Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)=S>C(#N)C>[C:2]([NH:3][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)=[N:6][CH3:5])#[N:1]
Reactant: N#CN
Reactant: CNC(=S)NCCSCc1c[nH]cn1
Agent: [Pb]
Solvent: CC#N
Product: CN=C(NC#N)NCCSCc1c[nH]cn1
Yield: 31.1 %

Procedure:
Lead cyanamide (24.7 g.) was added to a solution of N-methyl-N'-[2-(4-imidazolylmethylthio)ethyl]thiourea (11.5 g.) in acetonitrile (250 ml.) containing demethylformamide. The stirred suspension was heated under reflux for 48 hours. Filtration followed by concentration under reduced pressure and purification of the product on a column of silica gel with ethyl acetatle-isopropyl alcohol (2.1) as eluant gave N-cyano-N'-[2-(4-imidazolylmethylthio)ethyl]-N"-methylguanidine (3.7 g.), m.p. 138°-140° (from acetonitrile). (Found: C, 45.7; H, 5.9; N, 35.5; S, 13.5. 9H14N6S requires: C, 45.4; H, 5.9; N, 35.3; S, 13.5).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21]1>>[NH2:31][C:30]1[C:25]([CH:22]2[CH2:23][CH2:24][N:20]([C:11]3[CH:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:21]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccnc1C1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: Nc1cccnc1C1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 91 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.81 g, 3.1 mmol) and 2 -(3-pyrrolidinyl)-3-pyridinamine, a procedure analogous to that given in Example 1 provided the title compound (1.15 g, 91%) as an off-white solid, mp>270° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:4]=1.Cl[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:28]=[N:29][CH:30]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:24][C:25]2[CH:26]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:28]=[N:29][CH:30]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: COc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Product: COc1cccc(N(Cc2cncc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
4-(m-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][C:17]#[N:18])=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][C:17]#[N:18])=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CC#N)c2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(Cl)cc(CC#N)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a solution of 0.30 g (0.8 mmol) of 5-chloro-7-cyanomethyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in CH2Cl2 (8 ml) at RT was added 2 ml of TFA. The reaction mixture was stirred at RT for one hour and concentrated under vacuo. The crude was taken up in EtOAc and neutralized with aqueous NaHCO3. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Preparative HPLC (30% CH3CN/H2O) afforded 81 mg (35%) of 5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.[CH3:11][C:12]([SH:15])([CH3:14])[CH3:13]>ClCCCl.O.C(Cl)Cl.[I-].[Zn+2].[I-]>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(C)(C)S
Reactant: COc1ccc(CO)cc1
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(CSC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-methoxybenzyl alcohol (10.13 g) and zinc iodide (11.7 g) in 1,2-dichloroethane (120 mL) was treated with 2-methyl-2-propanethiol (9.92 mL) in one portion. The resulting mixture was stirred at room temperature. After about 18 hours, the reaction was diluted with water (100 mL) and methylene chloride (100 mL). The organic phase was removed, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 14.4 g of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=3)[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:9][N:8]2[CH:27]=1)=[O:4].[NH:28]1[CH2:31][CH:30]([C:32]2[NH:36][N:35]=[C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:33]=2)[CH2:29]1>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:28]4[CH2:29][CH:30]([C:32]5[N:33]=[C:34]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=6)[NH:35][N:36]=5)[CH2:31]4)=[CH:15][CH:14]=3)[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:9][N:8]2[CH:27]=1)=[O:4]
Reactant: COC(=O)c1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Product: COC(=O)c1cn2cc(-c3ccccc3)c(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)nc2n1
Yield: 17.5 %

Procedure:
The title compound has been prepared in analogy to the aforementioned descriptions by reacting 500 mg (1.4 mmol) 7-(4-formylphenyl)-6-phenyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid methyl ester with 383.6 mg (1.4 mmol) 2-(5-azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl, yielding 132.6 mg (15.7%) of the desired product after purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=2[O:9][CH:8]=1)(=O)=O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:49][OH:50].C(N(CC)CC)C.CN(C)[CH:60]=[O:61]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([C:49]([O:61][CH3:60])=[O:50])=[CH:8][O:9][C:10]=2[CH:15]=1
Reactant: COc1ccc2c(OS(=O)(=O)C(F)(F)F)coc2c1
Reactant: CN(C)C=O
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1coc2cc(OC)ccc12

Procedure:
6-Methoxybenzofuran-3-yl trifluoromethane sulfonate (500 mg, 1.69 mmol) was added to a stainless steel high-pressure reaction vessel then dissolved in N,N-dimethylformamide (6.5 mL). Carbon monoxide gas was bubbled through the solution for 10 minutes. 1,3-Bis(diphenylphosphino)propane (21 mg, 0.051 mmol), methanol (1.8 mL), triethylamine (342 mg, 3.38 mmol) and palladium acetate (11 mg, 0.051 mmol) were added to the reaction mixture, while continuing to bubble carbon monoxide gas through the mixture. The reaction vessel was sealed and charged with carbon monoxide (30 psi). The reaction mixture was heated at 80 C for 4.5 hours. The mixture was concentrated in vacuo. The remaining orange mixture was purified by silica gel chromatography (5% ethyl acetate/hexane) to afford methyl 6-methoxybenzofuran-3-carboxylate as a light yellow solid. MS (ESI, pos. ion) m/z: 207.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)=[O:7])([O-])=O.[H][H]>[C].[Pt].ClCCl>[NH2:1][C:4]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)=[O:7]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: ClCCl
Product: COc1ccc(N)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 28 °C
Reaction time: 16.5 h
Yield: 89.5 %

Procedure:
To a 780 L Hastelloy reactor, compound C (33 kg, 1.0 eq.), 5% platinum carbon (sulfided, 0.33 kg, 0.010 parts) and dichloromethane (578 kg, 17.5 parts) were charged. Agitation was started and reactor contents were adjusted to 22° C. (19-25° C.). The reactor was pressurized with ca. 30 psi hydrogen and the reaction mixture gently heated to 28° C. (25-31° C.). Hydrogenation of the reactor contents was performed under ca. 30 psi at 28° C. (25 to 31° C.; maximum 31° C.) until the reaction was complete by HPLC. After 16.5 hrs, the reaction was deemed complete after confirming the disappearance of starting material (0.472 A %). The contents of the reactor were circulated through a conditioned celite pad (0.2-0.5 kg celite conditioned with 20-55 kg dichloromethane) prepared in a 8″ sparkler filter to remove the platinum catalyst. The reactor and celite bed were rinsed forward with two portions of dichloromethane (83 kg, 2.5 parts each). The filtrate was transferred to and concentrated in a 570 L GLMS reactor under a atmospheric pressure to ca. 132 L (4 parts volume). Ethanol (69 kg, 2.1 parts) was charged and concentration continued under atmospheric pressure to ca. 99 L (3 parts volume). In-process NMR indicated that the dichloromethane content was 39%. Ethanol (69 kg, 2.1 parts) was charged again and concentration continued again to ca. 99 L (3 parts volume). In-process NMR indicated that the dichloromethane content was 5%. The reaction mixture was then adjusted to 3° C. (0 to 6° C.), agitated for ca. 1 hr, and the resulting slurry filtered onto a jacketed pressure nutsche fitted with a filter cloth. The reactor, pump, and lines were rinsed forward with cold [3° C. (0-6° C.)]ethanol (26 kg, 0.8 parts). The wet filter cake (36.6 kg) was dried under vacuum at 40-50° C. with a maximum temperature of water bath (to heat dryer jacket) of 50° C. LOD analysis after 12.5 hrs indicated solvent content was at 0.1%. The dry product (D) was discharged (26.4 kg) in 89.5% yield. HPLC showed 98.4 A % purity, with dechlorinated impurity at 0.083%.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13])=[CH:10][C:4]=2[NH:3]1.CCO.[OH-].[Na+].CC(O)=O>O>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]([CH3:17])[C:12]([OH:14])=[O:13])=[CH:10][C:4]=2[NH:3]1
Reactant: CCOC(=O)C(C)c1ccc2[nH]c(=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc2[nH]c(=O)[nH]c2c1
Temperature: 40 °C
Reaction time: 10 h

Procedure:
To the flask of Ethyl 2-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-5-yl)propanoate (175 mg, 0.747 mmol) was added 90% aq. EtOH (5 mL) at room temperature, and additionally added NaOH (70 mg). The reaction mixture was stirred for 10 hrs at 40° C. then cooled to room temperature. The mixture was diluted with H2O (25 mL) and acidified with AcOH (4 mL, pH=4) then extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using CH2Cl2:MeOH (10:1) as eluant.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].[CH2:27](N(CC)CC)C>C(Cl)Cl>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCc1ccc(S(=O)(=O)NCCc2c[nH]c3ccccc23)cc1

Procedure:
To a solution of tryptamine (19.2 mg, 0.12 mmol) in 2 ml CH2Cl2 was added 0.06 mmol of 4-n-butylphenylsulfonyl chloride in CH2Cl2, followed by 16.5 μl of triethylamine. After stirring the reaction for 6 hr at room temperature, the mixture was purified by loading on to a cation exchange resin and the resin was eluted using CH2Cl2. The appropriate fractions were combined and evaporated to give the product. 1H NMR (CDCl3): δ 0.89 (t, 3H), 1.3 (m, 4H), 1.6 (m, 2H), 2.65 (t, 2H), 2.96 (t, 2H), 3.3 (m, 2H), 6.9-7.4 (m, 6H), 7.6 (d, 2H), 8.0 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:18][C:19](=[O:35])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[CH2:28]([O:27][C:21]1[CH:22]=[CH:23][C:24]([Br:26])=[CH:25][C:20]=1[C:19]([NH:18][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[C:3]([OH:36])=[O:2])=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1cc(Br)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
2-(S)-(2-Benzyloxy-5-bromo-benzoylamino)-3-biphenyl-4-yl-propionic acid methyl ester (50 mg, 0.092 mmol) was dissolved in 5 mL of THF-MeOH (4-1), cooled to 0° C. and 1.1 equiv of 2 N LiOH added. After 30 minutes, 3.3 additional equiv of 2N LiOH was added and the reaction stirred for 60 minutes. The reaction was worked up according to general procedure C to give 2-(S)-(2-benzyloxy-5-bromo-benzoylamino)-3-biphenyl-4-yl-propionic acid (34 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]OC(=O)OC.N12CCCN=C1CCCCC2>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: COC(=O)OC
Reactant: O=C(O)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1c(Cl)cccc1Cl
Yield: 85.8 %

Procedure:
2,6-Dichlorobenzoic acid (5.00 g, 26.2 mmol) was diluted in dimethylcarbonate (44 mL, 530 mmol). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (3.91 mL, 26.2 mmol) was added last. The reacted was refluxed for 2 days. Upon cooling, the solution was diluted with ethyl acetate and water. The aqueous layer was removed and the organic layer was washed with water, 2N HCl (2×'s), sat. NaHCO3 (2×'s), and twice with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to yield 4.61 g (86%) of the desired compound as a clear oil.
Reaction SMILES: [CH3:1][C@H:2]([NH2:11])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[N:17]=[CH:16]2.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)CCC>[Cu]I>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([O:10][C@H:3]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[C@H:2]([CH3:1])[NH2:11])=[CH:21][CH:20]=3)[CH:16]=[N:17]2)[CH:23]=1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: Ic1ccc2c(cnn2-c2cccnc2)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2cccnc2)c1)c1ccccc1
Yield: 27 %

Procedure:
(1R,2S)-Norephedrine (500 mg, 3.31 mmol), 5-iodo-1-(3-pyridyl)-1H-indazole (1.08 g, 33.37 mmol), cesiumcarbonate (2.15 g, 6.61 mmol), copper (I)-iodide (314.9 mg, 1.65 mmol) and butyronitrile (2 mL) are stirred in a glass pressure tube at 120° C. for 20 h. The reaction mixture is filtered via a glass microfibre filter, the solvent evaporated and the residue purified by chromatography (silicagel, eluents: dichloromethane/methanol). 307.8 mg (27%) of the title compound are obtained.
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:15]=3)[NH:10][C:9](=[O:25])[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:27]([O-])([O-:29])=[O:28].[Na+]>S(=O)(=O)(O)O>[CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([N+:27]([O-:29])=[O:28])[CH:15]=3)[NH:10][C:9](=[O:25])[C:8]2=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)C(=O)Nc1ccc2c(c1)[nH]c(=O)c(=O)n2C1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(=O)Nc1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
48 g (0.133 mol) of ethyl N-(1-cyclohexyl-2,3(1H,4H)-quinoxalinedion-6-yl)oxamate were dissolved in 1 l of concentrated sulfuric acid and, at 0° C., 11.35 g (0.133 mol) of sodium nitrate were added a little at a time. The mixture was stirred at 0° C. for a further 2 h and poured into a large quantity of ice. The precipitate was filtered off with suction to yield 50.1 g (93%) of the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:26]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:28]([C:38]([O:40]C)=[O:39])[CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[Na+]>C1COCC1.O>[C:34]([O:33][C:31]([N:29]1[CH2:30][C@@H:26]([C:4]2[CH:5]=[CH:6][C:7]([C:8]3[S:9][C:10]4[C:15]([N:16]=3)=[CH:14][CH:13]=[C:12]([C:17]3([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH2:19][CH2:18]3)[N:11]=4)=[C:2]([F:1])[CH:3]=2)[CH2:27][C@H:28]1[C:38]([OH:40])=[O:39])=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)[C@@H]1C[C@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)pyrrolidine-1,2-dicarboxylate (0.100 g, 0.17 mmol) in 2 mL THF was added sodium hydroxide (0.70 mL, 0.70 mmol). The yellow cloudy reaction mixture was diluted with 0.7 mL water, and stirred rapidly at ambient temperature. After 6 h, the reaction mixture was quenched with ice and 5 N HCl until slightly acidic. The aq. Layer was extracted with DCM and the combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give (2S,4R)-1-(tert-butoxycarbonyl)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridine-2-yl)phenyl)pyrrolidine-2-carboxylic acid as a white solid. MS (ESI) m/z: Calculated: 559.2; Observed: 559.7 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([OH:15])=[CH:11][CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24].O>CC(C)=O>[CH2:24]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[CH:23]=[CH2:22]
Reactant: Oc1ccccc1-c1c(Cl)cccc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccccc1-c1c(Cl)cccc1Cl
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 2′,6′-dichloro-1,1′-biphenyl-2-ol (5.4 g, 0.0226 mol) in acetone (100 mL) was added potassium carbonate (3.75 g, 0.0271 mol) followed by allyl bromide (2.58 mL, 0.0298 mol) and the reaction mixture heated to reflux for 24 hours. The cooled reaction mixture was poured into water (300 mL), the mixture stirred vigorously for 1 hour then extracted with ethyl acetate (300 mL). The separated organic extract was washed with water (200 mL) and saturated brine (200 mL), dried over magnesium sulfate and concentrated under reduced pressure to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 1 to 2% ethyl acetate in hexane gave 5.84 g (93%) of 2′-(allyloxy)-2,6-dichloro-1,1′-biphenyl as a colorless oil. MS (EI) m/z 278 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.Cl[CH:21]([CH3:29])[CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH:21]([CH3:29])[CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Reactant: CC(Cl)CN1CCOCC1
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(C(C)CN1CCOCC1)C3

Procedure:
In the same way described in Example 5, .02 m of 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one was alkylated with N-(2-chloropropyl)morpholine to give, after recrystallization from 95% EtOH 1.3 g of product; mp 228°-230°C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH3:20])[CH2:18][Cl:19])=[CH:12][CH:11]=1)([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8]>C(Cl)Cl.[Fe]>[Br:1][C:14]1[CH:15]=[C:10]([C:4]([CH3:3])([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH:11]=[CH:12][C:13]=1[CH2:16][CH:17]([CH3:20])[CH2:18][Cl:19]
Reactant: BrBr
Reactant: CCCCC(C)(C)c1ccc(CC(C)CCl)cc1
Agent: [Fe]
Solvent: ClCCl
Product: CCCCC(C)(C)c1ccc(CC(C)CCl)c(Br)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.6 %

Procedure:
180 g of Br2 were added dropwise to amixture of 300 g of XII and 3 g of Fe powder at room temperature, and the mixture was stirred for 14 hours at room temperature. The crude product was dissolved in CH2Cl2, and the solution was washed with water, dried over Na2SO4 and distilled. 220 g of (XIII) of boiling point 160° C./0.1 mbar were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([CH:30]([NH2:32])[CH3:31])[CH:27]=[N:26]2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH:29]=[C:28]([C@H:30]([NH:32][C:2]3[N:7]=[C:6]([N:8]4[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]4=[O:16])[CH:5]=[CH:4][N:3]=3)[CH3:31])[CH:27]=[N:26]2)=[CH:23][CH:24]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH:29]=[C:28]([C@@H:30]([NH:32][C:2]3[N:7]=[C:6]([N:8]4[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]4=[O:16])[CH:5]=[CH:4][N:3]=3)[CH3:31])[CH:27]=[N:26]2)=[CH:23][CH:24]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: CC(N)c1cnn(-c2ccc(F)cc2)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2cnn(-c3ccc(F)cc3)c2)n1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@H](C)c2cnn(-c3ccc(F)cc3)c2)n1

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (98 mg, 0.41 mmol), 1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethanamine hydrochloride (502 mg, 2.08 mmol, 5.1 equiv) and iPr2NEt (0.637 mL, 3.65 mmol, 9.0 equiv) in DMSO (1.5 mL) was heated at 110° C. for 16 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 20 to 80%) provided (S)-3-(2-((R)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one and (S)-3-(2-((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.