Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C@H:9]([C:11]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(N(CC)CC)C>C(O)C.C1(C)C=CC=CC=1>[OH:7][CH2:8][C@H:9]([C:11]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:10]
Reactant: C[C@H](COC1CCCCO1)C1(O)CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@H](CO)C1(O)CCCC1
Reaction time: 10 h
Yield: 117 %

Procedure:
A mixture of 2a (3.42 g, 15.0 mmol) and pyridinium p-toluenesulfonate (188 mg) in ethanol (100 mL) was heated at 40°-50° C. with stirring for 10 hr. The mixture was diluted with toluene and a small amount of triethylamine was added to the mixture. After evaporation of ethanol, the residue was poured into brine and extracted with ethyl acetate until none of the product remained the in aqueous layer. The combined organic layers were washed with brine, and dried over sodium sulfate. Filtration and concentration gave 2.53 g of an oily material, which was purified by column chromatography (silica gel 20 g, ethyl acetate in n-hexane, 20-50%) to give 1.88 g (86.9%) of 3a, as a colorless oil.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[C:14]1(=[CH:5][C:6]#[N:7])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCCC1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.3 %

Procedure:
Sodium hydride (60% in oil, 0.80 g, 20 mmol) was suspended in 50 mL tetrahydrofuran and chilled in ice under nitrogen. Diethylcyanomethyl phosphonate (3.85 g, 22 mmol) was added dropwise in 10 mL tetrahydrofuran and stirring continued for 15 minutes to give a clear solution. Cyclohexanone (1.90 g, 19 mol) was added in 5 mL tetrahydrofuran and the reaction mixture allowed to warm up to room temperature. The liquor was decanted and the residue washed three times with ether. The liquor and washings were combined, washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 4:1 to give the required product as a colorless oil (1.5 g. 67%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:19])=[CH:5][C:6]=1[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O>>[Cl:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[C:7]([C:6]1[CH:5]=[C:4]([Br:19])[S:3][C:2]=1[Br:1])=[N:9][CH2:10][CH2:11]2
Reactant: O=C(NCCc1cccc(Cl)c1)c1cc(Br)sc1Br
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(c1)CCN=C2c1cc(Br)sc1Br
Temperature: 150 °C

Procedure:
To a mixture of 2,5-dibromo-N-[2-(3-chlorophenyl)ethyl]thiophene-3-carboxamide (5.15 g, 12.2 mmol) in xylenes (25.98 mL, 70.32 mmol) at 70° C. was added phosphorus pentoxide (13.0 g, 45.8 mmol) and then phosphoryl chloride (12.0 mL, 129 mmol). The mixture was heated at 150° C. for 60 h, then the mixture was cooled to rt. The solution was removed by decantation and washed with toluene twice. Water (20 mL) and 20% NaOH (20 mL) were added and the mixture was sonicated. The mixture was extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, and evaporated in vacuo to give a residue which was purified by chromatography to afford 6-chloro-1-(2,5-dibromo-3-thienyl)-3,4-dihydroisoquinoline as foam solid (2.8 g, 57%).
Reaction SMILES: CO[C:3](=[O:22])/[C:4](/[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5](\O)/[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.[CH3:24][C:25]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:30])[CH2:26][C:27](=[NH:29])[NH2:28].C[O-].[Na+].Cl>CO.O>[CH2:15]([O:14][C:4]1[C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[N:28][C:27]([CH2:26][C:25]([CH3:30])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:24])=[N:29][C:3]=1[OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(CC(=N)N)c1ccccc1
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)c1nc(CC(C)(C)c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: 0 °C
Yield: 42.4 %

Procedure:
4-tert-Butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate (4) (652 mg, 2.12 mmol, Eq: 1.5,) and 3-methyl-3-phenylbutanimidamide hydrochloride (54) (300 mg, 1.41 mmol, Eq: 1.00) were stirred in methanol (7.2 ml). The reaction mixture was cooled to 0° C. and sodium methoxide (229 mg, 4.23 mmol, Eq: 3) (powdered, Aldrich) was added. The reaction mixture was stirred at room temperature. The reaction mixture is a suspension. It was stirred overnight. 5 ml 1N aqueous HCl was added and the mixture was diluted with water, filtered through a sintered glass funnel. The solid was washed with water. The solid was placed under high vacuum to dry to give tert-butyl 5-(benzyloxy)-6-hydroxy-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxylate as a yellow solid (260 mg, 21%) as a 1:1 mixture of tert-butyl 5-(benzyloxy)-6-hydroxy-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxylate (55) and 3-methyl-3-phenylbutanimidamide. The product was used without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Li+].CS(O[CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)(=O)=O>CN(C=O)C>[N:1]([CH:14]1[CH2:15][CH2:10][CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(N=[N+]=[N-])C1
Temperature: 60 °C

Procedure:
Lithium azide (1.35 g, 27.6 mmol) was added to a solution of 3-methanesulfonyloxy-N-t-butoxycarbonylpiperidine (1.54 g, 5.51 mmol) in DMF (20 ml) and the resulting mixture heated at 60° C. for 48 h. Removal of the solvent in vacuo and chromatographic purification (3:1 hexane/ethyl acetate) of the residue afforded the title compound. 1H NMR (CDCl3) d 1.46 (s, 9 H), 1.75 (m, 2 H), 1.96 (m, 2 H), 3.13 (br s, 1 H), 3.46 (m, 2 H), 3.57 (m, 2 H).
Reaction SMILES: Cl.C[O:3]C(=O)[C@H](CC(C)C)N.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.COC(=O)[C@H](CC(C)C)N[C:42](=[O:65])[C@@H:43]([CH2:55][C:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[NH:58][CH:57]=1)[NH:44][C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]>CO.C(N(CC)CC)C.CN(C)C=O>[CH2:48]([O:47][C:45]([NH:44][C@@H:43]([C:42]([OH:65])=[O:3])[CH2:55][C:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[NH:58][CH:57]=1)=[O:46])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Temperature: 0 °C

Procedure:
, and L-leucine methyl ester hydrochloride 3.96 g., are dissolved in 60 ml. of dimethylformamide, cooled in an ice bath and 2.77 ml., of triethylamine added dropwise. The stirred and cooled solution is then treated with 2.97 g. of 1-hydroxy-benzotriazole and 4.53 g. of dicyclohexylcarbodiimide. The reaction is stirred to room temperature in the melting ice bath and for twenty-four additional hours at room temperature. It is then filtered and the solvent evaporated under reduced pressure. The residue is dissolved in 300 ml. of ethyl acetate and the solution is washed with 0.5 N hydrochloric acid, saturated sodium chloride solution, twice with 5% sodium bicarbonate solution and finally with a saturated sodium chloride solution. The ethyl acetate solution is dried over magnesium sulfate and the solvent evaporated to leave a crystalline solid. The product is crystallized from 125 ml. of hot methanol to give 4.3 g. of Nα -benzyloxycarbonyl-D-tryptophyl-L-leucine methyl ester, mp. 155°-156° C; [α]D23 -21.8°, (c 2.03, methanol).
Reaction SMILES: CS(O[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)(=O)=O.[I:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.CCOC(C)=O>CN(C=O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][CH2:7][CH:6]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[N:34]2[C:33]2[CH:35]=[CH:36][C:30]([I:29])=[CH:31][CH:32]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(I)cc1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(C2CCC(c3ccc(Br)cc3)N2c2ccc(I)cc2)cc1
Temperature: 45 °C

Procedure:
The product from Example 42B (1.39 g, 2.499 mmol) in DMF (6.25 mL) was treated with 4-iodoaniline (Aldrich, 4.38 g, 19.99 mmol), heated at 40-50° C. for two hours, cooled and diluted into EtOAc. The EtOAc layer was washed 3×50 mL with 1 M HCl, with water, brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on an ISCO 40 g silica cartridge eluting with 0-20% EtOAc in hexane afforded the title compound as a tan foam as a mixture of stereoisomers (0.96 g, 66%). MS (ESI) m/z 584 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][N+:11]([O-])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH2:11]
Reactant: COc1ccccc1C=C[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1CCN
Yield: 71 %

Procedure:
Using analogous reaction conditions and workup as described in Example 1, step 2, 1-methoxy-2-(2-nitro-vinyl)-benzene (I-13a: 4.5 g, 25.1396 mmol) in dry THF (50 mL) was reacted with LAH (1.91 g, 50.2793 mmol) in dry THF (50 mL) to afford 2.7 g of the crude product which was used in the next step without further purification.
Reaction SMILES: C[O-].[Na+:3].[CH:4]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:21]=3)[CH:13]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH2:6][CH2:5]1>CO>[CH:4]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:21]=3)[CH:13]=2)[CH2:8][C:9]([O-:11])=[O:10])[CH2:5][CH2:6]1.[Na+:3]
Reactant: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)nc2CC(C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)[O-])C4CC4)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.2 %

Procedure:
A 28% solution of sodium methoxide (117 mg) in methanol was added to a solution of 3-cyclopropyl-3-(3-(((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)oxy)methyl)phenyl)propanoic acid (299 mg) in methanol (4.0 mL), and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated under reduced pressure to give the title compound (316 mg) as a white amorphous solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([C:17]([F:20])([F:19])[F:18])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:24]=1[NH2:25]>>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:6]2[C:5]([C:17]([F:20])([F:19])[F:18])=[CH:4][N:3]=[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([N:30]4[CH2:35][CH2:34][CH:33]([N:36]5[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]5)[CH2:32][CH2:31]4)=[CH:29][C:23]=3[O:22][CH3:21])[N:7]=2)=[CH:9]1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1-c1c[nH]c2ccccc12
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(C(F)(F)F)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole (INTERMEDIATE 4) and 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[SH:18][CH:19]([OH:21])[CH3:20]>CC(C)=O>[CH2:7]([S:18][CH:19]([OH:21])[CH3:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCBr
Reactant: CC(O)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCSC(C)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
Under nitrogen, to a suspension of potassium carbonate (27 g, 200 mmol) in acetone (100 ml) was added decyl bromide (10 ml, 50 mmol) and mercaptoethanol (4.4 ml, 63 mmol). The suspension was stirred at room temperature for 2 days, then partitioned between water and 80% hexane/ethyl acetate. The organic phase was washed with 2N sodium hydroxide, dried over magnesium sulfate, and the volatiles removed under vacuum to give S-decyl mercaptoethanol (10.2 g, 47 mmol) as a /colorless liquid that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH:7]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:26]4[C@H:33]([CH3:34])[CH2:32][CH2:31][C:27]=4[N:28]=[CH:29][N:30]=3)[C@@H:21]([CH3:35])[CH2:20]2)=[O:18])[CH2:8][NH:9]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[F:38].[ClH:39]>C(Cl)Cl>[ClH:1].[ClH:39].[NH2:9][CH2:8][CH:7]([CH2:6][C:5]1[CH:36]=[CH:37][C:2]([Cl:1])=[C:3]([F:38])[CH:4]=1)[C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:26]3[C@H:33]([CH3:34])[CH2:32][CH2:31][C:27]=3[N:28]=[CH:29][N:30]=2)[C@@H:21]([CH3:35])[CH2:20]1)=[O:18]
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C(CNC(=O)OC(C)(C)C)Cc4ccc(Cl)c(F)c4)C[C@@H]3C)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C(CN)Cc4ccc(Cl)c(F)c4)C[C@@H]3C)c21
Yield: 99 %

Procedure:
tert-Butyl 2-(4-chloro-3-fluorobenzyl)-3-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate was treated with HCl (4M in dioxane, 2 mL) in DCM (5 mL) for 6 hours to provide 2-(aminomethyl)-3-(4-chloro-3-fluorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (50 mg, 99%). MS (APCI+) [M+H]+446.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11]C)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:6]2.[BrH:20]>O>[BrH:20].[F:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:6]2
Reactant: COc1ccc2c(c1F)CN(Nc1ccncc1)C2
Agent: Br
Solvent: O
Product: Oc1ccc2c(c1F)CN(Nc1ccncc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of 2,3-dihydro-4-fluoro-5-methoxy-N-(4-pyridinyl)-1H-isoindol-2-amine (3.25 g) in 48% hydrobromic acid (25 ml) was stirred, under reflux, for 5 hrs. The reaction mixture was diluted with water and stirred at ambient temperature overnight. The mixture was cooled to approximately 10° C. and filtered. The filter cake was washed with cold water and dried under vacuum at 80° C. to give 2.8 g (69%) of product. Recrystallization from water gave the analytical sample, mp. >250° C., dried at 80° C. under vacuum.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([OH:20])[C:15]([O:17]CC)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([OH:20])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(O)CC1NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CC1(O)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To a 0° C. solution of ethyl 2-(benzyloxycarbonylamino)-1-hydroxycyclopropanecarboxylate (6b, 12.5 g, 44.7 mmol) in THF (100 mL) was added K2CO3 (24.7 g, 179.0 mmol) as a solution in H2O (300 mL). The reaction was allowed to warm to room temperature and stirred for 4 h and then additional H2O (200 mL) was added. After stirring an additional 18 h at room temperature the reaction was concentrated to remove most of the THF. The remaining aqueous solution was washed with Et2O (2×500 mL), acidified with 2 N HCl to pH 2, and then extracted with EtOAc (5×200 mL). The combined EtOAc layers were washed with brine (500 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compounds (7.75 g, 69%) as a mixture of diastereomers. The mixture was triturated with Et2O to afford a white solid as mostly the major diastereomers. The supernatant was concentrated and then triturated with Et2O to afford a clean mixture of both diastereomers. Major Diastereomer: 1H NMR (300 MHz, MeOD) δ 7.50-7.14 (m, 5H), 5.22-4.96 (m, 2H), 3.23-3.10 (m, 1H), 1.60 (dd, J=8.9, 6.3 Hz, 1H), 1.10 (t, J=6.2 Hz, 1H); Multimode (APCI+ESI) MS m/z 250 [M−H]−. Mixture of Diastereomers: 1H NMR (300 MHz, MeOD) δ 7.45-7.14 (m, 5H), 5.24-5.01 (m, 2H), 3.25-3.15 (m, 0.46H), 3.14-3.01 (m, 0.54H), 1.71-1.53 (m, 1H), 1.42 (dd, J=9.1, 6.4 Hz, 0.54H), 1.12 (t, J=6.2 Hz, 0.46H); Multimode (APCI+ESI) MS m/z 250 [M−H]−.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:32])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20](Cl)[C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:22]=3[N:23]=2)=[CH:14][CH:13]=1>>[CH3:9][O:10][C:11](=[O:32])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:22]=3[N:23]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Reactant: NCc1ccccc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccccc3)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein benzylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-benzylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][CH:9]([C:14]([OH:16])=[O:15])[CH2:8][CH2:7][C:6]=2[N:5]=1)(=[O:3])[CH3:2].[CH3:17][Mg]Cl>C1COCC1>[OH:3][C:1]([C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][CH:9]([C:14]([OH:16])=[O:15])[CH2:8][CH2:7][C:6]=2[N:5]=1)([CH3:17])[CH3:2]
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc2c(n1)CCC(C(=O)O)C2
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(n1)CCC(C(=O)O)C2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 25 mL flask was added 2-acetyl-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (146 mg, 0.667 mmol) and tetrahydrofuran (2.7 mL). The system was purged with nitrogen and cooled to 0° C. 3M of methylmagnesium chloride in tetrahydrofuran (0.598 mL, 2.00 mmol) was added dropwise over 3 minutes. The mixture was stirred at 0° C. for 5 minutes then allowed to warm to room temperature. Additional THF (5 mL) was added and the mixture was sonicated for 1 minute to break up solids. After a total of 2 hours the reaction was carefully quenched by dropwise addition of 1M NaH2PO4 (10 mL). The mixture was diluted with DCM (10 mL) and citric acid (0.5 mL) was added to obtain a pH of 4. The layers were separated and the aqueous was extracted with 3:1 DCM/THF (10 mL) followed by with 3:1 CHCl3/IPA (15 mL×2), dried (Na2SO4), filtered and evaporated to obtain a reddish foam (160 mg, theoretical yield), which was used directly in the next step. m/z=236.2 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.55 (d, J=8.1 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 3.10-2.90 (m, 4H), 2.85-2.74 (m, 1H), 2.32-2.25 (m, 1H), 2.06-1.95 (m, 1H), 1.51 (s, 6H).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:21][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:5]
Reactant: CC(C)(C)CN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)CNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 1.00 g of Boc-Pro-OH, 0.58 ml of neopentylamine, 0.71 g of HOBt and 1.06 g of EDC hydrochloride were added and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 30 (Process 3) to give 605 mg of the title compound.
Reaction SMILES: CO.[Na].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].Cl[C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH3:30])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:13]=1)=[O:11]>ClCCl>[CH3:30][N:27]1[C:23]2[N:24]=[CH:25][N:26]=[C:21]([N:14]3[C:15]4=[N:16][CH:17]=[CH:18][CH:19]=[C:20]4[C:12]([C:10]([NH:7][C:6]([NH2:8])=[NH:5])=[O:11])=[CH:13]3)[C:22]=2[CH:29]=[CH:28]1
Reactant: Cn1ccc2c(-n3cc(C(=O)Cl)c4cccnc43)ncnc21
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: Cn1ccc2c(-n3cc(C(=O)NC(=N)N)c4cccnc43)ncnc21
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 42.1 %

Procedure:
To 40 cm3 of methanol at about 20° C. under argon atmosphere, was added portionwise 0.36 g (16 mmol) of sodium. Then, after total consumption of the latter, 1.5 g (16 mmol) of guanidine hydrochloride were added. The reaction mixture was stirred at about 20° C. for 1.5 hours and filtered. The precipitate was washed with 5 cm3 of methanol and the combined filtrates were concentrated to dryness in vacuo (2.7 kPa). The residue was diluted in 30 cm3 of dichloromethane and concentrated to dryness in vacuo (2.7 kPa). The residue was diluted in 70 cm3 of tetrahydrofuran under argon atmosphere at about 20° C. and a suspension of 1.3 g (3.2 mmol) of 3-chlorocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine in 70 cm3 of dichloromethane was added. The reaction mixture was stirred at about 20° C. for 60 hours and then concentrated to dryness in vacuo (2.7 kPa). The residue was diluted in 100 cm3 of water and the off-white precipitate was filtered and washed twice with 10 cm3 of water. The solid was dried in vacuo at about 50° C. and then recrystallized from 30 cm3 of methanol. The precipitate was washed twice with 5 cm3 of methanol and once with 10 cm3 of diisopropylether respectively, and dried in vacuo at about 50° C. to yield 0.45 g of N-[1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-guanidine as a gray cristalline powder: mp>260° C. IR spectrum (KBr): 3425; 3157; 1590; 1558; 1518; 1449; 1418; 1308; 1216; 1009; 805; 770; 723; 702 and 605 cm−1. Mass spectrum (EI): m/e 334 M+., m/e 276 (M−CH4N3)+. (base peak), m/e 145 (m/e=276−C7H5N3)+, m/e 132 (C7H6N3)+.