Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[Cl:39][C:40]1[CH:41]=[C:42]([CH:52]=[CH:53][C:54]=1[Cl:55])[O:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH:47]=[O:48]>>[Cl:39][C:40]1[CH:41]=[C:42]([CH:52]=[CH:53][C:54]=1[Cl:55])[O:43][C:44]1[CH:45]=[C:46]([CH:47]([OH:48])[C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])[CH:49]=[CH:50][CH:51]=1
Reactant: O=Cc1cccc(Oc2ccc(Cl)c(Cl)c2)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(O)c3cccc(Oc4ccc(Cl)c(Cl)c4)c3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-((3-(3,4-Dichlorophenoxy)phenyl)hydroxymethyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 3-(3,4-dichlorophenoxy)benzaldehyde instead of benzophenone) as a colourless foam.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:9][C:8]([CH3:20])=[N:7][C:6]=1[Cl:21])C.O.O.[OH-].[Li+:26]>O1CCOCC1>[Cl:21][C:6]1[N:7]=[C:8]([CH3:20])[CH:9]=[C:10]([O:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[Cl:19])[C:5]=1[C:4]([O-:22])=[O:3].[Li+:26]
Reactant: CCOC(=O)c1c(Oc2cc(Cl)ccc2Cl)cc(C)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)[O-])c(Cl)n1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 130 mg (0.36 mmol) 2-chloro-4-(2,5-dichloro-phenoxy)-6-methyl-nicotinic acid ethyl ester in 2 mL dioxane was added 2 mL water and 23 mg (0.541 mmol) lithium hydroxide monohydrate. The reaction mixture was stirred at 100° C. for 4 hours. The reaction mixture was allowed to cool down to room temperature and was concentrated under high vacuum. The so-obtained light yellow solid was pure enough for the next step without further purification. MS (ESI): 331.965 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].[CH3:11][C:12]1([CH3:29])[O:17][C:16](=[O:18])[C:15](=[C:19](SC)[NH:20][C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:14](=[O:28])[O:13]1>ClCCl.CO>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][C:19]([NH:20][C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)=[C:15]1[C:14](=[O:28])[O:13][C:12]([CH3:29])([CH3:11])[O:17][C:16]1=[O:18])[CH3:2]
Reactant: CCOC(CCN)OCC
Reactant: CSC(Nc1ccsc1)=C1C(=O)OC(C)(C)OC1=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(CCNC(Nc1ccsc1)=C1C(=O)OC(C)(C)OC1=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3,3-Diethoxypropylamine (210.7 g, 1.43 mol) was added in portions to the solution of 2,2-dimethyl-5-(methylsulfanyl-thiophene-3-ylamino-methylene)-[1,3]dioxane-4,6-dione (407.3 g, 1.36 mol) in dichloromethane (1.7 L) and methanol (0.36 L) over 60 min, while the reaction temperature was kept under 25° C. with a water bath. After stirring for 1.5 h at room temperature, the reaction mixture was diluted with dichloromethane (0.8 L). The organic layer was separated and washed with aqueous ammonium chloride solution (400 mL, made of 200 mL of sat. NH4Cl and 200 mL of water), brine (300 mL) and dried over magnesium sulfate. Concentration of the reaction mixture under reduced pressure afforded a dark oil. Xylenes (500 ml) were added and the mixture concentrated under reduced pressure to give the intermediate 5-((3,3-Diethoxypropylamino)(thiophene-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. The resultant dark oil was used directly in next step without further purification. 1H NMR (400 MHz, CDCl3) δ 1.65 (m, 6H), 1.73 (s, 6H), 1.78 (m, 2H), 2.98 (q, 2H, J=6.4 Hz), 3.45 (m, 2H), 3.60 (m, 2H), 4.50 (t, 1H, J=5.2 Hz), 6.98 (dd, 1H, J=1.6, 5.2 Hz), 7.05 (dd, 1H, J=1.2, 3.2 Hz), 7.33 (dd, 1H, J=3.2, 5.2 Hz), 10.2 (s, 1H), 11.3 (s, 1H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].[OH:27][CH:28]([CH3:37])[CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/B(O)O.OO>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](/[CH:33]=[CH:32]/[CH2:31][CH2:30][CH2:29][CH:28]([OH:27])[CH3:37])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(O)CCC/C=C/B(O)O
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(Br)cc2)nc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)O)cc2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
Apart from the above, inner atmosphere of a four-necked flask equipped with a stirring device, a reflux condenser and a thermometer was replaced with nitrogen gas, and then the flask was charged with 6.6 g (17 mmol) of 5-decyloxy-2-(4-bromophenyl)-pyrimidine, 0.23 g (0.2 mmol) of tetrakis-triphenylphosphine-palladium, 2.4 g (60 mmol) of sodium hydroxide and 60 ml of tetrahydrofuran. Subsequently, 50 ml of a solution prepared by dissolving 20 mmol of the above-obtained E-6-hydroxy-1-heptenyldihydroxyborane in tetrahydrofuran was dropwise added thereto at room temperature. Then, the whole mixture was heated under reflux with stirring for 6 hours. After cooling the reaction mixture to room temperature, 5 ml of 10% aqueous solution of sodium hydroxide and 2 ml of 30% aqueous solution of hydrogen peroxide were added, and the resulting mixture was stirred for one hour. The mixture was extracted with ether, and the organic layer was twice washed with each 20 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 5.9 g (yield 82%) of (-)-5-decyloxy-2-{4-(6-hydroxy-1-trans-heptenyl)-phenyl}-pyrimidine, [α]D20 =-1.2 (c=1.0, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:31])[N:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=2[Cl:26])=[O:20])[C:3]=1[N+:32]([O-])=O.O.[NH4+].[Cl-]>CCO.[Fe]>[NH2:32][C:3]1[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:31])[N:23]=[C:24]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:25]=2[Cl:26])=[O:20])=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])=[CH:7][C:2]=1[Cl:1]
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1N
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (109 mg, 0.211 mmol, prepared as described in the previous step) in EtOH (5 mL) and water (2.5 mL) was treated with NH4Cl (113 mg, 2.11 mmol) and iron powder (58.9 mg, 1.06 mmol). The mixture was heated to 60° C. for 5 h, then the EtOH was evaporated in vacuo. The remaining aqueous mixture was diluted with water (30 mL) and extracted twice with EtOAc (25 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 35 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:4 over 40 min) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-amino-4-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as a colorless glassy solid. Mass Spectrum (LCMS, ESI pos.): Calculated for C21H20N5OCl2F3: 486.1 (M+H); Measured: 486.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][C:13](=O)[C:12]2[C:11]3[C:10]([C:16]([O:18]C)=O)=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH2:3]1.O.NN.C1C2NC3C=CC=C4C(=O)[NH:37][N:38]=C(C=2C=34)CC1>>[CH3:1][N:2]1[CH2:3][C:4]2[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:16](=[O:18])[NH:37][N:38]=[C:13]([C:12]=2[C:11]=34)[CH2:14]1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(C)C3
Reactant: O=C1NN=C2CCCc3[nH]c4cccc1c4c32
Agent: NN
Solvent: O
Product: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 44 was prepared from Methyl 2-methyl-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and hydrazine hydrate according to the procedure similar to that for Compound 1. 1H NMR (DMSO-d6) δ 11.7 (s, 1H), 9.87 (s, 1H), 7.43 (d, 1H, J=8.0 Hz), 7.39 (d, 1H, J=7.6 Hz), 7.14 (dd, 1H, J=8.0, 7.6 Hz), 3.70 (s, 2H), 3.13 (s, 2H), and 2.39 (s, 3H). MS (ESI) m/e [M+1]+ 241.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[H-].[Na+].[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[C:29]([N:31]3[CH2:40][CH2:39][C:34]4([O:38][CH2:37][CH2:36][O:35]4)[CH2:33][CH2:32]3)[CH:28]=[C:27](Cl)[N:26]=2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:12]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[N:26]=[C:27]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=3)[CH:28]=[C:29]([N:31]3[CH2:32][CH2:33][C:34]4([O:35][CH2:36][CH2:37][O:38]4)[CH2:39][CH2:40]3)[N:30]=2)[CH2:23][CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1cc(N2CCC3(CC2)OCCO3)nc(N2CCN(Cc3ccccc3)CC2)n1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Nc2cc(N3CCC4(CC3)OCCO4)nc(N3CCN(Cc4ccccc4)CC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 43.7 %

Procedure:
A mixture of 3,4-dichloroaniline (1.7 g, 10.5 mmol) and NaH (0.50 g, 20.9 mmol) in tetrahydrofuran (20 mL) was heated at reflux for 30 minutes and then cooled to room temperature. A solution of 8-[2-(4-benzyl-1-piperazinyl)-6-chloro-4-pyrimidinyl]-1,4-dioxa-8-azaspiro[4.5]decane (3.0 g, 7.0 mmol) in tetrahydrofuran (30 mL) was added to this mixture and the resulting solution was stirred for 22.5 hours. The reaction mixture was quenched with saturated NH4Cl, concentrated under reduced pressure, and redissolved in EtOAc. The organic layer was separated and washed with aqueous citric acid (2×300 mL), water (2×300 mL), and brine (2×300 mL). The crude product was purified by column chromatography [eluent: EtOAc/hexane (1:4)], giving the desired product (1.7 g, 44%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH2:17](Br)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Reactant: BrCCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(SCCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, phenethyl bromide and sodium ethylate in ethanol. ES-MS m/e (%): 333 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13]COC[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[Br:16]C1C=C(C=CC=1)C(Cl)=O.CNC>>[Br:16][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:2]=1)[C:6]([N:8]([CH3:13])[CH3:9])=[O:7]
Reactant: O=C(c1ccc(Br)cc1)N1CCOCC1
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: CNC
Product: CN(C)C(=O)c1cccc(Br)c1
Yield: 85 %

Procedure:
Following the general method as outlined in Intermediate 174, starting from 3-bromobenzoyl chloride and dimethylamine, the title compound was obtained as a orange sticky solid in 85% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])O.[Na+].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37](ON3C(=O)CCC3=O)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]([OH:15])=[O:14])[C:37]([O:36][CH2:35][CH:33]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:34]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNCC(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 20 h

Procedure:
10.9 g (50 mmol) of N-(2-tert-butoxycarbonylaminoethyl)aminoacetic acid are stirred together with 50 ml of water, 11.3 g (135 mmol) of sodium hydrogen carbonate and 50 ml of tetrahydrofuran. Subsequently, 24.3 g (72 mmol) of N-(9-fluorenylmethoxycarbonyloxy)succinimide are added. The mixture is stirred at room tmeperature for 20 h and the salt removed by filtration; the filtrate is acidified and the phases separated, and the organic phase is then concentrated.
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:17]([O-])([O-])=O.[K+].[K+].C=O.O>CCOCC>[CH2:17]=[C:3]([CH2:2][CH3:1])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Agent: C=O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: C=C(CC)C(=O)OCC
Temperature: 80 °C
Yield: 86.2 %

Procedure:
A mixture of 5.0 g (0.019 mol) of triethyl 2-phosphonobutyrate, 5.5 g (0.039 mol) of K2CO3, 6.2 g (0.076 mol) of 37% aqueous formaldehyde solution, and 15 mL of water was heated to about 80° C. for about 45 min. After cooling to RT, 75 mL of ether was added and the organic layer was separated, washed with brine (1×20 mL), dried (MgSO4), and filtered. The ether was carefully removed by distillation, leaving behind 2.1 g (87%) of the title compound as a clear oil which was used directly without further purification. 1H NMR (CDCl3): δ 1.01 (3 H, t, J=7), 1.24 (3 H, t, J=7), 2.26 (2 H, q, J=7), 4.14 (2 H, q, J=7), 5.45 (1 H, s), 6.06 (1 H, s).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f1) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=O)[CH:3]=[CH:2]1.[NH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[SH:18]>CO>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[N:9]=[C:4]1[C:3](=[CH:2][C:1](=[O:8])[CH:6]=[CH:5]1)[S:18]2
Reactant: COc1cccc(S)c1N
Reactant: O=C1C=CC(=O)C=C1
Solvent: CO
Product: COc1cccc2sc3cc(=O)ccc-3nc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of p-benzoquinone (3.0 g) in 15 ml methanol was added 2-amino-3-methoxythiophenol (2.2 g) dissolved in 10 ml methanol. The mixture was stirred at room temperature for 45 minutes and concentrated in vacuo. The residue was triturated with ether and filtered. The resulting dark solid was chromatographed on silica gel and eluted with EtOAc, to afford the desired compound, m.p. 206°-207°.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:15]=[C:16]([C:20]2[N:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1>C(Cl)Cl>[CH2:31]([O:30][C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]1[CH:22]=[CH:21][C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:33])([F:12])[F:34])[CH:15]=2)=[N+:25]([O-:9])[CH:24]=1)[CH3:32]
Reactant: CCOC(=O)/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
m-CPBA (13.9 g, 80.97 mmol) was added portion wise to a solution of trans-ethyl 3-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)acrylate (13 g, 40.47 mmol) in DCM (150 mL) at 0° C. over a period of 30 min. and stirred at RT for 16 h. After completion, the reaction mixture was poured into ice water (100 mL), extracted with DCM (2×100 mL). Combined organic extracts were treated with sodium metabisulphite, washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography (SiO2) by using MeOH:chloroform (1:99) to afford (9 g, 66%) (E)-5-(3-ethoxy-3-oxoprop-1-enyl)-2-(3-(trifluoromethyl)phenyl)pyridine 1-oxide as yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[NH:12]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:13]1=[O:14]>C(=S)=S>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[NH:12][C:13](=[O:14])[CH2:15][CH2:16]2)=[O:6]
Reactant: O=C1CCc2ccccc2N1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
120 Milliliters of γ-chlorobutyryl chloride and 160 g of pulverized anhydrous aluminium chloride were suspended in 300 ml of carbon disulfide. The suspension was refluxed by heating and another suspension of 29.4 g of 3,4-dihydrocarbostyril in 100 ml of carbon disulfide was added dropwise to the first suspension in 1 hour and the reaction was continued for 4 hours under refluxing condition by heating. After the reaction was completed, the reaction mixture was poured into ice-water and the precipitates thus formed were collected by filtration, washed with water and with ether. Then the washed precipitates were recrystallized from acetone to obtain 25.5 g of 6-(4-chloro-1-oxobutyl)-3,4-dihydrocarbostyril in yellow needle-like crystals. Melting point: 158°-160° C.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17]P(=O)(OCC)OCC)=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Br:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O.O>C1COCC1>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14](/[CH:17]=[CH:35]/[C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[Br:32])=[N:15][N:16]=3)[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=Cc1ccccc1Br
Reactant: CCOP(=O)(Cc1nnc2ccc(N3CCCCCC3)nn12)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccccc1/C=C/c1nnc2ccc(N3CCCCCC3)nn12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of diethyl [(6-azepan-1-yl-1,2,4-triazolo[4,3-b]pyridazin-3-yl)methyl]phosphonate (367 mg) in THF (10 ml), potassium tert-butoxide (127 mg) was added with cooling in an ice bath, and the mixture was stirred at room temperature for 40 minutes. The resultant red solution was combined with 2-bromobenzaldehyde (0.128 ml), and stirred at room temperature for further 1 hour. The reaction solution was combined with water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant white solids were recrystallized from methanol to obtain 6-azepan-1-yl-3-[(E)-2-(2-bromophenyl)vinyl]-1,2,4-triazolo[4,3-b]pyridazine (152 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[C:19]([O:17][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][C:13]=1[CH:14]=[O:15])([CH3:26])[CH3:25])[CH3:24]
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C=O
Yield: 88.8 %

Procedure:
5-Benzyloxy-2-hydroxy-benzaldehyde (Kappe, T.; Witoszynskyj, T. Arch. Pharm., 1975, 308 (5), 339-346) (2.28 g, 10.0 mmol), ethyl bromoisobutyrate (2.2 mL, 15 mmol), and cesium carbonate (3.26 g, 10.0 mmol) in dry DMF (25 mL) were heated at 80° C. for 18 h. The reaction mixture was cooled and partitioned between water (30 mL) and ether (75 mL). The organic layer was washed with brine (15 mL). The aqueous layers were back-extracted with ethyl acetate (30 mL), and the organic layer was washed with brine (20 mL). The combined organic layers were dried (Na2SO4) and concentrated to a brown oil. The crude product was purified by flash chromatography using hexanes:ethyl acetate (2.5:1) to give a pale yellow solid (3.04 g, 89%): mp 65° C.; 1H NMR (400 MHz, CDCl3) δ 1.24 (t, 3H, J=7.1 Hz), 1.62 (s, 6H), 4.23 (q, 2H, J=7.1 Hz), 6.81 (d, 1H, J=8.8 Hz), 7.10 (dd, 1H, J=4.6, 9.0 Hz), 7.30-7.43 (m, 6H); MS (ES) m/e 343.1 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[C:6]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=O)[CH:7]=1>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]3[CH2:19][CH2:20][C:21]4[C:26]3=[C:25]([CH:24]=[CH:23][CH:22]=4)[C:9]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[N:8][C:6]=2[CH:7]=1
Reactant: CN1CCN(C(=O)Nc2cc(Cl)ccc2N2CCc3ccccc32)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3cc(Cl)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A stirred solution of 6.30 g (0.017 mole) of N-[5-chloro-2-(2,3-dihydro-1H-indol-1-yl)-phenyl]-4-methyl-1-piperazinecarboxamide of Example 4b in 100 ml of phosphorus oxychloride was refluxed for 6 hours under nitrogen, then cooled to room temperature. The excess phosphorus oxychloride was removed at aspirator pressure with gentle warming. The residue was chilled in an ice-bath (with exclusion of moisture) and then treated first with 250 ml of ice-cold 2N-NaOH, then with 250 ml of dichloromethane. The mixture was stirred vigorously until all the material passed into solution. The organic phase was separated, washed four times with water, dried over Na2SO4 and concentrated in vacuo to 5.7 g (95%) of a semi-crystalline material. Recrystallization from acetone afforded 2.20 g (37% overall yield) of 9-chloro-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine, m.p. 154°-156° C.