Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[CH2:13]([C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:14]
Reactant: CCC1(CC)C(=O)Nc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCC1(CC)C(=O)Nc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 94 %

Procedure:
To a solution of 3,3-diethyl-1,3-dihydro-indol-2-one (10.0 g, 52.84 mmol, A. Mertens et al., J. Med. Chem. 1987, 30, 1279-1287) in conc. sulfuric acid (50 ml) was added slowly a mixture of nitric acid (65%, 5.12 g, 3.63 ml, 52.84 mmol) and conc. sulfuric acid (10 ml) at 0° C. After 2 h at room temperature the mixture was poured into ice water. The precipitate was filtered off, washed with water and dried to yield 11.7 g 3,3-diethyl-5-nitro-1,3-dihydro-indol-2-one (49.95 mmol, 94%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:50][C:51]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][NH:56][CH2:55]1>CN(C=O)C.O>[F:50][C:51]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][N:56]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:55]1
Reactant: Fc1ccc(F)c(OC2CCNC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2F)C1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 76 %

Procedure:
DIPEA (166 mg, 1.28 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (70 mg, 0.28 mmol) in DMF (5 mL) followed by HOBt (42 mg, 0.31 mmol) and EDCI (136 mg, 0.71 mmol). After 2 minutes of stirring, 3-(2,5-difluoro-phenoxy)-pyrrolidine hydrochloride (prepared by the method used for the synthesis of Intermediate 72) (74 mg, 0.3 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added and the precipitate was collected. The solid was purified by recrystallisation from a mixture of 20% ethyl acetate in hexane (15 mL), water (0.5 mL) and MeOH (0.03 mL) to afford 92 mg (76% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[3-(2,5-difluoro-phenoxy)-pyrrolidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 427.15. 1H NMR (300 MHz, DMSO-d6): δ 13.8 (s, 1H), 8.1 (s, 1H), 7.84 (d, 2H), 7.54-7.12 (m, 6H), 7.14 (s, 1H), 6.88 (t, 1H), 5.3 (d, 1H), 4.1 (d, 2H), 3.9-3.5 (m, 4H), 2.3 (s, 1H), 2.1 (s, 1H).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:12][N:11]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3Cl)[CH:16]=2)=[O:14])[CH2:10]1)(C(C)(C)C)(C)C.[F:25][C:26]1[CH:43]=[C:42]([N+:44]([O-:46])=[O:45])[CH:41]=[CH:40][C:27]=1[O:28]C1C=CN=C2C=C(SC)SC=12>>[F:25][C:26]1[CH:43]=[C:42]([N+:44]([O-:46])=[O:45])[CH:41]=[CH:40][C:27]=1[O:28][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:16]=[C:15]([C:13]([N:11]3[CH2:10][CH:9]([OH:8])[CH2:12]3)=[O:14])[S:23][C:22]=12
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: CSc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Product: O=C(c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1)N1CC(O)C1
Yield: 39 %

Procedure:
Starting from the amide 297 and following the procedure described above for the synthesis of compound 230 (scheme 50, example 203), title compound 298 was obtained in 39% yield as a syrup. MS (m/z): 389.05 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][CH2:20][CH2:19][O:18][CH3:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: COCCCN
Solvent: CCN(CC)CC
Product: COCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(3-methoxypropylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-methoxypropylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N:14]1[C:23]2[C:18](=[CH:19][C:20](B(O)O)=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:14]=[CH:15][CH:16]=[CH:17]3)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: OB(O)c1ccc2ncccc2c1
Reactant: CCOC(=O)c1cc(Cl)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cc(Cl)ccc1-c1ccc2ncccc2c1
Yield: 39.1 %

Procedure:
A degassed mixture of ethyl 5-chloro-2-iodobenzoate (0.621 g, 2.00 mmol), Pd(PPh3)4 (0.116 mg, 0.1 mmol), quinolin-6-ylboronic acid (0.381 g, 2.2 mmol), K2CO3 (0.553 g, 4.0 mmol), dimethoxyethane (20 mL), and water (5 mL) was heated under reflux overnight. Solvents were removed under reduced pressure. The residue was diluted with sat'd NH4Cl (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried (MgSO4), concentrated in vacuo and purified by chromatography to afford ethyl 5-chloro-2-(quinolin-6-yl)benzoate (0.244 g, 39% yield) as a colorless oil. MS (ESI) m/z: 312.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([OH:23])[C:18]([O:20]CC)=O)=[CH:11][C:10]=1[O:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:27][C:28]#[N:29].[K+]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]2[O:23][C:28](=[O:27])[NH:29][C:18]2=[O:20])=[CH:11][C:10]=1[O:24][CH2:25][CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)CCc1ccc(OCc2ccccc2)c(OCC)c1
Reactant: N#C[O-]
Agent: [K+]
Product: CCOc1cc(CCC2OC(=O)NC2=O)ccc1OCc1ccccc1

Procedure:
In substantially the same manner as in Working Example 34, ethyl 4-(4-benzyloxy-3-ethoxyphenyl)-2-hydroxybutanoate was reacted with potassium cyanate (KCNO) to obtain 5-[2-(4-benzyloxy-3-ethoxyphenyl)ethyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.143-144° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:42]=[C:23]4[C:24]([C:28]5[CH:33]=[C:32]([CH:34]([F:36])[F:35])[CH:31]=[CH:30][C:29]=5[O:37][CH2:38][CH:39]([F:41])[F:40])=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[F:41][CH:39]([F:40])[CH2:38][O:37][C:29]1[CH:30]=[CH:31][C:32]([CH:34]([F:36])[F:35])=[CH:33][C:28]=1[C:24]1[C:23]2[N:22]([N:21]=[C:20]([NH:19][C:17]3[CH:16]=[CH:15][C:12]4[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=4[CH:18]=3)[N:42]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cc(C(F)F)ccc5OCC(F)F)cccn4n3)cc2CC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)COc1ccc(C(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12

Procedure:
{8-[2-(2,2-Difluoro-ethoxy)-5-difluoromethyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine was prepared from 7-{8-[2-(2,2-difluoro-ethoxy)-5-difluoromethyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester and trifluoroacetic acid (0.5 mL) in a manner analogous to Example 312 to give product (0.111 g). MP=92-93° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.47 (s, 1H), 8.78 (d, 1H), 7.90 (s, 1H), 7.65 (m, 2H), 7.42 (m, 3H), 7.05 (m, 2H), 7.02 (br m, 1H), 6.30 (br m, 1H), 4.42 (m, 2H), 2.76 (br m, 9H). MS=486 (MH)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:20][Si:21]([C:24]#[C:25][Sn](CCCC)(CCCC)CCCC)([CH3:23])[CH3:22]>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: Oc1ccc(-c2cc(Br)c3cc(O)ccc3n2)cc1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Product: C[Si](C)(C)C#Cc1cc(-c2ccc(O)cc2)nc2ccc(O)cc12
Yield: 83 %

Procedure:
This compound was prepared from 6a and (trimethylsilylethynyl)tributyltin according to method J. Yellow powder; Yield: 83%; mp 210° C. (dec.); 1H-NMR (300 MHz, acetone-d6) δ 0.38 (s, 9H), 7.02 (d, J=8.7 Hz, 2H), 7.44 (dd, J=9.1, 2.7 Hz, 1H), 7.63 (d, J=2.7 Hz, 1H), 7.99 (d, J=9.1 Hz, 1H), 8.05 (s, 1H), 8.18 (d, J=8.7 Hz, 2H), 8.70 (s, 1H), 9.15 (s, 1H); MS (ESI) m/z 332 ([M−H]−), 334 ([M+H]+); Anal. Calcd for C20H19NO2Si: C, 72.04; H, 5.74; N, 4.20. Found: C, 71.67; H, 5.79; N, 4.07.
Reaction SMILES: [O-:1][CH2:2]C.[Na+].C(O)C.[Cl:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(OCC)=O>C(OCC)C>[Cl:8][CH:9]([CH:2]=[O:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC[O-]
Reactant: CCOC(=O)CCl
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(Cl)C=O
Reaction time: 8 h

Procedure:
139 ml of a 21% strength solution of sodium ethoxide in ethanol (371 mmol, 0.91 equivalents) were initially charged in 200 ml of diethyl ether, and a solution consisting of 43.7 ml of ethyl chloroacetate (408 mmol, 1 equivalent) and 32.9 ml of ethyl formate (408 mmol, 1 equivalent) in 150 ml of diethyl ether was added dropwise at RT. The reaction mixture was stirred overnight and the solid was filtered off and washed with diethyl ether. The solid was dissolved in water and the aqueous phase was, with ice bath cooling, adjusted to pH4 using concentrated hydrochloric acid. The mixture was extracted repeatedly with diethyl ether and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried with magnesium sulphate, filtered and concentrated. The crude product obtained (8.2 g) was freed from residual solvent under high vacuum and used without further purification for the next reaction.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][NH2:34])[N:18]=[C:17]([CH:35]3[CH2:37][CH2:36]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[S:43](Cl)(=[O:45])=[O:44]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][NH:34][S:43]([C:39]3[S:38][CH:42]=[CH:41][CH:40]=3)(=[O:45])=[O:44])[N:18]=[C:17]([CH:35]3[CH2:37][CH2:36]3)[N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C2CC2)nc1OCCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C2CC2)nc1OCCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 200 mg p-tert.-butyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]benzene-sulfonamide was reacted with thiophene-2-sulfonylchloride to give 144 mg p-tert.-butyl-N-[6-(3-(2-thiophene-sulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]benzene-sulfonamide. LC-MS: tR=6.06 min, [M+1]+=673.20, [M−1]−=671.24.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9]Br)[C:3]=1[CH2:11]Br.C(=O)([O-])O.[K+].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC#N>[CH2:18]([N:25]1[CH2:11][C:3]2[C:4](=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[Br:1])[CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Fc1ccc(Br)c(CBr)c1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(Br)c2c1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
To a mixture of 1-bromo-2,3-bis(bromomethyl)-4-fluorobenzene (7.59 g, 21.0 mmol) and potassium hydrogen carbonate (5.26 g, 52.6 mmol) in 800 mL CH3CN was added benzylamine (2.25 g, 21.0 mmol). The resulting suspension was refluxed for 8 h then stirred at 25° C. for 18 h. The mixture was filtered, and the residue was purified by column chromatography on silica gel (gradient elution, 10 to 60% DCM in hexanes) and concentrated to give 2-benzyl-4-bromo-7-fluoroisoindoline (3.00 g, 46% yield) as colorless oil. LRMS (ESI) m/z 306.3 [(M+H)+; calcd for C15H14NBrF: 306.2].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:15][CH2:16][C:17]1[C:18]([F:37])=[CH:19][C:20]([Cl:36])=[C:21]([C:23]2[NH:24][C:25](=[O:35])[N:26]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:27]=2)[CH:22]=1.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[Cl:36][C:20]1[C:21]([C:23]2[NH:24][C:25](=[O:35])[N:26]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:27]=2)=[CH:22][C:17]([CH2:16][NH:15][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[C:18]([F:37])[CH:19]=1
Reactant: O=C(O)c1ccccc1F
Reactant: NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F)c1ccccc1F
Reaction time: 3 h
Yield: 9.5 %

Procedure:
A mixture of 2-fluoro benzoic acid (0.400 g), thionyl chloride (20 mL) and DMF (cat. amt.) was refluxed for 5 h and excess of solvent was removed under reduced pressure to obtain crude product. The obtained crude product was added to the solution of 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-chlorophenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-78, 0.250 g) and DIPEA (1.0 mL) in THF (20 mL) and the reaction mass was stirred for 3 h. After completion of reaction, reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was separated, concentrated to afford 0.032 g of the desired product. 1H NMR (300 MHz, DMSO): δ 4.53 (br s, 2H), 7.29 (m, 2H), 7.70 (m, 3H), 7.78 (m, 3H), 7.95 (br s, 2H), 8.94 (br s, 1H), 12.63 (br s, 1H); MS (m/z): 475.39 (M+H)+.
Reaction SMILES: BrCC1C=NSN=1.[S:8]1[N:12]=[CH:11][C:10]([CH2:13][S:14][CH2:15][CH2:16][SH:17])=[N:9]1.[C:18]([NH:20][C:21](=[N:24][CH3:25])SC)#[N:19]>>[S:8]1[N:12]=[CH:11][C:10]([CH2:13][S:14][CH2:15][CH2:16][S:17][C:21](=[N:24][CH3:25])[NH:20][C:18]#[N:19])=[N:9]1
Reactant: CN=C(NC#N)SC
Reactant: SCCSCc1cnsn1
Agent: BrCc1cnsn1
Product: CN=C(NC#N)SCCSCc1cnsn1

Procedure:
Conversion of 3-bromomethyl-1,2,5-thiadiazole into 2-((1,2,5-thiadiazol-3-yl)methylthio)ethane thiol by the procedure of Example 1 and treatment of this product with N-cyano-N',S-dimethylisothiourea according to the procedure of Example 2 leads to the production of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].BrC[C:21]1[CH:22]=[CH:23][C:24]2[S:28][C:27]([CH3:29])=[N:26][C:25]=2[CH:30]=1>CC#N>[CH3:12][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[S:8]([NH:11][C:21]1[CH:22]=[CH:23][C:24]2[S:28][C:27]([CH3:29])=[N:26][C:25]=2[CH:30]=1)(=[O:9])=[O:10]
Reactant: Cc1c(Cl)cccc1S(N)(=O)=O
Reactant: Cc1nc2cc(CBr)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2cc(NS(=O)(=O)c3cccc(Cl)c3C)ccc2s1

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonamide (103 mg, 0.5 mmol) in CH3CN was added potassium carbonate (100 mg), followed 5-bromomethyl-2-methylbenzothiazole (121 mg, 0.5 mmol). The mixture was refluxed under N2 for 6 h, partitioned between ethyl acetate and water. The organic phase was washed brine, dried over sodium sulphate and concentrated in vacuo to give a yellow residue, which was separated with flash chromatography (ethyl acetate/DCM, gradient elution). STX1029 was obtained as white solid. TLC single spot at Rf 0.55 (10% EtOAc/DCM); HPLC purity >99% (tR 2.0 min in 10% water-methanol); 1HNMR (270 MHz, CDCl3) δ7.89 (1H, d, J=7.9 Hz, ArH), 7.66 (1H, d, J=7.9 Hz, ArH), 7.65 (1H, d, J=1.3 Hz, ArH), 7.49 (1H, d, J=7.9 Hz, ArH), 7.17 (1H, t, J=7.9 Hz, ArH), 7.13 (1H, dd, J=7.9, 1.5 Hz, ArH), 5.35 (1H, t, J=5.9 Hz, NH), 4.24 (2H, d, J=5.9 Hz, CH2), 2.79 (3H, s, CH3), 2.62 (3H, s, CH3); APCI-MS 367 (MH)+; FAB-HRMS calcd for C16H16ClN2O2S2 (MH+) 367.0342, found 367.0330.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:21]([C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][N:25]=1)([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C>C(#N)C>[CH:21]([C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH:31][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=4[C:14]#[N:15])[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:26][N:25]=1)([CH3:23])[CH3:22]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: CC(C)c1ncc(CN)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4cnc(C(C)C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (80 mg, 0.28 mmol) and (2-isopropylpyrimidin-5-yl)methanamine (60 mg, 0.40 mmol) (prepared similarly according to the method for Intermediate 13) in acetonitrile (1 mL) and N,N-diisopropylethylamine (0.3 mL, 2 mmol) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and purified by semi-preparative HPLC (100×20.2 mm, C18 column; 40-60% CH3CN-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([NH:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([CH3:37])=[CH:31][C:32](=[O:36])[O:33]2)=[CH:28][CH:27]=1)=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:22])[NH2:21])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].C(N(CC)CC)C.[C:45](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:47])[CH3:46].CCOCC>CN(C=O)C>[C:45]([NH:1][C@H:2]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([NH:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([CH3:37])=[CH:31][C:32](=[O:36])[O:33]2)=[CH:28][CH:27]=1)=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:21])[NH2:22])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7])(=[O:47])[CH3:46]
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)[C@@H](N)CCC(=O)O)ccc12
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](CCC(=O)O)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc2c(C)cc(=O)oc2c1
Yield: 91.6 %

Procedure:
7-(L-glutamylglycyl-L-arginyl)amino-4-methyl-coumarin (100 mg, 0.18 mM) was dissolved in DMF (2 ml), and triethylamine (0.03 ml) was added thereto with stirring and cooling. This mixture was adjusted to pH about 7, and then p-nitrophenyl acetate (36.1 mg, 0.23 mM) was added thereto. This mixture was stirred for 2 days at room temperature. Excess ether was added to the mixture and the produced precipitate was separated by filtration and dried. This product was dissolved in 80% methyl alcohol (2 ml) and ethyl acetate (30 ml) was added thereto for re-precipitation to give 7-(Nα -acetyl-L-glutamylglycyl-L-arginyl)amino-4-methylcoumarin [VI] (99 mg, yield: 84.9%).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].O.O.O.C([O-])(=O)C.[Na+].C(O)(=O)C>CO.O>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:2]([F:1])[C:7]=1[OH:8]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(O)c1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(N)c(O)c1F
Temperature: 25 °C
Yield: 43.5 %

Procedure:
Methyl 2-fluoro-3-hydroxy-4-nitrophenylacetate (5.22 g, 14.9 mmol), reduced iron powder (2.66 g, 47.7 mmol), sodium acetate-trihydrate (2.03 g, 14.9 mmol) and acetic acid (5.54 ml) were heated and refluxed at 110° C. for 4 hours in methanol:water (1:4, 300 ml). After cooling to room temperature, the reaction mixture was filtered through Celite under reduced pressure to remove the insoluble matter. The filtrate was then concentrated, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from hexane/ethyl acetate (2/1) eluate fractions, the title compound (1.29 g, 44%) was obtained as a brown oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:8]1([C:9]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: Clc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(Cl)cc1)C1CC1
Temperature: 12.5 °C
Reaction time: 1 h

Procedure:
A mixture of anhydrous aluminium chloride (20 g) and chlorobenzene (100 ml) was cooled to 10-15° C and treated dropwise with a solution of 4-chlorobutyrylchloride (20 g) in chlorobenzene (20 ml) over a period of 10 minutes with continuous stirring. The solution was warmed to 20-25° C and stirring was continued for a further 1 hour. It was poured onto ice and extracted with ether and the dried ethereal extract evaporated. The resulting liquid was treated with a solution of potassium hydroxide (12 g) in methanol (60 ml) and left to stand for 30 minutes with occasional shaking. After filtration the residue was washed with methanol and the filtrate evaporated to dryness. The oil was dissolved in ether and washed with water. The dried ethereal solution (Na2SO4) was evaporated and distilled (b.p.125-127°/5mm), yield =21.3 g,nD = 1.5700
Reaction SMILES: [N:1]#[C:2][NH2:3].[NH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.[N+:14]([O-:17])([OH:16])=[O:15]>O.C(O)C>[N+:14]([O-:17])([OH:16])=[O:15].[NH:4]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)[C:2]([NH2:3])=[NH:1]
Reactant: N#CN
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: O=[N+]([O-])O
Solvent: CCO
Solvent: O
Product: N=C(N)Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.1 %

Procedure:
A freshly prepared solution of cyanamide (0.48 g, 11.43 mmol) in water (1 ml) was added to a solution of 5-aminoindole (1.00 g, 7.56 mmol) in ethanol (5 ml). The mixture was treated with concentrated nitric acid (69%, 0.51 ml, 7.90 mmol) and then refluxed for 18 h. A further quantity of cyanamide (0.24 g, 5.71 mmol) was added and then heating continued for 5 h. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was triturated with ethyl acetate and the resulting precipitate collected and washed with ethyl acetate, then diethyl ether to give 5-guanidinoindole nitrate (1.67 g) as a brown solid m.p. 132-134°. δH (d6DMSO) 6.46 (1H, s), 6.92 (1H, dd, J 1.8, 8.5 Hz), 7.07 (4H, s), 7.43 (3H, m), 9.35 (1H, s) and 11.25 (1H, br s).