Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[N:11]=[C:12]([N:15]=[C:16]([NH2:18])[NH2:17])[S:13][CH:14]=2)[N:9]=1.[CH2:19]([S:25][CH2:26][C:27](O)=[O:28])[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[NH2:17][C:16](=[N:15][C:12]1[S:13][CH:14]=[C:10]([C:8]2[N:9]=[C:5]([CH2:4][NH:3][C:27](=[O:28])[CH2:26][S:25][CH2:19][C:20]3[O:24][CH:23]=[CH:22][CH:21]=3)[S:6][CH:7]=2)[N:11]=1)[NH2:18]
Reactant: O=C(O)CSCc1ccco1
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(N)=Nc1nc(-c2csc(CNC(=O)CSCc3ccco3)n2)cs1
Yield: 11 %

Procedure:
A suspension of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride (1.6 g), (furfurylthio)acetic acid (0.98 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g) and triethylamine (1.0 g) in N,N-dimethylformamide (20 ml) was stirred with cooling on an ice-water bath for 2.5 hours. The solvent was removed under the reduced pressure. The residue was washed with water and then chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (10:1). The appropriate fractions was collected and the solvent was removed under the reduced pressure. The residue was suspended in water (20 ml) and the mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and water afforded 2-(diaminomethyleneamino)-4-[2-(furfurylthio)acetylaminomethylthiazol-4-yl]thiazole (0.22 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.Cl[C:15]([CH2:17][C:18]12[CH2:25][CH2:24][CH2:23][N:22]1[CH2:21][CH2:20][CH2:19]2)=[O:16]>>[NH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:15]([CH2:17][C:18]12[CH2:19][CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][CH2:25]2)=[O:16]
Reactant: Nc1cnc2ccccc2c1N
Reactant: O=C(Cl)CC12CCCN1CCC2
Agent: Cl
Product: Nc1c(NC(=O)CC23CCCN2CCC3)cnc2ccccc12
Yield: 53 %

Procedure:
3,4-Diaminoquinoline and 5-chlorocarbonylmethyl-1-azabicyclo[3.3.0]octane hydrochloride were reacted in the same manner as in Example 3 to obtain the titled compound in a yield of 53.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:18][C:19]3[CH:20]=[C:21]([B:25]4[O:33]C(C)(C)C(C)(C)[O:26]4)[CH:22]=[CH:23][CH:24]=3)=[C:7]([CH3:17])[N:8]2[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:18][C:19]3[CH:20]=[C:21]([B:25]([OH:33])[OH:26])[CH:22]=[CH:23][CH:24]=3)=[C:7]([CH3:17])[N:8]2[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(Sc2cccc(B3OC(C)(C)C(C)(C)O3)c2)c2ccc(Cl)cc2n1-c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Sc2cccc(B(O)O)c2)c2ccc(Cl)cc2n1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(6-Chloro-2-methyl-1-pyridin-3-yl-1H-indol-3-ylsulfanyl)-phenylboronic acid pinacol ester (0.400 g, 0.86 mmol) was dissolved in THF:MeOH (1:1, 10 mL) and sodium hydroxide (2.5 mL of 1.0M aqueous solution, 2.5 mmol) was added. The reaction was stirred at room temperature overnight then submitted to aqueous workup and purified by preparatory HPLC (30-100% ACN in H2O) to afford the title compound.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]>OS(O)(=O)=O>[CH2:11]1[O:12][C@@H:2]2[O:10][C@H:9]1[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]2[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Product: O[C@@H]1[C@@H](O)[C@@H]2OC[C@@H](O2)[C@H]1O
Temperature: 90 °C

Procedure:
Prior to the glucose determination, the maltodextrins and the various copolymers were hydrolysed following the following sulfuric acid procedure. About 500 mg sample was weighed in an acid digestion bomb equipped with 30 ml teflon insert (Parr Instruments) and diluted with 1 ml 70% H2SO4 followed by addition of approximately 3 ml of distilled (milliQ) water. The mixture was heated to 90° C. for about 5 hours. This hydrolysis was carried out in duplicate for all samples.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=O>C1(C)C=CC=CC=1>[C:2]1([NH:1][C:9]([C:8]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(Nc1ccccc1)C(=O)OCC
Reaction time: 1 h

Procedure:
Aniline (0.217 mol) and diethyl oxalacetate (0.217 mol) are mixed in toluene (500 ml) and heated to reflux, i.e., about 100° C., under a water separator for approximately one hour. The toluene is then removed under vacuum to afford the desired product, i.e., diethyl 3-phenylaminobut-2-ene-dioate.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11](=O)[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([Cl:23])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Cc3ccccc3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cc3ccccc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-benzyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:17]=[C:16]([O:18][CH2:19][CH3:20])[CH:15]=[C:6]([C:7]([N:9]([CH2:12][CH:13]=[CH2:14])[CH2:10][CH3:11])=[O:8])[CH:5]=1.[OH-].[Na+]>CO>[CH2:12]([N:9]([CH2:10][CH3:11])[C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:17]=[C:16]([O:18][CH2:19][CH3:20])[CH:15]=1)[C:3]([OH:21])=[O:2])[CH:13]=[CH2:14]
Reactant: C=CCN(CC)C(=O)c1cc(OCC)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCN(CC)C(=O)c1cc(OCC)cc(C(=O)O)c1
Reaction time: 18 h

Procedure:
A solution of 1.0 g (4.45 mmol) 5-ethoxy-isophthalic acid mono methyl ester, 10 ml toluene and 0.5 ml SOCl2 is treated with one drop DMF and heated to 80° C. till the evolution of gas ceases. After cooling down the mixture is evaporated, dissolved in 5 ml DCM and added to an at 0° C. stirred mixture of 10 ml 10% aqueous Na2CO3, 0.81 g (6.7 mmol) allyl ethyl amine hydrochloride (see IVb) and 5 ml DCM. After 1 h the layers are separated and the organic layer is washed with 1N HCl, brine, dried with sodium sulfate and evaporated to yield the N-allyl-5-ethoxy-N-ethyl-isophthalamic acid methyl ester. This ester is dissolved in 20 ml MeOH, treated with 15 ml 1N NaOH and stirred for 18 h. The methanol is evaporated, the residue acidified with 1N HCl and extracted with TBME. The organic layer is dried with sodium sulfate and evaporated to yield the title compound.
Reaction SMILES: [CH2:1]([C:4]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([C:34]([O:36]CC)=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)[C:7]2=[N:8][C:9]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:10][CH:11]=[C:6]2[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([C:4]1[N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:27]([C:34]([OH:36])=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:25]=2)[C:7]2=[N:8][C:9]([NH:12][C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])=[CH:10][CH:11]=[C:6]2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(NC(=O)C(C)C)nc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2ccc(NC(=O)C(C)C)nc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-propyl-5-(2-methylpropionylamino)-3-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]imidazo[4,5-b]pyridine and 1N sodium hydroxide solution in ethanol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]2[N:12]=[C:11]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[S:10][C:6]=2[N:7]=[CH:8][N:9]=1.C(N(CC)C(C)C)(C)C.Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[S:40]([CH3:43])(=[O:42])=[O:41].O>CN(C)C=O>[CH3:2][O:3][C:4]1[C:5]2[N:12]=[C:11]([NH:13][C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=4[S:40]([CH3:43])(=[O:42])=[O:41])[CH2:20][CH2:21]3)=[O:15])[S:10][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CS(=O)(=O)c1cc(Cl)ccc1CBr
Reactant: COc1ncnc2sc(NC(=O)N3CCNCC3)nc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ncnc2sc(NC(=O)N3CCN(Cc4ccc(Cl)cc4S(C)(=O)=O)CC3)nc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
A mixture of piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide hydrochloride (as prepared in Example 1, 625 mg, 1.70 mmol) in N,N-dimethylformamide (5 mL) was treated with N,N-diisopropylethylamine (660 mg, 5.10 mmol) followed by 1-(bromomethyl)-4-chloro-2-(methylsulfonyl)-benzene (530 mg, 1.87 mmol). The reaction mixture was allowed to stir at 80° C. for 3 h. At this time, the reaction was poured into water. The aqueous layer was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 4-(4-chloro-2-methanesulfonyl-benzyl)-piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (580 mg, 69%) as an off-white solid; LRMS for C19H21ClN6O4S2 (M+H)+ at m/z=496. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][C@@H:2](N(C)C)[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:14][C:15](C)([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:16]#C.C1(C=O)CCCCC1>[O-]S(C(F)(F)F)(=O)=O.[Zn+2].[O-]S(C(F)(F)F)(=O)=O.C(N(CC)CC)C>[CH:4]1([C@@H:3]([OH:10])[C:2]#[C:1][C:15]([CH3:16])([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH3:14])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C[C@H]([C@@H](O)c1ccccc1)N(C)C
Reactant: C#CC(C)(C)OC1CCCCO1
Agent: O=CC1CCCCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCN(CC)CC
Product: CC(C)(C#C[C@H](O)C1CCCCC1)OC1CCCCO1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A flask is charged with zinc triflate (545 mg, 3 mol % based on the aldehyde compound mentioned blow). Vacuum (0.5 hPa or lower) is applied and the flask is heated to 125° C. for 2 hours. The flask is cooled to 23° C., the vacuum released and (+)-N-methylephedrine (296 mg, 3.3 mol % based on the aldehyde compound mentioned below) is added. Vacuum (0.5 hpa or lower) is applied for 0.5 hour and then released. To the flask, triethylamine (607 mg, 12 mol % based on the aldehyde compound mentioned below) and 2-(1,1-dimethyl-prop-2-ynyloxy)-tetrahydropyran as the alkyne compound (55 mmol, 110 mol % based on the aldehyde compound mentioned below) are added, and stirred for 0.25 hour at 25-30° C. And then cyclohexanecarboxaldehyde (50 mmol) as the aldehyde compound is added. The reaction mixture is stirred at 50° C. for 20 hours. Then, the distillation under reduced pressure gives (R)-1-cyclohexyl-4-methyl-4-tetrahydropyranyloxy-2-pentyn-1-ol, bp 130° C. (0.04 hPa), a colorless oil, in 82% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:13]=[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:15]=2)=[O:10])=[CH:4][CH:3]=1.[NH:27]1[CH:31]=[CH:30][CH:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>C1(C)C=CC=CC=1.[Cu]I>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:14]1[N:15]=[C:11]([C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:3][CH:4]=2)[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:13]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(Br)cc1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-n2cccn2)cc1

Procedure:
2-[(4-bromophenyl)acetyl]-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 7) (1 g, 2.261 mmol) was added to a stirred, ambient temperature mixture of pyrazole (0.146 g, 2.148 mmol), potassium carbonate (0.656 g, 4.75 mmol), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.064 g, 0.452 mmol) and copper (I) iodide (0.022 g, 0.113 mmol) in toluene (2.5 mL). After stirring at reflux overnight, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 0-60% EtOAc/hexane afforded 4-(2,2-dimethylpropyl)-N,N-dimethyl-2-{[4-(1H-pyrazol-1-yl)phenyl]acetyl}-1H-imidazole-1-sulfonamide.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:33][CH:32]=2)O1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:31]3[CH:32]=[CH:33][C:34]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])=[CH:35][CH:36]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: OBO
Product: CS(=O)(=O)Nc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)methane sulfonamide as a boronic acid, the desired compound was obtained as a colorless solid.
Reaction SMILES: B(Br)(Br)Br.[N:5]1([N:10]([CH2:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)[CH:9]=[CH:8][N:7]=[CH:6]1.C([O-])(O)=O.[Na+]>ClCCl>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([N:10]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)[N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(N(Cc2ccc(C#N)cc2)n2ccnc2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(CN(c2ccc(O)cc2)n2ccnc2)cc1
Yield: 91.2 %

Procedure:
A solution of boron tribromide (60 ml, 60.00 mmol) in 20 ml of dichloromethane is added to a cold (0-5° C.) solution of 4-[N-(1H-imidazol-1-yl)-N-(4 methoxyphenyl)amino]methylbenzonitrile (4.60 g, 15.11 mmol). After 1 h at room temperature the mixture was hydrolysed with saturated aqueous NaHCO3, filtered, washed with water (50 ml) and with dichloromethane (20 ml) to give a brown solid (4.00 g). Crystallization from acetone yielded a brown solid (3.00 g, 68%) mp: 150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:21]=1)=[N:8][C:9]1[C:10]([C:18]([OH:20])=O)=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=1[CH:15]=2.[CH:22]1[N:26]=[CH:25][N:24]([C:27](N2C=NC=C2)=O)[CH:23]=1>C(#N)C>[CH3:25][N:24]([CH3:27])[CH2:23][CH2:22][NH:26][C:18]([C:10]1[C:9]2[N:8]=[C:7]3[CH:21]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]3=[CH:15][C:14]=2[C:13](=[O:16])[N:12]([CH3:17])[CH:11]=1)=[O:20]
Reactant: COc1ccc2cc3c(=O)n(C)cc(C(=O)O)c3nc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COc1ccc2cc3c(=O)n(C)cc(C(=O)NCCN(C)C)c3nc2c1
Yield: 80 %

Procedure:
From acid 18w, with a reflux time of 96 h and a recharge with an equal amount of CDI after 48 h, and obtained as a yellow solid (80%), mp 213-215° C. (from acetonitrile). 1H NMR (CDCl3): δ 2.50 [s, 6H, N(CH3)2], 2.78 (t, J=6.0 Hz, 2H, CH2CH2NMe2), 3.67 (s, 3H, NCH3), 3.77 (q, J=5.8 Hz, 2H, CH2CH2NMe2), 4.02 (s, 3H, ArOCH3), 7.22 (dd, J=9.1, 2.2 Hz, 1H, H-8), 7.43 (d, J=2.2 Hz, 1H, H-6), 7.85 (d, J=9.1 Hz, 1H, H-9), 8.53 (s, 1H, H-3), 9.14 (s, 1H, H-10), 11.36 (br s, 1H, CONH). 13C NMR (CDCl3): δ 36.8 (CH2CH2NMe2 and NCH3), 45.0 [N(CH3)2], 55.6 (ArOCH3), 57.7 (CH2CH2NMe2), 105.3 (CH, C-6), 108.8 (C-4), 117.3 (C-10a), 120.9 (CH, C-8), 121.4 (C-9a), 130.0 (CH, C-9), 138.3 (CH, C-10), 143.1 (CH, C-3), 149.7 (C-4a), 150.9 (C-5a), 162.5 (C-1), 163.4 (C-7), 164.4 (CONH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([N+:21]([O-])=O)[CH:12]=3)[N:10]=2)[CH:7]=1.CC(O)=O>[Fe].C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[C:13]([NH2:21])[CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2cn3cc(Br)ccc3n2)ccc1C(F)(F)F
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(-c2cn3cc(Br)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
Fe (0.447 g) is added to a mixture of 6-bromo-2-[3-nitro-4-(trifluoromethyl)phenyl]imidazo[1,2-a]pyridine (0.618 g), HOAc (0.733 mL), and EtOH—H2O (10 mL, 4:1). The mixture is stirred at 80° C. for 2 hours, then concentrated, taken into sat. aqueous NaHCO3 and extracted with EtOAc and CH2Cl2. Organics are dried and concentrated to give the title compound (463 mg), which is used without further purification. LCMS m/z=356.4 [M+H]+, tR=2.04 min.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[C:20](=[NH:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20](=[N:33][C:2]1[N:3]=[C:4]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1cc(Cl)c2nc(Br)cnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(Cl)c2nc(N=C(c3ccccc3)c3ccccc3)cnc21
Temperature: 100 °C
Yield: 59.3 %

Procedure:
2-Bromo-7-chloro-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (1.31 g, 3.61 mmol), benzhydrylideneamine (0.67 mL, 3.97 mmol), Cs2CO3 (2.35 g, 7.22 mmol), Pd(OAc)2 (81 mg, 0.361 mmol) and BINAP (225 mg, 0.361 mmol) were dissolved in THF (36 mL) and heated at 100° C. overnight, cooled to RT, partitioned between EtOAc and brine. The organic layer was dried (MgSO4), filtered, concentrated, and purified by SiO2 chromatography (150 g SiO2, hexanes/EtOAc 0-25% EtOAc) to give 992 mg of benzhydrylidene-[7-chloro-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-amine as a yellow liquid (59% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[S:26]1[C:30]2[CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:35]([C:32]1[CH:33]=[CH:34][C:29]3[N:28]=[CH:27][S:26][C:30]=3[CH:31]=1)=[O:36])=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc3ncsc3c2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
3-{[(Benzothiazole-6-carbonyl)-amino]-methyl}-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide was prepared starting from intermediate C and benzothiazole-6-carboxylic acid. MS calcd. for C27H21ClN4O3S [(M+H)+] 517.1, obsd. 516.9.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([CH3:18])[CH:12]=1)[NH2:7])[CH3:3].[C:20]([S:23][CH2:24][CH:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26](O)=[O:27])(=[O:22])[CH3:21]>CO>[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([CH3:18])[CH:12]=1)[NH:7][C:26](=[O:27])[CH:25]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:24][S:23][C:20](=[O:22])[CH3:21])[CH3:3]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CSCc1ccc(C)c(C)c1
Agent: Cl
Solvent: CO
Product: CCOC(=O)[C@H](CSCc1ccc(C)c(C)c1)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React S-(3,4-dimethylbenzyl)-L-cysteine ethyl ester hydrochloride (2.20 g) and 3-acetylthio-2-benzylpropionic acid (1.74 g) in the manner described in Example 1, Step 1 to give an amber oil. Place the oil on a column of silica gel (1 L) and elute with ethyl acetate:hexane 25:170 (4 L) and then methanol:hexane 25:170 to give a light orange oily solid. Repeat the chromatography to give Isomer A, a white solid (0.52 g), m.p. 89.5°-92.5°, [α]D26 =-71.1° (MeOH) and Isomer B, a white solid (0.60 g), m.p. 51°-55°, [α]D26 =-8.4° (MeOH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]2[C:20](=[CH:21][C:22]([NH:30][C:31](=[O:39])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[NH2:38])=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1(C)C=CC=CC=1.CC(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:31]([NH:30][C:22]2[CH:21]=[C:20]3[C:25]([C:26]([CH3:28])([CH3:29])[CH2:27][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:17])[CH2:19]3)=[CH:24][CH:23]=2)=[O:39])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3N)ccc2C(C)(C)C1
Reactant: CC(=O)c1ccnc(N)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(Nc1ccccc1C(=O)Nc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2(C)C)c1ccnc(N)n1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2-amino-pyrimidin-4-yl)-ethanone (Step B, 200 mg, 1.46 mmol) in toluene (15 mL) was added, 7-(2-amino-benzoylamino)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Example 15, Step A)(288 mg, 0.73 mmol), and HOAc (3 drops). The resulting mixture was heated at 95° C. under N2 for 20 h. The reaction was cooled to RT and NaBH(OAc)3 (620 mg, 2.92 mmol) was added and reheated for 3 h. The reaction was cooled to RT, quenched with Na2CO3 solution (2 M, 5 mL), solvent was evaporated in vacuo. The residue was extracted with CHCl3. The organic layer was washed with saturated NaHCO3, water, brine, dried over MgSO4, and evaporated in vacuo. The crude solid was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH (95:5) gave THE final compound. MS m/z: 517.3 (M+H). Calc'd. for C29H37N6O3-517.63.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][CH2:6][C:7]1([CH3:41])[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([C:38](=[O:40])[CH3:39])[C:15]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([OH:34])[C:26]=3[CH2:35][CH2:36][CH3:37])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)C.O.[OH-].[Li+]>O1CCCC1.O>[C:38]([C:14]1[C:15]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([OH:34])[C:26]=2[CH2:35][CH2:36][CH3:37])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]2[O:8][C:7]([CH3:41])([CH2:6][CH2:5][C:4]([OH:42])=[O:3])[CH2:12][CH2:11][C:10]=2[CH:13]=1)(=[O:40])[CH3:39]
Reactant: CCCc1c(OCCCOc2c(C(C)=O)cc3c(c2CCC)OC(C)(CCC(=O)OCC)CC3)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2c(C(C)=O)cc3c(c2CCC)OC(C)(CCC(=O)O)CC3)ccc(C(C)=O)c1O

Procedure:
A 191 mg sample of the product from Example 26 was saponified with lithium hydroxide monohydrate, (273 mg) in 5 ml of 3:2 tetrahydrofuran-water, using the procedure described in Example 4. After column chromatography on silica gel, racemic-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid was obtained as a yellow, viscous oil.