Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]#[N:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].CCOCC>C1COCC1>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([C:15]#[N:16])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: N#CC1CCC(OCc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C1(C#N)CCC(OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
To a solution of 4-(benzyloxy)cyclohexanecarbonitrile (1.26 g, 5.85 mmol, 1.0 equiv) in THF (dry, 30 mL) was added a solution of LDA (3.95 mL, 2.0 M Heptane/THF/toluene, 1.35 equiv) dropwise at −78° C. under N2. The resulting yellow solution was stirred at −78° C. for 2 hrs. Ethyl chloroformate (2.79 mL, 29.26 mmol, 5.0 equiv) was then added by syringe dropwise. The solution was stirred at −78° C. and allowed to warm to room temperature slowly and stirred overnight. The reaction was quenched by addition of H2O (20 mL), HCl (1.0 N, 20 mL). It was then extracted with EtOAc (3×40 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4 and then concentrated to give pale yellow residue. Ether (40 mL) was added and stirred for 5 min, filtered to remove the white solid. The ethereal solution was concentrated to give the yellow oil which was purified by CombiFlash (25 g silica gel column, EtOAc/Hexane: 0-20%) to afford 565 mg (yield 33%) of ethyl 4-(benzyloxy)-1-cyanocyclohexanecarboxylate as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]=[O:20])=[CH:14][CH:13]=1>O.CO>[F:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)/[CH:19]=[O:20])=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: O=CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C/C(=C\c1ccccc1)c1ccc(F)cc1
Temperature: 10 °C
Reaction time: 10 h

Procedure:
4.2 g of sodium hydroxide in 30 ml of water are added to a solution of 26.5 g of benzaldehyde in 300 ml of methanol. The reaction mixture is cooled to 10° C., and 36 g of 4-fluorophenylacetaldehyde are rapidly added, during which the solution rises to 30°-40° C. The reaction solution is stirred at 40° C. for 10 hours and then cooled and the crystals which have separated out are filtered off with suction. 31.6 g (56%) of E/Z-2-(4-fluorophenyl)-3-phenylpropenal of melting point 87°-94° C. are obtained.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]2)[C:14]2[CH:25]=[CH:26][C:27]([S:29]([N:32]3[CH:36]=[C:35]([CH:37]=[O:38])[CH:34]=[N:33]3)(=[O:31])=[O:30])=[CH:28][C:13]=2[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C>[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]2)[C:14]2[CH:25]=[CH:26][C:27]([S:29]([N:32]3[CH:36]=[C:35]([C:37]([OH:1])=[O:38])[CH:34]=[N:33]3)(=[O:31])=[O:30])=[CH:28][C:13]=2[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C=O)cn3)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxone® (0.60 g, 0.97 mmol) was added to a solution of 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-1H-pyrazole-4-carbaldehyde (0.41 g, 0.88 mmol) in DMF (15 mL). The reaction mixture was stirred overnight at ambient temperature and the solvent was concentrated. The product was recovered in DCM, washed with 10% HCl solution, brine and dried over anhydrous Na2SO4, The solvent was concentrated to provide the pure title compound as white solid. Yield: 0.38 g (89%); 1H NMR (400 MHz, CDCl3) δ 1.42-1.53 (m, 2 H), 1.56 (s, 9 H), 1.59-1.75 (m, 4 H), 2.02-2.20 (m, 3 H), 4.25 (d, J=7.42 Hz, 2 H), 7.46 (d, J=8.59 Hz, 1 H), 7.99 (dd, J=8.69, 1.86 Hz, 1 H), 8.01-8.08 (m, 2 H), 8.47 (d, J=1.56 Hz, 1 H), 8.68 (d, J=0.59 Hz, 1 H); MS (ESI) (M+H)+=481.0.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[CH:4]=1.[S:27]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])(=[O:29])[NH2:28]>>[S:27]([C:31]1[CH:32]=[C:33]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:26])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:34]=[CH:35][CH:36]=1)(=[O:29])(=[O:30])[NH2:28]
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(N)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.5) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 524.0 [(M−H)−]; mp 252° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[I:7][C:8]1[CH:9]=C([CH:14]=[CH:15][CH:16]=1)C(O)=O>C(Cl)Cl>[I:7][C:8]1[CH:9]=[C:1]([CH:14]=[CH:15][CH:16]=1)[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(I)c1
Solvent: ClCCl
Product: O=C(Cl)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (2.66 mL, 30.4 mmol) was added dropwise to a suspension of 3-iodobenzoic acid (6.98 g, 27.6 mmol) in DCM (140 mL) under a nitrogen atmosphere at room temperature. The mixture was then stirred at rt for 4 h. After the reaction was complete, solvent was removed in vacuum to yield a residue (3-iodobenzoyl chloride), which was dried in high vacuum and used without further purification. This residue was dissolved in DCM (25 mL) and added slowly to a 0° C., stirred solution of 3,5-diisopropyl-[1,1′-biphenyl]-4-amine (5.0 g, 19.73 mmol) and pyridine (2.71 ml, 33.5 mmol) in DCM (50 mL). The mixture was then warmed up and stirred at rt overnight. After the reaction was complete water was added. Aqueous mixture was extracted with DCM. The DCM layer was separated, washed with water (2×) and brine, and then dried over anhydrous Na2SO4. Filtration and evaporation gave an off-white solid which was recrystallized from 10% hexane in DCM to afford the title compound (5.3 g, 55%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:37][C:34]4[CH:35]=[CH:36][C:30]5[O:29][C:28]([C:25]6[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=6)=[N:32][C:31]=5[CH:33]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1CN(C2CCCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: Nc1ccc2oc(-c3ccncc3)nc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC1CN(C2CCCCC2)c2nc(Nc3ccc4oc(-c5ccncc5)nc4c3)ncc2N(C)C1=O

Procedure:
A solution of 0.05 g (0.00016 mole) of (rac)-2-chloro-9-cyclohexyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-19), 0.034 g, 0.00016 mole) of 2-pyridin-4-yl-benzooxazol-5-ylamine, 0.047 g, (0.00024 mole) of p-toluenesulfonic acid monohydrate and 4 mL of 2-propanol was heated at 180 degree for 2 hours in a microwave reactor. The reaction mixture was concentrated. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-95:5) to give 0.047 g of (rac)-9-cyclohexyl-5,7-dimethyl-2-(2-pyridin-4-yl-benzooxazol-5-ylamino)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diaze-pin-6-one (I-26). HRMS (ES+) m/z Calcd for C27H29N7O2+H [(M+H)+]: 484.2456. Found: 484.2456.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][O:13][C:14]1[N:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]1[O:21][CH2:20][CH:19]([C@H:28]3[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]3)[NH:18][C:17]2=1>N1C=CC=CC=1>[CH3:12][O:13][C:14]1[N:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]1[O:21][CH2:20][CH:19]([C@H:28]3[CH2:33][CH2:32][C@H:31]([N:34]4[C:1](=[O:11])[C:2]5[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:4]4=[O:6])[CH2:30][CH2:29]3)[NH:18][C:17]2=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](N)CC1)CO3
Solvent: c1ccncc1
Product: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)CO3

Procedure:
Phthalic anhydride (200 mg, 1.34 mmol, 2.53 eq) is added at room temperature to a stirred solution of trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexylamine (200 mg, 0.53 mmol, 1.0 eq) in pyridine (4 mL). The reaction mixture is heated to reflux for 3 hours, pyridine is then removed and acetic anhydride (1 mL) is added. The resulting mixture is heated to reflux for 2 hours, then extracted with ethyl acetate (3×10 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 2-[trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione as a light brown semisolid (190 mg, 69% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]3([C:18]([F:21])([F:20])[F:19])[CH2:17][CH2:16]3)=[O:13])[CH:9]=[CH:8][C:7]=2[N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)[CH2:3][CH2:2]1.[CH3:28][C:29]([O-])(CC)C.[Na+].ICC>CN(C=O)C>[CH2:28]([N:14]([C:15]1([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:17]1)[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:11]=1)=[O:13])[CH3:29]
Reactant: CCC(C)(C)[O-]
Reactant: O=C(NC1(C(F)(F)F)CC1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C1(C(F)(F)F)CC1
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(1-(trifluoromethyl)cyclopropyl)picolinamide (Example 16 a), 15 mg, 38 μmol) and sodium 2-methylbutan-2-olate (5 mg, 46 μmol) in DMF (150 μL) was stirred for 15 minutes at ambient temperature. Iodoethane (9 mg, 7 μL, 58 μmol) was added and stirring was continued for 1 h. The reaction mixture was poured onto ice/sat. aqueous NaHCO3 solution (15 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice/brine (2×20 mL), dried over Na2SO4 and brought to dryness. The crude product was purified by preparative TLC (silica gel, 1 mm, heptan/EtOAc 2:1, elution with EtOAc) to give the title compound (12 mg, 75%) as colorless oil; MS (EI): m/e=420.2 [MH]+.
Reaction SMILES: O1[C:3]23[C@:16]([CH3:21])([CH:17]=[CH:18][C:19](=[O:20])[CH:2]12)[C@@H:15]1[C@H:6]([C@H:7]2[C@@:11]([CH2:13][CH2:14]1)([CH3:12])[C:10](=[O:22])[CH2:9][CH2:8]2)[CH2:5][C:4]3=[CH2:23].[ClH:24]>C(O)(=O)C>[Cl:24][C:2]1[C:19](=[O:20])[CH:18]=[CH:17][C@@:16]2([CH3:21])[C:3]=1[C:4](=[CH2:23])[CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22]
Reactant: Cl
Reactant: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C=CC(=O)C3OC132
Solvent: CC(=O)O
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C(Cl)=C12

Procedure:
A solution of 4,5-epoxy-6-methylenandrost-1-ene-3,17-dione (1.0 g) in glacial acetic acid (10 ml) was treated with gaseous hydrogen chloride for 30 min at room temperature The precipitate was filtered off, washed with diethyl ether, dried and chromatographed on silica gel using hexane/ethyl acetate to yield 0.8 g of pure 4-chloro-6-methylenandrosta-1,4-diene-3,17-dione.
Reaction SMILES: [C:1]1([Mg])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)C.CN(OC)[C:15]([C@@H:17]1[CH2:21][C:20](=[O:22])[N:19]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:18]1)=[O:16].Cl>O1CCCC1>[C:1]1([C:15]([C@H:17]2[CH2:18][N:19]([C@@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:20](=[O:22])[CH2:21]2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Mg]c1ccccc1
Reactant: CON(C)C(=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
In an atmosphere of nitrogen, phenylmagnesium bride (3 mol/l diethyl ether solution, 15 ml) was added dropwise to tetrahydrofuran solution (50 ml) of N-methyl-N-methoxy-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-carboxamide (2.49 g, 9.0 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was mixed with 1 mol/l hydrochloric acid (50 ml) under ice-cooling and then extracted with ethyl acetate (8 ml×2). The organic layer was washed with saturated brine (100 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was applied to a silica gel column chromatography. By eluting with n-hexane:ethyl acetate (1:1), 2.36 g (89%) of the title compound was obtained as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:21])[CH2:16]3)=[O:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Br:22][C:23]1[CH:24]=[C:25]([C:29](O)=[O:30])[O:26][C:27]=1[Br:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:23]1[CH:24]=[C:25]([C:29]([N:18]2[CH2:19][CH2:20][N:15]([C:13]([C:10]3[N:11]=[CH:12][N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[N:9]=3)=[O:14])[CH2:16][C@@H:17]2[CH3:21])=[O:30])[O:26][C:27]=1[Br:28]
Reactant: O=C(O)c1cc(Br)c(Br)o1
Reactant: C[C@H]1CN(C(=O)c2ncn(-c3cccc(F)c3)n2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(C(=O)c2ncn(-c3cccc(F)c3)n2)CCN1C(=O)c1cc(Br)c(Br)o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 87 mg (0.30 mmol) [1-(3-fluoro-phenyl)-1H-[1,2,4]triazol-3-yl]-((S)-3-methyl-piperazin-1-yl)-methanone, 84 mg (0.30 mmol) 4,5-dibromo-2-furoic acid, 0.11 g (0.33 mmol) TBTU and 80 μL (0.45 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C(O)C>[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[N:16]1[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]1=[O:11]
Reactant: Nc1ccccc1Cl
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccccc2Cl)C1=O
Yield: 71.8 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and 2-chloroaniline (0.464 mL; 4.41 mmol) in ethanol (3 mL). 1-(2-chlorophenyl)-2-oxopyrrolidine-3-carboxylic acid 0.253 g (72%) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](OC2C=CC([N+]([O-])=O)=CC=2)=[O:24])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[NH2:36][CH2:37][CH2:38][C@H:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:40]([OH:42])=[O:41].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([NH:36][CH2:37][CH2:38][C@H:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:40]([OH:42])=[O:41])=[O:24])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Temperature: 75 °C

Procedure:
4.0 g (8.22 mmol) of the compound from example 1A was dissolved in 60 ml dichloromethane. 1.795 (8.22 mmol) (2S)-4-Amino-2-[(tert-butoxycarbonyl)amino]butanoic acid and 1.43 ml (8.22 mmol) N,N-diisopropylethylamine were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 75° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 600 ml silica gel. Solvents used were dichloromethane/ethyl acetate 4/1, dichloromethane/ethyl acetate 1/1, dichloromethane/methanol 4/1 and dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.02 g (6.54 mmol, 80% of theory) of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([CH2:5][N:6]1[C:12]2[CH:13]=[C:14]([N+:19]([O-])=O)[C:15]([O:17][CH3:18])=[CH:16][C:11]=2[CH2:10][N:9]([CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH2:8][C:7]1=[O:28])=[O:4]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]2[CH2:10][N:9]([CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH2:8][C:7](=[O:28])[N:6]([CH2:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:29])[C:12]=2[CH:13]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(CC(=O)N(C)C)C(=O)CN(CC(=O)N(C)C)C2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)N(CC(=O)N(C)C)C(=O)CN(CC(=O)N(C)C)C2
Yield: 100.2 %

Procedure:
A solution of 2-(1-dimethylcarbamoylmethyl-7-methoxy-8-nitro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-N,N-dimethyl-acetamide (150 mg, 0.37 mmol) in ethyl acetate (25 mL) and ethanol (25 mL) was treated with 10% Pd—C and hydrogenated on a Paar apparatus under 40 psi H2. After 14 hours the mixture was filtered and concentrated to give 2-(8-amino-1-dimethylcarbamoylmethyl-7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-N,N-dimethyl-acetamide (140 mg, 99%) as a pale yellow solid, used without further purification; MS (m/e) 378 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8]C.[CH:23]1(C2C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)=NC(C)=CN=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH:21]2[CH2:22][CH2:23]2)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cnc(C2CC2)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(3-cyclopropyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.95–1.08, 1.69–1.78, 2.49, 3.04, 3.24, 4.78, 5.39, 5.58, 7.24–7.33; MS (ESI+) for C17H18BrN3O m/z 360 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:22]=[CH:21][C:12]3[C:13]([C:17]([NH:19][CH3:20])=[O:18])=[C:14]([CH3:16])[O:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>CN(C=O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:28][C:2]2[N:7]=[C:6]([O:8][C:9]3[CH:22]=[CH:21][C:12]4[C:13]([C:17]([NH:19][CH3:20])=[O:18])=[C:14]([CH3:16])[O:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc(N)c1
Reactant: CNC(=O)c1c(C)oc2cc(Oc3ccnc(Cl)n3)ccc12
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc(Nc4cccc(OC)c4)n3)ccc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
6-(2-chloropyrimidin-4-yloxy)-N,2-dimethylbenzofuran-3-carboxamide (0.1 mmol) and 3-methoxyaniline (0.1 mmol) were dissolved in 0.5 ml DMF. To this was added p-TsOH monohydrate (0.2 mmol). The reaction mixture was stirred at 60° C. for 5 hours, and subjected to extraction with ethyl acetate. Then water was added and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by column chromatography to provide the title product in a yield of 80%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[C:8]([O:12][C:13](ON1C(=O)C2=CC=CC=C2C1=O)=[O:14])([CH3:11])([CH3:10])[CH3:9]>ClCCl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:7]1
Reactant: CC(C)(C)OC(=O)ON1C(=O)c2ccccc2C1=O
Reactant: C[C@H]1CNCCN1
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1

Procedure:
A solution of (2S)-2-methylpiperazine (3.8 g, 38 mmol) and N-(tert-butyloxycarbonyloxy)phthalimide (10 g, 38 mmol) in dichloromethane (100 mL) was stirred at room temperature for 3 hours. The mixture was washed with 2N sodium hydroxide solution, the organic solution dried over magnesium sulphate, and concentrated in vacuo to afford the title compound as a clear oil, 4.31 g.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9](N)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:14].[K+].[K+].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(Cl)Cl>O.S(=O)(=O)(O)O>[CH:7]1[C:8]2[C:9](=[O:14])[CH:10]=[CH:11][C:2](=[O:1])[C:3]=2[CH:4]=[CH:5][N:6]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: Nc1ccc(O)c2ccncc12
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C1C=CC(=O)c2cnccc21

Procedure:
Nineteen grams of 5-hydroxy-8-amino-isoquinoline were dissolved in 450 ml of water and 10 ml of concentrated sulfuric acid. The solution was cooled in an ice bath and then 50 ml of a potassium dichromate solution were added. (The dichromate solution was made by dissolving 50 g of potassium dichromate in 500 ml of water.) Forty ml of concentrated sulfuric acid were added, followed by 190 ml of the potassium dichromate solution, then 20 ml of concentrated sulfuric acid, and finally 400 ml of methylene chloride.