Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]([CH:12]=1)[C:10]1[CH2:13][CH2:14][CH2:15][CH2:16][C:9]=1[N:8]=2)([O-])=O.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>>[CH:12]1[N:11]2[C:7](=[N:8][C:9]3[CH2:16][CH2:15][CH2:14][CH2:13][C:10]=32)[CH:6]=[CH:5][C:4]=1[NH:1][C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:34])[F:35])=[CH:20][CH:21]=2)=[CH:30][CH:29]=1)=[O:32]
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=[N+]([O-])c1ccc2nc3c(n2c1)CCCC3
Product: O=C(Nc1ccc2nc3c(n2c1)CCCC3)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
Conducting the operations similar to those of Example 1 using 2-nitro-6,7,8,9-tetrahydropyrido[1,2-a]benzimidazole and 4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[O:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:10][N:9]1[C:32]([CH:29]1[CH2:30][CH2:31][O:26][CH2:27][CH2:28]1)=[O:33])=[O:7])#[N:3]
Reactant: O=C(O)C1CCOCC1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)C1CCOCC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K2 was coupled with tetrahydro-pyran-4-carboxylic acid in analogy to experiment A1 to give (2S,4R)-1-(tetrahydro-pyran-4-carbonyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 474.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[N+:19]([C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH2:31])=[NH:30])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20].[OH-].[Na+]>COCCO>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:31]=[C:29]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)[N:30]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc(C)c(-c2ccnc(Nc3cccc([N+](=O)[O-])c3)n2)s1
Yield: 46.1 %

Procedure:
A mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1.0 mmol, 0.21 g) and N-(3-nitro-phenyl)-guanidine nitrate (1.0 mmol, 0.24 g) in 2-methoxyethanol (5 mL) was treated with NaOH (40 mg). The reaction mixture was refluxed under N2 for 20 h. The solvent was evaporated and the residue was purified by flash chromatography (EtOAc/PE, 5:1) and recrystallisation from EtOAc/MeOH to afford the title compound as a yellow solid (151 mg, 46%). M.p. 176-178° C. LC−MS: m/z=328 (M+1). C15H13N5O2S requires: C, 55.03; H, 4.00; N, 21.39; found: C, 54.67; H, 3.88; N, 21.77. 1H-NMR (300 MHz, CDCl3) δ2.72 (s, 3H, CH3), 2.74 (s, 3H, CH3), 7.06 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.74-7.92 (m, 3H, Ph-H), 8.46 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 8.91 (t, 1H, J=4.3, 2.1 Hz, Ph-H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[C:13]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)(N1C=CN=C1)=O>>[CH2:21]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:13][N:20]1[CH2:24][CH2:23][NH:22][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCN1CCc2ccccc2C1)c1n[nH]c2ccccc12
Yield: 185.2 %

Procedure:
Same procedure followed as described in Example 5. The following amounts were used: 1H-indazole-3-carboxylic acid (1.49 g, 9.2 mmol), 1,1'-carbonyldiimidazole (1.49 g, 9.2 mmol) and the intermediate from Preparation 5 (1.62 g, 9.2 mmol). The ethyl acetate extracts were evaporated to a solid. Addition of cyclohexane and filtration provided 2.73 g of solid. Mass spectrum, m+ =321.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:17]1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccsc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(CNS(C)(=O)=O)c1ccc(-c2ccsc2)cc1
Temperature: 100 °C
Yield: 26.5 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.0 g (7.7 mmol) of thiophene-3-boronic acid and 1.1 g (7.7 mmol) of potassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 4 hours, cooled to ambient temperature and diluted with 20 mL of ethyl acetate. The mixture was then washed once with water, and the organic portion was separated. The aqueous portion was extracted twice with ethyl acetate and the combined organics were dried (MgSO4) , filtered and concentrated in vacuo. Chromatography on 50 g silica gel (35% ethyl acetate/hexane) afforded a solid which was recrystallized from bromobutane, filtered and dried in vacuo at 60° C. to afford 0.4 g (27%) of the title compound.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:14][N:12]2[CH2:13][C@@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@@:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:33]3([CH2:51][CH3:52])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH:4]=1.[O:59]=O.N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH3:1][CH2:2][C@@:3]12[O:59][C@@H:4]1[C@H:5]1[CH2:13][N:12]([CH2:11][CH2:10][C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[NH:21][C:8]=3[C@@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@:28]56[C@@H:32]7[C@:33]([CH2:51][CH3:52])([C@@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@@H:39]5[N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[CH:34]=[CH:35][CH2:36][N:31]7[CH2:30][CH2:29]6)[CH2:6]1)[CH2:14]2
Reactant: CCC1=C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Reactant: O=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@H](C3)[C@H]1O2

Procedure:
100 mg. of 3',4'-anhydro-vinblastine are oxidized with oxygen from the air in an analogeous manner to that set forth in the Example 16, with the only difference that the reaction is performed in the presence of 4 mg. of 2,2'-azo-bis-isobutyronitrile.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH-].[Na+].[NH2:9][CH2:10][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14]>>[CH2:5]([O:4][C:2]([NH:9][CH2:10][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14])=[O:3])[CH3:6]
Reactant: NCC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)NCC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Ethyl chloroformate (3.19 g, 29.4 mmol) was added to a 2N sodium hydroxide solution (26.3 ml, 52.4 mmol) of 4-amino-3-(3,4-dichlorophenyl)butyric acid (5.61 g, 22.6 mmol) under cooling with ice water and the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 4 hours. The reaction solution was washed with diethyl ether and the aqueous layer was adjusted to a pH of about 2 with 1N hydrochloric acid and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (7.23 g, quant.) as a light brown oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23])([O-:14])=[O:13]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])=[O:23]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1[N+](=O)[O-]
Yield: 42.7 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nitro phenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-nitro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.44 g, 44%). EI-MS m/z 319 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:5][S:6][CH3:7].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C@@H:3]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:4][CH2:5][S:6][CH3:7])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CSCC[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of (S)-tert-butyl 1-hydroxy-4-(methylthio)butan-2-ylcarbamate (1.0 g, 1.0 eq, Chem-Impex, Catalog #03206) in DCM at −25° C. was added triethylamine (2.5 eq), followed by methanesulfonyl chloride (2.0 eq). The mixture was stirred at −25° C. for 1 h and RT for 30 min, washed with 1 N HCl, sat. NaHCO3 and brine, dried and concentrated to give a residue, which was purified by flash chromatography column on silica gel using ethyl acetate and hexane (1:2) as eluent to give (S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butyl methanesulfonate (1.1 g, 75%). 1H NMR (CDCl3, 300 MHz) d 4.25 (m, 2H, OCH2), 4.0 (br s, 1H, BocNHCH), 3.05 (s, 3H, SO2CH3), 2.55 (m, 2H, SCH2), 2.15 (s, 3H, SCH3), 1.85 (m, 2H, BocNHCHCH2CH2S), 1.45 (s, 9H, OC(CH3)3).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]([O:16]CC3C=CC=CC=3)=[O:15])[CH:8]=2)[CH2:5][CH:4]([C:24]([NH:26][CH:27]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])[CH2:3]1.C(N(CC)CC)C>CO.[Pd]>[CH2:32]([O:31][C:29]([CH2:28][CH:27]([NH:26][C:24]([CH:4]1[CH2:5][N:6]([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[C:2](=[O:1])[CH2:3]1)=[O:25])[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(CC(=O)OCc3ccccc3)c2)C1)c1cccnc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(CC(=O)O)c2)C1)c1cccnc1
Reaction time: 5 h

Procedure:
To a solution of ethyl 3-{(5-oxo-1-(3-{(benzyloxycarbonyl)methyl}phenyl)pyrrolidin-3-yl)carbonylamino}-3-(3-pyridyl)propanoate (2.6 g, 5.0 mmol, 1.0 eq), triethylamine (1.5 mL) in methanol (20 mL), was added 10% Pd/C (Aldrich, 0.5 g, 0.5 mmol, 0.1 eq). Hydrogenation was carried out under a pressure of 1 atm. After stirring for 5 hours, the catalyst was filtered through a pad of celite and the filtrate was concentrated with rotary evaporator. The title compound was obtained as an off-white solid. MS (ES+): 440 (M+H)+; (ES−): 438 (M−H)−.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:6][CH2:5][N:4]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([O:36]CC3C=CC([N+]([O-])=O)=CC=3)=[O:35])[CH2:25][N:24]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:22])[CH2:3]1.[ClH:67]>O1CCCC1.O>[ClH:67].[CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([OH:36])=[O:35])[CH2:25][NH:24]2)=[O:22])[CH2:3]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)[C@@H](C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)CCN1

Procedure:
170 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3S)-3-methyl-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 3.5 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.19 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2.5 hours in the presence of 170 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 8(b), to give 25.0 mg of the title compound as a powder.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[C:7]([CH2:9][C:10]([F:16])([F:15])[C:11]([O:13]C)=O)[N:8]=1)([O-:3])=[O:2].[F:17][C:18]([F:24])([CH2:22][NH2:23])[C:19]([NH2:21])=[O:20]>CO>[N+:1]([C:4]1[NH:5][CH:6]=[C:7]([CH2:9][C:10]([F:16])([F:15])[C:11]([NH:23][CH2:22][C:18]([F:24])([F:17])[C:19]([NH2:21])=[O:20])=[O:13])[N:8]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Reactant: NCC(F)(F)C(N)=O
Solvent: CO
Product: NC(=O)C(F)(F)CNC(=O)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Yield: 35.8 %

Procedure:
To a solution of methyl 3-(2'-nitroimidazolyl)-2,2-difluoropropionate (10.0 g, 42.5 mmol) in methanol (60 ml), 2,2-difluoro-3-amino-propionic acid amide (10.4 g, 83.8 mmol) was added and reacted for 20 hours at a room temperature while stirring. Then, insoluble fraction was filtered off from the reaction mixture. The filtrate was concentrated, subjected to silica gel column chromatography and recrystallized from ethanol to obtain 3-[3'-(2"-nitroimidazolyl)-2',2'-difluoropropionylamino]-2,2-difluoropropionic acid amide (4.98 g). m.p. 134.5°-135.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:9][C:8]=1[O:20][CH3:21].C(N(CC)CC)C.[CH3:32][O:33][C:34](=[O:37])[CH2:35]Br>C(#N)C>[CH3:32][O:33][C:34](=[O:37])[CH2:35][N:15]([CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=2)=[C:8]([O:20][CH3:21])[CH:9]=1)[CH2:16][CH:17]1[CH2:19][CH2:18]1
Reactant: COc1cc(CCNCC2CC2)ccc1OCc1cccc(F)c1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CN(CCc1ccc(OCc2cccc(F)c2)c(OC)c1)CC1CC1
Reaction time: 8 h
Yield: 97.2 %

Procedure:
0.271 g (0.82 mmol) of [2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amine, 0.140 ml (1 mmol) of triethylamine and 0.155 g (0.89 mmol) of bromo-acetic acid methyl ester were dissolved in 5 ml of acetonitrile and the reaction was carried out at 70° C. overnight. Solvent was removed under vacuum, water was added to the residue and the product was extracted with ethyl acetate. The crude product was purified by flash chromatography (hexane/ethyl acetate 100:0→80:20 gradient v:v) and 0.32 g (97% yield) of the title compound was isolated as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][O-:7].[Na+]>ClC1C=CC=CC=1>[C:6]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:7]
Reactant: C[O-]
Reactant: c1c[nH]cn1
Agent: [Na+]
Solvent: Clc1ccccc1
Product: O=C(n1ccnc1)n1ccnc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
286.0 g of imidazole were introduced into 1400 g of chlorobenzene in a flask fitted with column and distillation bridge. 720 g of 30% strength methanolic sodium methoxide solution were added dropwise. First methanol was removed by distillation, followed by 300 ml of chlorobenzene. 202 g of phosgene were subsequently passed in at 80-85° C. over the course of one hour. When the addition was complete, the mixture was stirred at 90° C. for a further 1 hour while a vigorous stream of nitrogen was passed through the flask, and the precipitate then present was filtered off at 80° C. and rinsed with 200 g of chlorobenzene at 90° C. The filtrate and the washing liquid were combined and cooled to 0° C. The precipitate which deposited was filtered off, rinsed with 200 g of dry chlorobenzene at 20° C. and dried at 60° C. under reduced pressure (50 mbar). 278.3 g of carbonyldiimidazole were thus obtained in the form of colorless crystals and having a purity of 97.8%. This corresponded to a yield of 84.0% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[C:29]([O:33][C:34](=[O:38])[C@@H:35]([CH3:37])[NH2:36])([CH3:32])([CH3:31])[CH3:30]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][NH:36][C@H:35]([CH3:37])[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:38]
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: C[C@@H](NCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (101.1 mg, 0.270 mmol) and D-alanine tert-butyl ester hydrochloride (49.1 mg, 0.270 mmol) according to Reference R and the general procedure for reductive amination to give (R)-tert-butyl 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzylamino)propanoate as a yellow-orange solid. MS (ESI) m/z: Calculated: 503.2; Observed: 503.8 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].Br[C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1
Reactant: Oc1cc(F)ccc1F
Reactant: O=Cc1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2cc(F)ccc2F)o1
Reaction time: 1 h
Yield: 22.9 %

Procedure:
To a solution of 2,5-difluorophenol (3360 mg, 25.83 mmol) in N,N-dimethylformamide (60 mL) was sodium hydride (1032 mg, 25.83 mmol, 60% in oil), which was then stirred for 1 hour. 5-Bromo-2-furaldehyde (3826 mg, 21.52 mmol) was added to the reaction solution, and the solution was stirred at 60° C. for 12 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then, concentrated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (1104 mg, 4.92 mmol, 22.9%) was obtained.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]1[CH2:13]CC[CH2:10][CH2:9]1.O>CC(CC)=O>[CH2:8]([C:9]1([CH3:10])[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][O:4]1)[CH3:13]
Reactant: OCCNCCO
Reactant: C1CCCCC1
Solvent: O
Solvent: CCC(C)=O
Product: CCC1(C)OCCN1CCO
Yield: 78 %

Procedure:
A mixture of 315 g (3 mols) of diethanolamine, 432 g (6 moles) of methylethylketone, and 100 ml of cyclohexane is stirred and heated to reflux using a Dean-Stark trap to separate the water formed. The mixture is stirred and refluxed for a total of 311/2 hours during which 54 ml of aqueous layer, 85% water and 15% methylethylketone by NMR, is collected (85% of the theoretical amount of water of reaction). The mixture is then concentrated and the residue distilled to give 373 g (78% yield) of product, b.p. 85°-88° C./2.5-3.0 mm Hg.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:32])=[C:14]([C:16]2[NH:17][C:18]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[N:25]=3)=[CH:19][C:20]=2[C:21]([NH2:23])=[O:22])[CH:15]=1.O>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:32])=[C:14]([C:16]2[NH:17][C:18]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[N:25]=3)=[C:19]([I:1])[C:20]=2[C:21]([NH2:23])=[O:22])[CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CNc1nccc(-c2cc(C(N)=O)c(-c3cc(Cl)ccc3C)[nH]2)n1
Solvent: O
Solvent: CN(C)C=O
Product: CNc1nccc(-c2[nH]c(-c3cc(Cl)ccc3C)c(C(N)=O)c2I)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
N-iodosuccinimide (301 mg, 1.34 mmol) was added to a solution of 2-(5-chloro-2-methylphenyl)-5-[2-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide (433 mg, 1.27 mmol) in dry DMF (5 mL). The reaction mixture was stirred at room temperature for 5 h and poured into iced water (50 mL). The solid was then filtered with suction, washed thoroughly with water, dried in an oven under vacuum at 50° C. and purified by flash chromatography over silica gel (DCM/MeOH/7 N NH3 in MeOH 95/5/0.5) to afford the title compound (344 mg, 58%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)[CH:10]=[CH:9][C:6]=2[S:7][CH:8]=1)#[N:2]>C1COCC1>[NH2:2][CH2:1][CH2:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)[CH:10]=[CH:9][C:6]=2[S:7][CH:8]=1
Reactant: Cn1nnnc1-c1ccc2scc(CC#N)c2c1
Solvent: C1CCOC1
Product: Cn1nnnc1-c1ccc2scc(CCN)c2c1
Yield: 66.9 %

Procedure:
Following the procedure of Example 11, Step 7, 26.1 mg (0.102 mmol) of 3-cyanomethyl-5-(1-methyltetrazol-5-yl)benzo[b]thiophene in 2 ml of THF was reacted with 0.36 ml (0.36 mmol) of 1.0M borane-tetrahydrofuran complex in THF. Chromatography on flash silica, eluting with CH2Cl2 /MeOH/NH3 (aq)(60:8:1) gave 17.7 mg (67%) of the title product as a colourless oil. The oxalate salt was prepared using oxalic add in methanol/ether to give the title product oxalate as a white solid, m.p. 206°-212° C. Analysis found: C, 47.55; H, 4.05; N, 19.65%. Calcd for C12H13N5S.1.1 C2H2O: C, 47.59; H, 4.28; N, 19.54%. δ (D2O) 3.32-3.35 (2H,m), 3.40-3.44 (2H, m), 4.22 (3H, s), 7.64 (1H, s), 7.73 (1H, d, J=8.4 Hz), 8.19 (1H, s), 8.22 (1H, d, 8.5 Hz).
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20](Cl)=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20]([NH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:21]
Reactant: COC(=O)C(N)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 2 h

Procedure:
To a solution of methyl 2-amino-3-(4-nitrophenyl)propanoate 2 (9.5 g) in CH2Cl2 (40 ml) is added, at 0° C., 2,6-dichlorobenzoyl chloride (7.71 g) dissolved in CH2Cl2 (40 ml). DIPEA (2 equ.) is then added dropwise to the mixture at 0° C. The reaction is then risen at RT and pH is brought to 7-8 by addition of DIPEA. The mixture is stirred for 2 h, then evaporated and the residue is placed in AcOEt (175 ml). The organic phase is washed one time with 5% NaHCO3 (150 ml), one time with water, one time with 10% KHSO4 (150 ml) and one time with brine, dried over MgSO4 and evaporated. No further purification is needed.