Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:30])[C:14]([O:16][CH:17]([O:19][C:20](ON1C(=O)CCC1=O)=[O:21])[CH3:18])=[O:15]>>[CH3:12][CH:13]([CH3:30])[C:14]([O:16][CH:17]([O:19][C:20]([CH:10]([NH2:11])[C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:21])[CH3:18])=[O:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)C
Product: CC(OC(=O)C(C)C)OC(=O)C(N)[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl 2-methylpropanoate were reacted to yield the title compound 13 (333 mg, 53% yield) as a colorless powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 2H), 1.058 (d, J=6.4 Hz, 3H), 1.062 (d, J=6.8 Hz, 3H), 1.17-1.36 (br. m, 3H), 1.38 (d, J=5.6 Hz, 3H), 1.65-1.73 (br. m, 2H), 1.83-1.91 (br. m, 2H), 2.10 (tt, J=12.0, 3.6 Hz, 1H), 2.49 (hept., J=6.8 Hz, 1H), 2.77-2.85 (br. m, 2H), 6.62 (q, J=5.2 Hz, 1H), 7.45 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 338.08 (M+Na)+; 314.01 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].N1C=CC=CC=1C1C=CC=CN=1.C([Li])CCC.[F:27][C:28]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([CH3:40])[C:29]=1C(Cl)=O.Cl>C1COCC1>[F:27][C:28]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([CH3:40])[C:29]=1[C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: Cc1c(F)c(F)c(F)c(F)c1C(=O)Cl
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1c(C)c(F)c(F)c(F)c1F
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A solution of 10.1 g (76.5 mmol) of malonic acid monoethylester, bipyridyl (catalytic), and 200 ml of dry THF was cooled to -35° C. under argon, treated with 52 ml of 1.5M n-butyllithium (78 mmol), and warmed to -5° C. To this mixture was added 52 ml of 1.5M n-butyllithium (78 mmol) until a pale pink color persisted for 10 minutes. The suspension was cooled to -78° C. and was treated with a solution of 8.8 g (38.8 mmol) of 2,3,4,5-tetrafluoro-6-methylbenzoyl chloride in 100 ml of dry THF. The reaction mixture was stirred at -78° C. for 45 minutes, then warmed to -35° C. and poured into a mixture of ice and 1N hydrochloric acid (77 ml). The organic layer was washed with 5% sodium bicarbonate solution, 3M hydrochloric acid, and water and dried over magnesium sulfate. Concentration gave an orange oil which was chromatographed on silica gel (E. Merck 230-400 Mesh), eluting with 80:20 chloroform:ethyl acetate, to give 8.2 g of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][C:14]#[N:15].[H][H]>[Pd].C(O)C>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: N#CCCCc1ccc2cccnc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: N#CCCCc1ccc2c(n1)NCCC2

Procedure:
A mixture of 8-2 (14 g, 71 mmol), 10% Pd/C (2 g) and ethanol (200 mL) was stirred under a balloon of hydrogen gas for 1 h. Filtration and evaporation produced 8-3 as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([OH:24])=[CH:22][C:21]([C:25]([C:30]4[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=4[CH3:37])([CH3:29])[CH2:26][CH2:27][CH3:28])=[CH:20][C:15]=3[O:16][C:17]([CH3:19])([CH3:18])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][N:41]1[CH2:46][CH2:47][CH2:48][C:49](O)=[O:50].C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:36].[CH2:1]([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([O:24][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][N:41]4[CH2:42][CH2:43][CH2:44][CH2:45][CH:40]4[CH3:39])=[CH:22][C:21]([C:25]([C:30]4[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=4[CH3:37])([CH3:29])[CH2:26][CH2:27][CH3:28])=[CH:20][C:15]=3[O:16][C:17]([CH3:18])([CH3:19])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(C)(c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1)c1cc(Cl)ccc1C
Reactant: CC1CCCCN1CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCC(C)(c1cc(OC(=O)CCCN2CCCCC2C)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1)c1cc(Cl)ccc1C

Procedure:
2-Benzyl-5,5-dimethyl-10-hydroxy-8-(2-methyl-5-chlorophenyl-1-methylbutyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, γ-(2-methylpiperidino)-butyric acid hydrochloride and dicyclohexylcarbodiimide in equimolar amounts are reacted as in Example 7 to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.O.[NH2:14][NH2:15].O>CCO>[NH2:1][C:2]1[C:3]([C:9]([NH:14][NH2:15])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1nc(Br)cnc1N
Temperature: 70 °C
Yield: 96.3 %

Procedure:
Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (10.18 g, 43.87 mmol) was suspended in EtOH (50.90 mL) and hydrazine hydrate (4.392 g, 4.268 mL, 87.74 mmol) was added and the reaction mixture heated at 70° C. for 2 h. Water (50 mL) was added and the precipitate isolated by filtration. The solid was washed with methanol and dried under vacuum to leave the product as a pale yellow powder (9.8 g, 96% yield); 1H NMR (400 MHz, DMSO) d 4.53 (bs s, 2H), 7.62 (br s, 2H) and 9.78 (br s, 1H) ppm; MS (ES+) 232.06
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.S(Cl)(Cl)(=O)=O.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][C:2]1([C:22]2[CH:23]=[CH:24][C:19]([OH:25])=[CH:20][CH:21]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1
Reactant: CC1Sc2ccccc2N(C)C1=O
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CN1C(=O)C(C)(c2ccc(O)cc2)Sc2ccccc21
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a stirred solution of 3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzothiazine (4.8 g) in methylene chloride (25 ml), sulfuryl chloride (3.5 g) is added under ice-cooling. The mixture is stirred for 30 minutes, and added into a solution of phenol (2.4 g) and aluminum chloride (3.3 g) in methylene chloride (20 ml) with stirring under ice-cooling. The mixture is stirred for 1 hour under ice-cooling, and washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solution is dried over anhydrous sodium sulfate and concentrated in vacuo. A mixture of benzene and n-hexane (1:1) is added to the residue and the separated crystals are collected by filtration to give 6.4 g (90.2%) of the titled compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:54])[C@@H:5]([NH:21][C:22]([CH:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([CH3:52])=[C:48]([CH3:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[C:55]([NH:58][C:59]1[S:60][C:61]([S:65](Cl)(=[O:67])=[O:66])=[C:62]([CH3:64])[N:63]=1)(=[O:57])[CH3:56]>>[CH3:2][O:3][C:4](=[O:54])[C@@H:5]([NH:21][C:22]([CH:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([CH3:52])=[C:48]([CH3:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][N:25]1[S:65]([C:61]1[S:60][C:59]([NH:58][C:55](=[O:57])[CH3:56])=[N:63][C:62]=1[CH3:64])(=[O:66])=[O:67])=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(C)c(C)c2)cc1)CO3
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(C)c(C)c2)cc1)CO3
Yield: 73.1 %

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dimethyl-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester hydrochloride (11 mg) was reacted with 2-acetylamino-4-methyl thiazole-5-sulfonyl chloride (9 mg) according to General Procedure E to give (S)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dimethyl-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (10 mg). This was hydrolyzed according to General Procedures N and B to give the title compound (3 mg). LCMS: (m/z) 870.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]#[C:14][CH3:15].C(N(CC)CC)C>C(OCC)C>[CH2:18]([O:17][C:12]([C:13]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=2)=[N:2][O:1][C:14]=1[CH3:15])=[O:16])[CH3:19]
Reactant: CC#CC(=O)OCC
Reactant: O/N=C(\Cl)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)noc1C
Temperature: 25 °C
Yield: 41.8 %

Procedure:
To a solution of (E)- and/or (Z)—N-hydroxy-4-chloro-benzenecarboximidoyl chloride (26.0 g, 137 mmol) in diethylether (323 mL) was added ethyl 2-butynoate (15.4 g, 16.1 mL, 137 mmol) at 0° C. followed by the dropwise addition of triethylamine (24.1 g, 22.9 mL, 164 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The mixture was then poured onto ice-water, and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (15.2 g, 42%) which was obtained as a light yellow solid. MS: m/e=266.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]([C:14](=[O:30])[N:15]([CH2:26]CCC)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[CH:4][NH:5][C:6](=[NH:13])[N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])#[N:2].[C:31]([CH2:33]C(O)=O)#N>C(O)(=O)C>[CH3:26][N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=1)[C:14]([C:3]1[C:1]([NH2:2])=[N:13][C:6]([N:7]2[CH2:11][CH:10]([CH:31]=[CH2:33])[NH:9][C:8]2=[O:12])=[N:5][CH:4]=1)=[O:30]
Reactant: N#CCC(=O)O
Reactant: CCCCN(C(=O)C(C#N)=CNC(=N)N1CCNC1=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: C=CC1CN(c2ncc(C(=O)N(C)c3cccc(C(F)(F)F)c3)c(N)n2)C(=O)N1
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
A mixture of 2.84 g (7 mmol) of a compound II (R1 =CH=CH2 ; R2, R3, R5, R6 =H; R4 =CH3), 486 mg (5.5 mmol) of cyanoacetic acid and 5 ml of glacial acetic acid was stirred at 75° for 1.5 hours and subsequently worked up as in Example 5. Crystallization from ether resulted in 1.75 g (=61.6% yield) of 4-amino-2-(4-vinyl-2-oxo-1-imidazolidinyl)pyrimidine-5-carboxylic acid N-methyl-N-(3-trifluoromethylphenyl)amide, melting point 203°-204°.
Reaction SMILES: [Li][CH2:2]CCC.[F:6][C:7]1[C:12]([F:13])=[C:11]([O:14][CH2:15][CH2:16][CH3:17])[CH:10]=[CH:9][C:8]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[Se:25][CH:26]=[CH:27][CH:28]=2)=[CH:20][CH:19]=1.CI.[Cl-].[NH4+].N>C(OCC)C>[F:6][C:7]1[C:12]([F:13])=[C:11]([O:14][CH2:15][CH2:16][CH3:17])[CH:10]=[CH:9][C:8]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[Se:25][C:26]([CH3:2])=[CH:27][CH:28]=2)=[CH:20][CH:19]=1
Reactant: CCCOc1ccc(-c2ccc(-c3ccc[se]3)cc2)c(F)c1F
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: CCCOc1ccc(-c2ccc(-c3ccc(C)[se]3)cc2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2.0 ml (11.8 mmol) of TMP are initially introduced at −15° C. in 15 ml of diethyl ether, and 7.0 ml (11.1 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 25 min, a solution of 3.5 g (9.3 mmol) of 2-(2′,3′-difluoro-4′-propoxybiphenyl-4-yl)selenophene in 35 ml of diethyl ether is metered in, and the mixture is stirred at RT for 45 min. The batch is cooled to −70° C., and 3.0 ml (48.2 mmol) of methyl iodide are added. The mixture is warmed to RT and stirred for 3 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added successively, and the mixture is briefly stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with 2 N hydrochloric acid and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:toluene=1:1). The further purification is carried out by digestion in ethanol and recrystallisation from n-heptane/toluene (2:1). 2-(2′,3′-Difluoro-4′-propoxybiphenyl-4-yl)-5-methylselenophene is obtained as a solid having an m.p. of 143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][C:12]=1[O:21][CH3:22].[CH3:24][O:25][C@@H:26]1[CH2:30][NH:29][C@H:28]([CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:27]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:29]2[CH2:30][C@@H:26]([O:25][CH3:24])[CH2:27][C@H:28]2[CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[O:20])=[CH:13][C:12]=1[O:21][CH3:22]
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Cl)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 86.6 %

Procedure:
A mixture of 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (398 mg, 1.19 mmol), methyl 4-[(2S,4S)-4-methoxy-2-pyrrolidinyl]methoxybenzoate (317 mg, 1.19 mmol), EDC.HCl (342 mg, 1.79 mmol), HOBT (242 mg, 1.79 mmol) and Et3N (0.83 ml, 5.95 mmol) in DMF (5 ml) was stirred at room temperature for 13 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/Aectone (10/1)CHCl3/MeOH (20/1)], to give methyl 4-[(2S,4S)-1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-methoxy-2-pyrrolidinyl]methoxybenzoate (600 mg, 87%) as a colorless amorphous solid 1H-NMR (CDCl3) δ1.99-2.06 (m, 1H), 2.34 (d, J=13.9 Hz, 1H), 3.30 (s, 3H), 3.59 (d, J=7.4 Hz, 1H), 3.62 (d, J=3.2 Hz, 2H), 3.83 (s, 3H), 3.88 (s, 3H), 4.00-4.18 (m, 3H), 4.42-4.51 (m, 2H), 6.82-7.07 (m, 7H), 7.28 (d, J=8.3 Hz, 1H), 7.35 (dd, J=7.9, 1.5 Hz, 1H), 7.94-8.00 (m, 3H), 8.18 (d, J=8.3 Hz, 1H); MS (ESI) m/z 582 (M++1), 5.84 (M++3).
Reaction SMILES: CN(C)C=O.[N-:6]=[N+:7]=[N-:8].[Na+].[C:10]([O:13][C@@H:14]1[O:31][C@H:30]([CH2:32]S(C)(=O)=O)[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]1[O:16][C:17](=[O:19])[CH3:18])(=[O:12])[CH3:11]>C(OCC)(=O)C>[C:10]([O:13][C@@H:14]1[O:31][C@H:30]([CH2:32][N:6]=[N+:7]=[N-:8])[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]1[O:16][C:17](=[O:19])[CH3:18])(=[O:12])[CH3:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@@H]1O[C@H](CS(C)(=O)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1O[C@H](CN=[N+]=[N-])[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 70 °C
Yield: 39.4 %

Procedure:
A 100 mL round bottom flask was charged with 40 mL anhydrous dimethylformamide, sodium azide (2.19 g, 33.6 mmol), and crude 1,2,3,4-tetra-O-acetyl-6-deoxy-6-methanesulfonyl-β-D-glucopyranose (1.9374 g, 4.54 mmol). The resulting homogeneous solution was heated to 70° C. and allowed to react for 10 hours. The reaction was then diluted with 200 mL of ethyl acetate and washed with copious amounts of water. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo. The resulting brown solid was purified by column chromatography over silica gel to yield 668.3 mg of the title compound (39.5%). MS (FAB) calculated for C14H19N3O9 (M—OCOCH3) 314.1, found 314.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][C:10]1[CH:11]=[N:12][C:13](Cl)=[N:14][CH:15]=1.CCO.Cl>O>[Br:9][C:10]1[CH:11]=[N:12][C:13]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:14][CH:15]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Nc1cccc(F)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Fc1cccc(Nc2ncc(Br)cn2)c1
Temperature: 50 °C

Procedure:
In a microwave vial is added 3-fluorophenylamine (0.293 mL, 2.58 mmol), 5-bromo-2-chloropyrimidine (500 mg, 2.58 mmol), EtOH (10 mL) and concentrated HCl (0.2 mL). The reaction mixture is then heated at 50° C. for 15 min. Water (20 mL) is added and it is extracted with EtOAc. The organic layer is washed with NaHCO3, dried with Na2SO4 and concentrated. The residue is purified by column chromatography to give the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.83-6.88 (m, 1H) 7.24-7.26 (m, 1H) 7.28 (br. s., 1H) 7.34-7.40 (m, 1H) 7.74 (dt, J=11.37, 2.27 Hz, 1H) 8.56 (s, 2H); (M+H)+269.9.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:5][C:6](=[O:10])[N:7]([CH3:9])[N:8]=1)[CH3:2].Cl[C:12]1[N:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([O:10][C:6]2[N:7]([CH3:9])[N:8]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:13]=[N:14][CH:15]=1
Reactant: CCOC1=NN(C)C(=O)C1
Reactant: COc1cnnc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc(Oc2cc(OC)cnn2)n(C)n1
Reaction time: 42 h
Yield: 20 %

Procedure:
5-Ethoxy-2,4-dihydro-2-methyl-3H-pyrazol-3-one (0.63 g, 0.0044 mole), 3-chloro-5-methoxypyridazine (0.64 g, 0.0044 mole), potassium carbonate (1.50 g, 0.010 mole), cuprous bromide (0.05 g, 0.0003 mole) and anhydrous dimethyl sulfoxide (10 mL) were heated and held at 90° C. for 42 hours. The mixture was cooled, treated with 1% hydrochloric acid solution and extracted with ethyl acetate. The combined extracts were washed with 2% sodium hydroxide, dried with magnesium sulfate, filtered and concentrated in vacuo. Purification by chromatography on silica gel using ethyl acetate/cyclohexane gave a tan solid, which was recrystallized from ethyl acetate/methylcyclohexane to give 5-methoxy-3-[(3-ethoxy-1-methyl-1H-pyrazol-5-yl)oxy]pyridazine (0.22 g, 22% yield) as a white solid.
Reaction SMILES: OO.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:14]=[C:13]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)[N:12]=2)=[CH:6][CH:5]=1.C([O-])(O)=[O:36].[Na+]>C(Cl)Cl>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:14]=[C:13]([N:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N+:30]=4[O-:36])[CH2:27][CH2:28]3)[N:12]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(Nc2cc(N3CCCCC3)nc(N3CCN(c4ccccn4)CC3)n2)cc1
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Nc2cc(N3CCCCC3)nc(N3CCN(c4cccc[n+]4[O-])CC3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-cholorperbenzoic acid (450 mg, 2.6 mmol), and 30% H2O2 (0.1 mL) in CH2Cl2 (2 mL) was added to a solution of N-(4-methylphenyl)-6-(1-piperidinyl)-2-[4-(2-pyridinyl)-1-piperazinyl]-4-pyrimidinamine (150 mg, 0.300 mmol) in CH2Cl2 at 0° C. The resulting mixture was gradually warmed to room temperature and stirred for 24 h, crude product was treated with saturated NaHCO3 (50 mL) and extracted with EtOAC (3×50 mL). Combined organic layers were washed with brine (2×50 mL), dried over Na2SO4, filtered, concentrated in vacuo, and purified by chromatography on silica using hexane/EtOAc (1:3) to give the desired product.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([OH:27])[CH2:26][CH2:25][NH:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:24]3[CH2:25][CH2:26][C:22]([OH:27])([CH3:21])[CH2:23]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(O)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(O)CCN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3-methylpyrrolidin-3-ol (125032-87-3) in the presence of TBTU and DIEA to obtain the title compound as yellow solid; MS (EI): m/e=368.5 [MH+].
Reaction SMILES: N[C:2]1[C:3]([O:29][CH3:30])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][CH:7]2[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.N([O-])=O.[Na+].[OH-].[Na+].[ClH:37]>O>[CH2:12]([N:9]1[CH2:8][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:6]2[C:11](=[C:2]([Cl:37])[C:3]([O:29][CH3:30])=[CH:4][CH:5]=2)[CH2:10]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cl
Reactant: COc1ccc(C2CN(Cc3ccccc3)Cc3c2ccc(OC)c3N)cc1OC
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C2CN(Cc3ccccc3)Cc3c2ccc(OC)c3Cl)cc1OC

Procedure:
##STR57## 2.02 g of 8-amino-2-benzyl-7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 20% hydrochloric acid; and to the solution was added dropwise a solution of 0.38 g of sodium nitrite in 1.9 ml of water, under cooling. To the mixture was added dropwise a solution of 0.55 g of cuprous chloride in 11 ml of 20% hydrochloric acid. After the reaction was over, 4.84 g of sodium hydroxide was added to the mixture, and the mixture was extracted with chloroform 2 times. The chloroform layer was collected, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethanol, giving 1.23 g of 2-benzyl-8-chloro-7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, m.p. 88°-91° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: O=C(N[C@@H]1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: CC(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A149) and acetyl chloride the title compound is obtained as colorless solid.