Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[CH2:7]2.[C:31]([N:50]1[CH:54]=[C:53]([CH:55]=O)[CH:52]=[N:51]1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N1CCCC1>CO>[CH3:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[C:7]2=[CH:55][C:53]1[CH:52]=[N:51][N:50]([C:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:54]=1
Reactant: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2
Reactant: O=Cc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: C1CCNC1
Solvent: CO
Product: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2=Cc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 70 °C
Yield: 62.1 %

Procedure:
To a suspension of 4-(7-methyl-1-naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzonitrile (300 mg, 0.773 mmol) and 1-trityl-1H-pyrazole-4-carbaldehyde (303 mg, 0.928 mmol) in methanol (5 ml) was added pyrrolidine (0.323 ml, 3.87 mmol). The reaction mixture was heated at 70° C. overnight. After cooled to room temperature, the reaction mixture formed a precipitate. The solid was collected and washed with cold methanol to give the title compound of 13B as a bright yellow solid (340 mg, 63.2% yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17]3[N:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)=[N:21][CH:22]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[O:34][NH2:35].C1C=CC2N(O)N=NC=2C=1.O>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17]3[N:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25]([NH:35][O:34][CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33][O:28]4)=[O:27])=[N:21][CH:22]=3)[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)/C=C/c1cnc(N[C@@H]2CCCN(CCCc3ccccc3)C2)cn1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(/C=C/c1cnc(N[C@@H]2CCCN(CCCc3ccccc3)C2)cn1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.2 %

Procedure:
To a mixture of crude (2E)-3-[5-({(3R)-1-[3-phenylpropyl]- 3-piperidinyl}amino)-2-pyrazinyl] acrylic acid (345 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (166 mg), and HOBT in dichloromethane (8.6 mL) was added WSCD (271 mg), which was stirred at room temperature for 17 hours. Water was added to the resultant. The organic layer was extracted and dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel [chromatorexNH, 5 g, hexane:AcOEt=25:75) to give (2E)-3-[5-({(3R)-1-[3-phenylpropyl]-3-piperidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (277 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH:24]([CH2:28][O:29][CH3:30])[O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]#[N:48]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]([CH2:46][C:47]#[N:48])[C:25](=[O:27])[CH:24]([CH2:28][O:29][CH3:30])[O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: COCC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(CC#N)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
A solution of tert-butyl(1-(4-(3-(methoxymethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (60 mg, 0.116 mmol) in DMF (2 ml) was added potassium carbonate (48 mg) and 2-bromoacetonitrile (41.9 mg, 0.349 mmol). The reaction mixture was stirred at room temperature for 16 h then was diluted with ethyl acetate (20 ml). Washed with water, brine, and dried with Na2SO4, filtered and concentrated to give crude product which was purified by column (biotage, 25 g) eluted with ethyl acetate and cyclohexane to afford product (35 mg). 1H NMR (500 MHz, CDCl3): 7.20-7.33 (m, 10H), 5.10 (t, 1H), 4.97 (s, 1H), 4.82 (dd, 2H), 4.03 (dd, 2H), 3.36 (s, 3H), 2.44-2.50 (m, 4H), 2.06 (m, 1H), 1.80 (m, 1H), 1.24-1.36 (br, 9H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[OH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O>>[CH2:1]([NH:3][CH2:8][C:7]1[CH:6]=[C:5]([OH:4])[CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCN
Reactant: O=Cc1cccc(O)c1
Product: CCNCc1cccc(O)c1

Procedure:
prepared by reaction of ethylamine with 3-hydroxy-benzaldehyde
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17]Br)[N:3]=1.[F-:19].[Cs+]>C1S(=O)(=O)CCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17][F:19])[N:3]=1
Reactant: [F-]
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CBr)n1
Agent: [Cs+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CF)n1
Temperature: 100 °C

Procedure:
To a solution of 2,4-diamino-6-bromomethyl-5-(2,4-dichlorophenyl) pyrimidine (1.04 g) in tetramethylene sulphone (4.5 ml) was added cesium fluoride (1 g). The mixture was stirred and heated at 100° C. for 4 hours, cooled, diluted with water and extracted with chloroform. The combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (silica; 19:1:0.1 dichloromethane/methanol/triethylamine) to give the title compound, which was recrystallised from ethanol. 0.19 g, mp. 210°-211° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([F:8])[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.[OH-].[Na+]>CO>[CH2:19]([NH:1][CH2:2][C@@H:3]1[C@H:7]([F:8])[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(OCc1ccccc1)N1C[C@H](CNCc2ccccc2)[C@H](F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3S,4S)-3-Aminomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine (1.10 g) was dissolved in methanol (13 mL). To this solution, molecular sieve 4A (440 mg) and then benzaldehyde (0.44 mL) were added. The mixture was stirred at room temperature for 1 hour, followed by addition of a borane/pyridine complex (0.44 mL) and further stirring at room temperature for 3.5 hours. Subsequently, 6 mol/L hydrochloric acid (7.3 mL) was added and the mixture was stirred at room temperature for 1 hour. A 30% aqueous solution of sodium hydroxide was then added to make the mixture basic. The mixture was extracted with diethyl ether (2×100 mL). The diethyl ether layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=4:1->1:1) to give (3S,4S)-3-benzylaminomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine as a colorless tar (1.18 g).
Reaction SMILES: C([CH:5]1[CH:8](OC2C=CC=CC=2)[N:7]([C:16]2[S:17][CH:18]=[C:19]([C:21](=[O:62])[NH:22][CH:23]([CH2:43][O:44][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:24][O:25][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[N:20]=2)[CH:6]1OC1C=CC=CC=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:88]1CCCC1>>[OH:88][CH:5]1[CH2:6][N:7]([C:16]2[S:17][CH:18]=[C:19]([C:21](=[O:62])[NH:22][CH:23]([CH2:24][OH:25])[CH2:43][OH:44])[N:20]=2)[CH2:8]1
Reactant: CC(C)(C)C1C(Oc2ccccc2)N(c2nc(C(=O)NC(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cs2)C1Oc1ccccc1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(NC(CO)CO)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a solution of 3-t-butyldiphenyloxy-1-{4-[2-(t-butyldiphenylsilyloxy)-1-(t-butyldiphenylsilyloxymethyl)ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (3.19 g, 3.23 mmol) (obtained as described in Reference Example 39(3)) in anhydrous tetrahydrofuran (160 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (11.6 ml, 11.6 mmol) in an ice bath. The mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (9:1→8:2) as the eluant to afford 3-hydroxy-1-{4-[2-hydroxy-1-(hydroxymethyl)-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.21 g, yield 100%) as a white solid.
Reaction SMILES: [NH:1]=[C:2]([C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH3:20])[N:16]=[N:15][C:14]=12)[S:3][CH2:4][C:5](=O)[C:6]([OH:8])=O.ClC(OCC(C)C)=O.C(N(CC)CC)C.[CH2:36]([NH2:39])[C:37]#[CH:38]>C1COCC1>[CH3:20][N:17]1[C:18](=[O:19])[N:13]2[CH:12]=[N:11][C:10]([C:2]3[S:3][CH:4]=[C:5]([C:6]([NH:39][CH2:36][C:37]#[CH:38])=[O:8])[N:1]=3)=[C:14]2[N:15]=[N:16]1
Reactant: Cn1nnc2c(C(=N)SCC(=O)C(=O)O)ncn2c1=O
Reactant: C#CCN
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCNC(=O)c1csc(-c2ncn3c(=O)n(C)nnc23)n1
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 3-(imino(3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazin-8-yl)methylthio)-2-oxopropanoic acid (0.65 g; 2.2 mmol) in dry THF (30 mL) under nitrogen was added isobutyl chloroformate (0.60 mL; 4.4 mmol), followed by triethylamine (0.62 mL; 4.4 mmol). The mixture was stirred for 1 hour, and then propargylamine (0.28 mL; 4.4 mmol) was added, and stirring continued for a further 3 hours. The precipitate was washed with water (5×15 mL) and diethyl ether (2×15 mL) to yield the title compound as a pale yellow solid (0.250 g; 36%). δH (DMSO-d6) 3.13 (1H, m), 3.89 (3H, s), 4.10 (2H, m), 8.47 (1H, s), 8.68 (1H, t, J=5.9), 8.95 (1H, s).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:17]3[CH:18]=[N:19][N:20]([CH:22]4[CH2:24][CH2:23]4)[CH:21]=3)=[C:11]([N+:14]([O-])=O)[CH:12]=2)[N:7]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]>C(O)C.O.Cl.[Fe]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:17]3[CH:18]=[N:19][N:20]([CH:22]4[CH2:24][CH2:23]4)[CH:21]=3)=[C:11]([NH2:14])[CH:12]=2)[N:7]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc([N+](=O)[O-])c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
Iron powder (1.010 g, 18.09 mmol) was added to a solution of isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-6-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.86 g, 1.81 mmol) in ethanol (12 mL) and water (2.4 mL). 1 N aqueous HCl (1 drop) was added, and the reaction was heated at 90° C. for 2 h. The mixture was cooled to rt and filtered through a pad of Celite, washing with ethanol. The filtrate was concentrated, and ethyl acetate was added. The solution was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 398 [M+H]+.
Reaction SMILES: CN1CCOCC1.[CH3:8][O:9][C:10](=[O:61])[NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]1[NH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[NH:41][C:42]([CH:45]5[CH2:49][NH:48][CH2:47][N:46]5[C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])=[N:43][CH:44]=4)=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:26][N:27]=1)=[O:17])[CH:13]([CH3:15])[CH3:14].Cl[C:63]([O:65][CH3:66])=[O:64]>ClCCl>[CH3:66][O:65][C:63]([N:48]1[CH2:49][CH:45]([C:42]2[NH:41][C:40]([C:37]3[CH:36]=[CH:35][C:34]([C:31]4[CH:32]=[CH:33][C:28]([C:25]5[NH:24][C:23]([CH:19]6[CH2:20][CH2:21][CH2:22][N:18]6[C:16](=[O:17])[CH:12]([NH:11][C:10]([O:9][CH3:8])=[O:61])[CH:13]([CH3:15])[CH3:14])=[N:27][CH:26]=5)=[CH:29][CH:30]=4)=[CH:39][CH:38]=3)=[CH:44][N:43]=2)[N:46]([C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[CH2:47]1)=[O:64]
Reactant: COC(=O)Cl
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CNCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(C(=O)OC)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Yield: 16.8 %

Procedure:
4-Methylmorpholine (31 μL, 0.28 mmol) was added to a suspension of {1-[2-(5-{4′-[3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-3H,1′H-[2,4]biimidazolyl-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (41.1 mg, 0.056 mmol) [prepared via reaction of 3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester with HCl-solution] in dichloromethane (5 mL). Methyl chloroformate (16.5 μL, 0.21 mmol) was added to the resulting solution. After 20 minutes the solvent was removed in vacuo. The residue was taken into tetrahydrofuran (4 mL) and methanol (2 mL) and an aqueous solution of sodium hydroxide (2 N, 1 mL) was added. After 2 hours the organic solvents were removed in vacuo and the aqueous phase was decanted. The residue was dissolved in dimethylformamide (2 mL) and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA). The product-containing fractions were combined and the solvent was removed by lyophilization to provide 3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid methyl ester (7.5 mg)
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:29][C:30]1[CH:35]=[C:34]([O:36][C:37]2[C:42]([F:43])=[CH:41][C:40]([NH:44][C:45]([C:47]3([C:50]([NH:52][C:53]4[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=4)=[O:51])[CH2:49][CH2:48]3)=[O:46])=[C:39]([F:60])[CH:38]=2)[CH:33]=[CH:32][N:31]=1>C(Cl)Cl>[CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([NH:29][C:30]1[CH:35]=[C:34]([O:36][C:37]2[C:42]([F:43])=[CH:41][C:40]([NH:44][C:45]([C:47]3([C:50]([NH:52][C:53]4[CH:54]=[CH:55][C:56]([F:59])=[CH:57][CH:58]=4)=[O:51])[CH2:49][CH2:48]3)=[O:46])=[C:39]([F:60])[CH:38]=2)[CH:33]=[CH:32][N:31]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: C[C@@H](OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@H](OCc1ccccc1)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of (R)-2-benzyloxy-propionic acid (500 mg, 2.78 mmol) and N-methylmorpholine (416 mg, 4.16 mmol) in anhydrous CH2Cl2 was added isobutyl chloroformate (566 mg, 4.32 mmol) dropwise. The mixture was stirred at 25° C. for 1 h. N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.452 mmol) was added and the resulting mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated in vacuo to give (R)—N-(4-((2-(2-(benzyloxy)propanamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 71.5%). It was used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O>[CH2:17]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=3)[C:12]#[N:13])=[CH:4][CH:3]=2)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(N3CCN(Cc4ccccc4)CC3)cc2)[nH]c1=O

Procedure:
From 11.7 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 19.1 g. of N-benzylpiperazine in 150 ml. of dimethyl sulfoxide, there is obtained 6-[p-(4-benzyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile; m.p. 275°-286° (dec.).
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:12][C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1>C(O)(C)C>[Cl:12][C:13]1[N:14]=[N:15][C:16]([N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:5][CH2:6]2)=[CH:17][CH:18]=1
Reactant: OCC(O)CN1CCNCC1
Reactant: Clc1ccc(Cl)nn1
Solvent: CC(C)O
Product: OCC(O)CN1CCN(c2ccc(Cl)nn2)CC1

Procedure:
Grams 32 of 1-(2,3-dihydroxypropyl)piperazine and 15 g of 3,6-dichloropyridazine in 700 ml isopropanol were refluxed for 24 hours. The reaction mixture was settled, the solid undissolvable removed and the solution evaporated to dryness. The so obtained residue was purified on column eluting with chloroform:methanol (9:1). Grams 2.1 of 3-[4-(6-chloropyridazin-3-yl)piperazin-1-yl]propane-1,2-diol, which, recrystallized from acetone, melted at 126°-128° C.
Reaction SMILES: Cl.[NH2:2][OH:3].O.O.O.C([O-])(=O)C.[Na+].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=O>C(O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=[N:2][OH:3]
Reactant: O=C(c1ccncc1)c1ccc(F)cc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccncc1)c1ccc(F)cc1F
Yield: 94.5 %

Procedure:
62.6 g (0.900 mole) of hydroxylamine hydrochloride and 133.6 g (0.982 mole) of sodium acetate trihydrate were added to a suspension of 179.4 g (0.818 mole) of the compound of Example 1 in 1L of ethanol and the mixture was refluxed for 1 hour. The solvent was removed under low pressure evaporation, 1L of water was added to the residue and it was filtered. After drying for 3 hours at 45° C., 181 g (94% yield) of the title compound (mixture of sin- and anti-isomers) were obtained, as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:47].O>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][CH:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][F:47])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC(Cc1ccc(CCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-{4-[3-(tosyloxy)propyl]benzyl}-L-glutamate (see Example 10) (100 mg, 0.15 mmol) was dissolved in 1 ml acetonitrile, and tetra-n-butylammonium tetra-(tert-butyl alcohol)-coordinated fluoride (Angew. Chem. 2008, 120, 8532-8534) (169 mg, 0.30 mmol) were added. The mixture was stirred at 70° C. for 2 h. Another 169 mg of the fluoride source was added and the reaction stirred for further 1.5 h at 70° C. After cooling to room temperature, the mixture was poured into water (10 ml) and extracted with tert-butyl methyl ether (3×10 ml). The organic phases were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on a reversed phase (RP-18) column with an acetonitrile/water gradient. The appropriate fractions were collected, the acetonitrile evaporated under reduced pressure and the remaining aqueous solution was lyophilized.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([NH:29][C:2]3[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: COCCN1C(=O)C(Nc2ccc3[nH]ccc3c2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1H-indol-5-amine in a similar manner as described for e.g. Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 7.78 (bs, 1H), 7.18 (t, 1H), 7.14-7.10 (m, 2H), 7.09-7.05 (m, 2H), 7.03-6.98 (m, 3H), 6.69 (dd, 1H), 6.23-6.20 (m, 1H), 3.92 (t, 2H), 3.74 (t, 2H), 3.39 (s, 3H); Mass Spectrum: M+H+ 398.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]#[N:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C(N)(=[S:16])C.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12](=[S:16])[NH2:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2C#N
Reactant: CC(N)=S
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Yield: 63.8 %

Procedure:
3-Methyl-8-cyano-5,6,7,8-tetrahydroquinoline (1.7 g., 0.01 m.) and thioacetamide (1.5 g., 0.02 m.) were dissolved in dimethylformamide (50 ml.), the solution saturated with dry hydrogen chloride gas and then heated on a steam bath for 4 hours. The cooled reaction mixture was poured onto water (200 ml.), washed with ethyl acetate (2× 200 ml.) and the extracts discarded. The aqueous solution was adjusted to pH 10.0 with 46% sodium hydroxide and extracted into methylene chloride (2× 200 ml.). The combined extracts were dried (sodium sulphate), evaporated in vacuo and the residual oil triturated with isopropanol and filtered. Recrystallisation from benzene gave the title compound as pale yellow needles (1.3 g., 63%) m.p. 149°.