Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=1.[CH2:15]([NH2:18])[CH:16]=[CH2:17]>CN(C=O)C>[CH2:15]([NH:18][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:16]=[CH2:17]
Reactant: C=CCN
Reactant: CCCc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: C=CCNc1nc(Cl)nc2c(CCC)csc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.7 %

Procedure:
In 5 ml of DMF, 371 mg (1.5 mmol) of 2,4-dichloro-7-propylthieno[3,2-d]pyrimidine was dissolved, and then 188 mg (3.3 mmol) of allylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 244 mg (yield: 60.7%) of the title compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15]>C1COCC1>[CH3:11][C:12]([CH3:17])=[CH:13][C:14]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([Br:3])[CH:5]=1)=[O:15]
Reactant: Nc1cccc(Br)c1
Reactant: CC(C)=CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension of NaH (4.15 g, 173 mmol, 60% in oil) in 50 ml of THF was cannulated a solution of 20.322 g (118 mmol) of 3-bromoaniline in 50 ml of THF. The resulting mixture was stirred at 0° C. for 45 min and warmed to room temperature over a period of 15 min. To this solution was added through cannulation 13.123 g (173 mmol) of 3,3-dimethylacryloyl chloride. The mixture was stirred at room temperature for 24 h and thereafter slowly poured into ice water. The resulting mixture was extracted with methylene chloride (twice), dried over MgSO4 and concentrated to yield a solid. The solid was purified by recrystallization in hexane/EtOAc (2:1) to give the title compound as a light brown solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[CH3:23][O:24][C:25]1[C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=[C:27]([CH:35]=O)[CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:35][C:27]3[CH:26]=[C:25]([O:24][CH3:23])[C:30]4[O:31][CH2:32][CH2:33][O:34][C:29]=4[CH:28]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: COc1cc(C=O)cc2c1OCCO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc(OC)c5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To 10 mL of a chloroform solution containing 598 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 384 mg of 8-methoxy-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde, 113 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 639 mg of sodium triacetoxyborohydride was added, and stirred for 2 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=5:1] to give 492 mg of 7-methoxy-1-(2-(4-((8-methoxy-2,3-dihydro-1,4-benzodioxin-6-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[S:61][CH:62]=2)=[N:56]\[OH:57])[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:85]([O:88][C:89]1[C:97]([O:98][C:99](=[O:101])[CH3:100])=[CH:96][C:92]([C:93](Cl)=[O:94])=[C:91]([CH3:102])[CH:90]=1)(=[O:87])[CH3:86].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[S:61][CH:62]=2)=[N:56]\[O:57][C:93](=[O:94])[C:92]2[CH:96]=[C:97]([O:98][C:99](=[O:101])[CH3:100])[C:89]([O:88][C:85](=[O:87])[CH3:86])=[CH:90][C:91]=2[CH3:102])[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Oc1cc(C)c(C(=O)Cl)cc1OC(C)=O
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)Oc1cc(C)c(C(=O)O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4cc(C)nc5nc(C(=O)OC(c6ccccc6)c6ccccc6)nn45)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To an ice-cooled solution of (6R, 7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (0.7 g) in dry dichloromethane (10 ml) was added 4,5-diacetoxy-2-methylbenzoyl chloride (0.19 g) at once and then potassium carbonate (0.083 g). The yellow suspension was stirred at 0° C. for 30 minutes, the insoluble matters were removed by filtration, and the filtrate was washed with brine and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was crystallized with ether (20 ml), giving 0.80 g of the objective compound as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH3:20])=[CH:6]2.F[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1)=[C:8]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([CH3:20])=[CH:6]2
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A round-bottomed flask was charged with 3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenol (7) (2.5 g, 9.5 mmol), 4-fluorobenzaldehyde (1.22 mL, 11.4 mmol), Cs2CO3 (4.04 g, 12.4 mmol), and anhydrous DMF (25 mL) under N2. The reaction mixture was refluxed for 3 h. Reaction mixture was cooled at room temperature and purified by SiO2 column chromatography using hexanes:EtOAc (19:1 to 4:1) as an eluent to afford 3.41 g (98%) of the title compound as a white foam. 1H NMR (400 MHz, CDCl3): δ 9.80 (s, 1H), 7.68 (d, J=9.2 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.61 (d, J=5.2 Hz, 1H), 7.25 (d, J=7.6 Hz, 2H), 7.22 (d, J=5.2 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.14 (d, J=1.6 Hz, 1H), 7.11 (s, 1H), 7.07 and 7.04 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 6.71 (d, J=8.8 Hz, 2H), 3.94 (s, 3H), 2.26 (s, 3H). LCMS (ESI) m/z, 368.92 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)[CH2:39][NH2:40])[CH:35]=[CH:36][CH:37]=1>>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3[NH:40][CH2:39][CH:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCC(c1cccc(Cl)c1)c1cccc(Cl)c1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4cccc(Cl)c4)c4cccc(Cl)c4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The compound was prepared from (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (Preparation 45) and 2,2-bis(3-chlorophenyl)ethanamine (J. Med. Chem., 1988, 31(7), 1282) using a similar method to that of Preparation 64.
Reaction SMILES: BrC1C=CC(S[CH2:9][C:10]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=CC=1.Cl[C:22]1[CH:27]=CC=C(C(OO)=O)[CH:23]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:14][C:11]1([C:10]2([C:16]3[S:20][CH:19]=[N:18][CH:17]=3)[CH2:9][O:15]2)[CH2:12][CH2:27][CH2:22][CH2:23][CH2:13]1
Reactant: CC(C)(C)C(O)(CSc1ccc(Br)cc1)c1cncs1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C2(c3cncs3)CO2)CCCCC1

Procedure:
To 1.00 g (2.7 mmol) of 1-[(4-bromophenyl)sulphanyl]-3,3-dimethyl-2-(1,3-thiazol-5-yl)butan-2-ol dissolved in 100 ml of dichloromethane was added, at room temperature, 0.70 g (4.0 mmol) of meta-chloroperbenzoic acid, and the reaction mixture was stirred at room temperature for 16 h. After addition of saturated aqueous sodium hydrogen carbonate solution, the organic phase was removed and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried in the sodium sulphate, filtered and concentrated. The crude product was subsequently purified by column chromatography (1:1 tert-butyl methyl ether/petroleum ether). This gave 0.80 g (76%) of compound 8 and 0.25 g (23%) of compound 9.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([NH:28][NH2:29])=[O:27]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:29][NH:28][C:26]([C:22]1[O:21][CH:25]=[CH:24][CH:23]=1)=[O:27])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC(=O)c1ccco1
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1ccco1
Yield: 37.9 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 552 mg, 2.00 mmol) of Example 9 or 16 and furan-2-carbohydrazide (390 mg, prepared following a procedure analogous to Reference Example 6 from the compound described in Reference Example 3), 291.8 mg of the title compound was afforded (yield 37.9%).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[N:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:21]=2)[CH:11]=1
Reactant: CN(c1cncc(Br)c1)S(C)(=O)=O
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CN(c1cncc(C#Cc2cc(Cl)ccc2OCC(=O)O)c1)S(C)(=O)=O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and N-(5-bromopyridin-3-yl)-N-methylmethanesulfonamide (Intermediate 33), the title compound was obtained as an off-white solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13])[CH3:8].Cl>CCO>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([NH:13][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:8]
Reactant: Brc1nccs1
Reactant: CCOc1cccc(N)c1
Agent: Cl
Solvent: CCO
Product: CCOc1cccc(Nc2nccs2)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (0.15 mL, 1.66 mmol), 3-ethoxyaniline (0.11 mL, 0.83 mmol) and 37% HCl solution (0.14 mL, 1.66 mmol) in 10% aqueous EtOH solution (1 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 8/2) in 53% yield (97 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:19]1([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:22]2[CH2:23][CH2:24][N:19]([C:25]3[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=3)[CH2:20][CH2:21]2)=[O:11])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#Cc1cnc(N2CCNCC2)s1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: N#Cc1cnc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)s1
Yield: 24 %

Procedure:
Prepared in analogy to example 1 (b) from 2-morpholin-4-yl-5-nitro-benzoic acid (Example A27) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a yellow solid (yield 24%). MS (m/e): 429.5 (M+H+, 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.[NH2:19][C@H:20]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH3:44])=[C:39]([CH2:45][CH3:46])[CH:38]=1)[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH2:25][CH2:24]1)=[O:22]>>[CH2:45]([C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][C:40]=1[CH2:43][CH3:44])[CH2:36][C@@H:20]([NH:19]/[C:4](=[N:7]/[C:8]#[N:9])/[N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:5][CH2:6]1)[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)[CH2:25][CH2:24]1)=[O:22])[CH3:46]
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: CCc1ccc(C[C@@H](N)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1CC
Product: CCc1ccc(C[C@@H](N/C(=N/C#N)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 73 from 3-piperidin-4-yl-1,3,4,5-tetrahydrobenzo[d][1,3]diazepin-2-one and (R)-2-amino-3-(3,4-diethyl-phenyl)-1-[4-(4-methylpiperazin-1-yl)-piperidin-1-yl]-propan-1-one
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:5]O.S(Cl)([Cl:18])=O>C(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:5][Cl:18]
Reactant: CN(C)S(=O)(=O)c1ccc(CO)cc1Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)c1ccc(CCl)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of OBS02002 (5.0 g, 16.12 mmol) in anhydrous DCM (50 mL) was added thionyl chloride (1.76 mL, 24.18 mmol). The mixture was stirred at room temperature for 2 h and the volatiles removed in vacuo. The residue was re-dissolved and co-evaporated three times with DCM (3×20 mL) to give a yellow oil which solidified on standing. The solid was stirred in n-hexane, filtered and air-dried to give OBS02003 as an off-white solid (5.01 g, 95%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.79; 1H-NMR (270 MHz, CDCl3)=3.05 (6H, s), 4.51 (2H, s), 7.32 (1H, dd, J=2.2, 8.4), 7.48 (1H, d, J=8.4), 7.62 (1H, d, J=2.2). Dimethylsulfamic Acid 2-bromo-4-{[(4-cyano-phenyl)-[1,2,4]triazol-4-ylamino]methyl}phenyl ester (OBS02005, STX732)
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[Br:11][C:12]1[CH:13]=[C:14]2[C:20]([CH2:21]N(C)C)=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1.C(O)(=[O:28])CC>>[Br:11][C:12]1[CH:13]=[C:14]2[C:20]([CH:21]=[O:28])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1
Reactant: CCC(=O)O
Reactant: CN(C)Cc1c[nH]c2ncc(Br)cc12
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
To a refluxing (oil bath temp. 140° C.) solution of hexamethylenetetramine (8.83 g, 63 mmol) in 66% aqueous propionic acid (31.5 mL) was added a mixture of 5 (16.0 g, 63 mmol) and hexamethylenetetramine (8.83 g, 63 mmol) in 66% propionic acid (47 mL) over 2.5 h. The reflux was continued for 2.5 h, the reaction mixture allowed to cool to room temperature, then poured onto water (220 mL) and the suspension cooled in an ice-bath. The solid was filtered off, washed with ice-cold water (2×), and dried under high vacuum overnight to give 6 as a white solid (11.47 g, 81%); 1H NMR (400 MHz, CDCl3+4 drops d4-MeOH) δ 9.91 (s, 1H), 8.69 (d, J=2.2 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 7.95 (s, 1H).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:16][C@H:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]=2[N:27]=1)[CH3:4].Cl[C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=1.C(N(CC)CC)C>C(O)C>[CH2:3]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:29]4[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=4)[CH2:25][CH2:26]3)[CH2:16][C@H:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]=2[N:27]=1)[CH3:4]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCNCC1)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(c3ccc(C(N)=O)cn3)CC1)C2=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
Compound 24 (50.9 mg, 0.122 mmol) obtained in Example 24, and 6-chloronicotinamide (38.2 mg, 0.244 mmol) were dissolved in ethanol (1.0 mL), and the mixture was stirred at 140° C. for 2 hours under microwave (CEM; Discover, 300 watts) irradiation after adding triethylamine (169 μL, 1.22 mmol). Thereafter, ethanol (1.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was filtered off and dried to give the title compound (Compound 28) (34.7 mg, 62%).
Reaction SMILES: Cl[C:2]1[C:3]2[S:22][CH2:21][CH2:20][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:2]2[C:3]3[S:22][CH2:21][CH2:20][C:4]=3[N:5]=[C:6]([N:8]3[CH2:9][CH2:10][N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:12][CH2:13]3)[N:7]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Reactant: Nc1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Clc1cccc(Nc2nc(N3CCN(c4ccccc4)CC3)nc3c2SCC3)c1

Procedure:
0.320 g (0.96 mmol) of 4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (V), 1.0 mL (9.5 mmol) of 3-chlorophenylamine, and 0.33 mL (1.92 mmol) of diisopropylethylamine are combined and the mixture is reacted for 0.5 hours at 130° C. in the microwave. Then the reaction mixture is combined with ethyl acetate and acidically extracted. The organic phase is dried and evaporated to dryness. The residue is combined with acetonitrile, water, and trifluoroacetic acid. The phase containing the product I is purified by chromatography through an RP column by HPLC (column: Microsorb, RP-C18, 300 Å, 10 μm, 21.4*250 mm, eluant: acetonitrile+0.1% formic acid (A), water+0.13% formic acid (B)).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2)[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:51]1[C:52]([C:60]2[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=2)=[CH:53][N:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=12>CN(C=O)C>[N:51]1[C:52]([C:60]2[CH:61]=[C:62]([NH:66][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][CH2:10][CH3:11])=[O:26])[CH:63]=[CH:64][CH:65]=2)=[CH:53][N:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=12
Reactant: CCOc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cccc2cc(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 41.9 %

Procedure:
DIEA (40.9 μL, 0.23 mmol) was added to 8-ethoxy-3-carboxy-coumarin (50.0 mg, 0.21 mmol) and HATU (89.29 mg, 0.23 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (44.7 mg, 0.21 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 37.4 mg of product in 42% yield: LCMS (ESI) m/z 426 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]O)(=[O:3])[CH3:2].C(Br)(Br)(Br)[Br:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Br:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)OCCCCCCCCCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Intermediate 17-acetoxy-heptadecanol (220 mg, 0.7 mmol) and CBr4 (302 mg, 0.91 mmol) were dissolved in CH2Cl2 (2 ml) and a solution of Ph3P (238 mg, 0.91 mmol) in CH2Cl2 (1.5 ml) was added via cannula at 0° C. The reaction was stirred at 0° C. for 2 h and then quenched with MeOH (0.3 ml), stirred for additional 10 min at room temperature, diluted with EtOAc and washed with aqueous NaHCO3 solution. The organic extract was dried over Na2SO4 and evaporated. Silica gel chromatography in hexane-EtOAc (99:1, 95:5) provided 261 mg (99%) of 17-acetoxy-heptadecyl bromide (40).