Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[S:25][C:26]1[S:30][N:29]=[N:28][CH:27]=1)[C@H:20]([NH:31][C:32](=[O:62])[C:33]([C:55]1[N:56]=[C:57]([NH2:61])[S:58][C:59]=1[Cl:60])=[N:34][O:35]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]2=[O:63])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:61][C:57]1[S:58][C:59]([Cl:60])=[C:55]([C:33](=[N:34][OH:35])[C:32]([NH:31][C@@H:20]2[C:19](=[O:63])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([S:25][C:26]2[S:30][N:29]=[N:28][CH:27]=2)=[C:17]3[C:15]([OH:16])=[O:14])=[O:62])[N:56]=1
Reactant: Nc1nc(C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Sc4cnns4)CSC23)c(Cl)s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(C(=NO)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(Sc4cnns4)CSC23)c(Cl)s1

Procedure:
To a solution of (7R)-7-[2-(2-amino-5-chlorothiazol-4-yl)-2-trityloxyiminoacetylamino]-8-oxo-3-([1,2,3]thiadiazol-5-ylsulfanyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (570 mg, 0.61 mmol) in dichloromethane (5 mL) was added triethylsilane (2.5 mL) followed by addition of trifluoroacetic acid (5 mL). After 30 min at 0° C. the reaction mixture was concentrated under vacuum and disopropyl ether was added to the oily residue. The title compound precipitated and was filtered, washed with diisopropyl ether and dried under vacuum (380 mg). The crude product was dissolved in water/1.0 M aqueous sodium bicarbonate. The solution was loaded onto an HP20 column and inorganics were removed by washing the column thoroughly with water. The title compound was isolated by eluting with 4:1 acetonitrile/water mixture, removing acetonitrile under reduced pressure and lyophilizing the residue (145 mg, 43%).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:14][N:15]([CH3:19])[CH2:16][C:17]#[CH:18].C(NC(C)C)(C)C.Br[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1>O1CCOCC1.[Cu]I.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[CH3:14][N:15]([CH3:19])[CH2:16][C:17]#[C:18][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C#CCN(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Solvent: N#Cc1ccccc1
Product: CN(C)CC#Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 89.4 %

Procedure:
Tri-t-butylphosphine (0.25 M in dioxane, 11.9 ml, 3.0 mmol, 0.2 eq.), 3-dimethylamino-1-propyne (2.2 ml, 20.8 mmol, 1.4 eq.), and diisopropylamine (2.7 ml, 19.3 mmol, 1.3 eq.) are added sequentially to a mixture of 4-bromonitrobenzene (3 g, 14.9 mmol), copper (I) iodide (198 mg, 1.0 mmol, 0.07 eq.), and Pd(PhCN)2Cl2 (570 mg, 1.5 mmol, 0.1 eq.) in dioxane (20 ml), under an argon atmosphere. The resulting mixture is stirred for 22 h at RT and concentrated. The residue is dissolved in EE and water and filtered through a pad of celite. The aqueous layer is separated and extracted with EE. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) affords 2.72 g of the title compound as a brown oil: ESI-MS: 205.0 [MH]+; tR=2.51 min (purity: 100%, gradient J); TLC: Rf=0.41 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][OH:10].[F:11][C:12]([F:50])([F:49])[C:13]1[CH:14]=[C:15]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:16][N:17]([C:37]1[NH:41][N:40]=[N:39][N:38]=1)[C@H:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[C:20]2[C:31]([CH3:36])=[C:32]([CH3:35])[CH:33]=[CH:34][C:19]1=2.O>CN(C=O)C.C(OCC)(=O)C>[F:46][C:45]([F:48])([F:47])[C:43]1[CH:42]=[C:15]([CH:14]=[C:13]([C:12]([F:49])([F:11])[F:50])[CH:44]=1)[CH2:16][N:17]([C:37]1[N:38]=[N:39][N:40]([CH2:8][CH2:9][OH:10])[N:41]=1)[C@H:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[C:20]2[C:31]([CH3:36])=[C:32]([CH3:35])[CH:33]=[CH:34][C:19]1=2
Reactant: Cc1ccc2c(c1C)N(C(=O)OC(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1C)N(C(=O)OC(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCO)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
Add potassium carbonate (58 mg, 0.42 mmol) and 2-bromoethanol (0.038 mL, 0.53 mmol) to a solution of (S)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8,9-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 56, Step 5) (120 mg, 0.21 mmol) in DMF (0.4 mL) at room temperature in a tube. Seal the tube and stir the mixture at 50° C. for 3 h. Cool the mixture at room temperature and add water and ethyl acetate. Separate the layers, dry the organic phase over anhydrous Na2SO4, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexane/ethyl acetate, to provide 58 mg (45%) of the title compound. MS (ES+): 615 (M+H).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2]1>[Pd].CO>[CH3:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC1CO1
Agent: [Pd]
Solvent: CO
Product: CCCCCCC(C)O
Temperature: 25 °C

Procedure:
To a 50-ml reaction vessel were added 1,2-epoxyoctane (2.56 g, 20.0 mmol), methanol (18 mL), 10% palladium/carbon containing 50% water (425 mg, Pd: 0.20 mmol) and catalytic amount of an amine subsequently, and then the mixture was vigorously stirred under an atmosphere of hydrogen at 25° C. Twenty to forty hours later, 10% palladium/carbon was removed by filtration and methanol was removed by distillation. The selectivity of thus obtained colorless oil was checked by gas chromatographic analysis. The results obtained by adding a various amines and other additives were respectively shown as follows:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=2[O:8][CH:7]=1.[C:17]([Li])(C)(C)C.IC>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17]
Reactant: [Li]C(C)(C)C
Reactant: COc1ccc2c(C3OCCO3)coc2c1
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(C3OCCO3)c(C)oc2c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
3-(1,3-Dioxolan-2-yl)-6-methoxybenzofuran (0.144 g, 0.65 mmol) was dissolved in THF (5 mL) at −30 to −20° C. To this solution was added dropwise tert-butyllithium (15% in pentane, 0.56 mL, 1.31 mmol). The reaction mixture was continuously stirred at −30° C. for 30 min and then allowed to warm to 0° C. and stir for another 20 min. The reaction mixture was cooled to −30° C. again and iodomethane (0.138 g, 0.98 mmol) was added dropwise. After stirring at −30° C. for another 1 h, it was allowed to warm to room temperature overnight. After the solvent was removed under reduced pressure, the residue was dissolved in EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure to provide 3-[1,3]dioxolan-2-yl-6-methoxy-2-methyl-benzofuran.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]2[O:9][C:8]([CH:10]([OH:21])[C@H:11]([NH2:20])[CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:7][C:6]=2[CH:22]=1.C([NH:31][C@@H:32]([C:44](O)=[O:45])[CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])(OC(C)(C)C)=O>>[C:37]([N:20]([C@@H:11]([CH:10]([C:8]1[O:9][C:5]2[CH:4]=[C:3]([CH3:23])[C:2]([CH3:1])=[CH:22][C:6]=2[N:7]=1)[OH:21])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:44](=[O:45])[C@H:32]([NH2:31])[CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cc2nc(C(O)[C@H](N)CCc3ccccc3)oc2cc1C
Product: Cc1cc2nc(C(O)[C@@H](CCc3ccccc3)N(C(=O)OC(C)(C)C)C(=O)[C@H](N)CCCNC(=O)OC(C)(C)C)oc2cc1C

Procedure:
(1R)-1-[(RS)-(5,6-dimethyl-2-benzoxazolyl)hydroxymethyl]-3-phenylpropylamine (157 mg) is coupled with N,N′-bis-Boc-D-ornithine to afford the title compound (343 mg) as a white solid: 1H NMR (400 MHz, CDCl3, 3:2 mixture of diastereomers) δ 1.39-1.43 (bd, 19H), 1.43-1.64 (m, 4H), 1.83 (m, 1H), 2.38 (m, 6H), 2.61-3.21 (m, 4H), 4.08 (m, 1H), 4.59 (m, 1H), 5.02 (s, 1H), 5.18 (bd, 0.6H, NH), 5.28 (bd, 0.4H, NH), 7.12-7.35 (m, 6H), 7.41 (s, 0.4H), and 7.46 (s, 0.6H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2].Cl[CH2:19]CN1CCCC1.Cl.[H-].[Na+]>CN(C=O)C>[N:3]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:19])=[O:14])=[CH:16][CH:17]=2)[CH2:4][CH2:5][CH2:2][CH2:1]1
Reactant: CCN(CC)CCOc1ccc(C(=O)O)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN2CCCC2)cc1

Procedure:
Compound 23-2 (2 g, 11.8 mmol) and chloroethylpyrrolidine·HCl (Aldrich) (1.8 g, 11.8 mmol) were treated with NaH (0.94 g, 23.6 mmol) in DMF (30 mL) as described for 27-1 to give 27-6 as a clear oil. Rf (10% MeOH/CHCl3 saturated with NH3) 0.4
Reaction SMILES: ClCCl.[C:4]([O:8][C:9](=[O:25])[NH:10][C@H:11]1[CH2:24][C:14]2[NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]#N)=[CH:20][C:21]=3[C:13]=2[CH2:12]1)([CH3:7])([CH3:6])[CH3:5].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=[O:37].[Na+].[Na+]>C(OCC)(=O)C>[C:4]([O:8][C:9](=[O:25])[NH:10][C@H:11]1[CH2:24][C:14]2[NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH:22]=[O:37])=[CH:20][C:21]=3[C:13]=2[CH2:12]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2[nH]c3ccc(C=O)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine dichloromethane (15 ml) and (R)-[7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid tert-butyl ester (2 g, 6.73 mmol) and stir for 10 min under nitrogen at room temperature. Add diisobutylaluminum hydride (1 M solution in methylene chloride, 14.1 ml; 14.1 mmol) dropwise over 15 min. Add ethyl acetate (30 mL) to the reaction mixture and stir at room temperature for 1 h. Add a 20% aqueous solution of sodium tartrate (30 mL) and stir for 1 h at room temperature. Separate the organic layer and extract the aqueous layer with ethyl acetate (2×15 mL). Combine and dry (Na2SO4) organic layers, filter and concentrate to give 2.2 g [(R)-7-formyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid tert-butyl ester. Purify by chromatography on silica gel using methylene chloride/acetone (95/5) to give 1.3 g (64%). MS (m/z): 301 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:34][CH:35]([CH2:38][CH3:39])[CH2:36][NH2:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:37][CH2:36][CH:35]([CH3:34])[CH2:38][CH3:39])=[O:23])(=[O:16])=[O:15])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: CCC(C)CN
Product: CCC(C)CNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM) and 0.023 cm3 of 2-methylbutylamine. 49 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-methylbutyl)benzamide are thus obtained [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): from 0.80 to 0.95 (mt, 6H), from 1.05 to 120 (mt, 1H), 1.41 (mt, 1H), 1.64 (mt, 1H), 2.98 (s, 3H), 3.06 (mt, 1H), 3.19 (mt, 1H), 3.81 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.35 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.87 (broad d, J=8 Hz, 1H), 8.49 (t, J=5.5 Hz, 1H)].
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:34]C(F)(F)S([O-])(=O)=O.ClC1C=CC=C(Cl)[N+]=1F>ClCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][C:22]=3[F:34])[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(O)c1cnc(-c2cc(F)c(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]ethanol (420 mg) in dichloromethane (5 mL) was added 2,6-dichloro-1-fluoropyridinium trifluoromethanesulfonate (410 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give a mixture of the title compound and a positional isomer thereof (35.0 mg). The mixture of the obtained positional isomers was dissolved in hexane-ethanol (850:150, volume ratio, 114 mL), and the solution was subjected to HPLC using TSK GEL SHILICA-60 (20 mmID×250 mL, manufactured by Tosoh Corporation-silica). Using hexane-ethanol (850:150, volume ratio) as a mobile phase, the solution was eluted at flow rate 20 mL/min and at room temperature, and the fraction was separated at retention time 34.5 min, and concentrated. The obtained solid was dissolved in ethyl acetate and the insoluble material was filtered off. The filtration was concentrated to give the title compound (18.1 mg, yield 3%) as a colorless amorphous solid. MS: 505 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:13]2[C:8]([C:9]3([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=32)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][S:2]([C:5]1[N:13]2[C:8]([C:9]3([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=32)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1c2ccc1S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2n1-c1ccccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
To a solution of tert-butyl 1′-methylsulfonylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (200 mg, 0.48 mmol) in dry dichloromethane (1 mL) at 0° C. was added TFA (147 μL, 1.91 mmol). The cooling bath was removed and the mixture was stirred for 1.5 h at 25° C. The mixture was concentrated under reduced pressure and the residue obtained was taken up in dichloromethane (10 ml) and was washed with aqueous saturated NaHCO3 (5 ml). The aqueous phase was extracted twice with dichloromethane (2×10 ml) and the organic phases were combined, dried, filtered and concentrated to yield 1′-methylsulfonylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] as a light yellow foamy solid (150 mg, 99%). ESI-MS m/z calc. 318.1. found 319.3 (M+1)+; Retention time 0.93 minutes (3 min run). 1-(Methylsulfinyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] was also prepared using the procedure described above where only one aliquot of H2O2 was used in Step 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[CH2:10][CH2:11]Cl)=[C:4]([Cl:14])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([Cl:14])[CH:3]=1)[NH:8][C:9](=[O:13])[CH2:10][CH2:11]2
Reactant: O=C(CCCl)Nc1ccc(Br)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2cc(Br)cc(Cl)c2N1
Temperature: 140 °C
Yield: 26.9 %

Procedure:
A flame-dried 500-mL flask equipped with a magnetic stirring bar was charged with N-(4-bromo-2-chloro-phenyl)-3-chloro-propionamide (29.7 g, 0.1 mol) and aluminium chloride (53.3 g, 0.4 mol). In a pre-heated oil bath, the flask was heated at 140° C. for 1 hour. After cooling to room temperature, the mixture was treated slowly with ice-water and extracted with EtOAc. The organic layer was washed with water and brine in sequence, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was then purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound (7.0 g, 27%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]([NH:15][C:16]2(S(C)=O)[CH:19]([CH3:20])[NH:18][C:17]2=[O:21])=[O:14])=[O:10])[C:5](=[O:31])[C:4]1=[O:32])[CH3:2].[NH3:33]>O1CCOCC1>[NH2:33][C:16]1([NH:15][C:13](=[O:14])[CH:12]([NH:11][C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:32])[C:5]2=[O:31])=[O:10])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]([CH3:20])[NH:18][C:17]1=[O:21]
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2(S(C)=O)C(=O)NC2C)c2ccccc2)C(=O)C1=O
Reactant: N
Solvent: C1COCCO1
Product: CCN1CCN(C(=O)NC(C(=O)NC2(N)C(=O)NC2C)c2ccccc2)C(=O)C1=O

Procedure:
The sulphoxide (61) (145 mg) in dioxan (5 ml) was treated with ammonia (21 ml) overnight at room temperature. The solvent was then evaporated and the residue chromatographed on silica gel to give the product (62) as a white solid (95 mg), νmax. (CHCl3) 3400, 3280, 1770, 1715 and 1690 cm-1, δ(CDCl3) 0.87, 0.90, 1.10 and 1.14 (each d, J6 Hz, together 3H), 1.20 (t, J7 Hz, 3H), 1.6-2.9 br (2H, exch.), 3.40-3.65 (m, 4H) (irradiation at 0.90 caused this signal to simplify), 3.85 (2×q, J7 Hz, together 1H) (irradiation at 0.87 or 1.10 caused one of the above signals to collapse to a s), 3.95-4.13(m, 2H), 5.45(2×d, J7 Hz, together 1H, collapses to 2×s on exch), 6.50, 6.58, 6.63, and 6.72 br (each s, together 1H, exch.), 7.25-7.56 (m, 5H), 7.62, 7.76, 7.90, and 8.06 br (each s, 1H, exch.), and 9.90 (2×d, J7 Hz, together 1H, exch.).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:38])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:37])([F:36])[F:35])[CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[CH3:38][C:22]1[C:21]([CH2:20][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]3[CH:7]=[CH:6][N:5]=[N:4]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:36])([F:37])[F:35])[CH:28]=2)[N:23]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Cc1nc(-c2cccc(OC(F)(F)F)c2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(OC(F)(F)F)c2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
17 mg (0.42 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 87 mg (0.40 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 6.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 120 mg (0.40 mmol) 3-chloromethyl-2-methyl-6-(3-trifluoromethoxy-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 12 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, n-heptane, and ether. The residue was dried at 40° C. in vacuum to give 138 mg (71%) of the title compound as almost colorless powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.C([SiH](CC)CC)C>CO.[Pd]>[NH2:16][C:12]1[CH:11]=[C:10]([C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: CN1CCN(C(=O)c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: CN1CCN(C(=O)c2cccc(N)c2)CC1
Reaction time: 0.42 h
Yield: 85 %

Procedure:
To a stirred solution of (4-methylpiperazin-1-yl)(3-nitrophenyl)methanone (5.5 g, 22.06 mmol) in MeOH (50 ml) was added Pd—C (10%, 0.470 g) followed by triethylsilane (14.10 ml, 88 mmol) (slow addition) at RT. The reaction mixture was stirred at same temperature for 25 min and filtered through celite, washed with methanol (50 ml). The Filtrate was concentrated under vacuum to get the title product (4.11 g).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-tert-butylphenyl isocyanate (0.214 ml, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 235 mg (68.7%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][PH:11](=[O:13])[CH3:12].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:1][C:2]1[CH:8]=[C:7]([P:11]([CH3:12])([CH3:10])=[O:13])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: C[PH](C)=O
Reactant: Nc1ccc(I)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CP(C)(=O)c1ccc(N)c(Cl)c1
Reaction time: 0.33 h
Yield: 83.5 %

Procedure:
To a solution of 2-chloro-4-iodoaniline (0.507 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) to afford the desired product (0.340 g, 83% yield).