Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.[OH:65][CH2:66][C:67](O)=[O:68]>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][C:66](=[O:65])[CH2:67][OH:68])([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: O=C(O)CO
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNC(=O)CO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluoro-phenyl)-1,3-oxazinan-2-one stirred in anhydrous CH2Cl2 (5 ml) was added HOBT (36 mg, 0.264 mmol), EDCl (52 mg, 0.264 mmol), DIEA (0.5 ml) and hydroxy-acetic acid (50.1 mg, 0.66 mmol) at 0° C. under N2 atmosphere. The solution was stirred at rt overnight. Then the solvent was removed under reduced pressure to give the residue, which was purified by preparative HPLC to afford N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-2-hydroxyacetamide (19.2 mg, 28.6%). 1H NMR (CDCl3): 1.49-1.50 (d, 3H), 2.01-2.13 (m, 1H), 2.14-2.15 (m, 3H), 2.17 (m, 1H), 2.97-2.98 (m, 2H), 3.46-3.52 (m, 4H), 4.01-4.02 (m, 2H), 5.60-5.61 (m, 1H), 6.82-6.88 (m, 2H), 6.98-7.04 (m, 3H), 7.17 (s, 1H), 7.19-7.22 (m, 3H), 7.25-7.27 (m, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[CH:12]=CC=CC=1.[OH-:13].[Na+]>O>[C:5]([N:1]1[CH:7]=[CH:12][N:3]=[CH:2]1)([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:13]
Reactant: Clc1ccccc1
Reactant: c1c[nH]cn1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(n1ccnc1)n1ccnc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
286.0 g of imidazole were introduced into 1200 g of chlorobenzene in a flask fitted with water separator, and 320 g of 50% strength aqueous sodium hydroxide solution were added dropwise. Water was then separated out until the distillate no longer separated into two phases. After 224 ml of water had been separated out in this way, 100 ml of chlorobenzene were removed by distillation. 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, and dried at 60° C. under reduced pressure (50 mbar). 290.6 g of carbonyldiimidazole were thus obtained in the form of colorless crystals having a purity of 97%. This corresponded to a yield of 88% of theory.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[NH2:7][CH2:8][CH2:9][CH2:10]O.[BrH:12]>>[BrH:12].[BrH:12].[NH2:7][CH2:8][CH2:9][CH2:10][S:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1
Reactant: Sc1ncc[nH]1
Reactant: NCCCO
Agent: Br
Product: NCCCSc1ncc[nH]1

Procedure:
A solution of 2-mercaptoimidazole (2 g.) and 3-aminopropanol (1.14 ml.) in hydrobromic acid (48%, 25 ml.) was heated under reflux for 25 hours. The reaction mixture was evaporated to dryness and the oily residue solid recrystallised twice from ethanol/ether to give 2-(3-aminopropylmercapto)imidazole dihydrobromide (3.55 g.) m.p. 160°-162°. (ii) This amine dihydrobromide (7 g.) was converted to the free base and reacted with methyl isothiocyanate (1.75 g.), by the method described in Example 1 (ii), to give a crude yellow solid after evaporation of the reaction mixture. This crude product was washed with acetone/isopropyl acetate (1.1) and recrystallised from water to give N-methyl-N'-[3-(2-imidazolylthio)propyl]thiourea (3.46 g.) m.p. 139°-141°. (Found: C, 41.5; H, 6.1; N, 24.1; S, 27.7. C8H14N4S2 requires: C, 41.7; H, 6.1; N, 24.3; S, 27.8).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]([C:12]2[NH:13][C:14]([C:17]([C:19]3[C:20](Cl)=[N:21][CH:22]=[CH:23][CH:24]=3)=O)=[CH:15][CH:16]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:27][NH2:28]>C(O)C>[C:1]1([C@@H:7]([NH:9][C:10]([C:12]2[NH:13][C:14]([C:17]3[C:19]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:28][N:27]=3)=[CH:15][CH:16]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: C[C@H](NC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1)c1ccccc1
Solvent: CCO
Solvent: O
Product: C[C@H](NC(=O)c1ccc(-c2n[nH]c3ncccc23)[nH]1)c1ccccc1
Temperature: 80 °C
Yield: 19 %

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid ((S)-1-phenyl-ethyl)-amide (450 mg, 1.3 mmol) and hydrazine hydrate (2 mL) in ethanol (20 mL) was heated at 80° C. for 24 hours. The reaction was concentrated, the residue was triturated with water. The precipitate was collected by vacuum filtration, washed with water and DCM to give 80 mg (19%) of the titled compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[C@@:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([F:18])[CH2:17][C@@:11]1([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:12]([OH:24])[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:31][C:32]([F:46])([F:45])[C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:36]Br.C1OCCOCCOCCOCCOCCOC1>CCCC(C)C.C1COCC1>[CH2:3]([N:10]1[C@@H:15]2[C@@:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([F:18])[CH2:17][C@@:11]1([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:12]([O:24][CH2:36][C:35]1[CH:38]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:40]=[C:33]([C:32]([F:31])([F:45])[F:46])[CH:34]=1)[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCOC(=O)[C@]1(F)C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCC(C)C
Product: CCOC(=O)[C@]1(F)C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reaction time: 40 h
Yield: 62.3 %

Procedure:
Sodium hydride (60% in oil, 100 mg, 2.5 mmol) was washed twice with iso-hexane and added as a suspension in THF (3 ml) to a stirred mixture of (1R*,2R*,5S*,6S*)-8-benzyl-6-ethoxycarbonyl-6-fluoro-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 38; 512 mg, 1.3 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (0.5 ml, 2.7 mmol), 18-crown-6 (360 mg, 1.37 mmol) in THF (5 ml) at room temperature. The reaction mixture was stirred for 40 hours, quenched with saturated aqueous NH4Cl and extracted into a 1:1 mixture of iso-hexane:diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound (494 mg, 61%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:35])[CH3:38]
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCCNC4)c[nH]c13)OCO2
Reactant: CCOC(=O)Cl
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCCN(C(=O)OCC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-3-ylamide (example A180) and ethyl chloroformate the title compound was obtained as colorless solid.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].Cl>C1(C)C=CC=CC=1.CS(C)=O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 115 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a distillation device and a dropping funnel and having an inner volume of 500 ml were charged 11.0 g (0.2 mol) of sodium methoxide and 30 ml of dimethyl sulfoxide under argon atmosphere, and the temperature of the mixture was raised to 110 to 120° C. while stirring, then, 27.0 g (0.2 mol) of dimethyl malonate with a purity of 98% was gradually added dropwise to the mixture over 30 minutes, and the resulting mixture was stirred for 2 hours while removing methanol under reduced pressure of 0.010 to 0.013 MPa. Subsequently, the mixture was cooled to 100° C. under the same pressure, 16.2 g (0.1 mol) of 2,4-di-fluoronitrobenzene with a purity of 98% was gradually added dropwise to the mixture over 30 minutes, and the mixture was further reacted at the same pressure and the same temperature for one hour. After completion of the reaction, the mixture was cooled to room temperature, 100 ml of toluene was added to the mixture and 40 ml (0.2 mol) of 5 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 50 ml of water and 50 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. This organic layer was analyzed (absolute quantitative method) by high performance liquid chromatography, it can be found that 20.6 g (yield: 76%) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate was formed.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[CH:16][C:14](=[O:15])[CH2:13][C:12]([O:18][CH3:19])=[O:17])([O-:3])=[O:2]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)CC(=O)C=Cc1ccccc1[N+](=O)[O-]
Yield: 97.9 %

Procedure:
o-Nitrobenzaldehyde (7.6 g, 0.05 mole) and methyl acetoacetate (5.8 g, 0.05 mole) are dissolved in benzene (40 ml), and thereto are added piperidine (0.2 ml) and acetic acid (0.6 ml), and the mixture is refluxed for 5 hours. The produced water is removed, and when a stoichiometic amount of water is distilled off, the reaction is stopped. After completion of the reaction, the reaction mixture is washed with 5% hydrochloric acid and then with water, and the solvent is distilled off under reduced pressure to give the title compound (12.2 g, yield 98%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][N:7]=1
Reactant: CC(C)(C)CI
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Product: CC(C)(C)COc1ccc(Cl)nc1
Reaction time: 0.5 h

Procedure:
5.2 g (40.0 mmol) 6-chloropyridin-3-ol, 11.9 g (60.0 mmol) 1-iodo-2,2-dimethylpropane, 19.6 g (60.0 mmol) cesium carbonate and 120 ml diethylene glycol dimethyl ether are divided into five portions of equal size and are reacted in portions at 160° C. for 4 h in a single mode microwave (CEM Explorer). Thereafter, the five reaction mixtures obtained are combined, the solid is filtered off and rinsed with diethylene glycol dimethyl ether and the filtrate and wash solutions are combined. The majority of the solvent is removed and 300 ml water are added to the concentrated solution (approx. 50 ml). The mixture is stirred for 30 min and the solid obtained is filtered off, washed once with water and dried under a high vacuum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C@H:16]([O:32][CH:33]([CH3:35])[CH3:34])[C:17](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH:37]O.[OH-].[Li+].O>O1CCCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:10]=[C:11]([CH2:15][C@H:16]([O:32][CH:33]([CH3:35])[CH3:34])[C:17]([OH:18])=[O:37])[CH:12]=[CH:13][CH:14]=1)=[O:36])([CH3:2])([CH3:3])[CH3:4]
Reactant: OO
Reactant: CC(C)O[C@@H](Cc1cccc(CNC(=O)OC(C)(C)C)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)O[C@@H](Cc1cccc(CNC(=O)OC(C)(C)C)c1)C(=O)O
Reaction time: 8 h

Procedure:
15.3 g of {3-[3-(4 (S)-Benzyl-2-oxooxazolidin-3-yl)-2(S)-isopropoxy-3-oxopropyl]benzyl}carbamic acid t-butyl ester was dissolved in 300 ml of tetrahydrofuran, and 15 ml of 30% aqueous hydrogen peroxide and 75 ml of 1N aqueous lithium hydroxide were successively added under ice-cooling, and stirring was continued overnight at room temperature. The reaction solution was treated with water, extracted with dichloromethane, and the aqueous layer was acidified with 1N hydrochloric acid. The mixture was extracted (×3) with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 16.68 g of 3-[3-(t-butoxycarbonylaminomethyl)phenyl]-2(S)-isopropoxypropionic acid. The product was then dissolved in 100 ml of N,N-dimethylformamide, and 7 g of potassium hydrogen carbonate and 3.5 ml of iodomethane were successively added, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 8.58 g of the title compound as a white solid in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](O)=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.S(Cl)(Cl)=O.[CH3:36][S-:37].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](=[O:15])[S:37][CH3:36])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1
Reactant: C[S-]
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CSC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Yield: 9.4 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid (30 mg, 0.066 mmol) was treated with thionylchloride (1.5 mL) and stirred at reflux for 2 h. The mixture was concentrated under reduced pressure. The intermediate was treated with benzene (3×) and the benzene was evaporated to remove water. Then, the obtained mixture was dissolved in benzene (1.5 mL) and sodium methanethiolate (32.5 mg, 0.46 mmol) was added. The reaction mixture was stirred at reflux for 5 h. The mixture was diluted with dichloromethane and washed with water (3×), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product (example IB-68) was purified by pTLC (1:1 EE/PE) to give 3 mg of a white solid (yield 9%). Result of LC/MS MH+: 482.76; 1H NMR (CDCl3): 2.33 (t, 3H), 7.19 (t, 1H), 7.33-7.55 (m, 6H), 8.23 (s, 1H)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[ClH:7].[CH2:8]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][Cl:13])[CH3:9]>C(O)C>[ClH:13].[Cl-:7].[CH2:8]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][N+:4]1[CH:5]=[CH:6][N:2]([CH3:1])[CH:3]=1)[CH3:9]
Reactant: CCN(CC)CCCl
Reactant: Cn1ccnc1
Agent: Cl
Solvent: CCO
Product: CCN(CC)CC[n+]1ccn(C)c1
Product: [Cl-]

Procedure:
4.9 g (60 mmol) of N-methylimidazole are added to 8.6 g (50 mmol) of 2-(diethylamino)ethyl chloride hydrochloride in 50 ml of absolute ethanol and the mixture is refluxed for 12 hours.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([Br:22])[N:19]=[C:20](Br)[C:15]4=[N:14][C:13]=3[CH2:23][OH:24])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH3:26][CH:27]([CH3:30])[CH2:28][NH2:29].C1(C)C=CC=CC=1>CN(C)C=O>[Br:22][C:18]1[N:19]=[C:20]([NH:29][CH2:28][CH:27]([CH3:30])[CH3:26])[C:15]2[N:16]([C:12]([C:9]3[CH:8]=[CH:7][C:6]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:25])=[CH:11][CH:10]=3)=[C:13]([CH2:23][OH:24])[N:14]=2)[CH:17]=1
Reactant: O=C(NC1CC1)c1ccc(-c2c(CO)nc3c(Br)nc(Br)cn23)cc1
Reactant: CC(C)CN
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)CNc1nc(Br)cn2c(-c3ccc(C(=O)NC4CC4)cc3)c(CO)nc12
Temperature: 23 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of 50 mg (107 μmol) N-cyclopropyl-4-[6,8-dibromo-2-(hydroxymethyl)imidazo[1,2-a]pyrazin-3-yl]benzamide in 0.71 mL N,N-dimethylformamide were added 32 μL 2-methylpropan-1-amine and the mixture was stirred at 23° C. for 3 hours. Toluene was added and the solvents removed. The residue was purified by chromatography to give 40.7 mg (83%) of the title compound. 1H-NMR (300 MHz d6-DMSO): δ=8.52 (1H, d), 8.12 (1H, t), 7.95 (2H, d), 7.68 (2H, d), 7.50 (1H, s), 5.18 (1H, t), 4.46 (2H, d), 3.23 (2H, m), 2.85 (1H, m), 2.00 (1H, m), 0.87 (6H, m), 0.68 (2H, m), 0.55 (2H, m) ppm. UPLC-MS: RT=1.18 min; m/z 459.4 [MH+]; required MW=458.4.
Reaction SMILES: [N+:1]([C:4]1[C:14]2[C:13](=O)[NH:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].B.C1COCC1.CO>C1COCC1.C(OCC)(=O)C>[N+:1]([C:4]1[C:14]2[CH2:13][NH:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1NCCNc2cccc([N+](=O)[O-])c21
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1cccc2c1CNCCN2
Yield: 12.5 %

Procedure:
6-Nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (1.20 g, 5.8 mmol) was dissolved in THF (50 mL) and the solution was treated with 1N Borane-THF (2.77 mL, 28.95 mmol). The reaction mixture was then refluxed overnight. Upon cooling, the solution was treated with methanol (50 mL) and was then reduced in vacuo. The residue was taken up in ethyl acetate (40 mL) and was washed with saturated NaHCO3 (100 mL). Organics were extracted with ethyl acetate (3×40 mL) and were then dried over Na2SO4, filtered and reduced. The product was then purified and isolated by flash column chromatography (0% MeOH/DCM-30% MeOH/DCM) to afford 140 mg of 6-Nitro-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine as a yellow oil. LC/MS (ESI)=194.32 (M+H). 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 2H), 7.06 (d, 1H, J=8.08 Hz), 6.86 (d, 1H), J=8.34 Hz), 5.32 (s, 1H), 4.66 (s, 2H), 3.24 (t, 2H, J=5.05 Hz), 3.00 (t, 2H, J=5.05 Hz).
Reaction SMILES: COCCO[AlH2-]O[CH2:8][CH2:9][O:10]C.[Na+].[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(COC)[O:21]C>CCOCC>[C:13]1([C@H:19]([OH:21])[CH2:8][CH2:9][OH:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCCOC
Reactant: Cc1ccccc1
Reactant: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: CCOCC
Product: OCC[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (-)-(2S,3S)-epoxycinnamyl alcohol (1) (1.5 g, 10.0 mmol) (synthesized by the method disclosed in Gao et al., J. Org. Chem., Vol. 53, No. 17, pp. 4081-4084 (1988.), in dimethoxyethane (50 mL) was added a 3.4 molar solution of REd-Al in toluene (3.1 mL, 10.5 mmol) dropwise under nitrogen at 0° C. After stirring at room temperature for three hours, the solution was diluted with ether and quenched with 5% HCl solution. After stirring at room temperature for 30 min, the resulting white precipitate formed was filtered and boiled with ethyl acetate and filtered again. The combined organic solutions were dried with magnesium sulfate. Concentration gave (R)-3-phenyl-1,3-dihydroxypropane (2) as a slightly yellow oil which was used without further purification (1.5 g, 98%): 1H NMR (CDCl3) δ7.2-7.3 (m, 5 H), 4.88-4.98 (m, 1 H), 3.78-3.86(t, J=7.5 Hz, 2), 3.3-3.4 (br. s, 1 H), 2.85-2.95 (br. s, 1 H), 1.84-2.08 (m, 2 H); the ratio of 1,3-diol to 1,2-diol was 20:1 by 1H NMR analysis of the derived diacetate.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([S:9][C:10]1[NH:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][N:11]=1)[C:5]([O:7]C)=[O:6].CO.O1CCCC1.[Li]>O.Cl>[CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([S:9][C:10]1[NH:14][C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:12][N:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(CC(C)C)Sc1nnc(-c2ccccc2)[nH]1
Agent: Cl
Agent: [Li]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(Sc1nnc(-c2ccccc2)[nH]1)C(=O)O

Procedure:
Methyl 4-methyl-2-[(5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]pentanoate (473 mg, 1.54 mmoles) in a mixture of water (2 mL), methanol (2 mL) and tetrahydrofuran (4 mL) was treated with lithium hydroxyde monohydrate (193 mg, 4.6 mmoles) until disappearance of the starting material was observed by TLC. The reaction was diluted with 1.2 N hydrochloric acid until pH 1. The aqueous phase was extracted 3 times with dichloromethane. The organic phase was concentrated under reduced pressure to yield a crude residue of 4-methyl-2-[(5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]pentanoic acid which was used as such in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:28])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=O)[NH:21][C:20]=1[CH3:27])=[O:18]>>[CH3:12][N:13]([CH3:28])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:21][C:20]=1[CH3:27])=[O:18]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NCCN(C)C
Yield: 94.8 %

Procedure:
5-Chloro-1,3-dihydroindol-2-one (0.1 g, 0.6 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (0.15 g) to give 0.22 g (90%) of the title compound as a yellow solid.
Reaction SMILES: C[C:2]([CH3:8])([CH2:5][NH:6][CH3:7])[CH:3]=O.[C:9](OC(=O)C)(=[O:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:27]([O-:30])([O-])=O.[Na+].[Na+]>O>[CH3:8][C:2]([CH3:3])([CH:27]=[O:30])[CH2:5][N:6]([CH3:7])[C:9](=[O:11])[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OC(C)=O
Reactant: CNCC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Product: CC(=O)N(C)CC(C)(C)C=O
Temperature: 25 °C

Procedure:
In a round-bottom flask with a mounted reflux condenser and under nitrogen atmosphere, 20.0 g (0.17 mol) of 2,2-dimethyl-3-methylamino-propanal was introduced while being stirred. 30.0 g (0.52 mol) of acetic acid anhydride was slowly added in drops to this, the mixture was mixed wtih 0.1 g of para-toluenesulfonic acid, and it was heated for 1 hour to 120° C. After cooling to room temperature, the reaction mixture was mixed with 100 ml of water, neutralized with Na2CO3, extracted several times with ethyl acetate, and the combined organic phase was dried on MgSO4 and concentrated by evaporation. The thus obtained brown oil was fractionated in a vacuum. The product distilled at an overhead temperature of 93-95° C. and a pressure of 3 mbar. Yield: 8.2 g (30% of theory) of colorless and almost odorless liquid, which crystallized when left to stand.