Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH2:12])=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])C.Br[C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:4]([C:6]2[C:11]([NH:12][C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=2)=[O:5])=[N:23][CH:24]=1
Reactant: Brc1cncnc1
Reactant: Nc1ccc(F)cn1
Reactant: CCOC(=O)c1nc(C)cnc1N
Product: Cc1cnc(Nc2cncnc2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, MS: m/e=326.3 (M+H+), was prepared in accordance with the general method of example 10 from 3-amino-6-methyl-pyrazine-2-carboxylic acid ethyl ester (Example C), 5-bromopyrimidine and 2-amino-5-fluoropyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:16]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:18])[CH3:17].Br[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)Oc1ccc(Br)cc1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with Example 1(b), using 5-bromoindole-2-carboxylic acid ethyl ester, 4-isopropoxyphenylboronic acid and 4-bromo-1-isopropoxybenzene.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([O:19]CC)=[O:18])=[C:15]([CH:22]4[CH2:24][CH2:23]4)[N:14]=[C:13]3[CH2:25][CH3:26])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35]>CO.[OH-].[Na+].[Cl-].[Na+].O.O>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([OH:19])=[O:18])=[C:15]([CH:22]4[CH2:23][CH2:24]4)[N:14]=[C:13]3[CH2:25][CH3:26])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][S:34]([C:37]([F:40])([F:38])[F:39])(=[O:36])=[O:35]
Reactant: CCOC(=O)c1c(C2CC2)nc(CC)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc(C2CC2)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 104.6 %

Procedure:
A mixture of the product of Example 3 (1.72 g) and 2N aqueous sodium hydroxide (15 ml) in methanol (30 ml) was stirred at room temperature for 6 h. After standing overnight, the solution was diluted with further 2N aqueous sodium hydroxide (10 ml), stirred for a further 2 h at room temperature and then heated at 40° for 90 mins. After cooling, the solution was diluted with brine (80 ml) and water (50 ml) before being washed with ether (100 ml). The aqueous phase was then acidified with 2N hydrochloric acid to pH1 and the cloudy solution was extracted with ethyl acetate (3×90 ml). The combined ethyl acetate extracts were dried and concentrated in vacuo to afford the title compound (1.72 g) as an off-white foam.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.C1(S([C:24]2[N:33]=[C:32]3[C:27]([C:28](=[O:47])[C:29]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:30][N:31]3[C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])=[CH:26][C:25]=2[F:48])=O)C=CC=CC=1.C(OCC)C>C(O)C>[NH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:24]2[N:33]=[C:32]3[C:27]([C:28](=[O:47])[C:29]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:30][N:31]3[C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])=[CH:26][C:25]=2[F:48])[CH2:5]1
Reactant: NC1CCNC1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(S(=O)c3ccccc3)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(N)C3)c(F)cc2c1=O
Yield: 83.8 %

Procedure:
In 3 ml of ethanol was suspended 120 mg of 3-aminopyrrolidine dihydrochloride, and 250 mg of triethylamine was added thereto, after which 300 mg of ethyl 7-benzenesulfinyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was added thereto. The resulting mixture was subjected to reaction at room temperature for 3 hours, and to the reaction mixture was added 10 ml of diethyl ether, after which crystals were collected by filtration, and washed with 12 ml of water to obtain 230 mg (yield 83.8%) of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 64.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9]([NH:12][C:13]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([Cl:25])=[CH:17][C:14]=1[CH2:15]Br)(=[O:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl>[C:9]([NH:12][C:13]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([Cl:25])=[CH:17][C:14]=1[CH2:15][N:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:1])(=[O:11])[CH3:10]
Reactant: CNC1CCCCC1
Reactant: CC(=O)Nc1cc(C(C)(C)C)c(Cl)cc1CBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1cc(C(C)(C)C)c(Cl)cc1CN(C)C1CCCCC1

Procedure:
26 gm of N-methyl-cyclohexylamine were added to 29 gm of 2-acetylamino-4-tert.butyl-5-chloro-benzyl bromide in 1.5 liters of carbon tetrachloride, and the mixture was refluxed for 2 hours. After cooling, the precipitated N-methyl-cyclohexylamine hydrobromide was filtered off, and the filtrate was evaporated. The residue was taken up in 2 N acetic acid, the solution was extracted with chloroform, and the acid phase was made alkaline with concentrated ammonia, extracted three times with chloroform, and the organic phase was evaporated. After column-chromatographic purification on silicagel with ethyl acetate/chloroform (1:1), the 2-acetylamino-4-tert.butyl-5-chloro-N-cyclohexyl-N-methylbenzylamine thus obtained was crystallized from absolute ethanol and recrystallized from ethanol, whereupon it had a melting point of 174°-175.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:26])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:27][CH2:28][CH2:29][CH2:30][O:31][C:32](=[O:38])NC(=N)SC.[OH-].[Na+].[C:41](O)(=O)[CH3:42]>>[OH:26][C:9]1([C:4]2[CH:5]=[CH:6][C:7]3[N:8]=[C:41]([CH2:42][C:32]([O:31][CH2:30][CH2:29][CH2:28][Cl:27])=[O:38])[NH:1][C:2]=3[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc(C2(O)c3ccccc3C(=O)N2Cc2ccccc2)cc1N
Reactant: CC(=O)O
Reactant: CSC(=N)NC(=O)OCCCCl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Cc1nc2ccc(C3(O)c4ccccc4C(=O)N3Cc3ccccc3)cc2[nH]1)OCCCCl
Temperature: 0 °C
Yield: 71 %

Procedure:
A solution of (3,4-diaminophenyl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one) (0.42 g, 1.21 mmol) and 3-chloropropyl[imino(methylthio)methyl]carbamate (0.27 g, 1.31 mmol) in glacial acetic acid (5.0 mL) was heated to 80° C. for 20 minutes. The reaction mixture was poured into ice water and the pH was adjusted to 9 by the addition of 2M aqueous sodium hydroxide. The precipitated product was extracted with ethyl acetate (100 mL) and the organic layer was washed with brine and dried over anhydrous sodium sulfate, followed by the evaporation of the solvent. The resulting crude product was purified by silica gel flash chromatography (chloroform-acetonitrile 95:5 to 9:1 eluent) to give 3-chloropropyl {6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}acetate (0.64 g, 71% yield). MS (EI) for C26H23ClN4O4: 491 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][C:19]([F:34])([CH:31]([F:33])[F:32])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([F:34])([F:18])[CH:31]([F:33])[F:32])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ccc(OCC(F)(F)C(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)C(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=477.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4](OS(C(F)(F)F)(=O)=O)[N:3]=1.[C:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[N:41]=2)[CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]4[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=4)[N:5]=3)[N:41]=2)[CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(OS(=O)(=O)C(F)(F)F)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)n1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Temperature: 25 °C

Procedure:
A stirred mixture of trifluoro-methanesulfonic acid 4-methyl-6-(4-trifluoromethylphenyl)-pyrimidin-2-yl ester (Example A.62) (0.418 g, 1.08 mmol), N-tert-butyl-3-(6-tributylstannanyl-pyridin-2-yl)-benzenesulfonamide (Example F.6) (0.570 g, 0.98 mmol), tetrakis(triphenyl-phosphine)palladium (0.057 g, 5 mol %) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, extracted with ethyl acetate and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the title compound after trituration with diethyl ether as a white solid (260 mg, 50%). MS (ISP) 527.3 [(M+H)+]; mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[CH3:15][N:16]([CH2:18][C:19](Cl)=[O:20])[CH3:17].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:19](=[O:20])[CH2:18][N:16]([CH3:17])[CH3:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(N2CCNCC2)cn1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCN(c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(6-chloropyridin-3-yl)piperazine (250 mg, 1265 μmol) and dimethylaminoacetyl chloride hydrochloride, 85% (260 mg, 1644 μmol) were dissolved in DMF (6 mL) and DIEA (661 μl, 3794 μmol).). The reaction was stirred at room temperature for 4 hours and then 20 hours at 60° C. The resulting solution was taken up in ethyl acetate 80 mL) and washed with aqueous K2CO3 (10%, 70 mL), water (70 mL), and brine (70 mL). The organic phase was dried (MgSO4) and evaporated to give a brown oil. Silica gel chromatography (gradient elution dichloromethane/0-10% 2M NH3 in methanol) afforded compound 300 as an orange tar (174 mg, 49%).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O-].[Na+].[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[C:2]1([CH:1]([C:8]#[N:9])[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccccc1
Yield: 90 %

Procedure:
Reaction of benzyl cyanide, sodium ethylate and diethyl oxalate according to the method described in Org. Synth. Coll. Vol. II (1943) 287 and Chem. Ber. 107 (1974) 2974-2795 in alcohol, acidification with conc. (37%) hydrochloric acid to pH 2 and subsequent recrystallization of the separated precipitate from ethanol yielded ethyl phenylcyanopyruvate in 90% yield as yellow crystals, melting point 127°-128°.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(O[CH:16](OCC)[CH2:17][NH:18][C:19]1[S:20][CH:21]=[N:22][N:23]=1)C>Cl.C(O)C.O>[ClH:1].[S:20]1[CH:21]=[N:22][N:23]=[C:19]1[NH:18][CH2:17][CH:16]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=2)[CH2:6][CH2:7][NH:8]1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CNc1nncs1)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: Oc1cc2c(cc1O)C(CNc1nncs1)NCC2
Yield: 33.5 %

Procedure:
Conc. hydrochloric acid (2 drops) was added to a solution of 3,4-dihydroxyphenethylamine hydrochloride (1.8 g.) and (1,3,4-thiadiazol-2-yl)aminoacetaldehyde diethyl acetal (3.1 g.) in a mixture of ethanol (60 ml) and water (15 ml.). The resulting mixture was refluxed for 18 hours. After cooling, the reaction mixture was allowed to stand at ambient temperature. Precipitating crystals were collected by filtration and washed with ethanol to give 1-(1,3,4-thiadiazol-2-yl)aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.0 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][NH:7]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@@H:33]1[OH:41]>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][N:7]1[CH2:27][C:28]([NH:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@@H:33]1[OH:41])=[O:29]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(OC)c(CC2NCCc3c(OC)ccc(OC)c32)c1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Product: COc1ccc(OC)c(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)N[C@@H]2c3ccccc3C[C@@H]2O)c1

Procedure:
prepared by reaction of 1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[F:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[C:30]2[NH:29][C:28]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:27]=3[NH:26][CH2:25][C:24]=2[CH:23]=[N:22]1.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:26]2[CH2:25][C:24]3[CH:23]=[N:22][N:21]([CH3:20])[C:30]=3[NH:29][C:28]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:27]2=3)=[O:16])=[CH:12][C:11]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Yield: 59 %

Procedure:
A mixture of 4-(tert-butoxycarbonylamino-methyl)-3-fluoro-benzoic acid from Example E3 (1.38 g, 5.1 mmol) and 3,6-dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E2 (11.0 g, 4.7 mmol) in di-chloromethane (20 ml) at room temperature was treated with DIEA (2.44 ml, 14.0 mmol), DMAP (627 mg, 5.1 mmol) and WSCD (1.16 g, 6.1 mmol). The solution was heated at re-flux for 2 days then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (1.29 g, 59%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[CH2:12][NH:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH3:26])[C:17]=1[CH3:33])=[O:15].[O:34]1[CH2:36][CH2:35]1>C(Cl)Cl>[OH:34][CH2:35][CH2:36][N:30]1[CH2:29][CH2:28][CH:27]([CH:25]([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:14]([NH:13][CH2:12][C:5]3[C:6](=[O:11])[NH:7][C:8]([CH3:10])=[CH:9][C:4]=3[O:3][CH3:2])=[O:15])=[C:17]2[CH3:33])[CH3:26])[CH2:32][CH2:31]1
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCNCC2)c2ccccc12
Reactant: C1CO1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(CCO)CC2)c2ccccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a sealed tube charged with a magnetic stir bar was added (R or S)—N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (Compound 326) (0.1 g, 0.229 mmol) was added DCM (3 mL) and the reaction cooled to 0° C. To the cooled reaction mixture was added oxirane which was condensed into the reaction vial (˜1 mL). The reaction was allowed to stir to rt over 4 h and was then conc. in vacuo to afford the crude material which was purified via silica gel chromatography (12 g) using ethyl acetate/MeOH (4:1) as eluent to afford the title compound as a white solid (50 mg). LCMS 481 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ) δ 11.58 (s, 1H), 7.77-7.65 (m, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.11-6.99 (m, 2H), 6.14 (s, 1H), 4.54-4.44 (m, 1H), 4.31 (d, J=5.1 Hz, 3H), 4.13 (dd, J=7.1, 10.3 Hz, 1H), 3.83 (s, 3H), 3.42 (q, J=6.0 Hz, 2H), 2.93 (br. s., 1H), 2.71-2.56 (m, 4H), 2.31 (br. s., 2H), 2.19 (s, 3H), 2.03-1.83 (m, 2H), 1.64 (br. s., 1H), 1.53 (d, J=6.9 Hz, 3H), 1.32 (d, J=11.1 Hz, 1H), 1.02 (d, J=10.3 Hz, 1H), 0.65 (d, J=11.8 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[S:6](=[O:8])(=[O:7])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.C(O)C.C(OCC)(=O)C.[ClH:28]>[Pd].O>[ClH:28].[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[S:6]2(=[O:8])=[O:7])=[CH:15][CH:14]=1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)S1(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(Cc2ccc(N)cc2)S1(=O)=O
Yield: 99.5 %

Procedure:
A suspension of the product from Step 1 (20 g, 74.72 mmol) in a mixture of absolute ethanol (300 ml), ethyl acetate (150 ml), 2N hydrochloric acid (39 ml) and water (25 ml), was hydrogenated at 30 psi for 7 minutes over 10% palladium on carbon (2 g). The catalyst was removed by filtration, washed with ethanol (2×30 ml) and solvents were removed under vacuum. The remaining residue was azeotropically dried with absolute ethanol (1×150 ml) and further dried at high vacuum to give 20.36 g (99.5%) of the required title compound as a white solid. A sample recrystallised from absolute ethanol showed: mp 153°-156° C. (white needles); δH (250 MHz, DMSO-d6) 7.42 (2H, d, J=8.4 Hz, Ar--H), 7.29 (2H, d, J=8.4 Hz, Ar--H), 4.15 (2H, s, Ar--CH2 --N), 3.27--3.17 (4H, m, N--CH2CH2 --N), 2.62 (3H, s, --NMe); m/z (CI) 240 (M+ -1).
Reaction SMILES: [N:1]([C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][C:6]1[O:10][C:9](C(O)=O)=[CH:8][CH:7]=1)=[N+:2]=[N-:3].C([O-])(O)=O.[Na+].[B-](F)(F)(F)[F:25].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>CCOC(C)=O.CCCCCC>[N:1]([C:4](=[CH:5][C:6]1[O:10][C:9]([F:25])=[CH:8][CH:7]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:2]=[N-:3]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)C(=Cc1ccc(C(=O)O)o1)N=[N+]=[N-]
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=Cc1ccc(F)o1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
To 5-(2-azido-3-ethoxy-3-oxoprop-1-enyl)furan-2-carboxylic acid (0.50 g, 2.03 mmol) was added a mixture of NaHCO3 (0.34 g, 4.06 mmol) and Selectfluor® (1.08 g, 3.05 mmol), followed by water (4.0 mL), hexane (5.0 mL) and EtOAc (2.0 mL). The mixture was stirred at rt for 5 min. The organic layer was separated, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (0 to 30% EtOAc in heptane over 20 min) yielded pure ethyl 2-azido-3-(5-fluorofuran-2-yl)prop-2-enoate as a reddish oil (0.20 g, 45%). 1H NMR (400 MHz, CD3OD) δ ppm 1.35 (t, J=7.15 Hz, 3H) 4.32 (q, J=7.16 Hz, 2H) 5.74 (dd, J=6.83, 3.66 Hz, 1H) 6.63 (s, 1H) 7.05 (t, J=3.59 Hz, 1H). 19F NMR (376 MHz, CD3OD) δ ppm −115.12 (dd, J=6.60, 3.30 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: CC(C)(CN)CO
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCC(C)(C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-2,2-dimethyl-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.29 (1H, t, J=6 Hz), 8.51 (1H, s), 7.72 (1H, s), 7.31 (2H, dd, J=9, 5.6 Hz), 7.12 (2H, t, J=9 Hz), 5.13 (2H, s), 4.76 (1H, t, J=5 Hz), 4.11 (2H, s), 3.25 (2H, d, J=6 Hz), 3.17 (2H, d, J=5 Hz), 3.12 (3H, s), 2.82 (3H, s), 0.83 (6H, s); HRMS calcd for C25H29FN4O5+H+: 485.2200. Found: 485.2188.
Reaction SMILES: ClC1[CH:10]=[CH:9][C:5](C(O)=O)=[CH:4][N:3]=1.O(C1C=CC(CCN)=CC=1)C1C=CC=CC=1.Cl[C:28]1[CH:51]=[CH:50][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:39][CH:38]=2)=[O:33])=[CH:30][N:29]=1.N1CCCCC1>>[O:43]([C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][NH:34][C:32](=[O:33])[C:31]2[CH:50]=[CH:51][C:28]([N:3]3[CH2:4][CH2:5][CH2:9][CH2:10]3)=[N:29][CH:30]=2)=[CH:38][CH:39]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=C(NCCc1ccc(Oc2ccccc2)cc1)c1ccc(Cl)nc1
Agent: NCCc1ccc(Oc2ccccc2)cc1
Solvent: C1CCNCC1
Product: O=C(NCCc1ccc(Oc2ccccc2)cc1)c1ccc(N2CCCC2)nc1

Procedure:
In analogy to example 21, 6-chloro-nicotinic acid was coupled with 4-phenoxyphenethylamine. The intermediate 6-chloro-N-[2-(4-phenoxy-phenyl)-ethyl]-nicotinamide was reacted with piperidine. White solid. MS (ISP): 388.3 ([M+H]+)
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[O:5].C(O)(C)(C)C>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[CH2:3][C:4]1([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)[OH:5]
Reactant: CC(C)CC(=O)c1cnccn1
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Product: CC1(C)CC1(O)c1cnccn1
Reaction time: 40 h

Procedure:
A solution of 3-methyl-1-(pyrazin-2-yl)butan-1-one (1.0 g, 6.1 mmol) in 120 mL of a 19/1 mixture of tert-butanol and benzene was irradiated using a 6 W 366 nm lamp (TLC lamp) in a pyrex glass tube. The conversion was 50% after 16 h and 80% after 40 h. At this point the volatiles were removed in vacuo and the material was purified by column chromatography (silica, EtOAc/heptanes 1/4) to afford 2,2-dimethyl-1-(pyrazin-2-yl)cyclopropanol as a reddish-brown oil (375 mg; 38%). 1H NMR (CDCl3) 0.90 (3H, s), 1.00 (2H, d), 1.40 (2H, s), 3.20 (1H, s), 8.42 (1H, m), 8.50 (1H, m), 8.76 (1H, m).