Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@:7]23[CH2:15][NH:14][CH2:13][C@H:12]2[CH2:11][S:10][C:9]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:25][C:26]1[CH:27]=[N:28][C:29](Cl)=[N:30][CH:31]=1.O1CCOCC1.C(N(CC)CC)C>O>[F:25][C:26]1[CH:27]=[N:28][C:29]([N:14]2[CH2:13][C@@H:12]3[C@@:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([N:8]=[C:9]([NH:16][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[S:10][CH2:11]3)[CH2:15]2)=[N:30][CH:31]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3)CNC[C@H]2CS1)c1ccccc1
Reactant: Fc1cnc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC1=N[C@@]2(c3ccccc3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Yield: 79.6 %

Procedure:
A solution of N-[(4aR,7aS)-7a-phenyl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (250 mg, 0.629 mmol), 5-fluoro-2-chloropyrimidine (167 mg, 1.26 mmol), 1,4-dioxane (10 mL), and triethylamine (318 mg, 3.14 mmol) is stirred at 110° C. for 4 hours. The reaction is cooled, diluted with water and extracted with dichloromethane. The organic layers are combined, dried, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (0:1) to give the title compound (0.217 g, 80%). ES/MS (m/e): 434(M+H).
Reaction SMILES: [OH:1][C:2]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1)([CH3:4])[CH3:3].[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1.C1C=CC2N(O)N=NC=2C=1.CN(C=O)C>O>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:7]3[CH:6]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[NH:9][N:8]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: CC(C)(O)c1cc(C(=O)O)n[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)O)[nH]n1
Yield: 19.5 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) using 5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxylic acid (0.646 mmol, 110 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (0.539 mmol, 150 mg) and only a catalytic amount of HOBt (0.054 mmol, 7.28 mg). DMF was used as the solvent. Water was added to the reaction mixture and the mixture was extracted it three times with DCM. The combined organics were washed twice with water. The organic phase was evaporated and the residue was purified by flash chromatography and preparative HPLC, respectively. 45.4 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.13 (d, 3H), 1.43 (s, 6H), 4.17-4.55 (m, 3H), 5.27 (bs, 1H), 6.37 (bs, 1H), 6.99 (d, 1H), 7.82 (d, 1H), 7.86 (d, 1H), 7.97 (s, 1H), 8.08 (bs, 1H), 12.94 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[Br:43][C:44]1[CH:45]=[C:46]([C@H:50]([NH2:52])[CH3:51])[CH:47]=[CH:48][CH:49]=1>C(Cl)(Cl)Cl>[Br:43][C:44]1[CH:45]=[C:46]([C@H:50]([NH:52][C:35]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][CH:11]=3)=[CH:8][C:2]=2[Cl:1])=[O:41])[CH3:51])[CH:47]=[CH:48][CH:49]=1
Reactant: C[C@@H](N)c1cccc(Br)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4cccc(Br)c4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (83 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(3-bromophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (64 mg, yield 46%).
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O>>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cccnc1Br
Reactant: OB(O)c1ccco1
Agent: OBO
Product: O=Cc1cccnc1-c1ccco1

Procedure:
2-(furan-2-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and furan-2-ylboronic acid (38 mg, 93.2 mg theoretical, 40.8%). LC-MS m/z 174.2 (M+1).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO[CH2:16][N:17]([CH2:25][Si](C)(C)C)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:12]([O:11][C:1]([C@H:2]1[C@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:25][N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)/C=C/c1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
To a mixture of ethyl trans-cinnamate (2 g, 11.4 mmol) and N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine (2.37 mL) in dichloromethane (18 mL) was added 3 drops of trifluoroacetic acid and the mixture was stirred at 40° C. for 45 min. Then another 0.56 mL of N-(methoxymethyl)(phenyl)-N-((trimethylsilyl) methyl)methanamine and 1 drop of trifluoroacetic acid were added and the mixture was stirred at 40° C. for another 45 min. Then another 0.26 mL of N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine and 1 drop of trifluoroacetic acid were added and the mixture was stirred at 40° C. for overnight. After cooling down to room temperature, the mixture was concentrated under vacuum and purified by Flash Chromatography with from 8% ethyl acetate/92% hexane to 10% ethyl acetate/90% hexane over 20 min. to give the title compound as a clear colorless sticky oil (1.69 g, 48% yield). 1H NMR (400 MHz, CDCl3) δ 1.20 (3H, t, J=6.4, 9.6 Hz), 2.86 (1H, m), 3.00 (1H, t, J=9.6 Hz), 3.04–3.07 (2H, m), 3.65–3.68 (3H, m), 4.09–4.13 (2H, m), 7.19–7.37 (10H, m). HPLC purity (retention time): 93% (1.30 min, method C). MS: 310.30 (MH+).
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH3:11][C:12]1[O:13][C:14]([CH3:17])=[CH:15][CH:16]=1>CCOC(C)=O.CCCCCC>[CH3:11][C:12]1[O:13][C:14]([CH3:17])=[CH:15][C:16]=1[S:6]([Cl:10])(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(C)o1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)Cl)c(C)o1
Temperature: 60 °C
Yield: 22.3 %

Procedure:
DMF (2.2 ml, 28 mmol) and sulfuryl chloride (1.9 ml, 24 mmol) were stirred at 0° C. for 30 minutes and then the 2,5-dimethylfuran (1.5 ml, 14 mmol) was slowly added. The reaction mixture was heated to 60° C. for 30 minutes, then cooled to ambient temperature and poured into ice water (200 ml). The aqueous layer was extracted with EtOAc (100 ml) and then the organic layer was dried (MgSO4) filtered and concentrated to collect 0.69 g of a brown liquid. Flash chromatography (5% EtOAc/hexane) provided 0.607 g (22% yield) of a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:67]1[CH2:71][CH2:70][C@@H:69]([OH:72])[CH2:68]1.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([N:67]4[CH2:71][CH2:70][C@@H:69]([OH:72])[CH2:68]4)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: O[C@@H]1CCNC1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N5CC[C@@H](O)C5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (50 mg, 0.11 mmol), HATU (51 mg, 0.13 mmol) and N,N-diisopropylethylamine (31 mg, 0.24 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of (R)-3-pyrrolidinol (14 mg, 0.16 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=4˜5. The precipitates were filtered, washed with water and dried in vacuo to give 1-(2-fluoro-5-methylphenyl)-3-(4-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)urea as white solid. Yield: 40 mg, 71%.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5](C(O)=O)=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.P(Cl)(Cl)Cl.[C:19]1([OH:25])C=CC=CC=1>CN(C)C=O.O>[CH:19]([NH:1][C@@H:2]1[C:13](=[O:14])[N:4]2[CH:5]=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12)=[O:25]
Reactant: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Reactant: Oc1ccccc1
Solvent: ClP(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=CN[C@@H]1C(=O)N2C=C(Cl)CS[C@H]12

Procedure:
This invention relates to a process for the preparation of 7-amino-3-chloro-3-cephem-4-carboxylic acid and esters thereof and to useful intermediates. In particular, it relates to a process for preparing the 3-chloro nucleus which comprises reacting a 7-amino-3-hydroxy-3-cephem ester with a chlorinating agent, for example phosphorus trichloride, in dimethylformamide to produce a 7β-[(dimethylaminomethylene)amino]-3-chloro-3-cephem ester which, on reaction with a carboxylic acid, a percarboxylic acid, or a phenol having a pH in water of between about 2.0 and about 5, forms the corresponding 7β-formamido-3-chloro ester. The product is obtained as an isomeric mixture of 7β-formamido-3-chloro-3-cephem and the corresponding 2-cephem when the 7-amidino-3-chloro intermediate is reacted with a weakly acidic carboxylic acid or with a phenol.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[S:22][CH:23]([CH3:25])[CH3:24].C1C=C(Cl)C=C(C(OO)=[O:35])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:26][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[S:22]([CH:23]([CH3:25])[CH3:24])=[O:35]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SC(C)C)c1CC(C)C
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)C(C)C)c1CC(C)C

Procedure:
Prepared from product of Example 12 (5.97 g, 14.95 mmol) and MCPBA (3.03 g of an 85% mixture with MCBA, 14.95 mmol) as described above. Recrystallization (ether/petroleum ether) afforded the product as a white solid (4.03 g).
Reaction SMILES: [ClH:1].N1C=C([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9][C:8]=2[CH:18]([NH:20][C:21]2[C:22]3[S:29][CH:28]=[CH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH3:19])C=N1.Cl.Cl.[NH2:32][CH:33]([C:35]1[O:36][C:37](=[O:57])[C:38]2[C:43]([C:44]=1[C:45]1[S:46][C:47]([CH2:50][N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[CH:48][CH:49]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH3:34]>>[ClH:1].[ClH:1].[NH2:32][CH:33]([C:35]1[O:36][C:37](=[O:57])[C:38]2[C:43]([C:44]=1[C:45]1[S:46][C:47]([CH2:50][N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[CH:48][CH:49]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH3:34].[Cl:1][C:21]1[C:22]2[S:29][CH:28]=[CH:27][C:23]=2[N:24]=[CH:25][N:26]=1.[ClH:1].[O:54]1[CH2:55][CH2:56][N:51]([CH2:50][C:47]2[S:46][C:45]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10](=[O:17])[O:9][C:8]=3[CH:18]([NH:20][C:21]3[C:22]4[S:29][CH:28]=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH3:19])=[CH:49][CH:48]=2)[CH2:52][CH2:53]1
Reactant: CC(Nc1ncnc2ccsc12)c1oc(=O)c2ccccc2c1-c1cn[nH]c1
Agent: CC(N)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCOCC2)s1
Agent: Cl
Product: CC(Nc1ncnc2ccsc12)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCOCC2)s1
Product: Clc1ncnc2ccsc12
Yield: 53.3 %

Procedure:
The title compound was made in a similar way as that of the compound of example 80, from 3-(1-aminoethyl)-4-(5-(morpholinomethyl)thiophen-2-yl)-1H-isochromen-1-one dihydrochloride (Intermediate E3, 80 mg, 0.180 mmol) and 4-chlorothieno[3,2-d]pyrimidine (43.1 mg, 0.253 mmol) to give the title compound (52 mg, 53.3%) as yellowish solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[NH:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([B:27]3[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:60][O:61][C:62]([NH:64][C@@H:65]([CH:69]([CH3:71])[CH3:70])[C:66](O)=[O:67])=[O:63]>CN(C)C=O.C(OCC)(=O)C>[CH3:60][O:61][C:62](=[O:63])[NH:64][C@H:65]([C:66]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([B:27]3[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:67])[CH:69]([CH3:71])[CH3:70]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC1(C)OB(c2ccc(-c3cnc([C@@H]4CCCN4)[nH]3)cc2)OC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Yield: 68.2 %

Procedure:
Diisopropylethylamine (7.63 mL, 43.8 mmol) was added to a suspension of (S)-2-pyrrolidin-2-yl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole hydrochloride (7.33 g, 19.5 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.6 g, 19.9 mmol) and (S)-2-methoxycarbonylamino-3-methyl-butyric acid (3.59 g, 20.5 mmol) in dimethylformamide (75 mL). All solids dissolved. After 30 min the reaction mixture was diluted with ethyl acetate (300 mL) and was washed with ½ saturated sodium chloride (1×300 mL), half saturated sodium bicarbonate (2×150 mL) and brine (1×100 mL). The organic phase was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The resulting tan foam was subjected to silica gel chromatography with eluate of 20-100% ethyl acetate and hexanes, to provide (S,S)-[2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (6.6 g, 68%) as a white foam: 1H (DMSO-d6): δ=11.81 (br s, 1H), 7.72 (m, 2H), 7.61 (m, 2H), 7.51 (br s, 1H), 7.27 (d, J=8.4 Hz, 1H), 5.05 (m, 1H), 4.04 (m, 2H), 3.78 (m, 2H), 3.52 (s, 3H), 2.11 (m, 2H), 1.93 (m, 2H), 1.28 (s, 12H), 0.85 (dd, J1=6.6 Hz, J2=11.4 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Temperature: 25 °C
Yield: 70 %

Procedure:
To a mixture of 200 mg (0.85 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 130 μl (0.935 m mol) of triethylamine and 20 ml of methylene chloride were added 115 μl (0.935 m mol) of pivaloyl chloride (trimethylacetyl chloride) with stirring at the room temperature, followed by further stirring for 3.5 hours. After the completion of the reaction, the mixture solution was washed thrice with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain the pure intended compound. (yield: 191 mg, yield: 70%).
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO.OS(O)(=O)=O>O>[CH:11](=[C:1]([OH:10])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: OC[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccccc1

Procedure:
90 Parts by weight of xylitol (75 wt% aqueous solution), 42 parts by weight of benzaldehyde, 60 parts by weight of methanol, 6 parts by weight of conc. H2SO4 and 6 parts by weight of water were reacted with refluxing for two hours. After cooling, the solidified product was ground and washed with water and, then, neutralized with 10 wt% sodium hydroxide aqueous solution followed by washing with water and drying to obtain benzylidenexylitol.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:29])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27]I)[O:24][CH2:23]2)[CH:17]([CH:30]([OH:32])[CH3:31])[C:16]3=[O:33])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:38].O>[Pd].O1CCOCC1>[Na+:38].[OH:32][CH:30]([CH:17]1[C:16](=[O:33])[N:15]2[CH:18]1[CH:19]([CH3:29])[C:20]([S:21][CH:22]1[CH2:26][CH:25]([CH3:27])[O:24][CH2:23]1)=[C:14]2[C:12]([O-:13])=[O:11])[CH3:31]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CI)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1CC(SC2=C(C(=O)[O-])N3C(=O)C(C(C)O)C3C2C)CO1
Yield: 36.2 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.450 g of product from Example 58, 0.230 g of 10% palladium/carbon, 0.161 g of sodium bicarbonate, 5 ml of water, and 12 ml of dioxane to give 0.0967 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[OH:22][C:23]1[C:32]([N:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([N:33]([CH3:35])[CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2cccc(F)c2)nc2ccccc12
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccc(F)c3)nc3ccccc13)C2
Yield: 11 %

Procedure:
Reaction of 2-(3-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 45 (11% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.66 and 3.15 (2d, 6H), 2.85 and 3.07 (2t, 2H), 3.58 and 4.21 (2t, 2H), 4.49 and 5.09 (2s, 2H), 6.34 and 6.82 (2d, 1H), 6.97 and 7.15 (2d, 1H), 7.19-8.06 (m, 6H), 8.13-8.18 (m, 1H), 8.34-8.47 (m, 2H); MS (ESI) m/z 443 ([M+H]+).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=1>O>[F:1][CH:2]([F:5])[CH2:3][NH:13][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1
Reactant: FC(F)CCl
Reactant: COc1ccc(CN)cc1
Solvent: O
Product: COc1ccc(CNCC(F)F)cc1
Yield: 68 %

Procedure:
An amount of 23.15 g (214 mmol) of 2,2-difluoro-1-chloroethane and 10 g (71 mmol) of 4-methoxybenzylamine are heated in an autoclave at an internal temperature of 120° C. for 16 hours. Subsequently, 50 g of water are added and the aqueous phase is separated. The aqueous phase is again extracted with 2,2-difluoro-1-chloroethane and the combined organic phases are distilled as described in Example 1.1. Here also, the 4-methoxybenzylamine hydrochloride present in the aqueous phase can be converted back into free 4-methoxybenzylamine by addition of sodium hydroxide solution. After distillation, 4.93 g of 2,2-difluoro-N-(4-methoxybenzyl)ethanamine are obtained, which corresponds to a yield of 68%, based on reacted 4-methoxybenzylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:9][O:10][CH2:11]CO.S([O-])(O)(=O)=O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:9][O:10][CH2:11][CH2:1][O:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1sccc1C
Reactant: COCCO
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCCOc1sccc1C
Yield: 48.6 %

Procedure:
2-methoxy-3-methyl-thiophene, (1.5 g, 11.7 mmol) 2-methoxy-ethanol (3.8 g, 50.5 mmol, 4.3 equiv.) and sodium hydrogen sulfate anhydrous (100 mg, 0.833 mmol, 0.07 equiv.) were stirred in toluene at 120° C. for 3.5 hours. The mixture was diluted with ethyl acetate and extracted with sodium bicarbonate solution. The organic solvent washed with brine, dried over magnesium sulfate dihydrate, filtered and evaporated. After Kugelrohr distillation, 980 mg of the title compound were obtained as a light yellow oil GC-MS (EI) M=172.
Reaction SMILES: ClC1C=C2C(CC(=O)N2)=CC=1.ClC1C=C(C=O)C=NC=1.N1CCCC1.[Cl:26][C:27]1[CH:35]=[C:34]2[C:30](/[C:31](=[CH:37]/[C:38]3[CH:39]=[N:40][CH:41]=[C:42]([Cl:44])[CH:43]=3)/[C:32](=[O:36])[NH:33]2)=[CH:29][CH:28]=1>CO>[Cl:26][C:27]1[CH:35]=[C:34]2[C:30]([C:31](=[CH:37][C:38]3[CH:39]=[N:40][CH:41]=[C:42]([Cl:44])[CH:43]=3)[C:32](=[O:36])[NH:33]2)=[CH:29][CH:28]=1
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cncc(Cl)c1
Agent: O=C1Cc2ccc(Cl)cc2N1
Agent: O=Cc1cncc(Cl)c1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cncc(Cl)c1
Temperature: 70 °C

Procedure:
To the mixture of 6-chlorooxindole (0.93 g, 5.6 mmol) and 5-chloro-pyridine-3-carbaldehyde (0.8 g, 5.6 mmol) in methanol (10 mL) was added pyrrolidine (0.6 g, 5.6 mmol) dropwise. The mixture was then heated at 70° C. for 3 h and cooled to room temperature. The precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(5-chloro-pyridine-3-ylmethylene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 1.0 g, 63%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[C:57]([C:58](O)=[O:59])=[CH:56][O:55][N:54]=2)=[CH:49][CH:48]=1>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([C:58]([C:57]2[C:53]([C:50]3[CH:51]=[CH:52][C:47]([CH3:46])=[CH:48][CH:49]=3)=[N:54][O:55][CH:56]=2)=[O:59])[CH2:10]1
Reactant: OC1(c2ccccc2Cl)CCNC1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccccc3Cl)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of 3-(2-chlorophenyl)pyrrolidin-3-ol hydrochloride (9 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (11 mg). MS (ESI, pos. ion) m/z: calcd for C21H19ClN2O3: 382.1084, found 382.1080.