Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12]C(C)(C)C)=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1.FC(F)(F)C(O)=O>ClCCl>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2sc(C(=O)O)cc2/C1=C/c1ccc[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
tert-Butyl (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxylate (150 mg, 0.47 mmol) was dissolved in dichloromethane (8 ml), cooled to 0° C., treated with trifluoroacetic acid (0.75 ml) and stirred for 2 hours warming to room temperature. The reaction mixture was evaporated to dryness and triturated with diethyl ether to give 70 mg of (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxylic acid as a red solid. MS(ES): m/e 260 [M+H].
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([S:12](Cl)(=[O:14])=[O:13])[CH2:9][CH2:10][CH3:11].I.[CH:17]12[CH2:28][CH2:27][CH:20]([CH2:21][CH:22]1[C:23]([O:25][CH3:26])=[O:24])[CH2:19][NH:18]2>C(Cl)(Cl)Cl>[CH2:8]([S:12]([N:18]1[CH2:19][C@H:20]2[CH2:27][CH2:28][C@@H:17]1[C@H:22]([C:23]([O:25][CH3:26])=[O:24])[CH2:21]2)(=[O:14])=[O:13])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCS(=O)(=O)Cl
Reactant: COC(=O)C1CC2CCC1NC2
Agent: I
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)N1C[C@H]2CC[C@@H]1[C@H](C(=O)OC)C2
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Triethylamine (0.51 mL, 3.7 mmol) and 1-butanesulfonyl chloride (0.233 mL, 1.84 mmol) were added to a chloroform (5 mL) solution of methyl 2-azabicyclo[2.2.2]octane-6-carboxylate hydroiodide (298 mg, 0.989 mmol) synthesized according to the method described in literature (Chem. Pharm. Bull. 53(1) 81-85 (2005)), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was washed once with distilled water, and once with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the target (157 mg, 55%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:35])[N:17]([C:21]2[CH:22]=[C:23]([CH:30]=[C:31]([F:34])[C:32]=2[CH3:33])[C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].[CH2:36]([NH2:38])[CH3:37]>O1CCOCC1>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[C:31]([F:34])[C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:38][CH2:36][CH3:37])([CH3:13])[CH3:12])[C:16]3=[O:35])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Reactant: CCN
Solvent: C1COCCO1
Product: CCNCCOc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)cc(F)c2C)c1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide (Example 252k, 0.5 g) dissolved in 1,4-dioxane (2 mL) was treated with 70% ethylamine (2 mL) in a sealed tube. The resulting mixture was stirred at 100° C. for 1 h in a microwave (100 W). Evaporation and purification by preparative HPLC (Waters X-Terra column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent) gave the title compound (0.255 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]=[N:17][N:18]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[CH:5][CH:4]=1)=[O:2].O.[BH4-].[Na+]>CN(C)C(=O)C>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]=[N:17][N:18]([C:20]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: OCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1

Procedure:
5-(4'-formyl-1,1'-biphenyl-2-yl)-2-triphenylmethyl-2H-tetrazole was dissolved in N,N-dimethylacetamide and some water and reduced by sodium borohydride. The reaction mixture was then poured into water slowly to precipitate the title compound which is further purified by recrystallizations as described in Example 11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)(O)[CH3:14])[CH:7]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][CH:6]3[C:5]=2[CH:4]=1.[OH-].[K+]>S(Cl)(Cl)=O.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8](/[CH:12]=[C:13](/[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)\[CH3:14])[C:7]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C1CN(C)CCC1N2CC(C)(O)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1ccc2c(c1)c1c(n2/C=C(\C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-(8-Methoxy-2-methyl-2,3,4,4a-tetrahydro-1H-pyrido[4,3-b]indol-5(9bH)-yl)-2-(pyridin-4-yl)propan-2-ol (500 mg, 1.4 mmol) in thionylchloride (5 mL) and stirred at RT for 2 h. The reaction mixture was concentrated followed under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (4 mL) and the solution was stirred for 5 min. at RT. Powdered KOH (798 mg, 14.2 mmol) was added, the reaction mixture was stirred at RT for 5 min. and then at 100° C. for 1 h. The progress of reaction was monitored by TLC and NMR. Upon completion the reaction mixture was cooled at RT, diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.58 (d, 2H), 7.70 (d, 2H), 7.30 (s, 1H), 7.10 (d, 1H), 6.95 (s, 1H), 6.80 (d, 1H), 3.95 (s, 2H), 3.80 (s, 3H), 3.10 (t, 2H), 2.90 (t, 2H), 2.70 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]([O:14][C:15](=[O:20])[NH:16][CH2:17][CH2:18][NH2:19])([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:10]([O:14][C:15]([NH:16][CH2:17][CH2:18][NH:19][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:20])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)NCCNC(=O)OC(C)(C)C

Procedure:
Ethyl 2-bromo-2-methylpropanoate (2.0 g, 13.47 mmol) was added to tert-butyl(2-aminoethyl)carbamate (2.0 g, 12.48 mmol) and K2CO3 (4.31 g, 31.2 mmol) in DMF (35 ml) at room temperature. After 18 h at room temperature the reaction mixture was partitioned between aqueous saturated NaHCO3 and EtOAc, extracted 2× with EtOAc, the combined organic layers dried over Na2SO4 and evaporated. The residue was preabsorbed onto isolate and purified by normal phase chromatography: 120 g RediSep® column, eluting with a gradient from DCM to 9:1 DCM containing 0.3% NH3. The product containing fractions were combined and evaporated to give the title compound as a colourless oil. 1H NMR (400 MHz, DMSO-d6) δ 6.74 (t, 1H), 4.07 (q, 2H), 2.95 (q, 2H), 2.45-2.35 (m, 2H), 2.17-2.02 (m, 1H), 1.38 (s, 9H), 1.19 (d, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([OH:13])[C:8]([OH:12])=[N:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[NH:17]C(OCC)=O.[OH-].[K+].CCOCC>COCCO>[NH2:17][C:3]1[C:4]([N+:14]([O-:16])=[O:15])=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[N:9]=[C:8]([OH:12])[C:7]([OH:13])=[N:6]2
Reactant: CCOC(=O)Nc1c(Cl)cc2nc(O)c(O)nc2c1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: COCCO
Product: Nc1c(Cl)cc2nc(O)c(O)nc2c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 86 %

Procedure:
A mixture of 5 g (15,4 mmol) 7-chloro-6-ethoxycarbonylamino-5-nitro-2,3-dihydroxyquinoxaline and 10 g potassium hydroxide in 60 ml 2-methoxyethanol was refluxed for 15 min. After cooling to 25° C., the reaction mixture was added 20 ml 2-methoxyethanol and 40 ml ether. The precipitated black product was filtered off and washed with ether. The crude product was dissolved in 100 ml water. Addition of 4N hydrochloric acid to pH 5-6 gave 3,4 g (87%) 6-amino-7-chloro-5-nitro-2,3-dihydroxyquinoxaline as red crystals, m.p.>300° C. NMR (DMSO-d6) 12.3 (2H, broad m), 7.40 (1H,s), 6.8 (2H, broad s).
Reaction SMILES: [CH2:1]([C:4]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:11][C:12]1[C:17]([F:18])=[C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[C:15]([NH2:28])=[C:14]([O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:13]=1>>[CH2:1]([C:4]1([S:7]([NH:28][C:15]2[C:14]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:13][C:12]([F:11])=[C:17]([F:18])[C:16]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: COCCOc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Product: C=CCC1(S(=O)(=O)Nc2c(OCCOC)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Yield: 15.8 %

Procedure:
According to the general procedure B, 1-allyl-cyclopropanesulfonyl chloride (450 mg, 2.5 mmol) was reacted with 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-(2-methoxyethoxy)benzene-1,2-diamine (219 mg, 2.5 mmol) to obtain the title product (230 mg, 78%); m/z=581 [M−1].
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>C1COCC1>[NH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: N#CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a stirred solution of 3-(4,4-diphenylpiperidin-1-yl)propionitrile (2.00 g, 6.89 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0 M, 24.1 mL, 24 mmol, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 50 mL) was added and stirring was continued for 1 hour. The mixture was basified to pH 9 by addition of 6 N aq. NaOH, extracted 3 times with CH2Cl2, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, EtoAc-MeOH-isopropylamine 9:1:0 to 4:1:0.2) to give 1.35 g (66%) of tan solid, which was characterized spectroscopically.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[CH:22][CH:21]=1>>[C:1]1([NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]4)=[CH:24][CH:25]=3)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)Nc4ccccc4)cc3)cc2)CC1
Yield: 15.7 %

Procedure:
The title compound (7.4 mg, 16%) was prepared from {4-[(phenylamino)carbonyl]phenyl}boronic acid (24.1 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 495 (M+Na).
Reaction SMILES: C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:24][C@H:25]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:29][CH:28]=1.[NH:45]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[C@H:46]([C:50](O)=[O:51])[CH:47]([CH3:49])[CH3:48].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH:45]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[C@H:46]([C:50]([NH:24][C@H:25]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[CH:31][CH:32]=1)=[O:51])[CH:47]([CH3:49])[CH3:48]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
13 ml (approx. 0.1 mole) of N-ethylmorpholine and 22 g (107 mmoles) of dicyclohexylcarbodiimide are added at 0° C. to a solution in 150 ml of dimethylformamide of 33 g (0.1 mole) of H-Tyr(But)-OBut, 25.1 g (0.1 mole) of Z-Val-OH and 13.5 g of 1-hydroxybenzotriazole. The mixture is stirred for one hour at 0° C. and allowed to stand overnight at room temperature. The precipitate is filtered off and the filtrate is concentrated. The residue is partitioned between 300 ml of ethyl acetate and 300 ml of water. The ethyl acetate phase is extracted by shaking successively with 100 ml of saturated NaHCO3 solution, 100 ml of KHSO4 /K2SO4 solution, 100 ml of saturated NaHCO3 solution and 100 ml of water. After drying over Na2SO4 the solution is concentrated. The residue is triturated with petroleum ether, cooled and filtered off. Yield 31.2 g (60%), melting point 82°-83°, [α]D21 =-20.9° (c=1, methanol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.O[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([O:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:6]([CH2:7][OH:9])[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCCCCO
Reactant: COC(=O)c1cc(Cl)c(F)cc1O
Product: CC(C)(C)OC(=O)NCCCCCOc1cc(F)c(Cl)cc1CO

Procedure:
Intermediate I-30 was prepared from methyl 5-chloro-4-fluoro-2-hydroxybenzoate and tert-butyl 5-hydroxypentylcarbamate analogously to Examples 27-28.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][NH:12][CH2:11][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][N:28]=[CH:27][C:26]=1[CH3:34].C(N(CC)CC)C>C(O)(C)C>[Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:25]2[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][N:28]=[CH:27][C:26]=2[CH3:34])[CH2:11][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1cncc([N+](=O)[O-])c1Cl
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1cncc([N+](=O)[O-])c1N1C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 48 h
Yield: 37.3 %

Procedure:
A solution of tert-butyl ((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (23 mg, 0.067 mmol, Example 26, Step 7), 4-chloro-3-methyl-5-nitropyridine (from ACES Pharma, 16 mg, 0.096 mmol), and triethylamine (37 μL, 0.27 mmol) in isopropyl alcohol (0.60 mL) was heated at 75° C. in a sealed vial for 16 h. Another portion of 4-chloro-3-methyl-5-nitropyridine (19 mg) was added and stirring was continued for 2 days at 100° C. The crude reaction mixture was purified by flash chromatography (24 g silica gel column, eluting with 0-100% EtOAc/hexanes) to afford the sub-title compound (12 mg, 37% yield). LCMS (ESI) calc. for C23H41N4O5Si [M+H]+: m/z=481.3. found 481.3.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[PH:7](=[O:32])([O-:31])[O:8][CH2:9][C:10](CC1C=CC=CC=1)(CC1C=CC=CC=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-]>C1C=CC=CC=1>[Cl-:2].[PH:7](=[O:32])([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:31][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[PH]([O-])OCC(Cc1ccccc1)(Cc1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=[PH](OCCc1ccccc1)OCc1ccccc1

Procedure:
1 mmole of phosphorus pentachloride in benzene is added to a solution in benzene of 1 mmole of dibenzylphenylethyl phosphonate, which has been previously obtained. The mixture is refluxed at 70° C. for 3 to 4h under an anhydrous atmosphere until the chloride is completely obtained. The benzene of said mixture is then evaporated and is taken up in dichloromethane. This solution is used immediately for carrying out coupling with the peptide.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23].O>CN(C)C=O>[Cl:23][CH2:22][CH2:21][CH2:20][CH2:19][N:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[N:7][C:2]1=[O:1]
Reactant: Oc1nccc(C(F)(F)F)n1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(C(F)(F)F)ccn1CCCCCl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4.6 g (28.3 mmol) of 2-hydroxy-4-trifluoromethylpyrimidine were stirred in 60 ml of N,N-dimethylformamide (DMF) and 3.9 g (28.3 mmol) of K2CO3 at room temperature for 1 hour. Then 4.9 g (28.3 mmol) of 1-bromo-4-chlorobutane were added dropwise, and the reaction mixture was stirred at room temperature for 6 hours. Water was then added to the reaction mixture, and the aqueous mixture was extracted with diethyl ether. The aqueous phase was made alkaline by adding NaOH, and the aqueous phase was extracted with methylene chloride. The organic phase was then dried, the desiccant was removed by filtration, and the solvent was evaporated to dryness in vacuo; yield: 1.7 g.
Reaction SMILES: [CH2:1]([C:6]1([C:23]#[C:24][C:25]2([OH:36])[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:27][CH2:26]2)[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:37]([CH:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)[CH2:38][CH3:39]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:37]([CH:40]1[CH2:45][CH2:44][CH:43]([C:46]([O:36][C:25]2([C:24]#[C:23][C:6]3([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10][CH:9]([CH:12]4[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]4)[CH2:8][CH2:7]3)[CH2:26][CH2:27][CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:29][CH2:30]2)=[O:47])[CH2:42][CH2:41]1)[CH2:38][CH3:39]
Reactant: CCCCCC1CCC(C2CCC(C#CC3(O)CCC(CCCCC)CC3)(CCCCC)CC2)CC1
Reactant: CCCC1CCC(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC1CCC(C2CCC(C#CC3(OC(=O)C4CCC(CCC)CC4)CCC(CCCCC)CC3)(CCCCC)CC2)CC1
Reaction time: 8 h

Procedure:
1.10 g of 1-(4,4′-dipentylbicyclohexyl-4-ylethynyl)-4-pentylcyclohexanol and 0.394 g of 4-propylcyclohexanecarboxylic acid are dissolved in 4 ml of dichloromethane, and 0.283 g of 4-(dimethylamino)pyridine is added. 5.569 g of N,N-dicyclohexylcarbodiimide dissolved in 3 ml of dichloromethane are then added dropwise to the reaction mixture. The mixture is stirred overnight and subjected to conventional work-up, giving 1-(4,4′-dipentylbicyclohexyl-4-ylethynyl)-4-pentylcyclohexyl 4-propylcyclohexanecarboxylate (C 66 SmB 171 I, Δε −0.02).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[NH:2])=[CH:12][CH:11]=1
Reactant: Cc1ccc(N)cc1
Reactant: N#Cc1ccccn1
Product: Cc1ccc(NC(=N)c2ccccn2)cc1

Procedure:
The title compound was prepared from 2-cyanopyridine (9.7 g, 93 mmol) and 4-methylaniline (10 g, 93 mmol) by following the procedure described in preparation 10 (8.2 g, yield 41.6%). MS m/z:212.1(M+).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC>CS(C)=O.C([O-])(O)=O.[Na+]>[C:1]1([C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]=[O:24])=[CH:21][CH:22]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(-c2nc3ncccc3cc2-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2nc3ncccc3cc2-c2ccccc2)cc1

Procedure:
To a solution of [4-(3-phenyl-1,8-naphthyridin-2-yl)phenyl]methanol (9-2) (289 mg, 0.925 mmole) in DMSO (2 mL) was added Et3N (1.3 mL, 9.25 mmole) then a solution of pyridine-SO3 (442 mg, 2.78 mmole) in DMSO (2 mL). After 1 hr the mixture was diluted with saturated NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with H2O (2×), brine then dried (MgSO4), filtered, and concentrated to give the title compound as a greenish foam which was sufficiently for use in the next step: 1H-NMR (500 MHz, CDCl3) δ 10.02 (s, 1), 9.19 (dd, J=1.95, 2.20 Hz, 1 H), 8.28 (dd, J=1.95, 6.10 Hz, 1 H), 8.26 (s, 1 H), 7.79 (d, J=8.05 Hz, 2 H), 7.73 (d, J=8.30 Hz, 2 H), 7.56 (m, 1H), 7.35 (m, 3 H), 7.27 (m, 2 H).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([NH:14][NH2:15])=[N:12][CH:11]=[C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[C:25]([CH2:27][CH:28]([C:34](OCC)=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:24]=[CH:23]1>>[CH2:1]([C:8]1[C:13]2[N:12]([C:34]([CH:28]([CH2:27][C:25]3[N:24]=[CH:23][NH:22][CH:26]=3)[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:15][N:14]=2)[CH:11]=[C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncc(-c2cccnc2)nc1Cc1ccccc1
Reactant: CCOC(=O)C(Cc1c[nH]cn1)C(=O)OCC
Product: CCOC(=O)C(Cc1c[nH]cn1)c1nnc2c(Cc3ccccc3)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to that described in Example 1, by condensing 2-benzyl-3-hydrazino-6-(3-pyridyl)pyrazine with diethyl (imidazol-4-ylmethyl)malonate there is obtained ethyl rac-8-benzyl-α-(imidazol-4-ylmethyl)-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 453 (M)+, which is converted into the above acid by alkaline saponification.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=O)[CH:12]([F:14])[F:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.CC1C=CC(S(O)(=O)=O)=CC=1.O.[NH:28]1[CH:32]=CC=[N:29]1>C1(C)C=CC=CC=1>[F:13][CH:12]([F:14])[C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:28]([CH3:32])[N:29]=1
Reactant: c1cn[nH]c1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
The aminal (1.00 g, 2.81 mmol) was dissolved in 7 mL of toluene. Then, ethyl α-ethoxymethylene-4,4-difluoro-3-oxobutyrate (1.25 g, 5.62 mmol) and p-TsOH (107 mg, 0.56 mmol) were added, followed by water (101 mg, 5.62 mg). The mixture was stirred at rt for 90 min, then GC control showed >97% conversion to the pyrazole. The reaction mixture was extracted with water (2×1 mL); then, the organic phase was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, cyclohexane/EtOAc 100:0→70:30) to give the product (840 mg, 4.12 mmol, 73% yield) as a colorless solid.