Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12C=C3N=C(C=C3)C=C3NC(C=C3)=CC3=NC(C=C3)=CC(N1)=CC=2.[NH2:25][C:26]1[CH:27]=[C:28]([C:32]2[C:33]3[NH:37][C:36]([C:38]([C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[C:39]4[N:67]=[C:42]([C:43]([C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)=[C:44]5[NH:60][C:47](=[C:48]([C:54]6[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=6)[C:49]6[CH:50]=[CH:51][C:52]=2[N:53]=6)[CH:46]=[CH:45]5)[CH:41]=[CH:40]4)=[CH:35][CH:34]=3)[CH:29]=[CH:30][CH:31]=1.[Br:74][CH2:75][C:76](Br)=[O:77]>>[Br:74][CH2:75][C:76]([NH:25][C:26]1[CH:27]=[C:28]([C:32]2[C:33]3[NH:37][C:36]([C:38]([C:68]4[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=4)=[C:39]4[N:67]=[C:42]([C:43]([C:61]5[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=5)=[C:44]5[NH:60][C:47](=[C:48]([C:54]6[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=6)[C:49]6[CH:50]=[CH:51][C:52]=2[N:53]=6)[CH:46]=[CH:45]5)[CH:41]=[CH:40]4)=[CH:35][CH:34]=3)[CH:29]=[CH:30][CH:31]=1)=[O:77]
Reactant: O=C(Br)CBr
Reactant: Nc1cccc(-c2c3nc(c(-c4ccccc4)c4ccc([nH]4)c(-c4ccccc4)c4nc(c(-c5ccccc5)c5ccc2[nH]5)C=C4)C=C3)c1
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Product: O=C(CBr)Nc1cccc(-c2c3nc(c(-c4ccccc4)c4ccc([nH]4)c(-c4ccccc4)c4nc(c(-c5ccccc5)c5ccc2[nH]5)C=C4)C=C3)c1

Procedure:
A porphyrin (5-(3-aminophenyl)-10,15,20-triphenylporphyrin is derivatized by reacting with excess bromoacetyl-bromide (dissolved in acetone containing sodium carbonate) to form (5-(3-bromoacetamidophenyl)-10,15,20-triphenylporphyrin. 10 μmol of the derivatized porphyrin and 10 mg of the scFv-4-helix bundle-cys are dissolved separately in 20 ml of dry dimethyl formamide. These two solutions are added over a period of 3 hours to 50 ml dry dimethyl formamide containing 25 mg sodium carbonate. These reactions are performed in the dark, under argon. The final product is scFv-4-helix bundle-cys with optimally conjugated porphyrins (scFv-4-helix bundle-cys/porphyrin). The scFv-4-helix bundle-cys/porphyrin is dialysed into PBS and concentrated as above.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:41][CH2:42][CH3:43])[C:34]=1[C:35]1[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[O:45]=[C:46]1[O:50][N:49]=[C:48]([C:51]2[CH:52]=[C:53]3[C:63](=[CH:64][CH:65]=2)[O:62][C:56]2([CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:55][C:54]3=[O:66])[NH:47]1>O.CN(C=O)C.CCN(CC)CC>[CH2:42]([O:41][C:33]1[CH:32]=[C:28]([C:29]([N:59]2[CH2:60][CH2:61][C:56]3([CH2:55][C:54](=[O:66])[C:53]4[C:63](=[CH:64][CH:65]=[C:51]([C:48]5[NH:47][C:46](=[O:45])[O:50][N:49]=5)[CH:52]=4)[O:62]3)[CH2:57][CH2:58]2)=[O:31])[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[C:34]=1[C:35]1[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=1)[CH3:43]
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3noc(=O)[nH]3)cc21
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnn(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4noc(=O)[nH]4)ccc2O3)cc(OCC)c1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (58 μL), HOBT (32 mg) and WSC hydrochloride (40 mg) were added to a DMF (4 mL) solution of 3,5-diethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (50 mg) and 6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (70 mg), and stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, and the solid was fully washed with water and ether. The solid was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 12.96 (1H, s), 8.21 (1H, d, J=4.0 Hz), 8.06 (1H, s), 8.00 (1H, dd, J=8.0, 4.0 Hz), 7.92 (1H, s), 7.30 (1H, d, J=8.0 Hz), 6.68 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.86 (3H, s), 3.64-3.20 (3H, m), 2.97 (2H, s), 2.10-1.75 (4H, m), 1.37 (6H, t, J=8.0 Hz). MS [M+H]+=574.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH:2]=[CH2:3].Cl.[C:20](=O)(O)[O-].[Na+]>CO>[CH3:20][O:17][C:16](=[O:18])[C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6]
Reactant: O=C([O-])O
Reactant: C=CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)OC

Procedure:
A solution of 0.06 mol of N-(allyloxycarbonyl)phenylalanine, prepared as described by H. Kunz and C. Unverzagt in Angew. Chem. Int. Ed. Engl., 1984, 23, 436-437, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, dried over MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(allyloxycarbonyl)phenylalanine methyl ester.
Reaction SMILES: [CH3:1][I:2].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]=1>C(#N)C.CC(C)=O>[I-:2].[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][C:6]=1[CH:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH2:13][N+:14]1([CH3:1])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CI
Reactant: Cc1ccc(O)c(C(CCN2CCCCC2)c2ccccc2)c1
Solvent: CC#N
Solvent: CC(C)=O
Product: Cc1ccc(O)c(C(CC[N+]2(C)CCCCC2)c2ccccc2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
Methyl iodide (3.42 g, 1.5 mL, 0.024 mol) was added to a solution of the free base 4-methyl-2-(1-phenyl-3-piperidin-1-ylpropyl)phenol of Example 30 (0.3 g, 0.97 mmol) in a mixture of acetonitrile (6 mL) and acetone (2 mL). The reaction mixture was stirred overnight at room temperature. The solution was concentrated to initiate precipitation of the resulting quaternary ammonium salt. The white precipitate was filtered out, washed with chloroform and diethyl ether and dried under vacuum to give 0.397 g (90%) of the title compound. Characterization of the obtained compound:
Reaction SMILES: [C:1](Cl)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:16]([O:20][C:21]([NH:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].O>C(Cl)Cl>[C:16]([O:20][C:21]([NH:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:1](=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC1CCCCN1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)N1CCCCC1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
To a stirred, cooled (0° C.) solution of 14.3 grams (61.4 mmol) of tridecanoyl chloride in 50 mL of methylene chloride was added 7.49 grams (61.3 mmol) of N,N-dimethylaminopyridine. The resulting suspension was stirred for 10 minutes and then 11.0 grams (51.3 mmol) of 2-[N-(tert-butoxycarbonyl)aminomethyl]piperidine in 50 mL of methylene chloride was added. The mixture was allowed to warm to room temperature while stirring overnight and poured into water. The aqueous layer was extracted with methylene chloride and the combined organic layers were washed with brine and dried over MgSO4. Solvent was removed at reduced pressure and the crude product was chromatographed on 250 grams of silica gel eluting with 25% ethyl acetate in hexane to provide 20.9 grams (99%) of N-(tert-butoxycarbonyl)-N-([1-(1-oxotridecyl)-2-piperidinyl]methyl)amine as a viscous orange oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:8][CH:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)[N:10]=2)[CH2:6]1)[CH3:3].N1CC[CH2:34]1>>[N:2]1([CH2:4][C@@H:5]2[CH2:6][C@H:7]([C:9]3[N:13]4[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]4=[C:11]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:20]=4)[N:10]=3)[CH2:8]2)[CH2:1][CH2:34][CH2:3]1
Reactant: C1CNC1
Reactant: CN(C)CC1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn23)C1
Product: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1C[C@@H](CN2CCC2)C1

Procedure:
Procedures for 3-(3-Dimethylaminomethyl-cyclobutyl)-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine were followed, replacing dimethylamine with azetidine, LC-MS (ES, Pos.): m/z 440 [MH+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([OH:34])=[O:33])=[C:30]([CH2:35][OH:36])[N:29]=[C:28]2[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:22][CH:21]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:41]([O:47][CH2:48]Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43].C(OCC)(=O)C>CN(C)C(=O)C.O>[C:41]([O:47][CH2:48][O:33][C:32]([C:31]1[N:27]([CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])=[CH:21][CH:22]=2)[C:28]([CH2:37][CH2:38][CH2:39][CH3:40])=[N:29][C:30]=1[CH2:35][OH:36])=[O:34])(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]
Reactant: CCCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(CO)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
350 mg of potassium carbonate were added to a solution of 552 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylic acid (prepared as described in Example 4) and 220 mg of pivaloyloxymethyl chloride in 7 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate and water, and the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate; the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 0.62 g of the title compound as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][CH:6]1[CH2:12][CH:11]2[NH:13][CH:8]([CH2:9][CH2:10]2)[CH2:7]1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C.[OH2:32]>CN(C)C=O>[C:4]([OH:32])(=[O:5])/[CH:14]=[CH:19]/[C:20]([OH:22])=[O:21].[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:13]1[CH:8]2[CH2:9][CH2:10][CH:11]1[CH2:12][CH:6]([O:5][C:4]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=1)[CH2:7]2)[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: O
Reactant: Clc1ccc(OC2CC3CCC(C2)N3)cc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C2CCC1CC(Oc1ccc(Cl)c(Cl)c1)C2
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 g of 3-(3,4-dichloro-phenoxy)-8-aza-bicyclo[3.2.1]octane in 75 ml of N,N-dimethylformamide was first added 1.8 ml of ethyl bromoacetate then 4.5 ml triethylamine. The reaction mixture was stirred overnight at room temperature, then poured into 200 ml of water. The mixture was extracted twice with 150 ml of diethyl ether, the organic phase was dried with sodium sulphate and evaporated into an oil. 5.5 g 94%. 1.5 g of the oil was dissolved in a mixture of ethyl acetate and methanol. The solution was added 0.5 g of fumaric acid and evaporated, the residue was trituated with diethyl ether. Yield 1.3 g 65% Mp. 127-130° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH2:11]([NH2:13])[CH3:12]>C1COCC1.CO.CCOC(C)=O>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([NH:13][CH2:11][CH3:12])=[N:6][CH:7]=1
Reactant: CCN
Reactant: COc1nc(Cl)ncc1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCNc1ncc(Br)c(OC)n1
Temperature: 0 °C
Reaction time: 66 h

Procedure:
To a solution of 5-bromo-2-chloro-4-methoxypyrimidine (Frontier Scientific, Logan, USA, 0.895 mmol) in THF (2.5 ml) cooled with an ice-bath was added a 2 M solution of ethylamine in MeOH (Aldrich, Buchs, Switzerland, 0.492 ml). The RM was stirred at 0° C. for 1 h and at rt for 66 h then the reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (CH2Cl2/iPrOH 0% to 6%) to give after evaporation of the fractions containing the title compound an off-white solid. (HPLC: tR 2.16min (Method A); M+H=232, 234 MS-ES)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:44][O:45][C:46](=[O:53])[CH2:47][CH2:48][NH:49][CH:50]([CH3:52])[CH3:51]>CN(C=O)C>[CH3:44][O:45][C:46](=[O:53])[CH2:47][CH2:48][N:49]([C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]([Cl:1])[CH:3]=1)[CH:50]([CH3:52])[CH3:51]
Reactant: COc1cc(Cl)cc(C(=O)O)c1
Reactant: COC(=O)CCNC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCN(C(=O)c1cc(Cl)cc(OC)c1)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.1 %

Procedure:
To a stirred solution of 3-chloro-5-methoxy-benzoic acid (0.932 g), TBTU (3.21 g) and in DMF (10 ml) was added DIPEA (1.73 ml) followed by 3-isopropylamino propionic acid methyl ester (0.871 g) after 10 min. The reaction mixture was stirred at room temperature for 48 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with further water and 2M aqueous sodium hydroxide, water and dried with brine and over sodium sulphate and concentrated under reduced pressure to give the title compound as a brown oil (1.6 g).
Reaction SMILES: C[I:2].[CH3:3][O:4][C:5]1[C:6]([O:23][CH3:24])=[C:7]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[CH:9]3[CH2:10][N:11]=[CH:12][C:13]([CH:14]=1)=[C:8]23.[CH2:25](OCC)C>CC(C)=O>[I-:2].[CH3:3][O:4][C:5]1[C:6]([O:23][CH3:24])=[C:7]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[CH:9]3[CH2:10][N+:11]([CH3:25])=[CH:12][C:13]([CH:14]=1)=[C:8]23
Reactant: COc1cc2c3c(c1OC)CCc1ccccc1C3CN=C2
Reactant: CI
Reactant: CCOCC
Solvent: CC(C)=O
Product: COc1cc2c3c(c1OC)CCc1ccccc1C3C[N+](C)=C2
Product: [I-]

Procedure:
Methyl iodide (20 mL) was added to a solution of 5,6-dimethoxy-1,7,8,12b-tetrahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline (8.7 g, 29 mmol, described in example 2) in acetone (150 mL). The mixture was heated at reflux (reflux time=30 min.). After cooling, diethyl ether was added to the mixture. The solid material in the mixture was collected and dried to give 5,6-dimethoxy-2-methyl-1,7,8,12b-tetrahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinolinium iodide (11.8 g), a sample of which had mp 195°-210° C. after successive recrystallizations from acetone and methanol-diethyl ether.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.[CH3:16][O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[C:26]([C:37]3[CH:42]=[CH:41][C:40]([CH:43]=O)=[CH:39][CH:38]=3)=[N:25][C:24]=12)=[O:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[CH3:16][O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[C:26]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:39][CH:38]=3)=[N:25][C:24]=12)=[O:19]
Reactant: COC(=O)c1cnn2cc(-c3ccc(F)cc3F)c(-c3ccc(C=O)cc3)nc12
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnn2cc(-c3ccc(F)cc3F)c(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)nc12
Reaction time: 1 h

Procedure:
49.8 mg (0.18 mmol) 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 1.4 mL NMP. After addition of 0.06 mL triethylamine the reaction mixture is stirred for one hour. 65 mg (0.17 mmol) 6-(2,4-Difluorophenyl)-5-(4-formylphenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester in 1.5 mL NMP and 0.02 mL acetic acid are added. The reaction mixture is stirred overnight at room temperature. 38.5 mg (0.18 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is treated with saturated NaHCO3 and stirred vigorously for one hour. The precipitate is filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 23.4 mg (23%) of the desired product are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[C:10]=1[CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25](OCCC(C)C)=O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[C:16]([N:15]1[C:11]2[C:10](=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:14]=[CH:13][CH:12]=2)[C:19]([CH2:20][O:21][C:22](=[O:24])[CH3:23])=[N:25]1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1cccc(OCc2ccccc2)c1CCOC(C)=O
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1nn(C(C)=O)c2cccc(OCc3ccccc3)c12

Procedure:
This is obtained by nitrosation and subsequent ring closure by treating 2-(2-acetoxyethyl)-3-acetamidophenyl benzyl ether with isoamyl nitrite, sodium acetate and acetic anhydride in toluene at 80° C. It is obtained in the form of colorless crystals; m.p. 99°-100° C.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][N:18]=1.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29]>O.C(#N)C>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:29][CH2:28][C:27]([F:31])([F:30])[F:26])=[O:23])=[CH:19][N:18]=1
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
Triethylamine (1.03 ml, 7.4 mmol) and isobutyl chloroformate (0.76 ml, 5.5 mmol) were added to an acetonitrile solution (12 ml) of 6-chloronicotinic acid (0.58 g, 3.6 mmol) under ice cooling and the mixture was stirred at 0° C. for 30 minutes. To the solution mixture, 2,2,2-trifluoroethyl amine (0.88 ml, 11.2 mmol) was added and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1→1:1). The purified product was concentrated under reduced pressure and diisopropyl ether and n-hexane were added. The insoluble matter precipitated was obtained by filtration and dried to obtain 6-chloro-N-(2,2,2-trifluoroethyl)nicotine amide (0.58 g) as light yellow powder.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12]([CH3:18])[C:13](=[O:17])[NH:14]3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].I[CH3:22]>CN(C)C=O>[OH2:17].[N:1]1([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12]([CH3:18])[C:13](=[O:17])[N:14]3[CH3:22])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N:1]1([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12]([CH3:18])[C:13](=[O:17])[N:14]3[CH3:22])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1nc2ccc(Cn3ccnc3)cc2[nH]c1=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(Cn3ccnc3)cc2n(C)c1=O
Product: O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
A mixture of 3 parts of 7-(1H-imidazol-1-ylmethyl)-3-methyl-2(1H)-quinoxalinone, 0.3 parts of a sodium hydroxide dispersion 50% and 28 parts of N,N-dimethylformamide was stirred for 1.5 hours at room temperature. 2 Parts of iodomethane were added and stirring was continued for 12 hours at room temperature under nitrogen atmosphere. The reaction mixture was evaporated to dry and the residue was taken up in water and potassium carbonate. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanone. The product was filtered off and dried, yielding 2.2 parts (66.8%) of 7-(1H-imidazol-1-ylmethyl)-1,3-dimethyl-2(1H)-quinoxalinone hemihydrate; mp. 128.6° C. (comp. 79).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([SH:8])[CH:7]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13]>>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([S:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][CH3:10])=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: COc1ccc(F)cc1S
Product: COc1ccc(F)cc1Sc1ccc(S(C)(=O)=O)cc1Cl

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the is product from step (ii) and the product from example 7 step (ii), yield 0.8 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH2:18]([NH:25][CH2:26][CH2:27][NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:28][CH2:27][CH2:26][NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCCNCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCNCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and benzylethylenediamine in DME. ES-MS m/e (%): 335 (M+H+, 100), 228 ([M+H-BnNH2]+, 45).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][N:9]2[CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1.C(#N)C.C1([N:30]=[C:31]=[O:32])CCCCCC1.C(O)C(N)(CO)CO>C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:11]3([CH2:16][CH2:15][N:14]([C:31]([NH2:30])=[O:32])[CH2:13][CH2:12]3)[CH2:10][N:9]2[CH:17]([CH3:19])[CH3:18])=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCCC1
Reactant: CC(C)N1CC2(CCNCC2)C1c1ccc(Cl)cc1
Agent: NC(CO)(CO)CO
Solvent: CC#N
Solvent: ClCCCl
Product: CC(C)N1CC2(CCN(C(N)=O)CC2)C1c1ccc(Cl)cc1
Reaction time: 20 h

Procedure:
Treat 1-(4-Chlorophenyl)-2-isopropyl-2,7-diazaspiro[3.5]nonane, Isomer A (0.015 g) in ClCH2CH2Cl (1 mL) and acetonitrile (1 mL) with cycloheptyl isocyanate (18 uL), and the resulting mixture stirred at RT for 424 h. P—S Trisamine (Argoonaut, 4.64 mmol/g) (120 g) and ClCH2CH2Cl (2 mL) were added and the resulting mixture was shaken to 20 h. The reaction mixture was filtered, the resin washed with CH2Cl2 (2 mL). The resulting filtrate was concentrated in vacuo and then placed on a silica gel plate (1000 u) and eluted with CH2Cl2:MeOH (95:5) to give of 1-(4-chlorophenyl)-2-isopropyl-2,7-diazaspiro[3.5]nonane-7-carboxamide, white residue (0.0208 g). Add MeOH (0.5 mL) and 0.1N HCl in MeOH (1 mL), and concentrate in vacuo to give the title compound, as a white solid (0.0222 g).