Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C([O:7][C:8]([C:10]1[C:11]2[S:19][CH:18]=[C:17]([CH2:20][O:21][C:22]3[CH:27]=[C:26]([C:28]4[N:32]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[C:31]([CH3:42])=[N:30][N:29]=4)[CH:25]=[CH:24][C:23]=3[CH3:43])[C:12]=2[C:13]([NH2:16])=[N:14][CH:15]=1)=O)C>CS(C)=O.O>[OH:2][CH2:1][CH2:3][NH:4][C:8]([C:10]1[C:11]2[S:19][CH:18]=[C:17]([CH2:20][O:21][C:22]3[CH:27]=[C:26]([C:28]4[N:32]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[C:31]([CH3:42])=[N:30][N:29]=4)[CH:25]=[CH:24][C:23]=3[CH3:43])[C:12]=2[C:13]([NH2:16])=[N:14][CH:15]=1)=[O:7]
Reactant: NCCO
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(C)n4Cc4ccc(OC)cc4)ccc3C)csc12
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Cn2c(C)nnc2-c2ccc(C)c(OCc3csc4c(C(=O)NCCO)cnc(N)c34)c2)cc1
Temperature: 135 °C

Procedure:
Ethanolamine (1.8 mL; 29.9 mmol) (Aldrich) was added to a solution of 4-amino-3-{5-[4-(4-methoxy-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (50 mg; 0.08277 mmole) (from Example 59 supra) in dimethylsulfoxide (0.6 mL). The mixture was heated in a microwave reactor at 135° C. for 2.25 hours. After cooling to room temperature, the reaction mixture was diluted with water, resulting in precipitation of the product as a milky solid which was collected by centrifugation and dried. The crude solid was triturated with hot methanol, cooled slightly, filtered and dried, to give 4-amino-3-{5-[4-(4-methoxy-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide in two crops. (Yield 31.2 mg, 51.3%). HRMS (ES+) m/z Calcd for C29H30N6O4S+H [(M+H)+]: 559.2122. Found: 559.2120.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N+:9]([O-:32])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cncnc1-2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][N+]1=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2ncncc2C1

Procedure:
A solution of 6.8 g (20 mmole) of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine, 6 g (30 mmole) of 85% m-chloroperbenzoic acid in 200 ml of methylene chloride was stirred at room temperature for 4 hrs. The mixture was washed with an excess of ice cold dilute sodium hydroxide, dried over ahydrous sodium sulfate and filtered over hyflo. The filtrate was concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of methylene chloride and ether to give a crude product, mp 228°-229° C. Recrystallization from a mixture of methylene chloride and ether gave the product, mp 216°-217° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:3][CH2:2]1.[N+:17]([O-])([OH:19])=[O:18]>CCOC(C)=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=[CH:8][C:7]=2[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)Nc1ccccc1OCC1CC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1OCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
N-(2-(cyclopropylmethoxy)phenyl)methanesulfonamide (1.3 g, 5.39 mmol) was cooled to 0° C., and nitric acid (0.746 ml, 10.77 mmol) was added. The mixture was stirred at RT for 1 hour. The mixture was diluted with EtOAc and washed with NaHCO3 5% and brine. The organic phase was dried over Na2SO4, and the solvent was removed. The crude was purified by flash chromatography on silica gel cartridge (petroleum ether:EtOAc=80:20 to 60:40). 0.390 g of title product were obtained by collection and evaporation of clean fractions. Product obtained from mixed fractions was triturated with EtOAc affording 0.285 g of title compound. The mother liquor from trituration was evaporated and purified by flash chromatography on silica gel (DCM:petroleum ether=80:20) to give 0.155 g of title compound. Title product N-(2-(cyclopropylmethoxy)-4-nitrophenyl)-methanesulfonamide was obtained (0.830 g, 2.90 mmol, 53.8% yield, MS/ESI+ 286.9 [MH]+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5]([Br:11])=[C:4]([Br:12])[C:3]=1[Br:13].[H-].[Na+].C[O:17][C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>CN(C=O)C>[Br:11][C:5]1[C:6]2[N:7]=[CH:8][N:9]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([OH:27])=[O:17])[C:10]=2[C:2]([Br:1])=[C:3]([Br:13])[C:4]=1[Br:12]
Reactant: Brc1c(Br)c(Br)c2[nH]cnc2c1Br
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCn1cnc2c(Br)c(Br)c(Br)c(Br)c21
Reaction time: 48 h
Yield: 63.4 %

Procedure:
4,5,6,7-tetrabromo-1H-benzimidazole (115 mg, 0.26 mmol) and NaH suspension (12 mg, ˜0.28 mmol) were stirred in DMF for 30 min and then 8-bromooctanoic acid methyl ester (182 mg, 0.77 mmol) was added. The solution was stirred for 2 days and then evaporated to dryness. The residue was purified by flash chromatography (CHCl3: methanol; 20:1 by volume). The methyl ester was hydrolyzed in the mixture of methanol and aqueous KOH for 1 hour and the solvents were removed in vacuum. The obtained residue was partitioned between ethyl acetate and KHSO4, the organic layer was dried and evaporated to yield 8-(4,5,6,7-tetrabromo-1H-benzimidazole-1-yl)octanoic acid (95 mg, 62% over two steps). 1H NMR (200 MHz; DMSO6d; Me4Si) 1.28 (m, 6H), 1.48 (m, 2H), 1.76 (m, 2H), 2.19 (t, J=7.3 Hz, 2H), 4.48 (t, J=7.6 Hz, 2H), 8.51 (s, 1H), 11.91 (br, 1H). 13C NMR (50 MHz; DMSO6d; Me4Si) 24.3, 25.5, 28.1, 28.3, 31.5, 33.6, 46.4, 106.5, 116.6, 120.4, 122.3, 131.3, 143.7, 148.9, 174.4. B. Synthesis of TBBI-OcA-(D-Asp)-(L-Asp)5-(L-Lys)-OH
Reaction SMILES: [OH-].[K+].[C:3]1([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][CH2:24][CH2:25][CH3:26]>CS(C)=O>[CH2:23]([N:10]1[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:13]=[C:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCBr
Reactant: COc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCn1cc(-c2ccc(OC)cc2)nc1-c1ccccc1
Temperature: 0 °C

Procedure:
Potassium hydroxide (4.36, 76 mmol, 1.3 eq.) is suspended in 40 ml of anhydrous DMSO, to the suspension is added a solution 2-phenyl-4-(4-methoxyphenyl)imidazole (15.02, 60 mmol) and bromobutane (8.63 g, 63 mmol, 1.05 eq.) in 80 ml of DMSO at room temperature over 2h, the resulting mixture is stirred over 24h, and then poured into 400 ml of ice-water, extracted with ethyl acetate (100 ml×4), washed,with water and brine, dried over anhydrous sodium sulfate. The solvent is evaporated and the product is purified through flash chromatography to give 16.73 g of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazole. MS (+VE) m/z 307 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:27]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][N:25]=[CH:24][N:23]=4)[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:27]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][N:25]=[CH:24][N:23]=4)[C:17]([C:32]([F:35])([F:33])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1cncnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncncc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.7 %

Procedure:
To a suspension of 2-(4-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyrimidin-5-yl)acetamide (29) (0.029 g, 0.060 mmol) in anhydrous methanol (2 mL) was added a 37% aq. solution of formaldehyde (0.018 mL, 0.24 mmol) under an atmosphere of nitrogen, followed by sodium triacetoxyborohydride (0.063 g, 0.30 mmol). The reaction was stirred at room temperature for 2.5 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (50 mL) and sat. aq. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL), the combined organic layers were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice. The resulting off-white solid was suspended in DCM (5 mL) and cyclohexane was added (˜10 mL). The suspension was sonicated and the product was collected by filtration. The solid was washed with petroleum benzine 40-60° C. (5×10 mL), air-dried and subsequently dried under high-vacuum to give the title compound (30) (0.017 g, 57% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.01 (s, 1H), 8.94 (s, 1H), 8.63 (s, 1H), 8.53 (s, 1H), 7.64 (s, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 7.11 (s, 1H), 3.57 (s, 2H), 3.28-3.22 (m, 4H), 2.87 (d, J=11.2 Hz, 2H), 2.46-2.36 (m, 1H), 2.20 (s, 3H), 1.98 (t, J=10.6 Hz, 2H), 1.76-1.58 (m, 4H). LCMS Method C: it 4.52 min; m/z 500.1 [M+H]+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21]1([C:29](OCC)=[O:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22]1.[Cl-].[NH4+]>CCOCC>[CH2:27]([O:26][C:24]([C:21]1([C:29](=[O:30])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:23][CH2:22]1)=[O:25])[CH3:28]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CCOC(=O)C1(C(=O)CC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
A solution of n-butyllithium (2.5M in hexane, 40 ml) was added dropwise with stirring to a cooled solution of diisopropylamine (10.1 g) in anhydrous ether (100 ml) in an atmosphere of nitrogen, whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 0.5 hour and a solution of t-butyl acetate (11.6 g) in anhydrous ether (20 ml) was added dropwise, whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 1 hour and a solution of diethyl cyclopropane-1,1-dicarboxylate (18.6 g) in anhydrous ether (20 ml) was added dropwise whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 0.5 hour and the temperature was allowed to rise to room temperature. A saturated solution of ammonium chloride (150 ml) was added cautiously and the layers were separated. The organic extract was washed with water (2×50 ml) hydrochloric acid (2M, 2×50 ml) and water (2×50 ml). The solution was dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give t-butyl 3-(1-ethoxycarbonylcyclopropyl)-3-oxopropionate (11.66 g) as a clear oil bp 89°-90° C./0.5 mmHg.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20].CN(C)C=O.[N-:26]=[N+:27]=[N-:28].[Na+]>C1(C)C=CC=CC=1>[N:26]([C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCN1CC(C)=C(N=[N+]=[N-])C2=C1N1CN(OC)C=C1C=N2
Temperature: 60 °C
Reaction time: 5 h

Procedure:
1.5 g of intermediate A1 are stirred into 10 ml N,N-dimethylformamide. 1 g NaN3 is added at room temperature. The mixture is heated up to 60° C. and stirred for 5 hours. 100 ml toluol are added. The organic layer is separated and washed with 3×30 ml water. 90 ml of the solvent are removed. The reaction product precipitates. The crude product is purified by crystallisation from toluol.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[C:4]([C:9]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20]C)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[C:24]1C(OC)=C(C(CBr)=CC=1)C(OC)=O.SC1C=CC=CC=1O>>[Br:1][C:2]1[C:3]([O:22][CH3:24])=[C:4]([C:9]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Reactant: COC(=O)c1c(CSc2ccccc2OC)ccc(Br)c1O
Agent: Oc1ccccc1S
Product: COC(=O)c1c(CSc2ccccc2O)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 82, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 2-mercaptophenol and used without further characterization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([S:8]([N:11]([CH3:29])[N:12]=[CH:13][C:14]2[N:18]3[CH:19]=[C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)(=[O:10])=[O:9])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:36].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([S:8]([N:11]([CH3:29])[N:12]=[CH:13][C:14]2[N:18]3[CH:19]=[C:20]([C:23]4[CH:24]=[N+:25]([O-:36])[CH:26]=[CH:27][CH:28]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(F)cc1S(=O)(=O)N(C)N=Cc1cnc2ccc(-c3cccnc3)cn12
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(F)cc1S(=O)(=O)N(C)N=Cc1cnc2ccc(-c3ccc[n+]([O-])c3)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To an ice-cooled solution of 5-fluoro-N, 2-dimethyl-N′-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide (step 1, 18 mg, 0.043 mmol) in CH2Cl2 was added 3-chloroperoxybenzoic acid (14.46 mg, 0.065 mmol). The reaction mixture was stirred for 3 h at RT. The reaction mixture was then poured on to water. Organic layer was separated, washed with saturated solution of NaHCO3 and dried over Na2SO4. Crude compound was purified by column chromatography (silica gel, 5% EtOAc in petroleum ether) to obtain the title compound. Yield: 64%; 1H NMR (DMSO-d6; 300 MHz,): δ 9.45 (s, 1H), 8.57 (s, 1H), 8.32-8.31 (m, 2H), 8.03 (s, 1H), 7.83-7.79 (m, 2H), 7.67-7.64 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.56 (m, 1H), 7.43-7.36 (m, 3H), 3.40 (s, 3H), 2.54 (s, 3H); MS: m/z 440 (M+1)+.
Reaction SMILES: CS(O[C@@H:6]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH2:7][CH2:8][C@@H:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[C:33]([C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>CC1CCCO1.Cl>[C:33]([C:37]1[CH:38]=[CH:39][C:40]([N:41]2[C@H:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[CH2:8][CH2:7][C@H:6]2[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:42][CH:43]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CS(=O)(=O)O[C@H](CC[C@@H](OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC1CCCO1
Product: CC(C)(C)c1ccc(N2[C@H](c3ccc([N+](=O)[O-])cc3)CC[C@H]2c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To the crude product solution (1R,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate (7.35 g, 13.39 mmol) was added 4-tert-butylaniline (13.4 g, 90 mmol) at 23° C. over 1 minute. The reaction was heated to 65° C. for 2 h. After completion, the reaction mixture was cooled to 23° C. and diluted with 2-methyltetrahydrofuran (100 mL) and 1 M HCl (150 mL). After partitioning the phases, the organic phase was treated with 1 M HCl (140 mL), 2-methyltetrahydrofuran (50 mL), and 25 wt % aq. NaCl (100 mL), and the phases were partitioned. The organic phase was washed with 25 wt % aq. NaCl (50 mL), dried over MgSO4, filtered, and concentrated in vacuo to approximately 20 mL. Heptane (30 mL) and additional 2-methyltetrahydrofuran were added in order to induce crystallization. The slurry was concentrated further, and additional heptane (40 mL) was slowly added and the slurry was filtered, washing with 2-methyltetrahydrofuran:heptane (1:4, 20 mL). The solids were suspended in MeOH (46 mL) for 3 h, filtered, and the wet solid was washed with additional MeOH (18 mL). The solid was dried at 45° C. in a vacuum oven for 16 h to provide (2S,5S)-1-(4-tert-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine (3.08 g, 51% 2-step yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[CH:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]1=[O:21])=[O:5])[CH3:2].CN(C)C=O.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>O>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[C:8]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]1=[O:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)N(C(=O)OCC)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1C(=O)C(CC(=O)OC(C)(C)C)(C(=O)OCC)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl-5-chloro-2-oxoindoline-1,3-dicarboxylate, intermediate 50, (5.0 g, 16.04 mmol) in anhydrous N,N-dimethylformamide (80 ml) 1,8-diazabicyclo[5.4.0]undec-7-ene (2.63 ml, 17.64 mmol) was added dropwise at ambient temperature at such a rate that the internal temperature remained below 30° C. After continuous stirring at ambient temperature for one hour the solution was treated with tert-butyl bromoacetate (2.73 ml, 18.45 mmol) and stirring was allowed to continue for 72 h. Water (100 ml) was added, the product was extracted with tert-butyl methyl ether (2×50 ml), the combined extracts were washed with brine (50 ml) and dried (MgSO4) to give a red solid (7.11 g). Purification by flash chromatography (n-heptane/ethyl acetate=15%; increased up to 20%) yielded the title compound (4.00 g, 59%) as colorless solid (HPLC purity: 99%).MS (ESI+): 426.3
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][CH:11]1[CH2:14][CH:13]([C:15]2[C:20](Cl)=[N:19][N:18]3[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])=[N:23][N:24]=[C:17]3[CH:16]=2)[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1.O>[CH2:3]([O:10][CH:11]1[CH2:14][CH:13]([C:15]2[C:20](=[O:1])[NH:19][N:18]3[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])=[N:23][N:24]=[C:17]3[CH:16]=2)[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Fc1ccccc1-c1nnc2cc(C3CC(OCc4ccccc4)C3)c(Cl)nn12
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]n2c(-c3ccccc3F)nnc2cc1C1CC(OCc2ccccc2)C1

Procedure:
4N Sodium hydroxide (3 ml, 12 mmol) was added to a solution of 7-(3-benzyloxycyclobutyl)-6-chloro-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (0.98 g, 2.4 mmol) in 1,4-dioxane (30 ml) and water (8 ml), heated to reflux for 18 hours. The solvent was evaporated and the residue dissolved in diethyl ether (50 ml) and water (50 ml) and separated. The aqueous layer was acidified to pH 2 with 2N hydrochloric acid and the resultant solid collected by filtration, washed with water (50 ml), followed by diethyl ether (50 ml) and dried under vacuum at 100° C. for 18 hours. Data for the title compound: 1H NMR (400 MHz, CDCl3), cis and trans isomers present in 4:1 ratio, δ 1.95-2.03 (1.6H, m), 2.31-2.38 (0.4H, m), 2.50-2.56 (0.4H, m), 2.68-2.76 (1.6, m), 3.05-3.13 (1H, m), 3.65-3.73 (0.2H, m), 4.06-4.15 (0.8H, m), 4.46 (2H, s), 6.80-6.87 (2H, m), 7.22-7.37 (6H, m), 7.55-7.61 (1H, m), 7.63 (0.8H, m), 7.68 (0.2H, s); MS (ES+) m/e 391 [MH]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7].[O:21]1[C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=[N:22]1.C(N(CC)CC)C>ClCCl>[CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:26]([C:25]3[O:21][N:22]=[CH:23][CH:24]=3)=[O:27])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccno1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccno3)CC2)nn1

Procedure:
To a stirred solution of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide (277 mg, 1 mmol) in dichloromethane (15 mL) was added isoxazole-5-carbonyl chloride (1.0 mmol) as a dichloromethane solution in the presence of triethylamine (0.4 mL) at ambient temperature. After 1 hour the mixture was evaporated and the residue was subjected to column chromatography. Final product was isolated as a solid (0.107 g, yield 29%). 1H NMR (300 MHz, CDCl3) δ 8.34, 8.05, 7.83, 7.00, 6.86, 3.90-3.84, 3.51-3.45, 1.75-1.62, 1.53-1.46, 0.92. MS (ES+) m/z 373.3 (M+1).
Reaction SMILES: [S:1]1[C:5]([CH2:6][OH:7])=[CH:4][N:3]=[CH:2]1.[C:8]([Si:12](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:11])([CH3:10])[CH3:9].N1C=CN=C1.O>ClCCl>[C:8]([Si:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: OCc1cncs1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cncs1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2.12 g of 1,3-thiazol-5-ylmethanol in 48 ml of dichloromethane were added 5.2 ml of tert-butyl (chloro)diphenylsilane and 2.5 g of imidazole at 0° C., followed by stirring at room temperature for 15 hours. To the reaction mixture was added water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6.47 g of 5-({[tert-butyl (diphenyl)silyl]oxy}methyl)-1,3-thiazole.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@:7]12[CH2:13][CH:12]([CH3:14])[CH:11]1[CH2:10][N:9]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:8]2)=[O:6].Cl>O1CCCC1.CO>[CH2:18]([O:17][C:15]([N:9]1[CH2:10][CH:11]2[C@:7]([C:5]([OH:6])=[O:4])([CH2:13][CH:12]2[CH3:14])[CH2:8]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@]12CC(C)C1CN(C(=O)OCc1ccccc1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1C[C@]2(C(=O)O)CN(C(=O)OCc3ccccc3)CC12
Reaction time: 0.5 h

Procedure:
A 1N sodium hydroxide solution (23 mL) was added dropwise to a mixed solution of (R)-6-methyl-3-azabicyclo[3.2.0]heptane-1,3-dicarboxylic acid 3-benzyl ester 1-methyl ester (3.5 g, 11.5 mmol) in tetrahydrofuran (60 mL) and methanol (20 mL) under ice-cooling, and the mixture was stirred for 30 minutes. The reaction solution was neutralized with 1N hydrochloric acid, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure to give 3.4 g (quantitative) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.