Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:30]=[C:31]([NH:35][NH2:36])[CH:32]=[CH:33][CH:34]=1>>[F:24][C:21]([F:22])([F:23])[O:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([O:28][C:27]([F:37])([F:38])[F:26])[CH:30]=4)[N:36]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc(OC(F)(F)F)c1
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(OC(F)(F)F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 3-trifluoromethoxy-phenylhydrazine according to the method described for example 91. MS: M=483.2 (M+H)+
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[OH-].[Na+].[CH2:10]1[O:12][CH2:11]1>O>[OH:12][CH2:11][CH2:10][NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4]
Reactant: N[C@@H](CS)C(=O)O
Reactant: C1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@H](CS)NCCO
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
109 g (0.9 mol) of L-cysteine was added into a 2000 ml round-bottomed flask, dissolved with 1000 ml of distilled water, cooled to 10° C. in ice bath, and neutralized to PH˜7 with 24 ml of 1M NaOH solution. 100 ml of ethylene oxide which was pre-cooled was taken at 10° C. and added to the above mixture, the mixture was reacted for 1 h while keeping the temperature at 10° C., then the temperature was raised to room temperature and the reaction was continued for another 1.5 h.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:32]([CH2:34][O:35]C(=O)C)=[O:33]>>[OH:35][CH2:34][C:32]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:33]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Reactant: CC(=O)OCC(=O)Cl
Product: O=C(CO)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:14]([O-:16])=[O:15])[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.B(Br)(Br)Br.I.[CH3:22][O:23]COC>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:14]([O-:16])=[O:15])[CH:6]=[C:7]([O:12][CH2:13][O:23][CH3:22])[CH:8]=2)[N:3]=1
Reactant: COc1cc([N+](=O)[O-])c2nc(C)ccc2c1
Reactant: COCOC
Agent: BrB(Br)Br
Agent: I
Product: COCOc1cc([N+](=O)[O-])c2nc(C)ccc2c1

Procedure:
The preparation of chelators where R8 and R9 are part of a quinoline ring and W=OH begins, for example, with 2-methyl-6-methoxy-8-nitroquinoline. The methoxy group could be cleaved with BBr3 or hot HI to yield a 6-hydroxy group, which could then be protected by reaction with dimethoxymethane under acid catalysis to yield 2-methyl-6-methoxymethyloxy-8-nitroquinoline. This can be used as starting material for the synthesis outlined above for 2-methyl-6-W-8-nitroquinoline, leading to chelators with W=OCH2OCH3. Mild acid hydrolysis of this compound gives chelators with W=OH.
Reaction SMILES: [Br:1][C:2]1[CH2:7][C:6]([F:9])(I)[CH:5]=[CH:4][C:3]=1[F:10].[CH2:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=1)[CH2:12][CH3:13].Cl>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([C:21]#[C:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:11][CH2:12][CH3:13])=[CH:15][CH:16]=2)=[C:6]([F:9])[CH:7]=1
Reactant: C#Cc1ccc(CCC)cc1
Reactant: FC1=C(Br)CC(F)(I)C=C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: CCCc1ccc(C#Cc2cc(F)c(Br)cc2F)cc1
Temperature: 5 °C
Yield: 80.6 %

Procedure:
2-Bromo-1,4-difluoro-4-iodobenzene (19 g) was dissolved in diethylamine (28 ml) under nitrogen atmosphere, and then bis(triphenylphosphine)palladium(II) chloride (0.06 g) and copper(I) iodide (0.06 g) were added thereto, followed by stirring. The flask was cooled to 5° C. or lower, and then 4-propylphenylacetylene (10 g) was added dropwise thereto. After stirring at room temperature for 5 hours, the reaction solution was poured into a mixture of concentrated hydrochloric acid (15 ml) and ice (30 g). After extraction with chloroform, the resultant was washed with water twice, followed by distilling off chloroform. The residue was distilled under reduced pressure (b.p. 170° to 180° C./4 mmHg) to give 4-bromo-2,5-difluoro-4'-propyltolane (16 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([C:24]2[N:28]=[CH:27][S:26][N:25]=2)[CH:21]=[CH:22][CH:23]=1>>[S:26]1[CH:27]=[N:28][C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:18][C:19]=2[C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)=[N:25]1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: Brc1cccc(-c2ncsn2)c1
Product: CC1(C)OC(=O)Nc2ccc(-c3ccccc3-c3ncsn3)cc21
Yield: 35 %

Procedure:
According to procedure B, (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid was coupled with 3-[3-bromo-phenyl]-[1,2,4]thiadiazole to yield 6-(1,2,4-thiadiazol-3-yl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one as an off-white solid (0.5 g, 35%): mp 214-216° C.; 1H-NMR (DMSO-d6) δ 10.40 (s, 1H), 10.36 (s, 1H), 8.49 (s, 1H), 8.23 (d, 1H, J=7.7 Hz), 7.83 (d, 1H, J=7.9 Hz), 7.66-7.61 (m, 3H), 7.02 (t, 1H, J=4.4 Hz), 1.70 (s, 6H); MS ((+)APCI) [M+H]+@m/z 338.
Reaction SMILES: C(=[C:8]1[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(=O)=[O:19].CC(C)=O.O=[O+][O-].O=O>ClCCl.CO>[N:16]1[C:17]2[C:8](=[O:19])[CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: C(=C1CCCc2cccnc21)c1ccccc1
Reactant: O=C=O
Agent: O=O
Agent: O=[O+][O-]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CO
Product: O=C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5,6,7,8-tetrahydroquinoline (18.2 g, 137 mmol), benzaldehyde (17.67 g, 166.0 mmol), and acetic anhydride (24.5 mL, 254 mmol) was heated under a nitrogen environment at 165° C. for 16 hours. The reaction mixture was cooled to room temperature. Crushed ice was added, and the mixture was slowly basified with NaOH (solid then 2 N NaOH) to pH around 7. The aqueous layer was extracted with hexane/ethyl acetate (1:1 solution) 3 times. The pooled organic layers were dried over magnesium sulfate. The mixture was filtered, and the solvents were removed under vacuum to give 8-benzylidene-5,6,7,8-tetrahydro-quinoline (Intermediate 1) as a brown solid. A solution of Intermediate 1 in dichoromethane (100 mL) and methanol (500 mL) was cooled to −78° C. (dry ice/acetone bath), and charged with ozone/oxygen (3 psi, 1.5 ampere). The dark brown solution turned yellow after several hours. When Intermediate 1 was consumed (TLC), ozone/oxygen flow was stopped. The reaction mixture was purged with nitrogen for 10 minutes. Methyl sulfide (6 mL) was added, and the mixture was stirred for 30 minutes at room temperature. The solvents were removed under vacuum. The residue was dissolved in 1 N HCl (500 mL), and washed with diethyl ether (4×150 mL). The aqueous layer was basified to pH˜7 with NaOH (s), and extracted with ethyl acetate (2×200 mL). The pooled ethyl acetate layers were dried over magnesium sulfate. The mixture was filtered and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel with 90% EtOAc:hexane to give a clean product. The aqueous layer was extracted with chloroform/isopropanol (3:1) several times. The pooled chloroform/isopropanol layers were dried over magnesium sulfate. The mixture was filtered and the solvents were removed under vacuum to give 6,7-dihydro-5H-quinolin-8-one (Intermediate 2), 17.89 g (122.0 mmol, 89% over 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(CC(=O)O)sc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A mixture of methyl 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-acetate (2 g) and 4N sodium hydroxide solution (3.7 ml) in tetrahydrofuran (20 ml) as stirred at ambient temperature for 1 hour. The mixture was diluted with water and washed with toluene. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was recrystallized from a mixture of ethanol and water to give pale orange crystals of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-acetic acid (1.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[CH:7][N:6]=1)=[O:4]
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CC2)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (2.0 g, 13.1 mmol) in N,N-dimethylformamide was treated with potassium carbonate (2.71 g, 19.6 mmol) and 1-bromomethyl-cyclopropane (1.6 ml, 15.7 mmol). The reaction mixture was stirred at 100° C. for 16 hours. For the workup, the reaction mixture was diluted with ethyl acetate, solid material was filtered, and the filtrate evaporated at reduced pressure. The residue was purified by chromatography on silica using a gradient of n-heptane and ethyl acetate=100/0 to 20/80 as the eluent to give the 5-cyclopropylmethoxy-pyridine-2-carboxylic acid methyl ester as a yellow liquid (1.69 g, 62% of theory). Mass (calculated) C11H13NO3 [207.228]; (found) [M+H]+=208.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.FC(F)(F)S(O[C:33]1[C:42]([N+:43]([O-:45])=[O:44])=[C:41]([NH:46][CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1)(=O)=O>C1(C)C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:26][CH:25]=2)[C:33]2[C:42]([N+:43]([O-:45])=[O:44])=[C:41]([NH:46][CH2:47][CH2:48][CH2:49][NH:50][C:51](=[O:52])[O:53][C:54]([CH3:56])([CH3:55])[CH3:57])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)nc2ccccc12
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc3ccccc3c(NCCCNC(=O)OC(C)(C)C)c2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
Triethylamine (56.8 mL, 408 mmol) and N,N-bis(4-methoxybenzyl)amine (93.5 g, 0.340 mol) were sequentially added to a solution of 4-({3-[(tert-butoxycarbonyl)amino]propyl} amino)-3-nitroquinolin-2-yl trifluoromethanesulfonate (168 g, 0.340 mol) in toluene (200 mL) at ambient temperature. The solution was stirred at ambient temperature for a few minutes, heated at 65° C. overnight, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (>200 mL), and the resulting solution was washed three times with water, dried over magnesium sulfate, filtered through a layer of CELITE filter agent, concentrated under reduced pressure, and further dried under high vacuum to provide tert-butyl 3-({2-[bis(4-methoxybenzyl)amino]-3-nitroquinolin-4-yl} amino)propylcarbamate as a red oil, which was used without purification.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH2:12])=[O:11].[Cl:13][CH2:14][C:15]([CH2:17]Cl)=O>>[Cl:13][CH2:14][C:15]1[N:12]=[C:10]([C:2]2[S:1][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=3[CH:3]=2)[O:11][CH:17]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1cc2c(s1)CCCC2
Product: ClCc1coc(-c2cc3c(s2)CCCC3)n1
Yield: 53 %

Procedure:
In substantially the same manner as in Reference Example 47, 4,5,6,7-tetrahydro-2-benzothiophene carboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(4,5,6,7-tetrahydro-2-benzothienyl)oxazole. The yield was 53%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 102-103° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCO>[CH:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=1)([CH3:8])[CH3:1]
Reactant: NNc1ccccc1
Reactant: CC(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)c1cc(N)n(-c2ccccc2)n1
Temperature: 65 °C
Yield: 77.8 %

Procedure:
Using the procedure described in Example 308A Step 1, to a solution of 4-methyl-3-oxopentanenitrile (303 mg, 2.7 mmol) prepared as described in Example 122A Step 1, in anhydrous EtOH (6 ml) was added phenylhydrazine hydrochloride (473 mg, 3.3 mmol) and the reaction mixture was heated at 65° C. overnight. The residue was purified by silica gel chromatography (hexane/ethyl acetate 2-50%) to afford 3-isopropyl-1-phenyl-1H-pyrazol-5-amine (423 mg, 77%) as a solid. 1H NMR (300 MHz, CDCl3) δ 1.22 (d, J=6 Hz, 6H), 3.86 (brs, 2H), 5.35 (s, 1H), 7.21-7.49 (m, 5H); LC-MS (ESI) m/z 202 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48]1([N:54]=[C:55]=[O:56])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:55]([NH:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:56])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2ccccc2)CC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 53 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 53% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.49 (s, 1H), 9.38 (s, 1H), 9.35 (s, 1H), 8.47 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.72 (s, 1H), 7.43 (d, 2H), 7.20 (m, 3H), 7.04 (m, 2H), 6.90 (m, 2H), 6.78 (d, 1H), 4.15 (d, 2H), 2.82 (m, 6H), 2.30 (d, 2H), 2.00 (m, 1H), 1.72 (m, 2H), 1.20 (m, 2H). LCMS for C32H33ClN7O2 (M+H)+: m/z=582.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][CH:16]([CH:30]([CH3:32])[CH3:31])[CH2:17][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]3[CH2:21][O:20]3)[CH:13]=2)[N:8]([CH3:33])[CH:7]=1.[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+]>CO>[N:34]([CH2:21][CH:19]([CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17][CH:16]([CH2:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:33])[CH:7]=[C:6]2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:30]([CH3:32])[CH3:31])[OH:20])=[N+:35]=[N-:36]
Reactant: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C3CO3)C(C)C)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CN=[N+]=[N-])C(C)C)cc12

Procedure:
The solution of 0.59 g of tert-butyl {3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methyl-1-oxiranylpentyl}carbamate (Example 3Ab) in 12 ml of methanol is admixed with 0.21 g of sodium azide and 0.12 g of ammonium chloride and stirred at reflux over 6 hours. The reaction mixture is cooled, poured onto ice-water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:5]=[C:6]([Mg]Br)[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(S(/[N:18]=[CH:19]\[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=O)(C)(C)C>C1COCC1>[NH2:18][CH:19]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([S:3][CH2:1][CH3:2])[CH:5]=1)[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: CCSc1cccc([Mg]Br)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1/C=N\S(=O)C(C)(C)C
Solvent: C1CCOC1
Product: CCSc1cccc(C(N)C2CCCCN2C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-(ethylthio)phenylmagnesium bromide in THF (10 mL 11.6 mmol) was added to a cooled (0° C.) solution of tert-butyl 2-{(Z)-[(tert-butylsulfinyl)imino]methyl}piperidine-1-carboxylate (1.5 g, 4.7 mmol) in THF (10 mL) and the mixture was stirred for 60 min The mixture was quenched with 50 mL of a 1:1 mixture of saturated aqueous ammonium chloride and 33% aqueous ammonia before extracting into ethyl acetate (100 mL). The organic phase was dried (MgSO4) and concentrated. The residue was treated with methanol (20 mL), cooled to 0° C. and then 4N hydrogen chloride in dioxane (5 mL) was added. After stirring for 30 min 4N aqueous sodium hydroxide (6 mL) was added and the mixture was extracted into DCM. The organic extract was dried (Na2SO4) and concentrated. The residue was purified on silica gel eluting with iso-hexane on a gradient of ethyl acetate (0-60%) followed by dichloromethane on a gradient of methanol (2-10%) to give the title product as a 1.7:1 mixture of diastereoisomers (860 mg, 51%). 1H NMR (360 MHz, CDCl3): δ 7.30-7.09 (4H, m), 4.30-4.1 (2H, m), 4.05-3.88 (1H, br), 3.78-3.60 (2H, m), 2.99-2.88 (2H, m), 2.80 (1H, dt, J=2.8, 13.4 Hz), 2.11 (1H, d, J=13.6 Hz), 1.75-1.41 (5H, m), 1.34-1.30 (3H, m), 1.23 (3.5H, s), 1.20 (5.5H, s).
Reaction SMILES: [CH3:1][CH:2]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=O)[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH3:40][C:41]1[O:45][N:44]=[C:43]([NH2:46])[CH:42]=1.C(N(CC)C(C)C)(C)C.N#N>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][CH:2]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([NH:46][C:43]4[CH:42]=[C:41]([CH3:40])[O:45][N:44]=4)=[O:17])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1
Reactant: Cc1cc(N)no1
Reactant: CC1CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2ccc3cc4n(c3c2)C(C)CNC4=O)no1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
To a solution of 4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylic acid (50 mg, 0.21 mmol) in DMF (1 mL) are added N-hydroxybenzotriazole (39 mg, 0.29 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (61 mg, 0.32 mmol). After stirring for 10 min, 5-methyl-3-aminoisoxazole (38 mg, 0.39 mmol), N,N-diisopropylethylamine (0.07 mL, 0.42 mmol) and 4-dimethylaminopyridine (2.6 mg, 0.02 mmol) are added. The reaction mixture is heated at 50° C. for 15 h and simultaneously a stream of N2 is blown over the reaction mixture to remove DMF. The residue is cooled to room temperature and EtOAc (4 mL) and water (2 mL) are added. The resulting white solid is collected by filtration to afford the title compound (32 mg, 48%). LCMS (ESMS): m/z 325.61 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11](OC(=O)C)(=[O:13])[CH3:12]>CO>[OH:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:11](=[O:13])[CH3:12]
Reactant: COc1ccccc1CN
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)NCc1ccccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
2-Methoxybenzylamine (822 mg, 6.0 mmol) in methanol (10 mL) was treated with acetic anhydride (613 mg, 6.0 mmol) at room temperature for 2 h. The volatiles were removed in vacuo. The residue was dissolved in CH2Cl2, cooled to 0° C., 1M solution of BBr3 in CH2Cl2 (12 mL, 12.0 mml) was added slowly. After addition was completed the reaction mixture was stirred at room temperature overnight, cooled to 0° C., methanol (3 mL) was added and after 10 min volatiles were removed in vacuo. The residue was dissolved in ethyl acetate, washed successively with aqueous NaHCO3 and H2O. The organic layer was dried over Na2SO4 filtered and concentrated. The residue was purified by silica gel flash chromatography (0-50% ethyl acetate in petroleum spirit) to give the subtitled compound (400 mg).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>O1CCOCC1>[C:1]1([C:7]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]([NH:28][CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1-c1ccccc1
Reactant: NCc1cccs1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(NCc2cccs2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
The mixture of ethyl 4-phenyl-2-methanesulphonylpyrimidine-5-carboxylate (2.30 g, 7.5 mmol), 2-thienylmethylamine (2.12 g, 18.75 mmol) and dioxane (30 ml) were stirred at room temperature for 16 hours, the solvent was removed in vacuum. To the residue ethanol (10 ml) was added, the resulting crystals were filtered off in vacuum, washed with ethanol (5 ml) to obtain 1.99 g (78%) of the title ester in the form of white crystals, m.p.: 123-124° C.; [M+H]+ 340
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[C:4]([C:13]2[N:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:3]1.[CH3:32][Sn:33]([N:36]=[N+:37]=[N-:38])([CH3:35])[CH3:34]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:36]([Sn:33]([CH3:35])([CH3:34])[CH3:32])[N:37]=[N:38][N:12]=3)=[CH:8][CH:9]=2)[C:4]([C:13]2[N:21]([S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:23])=[O:24])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:3]1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C#N)cc34)cc3cccnc32)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(-c5nnnn5[Sn](C)(C)C)cc34)cc3cccnc32)cc1
Yield: 84.3 %

Procedure:
A solution of 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indole-5-carbonitrile [100 mg, Reference Example 13(c)] in toluene (10 mL) was treated with trimethyltin azide (56 mg, 0.28 mmol) then heated under reflux for 14 hours. The white precipitate was collected by filtration washed with toluene (10 mL) and then dried to give the title compound (125 mg) as a colourless solid, m.p. 240-243° C. (with decomposition). MS: 633(MH+).