Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:26])[C:15]([F:25])([F:24])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([C:41]3([C:44]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[O:45])[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)O1>>[F:24][C:15]([F:25])(/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:38]([C:41]3([C:44]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[O:45])[CH2:43][CH2:42]3)=[CH:39][CH:40]=2)=[CH:3][CH:4]=1)[OH:26]
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(F)(F)/C=C/c1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1C(O)C(F)(F)/C=C/c1ccccc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (E)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-4-phenyl-but-3-en-1-ol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][O:68][C:69]1[N:74]=[CH:73][C:72]([CH:75]=O)=[CH:71][CH:70]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:75]([C:72]3[CH:73]=[N:74][C:69]([O:68][CH3:67])=[CH:70][CH:71]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cn1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cn1
Reaction time: 6 h
Yield: 34 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (75 mg, 0.19 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.57 mmol, 0.57 mL) and 6-methoxy-3-pyridinecarboxaldehyde (1.1 eq, 0.21 mmol, 29 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (31 mg, 34%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.63 (br s, 4H, piperazine N(CH2)2), 3.62 (s, 2H, NCH2Ar), 3.68 (br s, 4H, piperazine N(CH2)2), 3.95 (s, 3H, OCH3), 7.00 (d, J=8.7 Hz, 1H, methoxypyridine H-5), 7.40 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.79 (d, br, J=7.8 Hz, 1H, pyridine H-4), 8.24 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.43 (dd, J=8.7, 2.3 Hz, 1H, methoxypyridine H-4), 8.50 (d, br, J=3.5 Hz, 1H, pyridine H-6), 8.57 (s, 1H, pyridine H-2), 8.96 (d, J=2.3 Hz, 1H, methoxypyridine H-2), 13.53 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH:14][CH3:15])[CH:8]=[N:7]2.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=1.O>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:14]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=1)[CH3:15])[CH:8]=[N:7]2
Reactant: CNc1cnc2cc(Br)ccc2n1
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(F)c(C(F)(F)F)c1)c1cnc2cc(Br)ccc2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
To a suspension of sodium hydride (0.08 g, 1.5 eq, 3.37 mmol) in DMF (15 mL) was added (6-Bromo-quinoxalin-2-yl)-methyl-amine (0.6 g, 1.0 eq, 2.51 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes. A mixture of 4-(bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene (0.7 g, 1.2 eq. 2.72 mmol) in DMF (15 mL) was added at room temperature and the reaction mixture was stirred for 2.0 hours at 0° C. After completion of the reaction, cold water (180 mL) was added and the reaction mixture was stirred for 15 minutes then filtered. The solid was dried under vacuum to afford the title compound (0.7 g, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=3)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:21][C:20]1[N:22]=[C:23]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[N:16]2[C:17]=1[CH:18]=[N:19][C:14]([NH:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[N:15]2
Reactant: COC(=O)c1ccc(C(=O)NC(C)c2cnc(Nc3cc(OC)c(OC)c(OC)c3)nn2)cc1
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2nc(C)c3cnc(Nc4cc(OC)c(OC)c(OC)c4)nn23)cc1
Yield: 20.4 %

Procedure:
In a similar manner as described for Example 9, methyl 4-{[(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)amino]carbonyl}benzoate (Intermediate 30) (56 mg, 0.12 mmol), and 1,2,4-triazole (55 mg, 0.80 mmol) in pyridine (2 mL) and phosphorous oxychloride (0.037 mL, 0.40 mmol) gave methyl 4-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}benzoate (11 mg, 20%) as a yellow solid. 1H NMR (CD3OD): δ9.06 (s, 1H), 9.01 (s, 1H), 8.58 (d, J=7.87 Hz, 1H), 8.08 (d, J=7.87 Hz, 1H), 7.62 (t, J=7.87 Hz, 1H), 7.04 (s, 2H), 5.48 (s, 1H), 3.87 (s, 3.75 (s, 3H), 3.71 (s, 6H), 2.59 (s, 3H). MS m/z 449 (M+1).
Reaction SMILES: [NH3:1].[NH2:2][N+:3]([O-:5])=[O:4].[NH2:6][N+:7]([O-:9])=[O:8].[NH4+]>>[NH2:2][N+:3]([O-:5])=[O:4].[NH2:6][N+:7]([O-:9])=[O:8].[NH4+:1].[N+:3]([O-:5])([O-:8])=[O:4].[NH4+:2]
Reactant: N
Agent: N[N+](=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])[O-]

Procedure:
The process of this invention produces ammonium dinitramide by using a substrate compound that functions as a protected form of ammonia. It allows for introduction of two nitro groups on the ammonia nitrogen (in high yield) followed by treatment with ammonia to give ammonium dinitramide, ammonium nitrate, and regenerated starting compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[IH:28]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[I:28][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1
Reactant: I
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(I)n2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 65.4 %

Procedure:
A mixture of 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1020 mg, 2.65 mmol) and 67% hydriodic acid solution (0.499 mL, 6.63 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 19 h. The reaction mixture was diluted with NaHCO3 (30 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow solid. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 50% CH2Cl2/hexanes to give 4-iodo-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (826 mg, 1.734 mmol, 65.4% yield) as a mixture of product and starting material (3:1).
Reaction SMILES: CB1OB(C)OB(C)O1.[CH3:10]C1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[C:58]([C:60]1[C:64]([S:65][C:66]([F:69])([F:68])[F:67])=[C:63]([CH3:70])[N:62]([C:71]2[C:76](Cl)=[CH:75][C:74]([C:78]([F:81])([F:80])[F:79])=[CH:73][C:72]=2[Cl:82])[N:61]=1)#[N:59]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:82][C:72]1[CH:73]=[C:74]([C:78]([F:80])([F:81])[F:79])[CH:75]=[C:76]([CH3:10])[C:71]=1[N:62]1[C:63]([CH3:70])=[C:64]([S:65][C:66]([F:67])([F:68])[F:69])[C:60]([C:58]#[N:59])=[N:61]1
Reactant: Cc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Pd]
Agent: CB1OB(C)OB(C)O1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)cc(Cl)c1-n1nc(C#N)c(SC(F)(F)F)c1C
Temperature: 25 °C

Procedure:
A solution of trimethylboroxine (83 mg), tris(dibenzylideneacetone)dipalladium (10 mg), Xantphos (18 mg), potassium carbonate (165 mg) and 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazole (250 mg) in dioxane was heated in a microwave for 20 minutes at 130° C. in a 10 ml sealed Pyrex glass tube. The reaction mixture was cooled to room temperature then diluted with ethyl acetate and filtered over Celite. The organic filtrate was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid. MS (ES): M/Z [M+NH4]=417. 1H NMR: (400 MHz, CDCl3): 2.13 (s, 3H), 2.26 (s, 3H), 7.60 (bs, 1H) and 7.73 (bs, 1H). 19F NMR (376 MHz, CDCl3): −44.25 (s, 3F) and −63.63 (s, 3F).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][N:3]=1.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[O:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][C:28]([NH:29][C:2]3[N:7]=[C:6]([S:8][C:9]4[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=4)[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][N:3]=3)=[CH:30][CH:31]=2)[CH2:23][CH2:24]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COC(=O)c1cccc(Sc2ccnc(Cl)n2)c1
Product: COC(=O)c1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Yield: 52.7 %

Procedure:
In a procedure analogous to Example 8, reaction of methyl 3-(2-chloropyrimidin-4-ylthio)benzoate (310 mg, 1.84 mmol) and 4-morpholinoaniline (394 mg, 2.21 mmol) furnished the product (410 mg, 87%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(OCC)(=O)C>[CH2:1]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][Br:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)CCBr
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CCBr)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzylamine (6.49 ml) and triethylamine (8.26 ml) in ethyl acetate (60 ml) was added dropwise to a solution of 3-bromopropionyl chloride (6 ml) in ethyl acetate (10 ml) at 0° C. The reaction mixture was stirred to room temperature for 1 hr. The organic phase was washed with water (2×150 ml), saturated brine (150 ml) and dried over magnesium sulphate. Removal of the solvent produced the amide as a crystalline solid.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])/[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:65][C@@H:66]1[C:84](=[O:85])[N:68]2[C:69]([C:81]([OH:83])=[O:82])=[C:70]([CH2:73][S:74][C:75]3[N:79]([NH2:80])[N:78]=[N:77][N:76]=3)[CH2:71][S:72][C@H:67]12.C(N(CC)CC)C.NC1C(CSC2N(NC(C)C)N=NN=2)=C(C(O)=O)N2C(=O)C[C@H]2S1>CC(N(C)C)=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])/[C:27]([NH:65][C@@H:66]2[C:84](=[O:85])[N:68]3[C:69]([C:81]([OH:83])=[O:82])=[C:70]([CH2:73][S:74][C:75]4[N:79]([NH2:80])[N:78]=[N:77][N:76]=4)[CH2:71][S:72][C@H:67]23)=[O:29])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.9 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(tert-butoxycarbonylmethoxyimino)acetic acid (3.80 g, 7 mmol), 1-hydroxybenzotriazole (1.09 g, 8.05 mmol) and N,N'-dicyclohexylcarbodiimide (1.59 g, 7.7 mmol) in dimethylacetamide (40 ml) was stirred at room temperature for 2 hours. To the solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.76 g, 8.4 mmol) and triethylamine (1.70 g, 16.8 mmol) in dimethylacetamide (20 ml) and water (2.8 ml) and the mixture was stirred at room temperature for 17 hours. Then the mixture was treated in a manner similar to that described in Example 6, (c) to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-(tert-butoxycarbonylmethoxyimino)acetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (4.96 g, 83%).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[C:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)(=[O:21])[CH3:20]>>[C:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:14]=[CH:13][C:12]3[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=3[CH:6]=2)=[CH:26][CH:25]=1)(=[O:21])[CH3:20]
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(=O)OCc1ccc(Br)cc1
Product: CC(=O)OCc1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 20.2 %

Procedure:
Following the basic procedure of Example 32, by reacting 2.42 g (10 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 2.52 g (11 mmol) of 4-bromobenzyl acetate, 790 mg (20%) of the expected compound were obtained in the form of a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[ClH:35].[Cl:36]CC1C=[CH:42][N:41]=[CH:40][CH:39]=1.Cl>>[ClH:36].[ClH:35].[CH2:1]([O:8][C:9]1[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=[C:11]([S:22][CH2:23][C:24]2[CH:25]=[CH:42][N:41]=[CH:40][CH:39]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccncc1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Cc1csc(Nc2ncc(SCc3ccncc3)cc2OCc2ccccc2)n1
Yield: 57.1 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 4-(chloromethyl)pyridine hydrochloride (27.6 mg, 0.17 mmol) were reacted according to the method of Example 43 to afford 3-(benzyloxy)-N-(4-methylthiazol-2-yl)-5-(pyridin-4-ylmethylthio)pyridin-2-amine dihydrochloride (47.9 mg, 57.6% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 8.72 (m, 2H), 7.77 (d, 1H), 7.71 (m, 2H), 7.58 (m, 3H), 7.45-7.34 (m, 3H), 6.73 (s, 1H), 5.30 (s, 2H), 4.42 (s, 2H), 2.27 (d, 3H); Mass spectrum (apci) m/z=421.0 (100), 330.0 (45), 238.0 (40).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC.CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:18][CH:17]([CH3:19])[C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:20])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(Nc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 33.6 %

Procedure:
388 mg of 4-fluoronitrobenzene, 500 mg of L-alanine tert-butyl ester and 0.9 ml of Et3N were added to a solution of 10 ml of N-methylpyrrolidinone. The reaction medium was heated at 70° C. for 20 hours and, after cooling to room temperature, then poured into a water and ice mixture. The yellow precipitate formed was filtered off, re-slurried in water and then dried over P2O5. 246 mg of tert-butyl 2-(4-nitrophenylamino)propionate (10) were obtained.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH2:19][NH2:20]>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
The compound was prepared as in Example 5 from 1-(4-carbomethoxymethoxyphenyl)propan-2-one (2.22 g) and 2-hydroxy-2-(3-chlorophenyl) ethanamine (1.71 g) and crystallised from hexane m.p. 82°-87° as a 58:42 mixture of diastereoisomers.
Reaction SMILES: [CH3:1][S:2][C:3]1(C(O)=O)[CH:8]=[CH:7][CH:6]=[CH:5][NH:4]1.B.C1C[O:16][CH2:15]C1>CO>[CH3:1][S:2][C:3]1[C:8]([CH2:15][OH:16])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: C1CCOC1
Reactant: CSC1(C(=O)O)C=CC=CN1
Agent: B
Solvent: CO
Product: CSc1ncccc1CO
Temperature: 80 °C
Yield: 30.3 %

Procedure:
To 2-(methylthio)picolinic acid (1.00 g, 5.91 mmol) was added BH3.THF (1.0 M/THF, 15 mL, 15 mmol) and the mixture heated at 80° C. for 24 h. Methanol (30 mL) was carefully added at room temperature and the solution was concentrated in vacuo. Purification of the crude material on silica gel (20% EtOAc/hexanes) gave the title compound as colourless crystals (278 mg, 30%). 1H NMR (CDCl3) □ 1.99 (t, 1H, J=6.0 Hz), 2.61 (s, 3H), 4.70 (d, 2H, J=6.0 Hz), 7.04 (dd, 1H, J=6, 3 Hz), 7.62 (d, 1H, J=6 Hz), 8.40 (d, 1H, J=3 Hz).
Reaction SMILES: [O-]CC.[Na+].[Na].Cl.[NH2:7][C:8]([NH2:10])=[NH:9].[C:11]([CH:13]([CH2:16][CH2:17][CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[C:14]#[N:15])#[N:12]>C(O)C>[NH2:9][C:8]1[N:10]=[C:14]([NH2:15])[C:13]([CH2:16][CH2:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[C:11]([NH2:12])[N:7]=1
Reactant: N=C(N)N
Reactant: N#CC(C#N)CCCc1cccc2ccccc12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(N)c(CCCc2cccc3ccccc23)c(N)n1

Procedure:
A solution of sodium ethoxide, prepared from 0.04 gram (0.002 mole) of sodium metal in 50 mL of ethanol, was stirred, and 0.2 gram (0.002 mole) of guanidine hydrochloride was added in one portion. The reaction mixture was stirred for 15 minutes and filtered to remove a precipitate. The filtrate was stirred, and 0.4 gram (0.002 mole) of 2-cyano-5-(naphth-1-yl)pentanenitrile was added in one portion. Upon completion of addition, the reaction mixture was heated at reflux for about 16 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was triturated with warm water, yielding, when dried, 0.4 gram of 2,4,6-triamino-5-[3-(naphth-1-yl)propyl]-pyrimidine, mp 181°-183° C., (dec.). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].C([Mg]Br)C.[CH3:14][C:15]1([CH3:37])[O:20][C:19](=[O:21])[C:18](=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)=[CH:25][CH:24]=2)[C:17](=[O:36])[O:16]1>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][CH:22]([CH:18]1[C:17](=[O:36])[O:16][C:15]([CH3:14])([CH3:37])[O:20][C:19]1=[O:21])[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:27][CH:28]=1)[CH3:2]
Reactant: CC1(C)OC(=O)C(=Cc2ccc(OC3CCCCO3)cc2)C(=O)O1
Reactant: C#CC(OCC)OCC
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCOC(C#CC(c1ccc(OC2CCCCO2)cc1)C1C(=O)OC(C)(C)OC1=O)OCC
Reaction time: 0.75 h

Procedure:
Propiolaldehyde diethyl acetal (5 g, 39 mmol) in anhydrous THF (65 mL) was cooled to −5° C. and treated with ethylmagnesium bromide (39 mmol in 14 mL of anhydrous THF) dropwise over 10 min. After 45 min., the solution of Grignard reagent was added to compound 52.1 in anhydrous THF (50 mL). After stirring 1 h, the reaction was quenched with saturated NH4Cl(aq) (20 mL) and diluted with hexanes (100 mL). After mixing vigorously, the layers were separated and the organic layer discarded. The aqueous layer was acidified and extracted twice with diethyl ether. The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used immediately without further purification. MS ESI (pos.) m/e: 478.3 (M+NH4)+.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][CH2:11][OH:12].Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]2[S:21][C:22]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])=[C:23]([CH3:25])[N:24]=2)=[CH:16][CH:15]=1>CN(C)C=O>[CH3:25][C:23]1[N:24]=[C:20]([C:17]2[CH:18]=[N:19][C:14]([O:12][CH2:11][CH2:10][CH2:9][N:5]3[CH2:6][CH2:7][CH2:8][CH:4]3[CH3:3])=[CH:15][CH:16]=2)[S:21][C:22]=1[C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]
Reactant: CC1CCCN1CCCO
Reactant: Cc1nc(-c2ccc(Cl)nc2)sc1C(=O)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(OCCCN3CCCC3C)nc2)sc1C(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 8 %

Procedure:
Sodium hydride 60% in oil (0.11 g, 2.2 eq, 2.82 mmol) is added to a mixture of 3-(2-methyl-1-pyrrolidinyl)-1-propanol (0.31 g, 2.2 eq, 2.18 mmol) in dimethylformamide (15 ml) cooled to 0° C. The mixture is stirred at 22° C. for 20 min, and cooled again to 0° C. 4-{[2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]carbonyl}morpholine i99 (0.415 g, 1 eq, 1.28 mmol) is then added to the solution and the mixture is stirred 48 h at room temperature. The solvent is evaporated, and the residue is taken up in ethyl acetate and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 97/2.7/0.3) affords 0.047 g of 4-[(4-methyl-2-{6-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridin-3-yl}-1,3-thiazol-5-yl)carbonyl]morpholine 147.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][O:5][NH2:6].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]([C:19]3[N:23]4[CH:24]=[CH:25][C:26]([CH:28]=O)=[CH:27][C:22]4=[N:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=2)[CH:8]=1>>[OH:2][CH2:3][CH2:4][O:5][N:6]=[CH:28][C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:9]4[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=4)[CH:14]=3)=[CH:20][N:21]=[C:22]2[CH:27]=1
Reactant: NOCCO
Reactant: O=Cc1ccn2c(-c3cccc(-c4cccnc4)c3)cnc2c1
Agent: Cl
Product: OCCON=Cc1ccn2c(-c3cccc(-c4cccnc4)c3)cnc2c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 14 using O-(2-hydroxyethyl)hydroxylamine hydrochloride and 3-[3-(pyridin-3-yl)phenyl]imidazo[1,2-α]pyridine-7-carboxaldehyde to afford a white crystalline solid, essentially as a single geometric isomer, m.p. 149-151° C. 1H NMR (400 MHz, CDCl3) δH 2.20 (1H, br s), 3.93-3.97 (2H, m), 4.32-4.36 (2H, m), 7.28 (1H, dd, J 2 and 7), 7.37-7.44 (1H, m), 7.58-7.68 (4H, m), 7.75 (1H, s), 7.80 (1H, s), 7.90-7.95 (1H, m), 8.17 (1H, s), 8.31 (1H, d, J 7), 8.63-8.67 (1H, m), 8.90 (1H, s); m/z (ES+) 359 (M++H).