Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12](I)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32]1([CH3:50])[C:36]2[CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=[CH:40][C:35]=2[O:34][CH2:33]1>>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:38]2[CH:39]=[CH:40][C:35]3[O:34][CH2:33][C:32]([CH3:31])([CH3:50])[C:36]=3[CH:37]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Reactant: CC1(C)COc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Product: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(-c2ccc3c(c2)C(C)(C)CO3)c1[C@H](OC(C)(C)C)C(=O)O
Yield: 84 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 87 from (S)-methyl 2-(tert-butoxy)-2-(1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-(3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (WO2009/062285) to afford the title compound (76 mg, 84%) after purification by reverse phase HPLC. 1H NMR (400 MHz, DMSO-d6, VT) δ ppm 7.49-7.19 (m, 5 H), 7.16 (d, J=2.0 Hz, 1 H), 6.92 (d, J=8.2 Hz, 1 H), 6.10 (br. s., 1 H), 5.42 (d, J=2.7 Hz, 2 H), 5.31 (s, 1 H), 4.32 (s, 2 H), 2.66-2.59 (s, 3 H), 1.42-1.32 (br. s., 3 H), 1.27 (br. s., 3H), 0.84 (s, 9 H); LC/MS ES+=535.52 (M+1).
Reaction SMILES: Cl.CO[C:4](=[NH:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[C:15]([O:19][C:20]([NH:22][NH2:23])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(O)C>[C:15]([O:19][C:20]([NH:22][NH:23][C:4](=[NH:14])[C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(=N)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NNC(=N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-nitro-benzimidic acid methyl ester hydrochloride (500 mg, 2.31 mmol) in ethanol (8 mL), hydrazinecarboxylic acid tert-butyl ester (305 mg, 2.31 mmol) was added followed by triethylamine. The mixture was stirred at rt over night. The solvent was removed and the residue was suspended in methylene chloride (10 mL). The mixture was filtered and the filtrate was concentrated to about 4 mL and loaded on a 20 g silica gel column. Eluting with 40-90% EtOAc/Hexanes on an ISCO machine gave a yellow solid. 410 mg. Which was directly used for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[C:32]([OH:34])=[O:33]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:31][CH2:30][CH2:29][CH:28]2[C:32]([OH:34])=[O:33])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1CCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 25.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with pyrrolidine-2-carboxylic acid (0.23 g, 2 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.27 g, 25%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH3:19][Si:20]([CH3:35])([CH3:34])[CH2:21][CH2:22][O:23][C:24](ON1C(=O)CCC1=O)=[O:25].O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([C:24]([O:23][CH2:22][CH2:21][Si:20]([CH3:35])([CH3:34])[CH3:19])=[O:25])[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(Br)c1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: C[Si](C)(C)CCOC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Br)CC1
Temperature: 20 °C
Reaction time: 6 h
Yield: 96.1 %

Procedure:
A solution of 1-(2-bromo-4-nitrophenyl)piperazine dihydrochloride (1.9 g, 5.8 mmol) in acetonitrile (50 mL) was treated with 1-({[2-(trimethylsilyl)ethoxy]carbonyl}oxy)pyrrolidine-2,5-dione (1.5 g, 5.9 mmol) followed by water (15 mL) and sodium carbonate (1.9 g, 18 mmol) and stirred at 20° C. for 6 h. The reaction mixture was diluted with ethyl acetate (400 mL) and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give a residue. This material was purified by flash column chromatography to give the desired product (2.4 g, 87%) as a solid. [TEOC: (2-(trimethylsilyl)ethoxy)carbonyl]
Reaction SMILES: [CH2:1]([N:3]([O:21][CH3:22])[S:4]([C:7]1[C:15]2[O:14]C(C(C)(C)C)=[N:12][C:11]=2[CH:10]=[CH:9][C:8]=1[Cl:20])(=[O:6])=[O:5])[CH3:2].S(=O)(=O)(O)O.O>O1CCOCC1>[NH2:12][C:11]1[C:15]([OH:14])=[C:7]([S:4]([N:3]([O:21][CH3:22])[CH2:1][CH3:2])(=[O:6])=[O:5])[C:8]([Cl:20])=[CH:9][CH:10]=1
Reactant: CCN(OC)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CCN(OC)S(=O)(=O)c1c(Cl)ccc(N)c1O
Temperature: 80 °C

Procedure:
2-tert-Butyl-6-chloro-benzooxazole-7-sulfonic acid ethyl-methoxy-amide (2.7 g, 7.78 mmol) in dioxane (15 ml) was treated with a mixture of concentrated sulphuric acid (3.5 ml) and water (3.5 ml). The reaction mixture was heated at 80° C. for a total of 8 h and then allowed to cool to RT. Dioxane was removed in vacuo and the resulting aqueous mixture was treated with 1M NaOH (aq) until pH7 was attained. The reaction mixture was extracted with EtOAc, dried (MgSO4) and concentrated in vacuo to afford the title compound as a brown solid; [M+H]+ 281.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[O:5][C:4](=[O:13])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:10]=2)[O:5][C:4](=[O:13])[CH2:3]1
Reactant: CC1(C)CC(=O)Oc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)Oc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 25 °C

Procedure:
The procedure used is substantially in accordance with (Journal of Organic Chemistry, Vol. 46, No. 11, (1981) p 2280-81). To a solution of 2.5 g (9.8 mmol) of 4,4-dimethyl-6-bromo-2-oxo-chroman and 0.087 g (0.3317 mmol) of triphenylphosphine in 36 ml of triethylamine under argon was added 1.74 g (2.5 ml, 17.7 mmol) of trimethylsilylacetylene and 0.027 g (0.12 mmol) of palladium(II) acetate. The mixture was refluxed for 20 hours then cooled to room temperature and filtered. The solvent removed in-vacuo and the resulting residue was purified using flash chromatography (SiO2 ; 5% ethyl acetate in hexanes) to give the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:15])[C:3]=1[F:16].[F:17][C:18]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:19]=1[NH2:20].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[F:16][C:3]1[C:4](=[O:15])[N:5]2[C:10](=[C:11]([C:12]([OH:14])=[O:13])[C:2]=1[NH:20][C:19]1[CH:21]=[CH:22][C:23]([I:25])=[CH:24][C:18]=1[F:17])[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)c1c(Cl)c(F)c(=O)n2c1CCCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCCC2
Reaction time: 4 h
Yield: 27.8 %

Procedure:
8-Chloro-7-fluoro-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylic acid (7d, 426 mg, 1.74 mmol, 1 eq) and 2-fluoro-4-iodoaniline (827 mg, 3.49 mmol, 2 eq) were mixed in anhydrous THF (10 ml) at 0° C. under N2. 1N lithium hexamethyldisilazide in THF (5.23 ml, 5.23 mmol, 3 eq) was added drop wise and the mixture stirred for 4 hours while allowing the temperature to return to RT. The solution was evaporated and purified by flash chromatography using 10-16% MeOH in DCM as eluent. This afforded the title compound as a tan solid (216 mg, 28%). [M+H] calc'd for C16H13F2IN2O3, 447. found, 447.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[C:20]([C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]([CH3:34])([CH3:33])[C:28](OCC)=[O:29])=[CH:24][CH:23]=1)#[N:21]>CCCCCC.O1CCCC1.O>[CH3:33][C:27]([CH3:34])([O:26][C:25]1[CH:35]=[CH:36][C:22]([C:20]#[N:21])=[CH:23][CH:24]=1)[C:28](=[O:29])[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1cnccn1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Oc1ccc(C#N)cc1)C(=O)Cc1cnccn1
Temperature: -78 °C
Yield: 48.8 %

Procedure:
10 ml of a 1.2M solution of butyllithium in n-hexane were added to a solution of 1.68 ml of diisopropylamine in 10 ml of tetrahydrofuran while stirring at -78° C. under a nitrogen atmosphere. The solution was stirred for a further 15 minutes and then 0.94 g of 2-methylpyrazine in 20 ml of tetrahydrofuran was added. The solution was allowed to warm to 20° C. and was stirred for 1 hour. The solution was then cooled to -78° C., 2.33 g of ethyl 2-(4-cyanophenoxy)-2-methylpropionate in 30 ml of tetrahydrofuran were added and the mixture was allowed to warm to 20° C. The mixture was treated with 20 ml of water and the solvent was removed by evaporation. The residue was chromatographed on silica gel using ethyl acetate for the elution to give 1.37 g of 4-[1,1-dimethyl-2-oxo-3-(2-pyrazinyl)propoxy]benzonitrile.
Reaction SMILES: [N+](C1SC=CC=1C1C=CC(C)=CC=1)([O-])=O.[N+:16]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)([O-])=O>>[NH2:16][C:19]1[S:20][CH:21]=[CH:22][C:23]=1[C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1sccc1-c1ccc(Cl)cc1
Agent: Cc1ccc(-c2ccsc2[N+](=O)[O-])cc1
Product: Nc1sccc1-c1ccc(Cl)cc1

Procedure:
The same procedures as described in Example 1 were carried out except that 2-nitro-3-(4-tolyl)thiophene was replaced by 2-nitro-3-(4-chlorophenyl)thiophene, and the filtrate thus obtained was used as intact for the next reaction.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21](O)=[O:22]>>[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:22]
Reactant: Cc1cc(C(=O)O)cc(Br)n1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(Br)n1
Yield: 29 %

Procedure:
The title compound is prepared in 29% yield (182 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (200 mg, 0.78 mmol, Amine-1, single enantiomer) and 2-bromo-6-methylisonicotinic acid (269 mg, 1.95 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:9][CH:10]=1)=[O:4].O.[OH-].[Li+].CO.O>C1COCC1>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:8]2[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cnc(-c2cccc(OC)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(-c2ncc(C(=O)O)cn2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 103.1 %

Procedure:
A mixture of 2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester (145 mg, 0.59 mmol), lithium hydroxide monohydrate (49.5 mg, 1.18 mmol), MeOH (1.5 mL), water (1.5 mL) and THF (1.5 ml) is stirred at rt for 3.5 hrs. The reaction mixture is concentrated, and water (1 mL) and 1 N aqueous HCl (1.2 mL) are added. The precipitated product is filtered and dried to afford 2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid (140 mg). MS: 231 (M+H); 1H NMR (DMSO-d6): δ 4.62 (s, 3H), 7.54 (m, 2H), 8.14 (s, 1H), 8.34 (m, 1H), 8.46 (s, 1H), 9.30 (s, 2H).
Reaction SMILES: NC1NC(C(N)=O)=NC=1.[N+:10](=[C:12]1[NH:16][CH2:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])=[N-:11].[CH3:20][N:21]=[C:22]=[O:23]>ClCCl>[CH3:20][N:21]1[N:11]=[N:10][C:12]2[N:16]([CH:15]=[N:14][C:13]=2[C:17]([NH2:19])=[O:18])[C:22]1=[O:23]
Reactant: [N-]=[N+]=C1NCN=C1C(N)=O
Reactant: CN=C=O
Agent: NC(=O)c1ncc(N)[nH]1
Solvent: ClCCl
Product: Cn1nnc2c(C(N)=O)ncn2c1=O

Procedure:
In this process, 5-amino-1H-imidazole-carboxamide (A) is converted into 5-diazo-1H-imidazole-4-carboxamide (B), which is then cyclized with methylisocyanate in dichloromethane to provide a high yield of clinical-grade Temozolomide. However, this process requires isolation of the unstable and potentially dangerous 5-diazo-1H-imidazole-4-carboxamide (B). Moreover, methylisocyanate is a difficult reagent to handle and ship, especially on the industrial scale, and indeed is better avoided in industrial manufacture. Furthermore, the cycloaddition of methylisocyanate requires a very long reaction time: Table I in J. Med. Chem. 1984, 27, 196-201, suggests 20 days.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(C)c2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)c1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 2) 30.0 mg (0.071 mmol) in 3 ml of EtOH and 2 ml of THF was added 28.0 mg (0.70 mmol, 0.7 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 7.46 (2H, s), 7.32-7.13 (4H, m), 7.10 (1H, s), 6.98 (1H, t, J=4.5 Hz), 2.34 (3H, s), 2.31 (2H, d, J=4.5 Hz), 1.30 (6H, s).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@@H:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:24][CH2:25][N:26]1[C:34]2[C:33]([O:35][CH3:36])=[N:32][CH:31]=[N:30][C:29]=2[C:28]([CH:37]=O)=[CH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O-]S([O-])(=O)=O.[Mg+2]>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]([CH2:9][C@@H:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)[CH2:37][C:28]1[C:29]2[N:30]=[CH:31][N:32]=[C:33]([O:35][CH3:36])[C:34]=2[N:26]([CH2:25][O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC[C@@H](CNCc2ccccc2)O1
Reactant: COc1ncnc2c(C=O)cn(COCc3ccccc3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ncnc2c(CN(Cc3ccccc3)C[C@@H]3COC(C)(C)O3)cn(COCc3ccccc3)c12
Reaction time: 6 h
Yield: 74.6 %

Procedure:
To a solution of (R)—N-benzyl-1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (0.372 g, 1.682 mmol) and 5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde (0.5 g, 1.682 mmol) in 1,2-dichloroethane (30 ml) was added sodium triacetoxyborohydride (0.463 g, 2.186 mmol) and anhydrous MgSO4 (1 g). The mixture was stirred for 6 h. Tlc (EtOAc-hexanes, 8:2) showed the reaction essentially over. After diluting with CH2Cl2 the mixture was washed with aqueous sat. NaHCO3, brine, dried and the solvent evaporated. The residue was chromatographed (EtOAc-hex, 1:1, uv and molybdate) to give (R)—N-benzyl-1-(5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methanamine (0.631 g, 1.255 mmol, 74.7% yield) as a colourless gum. [α]D21 −21.9 (c, 0.905, MeOH). 1H NMR (CDCl3, 300 MHz), 5 ppm, 8.55 (s, 1H), 7.41 (s, 1H), 7.37-7.18 (m, 10H), 5.73 (s, 2H), 4.46 (s, 2H), 4.38-4.29 (m, 1H), 4.10, (s, 3H), 4.05-3.98 (m, 2H), 3.79 (d, 1H, J 13.9 Hz), 3.63 (d, 1H, J 13.9 Hz), 3.53, (t, 1H, J 7.9 Hz), 2.73 (dd, 1H, J 13.3, 5.9 Hz), 2.64 (dd, 1H, J 13.3, 5.9 Hz), 1.32 (s, 6H). 13C NMR (CDCl3, 75.5 MHz), δ ppm, 156.2 (C), 150.7 (C), 150.0 (CH), 139.6 (C), 136.9 (C), 132.2 (CH), 128.8 (CH), 128.4 (CH), 128.2 (CH), 128.0 (CH), 127.7 (CH), 126.9 (CH), 115.7 (C), 114.7 (C), 109.0 (C), 77.0 (CH2), 74.7 (CH2), 70.1 (CH2), 68.4 (CH2), 59.2 (CH2), 56.2 (CH2) 53.5 (CH3), 47.8 (CH2), 26.8 (CH3), 25.6 (CH3). +ESMS Found 503.2643 (M+H)+ C29H35N4O4 requires 503.2658.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][C:10]=1[N+:23]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1COCC1.[Ni]>[NH2:23][C:10]1[CH:11]=[C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:13]=[CH:14][C:9]=1[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c(N)c1

Procedure:
6-(4-Benzylamino-3-nitro-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one E-4.1′ (662 mg; 1.96 mmol) is solved in 200 ml THF, a scoop of Raney Nickel is then added. The mixture is placed in the hydrogenation apparatus and stirred at RT for 1.5 hours under 4 bar hydrogen pressure. The Raney Nickel is filtered off and the reaction solution evaporated to dryness.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:16])=[CH:10][C:7]=1[C:8]#[N:9]>>[Cl:5][C:6]1[C:7]([C:8]#[N:9])=[CH:10][C:11]([NH:14][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:16])=[C:12]([N+:1]([O-:4])=[O:2])[CH:13]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc(Cl)c(C#N)c1
Product: CCOC(=O)C(=O)Nc1cc(C#N)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To 75 ml ice-cooled 100% nitric acid was added gradually 8.1 g (32.1 mmol) 2-chloro-5-ethoxalylaminobenzonitrile. Stirring was continued at 0° C. for 1.5 h, and then the reaction mixture was poured into 500 ml ice-water. The precipitated product was filtered off and recrystallized (ethanol-water) to give 8.25 g (86%) of 6-chloro-3-ethoxalylamino-4-nitrobenzonitrile. M.p. 143-45° C. 1H-NMR (CDCl3 -DMSO-d6): 11.3 (1H, broad s), 8.1 (2H, dd, J=10 Hz), 4.3 (2H, q), 1.4 (3H, t). The filtrate was extracted with 150 ml ethylacetate to give 2-chloro-3-ethoxalylamino-4-nitrobenzonitrile as an oil (0.67 g, 7%). 1H-NMR (CDCl3 -DMSO-d6) 11.4 (1H, broad s), 8.57 (1H, s), 8.33 (1H, s), 4.3 (2H, q), 1.4 (3H, t).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:15]([CH3:16])=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:24]([O:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][C:38]=1[O:39][C:40](=[O:42])[CH3:41])[CH:31]=[CH:32][C:33](Cl)=[O:34])(=[O:26])[CH3:25].Cl>CN(C)C=O>[C:24]([O:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][C:38]=1[O:39][C:40](=[O:42])[CH3:41])[CH:31]=[CH:32][C:33]([NH:13][C:12]1[CH:14]=[C:15]([CH3:16])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH3:17])[CH:11]=1)=[O:34])(=[O:26])[CH3:25]
Reactant: Cc1cc(N)cc(C)c1OCc1ccccc1
Reactant: CC(=O)Oc1ccc(C=CC(=O)Cl)cc1OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C=CC(=O)Nc2cc(C)c(OCc3ccccc3)c(C)c2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a solution of 1.6 g of 4-benzyloxy-3,5-dimethylaniline in 30 ml of dimethylformamide is added under ice-cooling 1.17 g of potassium carbonate, and then a solution of 2.0 g of 3,4-diacetoxycinnamoyl chloride in 10 ml of dimethylformamide is added dropwise at 5° to 7° C., followed by stirring at room temperature for 2 hours. The reaction mixture is poured into ice-water, adjusted to pH 1 with 10 % hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and then concentrated. Recrytallization of the residue from methanol gives 2.64 g of N-(3,4-diacetoxycinnamoyl)-4-benzyloxy-3,5-dimethylaniline.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][CH2:5][CH:4]([C:7]2[C:11]([CH2:12][OH:13])=[C:10]([C:14]([F:17])([F:16])[F:15])[S:9][N:8]=2)[CH2:3]1.O[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:22]([CH3:33])[C:21]=1[CH3:34].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>>[F:18][C:2]1([F:1])[CH2:6][CH2:5][CH:4]([C:7]2[C:11]([CH2:12][O:13][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:22]([CH3:33])[C:21]=3[CH3:34])=[C:10]([C:14]([F:16])([F:17])[F:15])[S:9][N:8]=2)[CH2:3]1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: OCc1c(C2CCC(F)(F)C2)nsc1C(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: CCOC(=O)CCc1ccc(OCc2c(C3CCC(F)(F)C3)nsc2C(F)(F)F)c(C)c1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [3-(3,3-difluorocyclopentyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (50 mg, 0.17 mmol, 1.00 equiv), tol (3 mL), ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (77 mg, 0.35 mmol, 1.99 equiv), ADDP (87 mg, 0.35 mmol, 2.00 equiv), n-Bu3P (70 mg, 0.35 mmol, 1.99 equiv). The resulting solution was stirred for overnight at 60° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLC plate with ethyl acetate/petroleum ether (1/5). This resulted in 50 mg (crude) of ethyl 3-(4-[[3-(3,3-difluorocyclopentyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-dimethylphenyl)propanoate as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[N:18]=[C:17](S)[N:16]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>[Ni].CO>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[N:18]=[CH:17][N:16]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(O)nc(S)n2)cc1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(O)ncn2)cc1
Temperature: 92.5 °C

Procedure:
Raney Nickel (6.0 g, in EtOH) is added to a suspension of [4-(6-hydroxy-2-mercapto-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (2.0 g, 5.99 mmol) in MeOH (58 mL), under an argon atmosphere. The resulting mixture is heated to reflux for 2 h (oil bath is pre-heated to 90-95° C.), allowed to cool to rt, filtered through a pad of celite and concentrated in vacuo. The residue is purified by silica gel (160 g) column chromatography (CH2Cl2/MeOH, 95/5, then 90/10) to provide the title compound as a white solid: ES-MS: 302.1 [M+H]+; single peak at tR=6.54 min (System 2); Rf=0.34 (CH2Cl2/MeOH, 90/10).