Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH3:16]>CN(C=O)C>[CH2:14]([N:3]1[C:2]([Br:1])=[C:6]([N+:7]([O-:9])=[O:8])[C:5]([Br:10])=[N:4]1)[CH2:15][CH3:16]
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc(Br)c([N+](=O)[O-])c1Br
Temperature: 55 °C
Yield: 67.4 %

Procedure:
A mixture of 3,5-dibromo-4-nitropyrazole (2) (25 g, 92 mmol) in DMF (120 ml) was added over 45 minutes to a suspension of NaH (4.0 g, 10 mmol; 60% dispersion in oil, prewashed with hexane) in DMF (200 ml) with stirring and under an inert atmosphere. After stirring for 30 minutes, a solution of 1-bromopropane (13.6 g, 111 mmol) in DMF (40 ml) was added over 10 minutes. The reaction mixture was heated at 50-60° C. for 3 hours (monitored by TLC) and the DMF was then evaporated off under reduced pressure. A mixture of DCM/water (300 ml, 1/5) was added and the organic phase was then extracted with water (2×50 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude reaction product was obtained as a black oil (19.4 g, 70%), which was used without further purification in the amination step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4C(NCC(O)=O)=O)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C1COCC1.C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][NH:22]4)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cccc4c3CCN4C(=O)NCC(=O)O)no2)cc1OCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1OCC
Yield: 43 %

Procedure:
To a solution of the product of Step B (0.06 g; 0.172 mmol) in 1M BH3 in THF (0.35 ml; 0.35 mmol) TFA (0.4 ml) was added drop wise at 0° C. with stirring. After the addition was completed (˜5 min), the reaction was quenched with H2O (0.5 ml) and solvents were removed under reduced pressure. The residue was diluted to 10 ml with EtOAc and was washed with 10% NaOH (2×2 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.026 g; 43%) as a creamy foam, which was used in the next step without further purification. 1H-NMR (CDCl3) 7.78 (dd, 1H, J=1.9, 7.2 Hz); 7.68 (d, 1H, J=1.9 Hz); 7.52 (d, 1H, J=7.2 Hz); 7.17 (t, 1H, J=7.7); 6.97 (d, 1H, J=8.5 Hz); 6.75 (d, 1H, J=7.7 Hz); 4.19 (m, 4H); 3.65 (t, 2H, J=8.9 Hz); 3.45 (tr, 2H, J=8.9 Hz); 1.7 (broad s, 1H+H2O); 1.49 (m, 6H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([F:11])[F:10])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([CH:45]=[O:46])=[CH:16][N:17]2[C@@H:22]1[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]1[O:24][C:25](=[O:27])[CH3:26].[Cl-].[NH4+]>O1CCCC1.BrCCBr>[F:10][CH:9]([F:11])[C:6]1[CH:7]=[CH:8][C:3]([CH:45]([C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[CH:21][C:13]=3[F:12])[N:17]([C@@H:22]3[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]3[O:24][C:25](=[O:27])[CH3:26])[CH:16]=2)[OH:46])=[CH:4][CH:5]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C=O)c3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: FC(F)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(O)c3ccc(C(F)F)cc3)c3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
To a mixture of magnesium turnings (71 mg) in tetrahydrofuran (2 ml) was added dropwise a solution of 1-bromo-4-difluoromethylbenzene (587 mg) in tetrahydrofuran (1.5 ml) under being stirred vigorously. The mixture was warmed with a dryer, and thereto was added 1,2-dibromoethane (4 drops). The resultant mixture was vigorously stirred at room temperature till a disappearance of magnesium turnings, and then dropwise added to a solution of the above 4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole-3-carboxaldehyde (350 mg) in tetrahydrofuran (4 ml) over 10 minutes at −78° C. under argon atmosphere. The mixture was stirred at same temperature for 1 hour, and thereto was added a saturated aqueous ammonium chloride solution (20 ml). The resultant mixture was extracted with ethyl acetate (50 ml) 3 times, and the combined organic layer was dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure to give crude 4-(difluoromethyl)phenyl 4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indol-3-yl methanol, which was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:1][NH2:2])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: NC=Cc1ccc(C(F)(F)F)cc1

Procedure:
Methylamine was passed into a solution of about 10.1 g of 4-(trifluoromethyl)benzaldehyde in about 100 ml of benzene over MgSO4 for four hours with stirring. The solution was filtered, and then the solvent was evaporated to give N-[4-(trifluoromethyl)benzylidene]methylamine as an oil. This was taken up in benzene and catalytically (5% Pd/C) hydrogenated to give the title product.
Reaction SMILES: [CH3:1]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C[C:24]1([C:34]([NH:36][C@H:37]([C:41]([NH:43][CH:44]([CH:53]([OH:65])[CH2:54][O:55][CH2:56][C:57]2[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=2[Cl:64])[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35])[C:32]([CH3:33])=[C:31]2[C:26]([CH:27]=[CH:28][CH:29]=[CH:30]2)=[N:25]1>CS(C)=O>[CH3:1][N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]([CH3:33])=[C:24]1[C:34]([NH:36][C@H:37]([C:41]([NH:43][CH:44]([C:53](=[O:65])[CH2:54][O:55][CH2:56][C:57]1[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:64])[CH2:45][C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])=[O:42])[CH:38]([CH3:39])[CH3:40])=[O:35]
Reactant: CC1=c2ccccc2=NC1(C)C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)COCc1c(Cl)cccc1Cl)C(C)C
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Temperature: 25 °C
Yield: 86.7 %

Procedure:
Dess-Martin periodinane (195 mg) was added as a solid to a solution of N-[(2,3-dimethylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-(2′,6′-dichlorobenzyloxy)pentanoic acid, t-butyl ester (96 mg) in DMSO (1.5 ml). The resulting solution was stirred under a nitrogen atmosphere at room temperature for thirty minutes, hen partitioned between EtOAc and water. The organic phase was washed with water 2×) and brine, dried (Na2SO4), and concentrated to give a white solid (83 mg). Flash chromatographic purification with EtOAc/hexanes (1:1) afforded the title product as a white solid (54 mg). TLC (EtOAc/hexanes; 1:1, silica gel): Rf=0.52.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:24][NH:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:25]([CH3:24])[CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CNCCCN1CCCCC1
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Product: CN(CCCN1CCCCC1)C(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N-methyl-3-(piperidin-1-yl)propyl amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (d, J=9.60 Hz, 1H) 1.66 (d, J=13.89 Hz, 3H) 1.82 (br. s., 2H) 2.01 (br. s., 2H) 2.83-3.13 (m, 7H) 3.32-3.58 (m, 4H) 7.79 (d, J=8.34 Hz, 2H) 8.13 (br. s., 3H) 8.58 (br. s., 3H) 9.05-9.50 (m, 1H) 12.43-14.49 (m, 1H). ESI-MS m/z [M+H]+ 445.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:11](=O)[CH2:12][CH3:13])=[C:6]([S:9][CH3:10])SC)[CH3:2].Cl.[Br:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([NH:25][NH2:26])=[C:20]([CH3:27])[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:11]([CH2:12][CH3:13])=[N:26][N:25]([C:21]2[C:20]([CH3:27])=[CH:19][C:18]([Br:17])=[CH:23][C:22]=2[CH3:24])[C:6]=1[S:9][CH3:10])=[O:15])[CH3:2]
Reactant: Cc1cc(Br)cc(C)c1NN
Reactant: CCOC(=O)C(C(=O)CC)=C(SC)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(CC)nn(-c2c(C)cc(Br)cc2C)c1SC
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of 8.58 g (34.5 mmol) of 3,3-bismethylthio-2-propionylacrylic acid ethyl ester, 8.67 g (34.5 mmol) of 4-bromo-2,6-dimethylphenylhydrazine hydrochloride and 7.31 g (69.0 mmol) of sodium carbonate in 150 mL of ethanol in a 250 mL RBF under an atmosphere of dry N2 was refluxed over the weekend. The reaction mixture was cooled to room temperature and evaporated to a reddish solid. This material was partitioned between 150 mL of water and 200 mL of methylene chloride (CH2Cl2). The organic layer was separated, dried over sodium sulfate and evaporated to a gum which was chromatographed on a silica gel column eluting with CH2Cl2 to give 2.6 g of pure product as a yellow oil. 1H-NMR (CDCl3) δ 1.26 (3H, t, J=7), 1.40 (3H, t, J=7), 1.94 (6H, s), 2.33 (3H, s), 2.93 (2H, q, J=7), 4.36 (2H, q, J=7), 7.30 (2H, s).
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:26][CH3:27])=[N:19][N:20]3[CH:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1>>[CH2:1]([C@@H:8]1[N:13]([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:26][CH3:27])=[N:19][N:20]3[CH:23]([CH3:24])[CH3:25])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cnccn1
Reactant: CCc1nn(C(C)C)c2cc(N3CCNC(Cc4ccccc4)C3)ccc12
Product: CCc1nn(C(C)C)c2cc(N3CCN(c4cnccn4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 12 %

Procedure:
Prepared using the same procedure described in Example 410 from 6-(3-benzyl-piperazin-1-yl)-3-ethyl-1-isopropyl-1H-indazole and chloropyrazine to afford the title compound as a yellow solid (7 mg, 12%). LC/MS (Method B) 4.47 min, [M+1]+ 441.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:22][CH:21]([CH3:23])[CH:14]([C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(c1nc(N2CCOCC2)cc(=O)[nH]1)C(C)C

Procedure:
The product is prepared according to the procedure described in example 67, using 600 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 1 and 0.29 ml of 2-iodopropane in place of the methyl iodide, and replacing the potassium carbonate with cesium carbonate. After purification by silica column chromatography, eluent: 900505 CH2Cl2/CH3CN/MeOH, 20 mg of ethyl 3-methyl-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]butanoate are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][C:12]=2[Cl:21])=[O:9])=[CH:4][CH:3]=1.[CH2:24]=O>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:6]2[CH2:7][C:8](=[O:9])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][C:12]=3[Cl:21])[CH2:24]2)=[CH:22][CH:23]=1
Reactant: C=O
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNc2ccc(Cl)cc2)c(Cl)c1
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(N2CN(c3ccc(Cl)cc3)CC2=O)c(Cl)c1

Procedure:
2-(p-Chloroanilino)-N-(2-chloro-4-sulphamoylphenyl)-acetamide (3g)was dissolved in ethanol (40 ml) and paraformaldehyde (0.5g) in water (80 ml) added thereto. The mixture was refluxed for 3 hours, cooled and filtered to yield the title product (2.1g), m.p. 222°-225°(ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]2=[O:19])=[N:5][N:4]=1.[C:20]1(C)C(S(O)(=O)=O)=CC=C[CH:25]=1>C(O)C>[CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][CH2:20][CH3:25])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]2=[O:19])=[N:5][N:4]=1
Reactant: C=CCCN1CCC(O)N(c2nnc(OC)s2)C1=O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Product: C=CCCN1CCC(OCC)N(c2nnc(OC)s2)C1=O

Procedure:
Tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-but-3-enyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), ethyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermomater and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-but-3-enyl-6 -ethoxy-2(1H)-pyrimidinone.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH3:21]>>[CH2:20]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])[CH3:21]
Reactant: CCNCc1ccncc1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)N(CC)Cc3ccncc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and ethyl-pyridin-4-ylmethyl-amine to afford the title compound. MS: m/e=377 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].CCCCCC.[CH3:19][O:20][CH2:21]Cl>O1CCCC1>[CH2:1]([N:3]([CH2:10][CH2:11][O:12][CH2:19][O:20][CH3:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCN(CCO)c1ccccc1
Reactant: COCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(CCOCOC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
55.7 g (0.34 mol) of N-ethyl-N-(2-hydroxylethyl)aniline was dissolved in 250 ml of anhydrous tetrahydrofuran, and 162 ml (1.2-fold equivalent weight) of a 2.5M hexane solution n-butyllithium was dropwise added thereto over a period of 30 minutes at 0° C. in an atmosphere of argon, followed by stirring at 0° C. for 30 minutes. Next, to the reaction solution obtained, 30.0 g (1.09-fold equivalent weight) of methoxymethyl chloride was dropwise added, and the solution was heated and refluxed for 12 hours, followed by cooling. The precipitate formed was removed by filtration, and thereafter the filtrate obtained was concentrated under reduced pressure. The oily residue thus obtained was distilled under reduced pressure to obtain 63 g of N-ethyl-N-[2-(methoxymethyl)oxyethyl]aniline (yield: 89%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][N:15]([CH2:23][CH2:24][CH2:25][NH:26][CH3:27])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([N:26]([CH3:27])[CH2:25][CH2:24][CH2:23][N:15]([CH3:14])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CNCCCN(C)C(=O)OC(C)(C)C
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C
Yield: 68.4 %

Procedure:
4-Amino-5-chloro-2-methoxybenzoic acid (500 mg, 2.48 mmol) and tert-butyl methyl[3-(methylamino)propyl]carbamate (652 mg, 3.22 mmol) were used to give the title compound (655 mg; yield, 68%) as a colorless oily substance according to the method described in Example 12a.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([CH2:12][O:13][CH3:14])[CH3:11].[H][H]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.ClCCl.O1CCCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][CH:10]([CH2:12][O:13][CH3:14])[CH3:11]
Reactant: [H][H]
Reactant: COCC(C)=Nc1c(C)cccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCC(C)Nc1c(C)cccc1C
Reaction time: 91 h

Procedure:
The general procedure described in Example B1 is repeated, with the following modifications to the reaction conditions: A catalyst solution is prepared consisting of 5.3 mg of [Ir((1,5-cyclooctadien)Cl]2 (0.0079 mmol), 10.2 mg of A (0.017 mmol) and 11.9 mg of tetrabutylammonium iodide (0.032 mmol) in 5 ml of tetrahydrofuran/dichloromethane (1:1). A substrate solution consisting of 1.5 g of N-(2', 6'-dimethylphenyl)-1-methoxymethyl-ethylideneamine (7.8 mmol) in 5 ml of tetrahydrofuran is also used. Hydrogenation is carded out with hydrogen under a pressure of 40 bar. The reaction temperature is 30° C. After 91 hours the conversion is 90%, the ee is 59% CR).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:15][CH:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:17]1>CN(C)C=O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([N:18]2[CH2:17][CH:16]([CH2:15][O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=3)[O:20][C:19]2=[O:21])=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C1OC(CCl)CN1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CN(c3ccc(Cl)cc3)C(=O)O2)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
A 1.52 g quantity of methyl 4-hydroxy-benzoate was added to a suspension of 0.42 g of 60% sodium hydride in anhydrous N,N-dimethylformamide (15 ml) with ice-cooling in a stream of nitrogen. To the mixture was added dropwise an anhydrous N,N-dimethylformamide (15 ml) solution of 2.46 g of 5-(chloromethyl)-3-(4-chlorophenyl)-2-oxooxazolidine obtained in Reference Example 7 at the same temperature, and the mixture was stirred at 40° C. for 48 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with water, dried with magnesium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified by hexane-ethyl acetate gradient elution to give 1.75 g of the title compound (compound 51) in a yield of 48%.
Reaction SMILES: [C:1](OC)([O:5][CH3:6])([O:3]C)[CH3:2].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[C:17]([CH3:19])=[CH2:18])=[CH:12][CH:11]=1.C(O)(=O)CC>CO>[CH3:19]/[C:17](=[CH:16]\[C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][CH:14]=1)/[CH2:18][CH2:2][C:1]([O:5][CH3:6])=[O:3]
Reactant: C=C(C)C(O)c1ccc(C)cc1
Reactant: COC(C)(OC)OC
Solvent: CCC(=O)O
Solvent: CO
Product: COC(=O)CC/C(C)=C/c1ccc(C)cc1
Yield: 40.1 %

Procedure:
Trimethyl orthoacetate (273 g, 2.24 mol) and 1-(4-methylphenyl)-2-methyl-2-propen-1-ol (91.4% pure, 39.92 g, 0.224 mol) were heated in the presence of propionic acid (0.5 ml) in an oil bath at 120°-150° C. The methanol formed during the reaction was distilled first, followed by the excess orthoacetate. The product was then freed from residual orthoacetate under vacuum and purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 25:1 to 5:1), followed by bulb-to-bulb distillation (100° C./0.001 mbar). 19.62 g (yield=40%) of the desired product were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]1([CH2:26]O)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1>CO>[N:17]1([CH2:26][NH:13][C:12]2[CH:14]=[CH:15][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[F:16])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: OCn1nnc2ccccc21
Reactant: Nc1ccc(OCc2ccccc2)cc1F
Solvent: CO
Product: Fc1cc(OCc2ccccc2)ccc1NCn1nnc2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 66.6 %

Procedure:
After dissolving 4-benzyloxy-2-fluoroaniline (11.25 g, 51.78 mmol) in methanol (300 ml), 1H-benzotriazole-1-methanol (8.11 g, 54.37 mmol) was added and the mixture was stirred for 10 hours at room temperature. The precipitated crystals were filtered out, washed with ethanol and dried by aspiration to obtain the title compound (12.01 g, 34.47 mmol, 66.57%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl>O1CCCC1>[Cl:11][C:3]1[C:2]([Cl:1])=[CH:10][C:6]([CH2:7][OH:8])=[CH:5][N:4]=1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: OCc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5,6-dichloronicotinic acid (9.6 g, 50 mmol) in anhydrous tetrahydrofuran (THF; 50 mL) cooled in an ice-water bath was rapidly added 1 M BH3 solution in THF (60 mL, 60 mmol) via a syringe. The mixture was stirred at 0° C. for 30 min while the mixture became orange in color and then at room temperature for 2 h. An additional portion of 1 M BH3 solution in THF (50 mL, 50 mmol) was added and the mixture stirred at room temperature overnight. The mixture was then carefully poured into cold aqueous 1 N HCl solution (100 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organic layer was washed with water, dried over anhydrous MgSO4, filtered, concentrated, and dried to give the desired 2,3-dichloro-5-hydroxymethylpyridine as a yellow oil. GC-MS: mass calcd for C6H5Cl2N [M]+ 162. Found 162.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=1.C([Mg]Cl)(C)C.CO[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1>C1COCC1>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][CH2:8][CH2:7][N:5]1[CH:6]=[C:2]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)[CH:3]=[N:4]1
Reactant: Ic1cnn(CCOC2CCCCO2)c1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazole (Stage 106.1.3, 8.50 g, 26.4 mmol) in THF at 0° C. under argon was added dropwise iPrMgCl 2 M in THF (26.4 ml, 52.8 mmol). The RM was stirred at 0° C. for 1 h. Then 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Aldrich, Buchs, Switzerland, 6.25 g, 52.8 mmol) was added at 0° C. and the solution was stirred again and allowed to warm to rt for 1 h. After that, the RM was quenched with saturated aqueous NH4Cl (140 ml) and extracted with EtOAc (3×). The combined organic layers were washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (hexane/EtOAc 5% to 45%). The fractions containing product were combined and evaporated to dryness to give the title compound as a colorless oil. (HPLC: tR 3.23 min (Method A); M+H=323 MS-ES)