Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([OH:19])=O)=[CH:14][C:13]=3[CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][NH:34][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:20][C:13]=3[CH:14]=2)=[O:19])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: O=C(O)c1cc2cc(OCCN3CCCC3)ccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OCCNC(=O)c2cc3cc(OCCN4CCCC4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a solution of 5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid (156 mg, 0.50 mmol) and 4-(2-aminoethoxy)benzoic acid methyl ester hydrochloride (129 mg, 0.56 mmol) in DMF (4.5 ml) in a 20 ml vial was added diisopropylethylamine (0.88 ml, 5.1 mmol). A solution of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (740 μL, 0.82 M, 0.61 mmol) in DMF was added to give a bright yellow solution. The vial was purged with nitrogen and stirred at room temperature for 18 h. The solution was removed and the residue was dissolved in EtOAc (25 ml) and washed with H2O, 1.0M aqueous K2CO3, and brine. The organic layer was dried over anhydrous MgSO4 and solvent was removed on a rotary evaporator. Purification of the residue by column chromatography on a silica gel column using 93:5:2 CH2Cl2:MeOH:TEA eluent provided 4-{2-[5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carbonylamino]-ethoxy}-benzoic acid methyl ester as a beige solid (174 mg).
Reaction SMILES: [F:1][C:2]([F:28])([C:24]([F:27])([F:26])[F:25])[C:3]([C:5]1[S:6][C:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].[CH3:29][Mg]Br>O1CCCC1>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:9]=[C:5]([C:3]([CH3:29])([C:2]([F:1])([F:28])[C:24]([F:25])([F:26])[F:27])[OH:4])[S:6][C:7]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=1
Reactant: O=C(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)s1)C(F)(F)C(F)(F)F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)s1)C(F)(F)C(F)(F)F
Reaction time: 3 h

Procedure:
A solution of 2-pentafluoropropionyl-4,5-bis(4-fluorophenyl)thiophene (5.83 g, 13.9 mmole) in 80 ml tetrahydrofuran was treated with 3 M methyl magnesium bromide (5.1 ml, 1.1 equiv.). After 3 hours, additional methyl magnesium bromide (2 ml) was added. After 4 hours total reaction time, the reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organics were washed with brine, dried and concentrated in vacuo. Chromatography on silica gel gave the title compound as an oil (4.4 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][CH:5]([C:8]2[S:25][C:11]3[N:12]=[C:13]([CH3:24])[N:14]=[C:15]([CH2:16][NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.C(Cl)Cl.[C:36](OC(=O)C)(=[O:38])[CH3:37]>O>[CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][CH:5]([C:8]2[S:25][C:11]3[N:12]=[C:13]([CH3:24])[N:14]=[C:15]([CH2:16][N:17]([CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:36](=[O:38])[CH3:37])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(CNC2CCOCC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1nc(C)nc2sc(C3CCC(C)(C)CC3)cc12)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of N-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}tetrahydro-2H-pyran-4-amine (60 mg), pyridine (129 μL), and DCM (1.8 mL) was added acetic anhydride (76 μL), followed by stirring at room temperature for 30 minutes. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column to obtain N-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-N-(tetrahydro-2H-pyran-4-yl)acetamide (23 mg).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([OH:17])[CH:12]=1.C(Cl)Cl>COCCOC.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:1]1([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([OH:17])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: Oc1cc(-c2ccccc2)ccn1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (164 mg, 0.14 mmol) was added to a stirred suspension of phenylboronic acid (345 mg, 2.84 mmol) and 4-bromo-2-hydroxypyridine (494 mg, 2.84 mmol) in DME (10 mL). The reaction mixture was stirred under an argon atmosphere for 90 min. Degassed 2N potassium carbonate solution (aq) (10 mL) was added and the reaction mixture stirred with heating at 90° C. for 72 h. The solvent was evaporated in vacuo, and the residue partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate (×2). The organics were combined, dried over Na2SO4 and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel. Elution with DCM with a gradient to 5:95 methanol:DCM afforded 4-phenylpyridin-2-ol (311 mg, 1.82 mmol, 64%) M.S. (ESI) (m/z): 172 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>CN(C=O)C.O>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[C:27]([F:28])([F:29])[F:30])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To 4-hydroxy-N-(t-butoxycarbonyl)piperidine (10.0 g) in DMF was added NaH (2.2 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours. 4-Flouro-3-trifluoromethyl-1-nitrobenzene (5.3 mL) was added and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with aqueous NaHCO3 and aqueous HCl, dried over sodium sulfate, concentrated and purified on silica gel column (hexane/ethyl acetate, gradient) to afford a compound of formula (C), 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-1-nitrobenzene in 80% yield.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:29])[CH3:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:28])[CH3:29])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:11]1
Reactant: CC(C)c1cc2c(cc1OC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc2c(cc1OC1CNC1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 3-(7-isopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.016 g, 0.067 mmol) in DCM (2 mL) was added TFA (0.35 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 6-(azetidin-3-yloxy)-7-isopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale solid (0.015 g, 51%). LC/MS (Table 1, Method 5) Rt=2.160 min.; MS m/z: 331 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[CH2:7](O)[C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].P(Br)(Br)[Br:17]>CCOCC.[Cl-].[Na+].O>[Br:17][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC#CCO
Reactant: BrP(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCC#CCBr
Reaction time: 1 h
Yield: 193.5 %

Procedure:
Under argon atmosphere, anhydrous pyridine (0.4 ml, 4.9 mmol) was added to a solution of 2-octyne-1-ol (9.4658 g, 75.0 mmol) in anhydrous ether (50 ml). To the mixture was added dropwise phosphorus tribromide (2.35 ml, 25.0 mmol) at -30° to -35° C. and the mixture was stirred at the same temperature for one hour and then stirred for one hour at room temperature under argon atmosphere. To the resulting mixture was added brine (100 ml), and the mixture was then extracted with ether (50 ml×4). The combined ether layers were washed with an aqueous saturated solution of sodium bicarbonate (150 ml), with water (150 ml) and with brine (150 ml), dried over anhydrous sodium sulfate (40 g), and concentrated. Distillation of the residue gave a colorless oily product of 1-bromo-2-octyne (9.1493 g, 65%, B.p.: 53°-58° C./0.39 mmHg). The product was assigned the structure by the following data.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:22]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:23]([C:39]([NH:41][C@H:42]([C:47](O)=[O:48])[CH2:43][C:44](=[O:46])[NH2:45])=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:22]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:23]([C:39]([NH:41][C@H:42]([C:47]([NH:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:48])[CH2:43][C:44](=[O:46])[NH2:45])=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Yield: 30.1 %

Procedure:
compound SP314C2. Same procedure as above with Trp-NHPh (102.9 mg, 0.368 mmol), N-Boc-Tyr(Bn)-Asn-OH (178.9 mg, 0.368 mmol), EDC (78.2 mg, 0.41 mmol) and HOBt (55 mg, 0.41 mmol) in CH2Cl2/DMF (1.5 mL, 1/1). The crude residue was purified by flash column chromatography on silica gel (0-5% MeOH/CH2Cl2) to give an off-white solid (82.8 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ 1.28 (s, 9H, (CH3)3), 2.57-3.26 (m, 6H, CH2 Tyr, CH2 Trp, CH2 Asn), 4.11 (m, 1H, CHα), 4.58 (m, 2H, 2 CHα), 5.03 (broad s, 2H, CH2 (Bn)), 6.86-7.65 (m, 22H), 8.2 (m, 2H), 9.82 (s, 1H), 10.78 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 27.3 (CH2 Trp), 28.1 ((CH3)3), 36.4, 37 (CH2 Tyr, CH2 Asn), 49.5, 54.5, 55.7 (CHα Tyr, Asn, Trp), 69 (CH2 (Bn)), 78.1 (C(CH3)3), 109.7, 110, 111.2, 114.2, 118.2, 119.6, 120.8, 123.4, 123.6, 127.2, 127.5, 127.7, 128.3, 128.5, 130.1, 136, 137.2, 138.7 (25 aromatic C), 155.2, 156.8 (Car-O, CO carbamate), 170, 171, 171.7, 171.9 (4 CO amide). Anal. Calcd. for C42H46N6O7: C, 67.54; H, 6.21; N, 11.25. Found: C, 67.14; H, 6.27; N, 11.27.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][C:5]1[NH:9][C:8]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[N:7][N:6]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:39])([CH3:40])[CH3:38])[NH:14][C@H:13]2[C:11]([NH:10][C:8]2[NH:9][C:5]([CH2:4][C:3]([OH:41])=[O:2])=[N:6][N:7]=2)=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1nnc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2nnc(CC(=O)O)[nH]2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.3 %

Procedure:
A mixture of rac-(5-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-4H-[1,2,4]triazol-3-yl)-acetic acid methyl ester (20 mg, 0.033 mmol) was dissolved in THF (0.6 mL) and methanol (0.2 mL), then 2N LiOH (0.2 mL) was added and stirred at room temperature for 3 hours. The mixture was concentrated and diluted with water and ethyl acetate. The organic phase was separated then concentrated to yield rac-(5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-4H-[1,2,4]triazol-3-yl)-acetic acid (6.7 mg, 34%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H26Cl2F2N6O3+H [(M+H)+]: 591.1485. found: 591.1483.
Reaction SMILES: Cl.[OH:2][NH2:3].[OH-].[K+].[Cl:6][C:7]1[C:11]([C:12](Cl)=[O:13])=[C:10]([Cl:15])[N:9]([CH3:16])[N:8]=1.Cl>O.O1CCCC1>[Cl:6][C:7]1[C:11]([C:12]([NH:3][OH:2])=[O:13])=[C:10]([Cl:15])[N:9]([CH3:16])[N:8]=1
Reactant: NO
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(Cl)c(C(=O)NO)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
In a solution of hydroxyamine hydrochloride (106.9 g, 1.538 mol) in water (200 ml), a solution of 85% potassium hydroxide (101.5 g, 1.538 mol) in water (200 ml) was added at 5 to 15° C., and stirred at room temperature for 5 minutes. Then, a solution of 3,5-dichloro-1-methylpyrazole-4-carboxylic acid chloride (100.0 g, 0.5128 mol) in tetrahydrofuran (170 ml) was added dropwise at 3 to 8° C. over 2 hours. After stirring at 5° C. for 0.5 hour, the mixture was adjusted to pH 3-4 by adding 35% hydrochloric acid. Precipitated solid was filtered off, washed with water, and dried to obtain the aimed product (94.9 g). Melting point 200-202° C. (decomposition). Proton nuclear magnetic resonance chemical shift values δ (ppm) (in dimethylsulfoxide-d6) 3.79 (s, 3H), 9.24 (brs, 1H), 10.83 (brs, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[O:4][N:3]=1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[CH3:19][N:20]([CH3:22])[CH:21]=[C:9]1[CH2:10][CH2:11][CH2:12][CH:7]([C:5]2[O:4][N:3]=[C:2]([CH3:1])[N:6]=2)[C:8]1=[O:13]
Reactant: Cc1noc(C2CCCCC2=O)n1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: Cc1noc(C2CCCC(=CN(C)C)C2=O)n1

Procedure:
2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-cyclohexanone (90 mg, 0.5 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (123 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 236.1 [(M+H)+].
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[NH:16][C:17]([NH2:19])=[NH:18])=O)C.[OH-].[Na+].Cl>O>[NH2:18][CH:17]1[N:16]=[C:8]2[N:9]=[C:10]3[C:15]([CH:14]=[CH:13][CH:12]=[CH:11]3)=[C:7]2[C:5](=[O:4])[NH:19]1
Reactant: CCOC(=O)c1c(NC(=N)N)[nH]c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC1N=C2N=c3ccccc3=C2C(=O)N1

Procedure:
A mixture of 2-guanidinoindole-3-carboxylic acid ethyl ester hydrochloride (1.00 g, 3.5 mmol) and sodium hydroxide (1.5 g) in water (50 mL) is heated to gentle reflux for 6 hr followed by the addition of sufficient 5% HCl to adjust the solution to pH 1, and filtration of the resulting mixture through celite, washing the pad with water. The filtrate is extracted with ethyl acetate (3×25 mL), and then basified with solid sodium carbonate. The tan precipitate which slowly forms is collected by filtration, washed with water, and dried in vacuo affording2-amino-4-oxo-3H-indolo[2,3-d]pyrimidine (561 mg, 78%) as light tan crystals, mp>275 C.
Reaction SMILES: [C:1]([N:4]1[CH:8]([CH3:9])[CH2:7][CH2:6][CH:5]1[C:10]1[C:15](F)=[CH:14][C:13]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=O)=[C:12]([N+:26]([O-])=O)[CH:11]=1)(=[O:3])[CH3:2].[CH3:29][C:30]1[N:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[C:1]([N:4]1[CH:8]([CH3:9])[CH2:7][CH2:6][CH:5]1[C:10]1[C:15]([O:36][C:33]2[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=2)=[CH:14][C:13]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[NH:26][C:12]=2[CH:11]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(O)cn1
Reactant: CC(=O)N1C(C)CCC1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Product: CC(=O)N1C(C)CCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(C)nc1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 338 (step 5) or in accordance with the method or by combining it with an ordinary method but using N-(4-(1-acetyl-5-methylpyrrolidin-2-yl)-5-fluoro-2-nitrophenyl)pyridine-2-carboxamide obtained in Example 545 and 6-methylpyridin-3-ol.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:15][NH:16][C@H:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([O:32]CCC)=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3>>[CH3:15][N:16]([C:12](=[O:14])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C@H:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)Cc1cccc2ccccc12)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 1-naphthylacetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 427
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[F:30][C:31]([F:38])([F:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[F:30][C:31]([F:38])([F:37])[CH2:32][S:33]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Agent: Cl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCN(S(=O)(=O)CC(F)(F)F)C3)cnc21

Procedure:
1-[1-(2,2,2-Trifluoro-ethanesulfonyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and 2,2,2-trifluoro-ethanesulfonyl chloride.
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][CH2:18][C:19](=[N:32]O)[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[C@@H:13]([C:34]([O:36][CH3:37])=[O:35])[CH2:12]1>CO.[Mo]=O>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][CH2:18][CH:19]([NH2:32])[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[C@@H:13]([C:34]([O:36][CH3:37])=[O:35])[CH2:12]1
Reactant: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(=NO)c1ccnc2ccc(OC)cc12
Agent: O=[Mo]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(N)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 18 h
Yield: 36.3 %

Procedure:
0.125 g of sodium borohydride and 0.066 g of molybdenum oxide are added with stirring and under an inert atmosphere, at a temperature in the region of −5° C., to a solution of 0.17 g of methyl (3R,4R)-1-[2-(thien-2-ylthio)ethyl]-4-[3-hydroxyimino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 10 cm3 of methanol. After 5 hours at a temperature in the region of 20° C., 0.125 g of sodium borohydride and 0.066 g of molybdenum oxide are again added and then the reaction mixture is stirred for an additional 18 hours at a temperature in the region of 20° C. The resulting mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is purified by chromatography under a pressure of 50 kPa of nitrogen on a column of silica gel (particle size 20-45 μ; mass 34 g; diameter of the column 2.3 cm), elution being carried out with a dichloromethane/methanol (95/5 by volume) mixture. Fractions 220 to 365 (containing the purified product) are combined and then concentrated to dryness under the above conditions to afford 0.06 g of methyl (3R,4R)-1-[2-(thien-2-ylthio)ethyl]-4-[3-(R,S)-amino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9](Cl)[CH:10]=[C:11]([Cl:13])[N:12]=2)=[CH:5][CH:6]=1.[NH2:15][C:16]1[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+]>C(O)CCC>[Cl:13][C:11]1[N:12]=[C:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[N:8]=[C:9]([NH:15][C:16]2[NH:17][N:18]=[C:19]([CH3:21])[CH:20]=2)[CH:10]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(Cl)nc(-c3ccccc3)n2)[nH]n1
Temperature: 117 °C
Yield: 29.4 %

Procedure:
A suspension of Fenclorim (4,6-dichloro-2-phenylpyrimidine)(0.1 g, 0.44 mmol), 3-amino-5-methylpyrazole (0.045 g, 0.47 mmol), N,N-diisopropylethylamine (0.08 ml, 0.47 mmol) and sodium iodide (0.067 g, 0.44 mmol) in n-butanol (5 ml) were heated at 117° C. for 18 hours. The solvent was removed in vacuo and the crude product purified by flash chromatography (silica gel, 3:2 Petrol:EtOAc) to afford 0.037 g (29% yield) of (6-Chloro-2-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine as a off-white solid. A suspension of the above pyrimidine (0.037 g, 0.13 mmol) and thioacetamidothiophenol (0.108 g, 0.64 mmol) in tert-butanol was heated at 85° C. under nitrogen for 2 days. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The concentrate was dissolved in EtOAc, and washed with NaHCO3 (sat, aq.). The organic layer is concentrated in vacuo, and the crude product by preperative HPLC. The residual disulfide that still remained in the mixture after HPLC may be removed by precipitation from EtOAc and filtration. The mother liquor was concentrated to afford IV-3 (7 mg, 13% yield) as an off-white solid: mp 235–236° C.; 1H NMR (DMSO) δ 2.10 (3H, s), 2.21 (3H, s), 6.33 (1H, br s), 7.50 (3H, m), 7.7–7.59 (2H, m), 7.76–7.78 (2H, m), 8.25 (2H, m), 9.72, 10.26 and 11.93 (3H, 3×br s); IR (solid) 1669, 1585, 1551, 1492, 1392, 1372, 1312, 1289, 1259, 1174, 1102, 1089, 1027, 1015, 984; MS 417.3 (M+H)+.