Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][O:33][C:34](=[O:44])[C:35]([CH3:43])=[CH:36][CH:37]([NH:41][CH3:42])[CH:38]([CH3:40])[CH3:39]>C(Cl)Cl>[CH3:32][O:33][C:34](=[O:44])[C:35]([CH3:43])=[CH:36][CH:37]([N:41]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH3:42])[CH:38]([CH3:40])[CH3:39]
Reactant: CNC(C=C(C)C(=O)OC)C(C)C
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(C)C(C=C(C)C(=O)OC)C(C)C)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 2,5-dimethyl-4-methylamino-hex-2-enoic acid methyl ester (86 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 630 (M+).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:10]=[C:9]([C:11]([NH2:13])=[O:12])[C:8]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[N:7][C:6]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-])=O)[CH:30]=1)([CH3:4])[CH3:3].O1CCCC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(C)C.O.CO>[NH2:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[O:28][C:6]1[N:7]=[C:8]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[CH:19][CH:20]=2)[C:9]([C:11]([NH2:13])=[O:12])=[N:10][C:5]=1[C:2]([OH:1])([CH3:3])[CH3:4]
Reactant: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)c(C(C)(C)O)nc3C(N)=O)cc2)CC1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CO
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc(N)c4)c(C(C)(C)O)nc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
To a mixture of 6-(2-hydroxypropan-2-yl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (300 mg), tetrahydrofuran (6 mL), and methanol (12 mL) were added sodium dithionite (1.03 g), sodium hydrogen carbonate (993 mg), and water (13.5 mL), followed by stirring at room temperature for 30 minutes, and then stirring at 50° C. for 2 hours. To the reaction mixture was added chloroform-isopropanol (4:1), and then the organic phase was washed with water. The organic phase was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH2 type, eluent; chloroform:methanol:28% aqueous ammonia=50:1:0.1-20:1:0.1) to obtain 5-(3-aminophenoxy)-6-(2-hydroxypropan-2-yl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (27 mg) as a yellow solid.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:50]([O:59][C:60]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[C:51]3[C:55](=[CH:56][CH:57]=4)[N:54]([CH3:58])[N:53]=[CH:52]3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:50]([O:59][C:60]=3[C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)=[C:51]3[C:55](=[CH:56][CH:57]=4)[N:54]([CH3:58])[N:53]=[CH:52]3)=[CH:43][CH:42]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: Cn1ncc2c3oc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(=O)c3ccc21
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: Cn1ncc2c3oc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)c(=O)c3ccc21
Yield: 84 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(7-methyl-4-oxo-2-phenyl-4,7-dihydro-pyrano[2,3-e]indazol-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (28 mg, 84%). 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J=1.0 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.76 (dd, J=1.0 and 8.8 Hz, 1H), 7.52-7.48 (m, 2H), 7.45-7.34 (m, 5H), 7.20-7.16 (m, 2H), 4.17 (s, 3H), 2.45-2.36 (m, 2H), 2.20-2.11 (m, 2H), 2.07-1.96 (m, 1H), 1.73-1.61 (m, 1H). LCMS (Method E): RT=3.33 min, [M+H]+=422.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1F)[C:13]([O:15]C)=[O:14])#[N:9].[Li+].[OH-]>CN(C=O)C.O>[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])[C:13]([OH:15])=[O:14])#[N:9]
Reactant: CC1CCCCN1
Reactant: COC(=O)c1ccc(F)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCCN1c1ccc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
2-Methylpiperidine (744 mg; 7.5 mmol; 5 eq.) was added to a solution of methyl 3-cyano-4-fluorobenzoate (269 mg; 1.5 mmol; 1 eq.) in DMF (2 mL) and the resulting mixture was stirred at room temperature for 2 days. The solution was partitioned between ethyl acetate and water and the phases separated. The organic layer was washed with HCl 0.1M then brine, dried over magnesium sulfate and concentrated in vacuo. The residue was taken up in THF (5 mL) and LiOH (126 mg; 3 mmol; 2 eq.) then water (5 mL) were added and the reaction mixture was stirred at room temperature for 5 hours. The resulting solution was diluted with water and washed with Et2O. The aqueous layer was acidified to pH 2 with HCl 0.1M and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (294 mg, 80%) as an off-white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:29]1[CH2:31][C@@H:30]1[CH2:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[N:40]=[CH:39][CH:38]=[CH:37]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:31][C@@H:30]([OH:29])[CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[N:40]=[CH:39][CH:38]=[CH:37]4)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Reactant: c1cnc2ccc(OC[C@H]3CO3)cc2c1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C[C@@H](O)COc2ccc3ncccc3c2)CC1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (100.0 mg; 0.264 mmol) is dissolved in ethanol (10 mL) at ambient temperature. (R)-6-Oxiranylmethoxy-quinoline (89) (53.0 mg; 0.264 mmol) is added, then the mixture is refluxed for 17 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (70%→90% ethyl acetate in hexanes, then 50%→70% acetone in hexanes) affording the desired product (50 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([NH:23]N)=[O:22])=[C:10]2[CH2:25][CH3:26])[CH:5]=[CH:6][CH:7]=1>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([NH2:23])=[O:22])=[C:10]2[CH2:25][CH3:26])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(CC(=O)NN)c2cc(OC)ccc2n1Cc1cccc(Cl)c1
Agent: [Ni]
Solvent: CCO
Product: CCc1c(CC(N)=O)c2cc(OC)ccc2n1Cc1cccc(Cl)c1
Yield: 74.3 %

Procedure:
A mixture of 340 mg (0.92 mmol) of 1-[(3-chlorophenyl)methyl]-2-ethyl-5-methoxy-1H-indole-3-acetic acid hydrazide and 200 mg of Raney Ni in 20 mL of ethanol was heated to maintain reflux for 2.5 hours. After cooling the solvent was decanted and the Raney Ni washed twice with methylene chloride. The combined organic solvents were filtered, concentrated at reduced pressure and the residue chromatographed on silica gel eluting with ethyl acetate to give 244 mg (74% yield) of 1-[(3-chlorophenyl)methyl]-2-ethyl-5-methoxy-1H-indole-3-acetamide.
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][C:17]1[CH:21]=[CH:20][O:19][CH:18]=1)=[N+:14]=[N-:15]>>[ClH:1].[O:19]1[CH:20]=[CH:21][C:17]([CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)=[CH:18]1
Reactant: [N-]=[N+]=NCc1ccoc1
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCCc2cn(Cc3ccoc3)nn2)c[nH]1
Yield: 58.1 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.063 g, 0.340 mmol) was reacted with 3-azidomethyl-furan (0.050 g, 0.406 mmol) following the general procedure for click reactions outlined above to produce 4-[3-(1-Furan-3-ylmethyl-1H-[1,2,3]triazol-4-yl)-propyl]-1Himidazol-2-ylamine hydrochloride (0.061 g, 58%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.70 (s, 1H), δ 7.56 (s, 1H), δ 7.41 (s, 1H), δ 6.44 (s, 1H), δ 6.35 (s, 1H), δ 5.35 (s, 2H), δ 2.65 (t, 2H), δ 2.45 (t, 2H), δ 1.86 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.3, 147.3, 144.2, 141.6, 127.2, 122.1, 120.2, 109.9, 108.8, 44.7, 27.8, 24.2, 23.6 ppms; HRMS (ESI) calcd for C13H16N6O (M+) 272.1458. Found 272.1462.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([N:29]3[CH:33]=[C:32]([C:34]([O:36]CC)=[O:35])[CH:31]=[N:30]3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[OH-].[Na+].Cl>C(#N)C>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([N:29]3[CH:33]=[C:32]([C:34]([OH:36])=[O:35])[CH:31]=[N:30]3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: CCOC(=O)c1cnn(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: C[C@@H]1CN2c3c(cc4c(-n5cc(C(=O)O)cn5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of ethyl 1-[(2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidin]-8-yl]-1H-pyrazole-4-carboxylate (Example 37, 100 mg, 0.19 mmol) in acetonitrile (0.5 mL) was added 5% NaOH solution (14 mg, 0.11 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified to pH ˜7 using 1.5 N HCl and extracted with EtOAc (5×10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give product as yellow solid. Yield: 45 mg
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].ClC(OC(Cl)C)=O>>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N(C(=O)NC2CCCN(Cc3ccccc3)C2)C2CCCCCC2)c1
Agent: CC(Cl)OC(=O)Cl
Product: N#Cc1cccc(N(C(=O)NC2CCCNC2)C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 104.8 %

Procedure:
A mixture of N-(3-cyanophenyl)-N'-((N-benzyl)piperidin-3-yl)cycloheptyl-urea (prepared in Example 60, 2.7 g, 6.98 mmol) and α-chloroethyl chloroformate (1.09 g, 7.65 mmol) was stirred at ambient temperature for 2.5 h, whereupon the reaction was complete as judged by TLC. The solvent was removed by evaporation in vacuo and was replaced with methanol (40 mL). The reaction was heated at reflux until all of the newly formed intermediate was consumed as indicated by TLC. Evaporation of the solvent gave 2.49 g of N-(3-cyanophenyl)-N'-(piperidin-3-yl)cycloheptylurea; LRMS (M+H)+ m/z=299.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[O:21][C:20]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.C(N(CC)CC)C>CO.[Pd]>[CH3:26][N:25]([CH3:27])[C:23]([C:20]1[O:21][C:22]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][CH:16]=[CH:17][C:18]=2[CH:19]=1)=[O:24]
Reactant: CN(C)C(=O)c1cc2cccc(N3CCN(Cc4ccccc4)CC3)c2o1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Reaction time: 3 h
Yield: 88.1 %

Procedure:
The reaction mixture of 7-(4-benzylpiperazin-1-yl)-N,N-dimethylbenzofuran-2-carboxamide (0.70 g, 1.93 mmol) and acetic acid (0.44 mL, 7.70 mmol) in methanol (30 mL) was debenzylated in a H-cube for 3 h at 50° C. using Catcart 30 Pd/C cartridge. Triethylamine (1.1 mL, 7.9 mmol) was added and the solvent was removed in vacuo. The crude material was purified by flash chromatography (SiO2; DCM/MeOH; gradient 0-10%) to give 0.47 g (1.70 mmol) of product in 88% yield.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:36])[CH:13]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([F:37])[CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:38])=[O:3])=[CH:6][C:7]=3[F:37])=[O:36])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[CH:27]3)=[N:22]2)=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)C(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 7.2, 4-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid ethyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as yellow oil. MS: m/e=506.2 [M+H+].
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:17][O:18][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:5])([CH3:7])[CH3:6]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)Cc1ccccc1
Temperature: 0 °C

Procedure:
500 mg (1.99 mmol) of N-Boc-L-phenylalaninol were dissolved in 5 ml DMF and cooled down to 0° C. under argon atmosphere. Then 159 mg (3.98 mmol) of a 60% suspension of sodium hydride was added in liquid paraffin. The reaction composition then was stirred until completion of gas formation and then mixed with 260 μl (2.19 mmol) of benzyl bromide. The cooling bath was removed and the reaction composition stirred for 2 hours at RT. Afterwards, the batch was evaporated, the residue absorbed in ice water and the composition extracted with dichlormethane. The organic phase was washed with saturated saline, dried over magnesium sulphate and evaporated. The residue was purified by means of a preparative HPLC. The yield was 226 mg (33% o. th.) of the title compound.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=O)[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>O1CCOCC1.C(OCC)(=O)C>[CH:3]1[C:4]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:44])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=4)[CH:21]=3)[C:5]=2[CH:11]=[CH:1][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1csc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)n1

Procedure:
A mixture of the product of step (iv) (2.1 g) and Lawesson's reagent (1.78 g) in dry 1,4-dioxane (36 ml) was heated at reflux for 16 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 50% ethyl acetate in isohexane. Yield 1.5 g.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5].[C:19]([O-:22])(=[O:21])[CH3:20].[K+]>CN(C=O)C>[C:19]([O:22][CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5])(=[O:21])[CH3:20]
Reactant: CC(=O)[O-]
Reactant: CC(O)(CCCl)c1ccccc1-c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCC(C)(O)c1ccccc1-c1ccccc1
Reaction time: 3 h

Procedure:
2.6 g. of 1-chloro-3-p-biphenylyl-3-butanol (obtainable from p-biphenylylmagnesium bromide and 1-chloro-3-buranone) are dissolved in 20 ml. of DMF, 3 g. of anhydrous potassium acetate are added and the mixture is stirred for 3 hours at 60°. After standard working up, 1-acetoxy-3-p-biphenylyl-3-butanol is obtained.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[C:26]([O:32][CH3:33])=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1>>[Cl:31][C:29]1[CH:30]=[C:25]([C:20]2([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][C:13]34[CH2:15][CH:6]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=53)[C:5]3[C:14]4=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19]2)[C:26]([O:32][CH3:33])=[N:27][CH:28]=1
Reactant: COc1ncc(Cl)cc1Br
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: COc1ncc(Cl)cc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 25 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromo-5-chloro-2-methoxypyridine, the title compound was formed in 25% yield as a white solid, mp 195°-200 C, (dec). free base: 1H NMR (CDCl3, 250 MHz) 7.99 (d, J=2.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.20 (m, 4H), 6.93 (m, 4H), 4.27 (s, 1H), 3.99 (s, 3H), 3.58 (s, 1H), 3.47 (s, 2H), 2.82 (m, 4H), 2.60 (d, J=0.8 Hz, 2H), 2.00 (m, 4H) MS (CI, CH4) m/z 447 (M+1,100), 475 (M+29,18), 429 (34), 449 (36) hydrochloride salt:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([C:11]([NH:13][C@@H:14]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[O:12])[CH2:10][CH2:9]1>C(Cl)Cl>[NH:16]1[CH2:17][CH2:18][C@@H:14]([NH:13][C:11]([CH:8]2[CH2:9][CH2:10]2)=[O:12])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)C2CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CCNC1)C1CC1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
TFA (1 mL) was added to a solution of (R)-tert-butyl 3-(cyclopropanecarboxamido)pyrrolidine-1-carboxylate (500 mg, 1.96 mmol) in 5 mL CH2Cl2. After stirring for 30 min, the reaction was quenched with 1M NaOH solution till neutral and extracted twice with EtOAc. The organic extracts were combined, dried over MgSO4, filtered, and concentrated to yield N—((R)-pyrrolidin-3-yl)cyclopropanecarboxamide (250 mg) which was used without further purification. LC/MS: m/z 155.3 (M+H)+ at 0.6 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C[N:2]1[C:6]([CH3:7])=[N:5][C:4]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])[N:16]=[C:10]3[CH:9]=2)=[N:3]1.Cl.N([O-])=O.[Na+].N[C:29](N)=O.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[CH3:29][N:3]1[C:4]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])[N:16]=[C:10]3[CH:9]=2)=[N:5][C:6]([CH3:7])=[N:2]1
Reactant: CCNC(=O)Nc1cn2ccc(-c3nc(C)n(C)n3)cc2n1
Reactant: NC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCNC(=O)Nc1cn2ccc(-c3nc(C)nn3C)cc2n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A mixture of finely powdered amine (5) (4.00 g, 0.014 mol) and 4 N hydrogen chloride (400 mL) was stirred vigorously at 23° C. for 30 min, by which time the hydrochloride salt had precipitated out as a yellow solid. The mixture was cooled to 5° C. and a solution of sodium nitrite (1.46 g, 0.021 mol) in water (5 mL) was added drop wise. The mixture was stirred at this temperature for 30 min, then urea (0.59 g, 9.91 mmol) was added. The mixture was stirred at 23° C. for a further 1 h, then basified by portion wise addition of solid sodium bicarbonate. ethyl acetate was added and the mixture was stirred vigorously for 30 min, then filtered through Celite to remove insoluble black material. The ethyl acetate layer was worked up, adsorbed onto silica and chromatographed. Ethyl acetate eluted foreruns, while ethyl acetate/methanol (95:5) gave the chloride (6) as a solid (1.21 g). APCI-MS Found: [M+H]+=304, 302.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]2[N:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1>C(#N)C>[Br:29][C:17]1[C:18]([NH2:21])=[N:19][CH:20]=[C:15]([CH:11]2[CH2:12][CH2:13][CH2:14][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:10]2)[N:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@@H](c2cnc(N)cn2)C1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC1CCCC(c2cnc(N)c(Br)n2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-((1R,3S)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-amine (110 mg, 0.358 mmol) in acetonitrile (5.50 mL) was added NBS (66.9 mg, 0.376 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. After quenched with sat sodium thiosulfate and sat NaHCO3, extracted with EtOAc three times. The organic layers were combined and washed with brine, dried over Na2SO4, filtered and concentrated to afford 138 mg of desired cis racemate compound, which was used as it was. LCMS (m/z): 388 (MH+), 0.72 min.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([CH:13]=[O:14])=[CH:11][N:10]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.S(=O)(=O)([OH:25])N.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+]>O1CCOCC1.O>[CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([OH:25])=[O:14])=[CH:11][N:10]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]3=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: NS(=O)(=O)O
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(C3CC3)cnc21
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (0.24 g, 0.75 mmol) in 1,4-dioxane (10 mL) and water (2 mL) at 0° C. was added sulfamic acid (0.44 g, 4.54 mmol). Then added dropwise a solution of sodium chlorite (0.09 g, 0.98 mmol) and potassium dihydrogen phosphate (1.22 g, 9.0 mmol) in 6 mL of water. After the addition, the reaction mixture was warmed to room temperature and stirred for 2 h then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with hexanes to obtain 0.22 g (87%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid as a light yellow powder.