Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]([C@@H:30]([CH3:38])[CH:31]([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])[C:8](=[O:29])[C@@H:9]([NH:11]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[CH3:10])[C:3]2[CH:39]=[CH:40][CH:41]=[CH:42][C:2]1=2.N1CCCCC1.CC(=O)OCC.CO>C(Cl)Cl>[NH2:11][C@@H:9]([CH3:10])[C:8]([N:7]([CH2:6][C:4]1[C:3]2[CH:39]=[CH:40][CH:41]=[CH:42][C:2]=2[S:1][CH:5]=1)[C@@H:30]([CH3:38])[CH:31]([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])=[O:29]
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CO
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.2 %

Procedure:
(9H-Fluoren-9-yl)methyl (S)-1-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-1-oxopropan-2-ylcarbamate (Compound III-12) 15.8 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 7.4 g, (yield 75%).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][Cl:26])[C@H:20]([NH:27][C:28](=[S:38])[CH2:29][C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=2[Cl:37])[C:19]3=[O:39])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:26][CH2:25][C:24]1[CH2:23][S:22][C@H:21]2[N:18]([C:19](=[O:39])[C@H:20]2[NH:27][C:28](=[S:38])[CH2:29][C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=2[Cl:37])[C:17]=1[C:15]([OH:16])=[O:14]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2[C@H](NC(=S)Cc3cc(Cl)ccc3Cl)C(=O)N12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1=C(CCl)CS[C@@H]2[C@H](NC(=S)Cc3cc(Cl)ccc3Cl)C(=O)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
A slurry of (6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate diphenylmethyl ester (10.0 g, 15.8 mmol) in CH2Cl2 (200 mL) at 0° C. was treated with anisole (24 mL) and then trifluoroacetic acid (80 mL). The resulting solution was stirred for 1 h at 0° C. and then concentrated under reduced pressure. The residue was stirred with Et2O, and the resulting solid was collected by filtration to give 5.20 g of (6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)-thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a white solid (70% yield), m.p. 125° C. 1H NMR (300 MHz, DMSO-d6) δ3.51 (d, J=18 Hz, 1H), 3.70 (d, J=18 Hz, 1H), 3.91 (s, 2H), 4.52 (d, J=11 Hz, 1H), 4.58 (d, J=11 Hz, 1H), 5.13 (d, J=5 Hz, 1H), 5.70 (dd, J=5, 8 Hz, 1H), 7.24 (dd, J=2, 8 Hz, 1H), 7.47 (dd, J=2, 8 Hz, 2H), 9.28 (d, J=8 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12](=[O:15])[NH:11]1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12](=[O:15])[NH:11]1
Reactant: O=c1ncn(-c2ccc(-c3ccccc3)cc2[N+](=O)[O-])[nH]1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(-c2ccccc2)ccc1-n1cnc(=O)[nH]1

Procedure:
A solution of 1-(3-nitro-4-biphenylyl)-1,2-dihydro-1,2,4-triazol-3-one in 96% ethanol (25 mL) was hydrogenated over 5% palladium on charcoal to give the desired amine.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][C:10]#[CH:11])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI.C(C(C)=O)C>O>[CH3:1][C:2]1[N:7]([CH3:18])[C:6](=[O:8])[C:5]([CH2:9][C:10]#[CH:11])=[C:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: C#CCc1c(-c2ccccc2)nc(C)[nH]c1=O
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Solvent: CI
Product: C#CCc1c(-c2ccccc2)nc(C)n(C)c1=O
Yield: 87.6 %

Procedure:
A mixture of 0.76 g (3.4 mmol) of 2-methyl-6-phenyl-5-propargyl-4(3H)-pyrimidinone, 0.72 g (5.2 mmol) of anhydrous potassium carbonate, 0.32 mL (5.1 mmol) of methyl iodide and 20 mL of methyl ethyl ketone was heated at reflux for 6 h. The mixture was cooled, diluted with 40 mL of water and extracted with two 60 mL portions of ethyl acetate. The ethyl acetate extracts were dried and rotovaped to leave 0.75 g of crude product. This material was purified by flash chromatography on silica gel to afford 0.71 g of 2,3-dimethyl-6-phenyl-5-propargyl-4(3H)-pyrimidinone as a white solid, mp 142°-144° C., 1H-NMR (CDCl3) δ2.10(3H,t,J=4), 2.60(3H, s), 3.40(2H,d,J=4), 3.60(3H,s), 7.45(3H,m), 7.65(2H, m); IR(nujol) 3200, 1650 cm-1. Calculated for C15H14N2O: C 75.61, H 5.92, N 11.76. Found: C 75.33, H 5.72, N 11.63.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][O:13]C2CCCCO2)=[C:6]([SiH:20]([CH3:22])[CH3:21])[CH:5]=1)[CH:2]=[CH2:3].CC1C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][OH:13])=[C:6]([SiH:20]([CH3:22])[CH3:21])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(CCCOC2CCCCO2)c([SiH](C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C=CCc1ccc(CCCO)c([SiH](C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
2-[3-(4-allyldimethylsilylphenyl)propoxy]tetrahydro-2H-pyran (3 Scheme 22, 600 mg, 1.9 mmol) was treated with catalytic amount of p-TsOH (20 mg) in methanol (10 mL). After being stirred for 16 h at room temperature, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (1:5 ethyl acetate/hexanes) to afford a colorless oil (342 mg, 77%); 1H NMR (300 MHz, CDCl3) δ 0.31 (s, 6 H), 1.79 (d, J=8.1 Hz, 2 H), 1.93 (m, 2 H), 2.74 (t, J=8.4 Hz, 2 H), 3.71 (d, J=6.6 Hz, 2 H), 4.87 (s, 1 H), 4.92 (m, 1 H), 5.81 (m, 1 H), 7.24 (d, J=7.8 2 H), 7.50 (d, J=7.8 Hz, 2 H); 13C NMR (75 MHz, CDCl3) −3.1, 24.1, 32.4, 34.4, 62.4, 113.6, 128.2, 133.9, 135.0, 135.9, 143.1; HRMS (EI) calcd for C14H22OSi 234.1439, found 234.1440.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])[CH:6]=[CH:5]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.6 %

Procedure:
A solution of 5-fluoroindole (5.4 g) and toluene-4-sulphonyl chloride (9.12 g) in toluene (300 mL) is treated with a cooled solution of sodium hydroxide pellets (23.2 g) in water (200 mL) followed by the tetrabutylammonium hydrogen sulfate catalyst (400 mg). The mixture is stirred at rt for 24 h. The organic phase is separated, washed with water and brine, dried (MgSO4) and concentrated in vacuo to afford 5-fluoro-1-(toluene-4-sulfonyl)-1H-indole (10.7 g, 78%). MS: 290 (M+H)
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[C:32]([Cl:33])=[CH:31][C:15]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][C@H:20]2[O:29][CH3:30])=[O:17])=[C:14]([O:34][CH3:35])[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC1C=CC=CC=1>[NH2:11][C:12]1[C:32]([Cl:33])=[CH:31][C:15]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][NH:28][C:2]3[S:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=3)[CH2:21][C@H:20]2[O:29][CH3:30])=[O:17])=[C:14]([O:34][CH3:35])[CH:13]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN)C[C@H]1OC
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCNc2nc3ccccc3s2)C[C@H]1OC
Yield: 41.2 %

Procedure:
A mixture of 1.9 parts of 2-chlorobenzothiazole, 3.7 parts of cis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide and 22.5 parts of methylbenzene was stirred and refluxed overnight. 1.6 Parts of sodium carbonate were added and the whole was stirred for 4 hours at reflux temperature. The methylbenzene layer was washed with water and set aside. The precipitated product, which was formed during the reaction, was filtered off and dissolved in trichloromethane. The solution was washed with water. The combined organic layers (trichloromethane and methylbenzene layers) were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.06 parts (41.2%) of cis-4-amino-N-[1-[3-(2-benzothiazolylamino)propyl]-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide; mp. 161.5° C. (compound 45).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[NH:1][CH2:2][CH2:3][CH2:4]3)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2c1NCCC2
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2NCCC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (173 mg, 0.97 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (200 mg, 0.97 mmol), HATU (553 mg, 1.46 mmol) in anhydrous DMF (20 mL) is added DIPEA (241 μL, 1.46 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (63) as white solid (300 mg, 85%).
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[CH2:13][CH2:14][C@:15]4([CH3:22])[C@:19]([OH:21])([CH3:20])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C@H:8]1[CH2:7][C:5](=[O:6])[CH2:4][CH2:3]2.I(C1C=CC=CC=1C(O)=O)(=O)=O>>[OH:21][C@@:19]1([CH3:20])[CH2:18][CH2:17][C@H:16]2[C@H:11]3[C@H:12]([CH2:13][CH2:14][C@:15]12[CH3:22])[C@:2]1([CH3:1])[C@H:8]([CH2:7][C:5](=[O:6])[CH:4]=[CH:3]1)[CH2:9][CH2:10]3
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O
Agent: O=C(O)c1ccccc1I(=O)=O
Product: C[C@]12C=CC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O

Procedure:
In a further aspect of the present invention, mestanolone is oxidized using IBX to form 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one. The 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one is hydroxylated using osmium tetroxide to form 1α, 2α, 17β-trihydroxy-17α-methylandrostan-3-one. The 1α, 2α, 17β-trihydroxy-17α-methylandrostan-3-one is cleaved using sodium metaperiodate to form 17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid. The 17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid is then reduced using sodium borohydride followed by an acid treatment to form oxandrolone.
Reaction SMILES: FC1C(F)=CC(C2C=CC(OCC3C=C4C(C=CN4CCC(O)=O)=CC=3)=CC=2)=C(OC)C=1.C([O:35][C:36](=[O:65])[CH2:37][N:38]1[C:46]2[C:41](=[C:42]([CH2:47][O:48][C:49]3[CH:54]=[CH:53][C:52]([C:55]4[CH:60]=[C:59]([F:61])[C:58]([F:62])=[CH:57][C:56]=4[O:63][CH3:64])=[CH:51][CH:50]=3)[CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39]1)C>>[F:62][C:58]1[C:59]([F:61])=[CH:60][C:55]([C:52]2[CH:53]=[CH:54][C:49]([O:48][CH2:47][C:42]3[CH:43]=[CH:44][CH:45]=[C:46]4[C:41]=3[CH:40]=[CH:39][N:38]4[CH2:37][C:36]([OH:65])=[O:35])=[CH:50][CH:51]=2)=[C:56]([O:63][CH3:64])[CH:57]=1
Reactant: CCOC(=O)Cn1ccc2c(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cccc21
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(CCC(=O)O)c3c2)cc1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2ccn3CC(=O)O)cc1

Procedure:
[4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic acid was synthesized by a procedure similar to 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid from starting material [4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic acid ethyl ester to yield the product as a white solid (23 mg, 82%). LC-MS (ES) calculated for C24H19F2NO4, 423.1; found m/z 424 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:14][CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:19][NH2:20]>>[CH3:19][NH:20][C:16](=[O:18])[CH2:15][S:14][CH:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(SCC(=O)O)c1ccc2c(c1)OCO2
Reactant: CN
Product: CCCC(SCC(=O)NC)c1ccc2c(c1)OCO2

Procedure:
2.5 g of the title compound was prepared from 2.7 g of [{1-(1,3-benzodioxol-5-yl)butyl}thio]acetic acid by using a 40% aqueous solution of methylamine as a colorless oil according to the same procedure as that described in Example 27.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16](F)=[O:17])=[N:9]1.[F:29][C:30]([F:36])([F:35])[S:31]([NH2:34])(=[O:33])=[O:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16]([NH:34][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])=[O:17])=[N:9]1
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: Cc1cc(CCC(=O)F)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(CCC(=O)NS(=O)(=O)C(F)(F)F)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of acid fluoride 9 (0.14 g, 0.33 mmol) and DMAP 0.161 g (1.3 mmol) in dry DCM, trifluoromethanesulfonamide 0.147 g (0.98 mmol) was added. The mixture was stirred under a nitrogen atmosphere for 16 hours before diluting with EtOAc. The organic phase was washed with 2M HCl, followed by brine, dried over MgSO4 and evaporated to dryness. The crude acyl sulphonamide 10 was purified on silica to yield 0.13 g as a white solid (72%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:24].C(O)C.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:24]
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Yield: 90.8 %

Procedure:
57.3 g (164 mmol) of ethyl (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxylate, 40 ml of ethanol, 60 ml of water and 51.5 ml (206 mmol) of 4N sodium hydroxide solution were heated to reflux on a steam bath for 30 min. The alcohol was evaporated on a rotary evaporator. The aqueous phase remaining behind was washed twice with methylene chloride and acidified to pH 3-4 with 51.5 ml (206 mmol) of 4N hydrochloric acid. The suspension obtained was cooled and filtered, and the filter residue was washed with a small amount of ice-water and dried. There were obtained 47.92 g (91%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid of m.p. 225°-226°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][C@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][N+:12]([O-:16])=[CH:11][C:10]=1[Cl:17])=[O:5].C(OC(NCC(O[C@H](C1C=CC(OC(F)F)=C(OCC2CC2)C=1)CC1C(Cl)=C[N+]([O-])=CC=1Cl)=O)=O)(C)(C)C.[N:71]([C:74]1[CH:79]=[CH:78][C:77]([O:80][CH3:81])=[C:76]([O:82][CH3:83])[CH:75]=1)=[C:72]=[O:73]>CN(C=O)C.O>[Cl:17][C:10]1[CH:11]=[N+:12]([O-:16])[CH:13]=[C:14]([Cl:15])[C:9]=1[CH2:8][C@@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[O:6][C:4](=[O:5])[CH2:3][NH:2][C:72]([NH:71][C:74]1[CH:79]=[CH:78][C:77]([O:80][CH3:81])=[C:76]([O:82][CH3:83])[CH:75]=1)=[O:73]
Reactant: COc1ccc(N=C=O)cc1OC
Reactant: NCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CC(C)(C)OC(=O)NCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)NCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
(S)-4-(2-(2-aminoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide hydrochloride (prepared in an analogous manner as described in Scheme 1, Step 1 and 2, Compound 3) (21 mg, 0.042 mmol) was dissolved in DMF dry (1 ml). 4-isocyanato-1,2-dimethoxybenzene (15.02 mg, 0.084 mmol) was added, and the reaction was stirred at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with HCl 1N, dried over Na2SO4 and concentrated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(3,4-dimethoxyphenyl)ureido)acetoxy)ethyl)pyridine 1-oxide (10 mg, 36.4% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Li])CCC.CCCCCC.CN(C)[CH:24]=[O:25]>O1CCCC1.O>[CH:24]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)=[O:25]
Reactant: Brc1cccc2cc[nH]c12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cccc2cc[nH]c12
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A solution of 7-bromoindole [Tet. Lett. 30, 2129 (1989)] (12.75 g, 0.065 mole) in dry tetrahydrofuran (230 ml) was cooled in a dry ice-acetone bath and 2.5M n-butyl lithium in hexane (78 ml, 0.195 mole) added dropwise over 1 hour, maintaining the reaction temperature below -60° C. The reaction mixture was stirred for a further 15 minutes at -70° C., then allowed to warm to 5° C. After 30 minutes at 5° C., the reaction was recooled to -70° C. and dimethylformamide (25 ml, 0.325 mole) added dropwise at a rate to maintain the temperature below -65° C. The mixture was allowed to warm to room temperature slowly, then was poured into water and extracted into diethyl ether. The combined dry extracts were washed with brine, dried and evaporated. Recrystallisation from 80°-100° C. petroleum ether with charcoal treatment yielded the product as fawn-coloured crystals.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:8][CH2:9][CH2:10][OH:11].[C:20](O)(=[O:22])[CH3:21]>>[C:20]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:19])(=[O:22])[CH3:21]
Reactant: Cc1ccccc1C(CCCO)c1ccccc1C
Reactant: CC(=O)O
Product: CC(=O)OCCCC(c1ccccc1C)c1ccccc1C

Procedure:
The crude 2,2-di-(2-tolyl)-tetrahydrofuran 33a (28 g) was dissolved in acetic acid (250 mL). 5% palladium on Carbon black (3 g) was added and the mixture was hydrogenated in a Parr apparatus at 3 ato at 55° C. for 5 hrs. The catalyst was filtered off and the solvent was evaporated in vacuo. The remaining oil was subjected to CC (n-heptane/ethyl acetate--15:1) to give 4,4-di-(2-tolyl)-1-butanol (17 g). A solution of 4,4-di-(2-tolyl)-1-butanol (19 g) in acetic acid (400 mL) was boiled under reflux for 3 hrs. The cooled solution was evaporated in vacuo to give 4,4-di-(2-tolyl)-1-butyl acetate (17 g) as an oil. A solution of 4,4-di-(2-tolyl)-1-butyl acetate (9.2 g) in 57% aqueous iodic acid (150 mL) was boiled under reflux for 3 hrs. The cooled solution was poured into a mixture of ice and water and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water and a saturated aqueous solution of NaCl, dried (Na2SO4) and evaporated in vacuo to give the title compound 34a (11.7 g) as an oil, which was used without further purification. 1H NMR (CDCl3) δ1.80-2.10 (m,4H), 2.28 (s,6H), 3.17 (t,2H), 4.26 (t,1H), 7.12 (s,8H)
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[N+:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-])=[O:11].C1N2CCN(CC2)C1>C(O)C>[CH2:1]([CH:2]1[O:11][N:10]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CCc1ccccc1
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CCOC(=O)C1=NOC(Cc2ccccc2)C1
Temperature: 80 °C
Yield: 84.3 %

Procedure:
To a mixture of allylbenzene (0.73 mL; 5.39 mmol) and ethyl 2-nitroacetate (1.53 mL; 13.48 mmol) in ethanol (12 mL) in an Ace pressure tube was added 1,4-diazobicyclo[2.2.2]octane (DABCO, 0.106 g; 0.92 mmol). The tube was heated at 80° C. for 60 h. The mixture was evaporated. The flash chromatography on silica gel (eluent: 15 to 100% of dichloromethane in heptane) of the residue provided 1.06 g (85%) of ethyl 5-benzyl-4,5-dihydroisoxazole-3-carboxylate as an oil.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])=[C:13]([CH3:28])[CH:12]=[C:11]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O>>[NH2:8][C:9]1[C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[O:16])=[C:13]([CH3:28])[CH:12]=[C:11]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[N:10]=1
Reactant: COc1ccc(CNc2nc(-c3cccc(C(F)(F)F)c3)cc(C)c2C(=O)N2CCC(N3CCCC3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(N)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 7, [2-(4-methoxy-benzylamino)-4-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 18) was reacted with trifluoroacetic acid to give the title compound as light yellow solid. MS: 433.5 (MH+).