Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:42])[CH:5]=[C:6]([Cl:41])[C:7]=1[CH2:8][C@@H:9]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[C:28]([O:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)[CH:27]=1)[O:10][C:11](=[O:25])[CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15](=[O:23])[C:14]1=[O:24].Cl[CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:42])[CH:5]=[C:6]([Cl:41])[C:7]=1[CH2:8][C@@H:9]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[C:28]([O:36][CH2:37][CH:38]2[CH2:39][CH2:40]2)[CH:27]=1)[O:10][C:11](=[O:25])[CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[C:15](=[O:23])[C:14]1=[O:24]
Reactant: O=C(Cn1c(=O)c(=O)[nH]c2ccccc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1c(=O)c(=O)n(CCN2CCOCC2)c2ccccc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reaction time: 5 h
Yield: 26.7 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)acetoxy)-ethyl)pyridine 1-oxide (70 mg, 0.112 mmol) dissolved in DMF (1 mL), 4-(2-chloroethyl)morpholine (34 mg, 0.225 mmol) and potassium carbonate (23 mg, 0.169 mmol) were added. The mixture was stirred at 40 degrees for 5 hours. The mixture was then diluted with H2O (10 mL) and the aqueous phase extracted with AcOEt (2×3 mL). The organic phase was washed with brine (10 ml), dried over Na2SO4 and the solvent was evaporated, to yield 22 mg of the title compound (yield 37%). MS/ESI+ 735.4 [MH]+; 1H NMR (400 MHz, acetone) δ ppm 8.01 (s, 2H), 7.53-7.62 (m, 1H), 7.28-7.39 (m, 1H), 7.09-7.24 (m, 3H), 6.99-7.07 (m, 2H), 6.93 (t, J=75.00 Hz, 1H), 5.97-6.21 (m, 1H), 5.10-5.21 (m, 1H), 4.76-4.84 (m, 1H), 4.36-4.56 (m, 2H), 3.89-4.12 (m, 2H), 3.61 (m, 4H), 3.35-3.51 (m, 1H), 3.15-3.27 (m, 1H), 2.76-2.80 (m, 2H), 2.52-2.65 (m, 4H), 1.25-1.39 (m, 1H), 0.55-0.68 (m, 2H), 0.37-0.52 (m, 2H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:28][CH:29]1[C:57](=[O:58])[N:31]2[C:32]([C:54]([OH:56])=[O:55])=[C:33]([CH:36]([S:48][C:49]3[NH:53][N:52]=[N:51][N:50]=3)[CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:34][S:35][C@H:30]12.C(=O)([O-])[O-].[Na+].[Na+]>O.CC(C)=O.O1CCCC1.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([NH:28][CH:29]2[C:57](=[O:58])[N:31]3[C:32]([C:54]([OH:56])=[O:55])=[C:33]([CH:36]([S:48][C:49]4[NH:50][N:51]=[N:52][N:53]=4)[CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:34][S:35][C@H:30]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCCNC(=O)OC(C)(C)C)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC=O)n1
Yield: 99.8 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer, 16.5 g.), N, N-dimethylformamide (4.4 g.), phosphoryl chloride (9.2 g.), 7-amino-3-[1-(3-tert-butoxycarbonylamino propyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (23.6 g.), sodium carbonate (5.3 g.), tetrahydrofuran (100 ml.), acetone (150 ml.) and water (150 ml.) were treated in a similar manner to that of Example 11-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[1-(3-tert-butoxycarbonylaminopropyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 39.1 g.).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=O.[NH3:26]>CO>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]([O:10][C:9]1[CH:8]=[C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[S:6][C:5]=1[C:3]([NH2:26])=[O:2])[CH3:12]
Reactant: N
Reactant: COC(=O)c1sc(-c2cccnc2)cc1OC(C)c1ccccc1Cl
Solvent: CO
Product: CC(Oc1cc(-c2cccnc2)sc1C(N)=O)c1ccccc1Cl
Temperature: 100 °C
Yield: 54 %

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-pyridin-3-yl-thiophene-2-carboxylic acid methyl ester (58 mg, 0.16 mmol, 1.0 Eq.) was suspended in 7M NH3 in MeOH (10 mL) and heated to 100° C. in a pressure tube for 3 days. The reaction was allowed to cool to ambient temperature, the solvent removed in vacuo and purified by tritruation with MeOH to give the title compound as an off-white solid (30 mg, 0.08 mmol, 54%); 1H NMR (400 MHz, d-6 DMSO) δ 1.72 (3H, d), 6.00 (1H, q), 7.10 (1H, br s), 7.35-7.52 (5H, m), 7.67 (1H, dd), 7.75 (1H, br s), 7.97-8.01 (1H, m), 8.56 (1H, dd), 8.84 (1H, d).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18](=[O:20])[NH:17][C:16]=2[CH:21]=1.Cl[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18](=[O:20])[N:17]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)CCl
Reactant: Cc1ccn2c(C)c(-c3ccc4oc(=O)[nH]c4c3)nc2c1
Product: Cc1ccn2c(C)c(-c3ccc4oc(=O)n(CC(=O)OC(C)(C)C)c4c3)nc2c1
Yield: 38 %

Procedure:
5-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)-3-t-butoxycarbonylmethyl-2-benzoxazolinone (1.5 g) was prepared in substantially the same manner as that of Example 47 from 5-(3,7-dimethylimidazo[1,2-a]pyridin-2yl)-2-benzoxazolinone (2.8 g) and t-butyl chloroacetate (2.25 g). mp. 198°-200° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH2:14][CH3:15])[C:4](=[O:16])[C:3]=1[C:17]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:20]=2[S:19](=[O:29])(=[O:28])[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][C:38]([NH2:40])=[O:39]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH2:14][CH3:15])[C:4](=[O:16])[C:3]=1[C:17]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([O:27][CH2:37][C:38]([NH2:40])=[O:39])=[CH:26][C:20]=2[S:19](=[O:28])(=[O:29])[N:18]=1
Reactant: CCCNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Reactant: NC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCNn1c(=O)c(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)c(O)c2ccccc21
Temperature: 165 °C
Yield: 42.4 %

Procedure:
The product of Example 358C (0.016 g, 0.04 mmol) in N,N-dimethylformamide (2 mL) was reacted with cesium carbonate (0.015 g, 0.045 mmol), bromoacetamide (0.006 g, 0.18 mmol), and a catalytic amount of tetrabutylammonium iodide at 25° C. for 3 hours. The reaction was concentrated under a stream of nitrogen stream of nitrogen warmed through a manifold heated to 165° C. and the resulting residue was triturated with water, filtered and dried. The resulting solid was triturated in hot ethyl acetate, filtered, and dried to give the title compound (0.008 g, 37%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. MS (ESI−) m/z 470 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.99 (m, 3 H)1.55 (t, 2 H) 2.73 (t, 2 H) 4.11 (d, 1 H) 4.41 (d, 1 H) 5.83 (d, 1 H) 7.05 (s, 3 H)7.39 (s, 1 H) 7.54 (s, 2 H) 7.98 (s, 1 H) 16.24 (s, 1 H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:5]1([CH2:20][CH3:21])[CH2:18][CH2:17][N:8]2[C:9]3[C:14]([C:15]([CH3:16])=[C:7]2[C:6]1=[O:19])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:4]>CO>[CH2:20]([C:5]1([CH2:3][CH3:4])[CH2:18][CH2:17][N:8]2[C:9]3[C:14]([C:15]([CH3:16])=[C:7]2[CH:6]1[OH:19])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:21]
Reactant: CCC1(CC)CCn2c(c(C)c3ccccc32)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1(CC)CCn2c(c(C)c3ccccc32)C1O
Temperature: 40 °C
Yield: 93.3 %

Procedure:
Sodium borohydride (19 g, 500 mmol) was added portionwise upon cooling to a solution 8,8-diethyl-6,7,8,9-tetrahydro-10-methylpyrido[1,2-a]indol-9-one (12.8 g, 50 mmol) in methanol (500 mL) at 25° C. The reaction mixture was heated at 40° C. for 18 hours. The solvent was removed in vacuo and the residue partitioned between 1% ammonium hydroxide (100 mL) and chloroform (120 mL). The separated organic layer was dried over MgSO4, filtered and evaporated to afford the desired alcohol 12 g, (93%) as a greenish oil.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([C:25]3[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=3)[N:8]=2)=[CH:3][CH:2]=1.[CH:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)=[CH2:39].C(=O)([O-])[O-].[Na+].[Na+]>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.C1COCC1>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([C:43]4[CH:44]=[CH:45][C:40]([CH:38]=[CH2:39])=[CH:41][CH:42]=4)=[CH:27][CH:26]=3)[N:8]=2)=[CH:3][CH:2]=1
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(-c2nc(-c3ccc(-c4ccccc4)cc3)nc(-c3ccc(-c4ccccc4)cc3)n2)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: C1CCOC1
Product: C=Cc1ccc(-c2ccc(-c3nc(-c4ccc(-c5ccccc5)cc4)nc(-c4ccc(-c5ccccc5)cc4)n3)cc2)cc1

Procedure:
1.0 g (0.00185 mol) of 2,4-bisbiphenyl-4-yl-6-(4-bromophenyl)-1,3,5-triazine, 0.4106 g of 4-vinylphenylboronic acid and 0.02368 g of Pd(PPh3)4 are brought to reaction under reflux for 48 h with addition of 15 ml of 1M sodium carbonate solution and 30 ml of THF.
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=C[CH:2]=1.[OH:12][CH2:13][C:14]([CH3:19])([CH2:17][OH:18])[CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:12][CH2:13][C:14]1([CH3:19])[CH2:17][O:18][C:1]([CH3:6])([CH3:2])[O:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(CO)COC(C)(C)OC1
Reaction time: 5 h
Yield: 8383.8 %

Procedure:
1.0 g of p-toluenesulfonic acid is added to 96.2 g (0.80 mol) of 2-(hydroxymethyl)-2-methyl-1,3propanediol in 600 ml of acetone, and the mixture is heated to reflux. After 5 hours, the solution is neutralized while still hot by adding 3.0 g of potassium carbonate, and the mixture is stirred for a further 30 minutes and subsequently allowed to stand at room temperature overnight. The mixture is filtered through kieselguhr, and the solvent is removed by distillation in vacuo, leaving about 180 ml of a turbid, oily residue, which is purified by distillation in a high vacuum, giving 78 g of the alcohol 31 as a colorless, viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].Cl.[C:23]([NH:27][CH2:28][C:29](O)=O)(=[O:26])[CH2:24][CH3:25].ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([S:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]3[NH:8][C:29]([CH2:28][NH:27][C:23](=[O:26])[CH2:24][CH3:25])=[N:1][C:2]=3[CH:3]=2)(=[O:12])=[O:11])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CCC(=O)NCC(=O)O
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2ccc(N)c(N)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)NCc1nc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a solution of N-(3,4-diamino-phenyl)-4-isopropyl-benzenesulfonamide×HCl (500 mg, 1.32 mmol) in DMF (20 ml) at 0° C. was added propionylamino-acetic acid (170 mg, 1.32 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (220 mg, 1.59 mmol). After stirring the mixture at 0° C. for 15 min EDC (N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide) (300 mg, 1.45 mmol) was added. DIPEA (diisopropylethylamine) (0.92 ml, 5.29 mmol) was added after stirring another 15 min at 0° C. The mixture was stirred at room temperature for 16 h, and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 and the organic layer was dried over MgSO4, filtered, and the solvent evaporated under reduced pressure. A solution of the obtained oil in acetic acid was heated to 70° C. for 6 h. After evaporation of the solvent in vacuo the residue was purified by column chromatography to give the product as a yellow oil (320 mg, 61%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>C(#N)C>[N:11]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CN=[N+]=[N-])cc1

Procedure:
A mixture of 1-(chloromethyl)-4-methoxybenzene (20 g, 128 mmol) and sodium azide (12.5 g, 192 mmol) in acetonitrile (255 mL) was refluxed for 5 h under N2 atmosphere. The mixture was filtered and concentrated in vacuo. The residue was diluted with DCM, washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 1-(azidomethyl)-4-methoxybenzene. The residue was used for the next reaction without further purification.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:16])([F:15])[C:9]1[CH:13]=[C:12]([NH2:14])[O:11][N:10]=1.[C:17](Cl)(=[O:19])[CH3:18].[OH-].[Na+].Cl>CO.C1C=CC=CC=1.O>[F:7][C:8]([F:16])([F:15])[C:9]1[CH:13]=[C:12]([NH:14][C:17](=[O:19])[CH3:18])[O:11][N:10]=1
Reactant: Nc1cc(C(F)(F)F)no1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)Nc1cc(C(F)(F)F)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
Dry benzene (56 ml) and pyridine (11.85 g, 150 mmole) were added to 3-trifluoromethyl-5-aminoisoxazole (9.12 g, 60.0 mmole) and the mixture was cooled. Acetyl chloride (10.37 g, 132 mmole) was added dropwise to the mixture, while keeping it below 10° C. After being added dropwise, the mixture was stirred with ice cooling for 10 minutes and at room temperature for 1 hour. Water (60 ml) was added and it was stirred for an additional hour. Benzene (60 ml) was added and the mixture was separated. The benzene layer was washed successively with 2% hydrochloric acid (60 ml) and a 8% solution of sodium bicarbonate and the solvent was evaporated under reduced presssure. Methanol (120 ml) and sodium hydroxide (4.80 g 120 mmole) were added to the residue and the mixture was stirred overnight at room temperature. After being neutralized with conc. hydrochloric acid, the solvent was evaporated under reduced pressure and the resulting residue was dissolved by the addition of benzene (100 ml) and ethyl acetate (20 ml). This solution was washed with water (60 ml) and the solvents were evaporated under reduced pressure to give 3-trifluoromethyl-5-acetylaminoisoxazole (9.51 g) as crystals. This product was recrystallized from benzene to give colorless plates. Yield: 5.67 g, m.p. 108.5°-109.5° C.
Reaction SMILES: N(C[C@@H](C1C=CC(OCC2C=CC=CC=2)=C2C=1C=CC(=O)N2)O)=[N+]=[N-].[Si]([O:33][C@H:34]([C:72]1[CH:81]=[CH:80][C:79]([OH:82])=[C:78]2[C:73]=1[CH:74]=[CH:75][C:76](=[O:83])[NH:77]2)[CH2:35][NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:71]=[CH:70][C:45]([C:46]([NH:48][CH2:49][C:50]2[C:51]([NH:63][CH:64]3[CH2:69][CH2:68][O:67][CH2:66][CH2:65]3)=[C:52]3[CH:60]=[N:59][N:58]([CH2:61][CH3:62])[C:53]3=[N:54][C:55]=2[CH2:56][CH3:57])=[O:47])=[CH:44][CH:43]=1)(C(C)(C)C)(C)C>>[CH2:61]([N:58]1[C:53]2=[N:54][C:55]([CH2:56][CH3:57])=[C:50]([CH2:49][NH:48][C:46](=[O:47])[C:45]3[CH:70]=[CH:71][C:42]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][NH:36][CH2:35][C@H:34]([OH:33])[C:72]4[CH:81]=[CH:80][C:79]([OH:82])=[C:78]5[C:73]=4[CH:74]=[CH:75][C:76](=[O:83])[NH:77]5)=[CH:43][CH:44]=3)[C:51]([NH:63][CH:64]3[CH2:69][CH2:68][O:67][CH2:66][CH2:65]3)=[C:52]2[CH:60]=[N:59]1)[CH3:62]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c3[nH]c(=O)ccc23)cc1
Agent: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 3, using Intermediate 44 as substrate.
Reaction SMILES: [O-]Cl=O.[Na+].[CH2:5]([O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[C:16]([F:22])[CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(=O)(=O)([OH:26])N.Cl>O.CC#N>[CH2:5]([O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:26])=[O:21])=[C:16]([F:22])[CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1F
Reactant: NS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: O=C(OCc1ccccc1)c1ccc(C(=O)O)c(F)c1
Reaction time: 1 h

Procedure:
A solution of 80% NaClO2 (0.19 mol) in H2O (100 mL) is added dropwise to a solution of crude 3-fluoro-4-formyl benzoic acid benzyl ester (6, 0.19 mol) and sulfamic acid (0.19 mol) in H2O (300 mL) and CH3CN (150 mL). After stirring for 1 h, the reaction mixture is poured into 1 N HCl and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, and evaporated in vacuo. Crystals are collected by filtration and washed with ether/hexane (1:1) to give 2-fluoroterephthalic acid 4-benzyl ester (7) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCC(c2ccc(O)c(Cl)c2)=NN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C2=NNC(=O)CC2)cc1Cl
Reaction time: 1 h

Procedure:
1.79 g of 6-(3-chloro-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as in Preparation 8) was dissolved in 15 ml of anhydrous dimethylformamide. 0.35 g of a 55% w/w suspension of sodium hydride in mineral oil was added, and the solution was stirred for 1 hour. To this solution, was added, whilst ice-cooling, 1 ml of a dimethylformamide solution containing 1.34 g of ethyl bromoacetate, and the mixture was stirred for 1 hour at room temperature and then for 3 hours at 80° C. At the end of this time, the dimethylforamide was distilled off under reduced pressure and the mixture was diluted with water and then extracted with ethyl acetate. The extract was washed with water, dried and then evaporated to dryness. The addition of hexane precipitated 1.85 g of the title compound as white needles melting at 134°-136° C.
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:13][C:14]#[N:15]>>[N:1]1([CH:6]2[CH2:11][CH2:10][N:9]([CH2:13][C:14]#[N:15])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCBr
Reactant: C1CCN(C2CCNCC2)C1
Product: N#CCN1CCC(N2CCCC2)CC1

Procedure:
The title compound is synthesized by coupling of 4-Pyrrolidin-1-yl-piperidine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=194.1: 1HNMR(DMSO-d6) 3.65 (s, 2H), 2.75-2.70 (m, 2H), 2.45-2.40 (m, 4H), 2.20-2.10 (m, 2H), 1.90-1.75 (m, 3H), 1.65-1.60 (m, 4H), 1.45-1.30 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([N:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH3:11])=[N:4][CH:5]=[C:6](C)[CH:7]=1.[CH2:18]1N2CCN(CC2)C1.Cl>CN(C)C=O>[CH3:18][C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:9][C:10]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[CH:11][C:2]=12
Reactant: C1CN2CCN1CC2
Reactant: CC(=Nc1ncc(C)cc1Br)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccnc2[nH]c(-c3ccncc3)cc12
Temperature: 120 °C
Reaction time: 36 h

Procedure:
To a solution of (3-bromo-5-methylpyridin-2-yl)-(1-pyridin-4-ylethylidene)amine (4.25 g, 14.65 mmol) in dimethylformamide (75 ml) was added DABCO® (4.93 g, 43.96 mmol) and ], bis-dichlorotriphenylphosphine palladium (0.52 g, 0.73 mmol). The reaction mixture was heated at 120° C. under argon atmosphere. After 1.5 days, the reaction mixture was cooled into room temperature and poured into 10% hydrochloric acid (100 ml). The solution was filtered through Celite® and the filtrate was neutralized to pH 7 with 10% sodium hydroxide and the solid was filtered off to give 4-methyl-2-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (1.57 g) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14](S(C)(=O)=O)[N:9]3[CH:8]=[CH:7][C:6]=2[CH:19]=1.[CH3:20][O-:21].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14]([O:21][CH3:20])[N:9]3[CH:8]=[CH:7][C:6]=2[CH:19]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1nnc2n1C=Cc1cc(Cl)ccc1C2
Agent: [Na+]
Product: COc1nnc2n1C=Cc1cc(Cl)ccc1C2

Procedure:
The reaction of 8-chloro-3-methylsulfonyl-11H-s-triazolo[3,4-b][3]benzazepine with sodium methoxide yielded 8-chloro-3-methoxy-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from aqueous acetone), melting point: 177°-178° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[N:12]1([C:18]2[N:19]=[C:20]([CH2:25][C:26]([O-])=[O:27])[NH:21][C:22](=[O:24])[CH:23]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[Na+].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[CH3:3][C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:26](=[O:27])[CH2:25][C:20]2[NH:21][C:22](=[O:24])[CH:23]=[C:18]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:19]=2)[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:2]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC(C)(C)c1cccc(N)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.5 %

Procedure:
224 mg of 3-(tert-butyl)aniline are added to a solution of 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 in 10 ml of methanol. The reaction mixture is stirred at ambient temperature for 5 minutes and then 442 mg of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride hydrate are added. The resulting mixture is thus stirred for 30 minutes at ambient temperature. The reaction mixture is concentrated under reduced pressure. The evaporation residue is taken up with 10 ml of water and 10 ml of ethyl acetate. The resulting product is then stirred for 30 minutes. The precipitate formed is filtered off. 235 mg of N-[3-(2-methylpropan-2-yl)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are thus obtained in the form of a white solid, the characteristics of which are the following: