Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13]1[CH2:30][CH2:29][C:16]2([C:21]3=[CH:22][CH:23]=[CH:24][N:20]3[C:19]3[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=3[O:17]2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:34]=[O:35])C>>[CH2:6]([N:13]1[CH2:30][CH2:29][C:16]2([O:17][C:18]3[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=3[N:20]3[C:24]([CH:34]=[O:35])=[CH:23][CH:22]=[C:21]23)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(CN2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
N,N-Dimethylformamide (723 μL, 9.40 mmol), under nitrogen, was cooled to 0° C. and POCl3 (876 μL, 9.40 mmol) was added dropwise. The reaction was stirred for 20 min at 0° C. and a white solid formed. A solution of 1-benzylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (2.07 g, 6.27 mmol) in dry DMF (15.5 mL) was added dropwise and the cooling bath was removed. The reaction mixture was stirred for 2 h at 50° C., then cooled down to room temperature and poured onto ice. Sodium hydroxide (1 M) was added until the pH reached 10, then the solution was acidified to pH 6 with 3 M HCl. The mixture was then extracted with EtOAc. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel: 10-70% EtOAc in hexanes) to give 1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (1.94 g, 86%). ESI-MS m/z calc. 358.4, found 359.3 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 8.17-8.07 (m, 1H), 7.38-7.30 (m, 4H), 7.29-7.24 (m, 1H), 7.20-7.13 (m, 2H), 7.09 (m, 2H), 6.20 (d, J=4.1 Hz, 1H), 3.59 (s, 2H), 2.76 (m, 2H), 2.58-2.45 (m, 2H), 2.10-1.96 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.[Na].[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].[I-].[Na+]>>[NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:17]2[C:18](=[O:20])[CH2:19][S:15][C:16]2=[O:21])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1OCCCCCl
Reactant: O=C1CSC(=O)N1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Product: Nc1ncccc1OCCCCN1C(=O)CSC1=O

Procedure:
Using 10.06 g (50 mmol) of 2-amino-3-(4-chlorobutyloxy)pyridine, 6.97 g (50 mmol) of thiazolidine-2,4-dione sodium salt and 7.49 g (50 mmol) of sodium iodide, the same procedure as in Reference Example 11 was followed, to yield 9.53 g (67.8%, light yellow oily substance) of the desired product.
Reaction SMILES: Cl.[CH:2]1([O:7][C:8]2[CH:9]=[C:10]([C:18]3([C:24]#[N:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C)C=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][N:21]1[CH2:20][CH2:19][C:18]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH:15]([F:17])[F:16])=[C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)([C:24]#[N:25])[CH2:23][CH2:22]1)[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: N#CC1(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(C#N)(c2ccc(OC(F)F)c(OC3CCCC3)c2)CC1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of the compound prepared in example 1 (19.8 g) in N,N-dimethylformamide (53 ml) were added potassium carbonate (18.4 g) and ethyl bromoacetate (5.89 ml) and the mixture was stirred for 1.5 hours at 50° C. To the reaction mixture was added water (160 ml) and it was extracted by tert-butyl methyl ether (160 ml). The organic layer was washed by water (80 ml×2) and concentrated to give the title compound (23.4 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][C:15]2[O:19][C:18]([C:20](Cl)=[O:21])=[CH:17][CH:16]=2)=[CH:4][C:5]2[C:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[CH3:24][O:25][C:26]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:27]=1[NH2:28].C(N(CC)CC)C>C(OCC)(=O)C>[O:25]([C:26]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:27]=1[NH:28][C:20]([C:18]1[O:19][C:15]([CH2:14][C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]([CH3:13])([CH3:12])[C:5]=3[CH:4]=2)=[CH:16][CH:17]=1)=[O:21])[CH3:24]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: Cc1cc2c(cc1Cc1ccc(C(=O)Cl)o1)C(C)(C)CCC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(NC(=O)c2ccc(Cc3cc4c(cc3C)CCCC4(C)C)o2)c(OC)c1
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 5-[(3,8,8-trimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furoyl chloride (10 eq, 0.32 mmol, 0.2M) in 2 mL ethyl acetate, the 2,4,6 trimethoxy aniline mono HCl salt (10 eq, 0.32 mmol) was added. Triethyl amine (excess) was added to this mixture and stirred overnight. The crude product was dried under vacuo and purified through plug column chromatography (1:100 crude mass/silicagel ratio) by eluting with 20 and 30 percent ethyl acetate/hexane solution. In some cases, the regio-isomers were separated by recrystallization in twenty five percent ethyl acetate/hexanes (1 g/75 mL compound/volume) to yield N-(2,4,6-trimethoxylphenyl)-5-[(3,8,8-trimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furamide (120 mgs, 82% yield). 1H NMR (CDCl3) 7.28 ppm (1H, broad), 7.12 (1H, s), 7.08 (1H, 3=3.40 Hz, d), 6.89 (1H, s), 6.19 (2H, s), 6.00 (1H, J=3.40 Hz, d), 3.97 (2H, s), 3.83 (3H, s), 3.82 (6H, s) 2.73 (2H, J=6.05 Hz, t), 2.25 (3H, s), 1.84-1.76(2H, multiplet), 1.69-1.63 (2H, multiplet), 1.59 (3H, s), 1.26(6H, s) elemental: expected C(72.55), H(7.18), N(3.02); actual C(72.67), H(7.22), N(2.98).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH3:12]/[C:13](/[CH2:17][CH2:18]/[CH:19]=[C:20](\[CH3:28])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:27])[CH2:25][CH3:26])=[CH:14]\CO>ClCCl>[Cl:1][CH2:26]/[CH:25]=[C:24](\[CH3:27])/[CH2:23][CH2:22]/[CH:21]=[C:20](\[CH3:28])/[CH2:19][CH2:18][CH:17]=[C:13]([CH3:14])[CH3:12]
Reactant: CCC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CSC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
(Note: all temperatures indicated are for the contents of the reaction flask). To a stirred solution of 299 mg (2.24 mmol) of N-chlorosuccinimide in 15 ml of dichloromethane at -30° C. under argon was added 0.18 ml (2.45 mmol) of distilled dimethyl sulfide over 5 minutes. After 10 minutes at -30° C., the reaction was allowed to warm to 0° C. for 10 minutes, followed by cooling to -40° C. A solution of 441.4 mg (1.99 mmol) of (E,E)-3,7,11-trimethyl-2,6,10-tridecatrien-1-ol in 5 ml of dichloromethane was added dropwise over 10 minutes. The reaction was allowed to warm gradually to 0° C. over 1 hour, and then maintained at 0° C. for 1 hour. After quenching with cold water, the mixture was extracted with hexane and the hexane extract was washed with cold water and cold brine, dried (MgSO4) and evaporated to afford 483 mg of a crude product. Rapid flash chromatography on 20 g of Merck 9385 silica gel eluted with 3:97 ethyl acetate:pet ether provided 406.5 mg (85%) of a colorless liquid. 13C NMR indicated that this material contained a trace (3%) impurity.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][S:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[CH3:19][S:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 4-methylthioaniline as the starting materials.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[CH:12]=[C:13](/[C:16](=O)[CH3:17])\[C:14]#[N:15])[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[NH2:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][C:22]#[N:23]>C(O)C.CC(O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]3[C:21]([C:22]#[N:23])=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:16]([CH3:17])=[C:13]3[C:14]#[N:15])[CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: N#CC=C(N)C(F)(F)F
Reactant: CCc1n[nH]c2ccc(/C=C(\C#N)C(C)=O)cc12
Solvent: CC(C)O
Solvent: CCO
Product: CCc1n[nH]c2ccc(C3C(C#N)=C(C)NC(C(F)(F)F)=C3C#N)cc12

Procedure:
A suspension of 300 mg (1.25 mmol) (2E)-2-[(3-ethyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 11A) and 853 mg (6.27 mmol) 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation: A. W. Lutz, U.S. Pat. No. 3,635,977; C. G. Krespan, J. Org. Chem. 34, 42 (1969)] in ethanol/2-propanol (8:1 v/v, 1.0 ml) was stirred at reflux temperature for 24 h. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to yield 59 mg (13% of th.) of the racemic title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1.[C:15](Cl)([Cl:17])=[O:16]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]([Cl:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Nc2ccccc2)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(N(C(=O)Cl)c2ccccc2)c1
Yield: 99.7 %

Procedure:
According to the procedure of Example 15, Step A, 3.66 g (20 mmole) of 3-methyldiphenylamine, 20 mL (38.6 mmole) of 1.93M phosgene is toluene solution, and 20 mL of toluene gave 4.9 g (100%) of a dark solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH2:17]>>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH:17][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12
Reactant: CN(C)CCCN
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Product: Cc1cc(NCCCN(C)C)c2[nH]ncc2n1

Procedure:
The title compound was prepared from 7-chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (D4) and 3-dimethylaminopropylamine by the method given in Example 2. On neutralization of the thus formed hydrochloride salt a clear solution was produced. After freeze drying, purification was carried out on Dowex 50W as described in Example 4, followed by crystallization from ethyl acetate to give the title compound as a white crystalline solid, m.p. 112°-117°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C@H:8]2[C@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[O:10][CH2:9]2)[CH:2]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Cl>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C@@H:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C@@H:17]2[OH:18]
Reactant: ClCc1ccccn1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Cc1cccnc1)CO2
Product: O[C@@H]1c2cc(OCc3ccccn3)ccc2OC[C@H]1Cc1cccnc1

Procedure:
By the method of Example 5, 500 mg (1.95 mmol) of trans-3-(3-pyridyl methyl)-4,6-chromandiol and 266 mg (2.09 mmol) of 2-picolyl chloride were converted to present title product, purified by flash chromatography on 100 g silica gel using 1:19 CH3OH:ether as eluant to yield 136 mg (20%) of present title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[NH2:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>>[C:14]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:4](=[O:6])[C@@H:3]([O:2][CH3:1])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:17][CH:16]=1)#[N:13]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CO[C@H](C(=O)O)c1ccccc1
Product: CO[C@H](C(=O)NCc1ccc(C#N)cc1)c1ccccc1

Procedure:
(S)-(+)-Methoxyphenylacetic acid was coupled with 4-aminomethyl benzonitrile (CAS No: 10406-25-4) according to general procedure C to give (S)-N-(4-cyano-benzyl)-2-methoxy-2-phenyl-acetamide as an off-white solid. MS 281.2 ([M+H]+)
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:27][CH2:26][C:25]3[N:24]=[C:23]([CH3:28])[O:22][C:21]=3[C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)=[O:17])=[CH:12][C:11]=1[CH3:33].C(N(CC)CC)C>ClCCl>[CH3:33][C:11]1[CH:12]=[C:13]([C:16]([N:18]2[CH2:27][CH2:26][C:25]3[N:24]=[C:23]([CH3:28])[O:22][C:21]=3[C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)=[O:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5]
Reactant: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccc(CN)c(C)c1)CC2
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccc(CNC(=O)C3CC3)c(C)c1)CC2
Reaction time: 1 h
Yield: 67 %

Procedure:
Cyclopropanecarbonyl chloride (26 mg, 0.25 mmol) was added to a solution of (4-aminomethyl-3-methyl-phenyl)-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulen-6-yl)-methanone hydrochloride from Example E119.2 (85 mg, 0.22 mmol) in dichloromethane (5 ml) and triethylamine (to pH9) at room temperature. The mixture was stirred for 1 h then purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to give a white solid identified as the title compound (62 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].CN(C)C=O.[H-].[Na+].[CH3:30][O:31][C:32](=[O:37])[C:33](Br)([CH3:35])[CH3:34]>O>[CH3:30][O:31][C:32](=[O:37])[C:33]([O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9](=[O:12])[NH:10]2)([CH3:35])[CH3:34]
Reactant: COC(=O)C(C)(C)Br
Reactant: Cc1c(Cc2ccc(Cl)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)Oc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of 8-chloro-3-(4-chlorobenzyl)-5-hydroxy-4-methyl-1H-quinolin-2-one (0.14 g), N,N-dimethylformamide (10 mL), sodium hydride (60% in oil, 0.020 g) and 2-bromo-2-methylpropionic acid methyl ester (0.11 g) was stirred at 100° C. for 3 days. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3:7 by volume) to afford title compound, 0.056 g.
Reaction SMILES: [NH2:1][CH:2]([CH3:13])[CH2:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][N:5]=1>C(OCC)(=O)C.C(O)C>[NH2:1][CH:2]([CH3:13])[CH2:3][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(N)Cc1ncccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(N)Cc1ncccc1N
Yield: 100.1 %

Procedure:
2-aminopropyl-3-nitropyridine (171)(6.3 g, 35 mmol) is dissolved in 100 mL 1/1 ethyl acetate/ethanol in a Parr shaker bottle. Nitrogen is bubbled through the solution for 2 minutes followed by the addition of 10% Pd/C (500 mg). The suspension is hydrogenated on a Parr apparatus under 40 psi of H2 until hydrogen uptake ceased. The suspension is filtered through Celite and the solvent evaporated in vacuo to afford 5.3 g of the 2-aminopropyl-3-aminopyridine (182).
Reaction SMILES: [N:1]([C@@H:4]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]([F:22])[F:21])=[N:18][CH:19]=1)[CH2:5][O:6][Si](C(C)(C)C)(C)C)=[N+:2]=[N-:3].Cl>CCO>[N:1]([C@@H:4]([C:14]1[CH:19]=[N:18][C:17]([CH:20]([F:21])[F:22])=[CH:16][CH:15]=1)[CH2:5][OH:6])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](N=[N+]=[N-])c1ccc(C(F)F)nc1
Agent: Cl
Solvent: CCO
Product: [N-]=[N+]=N[C@H](CO)c1ccc(C(F)F)nc1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a stirred solution of (S)-5-(1-azido-2-(tert-butyldimethylsilyloxy)ethyl)-2-(difluoromethyl)pyridine (1.9 g, 5.79 mmol) in 20 mL of EtOH at 0° C. was added 5 mL 6N HCl and the resultant reaction mixture was slowly warmed to room temperature over a period of 2 h. The solvents were evaporated and the residue was separated between 10% NaHCO3 solution and CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated in vacuo to afford the title compound (1.1 g, 89% yield). MS: 215 [M+1]+; 1H-NMR (300 MHz, CDCl3): 8.63 (s, 1H), 7.86 (d, 1H, J=8.3 Hz), 7.68 (d, 1H, J=8.3 Hz), 6.65 (t, 1H, J=55.2 Hz), 4.75-4.79 (m 1H), 3.70-3.90 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].N1C=CN=C1.Cl[Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>O.Cl.CN(C1C=CC=CN=1)C>[CH3:29][C:28]([Si:25]([CH3:27])([CH3:26])[O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: O
Product: CCOC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Yield: 88.4 %

Procedure:
1-(1,1-dimethylethyl) 2-ethyl(2S,3S)-3-hydroxy-1,2-pyrrolidinedicarboxylate (8.98 g, 34.7 mmol), imidazole (2.36 g, 34.7 mmol), dimethylaminopyridine (50 mg, catalytic) and chloro(1,1-dimethylethyl)dimethylsilane (4.96 g, 32.9 mmol) were stirred at room temperature for 16 hours. The reaction was diluted with water and 1N HCl to make the mixture acidic. The mixture was extracted three times with methylene chloride. The organic layer was washed with 1M HCl, dried over MgSO4 to give the title compound as a clear brown oil (10.88 g, 29.1 mmol). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.0 (m, 6 H) 0.8 (m, 9 H) 1.2 (m, 3 H) 1.3 (m, 9 H) 1.7 (m, 1 H) 1.9 (m, 1 H) 3.4 (m, 2 H) 3.9 (m, 1 H) 4.1 (m, 2 H) 4.4 (m, 1 H). ES+=374.30.
Reaction SMILES: N#N.C([Si](C)(C)[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[C:27]([CH3:37])[O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[OH:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[C:27]([CH3:37])[O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10]
Reactant: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c(-c2cccc(Cl)c2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O)o3)n2)c(-c2cccc(Cl)c2)o1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid (2-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-yl)-amide (106 mg, 0.20 mmol) in dry THF (1.9 mL) was treated at 0° C. with TBAF (0.39 mL of a 1M solution in THF, 0.39 mmol). The reaction mixture was stirred at 0° C. for 45 min. The mixture was then diluted with EA (10 mL), washed with NaHCO3 (10 mL) followed by brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (19:1 CH2Cl2-MeOH) gave the title compound as a white solide. TLC:rf (19:1 CH2Cl2-MeOH)=0.22. LC-MS-conditions 01: tR=0.93 min; [M+H]+=428.97.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.C(=O)([O-])O.[Na+].[C:16](Cl)(Cl)=[S:17]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([N:7]=[C:16]=[S:17])=[C:5]([CH3:10])[CH:4]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(N=C=S)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a solution of 4-methoxy-2-methylaniline (2.51 mL, 19.7 mmol) and saturated aqueous sodium hydrogen carbonate (13.5 mL) in tetrahydrofuran (13.5 mL) was added thiophosgene (1.50 mL, 19.7 mmol), and the mixture was stirred at 0° C. for 30 min. The reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-10% ethyl acetate/n-hexane gradient mixture. The desired fractions were concentrated in vacuo to give the title compound as a colorless oil (2.80 g, 15.6 mmol, 79%).
Reaction SMILES: [C:1]12([C:11]3[C:12]([O:24][SiH:25]([CH3:27])[CH3:26])=[C:13]([CH:17]=[CH:18][C:19]=3[C:20]([CH3:23])([CH3:22])[CH3:21])[C:14](O)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[SH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1.N1C=CC=CC=1>ClCCl>[C:1]12([C:11]3[C:12]([O:24][SiH:25]([CH3:27])[CH3:26])=[C:13]([CH:17]=[CH:18][C:19]=3[C:20]([CH3:21])([CH3:22])[CH3:23])[C:14]([S:28][C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)=[O:15])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)c1ccc(S)cc1
Reactant: C[SiH](C)Oc1c(C(=O)O)ccc(C(C)(C)C)c1C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[SiH](C)Oc1c(C(=O)Sc2ccc(C(=O)O)cc2)ccc(C(C)(C)C)c1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
The crude 3-(1-adamantyl)-4-tert.butyl-dimethylsilyloxybenzoic acid, prepared starting with 3.8 g (9.95 mmoles) of the corresponding acid, described in Example 3 of European Patent No. 0.232.199, is dissolved in 40 ml of dichloromethane. The solution is slowly added to a mixture of 1.54 g (9.95 mmoles) of 4-mercaptobenzoic acid and 15 ml of pyridine. The reaction mixture is stirred at ambient temperature for 12 hours, evaporated to dryness, taken up in water and acidified to pH 5 with 1N HCl. The solid is filtered, washed with water, ground with 50 ml of ethyl ether and dried at 60° C. under a vacuum. 5 g (96% yield) of a white powder whose melting point is 232°-233° C. are recovered.
Reaction SMILES: [I-].[K+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[C:16]([CH2:19]Cl)=[N:17][N:18]=[C:14]3[CH2:13][N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:10]=2[CH:28]=1)([O-:5])=[O:4].[CH:29]1([NH2:32])[CH2:31][CH2:30]1>O1CCCC1>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[C:16]([CH2:19][NH:32][CH:29]4[CH2:31][CH2:30]4)=[N:17][N:18]=[C:14]3[CH2:13][N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:10]=2[CH:28]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: NC1CC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNC3CC3)n1-2

Procedure:
In the manner given in Example 1, potassium iodide and 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 8-nitro 1-[(cyclopropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine.