Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].Br[CH2:18][CH2:19][CH:20]=[CH2:21]>O1CCCC1>[CH2:9]([O:8][P:6]([CH:11]([CH2:21][CH2:20][CH:19]=[CH2:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:5][CH2:3][CH3:4])=[O:7])[CH3:10]
Reactant: C=CCCBr
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC(C(=O)OCC)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Sodium hydride (60% in oil, 65.0 g) was suspended in tetrahydrofuran (800 mL) under a nitrogen atmosphere, and ethyl (diethoxyphosphoryl)acetate (200 g) was added dropwise at room temperature over 30 min. After the completion of the dropwise addition, the mixture was further stirred by a mechanical stirrer for 30 min. 4-Bromobut-1-ene (217 g) was added dropwise to the reaction mixture over 30 min. The reaction mixture was heated under reflux for 5 hr, allowed to cool to room temperature, and quenched by adding 1M aqueous ammonium chloride solution (300 mL). The mixture was concentrated under reduced pressure, to the residue were added water (500 mL) and diethylether (500 mL), and the mixture was partitioned. The aqueous layer was saturated with sodium chloride, and the mixture was extracted with diethylether (500 mL×2). The combined extracts were washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product (241.6 g) of the title compound as a yellow oil. This was used for the next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[N:15]=[CH:14][C:13]=3[CH:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[N:15]=[CH:14][C:13]=3[CH:12]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(ccn2-c2ccc([N+](=O)[O-])cc2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc2c(ccn2-c2ccc(N)cc2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.4 %

Procedure:
A mixture of tert-butyl 1-(4-nitrophenyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (35 mg, 0.10 mmol), zinc powder (80 mg), and NH4Cl (100 mg) in MeOH (3 mL) and THF (2 mL) was stirred at rt for 15 h. The mixture was diluted with EtOAc, filtered through a pad of Celite®. The filtrate was washed with brine, dried over MgSO4 and concentration in vacuo to afford the title compound as a solid (29 mg, 89%) was obtained. LC-MS: m/z 325 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]#[CH:13])=[CH:6][C:5]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)[OH:15])([O-])=O.O.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]#[CH:13])=[CH:6][C:5]=1[C:14]([C:16]1[CH:17]=[CH:18][C:19]([CH:22]2[CH2:23][CH2:24]2)=[CH:20][CH:21]=1)=[O:15]
Reactant: C#CCOc1ccc([N+](=O)[O-])c(C(O)c2ccc(C3CC3)cc2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOc1ccc(N)c(C(=O)c2ccc(C3CC3)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2.2 g (6.85 mmol) of (2-nitro-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)-methanol (step C above) in 40 ml glacial acetic acid is heated to 50° C. and treated with 3.06 g (8 equiv.) of iron powder. After 5 h stirring at that temperature the reaction is complete. The green-grey suspension is cooled to rt, diluted by the addition of 500 ml water and 200 ml ethyl acetate and filtered through a pad of Celite. The layers are separated and the organic phase washed with water and sat. bicarbonate solution. The yellow and sticky crude product is purified by chromatography (dichloromethane/MeOH) to yield a viscous yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:29])([O:26]CC)[O:23]CC)[P:14](=[O:21])([O:18]CC)[O:15]CC.[ClH:30]>>[OH2:7].[ClH:30].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:23])([OH:26])[OH:29])[P:14](=[O:15])([OH:18])[OH:21].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:23])([OH:26])[OH:29])[P:14](=[O:15])([OH:18])[OH:21].[ClH:30]
Reactant: CCOP(=O)(OCC)C(NCCCCOc1ccccn1)P(=O)(OCC)OCC
Agent: Cl
Product: O
Product: O=P(O)(O)C(NCCCCOc1ccccn1)P(=O)(O)O
Yield: 65 %

Procedure:
A mixture of tetraethyl 4-(2-pyridyloxy)butylaminomethylenebisphosphonate (0.85 g) and conc. hydrochloric acid (10 ml) was heated for 2 hours under reflux. The reaction mixture was concentrated under reduced pressure. The concentrate was treated with methanol to give a solid matter, which was recrystallized from water-methanol to give 4-(2-pyridyloxy)butylaminomethylenebisphosphonic acid hydrochloride hemihydrate (0.471 g, 65%), m.p. 155° C. to 157° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[NH:7][CH2:6][CH2:5]2.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=1)[N:7]([C:39]([NH:38][C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1)=[O:40])[CH2:6][CH2:5]2
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Fc1ccc2c(c1)CCNC2c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)N1CCc2cc(F)ccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
A solution of 6-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.3 g, 1.0 mmol) and diisopropylethylamine (0.2 mL, 0.919 mmol) in anhydrous dichloromethane (6 mL) was treated with 4-fluorophenyl isocyanate (0.14 g, 1.0 mmol) and stirred at RT for 16 h. Formation of a white precipitate was observed which was collected by filtration. The solid was dried under high vacuum to give 6-fluoro-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (0.35 g, 80%). MS (ESI pos. ion) m/z: 433 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][C@H:15](C)[NH:14][C:13]2=[O:18])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:19][C:20]1N=C(N2CCNC2=O)S[C:24]=1[C:25](OCC)=O.BrCCC=C>>[CH2:25]([N:14]1[CH2:15][CH2:16][N:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[C:13]1=[O:18])[CH2:24][CH:20]=[CH2:19]
Reactant: CCOC(=O)c1sc(N2C[C@H](C)NC2=O)nc1C
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: C=CCCBr
Product: C=CCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O

Procedure:
Following the procedure as described in Preparation 5, making variations as required to replace (S)-ethyl 4-methyl-2-(4-methyl-2-oxoimidazolidin-1-yl)thiazole-5-carboxylate and with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate to react with 4-bromobut-1-ene, the title compound was obtained as an off-white solid (2.05 g, 85%): mp 97-98° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d5) δ 5.86-5.72 (m, 1H), 5.16-5.02 (m, 2H), 4.22 (q, J=7.1 Hz, 2H), 4.02-3.79 (m, 2H), 3.60-3.55 (m, 2H), 3.34-3.29 (m, 2H), 2.51 (s, 3H), 2.33-2.26 (m, 2H), 1.27 (t, J=7.1 Hz, 3H); MS (ES+) m/z 309.8 (M+1).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:26])[C:11]2[C:16]([C:17]34[CH2:22][CH:21]3[CH2:20][NH:19][CH2:18]4)=[C:15](N)[C:14]([NH:24][CH3:25])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1.[C:29]([O:33][C:34](=[O:48])[NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([N:44]=[C:45]=S)[C:38]=1[Cl:47])([CH3:32])([CH3:31])[CH3:30].CC(C)[N:51]=C=NC(C)C>CC#N>[F:1][C:2]([F:28])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:16]([C:17]34[CH2:22][CH:21]3[CH2:20][NH:19][CH2:18]4)=[CH:15][C:14]3[N:24]([CH3:25])[C:45]([NH:44][C:39]4[C:40]([Cl:43])=[CH:41][CH:42]=[C:37]([CH2:36][NH:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:48])[C:38]=4[Cl:47])=[N:51][C:13]=3[CH:12]=2)=[O:26])[CH2:5][CH2:4]1
Reactant: CNc1ccc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(C23CNCC2C3)c1N
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)OC(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(C34CNCC3C4)cc21

Procedure:
The title compound is prepared in analogy to 1e from N-(trans-4-trifluoromethyl-cyclohexyl)-6-[3-aza-bicyclo[3.1.0]hex-1-yl]-4-methylamino-5-amino-benzoic acid amide (3.2 g, 8.0 mmol), (2,4-dichloro-3-isothiocyanato-benzyl)-carbamic acid tert.-butyl ester (compound B; 2.69 g, 8.0 mmol), DIC (1.25 mL) and MeCN (30 mL).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][N:51]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:54]6[CH2:55][CH2:56][CH2:57][N:51]([CH3:50])[CH2:52][CH2:53]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Reactant: CN1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCCN(C)CC4)c3)c2C)c1
Yield: 42 %

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) with 1-methylhexahydro-1H-1,4-diazepine (30.4 μL., 0.00024 mol) and sodium triacetoxyborohydride (68 mg., 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a pale brown colored solid [48.3 mg (42%)]. LC-MS m/z 757.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([Cl:6])=[O:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=1>C(Cl)Cl>[ClH:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][N:24]([C:4](=[O:5])[C:3]3[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:11])[CH2:25][CH2:26]2)=[CH:15][CH:14]=1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: Cc1cccc(C)c1C(=O)Cl
Solvent: ClCCl
Product: Cc1cccc(C)c1C(=O)N1CCN(CCc2ccc(Cl)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 11.1 g of 2,6-dimethylbenzoyl chloride in 50 ml of methylene chloride is added dropwise, over a period of 10 minutes, to a solution, stirred at room temperature, of 13.5 g of 1-[2-(4-chlorophenyl)-ethyl]-piperazine in 100 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature. The suspension is filtered with suction and washed with ice-cold methylene chloride and finally with ether, dried and characterised in the form of the hydrochloride which has a melting point of 259°-261°. 1-[2-(4-chlorophenyl)-ethyl]-4-(2,6-dimethylbenzoyl)-piperazine hydrochloride is thus obtained.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:18]3[O:17][CH:16]=[CH:15][C:14]=3[CH:13]=[C:12]([N+:19]([O-])=O)[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)C.O.NN>C1COCC1.[Ni]>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:18]3[O:17][CH:16]=[CH:15][C:14]=3[CH:13]=[C:12]([NH2:19])[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(NCCN2CCOCC2)c2occc2c1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1cc(NCCN2CCOCC2)c2occc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-Morpholin-4-ylethyl)(5-nitro-1-benzofuran-7-yl)amine (450 mg, 1.545 mmol; Intermediate 27) was dissolved in THF (5 mL). After addition of ethanol (100 mL), Raney-nickel (cat.) and hydrazine hydrate (2 mL), the mixture was left stirring at room temperature for 2 h. The product was used directly in the subsequent reaction after filtration through Celite and evaporation of solvent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(OC(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example J26) (219 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (275 mg, 69%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=O.NN>C(O)CO>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:7][C:8]1=[O:11]
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: NN
Solvent: OCCO
Product: O=C1Cc2ccccc2N1

Procedure:
In still a further embodiment, a process is provided for preparing 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile, including reacting 7-fluoro-1H-indole-2,3-dione and aqueous hydrazine in ethylene glycol to form the 2-oxindole; brominating the 2-oxindole; reacting the 2-oxindole with 5-[1,3,6,2]dioxazaborocan-2-yl-1-methyl-1H-pyrrole-2-carbonitrile, sodium carbonate, and PdCl2(PPh3)2; removing residual PdCl2(PPh3)2 or a by-product thereof using N-acetyl-L-cysteine; and isolating 5-(7-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([CH2:17][O:18][C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CC(O)C>[ClH:1].[CH:11]1([CH2:17][O:18][C:19]2[CH:25]=[CH:24][C:22]([NH:23][C:2]3[C:3]4[S:10][CH:9]=[CH:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:21][CH:20]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Nc1ccc(OCC2CCCCC2)cc1
Reactant: Clc1ncnc2ccsc12
Solvent: CC(C)O
Product: Cl
Product: c1nc(Nc2ccc(OCC3CCCCC3)cc2)c2sccc2n1
Yield: 68 %

Procedure:
4-Chlorothieno[3,2-d]pyrimidine (0.171 g, 1.00 mmol) and 4-cyclohexylmethoxy-aniline (prepared according to the published method: WO 96/09294) (0.205 g, 1.00 mmol) were reacted in 2-propanol (5 ml) for 5 hours, according to Procedure A. The product was obtained as cream prisms (0.255 g, 68%) with m.p. 232-233° C.; (Found: C, 60.65; H, 5.68; N, 11.25. C19H21N3OS.HCl requires: C, 60.71; H, 5.90; N, 11.23%); δH [2H6]-DMSO 11.11 (1H, br s, NH), 8.71 (1H, s, 2-H), 8.41 (1H, d, J 7,6 H or 7 H) 7.44-7.58 (3H, m, 6H or 7H, 2′-H, 6′-H), 7.03 (2H, d, J 9, 3′-H, 5′-H), 3.84 (2H, s, CH2), 1.58-1.90 (6H, m) and 0.98-1.33 (5H, m) (cyclohexyl-H11); m/z 339 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]2[CH2:13][CH2:12]2)=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:14][CH2:15][CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[N:3]=1.O=P(Cl)(Cl)Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:1][C:2]1[C:10]([CH:11]2[CH2:12][CH2:13]2)=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:14][CH2:15][CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[N:3]=1
Reactant: CC(=O)CCCOc1nc(Cl)c(C2CC2)cc1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)CCCOc1nc(Cl)c(C2CC2)cc1C#N
Reaction time: 2 h

Procedure:
To a solution of 6-chloro-5-cyclopropyl-2-(4-oxopentyloxy)nicotinamide (298 mg, 1 mmol) in acetonitrile (20 mL) was added POCl3 (460 mg, 3 mmol) and pyridine (474 mg, 6 mmol). After stirred at r.t for 2 hrs, the mixture was poured into aq. NaHCO3, extracted with EtOAc. The separated organics was dried and concentrated in vacuo to afford 6-chloro-5-cyclopropyl-2-(4-oxopentyloxy)nicotinonitrile. (300 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]2[O:13][CH2:12][O:11][C:10]=12)[CH:6]=[O:7].[CH2:14]([Mg]Br)[CH3:15].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH2:14][CH3:15])[CH:8]=[C:9]2[O:13][CH2:12][O:11][C:10]=12
Reactant: CC[Mg]Br
Reactant: COc1cc(C=O)cc2c1OCO2
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=O)c1cc(OC)c2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Methoxy-4,5-methylenedioxybenzaldehyde (5.55 g) was dissolved in tetrahydrofuran (150 ml), and ethylmagnesium bromide (IM tetrahydrofuran solution, 46.2 ml) was added thereto, followed by stirring at room temperature for 30 minutes. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, a 5% aqueous solution of sodium bicarbonate and a saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetone (300 ml), and Jones' reagent (5.3 ml) was added thereto under ice-cooling, followed by stirring at the same temperature for 30 minutes. 2-Propanol (5.3 ml) was added to the reaction solution and the mixture was concentrated under reduced pressure. The residue was subjected to partitioning between ethyl acetate and water. The organic layer was washed successively with water and a saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3'-methoxy-4',5'-methylenedioxypropiophenone (5.27 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:15]2=[C:16](Cl)[N:17]3[C:21]([N:22]=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[N:18]3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:15]2=[C:16]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:17]3[C:21]([N:22]=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[N:18]3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(Cl)c2CC1
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(N3CCOCC3)c2CC1
Temperature: 60 °C

Procedure:
To 0.15 g 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid benzyl ester (0.42 mmol), in a sealed tube in 8 mL ethanol, was added 78 μL (0.88 mmol) morpholine, and the reaction was heated at 60° C. for 16 hours. 5 mL of H2O was added and the mixture was extracted with EtOAc (2×10 mL), the organic layers were combined and dried with MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, DCM/MeOH 2%).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[NH2:15][C:16]1[N:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1.CO.ClCCl.CCOCC>ClCCl.CO>[C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10].[NH2:13][N+:17]1[CH:18]=[CH:19][C:20]([CH3:22])=[N:21][C:16]=1[NH2:15]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Cc1ccnc(N)n1
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Cc1cc[n+](N)c(N)n1
Reaction time: 4 h

Procedure:
O-(Mesitylenesulfonyl)hydroxylamine containing ca. 18% water (3.5 g, 2.88 g dry wt., ca. 13.4 mmole) was dissolved in dichloromethane (18 mL) and dried over Na2SO4 and filtered. This was added dropwise to a solution of 2-amino-4-methylpyrimidine (1 g, 9.14 mmole) in 3:4 methanol-dichloromethane (14 mL) in an ice bath with stirring. Stirring was continued at 4 C. overnight. Ether (30 mL) was added and the mixture was stirred at 4 C. for 4 hr. Filtration and drying afforded a mixture of the crude aminated product. (2.4 g). This was dissolved in methanol and filtered, and concentrated under reduced pressure to 15-20 mL. Ether (20 mL) was added, and the mixture was stirred at room temp. for 2 hr. Filtration, washing with 1:1 dichloromethane-ether and drying gave 0.92 g of a fraction, mp 209-212 C., consisting mainly of 1,2-diamino-6(or 4)-methylpyrimidinium mesitylene-2-sulfonate. Storage of the filtrate overnight resulted in deposition of more crystals, which were filtered out and washed with 1:1 dichloromethane-ether to give 1.06 g of a fraction, mp 166-168 C, consisting mainly of 1,2-diamino-4(or 6)-methylpyrimidinium mesitylene-2-sulfonate. Isomer assignment is tentative.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[O:11]1[CH:15]=[CH:14][CH2:13][CH2:12]1>C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]([NH:9][N:10]=[CH:15][CH2:14][CH2:13][CH2:12][OH:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1cccc(Br)c1
Reactant: C1=COCC1
Agent: Cl
Solvent: C1CCOC1
Product: OCCCC=NNc1cccc(Br)c1
Yield: 99.6 %

Procedure:
Under anhydrous conditions a solution of 3-bromophenylhydrazine hydrochloride (22.5 g, 100 mmol) and 2,3-dihydrofuran (7.55 ml, 100 mmol) in 200 ml of dry THF was stirred at ambient temperature for 3 h. The reaction mixture was partitioned between EtOAc and H2O. The organic phase was washed with H2O and brine. After drying (Na2 SO4), the solvent was evaporated to give 25.6 g of the product as a brown oil. The product was of suitable purity for use in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[O:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:17]O>>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH:5][CH:11]([O:10][CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CCOC(=O)C=O
Reactant: CO
Product: CCOC(=O)C(Nc1ccc(F)c(F)c1)OC
Reaction time: 14 h

Procedure:
To a stirred solution of 2.0 g (15 mmol) of 3,4-difluoroaniline in methanol is added 4.0 g (39 mmol) of ethyl 2-oxoacetate. After stirring for 14 h, the mixture is concentrated to provide 3.7 g of I-03a that is used directly without purification.