Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[O:51][CH3:52])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][N:43]([CH2:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[O:51][CH3:52])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(CBr)C(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1CNC[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1CN(CC(=O)C(c1ccccc1)c1ccccc1)C[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
3-Bromo-1,1-diphenyl-2-propanone (12.7 g) and N,N-diisopropylethylamine (15.7 ml) were added successively to a solution of (2S)-2-[(2-methoxybenzylamino)methyl]pyrrolidine-1-carboxylic acid benzyl ester (15.6 g) in tetrahydrofuran (156 ml) at 0° C. After being stirred at room temperature for 2 hours, the mixture was poured into ice-water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (3:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give a colorless syrup of (2S)-2-[[N-(2-oxo-3,3-diphenylpropyl)-N-(2-methoxybenzyl)amino]methyl]pyrrolidine-1-carboxylic acid benzyl ester (1.51 g).
Reaction SMILES: O=C1CCC(=O)C1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[OH:25]>CO>[OH:25][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[NH:18][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)C1C(=O)OCc1ccccc1
Reactant: NC1CCCCC1O
Solvent: CO
Product: O=C(NC1CCCCC1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
At 0° C. to a solution of benzyl 2,5-dioxocyclopentanecarboxylate (2.58 g, 10.35 mmol) in MeOH (20 mL) was added 2-aminocyclohexanol (1.25 g, 10.87 mmol). The reaction mixture was stirred at room temperature for 18 h and quenched with 0.25 N HCl (8 mL). MeOH was removed under vacuum and the aqueous layer was extracted with CH2Cl2 (4×10 mL). The combined organic layers were washed with sat. NaCl (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO chromatography (40 g column) using hexanes/EtOAc (0-5% over 15 min, 5-10% over 7 min) to give benzyl 2-hydroxycyclohexylcarbamate as a light yellow solid at a retention time of 11-13 min (2.15 g, 83% yield). HPLC: RT=2.83 min, Purity 95% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm) NMR: 400 MHz 1H (CDCl3) 7.33 ppm, 5H, m; 5.16 ppm, 1H, m; 5.09 ppm, 2H, s; 3.95 ppm, 1H, s; 3.68 ppm, 1H, m; 1.54 ppm, 8H, m.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([O:16][C:17]([N:19]([CH3:23])[CH2:20][CH2:21]O)=[O:18])([CH3:15])([CH3:14])[CH3:13].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:12]([O:16][C:17]([N:19]([CH2:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:23])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCCN(C)C(=O)OC(C)(C)C)c1
Reaction time: 18 h
Yield: 72.3 %

Procedure:
Methyl 3-hydroxybenzoate (6.4 g, 42 mmol), alcohol 121a (7.4 g, 42 mmol), diisopropyl azodicarboxylate (8.3 mL, 42 mmol), and triphenylphosphine (11.1 g, 42 mmol) were stirred in dry THF (120 mL) at 0 ° C. for 1 h, then for 18 h at room temperature. After evaporation of solvent, the product was isolated by chromatography on silica gel, eluting with 0% to 30% EtOAc in hexane to yield a clear oil (9.4 g). IR(film) cm-1 1726, 1696. 1H NMR(300 MHz, CDCl3): 7.64-7.09 (m, 4H), 4.13 (m, 2H), 3.92 (s, 3H), 3.62 (br, 2H), 2.99 (s, 3H), 1.46 (s, 9H). Anal. Cald'd for C16H23NO5 : C, 62.11; H, 7.51; N, 4.53; Found: C, 61.67; H, 7.43; N, 4.47. HR-MS: Calc'd. 310.1654, Found 310.1650.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.C1C(=O)N([Br:20])C(=O)C1>C(#N)C.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][C:7]=1[Br:20]
Reactant: CCOC(=O)c1cnc(N)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(N)c(Br)n1
Yield: 78 %

Procedure:
To a solution of ethyl 5-aminopyrazine-2-carboxylate (880 mg, 5.26 mmol) in acetonitrile (20 mL) at RT was added NBS (984 mg, 5.53 mmol), the resultant solution was stirred at RT for 1 hour. The reaction mixture was diluted with EtOAc, washed with sat NaHCO3, brine and water, dried, filtered, and concentrated to afford the crude product, which was purified by ISCO 24 g silica gel column, 0 to 50% EtOAc in Heptane, 30 min). 1.01 g, 78% yield. LC-MS (m/z): 247.9 (MH+), 0.51 min.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=3[C:33]3[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=[O:40])=[N:37][CH:38]=3)=[CH:17][CH:16]=2)=[C:11]([CH3:49])[CH:10]=1>CO>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][C:24]=3[C:33]3[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:40])=[N:37][CH:38]=3)=[CH:17][CH:16]=2)=[C:11]([CH3:49])[CH:10]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3C)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2-c2ccc(C(=O)NCCC(=O)O)nc2)cc1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.10 mL, 0.30 mmol) was added to a THF (4 mL) and MeOH (2 mL) solution of ethyl 3-(5-(2-(((4′-chloro-2′-methyl-[1,1′-biphenyl]-4-yl)amino)methyl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (60 mg, 0.10 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off, dried in vacuo, and purified via HPLC to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.N1C=CC=CC=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>CN(C=O)C>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[CH2:7][CH2:8]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1cccc2c1NCC2
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc2ncnc(N3CCc4cccc(C)c43)c2cc1OC
Yield: 65 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 65% yield from 7-methyl-indoline (1 eq.), pyridine (2 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in DMF. (M.P. 146°-147° C.; GC-MS: 321 (M+); anal. RP18-HPLC RT: 4.41 min.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)[C:5]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35](=[O:40])[CH2:34][CH2:33]2>C(O)CCC>[NH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]2[C:5]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[CH:4][N:3]=[C:2]([NH:29][C:30]3[CH:31]=[C:32]4[C:37](=[CH:38][CH:39]=3)[NH:36][C:35](=[O:40])[CH2:34][CH2:33]4)[N:7]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)ncc2-c2ccncc2)CC1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Solvent: CCCCO
Product: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2-c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (1-(2-chloro-5-(pyridin-4-yl)pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (80 mg, 0.20 mmol) and 6-amino-3,4-dihydroquinolin-2(1H)-one (50 mg, 0.30 mmol) in nBuOH (3 mL) was stirred at 116° C. for 20 h. It was concentrated in vacuo. The residue was dissolved in TFA (4 mL). After being stirred at room temperature for 30 min, TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound. MS 430.4 (M+H); UV 207.7, 264.5 nm.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][C:25]([O:27]CC)=[O:26])=[N:16]3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].O.[OH-].[Li+].O.Cl>O1CCCC1>[C:1]([C:3]1[CH:33]=[CH:32][C:6]([C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][C:25]([OH:27])=[O:26])=[N:16]3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(C#N)cc3)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)Nc2ccc(Cn3nc(CC(=O)O)c4ccccc43)cc2)cc1
Yield: 60.9 %

Procedure:
Ethyl 2-[1-[4-(4-cyanobenzamido)benzyl]-1H-indazol-3-yl]acetate (121 mg, 0.276 mmol) was dissolved in tetrahydrofuran (20 mL), and in an ice bath 10 mL aqueous solution dissolving lithium hydroxide monohydrate (58 mg, 1.38 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried, and the resulting solid was recrystallized from ethyl acetate to obtain a white solid 69 mg, at a yield of 60.9%.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.C([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])C>O1CCCC1>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=[C:2]1[N:18]1[C@@H:19]2[CH2:20][CH2:10][CH2:4][CH2:5][C@H:6]2[O:9][CH2:22][CH2:21]1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCO[C@@H]3CCCC[C@H]32)nc(-c2ccncn2)cc1=O
Yield: 128.1 %

Procedure:
A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.34 g, 1.53 mmol), (4aRS,8bRS)-trans-octahydrobenzo[1,4]oxazine hydrochloride (0.3 g, 1.69 mmol) and triethylamine (0.5 g, 4.94 mmol) in tetrahydrofuran (20 ml) was stirred for 10 hours at 100° C. The solution was partitioned between water and chloroform, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 1-methyl-2-((4aRS,8aRS)-trans-octahydro-benzo[1,4]oxazin-4-yl)-1H-[4,4′]bipyrimidinyl-6-one (0.32 g, 0.98 mmol, 64%) as white crystals.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C@@H:9]2[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@@H:8]2[CH2:7]1)=O)C.[OH-].[Na+]>C(O)C>[C:13]1([C@@:9]23[O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C@@H:8]2[CH2:7][NH:6][CH2:11][CH2:10]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)N1CC[C@@H]2Oc3ccccc3[C@@H]2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc([C@]23CCNC[C@H]2c2ccccc2O3)cc1
Yield: 150.4 %

Procedure:
To a solution of 3.56 g of cis-2-ethoxycarbonyl-1,2,3,4,4a,9b-hexahydro-benzofuro[3,2-c]pyridine in 42 ml of absolute ethanol was added 28 ml of 20% aqueous NaOH solution. The resulting mixture was heated at reflux under nitrogen for 32 hours. Most of the ethanol was removed in vacuo. The residue was diluted with 50 ml of water and extracted with methylene chloride (2×100 ml). There were initially some problems with emulsions. The combined extracts were dried over anhydrous Na2SO4 and evaporated in vacuo to give 2.72 g (98.4%) of crystalline solid. Recrystallization from hexane afforded 1.98 g (71.6%) of crystals, m.p. s 91, 95°-98°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:27])[N:18]=[C:19]([CH2:20][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:22][CH3:23])[N:12]2[N:11]=1)[CH3:2].[S:28]([Cl:32])(=O)(=[O:30])[OH:29].S(Cl)(Cl)(=O)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:28]([Cl:32])(=[O:30])=[O:29])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:27])[N:18]=[C:19]([CH2:20][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:22][CH3:23])[N:12]2[N:11]=1)[CH3:2]
Reactant: CCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Reactant: O=S(=O)(O)Cl
Solvent: O=S(=O)(Cl)Cl
Product: CCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 300 mg (0.81 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-(2-n-propylbutyl)-3H-imidazo[5,1-f][1,2,4]-triazin-4-one (Example 25A) and 950 mg. (8.1 mmol) of chlorosulphuric acid. This gives 300 g (78.9%) of sulphonyl chloride which is directly reacted further.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][N:17]=2)[C:8]([C:18]([N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:21]2[CH2:26][C@@H:25]([C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[ClH:52]>>[ClH:52].[ClH:52].[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][N:17]=2)[C:8]([C:18]([N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:21]2[CH2:26][C@@H:25]([C:27]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[O:28])[CH2:24][NH:23][CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ncco1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ncco1)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(1,3-oxazol-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (108 mg) was dissolved in 2 M hydrogen chloride-ethyl acetate (2 ml), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, ethyl acetate was added and the precipitate was collected by filtration and washed with ethyl acetate to give the object compound (85 mg).
Reaction SMILES: [N:1]1([CH2:6][C:7]23[CH2:15][CH:11]4[CH2:12][CH:13]([CH2:14]2)[C:9](C(O)=O)([CH2:10]4)[CH2:8]3)[CH:5]=[N:4][CH:3]=[N:2]1.OS(O)(=O)=O.[N-:24]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[N:1]1([CH2:6][C:7]23[CH2:15][CH:11]4[CH2:12][CH:13]([CH2:14]2)[C:9]([NH2:24])([CH2:10]4)[CH2:8]3)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C12CC3CC1CC(Cn1cncn1)(C3)C2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC12CC3CC1CC(Cn1cncn1)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a stirred suspension of 1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.03,7]nonane-3-carboxylic acid (0.13 g, 0.52 mmol) obtained in step III, in CHCl3 (2.6 mL) was added conc. H2SO4 (0.25 mL, 5.2 mmol). To this homogenous solution NaN3 (0.1 g, 1.56 mmol) was added in portions over a period of 30 minutes, while keeping the temperature of the reaction below 40° C. After stirring the reaction mixture for 2 h at r.t., the reaction mixture was cooled to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified by adding 50% aq. NaOH solution and extraction with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure to obtain 1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.03,7]nonan-3-amine (0.08 g) as a viscous liquid in 70% yield. m/z (M+1) 219; 1H NMR (CDCl3) 300 MHz δ 7.98 (s, 1H), 7.93 (s, 1H), 4.07 (s, 2H), 2.38-2.30 (m, 1H), 2.06-1.98 (m, 1H), 1.96-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.55-1.36 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:12]#[C:11][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: C#Cc1ccccn1
Reactant: Cc1nc(N)nc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(Cl)c1C#Cc1ccccn1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.5 g (5.6 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 0.84 mL (8.4 mmol) 2-ethynyl-pyridine using 106 mg (0.57 mmol) CuI, 390 mg (0.56 mmol) PdCl2(PPh3)2 and 7.8 mL (56 mmol) triethylamine in 10 mL dry DMF. Additional amounts are added after 24 h and 48 h reaction time, respectively. For the work-up the solvent is removed in vacuo and the product is purified by chromatography on silica gel using a DCM/MeOH gradient. Yield: 2.0 g (>100%, approximately 70% pure).
Reaction SMILES: C=O.[BH3-][C:4]#[N:5].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16]([N:18]2[CH:27]3[CH:22]([CH2:23][CH2:24][CH2:25][CH:26]3[N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)N[CH2:20][CH2:19]2)=[O:17])[CH:11]=[CH:12][C:13]=1[Cl:14].C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16]([N:18]2[CH:27]3[CH:22]([CH2:23][CH2:24][CH2:25][CH:26]3[N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:5]([CH3:4])[CH2:20][CH2:19]2)=[O:17])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: [BH3-]C#N
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C1CCCC2N1CCCC1
Reaction time: 1.5 h

Procedure:
Formalin (37%, 223 mg, 2.7 mmol) was dissolved in 5 ml of MeOH and NaBH3CN (17.2 mg, 0.27 mmol) was added. The pH was adjusted to 5 with concentrated acetic acid. 2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (109 mg, 0.27 mmol), dissolved in MeOH (15 ml), was then added to the mixture and the mixture was stirred for 1.5 hours. After addition of saturated Na2CO3 solution (12 ml), the mixture was stirred at room temperature for 15 minutes. The precipitate formed was filtered off and MeOH was evaporated off from the filtrate under 100 mbar. The aqueous phase was extracted by shaking five times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.05, l=16 cm, V=5 ml). A yellowish resin was isolated.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@:8]3([OH:24])[CH2:9][CH2:10][C@@H:11]2[CH2:12][C:13]#N)[CH2:3]1.[O:25]1CCCC1>[AlH](CC(C)C)CC(C)C.CCCCCC>[OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@:8]3([OH:24])[CH2:9][CH2:10][C@@H:11]2[CH2:12][CH:13]=[O:25])[CH2:3]1
Reactant: C1CCOC1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](CC#N)CC[C@]12O
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](CC=O)CC[C@]12O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.50 g of 3β,14β-dihydroxy-5β-pregnane-21-nitrile in 500 ml of dry tetrahydrofuran, 105 ml of 1M i-Bu2AlH in hexane were added dropwise under nitrogen at 0° C. After 1 hr the reaction was quenched with aqueous citric acid (7.05 g in 32.5 ml of water) and stirred at room temperature for 1 hr. The mixture was then filtered through Celite and washed with ethyl acetate. The organic solution was dried over anhydrous sodium sulfate and evaporated to dryness to give 6.05 g of the title compound (II-b) partially in the internal hemiacetal form, as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10]O.Cl.[Na+].[I-].O>C(#N)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(F)cc1
Temperature: 30 °C
Yield: 77.4 %

Procedure:
To a solution of 4-fluoro benzaldehyde (8 g, 64 mmol) in acetonitrile (100 mL) was added NH2OH.HCl (5.78 g, 83 mmol) and NaI (4.8 g, 32 mmol) with stirring. The mixture was then stirred for 7 hours at refluxing temperature, cooled at the temperature in the range of 20-40° C., poured into water (200 mL) and extracted with EtOAc (2×250 mL). The organic layers were collected, combined, washed with brine solution, dried over anhydrous Na2SO4 and concentrated under vacuum to give the 4-fluoro-benzonitrile (6.0 g, 76% yield).
Reaction SMILES: C([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[CH:15]=[N:16][C:17]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[CH:19]=3)=[C:7]2[C:6]1=[O:24])(C)(C)C.O>C(O)C.Cl>[CH3:23][C:20]1[CH:19]=[C:18]([C:17]2[N:16]=[CH:15][N:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[NH:5][C:6](=[O:24])[C:7]=23)[O:22][N:21]=1
Reactant: Cc1cc(-c2ncn3c2c(=O)n(C(C)(C)C)c2ccccc23)on1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2ncn3c2c(=O)[nH]c2ccccc23)on1
Temperature: 25 °C

Procedure:
A stirred suspension of 5-tert-butyl-4,5-dihydro-3-(3methyl-5isoxazolyl)-4oxo-imidazo[1,5-a]quinoxaline (0.65 g) in a mixture of ethanol (10 ml) and 4 M hydrochloric acid (1 ml) was refluxed for 10 min. Then the mixture was cooled to room temperature and water (10 ml) was added. The precipitated product was collected by filtration and dried to give the title compound as a white solid, m.p. 393° C. (Compound 18).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]2)=[O:10])=[CH:24][CH:25]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
7.08 g (20.3 mmol) of t-butyl 4-(4-methoxycarbonylbenzoyl)piperazine-1-carboxylate was stirred in 40 ml of methanol and 40 ml of THF. 51 ml (51 mmol) of 1 N aqueous sodium hydroxide solution was added to the resultant solution, and they were stirred at 80° C. for 20 minutes. The reaction liquid was evaporated under reduced pressure and 1 N hydrochloric acid was added to the residue. After the extraction with ethyl acetate followed with the treatment in an ordinary manner, the title compound was obtained.