Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@@H:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)[C:13]2=[O:23])=[CH:8][CH:7]=1)[O:4][CH3:5].[BH4-].[Na+]>CO>[OH:22][CH:19]1[CH2:18][CH2:17][C:14]2([C:13](=[O:23])[N:12]([C:9]3[CH:8]=[CH:7][C:6]([C@@H:3]([O:4][CH3:5])[C:2]([F:1])([F:24])[F:25])=[CH:11][CH:10]=3)[CH2:16][CH2:15]2)[CH2:21][CH2:20]1
Reactant: CO[C@H](c1ccc(N2CCC3(CCC(=O)CC3)C2=O)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CO[C@H](c1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1)C(F)(F)F
Temperature: 0 °C

Procedure:
2-(4-((R)-2,2,2-trifluoro-1-methoxyethyl)phenyl)-2-azaspiro[4.5]decane-1,8-dione (1.15 g) was dissolved in methanol (30 mL) under argon. The mixture was cooled to 0° C. and sodium borohydride (184 mg) was added in three portions to the cold reaction mixture. The mixture was allowed to warm to RT for 2 hours. The reaction mixture was poured into ice/water and was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was dried at high vacuum and was used without further purification. Colorless foam (1.2 g), mixture of cis and trans alcohols. MS (ESI): 358.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C=O.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH3:42]
Reactant: COC(=O)[C@H](CNCc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Product: COC(=O)[C@H](CN(C)Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)amino]-propionic acid methyl ester (0.050 g, 0.093 mmol) prepared as per the above listed example 656 was subjected to reductive amination as per procedure E with formaldehyde (0.010 ml, 0.093 mmol) and sodium triacetoxyborohydride (0.039 gms, 0.186 mmol) to yield the corresponding 3-(Biphenyl-4-ylmethyl-methyl-amino)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per general procedure C to yield the title compound (0.040 g, 80%). 1H-NMR (400 MHz, DMSOd6): 3.17 (s, 3H), 3.9 (m, 2H), 4.76 (m, 2H), 5.31 (s, 1H), 7.69 (m, 1H), 7.77 (m, 2H), 7.97 (m, 4H), 8.05 (bd, 2H), 8.19 (m, 4H), 8.27 (d, 2H), 8.40 (d, 2H), 9.5 (s, 1H); LC/MS (m/z): 533.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:18])[N:15]([CH3:17])[N:16]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:26]([Mg]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CO>C1COCC1>[CH2:26]([CH:13]1[NH:12][N:11]2[C:14](=[O:18])[N:15]([CH3:17])[N:16]=[C:10]2[C:9]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc2n(c1=O)NC(Cc1ccccc1)C(c1ccc(Cl)cc1)=C2c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-2-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (50 mg, 0.135 mmol), prepared as described in Example 474, in THF (1 mL) at −20° C. was added benzyl magnesium bromide (0.34 mL, 0.675 mmol, 2.0 M in THF). The reaction was stirred at −20° C. for 30 min. After this time MeOH (5 mL) was added to quench the reaction. The reaction was allowed to warm to RT and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an automated system eluting with a gradient of (0% to 80% EtOAc for 20 min. and holds at 80% for 20 min.) to give the title compound, 6-benzyl-7,8-bis(4-chlorophenyl)-2-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (29 mg, 46%) as a beige solid. HPLC retention time: 4.10 min; MS [M+H]+: found 463. 1H NMR (CDCl3, 400 MHz) δ 7.30-6.90 (m, 13H), 4.22 (t, 1H), 3.36 (s, 3H), 2.90-2.75 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:35]([O-:38])([O-])=[O:36].[K+].[K+].Br[C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>CN(C=O)C.CO>[F:22][C:21]([F:24])([F:23])[C:35]([OH:38])=[O:36].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)=[CH:18][CH:19]=3)=[N:11][N:10]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: Brc1cccnc1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)c1cc(Nc2nnc(-c3ccc(Oc4cccnc4)cc3)o2)ccc1Cl
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Yield: 26.9 %

Procedure:
4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (100 mg, 0.281 mmol) was dissolved in ca. 2 mL of anhydrous DMF under argon. Solid potassium bis(trimethylsilyl)amide (140.2 mg, 0.702 mmol) was added and the resulting yellow solution was heated at 80° C. for 15 min. Then solid K2CO3 (19.4 mg, 0.140 mmol) was added, followed by 3-bromopyridine (89.0 mg, 0.562 mmol). The reaction mixture was microwaved at 250° C. for 10 min. Then it was diluted with 1 mL of MeOH, filtered and purified by preparative reverse-phase chromatography using acetonitrile/water with 0.1% TFA gradient. The major peak having the mass of the product was collected; solvent was removed in vacuo to give the title product as a brown oil (20.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11](SN(CCC)CCC)[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[O:13])=[C:7]([F:33])[CH:6]=1.[CH:42]([N:45]([CH:48]([CH3:50])[CH3:49])[S:46]Cl)([CH3:44])[CH3:43]>>[Cl:1][C:2]1[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([S:46][N:45]([CH:48]([CH3:50])[CH3:49])[CH:42]([CH3:44])[CH3:43])[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[O:13])=[C:7]([F:33])[CH:6]=1
Reactant: CCCN(CCC)SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reactant: CC(C)N(SCl)C(C)C
Product: CC(C)N(SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F)C(C)C

Procedure:
39 was prepared, as a white solid, m.p.: 147°-149° C. in a similar manner to (38). The intermediate compound, di(isopropyl)aminosulphenyl chloride, boiled at 92°-4° C. at 20 Torr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH2:16]([NH2:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:24][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=CC(=O)CCC2)cc1
Reactant: NCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CC(NCCc3ccccc3)CCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A mixture of 3-(4-methoxy-phenyl)-cyclohex-2-enone (prepared following the procedure described in CA:54-10947d) (2.0 g, 9.89 mmol), phenethylamine (1.20 g, 9.89 mmol), toluene (50 ml) and a catalytical amount of p-toluenesulfonic acid was refluxed in a Dean-Stark apparatus overnight. After removal of the solvent, the residue was dissolved in MeOH (30 ml) and sodium borohydride (excess) was added. After stirring for 1 h at RT, the solvent was evaporated, H2O was added to the residue. Extraction with CH2Cl2, drying of the organic layer over Na2SO4, evaporation of the solvent and flash-chromatography of the residue over SiO2 (Biotage-40, 90 g) eluting with CH2Cl2—MeOH 95:5 gave (RS)-[3-(4-methoxy-phenyl)-cyclohex-2-enyl]-phenethyl-amine (1.7 g, 56%, light yellow solid, MS: m/e=308.2 (M+H+)).
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]([CH3:9])([OH:8])[C:6]#[CH:7])[CH3:2].[H-].[Na+].I[CH3:13]>CN(C)C=O>[CH2:1]([S:3][CH2:4][C:5]([O:8][CH3:13])([CH3:9])[C:6]#[CH:7])[CH3:2]
Reactant: CI
Reactant: C#CC(C)(O)CSCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(C)(CSCC)OC
Reaction time: 8 h

Procedure:
1-Ethylsulfanyl-2-methyl-but-3-yn-2-ol (0.29 g, 2.0 mmol) was added to a mixture of sodium hydride (60% dispersion in mineral oil, 88 mg, 2.2 mmol) in dimethylformamide (5 mL) under argon. Iodomethane (0.12 mL, 2.0 mmol) was then added to the reaction mixture via syringe and the mixture allowed to stir overnight. The mixture was poured onto water and extracted twice with diethyl ether. The diethyl ether extracts were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to yield a yellow oil. The oil was purified by column chromatography eluting with dichloromethane to yield the title compound as a clear liquid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1.[CH:15]1([C:20]2[C:24]3[N:25]=[C:26]([C:30]4[CH:31]=[C:32]([S:39](Cl)(=[O:41])=[O:40])[CH:33]=[CH:34][C:35]=4[O:36][CH2:37][CH3:38])[NH:27][C:28](=[O:29])[C:23]=3[O:22][N:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1>ClCCl>[CH:15]1([C:20]2[C:24]3[N:25]=[C:26]([C:30]4[CH:31]=[C:32]([S:39]([N:2]([CH2:3][CH2:4][C:5]5[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=5)[CH3:1])(=[O:40])=[O:41])[CH:33]=[CH:34][C:35]=4[O:36][CH2:37][CH3:38])[NH:27][C:28](=[O:29])[C:23]=3[O:22][N:21]=2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nc2c(C3CCCC3)noc2c(=O)[nH]1
Reactant: CNCCc1ccc(OC)c(OC)c1
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)N(C)CCc2ccc(OC)c(OC)c2)cc1-c1nc2c(C3CCCC3)noc2c(=O)[nH]1

Procedure:
89.8 mg (0.46 mmol) of N-methylhomoveratrylamine are added to a solution of 65 mg (0.153 mmol) of the sulfonyl chloride from example IX in 5 ml of dichloromethane. The mixture is stirred overnight at room temperature before the crude product, after concentrating the mixture, is purified by means of preparative TLC chromatography using dichloromethane/methanol 95:5. The oily residue is crystallized with ether.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:28][CH2:29][OH:30])[CH:17]=[C:18]([C:20]3[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=3)[N:19]=2)=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3[N:16]([CH2:28][CH2:29][O:30][C:11]=2[CH:10]=1)[CH:17]=[C:18]([C:20]1[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=1)[N:19]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1ncnc1-c1cn(CCO)c(-c2ccc(OCc3ccccc3)cc2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(OCc3ccccc3)cc1OCC2
Yield: 58.4 %

Procedure:
A solution of 2-[2-(4-benzyloxy-2-fluoro-phenyl)-4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol (25.0 g, 59.31 mmol) in DMF (890 mL) was treated with sodium hydride (3.51 g, 94.89 mmol) by portionwise addition. The resultant mixture was stirred for 23 h at RT and quenched with ice and H2O. The precipitate was collected by filtration, washed with H2O and dried in vacuo at 60° C. to give 8-Benzyloxy-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as an off-white solid (13.9 g, 58%). 1H NMR (400 MHz, CDCl3): 8.43 (1 H, d, J=8.97 Hz), 7.87 (1 H, s), 7.63 (1 H, s), 7.41-7.39 (5 H, m), 6.82 (1 H, dd, J=8.98, 2.58 Hz), 6.64 (1 H, d, J=2.55 Hz), 6.00 (1 H, m), 5.10 (2 H, s), 4.50-4.48 (2 H, m), 4.42-4.41 (2 H, m), 1.59 (6 H, d, J=6.63 Hz). LCMS: RT=3.80 min, [M+H]+=402.
Reaction SMILES: [O:1]=[PH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[OH:12]O>>[OH:1][P:2]1(=[O:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: OO
Reactant: O=[PH]1CCCc2ccccc21
Product: O=P1(O)CCCc2ccccc21

Procedure:
Evaporation of the original chloroform extract, gave colourless crystals (28g). The n.m.r. spectrum of this material indicated the presence of some of the secondary phosphine oxide, 1-oxo-1,2,3,4-tetrahydrophosphinoline. This mixture was again treated with alkaline hydrogen peroxide, and a similar work-up gave a further 25g of crystalline 1-hydroxy-1-oxo-1,2,3,4-tetrahydrophosphinoline, m.p. 142°-4°.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([CH3:31])([CH2:10][C:11]([NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:19]=1)=[O:12])[C:7](O)=[O:8].N1C=CC=CC=1>ClCCl>[CH3:5][C:6]1([CH3:31])[CH2:10][C:11](=[O:12])[N:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][CH:15]=2)[C:7]1=[O:8]
Reactant: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)C(=O)O)cn1)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C(=O)Oc1ccc(N2C(=O)CC(C)(C)C2=O)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
A mixture of thionyl chloride (0.726 mL, 10.00 mmol) and 2,2-dimethyl-N-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-yl]-succinamic acid (0.74 g, 2.00 mmol) in dichloromethane (25 mL) was stirred at room temperature for 18 hours. The solvent and excess thionyl chloride were evaporated in vacuo. The crude product was redissolved in dichloromethane (25 mL) and pyridine (316 mg, 4.00 mmol) was added. The solution was extracted with water, dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50), yielding the title compound (490 mg, 69% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[C:6]([Br:8])[CH:7]=1>[Cl-].[Cl-].[Cl-].[Ti+3]>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCN(c3cc(Br)cc(Br)c3)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: Nc1ccc(CN2CCN(c3cc(Br)cc(Br)c3)CC2)cc1

Procedure:
In the manner given in Example 1B, 1-(3,5-dibromophenyl)-4-(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-(3,5-dibromophenyl)-4-[(4-aminophenyl)methyl]piperazine.
Reaction SMILES: [NH:1]1C2=NC=CC2=C[NH:3][CH2:2]1.C([O:12][C:13](=O)[CH:14]([C:21]([O:23]CC)=O)[CH2:15][C:16]([O:18][CH2:19]C)=[O:17])C.C(N)=N>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][C:14]1[C:21]([OH:23])=[N:1][CH:2]=[N:3][C:13]=1[OH:12]
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: C1=CC2=CNCNC2=N1
Agent: N=CN
Product: COC(=O)Cc1c(O)ncnc1O

Procedure:
Dihydropyrrolo[2,3-d]pyrimidine derivatives may be prepared as shown in FIG. 39. 2-Ethoxycarbonyl-succinic acid diethyl ester (200) was heated with formamidine to provide (4,6-Dihydroxypyrimidin-5-yl)-acetic acid methyl ester (201). Halogenation of compound (201) with (for example) POCl3 gave the dichloropyrimidine derivative (202). Treating compound (142) with base (e.g., KH) in THF and an electrophile R3X affords the intermediate (203). Reduction with an agent such as DIBAL-H gives the alcohol, which was activated with (for example) MsCl in the presence of base (e.g., TEA) to provide the mesylate intermediate (204). Treating the mesylate (204) with (for example) p-methoxybenzylamine yielded the dihydropyrrolo[2,3-d]pyrimidine derivative (205). SNAr reaction of the compound (205) with 1-Boc-piperazine formed the intermediate (206). Deprotection of the compound (206) with acid (e.g., TFA) gave the free amine (207). Amide coupling of the free amine (207) with an appropriately substituted/protected amino acid and followed by deprotection (if necessary) gave the product (208).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26](I)=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:40]1[S:41](=[O:46])(=[O:45])[CH2:42][CH2:43][CH:44]=1)CCC>CN(C)C=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>[O:45]=[S:41]1(=[O:46])[CH2:42][CH2:43][CH:44]=[C:40]1[C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:18]([C:15]3[C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=4)[C@@H:8]4[C@H:13]([C:14]=3[OH:31])[C@@H:12]3[CH2:32][C@H:9]4[CH2:10][CH2:11]3)=[N:19][S:20](=[O:30])(=[O:29])[C:21]=2[CH:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCS1(=O)=O
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 22 h
Yield: 19.1 %

Procedure:
To a solution of (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 19, 200 mg, 0.34 mmol) and tributyl-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-stannane (prepared as described in US patent application US 2008/0031852, 180 mg, 0.44 mmol) in anhydrous N,N-dimethylformamide (7 mL) under a nitrogen atmosphere, Pd(PPh3)4 (20 mg, 0.017 mmol) was added. The resulting mixture was stirred at 90° C. for 22 h, and then allowed to cool to 25° C. The reaction mixture was concentrated in vacuo and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (1R,2S,7R,8S)-5-[7-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (38 mg, 0.065 mmol, 20%), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.19 (2H, m), 1.42-1.61 (4H, m), 2.50 (1H, m), 2.65 (1H, m), 2.97 (2H, m), 3.05 (1H, m), 3.53 (3H, m), 4.43 (1H, d, J=14.4 Hz), 4.96 (1H, d, J=15.6 Hz), 7.15 (2H, m), 7.33 (2H, m), 7.41 (1H, t, J=3.6 Hz), 7.66 (1H, d, J=9.2 Hz), 7.96 (1H, dd, J=8.8, 2.4 Hz), 8.10 (1H, d, J=2.4 Hz). LC-MS (ESI) calcd for C28H26FN3O6S2 583.12, found 584.2 [M+H+].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH2:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH3:16]>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([C:21]1[CH:20]=[CH:19][C:18]([O:23][CH3:24])=[C:17]([CH2:15][CH3:16])[CH:22]=1)=[O:9]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1cc(C(=O)c2ccccc2Cl)ccc1OC
Reaction time: 4 h
Yield: 94.2 %

Procedure:
At ambient temperature, to a stirred solution containing aluminum chloride (20 g, 0.150 mol), 2-chlorobenzoylchloride (19 mL, 0.150 mol) in CH2Cl2 (100 mL) was added dropwise 2-ethylanisole (20.4 g, 0.150 mol). After 4 h, the reaction was diluted with CH2Cl2 (400 mL) washed with aq. KH2PO4 (2×200 mL), brine (1×200 mL), filtered though Celite and concentrated to give 38.82 g (94%) of the title compound. 1H NMR: consistent.
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[CH:15]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:16]1([CH:15]2[CH:13]3[CH2:12][CH2:11][CH:10]2[CH2:9][NH:8][CH2:14]3)[CH:20]=[N:19][N:18]=[N:17]1
Reactant: [H][H]
Reactant: c1ccc(CN2CC3CCC(C2)C3n2cnnn2)cc1
Agent: [Pd]
Solvent: CO
Product: c1nnnn1C1C2CCC1CNC2
Yield: 91.4 %

Procedure:
To a nitrogen flushed solution of the title compound from Step D (790 mg, 2.93 mmol) in methanol (10 ml) was added 10% Palladium on carbon (75 mg) and the resulting mixture stirred under a balloon of hydrogen for 2 h. The mixture was filtered through Celite® and the filtrate evaporated to give the title compound 480 mg (91%) as a clear oil. 1H NMR (CDCl3): 1.80 (m, 4H), 2.82 (m, 2H), 2.95 (dd, J 13.1 and 2.7 Hz, 2H), 3.03 (d, J 12.7 Hz, 2H), 4.55 (s, 1H), 8.62 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:32]=[C:18]3[C:19]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[C:24]=4[F:31])=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)[C:10]([F:34])([F:33])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:10]1([F:33])[CH:11]([NH:14][C:15]2[N:32]=[C:18]3[C:19]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[C:24]=4[F:31])=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(-c4ccc(F)c(F)c4F)cccn3n2)C(F)(F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(-c2cccn3nc(NC4CCNCC4(F)F)nc23)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,3-difluoro-4-[8-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (110 mg, 228 μmol) in CH2Cl2 (4 mL) at 0° C. was added TFA (182 mg, 123 μl, 1.59 mmol) and stirred at room temperature for 18 hours. Further TFA (182 mg, 123 μl, 1.59 mmol) was added and stirred at 50° C. for 6 hours. The reaction mixture was extracted with saturated NaHCO3 solution and ethyl acetate, the organic layers were combined, dried over Na2SO4, filtered and the solvents were evaporated. The product was coevaporated four times with toluene. The title compound was obtained as light yellow foam (87 mg, 100%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:14]1([CH2:20][CH2:21][C:22](Cl)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[CH2:21]([C:22]1[S:34][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1)[CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Product: c1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg; 1 mmol), TEA (0.153 ml; 1.1 mmol), phenylpropionylchloride (0.163 ml; 1.1 mmol) and Lawesson's reagent (606 mg; 1.5 mmol) as described in method 1; yield: 0.067 g (21.9%);
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH3:14].[C:15]([O:19][C:20]([N:22]1[CH2:30][CH2:29][CH2:28][CH:24]([C:25](O)=[O:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:30][CH2:29][CH2:28][CH:24]([C:25]([NH:1][C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)=[N:4][C:3]=2[CH3:14])=[O:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1N
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1NC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Yield: 30.1 %

Procedure:
Using 5-amino-2-(4-chlorophenyl)-4-methylthiazole (197 mg, 0.877 mmol) and 1-(tert-butoxycarbonyl)nipecotic acid (205 mg, 0.877 mmol), the same procedure was followed as in Step 3a of Example 3 to give 115 mg (30%) of the desired compound as a yellow powder.