Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:36])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[O:12][C:13]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:14]=3[C:15]=2[C:16](=[O:29])[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH:8]=[N:7]1)C.[NH3:37]>>[CH3:35][O:34][C:32]1[CH:31]=[CH:30][C:14]2[C:15]([C:16](=[O:29])[C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)=[C:11]([C:9]3[CH:8]=[N:7][N:6]([CH2:5][C:4]([NH2:37])=[O:36])[CH:10]=3)[O:12][C:13]=2[CH:33]=1
Reactant: CCOC(=O)Cn1cc(-c2oc3cc(OC)ccc3c2C(=O)c2cc(OC)c(OC)c(OC)c2)cn1
Reactant: N
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cnn(CC(N)=O)c3)oc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 14 %

Procedure:
{4-[6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-benzofuran-2-yl]-pyrazol-1-yl}-acetic acid ethyl ester (30 mg, 0.061 mmol) was treated with 28% aqueous ammonia solution and the resulting reaction mixture was stirred at 80° C. for 3 h. After cooling to room temperature the solution was concentrated under vacuum and the residue subjected to flash column chromatography (silica gel, sequential elution—1:1 hexane:ethyl acetate, ethyl acetate). The resulting product was further purified by trituration with 1:1 hexane:diethyl ether to give the title compound as a yellow solid (4 mg, 14%). 1H-NMR (CDCl3) δ 8.29 (s, 1H), 8.14 (s, 1H), 7.13 (s, 2H), 7.12 (d, J=8.7 Hz, 1H), 7.05 (d, J=2.1 Hz, 1H), 6.81 (dd, J=8.7, 2.1 Hz, 1H), 6.14 (br s, N—H), 5.46 (br s, N—H), 4.83 (s, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.78 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][O:45][CH2:46][CH2:47][NH2:48].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:48][CH2:47][CH2:46][O:45][CH3:44])=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Reactant: COCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCNC(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), 2-methoxyethylamine (20 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C14H20ClN6O3, 342.13. found 342.2.
Reaction SMILES: FC1C=C(C[C@H](C2C([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=CN=C(NCCOC)N=2)NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C=C(F)C=1.Br[C:50]1[C:51]([C@@H:66]([NH:76][C:77](=[O:95])[CH2:78][N:79]2[C:87]3[C:86]([F:89])([F:88])[CH2:85][CH2:84][C:83]([F:91])([F:90])[C:82]=3[C:81]([CH:92]([F:94])[F:93])=[N:80]2)[CH2:67][C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[C:70]([F:75])[CH:69]=2)=[N:52][C:53]([N:56]2[CH2:65][CH2:64][C:59]3([O:63][CH2:62][CH2:61][O:60]3)[CH2:58][CH2:57]2)=[N:54][CH:55]=1>>[F:94][CH:92]([F:93])[C:81]1[C:82]2[C:83]([F:91])([F:90])[CH2:84][CH2:85][C:86]([F:88])([F:89])[C:87]=2[N:79]([CH2:78][C:77]([NH:76][C@H:66]([C:51]2[C:50]([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=[CH:55][N:54]=[C:53]([N:56]3[CH2:57][CH2:58][C:59]4([O:63][CH2:62][CH2:61][O:60]4)[CH2:64][CH2:65]3)[N:52]=2)[CH2:67][C:68]2[CH:69]=[C:70]([F:75])[CH:71]=[C:72]([F:74])[CH:73]=2)=[O:95])[N:80]=1
Reactant: O=C(Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(N2CCC3(CC2)OCCO3)ncc1Br
Reactant: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Product: NC(=O)c1cc(-c2cnc(N3CCC4(CC3)OCCO4)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (19B) was prepared according to the method presented for the synthesis of compound 11J of Example 11 utilizing 19A. MS (m/z) 798.63 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[O:12]2)=[C:4](Cl)[N:3]=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C)C>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[O:12]2)=[C:4]([NH:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: NC1CCCC1
Agent: CN(C)C
Solvent: CCO
Product: Nc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To suspension of (4S,2R,3R,5R)-2-[2-amino-6-chloro-purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol in 15 mL of ethanol was added 0.4 g of cyclopentyl amine and 10 mmol of trimethyl amine. The mixture was stirred at 80° C. for 24 hours. The residue was purified using preparative thin layer chromatography (15:1 dichloromethane:methanol) to yield (4S,2R,3R,5R)-2-[2-amino-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (8).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[NH2:12]OS(O)(=O)=O.O.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1>O.C(Cl)(Cl)Cl>[C:19]1([CH3:29])[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:23][CH:24]=1.[NH2:12][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: NOS(=O)(=O)O
Reactant: c1c[nH]cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nn1ccnc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In 50 ml of water was dissolved 2.76 g (20 mmol) of potassium carbonate and 1.36 g (20 mmol) of imidazole was added thereto. 2.26 g (20 mmol) of hydroxylamine-O-sulfonic acid was added thereto and the mixture was stirred at room temperature for 6 hours. The resulting precipitate was filtered off and the filtrate was concentrated under the reduced pressure. To the concentrate were slowly added 10 ml of chloroform and a solution of 3.8 g (20 mmol) of p-toluenesulfonic acid monohydrate in 10 ml of chloroform. Stirring for 30 min, filtration and drying of the mixture gave 1.74 g of the desired compound(34%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[C:14]([C:17](=O)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:21][C:22]1[CH:23]=[C:24]([CH:29]=[C:30]([OH:32])[CH:31]=1)[C:25]([NH:27][NH2:28])=[O:26]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:28][NH:27][C:25](=[O:26])[C:24]3[CH:23]=[C:22]([OH:21])[CH:31]=[C:30]([OH:32])[CH:29]=3)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC(=O)c1cc(O)cc(O)c1
Reactant: CC(=O)c1c(C)nn(-c2ccc(C(C)(C)C)cc2)c1O
Product: CC1=NN(c2ccc(C(C)(C)C)cc2)C(=O)C1=C(C)NNC(=O)c1cc(O)cc(O)c1

Procedure:
From 1-(1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 3,5-dihydroxybenzoic hydrazide, 40.1 mg of the desired product was obtained in the same manner as in Synthetic Example 1 as a yellow solid (yield 40%).
Reaction SMILES: O[CH2:2][C:3]#[C:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:12][CH2:2][C:3]#[C:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C#CC#CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)C#CC#CCBr
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A solution of 5.0 g (37.3 mmole) of 1-hydroxy-6,6-dimethyl-2,4-heptadiyne and 14.8 g (44.7 mmole) of carbon tetrabromide in 250 mL of H2CCl2 was cooled to 0°-5° C. and 12.7 g (48.4 mmole) of triphenylphosphine was added thereto. The so formed mixture was stirred for 2 hours at 0°-5° C. The reaction mixture was concentrated to about 50 ml and poured into 1 liter of petroleum ether. The mixture was stirred 15 min. and the petroleum ether was removed by decantation. The oily residue was stirred for 15 min. with another 1 liter of petroleum ether which was decanted off. The combined petroleum ether extracts were concentrated to an oil which was chromatographed on silica gel, eluting with petroleum ether to give 6.87 g of the title compound, M/e, M+ 200.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>O>[NH2:19]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: N
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Solvent: O
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 10.0 gm (0.0393 mol) of 2-benzoylbenzo[b]-thiophen-3-ol, 60 cc of concentrated aqueous ammonia and 250 cc of ethanol was heated for 20 hours at a temperature of 120° C. after introducing 5 bar of ammonia gas into the vessel. After cooling, the mixture was stirred into 1.5 liters of water, the precipitated pale yellow reaction product was filtered off with suction, washed thoroughly several times with 50 cc each of water and dried in the air. 4.23 gm (42% of theory) of yellow crystals, m.p. 121°-122° C., were obtained (after twice recrystallizing from petroleum ether/ethyl acetate 1:1 using activated carbon) and were found to be completely identical with the product obtained in Example 1 based on elemental analysis, IR and UV spectra.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cncnc3)c2)=Nc2cc(C(F)(F)F)c(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M102) (0.31 g, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (110 mg, 46%).
Reaction SMILES: [F:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.CN(C)C>[F:1][C:2]1[N:3]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Fc1ncc[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C
Solvent: ClCCl
Product: Fc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 80.2 %

Procedure:
To a solution of 2-fluoroimidazole (4.45 g.) in CH2Cl2 (100 ml.) and trimethylamine (7.93 ml.) was added triphenylmethyl chloride (14.4 g.) and the mixture was stirred for 2.5 hours. The solution was washed with water and brine, dried (MgSO4), treated with decolourising charcoal, filtered and evaporated. The solid residue was triturated with ether followed by methanol to give 2-fluoro-1-triphenylmethylimidazole (13.6 g.), m.p. 182°-185°.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[N:10]=[C:11]([O:21][CH:22]3[CH2:39][CH:38]4[N:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41]([OH:43])=O)([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:23]3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=3)[S:7][CH:8]=1)([CH3:3])[CH3:2].ClC1N=C(OC2CC3N(C(=O)N(C)CCCCC=CC4C(C([NH:81][S:82]([CH:85]5[CH2:87][CH2:86]5)(=[O:84])=[O:83])=O)(NC3=O)C4)C2)C2C(C=1)=CC(OC)=CC=2>>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[N:10]=[C:11]([O:21][CH:22]3[CH2:39][CH:38]4[N:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41]([NH:81][S:82]([CH:85]6[CH2:87][CH2:86]6)(=[O:84])=[O:83])=[O:43])([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:23]3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=3)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3nc(C(C)C)cs3)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3nc(C(C)C)cs3)cc2c1

Procedure:
The title product 70 was prepared from 17-[3-(4-isopropylthiazol-2-yl)-6-methoxyisoquinolin-1-yloxy]-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (69) following the same procedures described for the preparation of N-[17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (43, Example 11): m/z=737 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f48) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.N.[OH-].[Na+].C(OC(C)C)(C)C.O=C(C)C(=S)[NH2:37]>N.CCOC(C)=O>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:37])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC(=O)C(N)=S
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(=S)N1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(N)=N1
Temperature: 74 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 19 Step 3, 22.7 g, 57.7 mmol) and ammonia (7 M in MeOH, 180 mL, 1.26 mol) was put in a pressure reactor and heated to 74° C. overnight. The residue was allowed to reach r.t. and the mixture was concentrated. The residue was partitioned between 2 M citric acid (400 mL) and EtOAc (400 mL). Any insoluble material was filtered off and was determined to be unreacted starting material. The organic phase (org 1) was concentrated in vacuo to give additional unreacted starting material. To the aqueous phase was EtOAc (300 mL) added and then 50% NaOH was added until pH ˜12, and the mixture was stirred for 10 min. The resulting organic phase (org 2) was saved. The residue from org 1, and the solid filtered off were combined and suspended in ammonia (7 M in MeOH, 180 mL, 1.26 mmol) and put in a pressure reactor and heated 100° C. overnight. The obtained solution was concentrated in vacuo. The residue was partitioned between 2 M citric acid (300 mL) and EtOAc (300 mL). To the aqueous phase was EtOAc (300 mL) added and then 50% NaOH was added until pH ˜12, and the mixture was stirred for 10 min. The organic phase was combined with org 2 from above. Activated charcoal was added to the organic phase and the mixture was stirred for 30 min before it was filtered through diatomaceous earth. The organic phase was concentrated and dried in vacuo overnight to give a solid. To the solid was diisopropyl ether (125 mL) added and the mixture was refluxed overnight. The mixture was allowed to reach r.t. and the solid was filtered off to give the title compound (equivalent to Example 19 Isomeric Mixture 2 above) (15 g, 69% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 0.93 (m, 1 H) 1.1-1.25 (m, 2 H) 1.35-1.45 (m, 3 H) 1.81 (br. d, 2 H) 2.16 (s, 3 H) 2.87-3.03 (m, 3 H) 3.18 (s, 3 H) 6.59 (br. s., 2 H), 6.64 (d, 1 H), 7.25 (d, 1 H), 7.34 (dd, 1 H); ES+) m/z 376 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:12][CH:11](O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:14]#[N:15].[K+].CO.[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]\[C:22]([OH:24])=[O:23]>CC(O)C>[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]\[C:22]([OH:24])=[O:23].[C:1]1([CH:7]([N:9]2[CH2:12][CH:11]([C:14]#[N:15])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)N1CC(O)C1
Reactant: [C-]#N
Agent: O=C(O)/C=C\C(=O)O
Agent: [K+]
Solvent: CC(C)O
Solvent: CO
Product: CC(c1ccccc1)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A slurry of methanesulfonate ester of 1-(1-phenylethyl)azetidin-3-ol (60.4 g, 223 mmol), potassium cyanide (43.5 g, 669 mmol) and methanol (350 mol) were allowed to stir at ambient temperature for 72 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between 300 mL of an aqueous 20% potassium carbonate solution and 400 mL of diethyl ether. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2, flash, ethyl acetate/hexane 1:3) to give 25.1 g (56%). A 1-g portion was dissolved in 2-propanol and treated with maleic acid (0.75 g, 6.5 mmol). The resulting solid was recrystallized from 2-propanol to give a white solid, mp 147°-148° C.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH2:5]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)(=O)C>[CH2:5]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:1][CH:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1CN(Cc2ccccc2)CCC(=O)N1
Temperature: 0 °C
Reaction time: 16 h
Yield: 48.6 %

Procedure:
Sodium azide (1.58 g, 24.4 mmol) was added portionwise over 6 h to a solution of 1-benzyl-3-methylpiperidin-4-one (5.00 g, 24.4 mmol) at 0° C., then the reaction mixture was allowed to reach room temperature over 16 h. The reaction mixture was then poured upon ice/40% aq. sodium hydroxide solution/ethyl acetate, the organic layer was washed with brine, dried (MgSO4), and evaporated. Recrystallization in n-heptane/ethyl acetate 2:1 (60 ml) produced the title compound (2.59 g, 49%). White solid, MS: 219.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C=O.Cl.O.[Cl:20][CH:21](Cl)C(Cl)Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])[C:5]([CH2:21][Cl:20])=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)NC(C)Cc1ccc(C)c(C)c1
Reactant: ClC(Cl)C(Cl)Cl
Agent: C=O
Agent: Cl
Solvent: O
Product: CC(=O)NC(C)Cc1cc(C)c(C)cc1CCl
Reaction time: 8 h

Procedure:
4.1 g of rac. 1-(3,4-dimethylphenyl)-2-acetamidopropane was dissolved in 40 ml of 1,1,2,2-tetrachlorethane in a 100-ml RB flask provided with a stirrer, thermometer, condenser, and gas inlet tube. Twelve ml of 37% formaldehyde was added, and a stream of hydrogen chloride passed into the stirred mixture as the temperature rose to 50°, where it was maintained for 5 hrs. At this point, the mixture remained overnight at room temperature. The reaction mixture was poured into water, the organic phase was washed twice with water, dried, and the solvent distilled in the rotary evaporator, leaving 4.2 g of a colorless oil. The oil was refluxed with four 100-ml-portions of petroleum ether (b.p. 60-0-°), and from the combined extracts, a mass of cottony needles separated. The solid was collected by filtration and freed of solvent in vacuo to yield the above-named product, m.p. 72°-73°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g of 4-(4-bromophenyl)piperidin-4-ol is placed in 20 ml of dichloromethane. 0.65 ml of triethylamine and then 0.33 ml of methanesulphonyl chloride are added. The reaction mixture is stirred at ambient temperature for 2 h. It is washed with water and then with a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and then evaporated under reduced pressure. The crude product obtained is chromatographed on silica gel, elution being carried out with a dichloromethane/methanol (99/1) solvent mixture. 1.1 g of 4-(4-bromophenyl)-1-(methanesulphonyl)piperidin-4-ol are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[C:11](=[O:20])[NH:12][C:13]([NH:16][N+]([O-])=O)=[N:14][CH:15]=2)[CH:5]=[N:6][C:7]=1[CH3:8].N[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>C(O)C>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:16][C:13]1[NH:12][C:11](=[O:20])[C:10]([CH2:9][C:4]2[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:15][N:14]=1
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Reactant: NCCCCCO
Solvent: CCO
Product: Cc1cc(Cc2cnc(NCCCCCO)[nH]c2=O)cnc1C

Procedure:
5-(5,6-Dimethyl-3-pyridylmethyl)-2-nitroamino-4-pyrimidone is reacted with 5-aminopentanol in refluxing ethanol to give 2-(5-hydroxypentylamino)-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone which is reacted with cyanamide and hydrogen chloride to give 2-[5-(O-isoureido)pentylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][O:10]2)=[CH:5][CH:4]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14].C(O)C>CO>[OH:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)[CH2:11][NH:14][CH2:13][CH2:12][NH2:15]
Reactant: CSc1ccc(C2CO2)cc1
Reactant: NCCN
Solvent: CCO
Solvent: CO
Product: CSc1ccc(C(O)CNCCN)cc1
Reaction time: 16 h

Procedure:
2-(4-Methylthiophenyl)oxirane (37 g.) is added, over the course of 20 minutes and at 30° C., to a solution of ethylenediamine (75 cc.) in methanol (56 cc.). After 16 hours at 20° C., ethanol (250 cc.) is added; the precipitate which forms is filtered off. Distilled water (375 cc.) is added to the ethanol solution and the oily impurity which separates out is extracted with diisopropyl ether (200 cc.). After concentrating the aqueous ethanolic solution under reduced pressure, N-[2-hydroxy-2-(4-methylthiophenyl)ethyl]ethylenediamine (37.9 g.) is obtained in the form of an oil.