Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][CH3:28].C[N:31](C=O)C>O>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:31][CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[CH:12]=3)[CH:7]=1
Reactant: CCCN(C)C
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Reactant: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NCCCN(C)C)cc21
Temperature: 100 °C
Yield: 93 %

Procedure:
To a solution of Example A3 (1.00 g, 2.84 mmol) in DMF (10 mL) was added N,N-dimethylpropaneamine (0.870 g, 8.52 mmol) and the resulting reaction mixture was heated at 100° C. for 36 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), and the solvent evaporated to provide 3-(5-amino-2-chloro-4-fluorophenyl)-7-(3-(dimethylamino)propylamino)-1-ethyl-1,6-naphthyridin-2(1H)-one (1.10 g, 93% yield) as an orange foam. 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.64 (s, 1H), 7.20 (d, J=11 Hz, 1H), 7.03 (m, 1H), 6.76 (d, J=9 Hz, 1H), 6.27 (s, 1H), 5.30 (s, 2H), 4.08 (m, 2H), 3.30 (m, 2H), 2.26 (t, J=6 Hz, 2H), 2.05 (m, 6H), 1.66 (m, 2H), 1.18 (t, J=6 Hz, 3H); MS (ESI) m/z: 418.2.2 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)O1.Br[C:22]1[CH:23]=[C:24]([CH2:28][N:29]([CH3:39])[C:30](=[O:38])[C:31]2[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:25]=[N:26][CH:27]=1>>[CH3:39][N:29]([CH2:28][C:24]1[CH:25]=[N:26][CH:27]=[C:22]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[CH:23]=1)[C:30]([C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=1)=[O:38]
Reactant: CN(Cc1cncc(Br)c1)C(=O)c1ncccc1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)CCC(=O)N3)OC1(C)C
Product: CN(Cc1cncc(-c2ccc3c(c2)CCC(=O)N3)c1)C(=O)c1ncccc1Cl

Procedure:
In analogy to the procedure described for the preparation of example 45, 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (intermediate A-34) has been coupled to N-((5-bromopyridin-3-yl)methyl)-3-chloro-N-methylpicolinamide (intermediate A-57) to give the title compound as a light brown amorphous solid. MS: 407.5 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([C@@H:7]([C@H:9]([C:11]([O:13][CH3:14])=[O:12])[OH:10])[OH:8])([O:5][CH3:6])=[O:4].Br[CH2:16][C:17]([CH3:19])=[CH2:18]>CN(C=O)C>[CH3:16][C:17](=[CH2:18])[CH2:19][O:10][C@H:9]([C@@H:7]([O:8][CH2:18][C:17]([CH3:19])=[CH2:16])[C:3]([O:5][CH3:6])=[O:4])[C:11]([O:13][CH3:14])=[O:12]
Reactant: C=C(C)CBr
Reactant: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)CO[C@@H](C(=O)OC)[C@@H](OCC(=C)C)C(=O)OC
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a cooled (−10° C.) suspension of NaH (60% dispersion in mineral oil, 6.73 g, 168 mmol) in DMF (240 mL) was added dropwise a solution of (+)-dimethyl L-tartrate (15.0 g, 84.0 mmol) in DMF (40 mL) over a period of 30 min. After the addition was complete, the mixture was stirred for another 30 min at −10° C., and then 3-bromo-2-methylpropene (25.5 mL, 253 mmol) was added while maintaining the reaction temperature below 0° C. The mixture was stirred for 1.5 h at −10° C., quenched with H2O and saturated aqueous sodium chloride (NaCl, brine), and extracted with EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated to yield a yellow oil. Purification by flash chromatography (SiO2, hexanes/EtOAc gradient) yielded the title compound as a colorless oil (17.05 g, 71%): IR (neat) 2953, 1758, 1435, 1270, 1203, 1106 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.92-4.86 (m, 4H), 4.37 (s, 2H), 4.19 (d, J=12.3 Hz, 2H), 3.82 (d, J=12.3 Hz, 2H), 3.77 (s, 6H), 1.68 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 169.84, 141.04, 114.10, 78.60, 75.66, 52.22, 19.52; HRMS-ESI (m/z) [M]+ calcd for C14H22O6, 286.1416; found, 286.1417.
Reaction SMILES: Cl[N:2]1[CH:7](Cl)[CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:9][O-:10].[Na+].[CH3:12][OH:13]>>[CH3:9][O:10][N:2]1[CH:7]([O:13][CH3:12])[CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CO
Reactant: C[O-]
Reactant: ClC1CNCCN1Cl
Agent: [Na+]
Product: COC1CNCCN1OC

Procedure:
A mixture of 1,6-dichloropiperazine U (3.9 g; 26 mmol) and freshly prepared sodium methoxide (62 mmol) in anhydrous methanol (50 ml) was refluxed overnight and the solvent was removed under reduced pressure. The residue was diluted to 100 ml with CH2Cl2 and the solution washed with water, brine and dried over anhydrous MgSO4 and filtered off. The filtrate was evaporated under reduced pressure to give pure 1,6-dimethoxypiperazine V (3.6 g; 98%) as a colourless crystals. 1HNMR (CDCl3) 3.94 (s, 6H); 7.76 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH2:20][CH3:21])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:15]1[C:14]2[CH:13]=[C:12]([CH2:20][CH3:21])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccncc1
Reactant: CCOC(=O)c1cc(CC)sc1N
Product: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 4-cyanopyridine and 2-amino-5-ethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][SH:9].Cl[CH2:11][CH2:12][CH2:13][C:14]#[N:15]>O.C(O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][S:9][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: SCc1ccco1
Reactant: N#CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CCCCSCc1ccco1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 94.1 %

Procedure:
A solution of sodium hydroxide (12.7 g) in water (50 ml) and ethanol (50 ml) was added dropwise over 30 minutes to a solution of furanylmethyl mercaptan (34.25 g) and 4-chlorobutyronitrile (31.58 g) in ethanol (150 ml) under nitrogen at 10° C. (ice-bath). The temperature rose slightly (to 18° C.) and the solution went cloudy. It was stirred at room temperature for 6.5 hours and allowed to stand for 20 hours. Ethanol was removed by evaporation at reduced pressure. The residue was dissolved in water (100 ml) and the solution was extracted with chloroform . The combined extracts were washed with water, dried (MgSO4) and chloroform evaporated at reduced pressure. The residual light-brown liquid was vacuum-distilled to give 4-(2-furanylmethylthio)butyronitrile (51.16 g), b.p.0.05 mm 112°-5° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36](B(O)O)[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.CCCCCCC>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([O:41][CH3:42])=[C:34]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:33]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)nccc3c2)cc1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
A vial was charged with 1-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (INTERMEDIATE ZZZZ; 100 mg, 0.227 mmol), (5-chloro-2-methoxyphenyl)boronic acid (63.4 mg, 0.340 mmol), potassium carbonate (94 mg, 0.680 mmol), and pd(ph3p)4 (26.2 mg, 0.023 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (851 μl) and water (284 μl) were added. The vial was sealed and heated to 100° C. for 30 min in a Biotage Initiator microwave reactor. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-40% EtOAc/Heptane, then 70% EtOAc/Heptane) to give 1-(5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (91.2 mg, 0.167 mmol, 73.5% yield) as an off-white foam. m/z (ESI) 547.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1)#[N:29]>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([C:28]#[N:29])=[N:31][CH:32]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(C#N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-cyanopyridine-5-boronic acid pinacol ester in General Procedure A. Purification on silica gave 280. NMR (CDCL3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H, m), 7.38 (1H, s), 7.80 (1H, d, J=8.1), 8.84 (1H, d, J=8.2), 9.75 (1H, s). MS (ESI+): MH+ 541.30 (50%)
Reaction SMILES: [Li+].[OH-].[O:3]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[C:10]([C:13]([NH:15][C@@H:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:18]([C:29]([O:31]C)=[O:30])[CH2:17]3)=[O:14])[CH:11]=[CH:12][C:4]1=2.Cl>C1COCC1.CO.O>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][C@@H:16]([NH:15][C:13]([C:10]2[CH:11]=[CH:12][C:4]3[O:3][CH2:8][CH2:7][O:6][C:5]=3[CH:9]=2)=[O:14])[CH2:17][C@@H:18]1[C:29]([OH:31])=[O:30])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc3c(c2)OCCO3)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
LiOH (1.23 g, 51.4 mmol) was added to a solution of (2R,4R)-1-tert-butyl 2-methyl 4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-1,2-dicarboxylate (5.4 g, 12.8 mmol) in THF/MeOH/water (3:2:1) (60 mL) and the resulting solution was stirred at room temperature for 18 hours. 1M HCl solution was added to reaction solution to adjust pH to about 3, extracted with ethyl acetate (2×100 mL). The organic layers were dried over MgSO4 and concentrated to give the acid as a white solid 5.0 g (96%). LC-MS: 407.3; 405.3 (t=2.2 min).
Reaction SMILES: C(OC[C@H]([C:15]1[C:24](C)=[CH:23][C:18]2[N:19]=[C:20](Br)S[C:17]=2[C:16]=1C1C=CC(Cl)=CC=1)OC(C)(C)C)(=O)C(C)(C)C.Cl[C:34]1C=C(B(O)O)C=C[N:35]=1.C(=O)([O-])[O-].[K+].[K+].C([O:55][CH2:56][C@@H:57]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])[C:58]1[C:73]([CH3:74])=[CH:72][C:61]2[N:62]=[C:63]([C:65]3[CH:70]=[CH:69][N:68]=[C:67](Cl)[CH:66]=3)[S:64][C:60]=2[C:59]=1[C:75]1[CH:80]=[CH:79][C:78]([Cl:81])=[CH:77][CH:76]=1)(=O)C(C)(C)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:83]([O:82][C@@H:57]([C:58]1[C:73]([CH3:74])=[CH:72][C:61]2[N:62]=[C:63]([C:65]3[CH:70]=[CH:69][N:68]=[C:67]([C:24]4[CH:23]=[C:18]5[C:17]([CH:34]=[N:35][N:19]5[CH3:20])=[CH:16][CH:15]=4)[CH:66]=3)[S:64][C:60]=2[C:59]=1[C:75]1[CH:80]=[CH:79][C:78]([Cl:81])=[CH:77][CH:76]=1)[CH2:56][OH:55])([CH3:85])([CH3:84])[CH3:86]
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1cc2nc(-c3ccnc(Cl)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3ccnc(-c4ccc5cnn(C)c5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 90 °C

Procedure:
A mixture of (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (0.190 g, 0.35 mmol), 2-chloropyridin-4-ylboronic acid (0.66 g, 0.42 mmol), Pd(PPh3)4 (0.020 g, 0.0175, aq. 2M potassium carbonate solution (0.7 mL, 1.4 mmol) in degassed dioxane (2.0 mL) was heated at 90° C. for 3 hr. LC/MS indicated a 1.5:1 ratio of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate to (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate. Reaction mixture was used in next step without further purification.
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])([CH3:5])O.C[Si](C)(C)[Cl:14]>[Bi+]=O>[Cl:14][CH2:1][CH:2]=[C:3]([CH3:5])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: C=CC(C)(O)CCC=C(C)C
Reactant: C[Si](C)(C)Cl
Agent: O=[Bi+]
Product: CC(C)=CCCC(C)=CCCl
Temperature: 60 °C
Yield: 83.2 %

Procedure:
To a mixture of 170 g linalool and 20 mg bismuth(III)-oxide heated to 60° C., 130.5 g trimethylchlorosilane were dropped in. Then the mixture was cooled to room temperature and the organic layer was separated. The resulting oil was purified by distillation to yield 158.35 g of a colorless oil.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)CCC>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][N:6]1[C:7](=[O:8])[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:3][C:4]([C:10]([O:12][CH3:13])=[O:11])=[CH:5]1
Reactant: COC(=O)c1cc(Br)c(=O)n(C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccccn2)c(=O)n(C)c1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
Methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (57 mg, 0.23 mmol), 2-(tributylstannyl)pyridine (85 mg, 0.23 mmol) and tetrakis(triphenylphosphine)palladium (13 mg, 0.012 mmol, Strem) were stirred in 1.5 mL of dioxane at 90° C. for 16 h. The reaction mixture was cooled to RT, diluted with H2O and extracted with EtOAc (2×). The combined organic extracts were washed 1× with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude residue by column chromatography (4 g pre-packed column, elution 0-30% EtOAc/Hexanes) gave the title compound (22 mg, 39%) as a light yellow solid. MS m/z: 245 (M+1).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[F:9][C:10]([F:28])([F:27])[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][N:15]1[CH2:19][CH:18]2[C:20](=O)[CH2:21][CH2:22][CH:17]2[CH2:16]1>O.C(O)C>[F:9][C:10]([F:28])([F:27])[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][N:15]1[CH2:19][CH:18]2[C:20](=[N:2][OH:3])[CH2:21][CH2:22][CH:17]2[CH2:16]1
Reactant: O=C1CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (3.47 g, 50.0 mmol) and sodium acetate (4.27 g, 52.0 mmol) were dissolved in water (15 mL) and added to a solution of 2-(3-(trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-one (Example 56C, 11.33 g, 40 mmol) in ethanol (80 mL). The reaction was brought to reflux and then allowed to cool to 70° C. After 1 hour, the solvent was removed in vacuo to give the title compound.
Reaction SMILES: C(O[CH2:4][NH:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][CH2:13][C:14]2[S:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:8][N:7]=1)C.[BH4-].[Na+].O.C(OCC)(=O)C>CS(C)=O>[CH3:4][NH:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][CH2:13][C:14]2[S:15][C:16]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:8][N:7]=1
Reactant: CCOCNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)cn1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
To a solution of 6-(ethoxymethyl-amino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-153 (427 mg, 0.92 mmol) in dimethylsulfoxide (5 mL) was added sodium borohydride (100 mg, 2.7 mmol), and the solution was stirred for 15 minutes at 100° C. Water and ethyl acetate were added to the reaction solution, which was then partitioned, and the organic layer was washed with water three times. Silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, and purified by silica gel column chromatography (ethyl acetate). The solvent was evaporated in vacuo, hexane, diethyl ether and ethyl acetate were added to the residue for solidification, and the title compound (150 mg, 0.44 mmol, 48.1%) was obtained as a white solid.
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.[CH2:9]([Li])[CH2:10]CC.C([C@@H:17]1[CH2:22][C:21](=[O:23])[C:20]([CH3:24])=[CH:19][CH2:18]1)(=O)C>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[CH3:24][C:20]1[C:21](=[O:23])[CH2:22][C@@H:17](/[C:3](/[CH3:4])=[CH:9]\[CH3:10])[CH2:18][CH:19]=1
Reactant: CC(=O)[C@H]1CC=C(C)C(=O)C1
Reactant: CN(C)CCN(C)C
Reactant: [Li]CCCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C/C=C(/C)[C@H]1CC=C(C)C(=O)C1
Reaction time: 0.25 h

Procedure:
4.5 g of ethyltriphenylphosphonium bromide and 1.8 ml of N,N,N',N'-tetramethyl-ethylenediamine are cooled to 0° in 300 ml of tetrahydrofuran under argon. 7.5 ml of n-butyllithium (1.6M in hexane) are then added dropwise thereto while stirring and the mixture is stirred for a further 1 hour without cooling with ice. The red solution is cooled to -70°, whereupon 1.52 g of (S)-5-acetyl-2-methyl- 2-cyclohexen-1-one dissolved in 10 ml of tetrahydrofuran are added dropwise thereto during 15 minutes. The cooling bath is removed and the mixture is stirred for a further 45 minutes. After adding 20 ml of water the mixture is evaporated. The residue is taken up in ether and extracted twice with 0.3N sulphuric acid and twice with saturated sodium chloride solution. The ether phase is dried over sodium sulphate and evaporated. The crude product is purified by flash chromatography on silica gel while eluting with hexane/methylene chloride (1:1). There is obtained (5S)-2-methyl-5-[(Z)-1-methylpropenyl]-2-cyclohexen-1-one as a colourless oil [mass spectrum: peaks inter alia at m/e 164 (M+), 149 (M+ -15,CH3), 135 (M+ -29,COH), 82 and 54].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(=O)[C:14](Cl)=O.C(O)C>ClCCl.CN(C)C=O>[CH2:13]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:2]=1[F:1])[CH3:14]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)c(F)cc1F
Reaction time: 0.75 h
Yield: 97.3 %

Procedure:
To a solution of 2,4,5-trifluorobenzoic acid (10.85 g, 61.6 mmol) in dichloromethane (100 mL) is added oxalyl chloride (13.5 mL, 154 mmol) and N,N-dimethylformamide (1 drop). After 45 minutes, the reaction mixture is concentrated under vacuum. The resulting residue is dissolved in dichloromethane (100 mL), and to this solution is added ethanol (18 mL, 310 mmol). After 30 minutes, the reaction mixture is diluted with dichloromethane and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound as an oil (12.23 g). 1H NMR (CDCl3): δ 7.85-7.73 (m, 1H), 7.06-6.94 (m, 1H), 4.38 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][C:12]1=[O:18]>COC(OC)N(C)C>[CH3:3][N:11]([CH:16]=[C:13]1[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[CH3:1])[C:12]1=[O:18])[CH3:12]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCC(=O)CC1=O
Agent: COC(OC)N(C)C
Product: Cc1ccc([N+](=O)[O-])cc1N1CCC(=O)C(=CN(C)C)C1=O
Temperature: 25 °C

Procedure:
A solution of 1-(2-Methyl-5-nitro-phenyl)-piperidine-2,4-dione [100 mg, 0.402 mmol] in N,N-Dimethylformamide dimethyl acetal (DMA.DMF) [1 ml] was heated to reflux for 3 hrs. After cooling to room temperature, reaction mixture was concentrated under vacuum. The crude product obtained was further purified by silica gel chromatography using 30-60% ethylacetate/hexane as eluent to obtain pure desired product i.e., 3-Dimethylaminomethylene-1-(2-methyl-5-nitro-phenyl)-piperidine-2,4-dione [9] as dark red solid [Yield: 79.02 mg, 65.02%]
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]OCC2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[O:50]1[CH2:55][CH2:54]CCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:54][CH2:55][O:50]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: C1CCONC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCCCO2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and [1,2]oxazinane and isolated as light-yellow gum (13.6 mg, 75%). MS (m/e): 387.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH3:10])[C:6]=2[CH:11]=1.[Li+].CC([N-]C(C)C)C.[I:20]CCI.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([I:20])[N:7]([CH3:10])[C:6]=2[CH:11]=1
Reactant: ICCI
Reactant: Cn1cnc2ccc(Cl)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(I)nc2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flask charged with a solution of 6-chloro-1-methyl-1H-benzo[d]imidazole (2 g, 12 mmol) in THF (100 mL) was cooled to −78° C. and 1.8M LDA in THF/hexanes/ethylbenzene (9.34 mL, 16.81 mmol) was added dropwise, and the mixture was stirred at −78° C. for 1 h. A solution of 1,2-diiodoethane (3.72 g, 13.2 mmol) in THF (50 mL) was added dropwise and the mixture was stirred at −78° C. for 1 h. Water (0.3 mL) was added followed by silica gel (20 g) and the mixture was concentrated in vacuo. The residue was purified by silica chromatography eluting with EtOAc in heptane (v/v, 10 to 50%) to give 6-chloro-2-iodo-1-methyl-1H-benzo[d]imidazole. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3H) 7.19 (dd, J=8.59, 2.02 Hz, 1H) 7.58 (d, J=8.59 Hz, 1H) 7.78 (d, J=2.02 Hz, 1H).