Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH:32]=5)=[N:23][N:22]=4)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH2:36][CH2:35][NH:34][CH2:33][CH:32]=5)=[N:23][N:22]=4)=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(C5=CCN(C(=O)OC(C)(C)C)CC5)c5ccccc45)cc3)ccnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2c(Sc3ccc(Nc4nnc(C5=CCNCC5)c5ccccc45)cc3)ccnc2c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In a 20 mL sealed tube was dissolved tert-butyl 4-(4-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenylamino)phthalazin-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.200 g, 0.337 mmol) in DCM (1.00 mL). To the mixture was added TFA (0.130 mL, 1.69 mmol). The mixture was stirred at 50° C. for 3 hours, then cooled to RT and concentrated. The crude material was purified on an Isco silica gel chromatography using 0-100% CH2Cl2:MeOH:NH4OH (90:10:1)/CH2Cl2. The product fractions were concentrated to yield N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phthalazin-1-amine as a light yellow solid. MS: [M+H]=493.0; Calc'd 492.6 for C28H24N6OS.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([OH:18])[CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:18][C:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[N:14][CH:15]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Oc1cncc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Oc2cncc(Cl)c2)cc1
Yield: 44.5 %

Procedure:
To a stirred solution of 4-fluoro-nitrobenzene (913 μL, 8.61 mmol, from Aldrich) in dioxane (1 mL) was added 3-chloro-5-hydroxypyridine (558 mg, 4.31 mmol, from Aldrich) followed by triethylamine (661 μL, 4.74 mmol). The solution was refluxed for 4.5 hours, evaporated and the crude solid was dissolved in ethyl acetate. The solution was washed three times with saturated K2CO3 solution, once with brine and then back-extracted with ethyl acetate. The two organic solutions were combined, concentrated and the residue was purified by chromatography (diethyl ether as eluant) to provide 481 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].S(Cl)(Cl)=O.C[N:20](C=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([NH2:20])=[O:9]
Reactant: CN(C)C=O
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc([N+](=O)[O-])c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 5-methoxy-2-nitrobenzoic acid (7.5 g, 38.0 mmol) in anhydrous benzene (50 mL), was added thionyl chloride (3.8 mL, 52.05 mmol) followed by the addition of anhydrous DMF (0.4 mL). The resulting reaction mixture was refluxed for 5 h, upon which the volatiles were removed in vacuo. The residue was dissolved in anhydrous THF (60 mL) and added to an ice-cold saturated solution of ammonia in THF (60 mL). The resulting heterogeneous reaction mixture was allowed to warm room temperature and stirring was continued at RT for 48 h. The s volatiles were removed in vacuo and the residue was used without further purification for next step. HPLC retention time 3.29 mins.
Reaction SMILES: [Cl-].[CH2:2]([NH2+:9][CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([N:21]=[C:22]=[S:23])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([N:21]=[C:22]2[N:9]([CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:10][CH2:11][S:23]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: ClCC[NH2+]Cc1ccccc1
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2Cc2ccccc2)cc1Cl

Procedure:
2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3-benzyl-1,3-thiazolidine.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:3].CCN(C(C)C)C(C)C.Cl[CH2:46][CH2:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:3])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([S:48]([CH:47]=[CH2:46])(=[O:50])=[O:49])[CH2:33][CH2:34]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:11]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNCC3)nc1-2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)N1CCC(Nc2ncc3c(n2)-c2c(c(C(=O)Nc4c(CC)cccc4CC)nn2C)CC3)CC1
Temperature: -78 °C
Yield: 55.5 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (300 mg, 0.606 mmol) under nitrogen, in dry dichloromethane (15 mL), DIPEA (0.527 mL, 3.03 mmol) and 300 mg of molecular sieves were added, and the mixture was cooled at −78° C. 2-chloroethanesulfonyl chloride (0.063 mL, 0.606 mmol) was added. Temperature was allow to rise to room temperature then the solvent was evaporated to dryness and the crude was purified by flash chromatography on silica gel (eluant: ethyl acetate/dichloromethane: 2/8) to give 185 mg of the title compound (56% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:28])=[C:12]([CH2:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18][N:17]=3)[CH:13]=2)[NH:8][C:7]=1[CH3:29])=[O:5])[CH3:2].N1C=CC=CC=1.[C:36](OC=O)(=[O:41])C(C)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:28])=[C:12]([CH:15]=[C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18][N:17]3[CH:36]=[O:41])[CH:13]=2)[NH:8][C:7]=1[CH3:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c2cc(Br)c(CC3=NCCc4cc(OC)ccc43)cc12
Reactant: CC(C)(C)C(=O)OC=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)[nH]c2cc(Br)c(C=C3c4ccc(OC)cc4CCN3C=O)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a solution of 6-bromo-5-(6-methoxy-3,4-dihydro-isoquinoline-1-ylmethyl)-2-methyl-1H-indole-3-carboxylic acid ethyl ester (2.03 g, 4.5 mmol) in CH2Cl2 (50 mL) is added pyridine (2.3 g, 30 mmol) and 3N formic pivalic anhydride (5 mL; 14.5 mmol) at 0° C., and the reaction is stirred at room temperature for 3 hours. CH2Cl2 (50 mL) is then added to the reaction mixture and the organic layer is washed with water (2×50 mL), IN HCl (50 mL), 1N NaOH (50 mL), and brine (50 mL). The solution is dried (Na2SO4), filtered, and concentrated in vacuo to give the desired product (1.3 g, 60%). MS: 483, 485 (M+1)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:14]O>C(O)(=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[O-:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OO
Reactant: c1ccc(Cc2ccccn2)cc1
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1Cc1ccccc1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A solution of 2-benzylpyridine (10.0 g, 0.059 moles) and hydrogen peroxide (33% w/v, 4.02 g, 12.2 ml, 0.118 moles) in glacial acetic acid (40 ml) was heated at 60° C. for 17 hours. The reaction mixture was cooled to room temperature, the acetic acid evaporated under reduced pressure and the residue dissolved in chloroform. After neutralisation with potassium carbonate (20 g) the chloroform was removed to give 2-benzylpyridine-N-oxide (10.86 g, 99%) as a viscous oil which crystallised on standing.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(c1cccc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-bromobenzoic acid (500 mg, 2.49 mmol) in DCM (12 mL) was added morpholine (260 mg, 2.99 mmol), EDCI (1.43 g, 7.47 mmol) and HOBt (1.0 g, 7.47 mmol). The mixture was stirred at room temperature for 4 h. The reaction solution was diluted with water and extracted with DCM. The organic layer was concentrated to give the desired (3-bromophenyl)(morpholino) methanone as a crude product which was used in next step without further purification. LCMS (m/z): 270.1/271.1 [M+H]+/[M+2H]+
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](Cl)(=O)C>CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CO
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A 1 L 3-necked round bottomed flask equipped with a nitrogen inlet, stirbar, addition funnel and thermocouple was charged with 4-fluoro-3-nitrobenzoic acid (50 g, 0.27 mol) and methanol (300 mL). The system was cooled to 0 C and acetyl chloride (27 mL, 0.37 mol) was added dropwise. The system was warmed to room temperature, the addition funnel was replaced with a reflux condenser, and was heated to reflux for 1.5 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic extract was washed with brine, dried with Na2SO4 and concentrated in vacuo to give methyl 4-fluoro-3 nitrobenzoate as an orange solid (40.6 g, 75%). 1H NMR (400 MHz, CD3OD) δ 8.67 ((dd, J=2.2 and 6.8 Hz, 1H), 8.34 (dddd, J=2.2, 4.4, 6.4 and 8.8 Hz, 1H), 7.55 (dd, J=8.8 and 10.8 Hz, 1H), 3.94 (s, 3H) ppm. ES-HRMS m/z 200.02446 (M+H calcd for C8H7FNO4 requires 200.0354).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:51][CH2:52][CH3:53])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])=O.CC(C[AlH]CC(C)C)C.C(OCC)(=O)C.[NH4+].[Cl-]>C1COCC1>[CH3:13][O:12][C:10]([C:9]1[N:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:7]([CH2:51][CH2:52][CH3:53])=[N:6][C:5]=1[CH2:3][OH:2])=[O:11]
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(CO)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: -75 °C
Reaction time: 2.5 h
Yield: 93.4 %

Procedure:
To a solution of 7.03 g (10.0 mmole) of 4,5-bis (methoxycarbonyl)-2-propyl-1-[(2'-(N-trityltetrazol-5-yl)biphen-4-yl)methyl]-imidazole in 80 mL anhydrous THF was added 20.0 mL 1.0 M DIBAL-H (20.0 mmole, in THF) at -75° C. The mixture was stirred at -75° C. for 2.5 hours and then warmed to room temperature. After stirring overnight at room temperature, TLC (ethyl acetate) showed no starting material. The mixture was poured into 100 mL saturated aqueous NH4Cl solution and stirred for 20 min.; the product was extracted with 4×200 mL ethyl acetate, and the combined organic layer was washed with brine, dried over MgSO4, and filtered. Solvents were then removed under reduced pressure to yield 6.30 g (89.4%) of the title compound as a white foam. 1H NMR (300 MHz, DMSO-d6): δ 0.77 (t, J=7.3 Hz, 3H); 1.55 (m, 2H); 2.44 (t, J=7.7 Hz, 3H); 3.66 (s, 3H); 4.59 (d, J=6.2 Hz, 2H); 4.82 (t, J=6.2 Hz, 1H); 5.49 (s, 2H); 6.80-7.80 (m, 23H). MS (NH3 -CI/DDIP): m/z 675 (M+H, 26%); 619 (M+H-N4, 100%); 243 (Tr, 19%). Calculated mass for C42H39N6O3 (M+H): 675.308365; found: 675.308581.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[CH:33]=O)=[CH:28][CH:27]=1>C(Cl)Cl.[Zn]>[Br:21][C:20]([Br:24])=[CH:36][C:32]([C:29]1[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=1)([CH3:33])[CH3:35]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C=O)c1ccc(Cl)cc1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C=C(Br)Br)c1ccc(Cl)cc1
Yield: 66.9 %

Procedure:
A solution of triphenyl phosphine (89.34 g, 0.34 mol) in methylene chloride is added dropwise to a mixture of zinc powder (22.27 g, 0.34 mol) and carbon tetrabromide (112.8 g, 0.34 mol) in methylene chloride at 20° C. over one hour. The resultant mixture is stirred at room temperature overnight, treated dropwise with a solution of 2-(p-chlorophenyl)-2-methylpropionaldehyde (31.1 g, 0.17 mol) in methylene chloride over 20 minutes, refluxed for 2 days, and poured into petroleum ether. The organic mixture is filtered through diatomaceous earth and concentrated in vacuo to obtain a residue. The residue is distilled to give the title product as an oil (38.5 g, bp 121°-123° C./0.3 mm Hg, 66.8% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][CH:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16][C:17]([OH:19])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Cl.[CH3:29][NH:30][CH3:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][CH:15]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[CH2:16][C:17]([N:30]([CH3:31])[CH3:29])=[O:19])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CNC
Reactant: Cc1ccc2c(c1)c1c(n2CC(CC(=O)O)c2ccncc2)CCN(C)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(CC(=O)N(C)C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.1 %

Procedure:
4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyric acid (130 mg, 0.358 mmol) was dissolved in DCM (5 mL), dimethyl amine hydrochloride (57 mg, 0.716 mmol), PYBOP (223 mg, 0.429 mmol) and triethylamine (0.51 mL, 3.58 mmol) were added and the reaction mixture was stirred at RT for 4 h. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated and the crude product was purified by reverse phase chromatography to obtain 77 mg of 4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-N,N-dimethyl-3-pyridin-4-yl-butyramide as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.56 (d, 2H), 7.28 (d, 2H), 7.19 (s, 1H), 7.17 (d, 1H), 6.94 (d, 1H), 4.63 (dd, 1H), 4.54 (dd, 1H), 4.39 (d, 1H), 4.37 (t, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.45 (m, 1H), 3.3 (m, 1H), 3.1 (s, 6H), 3.0 (d, 3H), 2.9 (m, 2H), 2.8 (d, 3H). Separation by chiral HPLC provides enantiomers II-230a-b.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.C[Si]([N:27]=[N+:28]=[N-:29])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[C:4]([C:21]2[NH:29][N:28]=[N:27][N:22]=2)[CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(C#N)cc(Br)cc32)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnn[nH]4)cc(Br)cc32)cc1
Yield: 34.1 %

Procedure:
A stirred solution of 6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carbonitrile (0.79 g, 2.1 mmol), trimethylsilyl azide (0.484 g, 4.20 mmol) and dibutyltin oxide (0.105 g, 0.420 mmol) in toluene (10 ml) was heated at 110° C. for 1 h in the microwave (biotage initiator). The resulting cream coloured solid was collected by filtration, washed with toluene and dried in vacuo at 65° C. to give the title compound as a near colourless solid (0.3 g). The mother liquor was evaporated and the residue triturated with cyclohexane (10 ml) to give a further quantity of the title compound as a pale yellow solid (0.38 g).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][CH:5](C)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8].[OH-].[Li+].[CH3:23]O>>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][O:9][C:7]([NH:6][CH2:5][CH:4]([CH3:23])[C:3]([OH:2])=[O:20])=[O:8])=[CH:16][CH:15]=1
Reactant: CO
Reactant: COC(=O)CC(C)NC(=O)OCc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Product: COc1ccc(COC(=O)NCC(C)C(=O)O)cc1
Yield: 97 %

Procedure:
A solution of N-4-methoxybenzyloxycarbonyl β-methyl β-alanine methyl ester (2.81 g, 10.0 mmol) in 30 mL of 25% aqueous methanol was treated with lithium hydroxide (1.3 equivalents) at room temperature for a period of 2 h. The solution was concentrated in vacuo and the residue taken up in a mixture of water and ether and the phases separated and the organic phase discarded. The aqueous phase was acidified with aqueous potassium hydrogen sulfate to pH=1.5 and then extracted three times with ether. The combined ethereal phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2.60 g, 97% of N-4-Methoxybenzyloxycarbonyl α-methyl β-alanine (N-Moz-AMBA) which was purified by recrystallization from a mixture of ethyl acetate and hexane to give 2.44 g, 91% of pure product, mp 96–97° C., MH+=268. 1H NMR (D6-acetone/300 MHz) 1.16 (3H, d, J=7.2 Hz), 2.70 (1H, m), 3.31 (2H, m), 3.31 (3H, s), 4.99 (2H, s), 6.92 (2H, 4, J=8.7 Hz), 7.13 (2H, d, J=8.7 Hz)
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[CH2:39][C:40]([NH:42][CH2:43][CH3:44])=[O:41]>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:43]([NH:42][C:40](=[O:41])[CH2:39][N:27]1[CH2:28][CH2:29][CH:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH:11]=[C:10]([C:9]5[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([CH3:30])[N:8]=5)[N:19]=4)[CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH2:25][CH2:26]1)[CH3:44]
Reactant: CCNC(=O)CCl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)CN1CCC(c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 54.3 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (150 mg, 0.35 mmol) in DCM (2 mL) was added triethylamine (107 μL, 0.77 mmol). The resultant mixture was stirred for 10 minutes before the addition of 2-chloro-N-ethyl-acetamide (46 mg, 0.38 mmol) and tetrabutylammonium iodide (13 mg, 0.04 mmol). The reaction was stirred at RT for 4 days before the reaction was washed with sodium hydrogen carbonate solution (sat. aq.). The aqueous phase was extracted with 10% MeOH in DCM (×3) and the combined organic layers dried (Na2SO4) then concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM) affording 276 (91 mg, 0.19 mmol, 55%). LCMS: RT=2.75 min, [M+H]+=478. 1H NMR δ (ppm) (CDCl3): 8.43 (1H, d, J=8.29 Hz), 7.59 (1H, s), 7.16 (1H, s), 7.00 (1H, dd, J=8.34, 1.81 Hz), 6.88 (1H, d, J=1.76 Hz), 5.91-5.80 (1H, m), 4.48-4.44 (2H, m), 4.42-4.37 (2H, m), 3.37-3.26 (2H, m), 3.06-2.88 (4H, m), 2.57-2.47 (1H, m), 2.38 (3H, s), 2.30 (2H, s), 1.87 (2H, d, J=12.74 Hz), 1.76 (2H, s), 1.54 (6H, d, J=6.65 Hz), 1.15 (3H, t, J=7.26 Hz).
Reaction SMILES: [NH2:1][CH:2]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][CH2:5][CH:6]([NH2:16])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O:27][C:28](=O)[CH2:29][O:30][CH2:31][C:32](OC)=[O:33]>CO>[CH2:19]([O:18][CH2:17][CH:2]1[CH2:3][NH:4][CH2:5][CH:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:16][C:32](=[O:33])[CH2:31][O:30][CH2:29][C:28](=[O:27])[NH:1]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(CNCC(N)COCc1ccccc1)COCc1ccccc1
Reactant: COC(=O)COCC(=O)OC
Solvent: CO
Product: O=C1COCC(=O)NC(COCc2ccccc2)CNCC(COCc2ccccc2)N1

Procedure:
1,5-Diamino-1,5-dibenzyloxymethyl-3-aza-pentane (0.250 g, 0.73 mmol) (Example 6 (d)) and diglycolic acid dimethyl ester (0.118 g, 0.73 mmol) were dissolved in methanol (20 ml). The mixture was refluxed for 6 days. The solvent was evaporated and the mixture chromatographed on a silica column. 5,9-Bis(benzyloxymethyl)-1-oxa-4,7,10-triazacyclododecane -3,11-dione was isolated as a yellow oil. Yield 0.273 g (85%). FAB MS: 442(M+1).
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([O:15]C)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([NH2:2])=[O:15])[CH3:5]
Reactant: [NH4+]
Reactant: COC(=O)c1sccc1N=NN(C)C
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)N=Nc1ccsc1C(N)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (20 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (600 mg) in THF (5 mL) for 5 min and stirred at rt for 20 h. The solution was poured into ice cooled water and the precipitated solid was filtered and dried to give crude product, which was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product as an off-white solid (400 mg, 72%), mp 168-170° C. IR (neat) νmax 3337, 3172, 2923, 1636, 1599, 1348, 1219, 1117, 884, 771 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.28 (2H, br s), 7.35 (1H, d, J=5.6 Hz), 7.31 (1H, d, J=5.6 Hz), 3.58 (3H, br s), 3.20 (3H, br s); LC-MS (positive ion mode): m/z 221 (M+Na)+.