Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:9]#[N:10])=[CH:4][NH:5][C:6](=[O:8])[CH:7]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.[Cu]I.O>[OH:1][C:2]1[C:3]([C:9]#[N:10])=[CH:4][N:5]([C:18]2[CH:19]=[CH:20][C:15]([S:12]([CH3:11])(=[O:14])=[O:13])=[CH:16][CH:17]=2)[C:6](=[O:8])[CH:7]=1
Reactant: N#Cc1c[nH]c(=O)cc1O
Reactant: CS(=O)(=O)c1ccccc1
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C#N)c(O)cc2=O)cc1
Temperature: 190 °C
Yield: 5.7 %

Procedure:
A mixture of 4-hydroxy-6-oxo-1,6-dihydropyridine-3-carbonitrile (200 mg, 1.469 mmol, Medinoah), 1-bromo-4-(methylsulfonylbenzene (345 mg, 1.469 mmol), 4,7-dimethoxy-1,10-phenanthroline (70.6 mg, 0.294 mmol), copper(I) iodide (56.0 mg, 0.294 mmol) and potassium carbonate (609 mg, 4.41 mmol) in DMSO (3 mL) was heated at 190° C. To the reaction mixture was added H2O (10 mL) and the pH adjusted to ˜2 using with 1N HCl. The resulting aqueous mixture was extracted with EtOAc (40 mL, 2×). The combined extracts were dried over Na2SO4 and concentrated to give a brown oil. The crude oil was purified by flash chromatography (SiO2, 0-5% MeOH/CH2Cl2) to give a yellow solid (35 mg, 0.084 mmol, 5.74%). MS (ESI) 291 (M+H).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[NH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(O)=O.[OH-].[K+].[S:21]([CH2:26][C:27](=O)[CH3:28])[CH2:22][C:23](=O)[CH3:24].[BH3-]C#N.[Na+]>CO>[CH:7]([N:8]1[C@H:27]([CH3:28])[CH2:26][S:21][CH2:22][C@H:23]1[CH3:24])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(=O)CSCC(C)=O
Agent: [BH3-]C#N
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1CSC[C@@H](C)N1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.8 %

Procedure:
To a stirred solution of diphenylmethanimine (2.36 mL, 13.7 mmol), HOAc (0.86 mL, 15.1 mmol), and potassium hydroxide (0.19 g, 3.4 mmol) in CH3OH (25 mL) cooled to 0° C. was added a solution of 1,1′-thiodipropan-2-one (2.0 g, 13.7 mmol) in CH3OH (10 mL). NaCNBH3 (0.86 g, 13.7 mmol) was then added and the reaction mixture stirred at ambient temperature for 16 h. A further portion of NaCNBH3 (0.43 g, 6.9 mmol) was added and the reaction mixture stirred for another 4 h. The reaction mixture was partitioned with EtOAc (150 mL) and H2O (150 mL) and the layers separated. The organic layer was washed with H2O (150 mL), brine (150 mL) then dried over Na2SO4. After concentration under reduced pressure, the resulting residue was purified by flash column chromatography (silica gel, 10-50% EtOAc in hexanes) to afford (3S,5S)/(3R,5R)-4-benzhydryl-3,5-dimethylthiomorpholine (0.52 g, 13%). 1H NMR consistent.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12](Cl)=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH2:24].[Na]>>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([SH:24])=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1cnc(-c2ccccc2)nc1Cl
Reactant: S
Agent: [Na]
Product: O=C(NCc1ccccc1)c1cnc(-c2ccccc2)nc1S
Yield: 65.2 %

Procedure:
Using the procedure from Preparation 34, 5.8 g (17.9 mmol) of 4-chloro-2-phenyl-pyrimidine-5-carboxylic acid benzylamide was reacted with 5.1 g (72 mmol) of sodium hydrogen sulfide to give 3.75 g of the title compound, mp 189°-193° C.
Reaction SMILES: C(O[C:6]([C:8]1[N:13]=[CH:12][C:11]2[CH:14]=[C:15]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:16][C:10]=2[C:9]=1[OH:24])=[O:7])CCC.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>C[O-].[Na+].CO.Cl>[OH:24][C:9]1[C:10]2[S:16][C:15]([S:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][C:11]=2[CH:12]=[N:13][C:8]=1[C:6]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:7]
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2cc(Sc3ccccc3)sc2c1O
Temperature: 120 °C

Procedure:
7-Hydroxy-2-phenylsulfanyl-thieno[3,2-c]pyridine-6-carboxylic acid n-butyl ester, example 17.c.A, (25 mg, 0.07 mmol) and glycine (52 mg, 0.7 mmol) were suspended in 1.4 mL of 0.5 N NaOMe in methanol. The reaction mixture was heated at 120° C. for 10 minutes using a CEM microwave reactor, cooled, and diluted with 0.25 N HCl to precipitate out a white solid. The precipitate was collected on a fine glass fritted filter, washed twice with water, and dried under hi-vacuum to isolate 23 mg of the title compound. MS: (+) m/z 361.4 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)[CH2:21][CH2:20]2)=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.C1(=O)C2C(=CC=CC=2)CC1.CP(OC(OC(CC)(CC)C)=O)(=O)[O-].COC1C=C(C2CCNCC2)C=CC=1OC>C1COCC1.[H][H].[Pd].O.CO>[CH:7]1([CH2:16][CH2:17][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)[CH2:21][CH2:20]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: COc1ccc(C2CCN(C(=O)CC3CCc4ccccc43)CC2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: CCC(C)(CC)OC(=O)OP(C)(=O)[O-]
Agent: COc1ccc(C2CCNCC2)cc1OC
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2CCN(CCC3CCc4ccccc43)CC2)cc1OC
Reaction time: 2 h

Procedure:
A suspension of 0.6 g of lithium aluminium hydride in 35 ml of THF is treated dropwise with stirring under inert reaction conditions with a solution of 6.3 g of 1-(indan-1-ylacetyl)-4-(3,4-dimethoxyphenyl)piperidine [obtainable by reaction of 1-indanone with diethylethoxycarbonyl methanephosphonate, subsequent hydrogenation with H2 /Pd-C, conversion of the ester present to an acid chloride and amide formation with 4-(3,4-dimethoxyphenyl)piperidine] in 70 ml of THF and the mixture is boiled for 2 hours. A further 0.8 g of lithium aluminium hydride is then added and the mixture is refluxed for a further 3 hours. The reaction mixture is then treated with methanol and subsequently with water and worked up in the customary manner. Chromatography (methyl tertbutyl ether/petroleum ether/diethylamine) gives 1-(2-(indan-1-yl)ethyl)-4-(3,4-dimethoxyphenyl)piperidine.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:6]=[C:7]([CH3:15])[C:8]2[S:12](=[O:13])[CH:11]=[N:10][C:9]=2[CH:14]=1)([O-:4])=[O:3].Br[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH3:15][C:7]1[C:8]2[S:12](=[O:13])[CH2:11][N:10]([CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:9]=2[CH:14]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cc2c1S(=O)C=N2
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)N1CS(=O)c2c(C)cc([N+](=O)[O-])cc21
Yield: 36 %

Procedure:
0.69 g (0.03 g atom) of sodium is dissolved in 100 ml of ethanol. 6.3 g (0.03 mol) of 5-nitro-7-methylbenzothiazolone and then 7.17 g (0.03 mol) of diethyl bromomalonate are added to the solution. The reaction mixture is heated under reflux for 8 hours, poured onto ice and the precipitated product is recrystallized from a little ethanol. 4 g (36% of theory) of 7-methyl-5-nitro-3-(bis-ethoxycarbonyl-methyl)-benzothiazolone are obtained in the form of colorless needles of melting point 97° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]([C:15]1[C:19]([NH2:20])=[CH:18][NH:17][N:16]=1)=[O:14].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:11][O:12][C:13]([C:15]1[C:19]([NH:20][C:8](=[O:10])[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:18][NH:17][N:16]=1)=[O:14]
Reactant: COC(=O)c1n[nH]cc1N
Reactant: Cc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1n[nH]cc1NC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.8 %

Procedure:
A mixture of p-toluic acid (272 mg), 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (310 mg), EDC (460 mg) and HOBt (324 mg) in DMF (8 ml) was stirred at ambient temperature for 48 h. The mixture was reduced in vacuo, partitioned between EtOAc and saturated aqueous NaHCO3 and then the organic portion washed with brine, dried (MgSO4) and reduced in vacuo to give 4-(4-methyl-benzoylamino)-1H-pyrazole-3-carboxylic acid methyl ester (486 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][CH2:42][C:43]([CH3:46])([OH:45])[CH3:44])=[CH:38][C:37]=1[CH3:50]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][CH2:42][C:43]([OH:45])([CH3:44])[CH3:46])=[CH:38][C:37]=2[CH3:50])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: Cc1cc(OCCC(C)(C)O)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCC(C)(C)O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 4-(4-bromo-3,5-dimethylphenoxy)-2-methylbutan-2-ol following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 4): tR=1.90 min; Mass spectrum (ESI+): m/z=571 [M+Na]+.
Reaction SMILES: CN1C2C(C(F)(F)F)=CC(NC3C=NC=CC=3)=CC=2C2CNCCC12.C(OC([N:33]1[CH2:51][CH2:50][C@@H:36]2[N:37]([C:47](O)=O)[C:38]3[C:39]([C:45]#[N:46])=[CH:40][C:41]([NH2:44])=[CH:42][C:43]=3[C@@H:35]2[CH2:34]1)=O)(C)(C)C.Br[C:53]1[C:54]([C:59]#[N:60])=[N:55][CH:56]=[CH:57][CH:58]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[C:59]([C:54]1[C:53]([NH:44][C:41]2[CH:42]=[C:43]3[C:38](=[C:39]([C:45]#[N:46])[CH:40]=2)[N:37]([CH3:47])[C@H:36]2[CH2:50][CH2:51][NH:33][CH2:34][C@@H:35]32)=[CH:58][CH:57]=[CH:56][N:55]=1)#[N:60]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc(C#N)c1N2C(=O)O
Reactant: N#Cc1ncccc1Br
Agent: CN1c2c(cc(Nc3cccnc3)cc2C(F)(F)F)C2CNCCC21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN1c2c(C#N)cc(Nc3cccnc3C#N)cc2[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method B) as a yellow solid (35 mg, 35%) from (4aS,9bR)-8-amino-6-cyano-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylic acid tert-butyl ester (Example 162, 100 mg, 0.31 mmol), 3-bromo-pyridine-2-carbonitrile (56 mg, 0.31 mmol) and Cs2CO3 (199 mg, 0.6 mmol). MS (ESI): 331 (base, M+H).
Reaction SMILES: CO[C:3]1([CH3:24])[CH2:8][CH2:7][C:6]2[C:9]([CH3:23])=[C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1.[Cl-:25].[Ca+2].[Cl-].CCCCCC.Cl>C(OCC)C>[Cl:25][C:3]1([CH3:24])[CH2:8][CH2:7][C:6]2[C:9]([CH3:23])=[C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: [Cl-]
Reactant: COC1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Agent: Cl
Agent: [Ca+2]
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(Cl)O2
Reaction time: 2 h
Yield: 100.6 %

Procedure:
A mixture of 10 g of rac-2-methoxy-3,4-dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran, 10 g of calcium chloride, 100 ml of hexane and 50 ml of diethyl ether was stirred at -5° to -10° C. while HCl gas was bubbled in for 1 hr. An additional 10 g of calcium chloride was added and stirring was continued at room temperature for 2 hr. The mixture was filtered and the filtrate was concentrated in vacuo giving 10.2 g of title product as a light-brown oil. Proton NMR analysis revealed that this product consisted of 66% of the title compound and 33% of the starting 2-methoxy chroman.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:12].I[CH2:14][CH3:15]>>[CH2:14]([O:12][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:2]=1[Br:1])[CH3:15]
Reactant: Oc1ccc2c(c1Br)CCCC2
Reactant: CCI
Product: CCOc1ccc2c(c1Br)CCCC2
Yield: 66 %

Procedure:
Following the general procedure of Preparation 1 Step 2 and making non-critical variations but substituting 3-bromo-5,6,7,8-tetrahydronaphthalen-2-ol with 1-bromo-5,6,7,8-tetrahydronaphthalen-2-ol (900 mg, 3.96 mmol) and substituting iodomethane with iodoethane gave 980 mg of a crude oil. The crude was purified by Biotage MPLC (120 g column, 3% ethyl acetate in heptane) to give 657 mg (66%) of 1-bromo-5,6,7,8-tetrahydronaphthalen-2-yl ethyl ether as a white solid.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH:9]([O:30][CH3:31])[CH2:10][O:11][CH2:12][C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[O:29]=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:12][O:11][CH2:10][CH:9]([O:30][CH3:31])[CH2:8][OH:7]
Reactant: CCCCCCCCCCCCCCCC(=O)COCC(COC1CCCCO1)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCCCCCCCCCCCCCCC(=O)COCC(CO)OC
Temperature: 55 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
In 80 ml of ethanol was dissolved 4.17 g (9.4 mmoles) of the above tetrahydropyranyl ether (3), and 248 mg (0.98 mmoles) of pyridinium p-toluenesulfonate was added. The mixture was stirred at 55° C. for 3 hours. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel chromatography [eluent: n-hexane-ethyl acetate (2:1)] to give 2.9 g (86%) of the desired compound as a colorless wax.
Reaction SMILES: [N-]=[N+]=[N-].O.[CH2:5]([N:7]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])[CH2:8][CH3:9])[CH3:6].[N-:18]=[N+]=[N-].[Na+].[ClH:22]>C(OCC)(=O)C.CO>[ClH:22].[CH2:5]([N:7]([CH2:10][CH:11]1[NH:18][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:8][CH3:9])[CH3:6]
Reactant: CCN(CC)CC1CCCCC1=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(CC)CC1CCCCC(=O)N1
Temperature: 25 °C
Reaction time: 0.8 h

Procedure:
While maintaining a reaction temperature of from -10° to -5° C., a solution azide (10.0 g, 0.154 mol) in as little water as possible is added dropwise to a solution of 2-[(diethylamino)methyl]-cyclohexanone (22.0 g, 0.1 mol) in concentrated hydrochloric acid (200 ml). After the cooling has been stopped, the mixture is stirred (48 minutes) at ambient temperature. After further cooling to -10° to -5° C., sodium azide, (5.0 g, 0.77 mol) is added in the same way as described above, after which the mixture is stirred for a further 24 hours at ambient temperature. Then, the reaction mixture is concentrated under water jet vacuum, the syrupy residue is taken up in 10 ml of water, mixed with substantially anhydrous sodium carbonate and stirred thoroughly with ethyl acetate (200 ml). After removal of the solvent the organic phase leaves an oily residue which can be converted into a hydrochloride by treatment with ethereal hydrogen chloride solution. M.p. 171° C. (ethyl acetate/methanol 3:1 v/v). Yield: 10.1 g.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[CH3:10][N:11]([CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1>>[CH3:10][N:11]([CH3:19])[C:12]1[CH:13]=[C:14]([NH:18][C:2]2[CH:3]=[C:4]([NH:8][CH3:9])[N:5]=[CH:6][N:7]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CNc1cc(Cl)ncn1
Reactant: CN(C)c1cccc(N)c1
Product: CNc1cc(Nc2cccc(N(C)C)c2)ncn1

Procedure:
The title compound is prepared analogously as described in Example 105A from (6-chloro-pyrimidin-4-yl)-methylamine and N,N-dimethyl-m-phenylenediamine. The crude product obtained after evaporation of the ethyl acetate layer is purified by flash chromatography (CH2Cl2/CH3OH).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:21]([OH:23])=[O:22])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:14]([O:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([C:21]([OH:23])=[O:22])[CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OCc2ccccc2)C[C@H]1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@H](OCc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
(2S,4S)-1-(tert-butoxycarbonyl)-4-(benzyloxy)-pyrrolidine-2-carboxylic acid (Preparation 17, 150 mg, 0.47 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added and the mixture left stirring overnight at room temperature. The reaction mixture was partitioned between dichloromethane (25 ml) and water (25 ml). The aqueous layer was separated, washed with more dichloromethane (25 ml) and evaporated to dryness. The product was purified using an ion exchange column (Dowex 50WX8-200 resin), eluting first with water then 9:1 water:ammonia yielding the title compound (34 mg, 33% yield) as a white solid.
Reaction SMILES: C(O/[C:5](/[C:15]([O:17][CH3:18])=[O:16])=[C:6](/[O:11]C(=O)C)\[C:7]([O:9]C)=O)(=O)C.[NH2:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>CO>[CH3:18][O:17][C:15]([C:5]1[N:19]=[C:20]2[NH:24][CH:23]=[CH:22][N:21]2[C:7](=[O:9])[C:6]=1[OH:11])=[O:16]
Reactant: COC(=O)/C(OC(C)=O)=C(\OC(C)=O)C(=O)OC
Reactant: Nc1ncc[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1nc2[nH]ccn2c(=O)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 41 %

Procedure:
Dimethyl diacetoxyfumarate (3.2 g, 12 mmol), 2-amino imidazole (1.03 g, 12 mmol) and p-toluenesulphonic acid (395 mg, 2.0 mmol were mixed in a 25 mL flask and immersed in a preheated oil bath (120° C.). After 6 h, the reaction mixture was cooled to room temperature and ethyl acetate (10 mL) and methanol (0.6 mL) were added to the residue and the mixture was sonicated for 2 min. The resulting precipitate was collected by filtration, washed with cold ethyl acetate (1 mL) and dried on the pump to give crude product. Recrystallization from methanol gave 6-hydroxy-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester (1.03 g, 41%).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])(=[O:11])[NH2:10]>CCCCCC>[CH3:3][N:4]([CH:6]=[N:10][C:9]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:11])[CH3:5]
Reactant: NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CCCCCC
Product: CN(C)C=NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 120 °C

Procedure:
Part A: N,N-Dimethylformamide dimethyl acetal (5 mL) was added to benzyl (2S)-2-carbamoyl-pyrrolidine-1-carboxylate (1.05 g, 4.23 mmol) at ambient temperature. The resulting slurry was heated to 120° C. for 2 h then allowed to cool and poured into hexane (50 mL). The solvents were removed under reduced pressure yielding benzyl (2S)-2-(dimethylaminomethylenecarbamoyl)pyrrolidine-1-carboxylate as a colorless oil (1.35 g, crude quantative yield). HPLC (method 1) tR=1.70 min, Purity 100%; LCMS (method 4) tR=0.94 min, m/z 304 (M+1)
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O.NN.[OH-].[K+]>C(O)CO>[CH3:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCCCC(C)=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCC

Procedure:
reacting 2,4-alkaneanedione with 1-bromooctadecane in absolute ethanol in the presence of 18-crown-6 as catalyst to produce 2-heneicosanone; and (b) reducing said 2-heneicosanone using hydrazine hydrate and potassium hydroxide in ethylene glycol to obtain n-heneicosane.
Reaction SMILES: N1C2C(=CC(C(O)=O)=CC=2)N=CC=1.N1CCCCC1.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([N:32]3[CH2:37][CH:36]=[CH:35][CH2:34][CH2:33]3)=[O:31])=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1.C(C1NC=CN=1)(C1NC=CN=1)=O>>[N:20]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: O=C(c1ccc2nccnc2c1)N1CC=CCC1
Agent: O=C(O)c1ccc2nccnc2c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCNCC1
Product: O=C(c1ccc2nccnc2c1)N1CCCCC1

Procedure:
The coupling of 6-quinoxalinecarboxylic acid to piperidine is accomplished in a manner similar to that used for the preparation of Invention Compound XIII, or by any other method known in the art for activation of aromatic carboxylic acids, such as, for example, activation by carbonyl diimidazole. 1H NMR δ 1.56 and 1.73 (br, 6), 3.40 (br s, 2), 3.79 (br s, 2), 7.82 (dd, 1, J=8.8, 1.9 Hz), 8.13 (d, 1, J=1.6 Hz), 8.17 (d, 1, 8.6 Hz), and 8.9 ppm (m, 2).
Reaction SMILES: [C:1]1([S:7]([CH3:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:16]Br>C(#N)C>[C:1]1([S:7]([CH2:9][Br:16])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)c1ccccc1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(CBr)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Methyl phenyl sulfoxide (21.644 g, 154.4 mmol) was dissolved in anhydrous pyridine (27.4 mL, 2.2 eq) and dry acetonitrile (100 mL). The solution was cooled to −40° C. under an argon atmosphere. A solution of bromine (49.4 g, 2eq) in dry acetonitrile (50 mL) was added slowly, maintaining the same temperature. The mixture was stirred at −40° C. for 1 h and then overnight at room temperature. The solvent was evaporated under vacuum and the residue was dissolved in dichloromethane. The organic layer was washed with Na2S2O3 20%, dried over anhydrous Na2SO4 and concentrated to dryness.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[CH3:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[CH3:31])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cc([N+](=O)[O-])ccc1C)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under argon, 155 g (561 mmol) of the compound of Example 4A together with 133 g (617 mmol) of 2-bromo-4-nitrotoluene, 12.6 g (56.1 mmol) of palladium(II) acetate, 48.7 g (84.1 mmol) of xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] and 548 g (1683 mmol) of caesium carbonate in 3.1 liters of 1,4-dioxane were heated at reflux. After 4 h, the mixture was cooled to RT and filtered through kieselguhr, and the filtrate was concentrated on a rotary evaporator. The crude product obtained in this manner was purified by filtration with suction through silica gel (mobile phase gradient ethyl acetate/petroleum ether 4:1→100% ethyl acetate). The product fractions were combined and freed from the solvent on a rotary evaporator. Trituration with diisopropyl ether at RT, removal of the solid by filtration with suction and drying under high vacuum gave 195 g (84% of theory) of the title compound.