Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[NH:26][C:25](=[O:39])[CH2:24]2>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13](/[CH:16]=[C:24]3\[C:25](=[O:39])[NH:26][C:27]4[C:23]\3=[CH:22][C:21]([F:20])=[C:29]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:28]=4)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Reactant: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Product: Cc1c(/C=C2\C(=O)Nc3cc(NCc4ccc(F)cc4)c(F)cc32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 43.7 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one 3e obtained from step 4 of Example 3 were used as starting materials to obtain (Z)-5-(2-dimethylamino-ethyl)-2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 43 (50 mg, yield 43.7%) as a red solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](Cl)=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:10]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Product: Nc1ccc(F)cc1F

Procedure:
hydrogenating the 2,4-difluoro-5-chloronitrobenzene with hydrogen in the presence of a hydrogenation catalyst to form 2,4-difluoroaniline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:18]2[N:23]=[C:22]([C:24]3[CH:50]=[CH:49][CH:48]=[CH:47][C:25]=3[O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH:39]=4)=[CH:30][CH:29]=3)[CH:21]=[CH:20][CH:19]=2)[C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[H][H]>CCOC(C)=O.[Pt](=O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:18]2[N:23]=[C:22]([C:24]3[CH:50]=[CH:49][CH:48]=[CH:47][C:25]=3[O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH:34]4[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])[CH2:38][CH2:39]4)=[CH:30][CH:29]=3)[CH:21]=[CH:20][CH:19]=2)[C:10]=1[C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)C(F)(F)F
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)C(F)(F)F
Reaction time: 0.33 h

Procedure:
To a degassed solution of the title compound from Example 8 Step E (549 mg, 0.79 mmol) in EtOAc (15 mL) was added platinum(IV) oxide (200 mg). The reaction flask was fitted with a hydrogen balloon attached to a 3-way adapter. The reaction mixture was then evacuated and back-filled with hydrogen. After this process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere, and was stirred vigorously. After 20 min, the reaction mixture was filtered though Celite, rinsing with EtOAc. The filtrate was then concentrated in vacuo. Purification by chromatography on silica gel (0 to 40% EtOAc in hexanes, then 40 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 700.8 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.21 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.86-7.82 (m, 2H), 7.38-7.35 (m, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.09-7.06 (m, 2H), 5.12 (s, 2H), 4.37 (q, J=7.0 Hz, 2H), 4.29-4.20 (br m, 2H), 2.83-2.76 (br m, 2H), 2.68-2.63 (m, 1H), 1.84-1.81 (m, 2H), 1.49 (s, 9H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[OH:24][CH:25]1[CH2:30][CH2:29][N:28]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:27][CH2:26]1
Reactant: OC1CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC(O)CC2)cn1
Yield: 73 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.50 mmol) was converted, using 4-hydroxypiperidine instead of methylamine, to the title compound (145 mg, 73%) which was obtained as a white solid. MS: m/e=394.2 [M+H]+.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[F:6][C:7]([F:18])([F:17])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.[H-].[Na+]>CN(C=O)C>[F:6][C:7]([F:17])([F:18])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][O:5][CH2:4][CH:2]2[CH2:1][O:3]2)=[CH:11][CH:10]=1
Reactant: OCC1CO1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(COCC2CO2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 61.6 %

Procedure:
A mixture of glycidol (115) (303 mg, 4.09 mmol) and 4-(trifluoromethoxy)benzyl bromide (0.810 mL, 5.06 mmol) in anhydrous DMF (6 mL) under N2 at 0° C. was treated with 60% NaH (246 mg, 6.15 mmol), then quickly degassed and resealed under N2. After stirring at room temperature for 7 h, the mixture was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (20 mL), added to water (100 mL) and extracted with EtOAc (4×100 mL). The extracts were washed with brine (100 mL) and evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-5% Et2O/petroleum ether firstly gave foreruns, and then further elution with 5-10% Et2O/petroleum ether gave 2-({[4-(trifluoromethoxy)benzyl]oxy}methyl)oxirane (116) (625 mg, 62%) as an oil; 1H NMR (CDCl3) δ 7.38 (dt, J=8.7, 2.3 Hz, 2H), 7.20 (br dd, J=8.7, 0.7 Hz, 2H), 4.62 (d, J=12.0 Hz, 1H), 4.56 (d, J=12.0 Hz, 1H), 3.82 (dd, J=11.5, 2.8 Hz, 1H), 3.43 (dd, J=11.5, 6.0 Hz, 1H), 3.21 (m, 1H), 2.82 (dd, J=4.9, 4.2 Hz, 1H), 2.63 (dd, J=5.0, 2.7 Hz, 1H); HRESIMS calcd for C11H11F3NaO3 m/z [M+Na]+ 271.0552. found 271.0557.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.Br[CH2:23][CH2:24][CH2:25][OH:26].C1CN2C(=NCCC2)C1.C(#N)C>ClCCl>[NH2:20][S:17]([C:11]1[C:10]([Cl:21])=[CH:9][C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)=[C:13]([CH:12]=1)[C:14]([O:16][CH2:23][CH2:24][CH2:25][OH:26])=[O:15])(=[O:19])=[O:18]
Reactant: OCCCBr
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: C1CN=C2CCCN2C1
Solvent: ClCCl
Solvent: CC#N
Product: NS(=O)(=O)c1cc(C(=O)OCCCO)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid), (10) (Aldrich) (0.060 mole), 3-bromo-1-propanol (Aldrich) (0.055 mole), DBN (1,5-diazabicyclo[4.3.0]non-5-ene, (Aldrich) (0.060 mole) and dry acetonitrile (100 mL) is stirred at ambient temperature for 10 hours. The reaction mixture is diluted with dichloromethane (200 mL) and extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give 3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propanol (805). See eg., T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, p. 228 (1991).
Reaction SMILES: C[O-].[Na+].[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:18]([CH2:32][C:33]3[O:34][CH:35]=[C:36]([CH3:38])[N:37]=3)[C:19]#[C:20][C:21]3[CH:22]=[N:23][C:24]([NH:27]C(=O)CC)=[N:25][CH:26]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5]1.O>CO>[NH2:27][C:24]1[N:23]=[CH:22][C:21]([C:20]#[C:19][CH:18]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][CH:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:11]=2)[CH2:32][C:33]2[O:34][CH:35]=[C:36]([CH3:38])[N:37]=2)=[CH:26][N:25]=1
Reactant: CCC(=O)Nc1ncc(C#CC(Cc2nc(C)co2)c2ccc(OC)c(OC3CCCC3)c2)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(C#Cc2cnc(N)nc2)Cc2nc(C)co2)cc1OC1CCCC1
Yield: 64 %

Procedure:
To a suspension of sodium methoxide (0.12 g, 2.2 mmol) in methanol (20 mL) was added (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)4(4-methyloxazol-2-yl)-1-(2-propionamidopyrimidin-5-yl)but-1-yne (0.29 g, 0.60 mmol). The mixture was heated at reflux for 1 h (forming a solution) and was cooled. Water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and the solvent was evaporated and gave the titled compound (64%) as an off-white solid, mp 103-105° C. Anal (C24H26N4O3 ·0.6 H2O) calcd: C, 67.15, H, 6.39, N, 13.05; C, 67.07, H, 6.22, N, 12.67.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[C:16]([NH:22][C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[CH3:31])=[N:17][C:18]([CH3:21])=[N:19][CH:20]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.C[N+]1([O-])CCOCC1>CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O.C(Cl)Cl>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2[C:16]([NH:22][C:23]3[C:24]([CH3:31])=[CH:25][C:26]([CH3:30])=[CH:27][C:28]=3[CH3:29])=[N:17][C:18]([CH3:21])=[N:19][CH:20]=2)(=[O:13])=[O:14])=[CH:10][CH:11]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(C3=NCCN3)cc2)c(C)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(-c3ncc[nH]3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
A mixture of {5-[4-(4,5-dihydro-1H-imidazol-2-yl)-benzenesulfonyl]-2-methyl-pyrimidin-4-yl}-(2,4,6-trimethyl-phenyl)-amine (14 mg, 0.032 mmol), prepared by the method described in Example 29, NMO (5.6 mg, 0.048 mmol), TPAP (2.2 mg, 0.006 mmol), 4 Å molecular sieves (100 mg) and CH2Cl2 (2 mL) was stirred under N2 at room temperature for 10 min, and then filtered through a pad of silica gel. The filtrate was concentrated in vacuo, and the residue was purified by chromatography on silica gel (EtOAc) to provide the target compound (5 mg, 36%) as a white solid: mp 282–284° C.; 1H NMR (500 MHz, CDCl3) δ 9.54 (br s, 1H), 8.78 (s, 1H), 8.27 (br s, 1H), 8.02 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.5 Hz, 2H), 7.28 (s, 1H), 7.18 (s, 1H), 6.91 (s, 2H), 2.40 (s, 3H), 2.30 (s, 3H), 2.02 (s, 6H); ESI MS m/z 434 [(M+H)+, calcd for C23H24N5O2S, 434.2].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[OH:12][C:13]1[C:19]([Br:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:14]=1[NH2:15].C(N1C=CN=C1)(N1C=CN=C1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:15][C:14]2[CH:16]=[C:17]([Cl:21])[CH:18]=[C:19]([Br:20])[C:13]=2[OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)cc(Br)c1O
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(Cc1cccc(Cl)c1)Nc1cc(Cl)cc(Br)c1O
Yield: 67.5 %

Procedure:
Using the normal amide forming conditions, the condensation of 3-chlorophenylacetic acid (13.54 g, 0.079 mol) and 2-hydroxy-3-bromo-5-chloroaniline (17.7 g, 0.079 mol) with 1,1′-carbonyl diimidazole (13.5 g, 0.083 mol) gave the title compound (20 g).
Reaction SMILES: [Br:1][C:2]([F:16])([F:15])[C:3]#[C:4][Si](C(C)C)(C(C)C)C(C)C.[CH3:17][C:18]([CH3:22])([CH3:21])[CH:19]=[O:20]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Br:1][C:2]([F:15])([F:16])[C:3]#[C:4][CH:19]([OH:20])[C:18]([CH3:22])([CH3:21])[CH3:17]
Reactant: CC(C)[Si](C#CC(F)(F)Br)(C(C)C)C(C)C
Reactant: CC(C)(C)C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)C(O)C#CC(F)(F)Br
Reaction time: 0.5 h

Procedure:
To a solution of (3-bromo-3,3-difluoro-prop-1-ynyl)-triisopropyl-silane (156 mg, 0.5 mmol) and 2,2-dimethyl-propionaldehyde (52 mg, 0.6 mmol) in THF (5 mL), TBAF (1M, 0.75 mL) was added dropwise at −90° C. After the addition was completed, the reaction mixture was stirred for 0.5 hour and quenched saturated aq. NH4Cl. The mixture was extracted with ether (20 mL×3) and washed with water (20 mL×2). After drying over Na2SO4 the solvent was removed and the product was purified by silica gel chromatography (AcOEt:hexane=1:20) to afford the title compound as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 4.08-4.09 (m, 1H), 1.83 (d, J=6.0 Hz, 1H), 0.965 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: Oc1cccnc1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cncc(Oc2cccnc2)n1
Temperature: 150 °C
Yield: 93.5 %

Procedure:
2,6-Dichloropyrazine (1.0 g, 6.7 mmol, 1.0 eq), 3-hydroxypyridine (638 mg, 6.71 mmol, 1.00 eq) and K2CO3 (1.11 g, 8.03 mmol, 1.20 eq) were dissolved in DMF (10 mL) and heated in a microwave for 15 minutes at 150° C. The reaction was cooled, diluted with EtOAc and washed with H2O (3×). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 1.3 g (93%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=2.3 Hz, 1H), 8.56 (d, J=4.4 Hz, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 7.71 (dq, J=8.4, 1.3 Hz, 1H), 7.51 (dd, J=8.4, 4.9 Hz, 1H); ES-MS [M+1]+: 208.1.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:36]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:41][CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: NC1CCCC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNC2CCCC2)no1
Yield: 53 %

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and cyclopentylamine (170 mg, 1.98 mmol) as starting materials to afford the title compound as a colourless oil (220 mg).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].N([C:15]1[NH:16][CH2:17][CH2:18][N:19]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>CC(C)=O>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH:4][C:15]1[NH:19][CH2:18][CH2:17][N:16]=1
Reactant: NCC(O)c1ccccc1
Reactant: O=[N+]([O-])NC1=NCCN1
Solvent: CC(C)=O
Solvent: Cc1ccccc1C
Product: OC(CNC1=NCCN1)c1ccccc1
Temperature: 160 °C

Procedure:
A mixture of 15.8 parts β-hydroxy-phenethyl-amine, 13 parts 2-nitramino-2-imidazoline and 8 parts xylene is stirred and heated for 30 minutes at 160°C. (oil-bath). After cooling the reaction mixture to a temperature of about 70°C., there are added 40 parts acetone. The whole is filtered warm and after cooling the filtrate to room temperature, the precipicated product is filtered off and dried, yielding 2-(β-hydroxy-phenethyl-amino)-2-imidazoline; m.p. 147°-149°C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[CH2:4][CH2:3]1>CO.[Pd]>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][N:2]2[CH3:1])=[CH:6][CH:7]=1
Reactant: CN1CCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CN1CCc2ccc(N)cc21
Yield: 82.8 %

Procedure:
1-Methyl-6-nitroindoline (0.9 g) was hydrogenated at 40 psi in methanol (100 ml) containing 10% palladium on carbon (0.9 g). The reaction mixture was filtered then evaporated and the residue was purified by column chromatography on silica using hexane→50% ethyl acetate/hexane to afford the title compound (0.62 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[C:17]#[N:18])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2].[H][H]>C(OC(=O)C)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:15][CH:16]([P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[C:17]#[N:18])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOP(=O)(OCC)C(C#N)=Cc1ccc(OC(C)=O)c(OC(C)=O)c1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CCOP(=O)(OCC)C(C#N)Cc1ccc(OC(C)=O)c(OC(C)=O)c1

Procedure:
3-(3,4-Diacetoxyphenyl)-2-(diethoxyphosphinyl) acrylonitrile (Table 1, No. 56; 2.5 g; 0.0066 mol) was hydrogenated in 100 ml of acetic anhydride over 0.5 g of 10 percent Pd/C catalyst in a Parr hydrogenation apparatus under an initial pressure of 3.45 bar until hydrogen uptake was complete (16 hours), adding an additional 0.3 g of catalyst after 8 hours had elapsed. Finally, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was chromatographed on silica gel, eluted with the solvent mixture dichloromethane:ethyl acetate (7:3). This results in the title compound as a pale oil in a yield of 1.7 g (67.7% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[C:14]([N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=1)(=[O:10])=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[C:14]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=1)(=[O:9])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(NS(=O)(=O)c3ccccc3Cl)cc3ccoc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(N2CCNCC2)c2occc2c1)c1ccccc1Cl
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
tert-Butyl 4-(5-{[(2-chlorophenyl)sulfonyl]amino}-1-benzofuran-7-yl)piperazine-1-carboxylate (0.66 g, 1.34 mmol; Intermediate 19) was dissolved in DCM (5 mL) and TFA was added (30% solution of TFA in DCM; 5 mL) and the mixture was stirred for 30 min. The solvents were evaporated. The residue was dissolved in water, pH adjusted to pH 8 and extracted with EtOAc. The organic layer was dried and evaporated to give 0.41 g (80%) of the title product that was used in the next step without further purification. HPLC purity 93%, RT=1.61 min (System A; 10-97% MeCN over 3 min).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[C:21]1[C:22]2[N:23]([C:27]([N:32]([CH2:36][CH:37]3[CH2:39][CH2:38]3)[CH2:33][CH2:34][CH3:35])=[C:28]([S:30][CH3:31])[N:29]=2)[CH:24]=[CH:25][N:26]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[C:21]1[C:22]2[N:23]([C:27]([N:32]([CH2:36][CH:37]3[CH2:39][CH2:38]3)[CH2:33][CH2:34][CH3:35])=[C:28]([S:30]([CH3:31])=[O:9])[N:29]=2)[CH:24]=[CH:25][N:26]=1
Reactant: CCCN(CC1CC1)c1c(SC)nc2c(-c3ccc(OC)cc3Cl)nccn12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(CC1CC1)c1c(S(C)=O)nc2c(-c3ccc(OC)cc3Cl)nccn12
Reaction time: 0.33 h
Yield: 12.2 %

Procedure:
m-chloroperbenzoic acid (148 mg) was added to N-[8-(2-chloro-4-methoxyphenyl)-2-(methylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylmethyl-N-propylamine (166 mg) and dichloromethane (2 mL) at room temperature, and the mixture was stirred for 20 minutes. An aqueous sodium thiosulfate solution and an aqueous sodium bicarbonate solution were added thereto, which was extracted with ethyl acetate and evaporated. The resulting residue was separated and purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (21 mg) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:4][O:3]1.CNN>ClCCl>[CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([O:8][NH2:9])[CH2:4][O:3]1
Reactant: CC1(C)OCC(ON2C(=O)c3ccccc3C2=O)CO1
Agent: CNN
Solvent: ClCCl
Product: CC1(C)OCC(ON)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
To a stirring solution of 2-(2,2-dimethyl-[1,3]dioxan-5-yloxy)-isoindole-1,3-dione (1.72 g, 6.20 mmol) in dichloromethane (15 mL) at 0° C. under nitrogen was added methylhydrazine (0.36 mL, 6.82 mmol) and allowed to warm to room temperature. After stirring for two hours the reaction mixture was concentrated in vacuo and charged with diethylether. The solids were filtered off and the filtrate was collected and concentrated to afford O-(2,2-dimethyl-[1,3]dioxan-5-yl)-hydroxylamine as a yellow oil (0.97 g, 100%). 1H NMR (400 MHz; DMSO-d6) δ 5.98 (bs, 2H), 3.84-3.87 (m, 2H), 3.66-3.68 (m, 2H), 3.30-3.35 (m, 1H), 1.29 (s, 3H), 1.22 (s, 3H); MS (APCI+)=147.9.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]2[O:8][CH2:9][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C)=[O:21])=[CH:15][C:14]=3[CH2:24][CH2:25][CH3:26])[CH2:11][C:6]=2[C:5]=1[OH:29])(=[O:3])[CH3:2].Cl>[OH-].[Na+].C1COCC1>[C:1]([C:4]1[CH:28]=[CH:27][C:7]2[O:8][CH2:9][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=3[CH2:24][CH2:25][CH3:26])[CH2:11][C:6]=2[C:5]=1[OH:29])(=[O:3])[CH3:2]
Reactant: CCCc1cc(CC(=O)OC)ccc1OC1COc2ccc(C(C)=O)c(O)c2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1cc(CC(=O)O)ccc1OC1COc2ccc(C(C)=O)c(O)c2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The compound of Example 10 (25 mg) was dissolved in 1N NaOH (0.2 ml) and THF (1 ml). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was poured into a mixture of ice and dilute HCl and extracted with ethyl acetate. The combined organic extracts were dried and evaporated to yield the title compound which was recrystallized from ether-hexane, m.p. 129°-129.5°.
Reaction SMILES: [C:1]([Si:5]([CH3:27])([CH3:26])[O:6][C@@H:7]([C@H:9]1[C:15](=[O:16])[N:14]2[C@@H:10]1[C@@H:11]([CH3:25])[C:12]([S:23][CH3:24])=[C:13]2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:36])C=1>ClCCl>[Si:5]([O:6][C@@H:7]([C@H:9]1[C:15](=[O:16])[N:14]2[C@@H:10]1[C@@H:11]([CH3:25])[C:12]([S:23]([CH3:24])=[O:36])=[C:13]2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH3:8])([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:27])[CH3:26]
Reactant: C=CCOC(=O)C1=C(SC)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C=CCOC(=O)C1=C(S(C)=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
To a solution of allyl (4R,5S,6S)-6-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-4-methyl-3-methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (66 mg) in dichloromethane (1 ml) cooled to 0° C. was added meta-chloroperbenzoic acid (27.7 mg). The mixture was stirred for 10 minutes at the same temperature, washed with aqueous sodium bicarbonate solution and dried. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give allyl (4R,5S,6S)-6-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-3-methylsulfinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (64 mg).