Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.[C:30]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[C:31]([CH3:33])=[CH2:32]>>[C:36]([O:35][C:30](=[O:34])[CH:31]([CH3:33])[CH2:32][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[NH:19][S:20]2(=[O:21])=[O:22])=[C:9]([OH:8])[CH:14]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=C(C)C(=O)OC(C)(C)C
Product: CC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)C(=O)OC(C)(C)C

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and t-butyl methacrylate analogous to Example 133 with the modification that the TMS-ethyl group is removed after the Heck reaction.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[C:23]1[N:27]2[CH:28]=[C:29](F)[CH:30]=[CH:31][C:26]2=[N:25][N:24]=1>CN(C=O)C>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[C:23]1[N:27]2[CH:28]=[C:29]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:30]=[CH:31][C:26]2=[N:25][N:24]=1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 323 mg, 8.06 mmol) in DMF (10.0 mL) was added (1R,4S)-4-amino-1,2,3,4-tetrahydro-naphthalen-1-ol (329 mg, 2.02 mmol) and the reaction stirred for 20 min. Intermediate 96b (500 mg, 2.02 mmol) was added in DMF (2.00 mL) and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH. The residue was purified by FCC, using 0-10% (2M NH3 in MeOH) in DCM, to give the title compound (453 mg, 57%). LCMS (Method 4): Rt 2.13, m/z 392 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH3:32])[C:26]=1[Cl:33].O>O1CCOCC1>[Cl:33][C:26]1[C:27]([CH2:31][CH3:32])=[N:28][CH:29]=[CH:30][C:25]=1[NH:24][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: CCc1nccc(N)c1Cl
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1COCCO1
Product: CCc1nccc(NC(=O)Cc2ccc(O)cc2)c1Cl
Temperature: 5 °C
Yield: 48.2 %

Procedure:
0.76 g (5.0 mmol) of 4-hydroxyphenyl acetic acid was dissolved in 20 ml of 1,4-dioxane, and the solution was stirred at 5° C. Then, 0.97 g (6.0 mmol) of 1,1'-carbonyldiimidazole was added thereto, and the mixture was stirred for one hour at 5° C. Then, 0.76 g (5.0 mmol) of 4-amino-3-chloro-2-ethylpyridine was added thereto, and the mixture was refluxed under heating for 20 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) and then recrystallized from ethanol to obtain 0.7 g of the desired product as a white powder (melting point: 158° to 161° C.).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:19]=[C:18]([CH:27]([CH3:29])[CH3:28])[CH:17]=2)=[CH:12][CH:11]=1.O>CN(C=O)C>[Br:1][C:17]1[C:18]([CH:27]([CH3:29])[CH3:28])=[N:19][N:20]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cc(-c2ccc(F)cc2)n(-c2ncccn2)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nn(-c2ncccn2)c(-c2ccc(F)cc2)c1Br
Temperature: 25 °C
Yield: 82.6 %

Procedure:
N-Bromosuccinimide (9.97 g, 0.056 mol) was added to a solution of 2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1H- pyrazol-1-yl]pyrimidine (15.8 g, 0.056 mol) in DMF at 0° C. The resulting mixture was allowed to warm to room temperature over 24 hours. This was then poured into 500 ml water. The white solid which precipitated was collected by filtration and dried to yield 16.7 g of 2-[4-bromo-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]pyrimidine (3), mp 130°-133° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:17][C@H:18]([OH:30])[C:19]2[C:27]3[S:26][C:25](=[O:28])[NH:24][C:23]=3[C:22]([OH:29])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)(=O)=O.FC(F)(F)C(O)=O.[CH:45]([C:48]1[S:49][CH:50]=[C:51]([C:53]([N:55]2[CH2:60][C:59]3([CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)[O:58][CH2:57][CH2:56]2)=[O:54])[N:52]=1)([CH3:47])[CH3:46].C(N(CC)CC)C>CC#N>[OH:30][C@H:18]([C:19]1[C:27]2[S:26][C:25](=[O:28])[NH:24][C:23]=2[C:22]([OH:29])=[CH:21][CH:20]=1)[CH2:17][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:63]2[CH2:62][CH2:61][C:59]3([O:58][CH2:57][CH2:56][N:55]([C:53]([C:51]4[N:52]=[C:48]([CH:45]([CH3:47])[CH3:46])[S:49][CH:50]=4)=[O:54])[CH2:60]3)[CH2:65][CH2:64]2)=[CH:14][CH:13]=1)[C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(CN(C[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)C(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Temperature: 60 °C
Reaction time: 34 h

Procedure:
A solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.295 g) in MeCN (1.1 mL) was added dropwise to a solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.150 g) and triethylamine (0.11 mL) in MeCN (1.1 mL) at RT under argon. The resulting mixture was stirred at 60° C. under argon for 34 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM, washed with brine (×2), dried over sodium sulphate, filtered and evaporated in vacuo. The yellow solid was purified by silica gel chromatography eluting with 0-5% MeOH in DCM to give the subtitled compound as a green solid. Yield 0.135 g.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[N+:34]([O-:36])=[O:35].Cl.[C:38]([C:41]1[O:42][CH:43]=[CH:44][CH:45]=1)(=[NH:40])[NH2:39].N1CCOCC1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)C>[O:42]1[CH:43]=[CH:44][CH:45]=[C:41]1[C:38]1[NH:40][C:11]([CH2:10][O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[O:14])[CH:30]([C:29]2[CH:32]=[CH:33][C:26]([CH3:25])=[C:27]([N+:34]([O-:36])=[O:35])[CH:28]=2)[N:39]=1
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: N=C(N)c1ccco1
Reactant: O=C(COCCN1CCCCC1)CC(=O)OCCCc1cccs1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCN1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C2N=C(c3ccco3)NC(COCCN3CCCCC3)=C2C(=O)OCCCc2cccs2)cc1[N+](=O)[O-]
Temperature: 40 °C
Yield: 1.8 %

Procedure:
A mixture of 3-(2-thienyl)propyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (4.0 g, 11.32 mmol), 4-methyl-3-nitrobenzaldehyde (1.87 g, 11.32 mmol), 2-amidinofuran hydrochloride (1.65 g, 11.32 mmol), morpholine (1.48 ml, 16.98 mmol), acetic acid (1.29 ml, 22.64 mmol), and sodium sulfate (3.21 g, 22.64 mmol) was stirred in ethanol (45 ml) for 1 hour at room temperature and then heated to 40° C. for 9 days. The ethanol was removed in vacuo and ethyl acetate was added to the residue. The filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (120 mg) as an oil. Electrospray MS m/z 593 [M+H]+, m/z 297 [M+2H]++.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1.[C:13]1(/[C:19](=[C:21]2/[C:22](=[O:30])[NH:23][C:24]3[C:29]/2=[CH:28][CH:27]=[CH:26][CH:25]=3)/[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)/[C:21](=[C:19](\[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)/[CH3:20])/[C:22]2=[O:30])[CH:6]=1
Reactant: C/C(=C1\C(=O)Nc2ccccc21)c1ccccc1
Reactant: COC(=O)Cc1cccc(Br)c1
Product: COC(=O)Cc1cccc(N2C(=O)/C(=C(\C)c3ccccc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 1 starting from (3-bromo-phenyl)-acetic acid methyl ester (commercially available) and 3-[1-phenyl-eth-(E)-ylidene]-1,3-dihydro-indol-2-one. 1H NMR (400 MHz, DMSO-d6) δppm 2.77 (s, 3H) 3.65 (s, 3H) 3.81 (s, 2H) 6.08 (d, J=7.33 Hz, 1H) 6.66-6.72 (m, 2H) 7.11 (t, J=7.33 Hz, 1H) 7.35-7.44 (m, 5H) 7.51-7.61 (m, 4H).
Reaction SMILES: [Cu][C:2]#[N:3].CN1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].O.C(O[CH2:16][CH3:17])(=O)C>>[O:10]=[C:6]1[CH2:17][CH2:16][C:9]2[CH:9]=[C:8]([C:2]#[N:3])[CH:7]=[CH:6][C:8]=2[CH2:7]1
Reactant: CCOC(C)=O
Reactant: CN1CCCC1=O
Reactant: N#C[Cu]
Solvent: O
Product: N#Cc1ccc2c(c1)CCC(=O)C2
Temperature: 190 °C
Yield: 78 %

Procedure:
See also generally Org. Prep. Proced. Int. Vol. 32, No. 1, 2000, p. 88. Charged 50 mL round bottom flask with copper(I) cyanide (1.34 g., 0.0150 moles, 1.12 eq.), 6-bromo-2-tetraline (3.0 g., 1.33 mmoles, 1.0 eq.) and 13 mL N-methylpyrrolidinone. Heated for 5 hours at 180-200° C. Allowed reaction mixture to stir at room temperature over the weekend. Transferred reaction mixture to 250 mL 3-necked, round bottomed flask fitted with a mechanical stirrer, a condenser, and an addition funnel. Added 6.0 g. Celite® and heated with stirring to 80° C. Added 70 mL water and 90 mL ethyl acetate to hot stirring reaction mixture. Turned off heat and allowed to cool overnight with stirring. The next day, filtered the reaction mixture through a Celite® pad. Partitioned off water layer from filtered reaction mixture. Washed ethyl acetate layer with water once, then washed with a 50:50 mixture of brine and water twice. Dripped organic layer through sodium sulfate to dry and removed solvents under reduced pressure to obtain 2.67 g. of light brown solid. Purified crude material via Biotage FLASH 40 L® cartridge (175 g. of silica gel) using an ethylacetate:hexane stepwise gradient. Obtained 1.77 g. (yield=78%). Product was not completely pure, but used it as is in the next reaction. H-NMR (CDCL3): 7.55 (1H, s), 7.53 (1H, d), 3.64 (2H, s), 3.12 (1H, t, J=7 Hz), 2.58 (1H, t, J=7 Hz.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1([F:46])[CH2:5][CH2:6][N:7]([C:32]([C:34]2[S:38][C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[N:36][C:35]=2[CH3:45])=[O:33])[C:8]2[CH:31]=[CH:30][CH:29]=[CH:28][C:9]=2/[C:10]/1=[CH:11]/[C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]1)=[O:13]>O1CCCC1CCO.C(OCC)(=O)C>[F:46][C:4]1([F:3])[CH2:5][CH2:6][N:7]([C:32]([C:34]2[S:38][C:37]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[N:36][C:35]=2[CH3:45])=[O:33])[C:8]2[CH:31]=[CH:30][CH:29]=[CH:28][C:9]=2/[C:10]/1=[CH:11]/[C:12]([N:14]1[CH2:15][CH2:16][CH:17]([CH:20]([OH:27])[CH2:21][CH2:22][OH:23])[CH2:18][CH2:19]1)=[O:13].[F:46][C:4]1([F:3])[CH2:5][CH2:6][N:7]([C:32]([C:34]2[S:38][C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[N:36][C:35]=2[CH3:45])=[O:33])[C:8]2[CH:31]=[CH:30][CH:29]=[CH:28][C:9]=2/[C:10]/1=[CH:11]/[C:12]([N:14]1[CH2:15][CH2:16][CH:17]([CH:20]([OH:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:19]1)=[O:13]
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)/C=C2/c3ccccc3N(C(=O)c3sc(-c4ccccc4)nc3C)CCC2(F)F)CC1
Agent: OCCC1CCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(O)C1CCN(C(=O)/C=C2/c3ccccc3N(C(=O)c3sc(-c4ccccc4)nc3C)CCC2(F)F)CC1
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(C(O)CCO)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 28 h

Procedure:
Sodium borohydride (36 mg) was added to a solution of 400 mg of ethyl (Z)-3-(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}-4-piperidyl)-3-oxopropionate in 10 ml of tetrahydrofuran-ethanol (1:1), and the mixture was stirred at room temperature for 28 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous solution of NaCl and dried over magnesium sulfate, and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (eluting with chloroform-methanol). The resulting residue was collected by filtration to give 300 mg of (Z)-1-(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}-4-piperidyl)propane-1,3-diol (29a) as a colorless amorphous solid and 90 mg of ethyl (Z)-3-(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}-4-piperidyl)-3-hydroxypropionate (29b) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[OH:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[C:20](=[O:26])[NH:21][CH2:22][C:23]([OH:25])=O.[C:31]([O-])(=[O:33])[CH3:32].[Na+]>C(OC(=O)C)(=O)C>[C:31]([O:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[C:20]1[O:26][C:23](=[O:25])/[C:22](=[CH:9]/[C:8]2[CH:11]=[CH:12][C:5]([O:4][C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[Cl:1])=[CH:6][CH:7]=2)/[N:21]=1)(=[O:33])[CH3:32]
Reactant: O=Cc1ccc(Oc2ccccc2Cl)cc1
Reactant: CC(=O)[O-]
Reactant: O=C(O)CNC(=O)c1ccccc1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccccc1C1=N/C(=C\c2ccc(Oc3ccccc3Cl)cc2)C(=O)O1
Temperature: 60 °C

Procedure:
A suspension of 4-(2-chlorophenoxy)benzaldehyde-(0.193 g, 0.83 mmol, 2-hydroxy hippuric acid (0.147 g, 0.75 mmol) and sodium acetate (0.08 g, 0.975 mmol) in acetic anhydride (0.5 mL) is heated to 60° C. on an orbital shaker for one hour and is cooled to room temperature. The reaction mixture is concentrated under reduced pressure at 45° C. to provide an orange solid. The solid is washed with ice water (150 mL) and heptane (100 mL) and dried under vacuum at 40° C. to provide 0.32 g 2-{(4Z)-4-[4-(2-chlorophenoxy)benzylidene]-5-oxo-4,5-dihydro-1,3-oxazol-2-yl}phenyl acetate.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([NH:9][C:10]1[C:11]2[C:16]([N:17]=[C:18]3[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8].O>CN(C)C=O>[N:1]([CH2:6][C:7]([NH:9][C:10]1[C:11]2[C:16]([N:17]=[C:18]3[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)Nc1c2c(nc3ccccc13)CCCC2
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)Nc1c2c(nc3ccccc13)CCCC2
Yield: 94.7 %

Procedure:
In 40 ml of dimethylformamide was suspended 2.84 g of sodium azide, and 10 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine was added thereto and the mixture was reacted at room temperature for 2 hours. After addition of 32 ml of water to the mixture, precipitated crystals were filtered to give 9.7 g of 9-azidoacetylamino-1,2,3,4-tetrahydroacridine. Melting point: 190° C. (decomposed). These crystals were suspended in 500 ml of methanol, and hydrogenolysis was carried out by adding 0.5 g of palladium black at room temperature for one hour. After removal of the catalyst by filtration, the filtrate was condensed and recrystallized from methanol - isopropanol, and then filtered to give 7.4 g of the title compound. Melting point: 225° to 230° C.
Reaction SMILES: [C:1](OCC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:12](OCC)(=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:8][CH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:19][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccncc1
Reactant: CCOC(=O)c1cccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cccnc1
Product: OCc1ccncc1

Procedure:
In Mosher, Harry S. et al., Journal Of American Chemical Society, 73 October (1951) pp. 4925-4927, 3-chloromethyl and 4-chloromethyl pyridinium hydrochloride was prepared by first reducing ethyl nicotinate and ethyl isonicotinate with lithium aluminum hydride in anhydrous ether to produce 3-hydroxymethyl pyridine and 4-hydroxymethyl pyridine respectively. The resulting liquid 3-hydroxymethyl pyridine was separated from the distillate by converting to the hydrochloride. The 3- and 4-hydroxymethyl pyridine hydrochloride were added to a substantial excess amount of thionyl chloride and then refluxed followed by the addition of benzene to precipitate out the 3- and 4-chloromethyl Pyridine hydrochloride, respectively. Although the resulting 3-chloromethyl pyridine hydrochloride compound appears to be very pure, it apparently exists as a fluffy dusty powder which is difficult to process on a large scale basis.
Reaction SMILES: [N+:1]([C:4]1[C:5]([S:13][CH3:14])=[N:6][C:7]([CH3:12])=[CH:8][C:9]=1[S:10][CH3:11])([O-])=O.O1CCOCC1.[H][H]>[Ni].CO>[NH2:1][C:4]1[C:5]([S:13][CH3:14])=[N:6][C:7]([CH3:12])=[CH:8][C:9]=1[S:10][CH3:11]
Reactant: CSc1cc(C)nc(SC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1COCCO1
Product: CSc1cc(C)nc(SC)c1N
Yield: 85 %

Procedure:
A mixture of 18.9 g (0.082 mol) 3-nitro-2,4-bis(methylthio)-6-methylpyridine and 18.9 g Raney nickel in 600 ml. 1,4-dioxane and 300 ml methanol was shaken with hydrogen (15 psi) in a Parr hydrogenation apparatus for 3.5 hr. The catalyst was filtered and the filtrate was concentrated to dryness in vacuo. The solid residue was chromatographed on silica gel (650 g), eluting with 9:1 hexane/ethyl acetate to yield 14.0 g. (85% yield) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([CH2:26][CH2:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])=[C:24]([CH3:36])[NH:23][C:22]=1[CH:37]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:37][C:22]4[NH:23][C:24]([CH3:36])=[C:25]([CH2:26][CH2:27][C:28]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[O:29])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCOCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (86 mg, 0.31 mmol), 3,5-dimethyl-4-(3-morpholin-4-yl-3-oxo-propyl)-1H-pyrrole-2-carbaldehyde (83 mg, 0.31 mmol) and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 3 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound. MS 525 [M++1].
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3C(=O)[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.C1(C[C@H:33]2[NH:37][C:36](=[O:38])[N:35]([C@H:39]([C:48]3[NH:49]C(C4C=CC(I)=CC=4F)=C(C)[N:52]=3)[C@H:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)C)[C:34]2=[O:62])CC1.[Br:63][C:64]1[CH:69]=[CH:68][C:67]([C:70](=O)[CH2:71][CH3:72])=[CH:66][CH:65]=1.C(OC(N[C@H]([C:86]1[CH:91]=[CH:90][C:89]([O:92][CH2:93][C:94](=[O:98])N(C)C)=[CH:88][CH:87]=1)C(O)=O)=O)(C)(C)C.ClN1C(=O)CCC1=O>>[Br:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[NH:52][C:48]([C@@H:39]([N:35]3[C:34](=[O:62])[C@@H:33]([C:86]4[CH:91]=[CH:90][C:89]([O:92][CH2:93][CH2:94][OH:98])=[CH:88][CH:87]=4)[NH:37][C:36]3=[O:38])[CH2:40][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[N:49][C:71]=2[CH3:72])=[CH:66][CH:65]=1
Reactant: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](CC3CC3)C2=O)[nH]c1-c1ccc(I)cc1F
Reactant: CCC(=O)c1ccc(Br)cc1
Agent: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Agent: O=C1CCC(=O)N1Cl
Product: Cc1nc([C@H](Cc2ccccc2)N2C(=O)N[C@H](c3ccc(OCCO)cc3)C2=O)[nH]c1-c1ccc(Br)cc1

Procedure:
Prepared by the same method as described in example 1 except that (i) steps A, B and C were omitted; (ii) commercially available 1-(4-bromo-phenyl)-propan-1-one was used in place of 1-(2-fluoro-4-iodo-phenyl)-ethanone in step 105-D; (iii) (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid was used in place of (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 105-E and (iv) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 105-F was omitted. HR-MS: calcd for C29H27BrN4O4 [M+H+] 575.1289. Found 575.1286.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Ag:13]=O.[Ag]>C1(C(C)C)C=CC=CC=1>[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10].[Ag+:13].[C:6]1([CH:7]([CH3:9])[CH3:10])[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: O=[Ag]
Reactant: CC(C)(C)CCCCCC(=O)O
Agent: [Ag]
Solvent: CC(C)c1ccccc1
Product: CC(C)(C)CCCCCC(=O)[O-]
Product: [Ag+]

Procedure:
A silver neo-decanoate/cumene solution is prepared from 539.00 gm of neo-decanoic acid (obtained from Exxon Chemical Co.), 350.00 gm of cumene (obtained from Aldrich Chemical Co.), and an excessive amount of silver oxide (392.21 gm) in a similar manner to that described in Example 1 of U.S. Pat. No. 4,663,303. A 496.42 gm sample of this solution is diluted with 19.35 gm of cumene to yield a solution having a weight ratio of silver salt/cumene of 2.2/1.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[CH:16](Br)([CH3:18])[CH3:17]>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([C:8]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cn2cncn2)cc1
Reactant: CC(C)Br
Product: Cc1ccc(C(=Cn2cncn2)OC(C)C)cc1

Procedure:
Analogously to Example 1a,b, after reacting 1-(4-methylphenyl)-2-[1,2,4]triazol-1-yl-ethanone with isopropyl bromide there was obtained 1-[2-(4-tolyl)-2-isopropoxy-vinyl]-1H-[1,2,4]triazole. After reaction with HCl in dioxan there was obtained a salt of the composition C14H17N3O.HCl. [M+H]+=243.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)NCc1ccccc1
Yield: 90 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using benzylamine (20 μL, 0.21 mmol) as the coupling partner. Concentration (no chromatography) yielded 58 mg (90%) of the titled compound. ESI-MS m/z 381 (MH+), 379 (M−H−).