1960) and anhydrous potassium carbonate (33 g, 0.24 mole) in dry N,N-dimethylformamide (250 ml) and the mixture was stirred at ambient temperature overnight. After removal of the solvent in vacuo the residue was partitioned between ether and water and the ethereal phase washed with aqueous sodium thiosulphate and then brine and dried (MgSO4). Evaporation gave a pale yellow oil which distilled at 116°-118° C. (0.2 mm) to give 36.91 g (95%) of the title ester as a colourless oil, νmax 2950, 1740, 1570, 1470, 1440 cm-1, δ(CDCl3), 2.63 (2H, m, ArCH2), 3.07 (2H, m, CH2CO2), 3.70 (3H, s, CH3), 7.12 (3H, m, arom), 7.50 (1H, d, arom).
Reaction SMILES: Cl.[Sn](Cl)Cl.[N+:5]([C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1)([O-])=O.C(=O)(O)[O-].[Na+]>CO>[NH2:5][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:9]=1[N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Concentrated hydrochloric acid (1.28 ml, 15.4 mmol) and anhydrous tin dichloride (1.57 g, 8.30 mmol) were sequentially added at 0° C. to a methanol (7 ml) solution of 1-(2-nitro-4-(trifluoromethyl)phenyl)indoline (730 mg, 2.37 mmol), obtained as described in Referential Example 19-1. The resulting mixture was warmed to room temperature, and stirred for eight hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture. The resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate=10/1). Thus, 1-[2-amino-4-(trifluoromethyl)phenyl]indoline (619 mg, 93.9%) was yielded as a red-orange colored oily material.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([NH2:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1>C(O)=O>[CH:1]([NH:18][CH:14]([C:11]1[CH:10]=[CH:9][CH:8]=[CH:13][CH:12]=1)[C:15]([OH:17])=[O:16])=[O:3]
Reactant: N[C@@H](C(=O)O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNC(C(=O)O)c1ccccc1
Reaction time: 0.5 h

Procedure:
40.8 ml. of acetic anhydride are cooled to 0°-5° and 54.4 ml. of formic acid are added dropwise with stirring at this temperature. The mixture is let stand for 30 minutes at this temperature and then 15.2 g. (0.1 mol.) of D-phenylglycine are added. After about 10 minutes, a clear solution results and after an additional 15 minutes α-(formylamino)benzeneacetic acid crystallizes. The temperature is allowed to rise to room temperature and 300 ml. of ice water are added. The mixture is then stirred for five minutes, filtered under suction, washed with water and dried, yield 11.4 g., m.p. 170°-175°. The product, α-(formylamino)benzeneacetic acid, is recrystallized from ethanol. The melting point remains unchanged.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Cl[C:30]1[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[C:33]([C:40]([O:42][CH3:43])=[O:41])=[CH:32][N:31]=1.C1N2CCN(CC2)C1>>[CH3:43][O:42][C:40]([C:33]1[C:34]([C:36]([F:39])([F:37])[F:38])=[N:35][C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:31][CH:32]=1)=[O:41]
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: C1CN2CCN1CC2
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)nc1C(F)(F)F

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with methyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate and DABCO (17 h, r.t.) to give the title compound as a white solid. MS (m/e)=620.2 [M+H+].
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C1CCNC1
Reactant: O=C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=C(N2CCCC2)CCC1
Yield: 140 %

Procedure:
Reflux a mixture of cyclopentanone (600 g, 7.14 mol), pyrrolidine (550 g, 4.68 mol) and toluene-4-sulfonic acid (5.0 g) in toluene (3 L) for 4 hours. After removal of solvent under vacuum, purify the residue by distillation carefully to give 1-cyclopent-1-enyl-pyrrolidine as colorless oil (898 g, 6.55 mol, 91.8%). 1H NMR (CDCl3, 400 MHz): δ 4.04 (m, 1H), 3.06 (m, 4H), 2.39 (m, 4H), 1.85 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:33][CH2:34][C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=O)=O)=CC=1>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:33][CH2:34][C:35]3[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH2:15][C:16]([F:17])([F:19])[F:18])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(CC(F)(F)F)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(CC(F)(F)F)C1
Temperature: 25 °C

Procedure:
To a solution of 8-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.372 mmol) in DMF (2 mL) were added sodium hydride (50 mg, 1.11 mmol) and 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (271.3 mg, 0.932 mmol). The reaction mixture was irradiated in a microwave reactor at 90° C. for 1 h. The reaction mixture was cooled to RT, quenched with water and extracted with EtOAc (3×10 mL). The organic layer was washed with water (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC. 1H NMR (CD3OD, TFA salt) d (ppm): 8.16 (s, 1H), 8.1 (d, 1H), 7.65 (d, 1H), 7.2 (s, 1H), 7.0 (d, 1H), 6.9 (d, 1H), 4.48 (s, 2H), 4.4 (t, 2H), 4.17 (q, 2H), 3.62 (t, 2H), 3.2 (t, 2H), 3.08 (t, 2H), 2.64 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:6]2[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:3]=1.CN(C=O)C.[C:22](OC(=O)C)(=[O:24])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:22]([O:12][CH2:11][C:9]1[N:10]=[C:6]2[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:3]=[C:2]([OH:1])[N:7]2[N:8]=1)(=[O:24])[CH3:23]
Reactant: COC(=O)c1cc(O)n2nc(CO)nc2n1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)n2nc(COC(C)=O)nc2n1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of 25.7 g of 7-hydroxy-2-hydroxymethyl-5-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine, 200 of DMF, 47 ml of acetic anhydride and 1 g of p-toluenesulfonic acid was stirred at 60° C. for 24 hours. The reaction mixture was condensed and 100 ml of methanol was added to the crystals precipitated residue, and the mixture was stirred. Then, crystals were collected by filtration, washed with methanol and dried to obtain 8.9 g of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([CH3:15])[CH2:13]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C@H:17]1[O:22][C@@H:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>>[CH3:23][C@H:21]1[O:22][C@@H:17]([CH3:16])[CH2:18][N:19]([CH2:13][C@H:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH3:15])[CH2:20]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: C[C@H](CCl)Cc1ccc(C(C)(C)C)cc1
Product: C[C@@H](Cc1ccc(C(C)(C)C)cc1)CN1C[C@@H](C)O[C@@H](C)C1

Procedure:
The reaction of (a) with cis-2,6-dimethylmorpholine gives the known (S)-fenpropimorph.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH:24]=[O:25])=[CH:23][C:18]=2[O:17][CH2:16]1.C(O)(C)C>C1COCC1.O>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH:24]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)[OH:25])=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(O)c2ccc3c(c2)OCO3)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A stirred mixture of 1-bromo-4-methoxy-benzene (1.79 g, 9.6 mmol) and dry THF (25 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (3.6 mL, 9.1 mmol) and stirred for 20 min. Then a mixture of benzo[1,3]dioxole-5-carbaldehyde (1.23 g, 8.2 mmol) in dry THF (20 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (4.2 mL, 55 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4 and concentrated to give benzo[1,3]dioxol-5-yl-(4-methoxy-phenyl)-methanol as an oil (2.54 g, 108% crude yield, HPLC purity 88%): 1H NMR (CDCl3) δ 2.13 (d, J=3 Hz, 1H, OH), 3.79 (s, 3H, —OCH3), 5.72 (d, J=3 Hz, 1H, CH), 5.93 (s, 2H, CH2), 6.74-7.39 (m, 7H, Ar). The product was used in the next step without further purification.