Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:24])[CH2:14][CH:15]([C:20]([F:23])([F:22])[F:21])[CH2:16][C:17](O)=[O:18])=[C:4]([F:25])[CH:3]=1.[Na].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:24])[CH2:14][CH:15]([C:20]([F:22])([F:21])[F:23])[CH2:16][CH2:17][OH:18])=[C:4]([F:25])[CH:3]=1
Reactant: CC(C)Oc1cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(F)cc1Cl
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(NC(=O)CC(CCO)C(F)(F)F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 150 h
Yield: 39.2 %

Procedure:
To a solution of N-(4'-chloro-2'-fluoro-5'-isopropyloxyphenyl)-3-(trifluoromethyl)glutaramic acid (4.32 g, 11.4 mmol) in 20 ml of tetrahydrofuran, (freshly distilled from sodium/benzophenone) was slowly added 10M borane-methyl sulfide complex (1.18 ml) via syringe. The temperature was maintained at 10°-20° C. with an ice bath while vigorous bubbling was evident. The mixture was allowed to warm slowly to room temperature and stirred 150 hrs while kept under nitrogen, heated to 55° C. for 6 hours, then cooled to room temperature and allowed to stand for 16 hours. The flask was cooled in an ice/water bath, then 7 ml of methanol (MeOH) were added slowly via addition funnel. The reaction mixture became too thick to continue stirring. It was allowed to warm slowly to room temperature, when the stir bar was again able to stir the mixture. The MeOH and THF were removed in vacuo (20-50 Torr) and the residue was flash chromatographed (2"×7" column, 3:1 hexanes/ethyl acetate, 75 ml fractions). Fractions 18-45 were combined and the solvent was removed in vacuo. The residue was dried in the vacuum oven at 50° C. to yield 1.66 g (39% yield) of the pentanamide as a nearly colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([NH:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1
Reactant: NCc1ccccc1
Reactant: Nc1ncc(Cl)cc1/C=C/C(=O)O
Product: Nc1ncc(Cl)cc1/C=C/C(=O)NCc1ccccc1

Procedure:
The title compound was prepared from (E)-3-(2-amino-5-chloro-3-pyridinyl)-2-propenoic acid and benzylamine as a yellow solid:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][O:32][C:31]([CH3:35])([CH3:36])[CH2:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC1(C)CC(CCCBr)CCO1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCOC(C)(C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 224 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(3-bromopropyl)-2,2-dimethyltetrahydro-2H-pyran.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([NH:22][C:23]([N:25]4[C:29]5[N:30]=[CH:31][N:32]=[C:33](Cl)[C:28]=5[CH:27]=[CH:26]4)=[O:24])[CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)(=O)C.[F:39][C:40]([F:49])([F:48])[C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].Cl>C(O)CCC>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([NH:22][C:23]([N:25]4[C:29]5[N:30]=[CH:31][N:32]=[C:33]([NH:44][C:43]6[CH:45]=[CH:46][CH:47]=[C:41]([C:40]([F:39])([F:48])[F:49])[CH:42]=6)[C:28]=5[CH:27]=[CH:26]4)=[O:24])[CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)c1cccc(NC(=O)n2ccc3c(Cl)ncnc32)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCCCO
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1cccc(NC(=O)n2ccc3c(Nc4cccc(C(F)(F)F)c4)ncnc32)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [3-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-amide resin(50 mg, 0.05 mmol), prepared as in reference 1, in n-butanol (2 mL) is mixed with acetyl chloride (17.8 μL, 0.25 mmol) and 3-trifluoromethyl-aniline (31 μL, 0.25 mmol), or only mixed with HCl salt of 3-trifluoromethyl-aniline (50 mg, 0.25 mmol), and shaken at 80° C. for 24 hours. The resulting mixture is filtered and the resin is treated with TFA/CH2Cl2/H2O (45/50/5) (600 μL) for 30 minutes before filtering and washing with CH2Cl2 (3×2 mL), MeOH (3×2 mL). The washes are then combined together and concentrated. The residue is purified by preparative HPLC to give 4-(3-trifluoromethyl-phenylamino)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [3-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-amide (19.0 mg, yield 64%). 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.16 (s, 1H), 10.09 (s, 1H), 8.69 (s, 1H), 8.31 (s, 1H), 8.22 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.92 (d, J=3.9 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.63 (d, J=6.9 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.13 (d, J=4.0 Hz, 1H), 6.95 (d, J=9.0 Hz, 2H), 3.74 (t, J=4.6 Hz, 4H), 3.08 (t, J=4.7 Hz, 4H); ESIMS m/z 602.20 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH:8]=[C:7]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)cc(Cl)c2C1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Clc1cc(Cl)c2c(c1)CCC(N1CCCC1)=C2

Procedure:
30.0 g of 6,8-dichloro-3,4-dihydro-2(1H)-naphthalenone were boiled at reflux for 2 hours in 250 ml of benzene and 11.5 ml of pyrrolidine in the presence of 0.5 g of anhydrous p-toluenesulphonic acid. For purification, the 1-(6,8-dichloro-3,4-dihydro-2-naphthyl)pyrrolidine obtained was triturated with 150 ml of isopropyl ether. The filtered-off solid exhibits a melting point of 84°-86°. A further portion of melting point 84.5°-85.5° can be isolated from the mother liquors. The two portions were combined and, after recrystallization from isopropyl ether, there was obtained 1-(6,8-dichloro-3,4-dihydro-2-naphthyl)pyrrolidine of melting point 85.5°-86°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@H:10]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34]([NH2:36])=[O:35])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37](OC(=O)C)(=[O:39])[CH3:38]>CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34](=[O:35])[NH2:36])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:11][C@H:12]1[CH2:13][O:14][C:37](=[O:39])[CH3:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3C[C@@H](CO)N(C(=O)OC(C)(C)C)C3)c12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)OC[C@@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CN1C(=O)OC(C)(C)C

Procedure:
Prepared analogously to example 96.4 from 4-[2-((3S,5S)-1-tert-butoxycarbonyl-5-hydroxymethyl-pyrrolidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid amide and acetic anhydride. The acetic anhydride was added at 0° C. and a catalytic amount of DMAP was used.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Br)[C:10]=1/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]([Si:48]([CH3:57])([CH3:56])[O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]=O)([CH3:47])([CH3:46])[CH3:45]>C(#N)C.O1C(CC)C1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH:54][CH2:53][CH2:52][CH2:51][CH2:50][O:49][Si:48]([C:44]([CH3:45])([CH3:47])[CH3:46])([CH3:57])[CH3:56])[C:10]=1/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(CBr)cccc1OCCCC(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)OCCCCC=O
Agent: CCC1CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)/C=C/c1c(C=CCCCCO[Si](C)(C)C(C)(C)C)cccc1OCCCC(=O)OCC
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A solution of 4-[3-bromomethyl-2-((E)-2-ethoxycarbonyl-vinyl)-phenoxy]-butyric acid ethyl ester (2.0 mmol, 798 mg) and triphenylphosphine (2.2 mmol, 577 mg) in acetonitrile (12 mL) was heated to reflux for 1 h under nitrogen atmosphere. Then, it was cooled to room temperature and a solution of 5-(tert-butyl-dimethyl-silanyloxy)-pentanal (2.8 mmol, 606 mg) in 1,2-epoxybutane (22 mL) was added at room temperature and the mixture was again heated to reflux for 15 h. During this period, the mixture first turned to a brick red color and at the end of the reaction it had become a pale yellow solution. Then, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was dissolved in a solution of ethyl acetate and hexanes (1:3, 150 mL) and the resulting cloudy solution was washed with a mixture of methanol and water (2:1, 225 mL). The aqueous layer was extracted one more time with ethyl acetate and hexanes (1:3, 50 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave light brown oil. The crude mixture was purified by using a Biotage™ (40 L) column chromatograph eluting with 5 and 15% ethyl acetate in hexanes to obtain the desired 4-[3-[6-(tert-butyl-dimethyl-silanyloxy)-hex-1-enyl]-2-((E)-2-ethoxycarbonyl-vinyl)-phenoxy]-butyric acid ethyl ester (760 mg, 74%) as a colorless oil: ES(+)-HRMS m/e calculated for C29H46O6Si (M+Na)+ 541.2956. found 541.2953.
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:14])[C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>CN(C)C=O.O>[CH3:17][CH:18]([CH3:20])[CH2:19][N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:14])[C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)CBr
Reactant: Nc1nc2ccccc2c2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 100 °C

Procedure:
To a stirred suspension of 1.0 g (0.0054 mole) of 1H-imidazo[4,5-c]quinolin-4-amine in 10 mL of N,N-dimethylformamide was added 0.15 g (0.0059 mole) of sodium hydride. To this stirred mixture was added 0.74 g (0.0054 mole) of isobutyl bromide. After 30 minutes the mixture was heated at about 100° C. for one hour. The mixture was cooled to about 20° C., diluted with 20 mL of water, and the solid was separated by filtration. Recrystallization from N,N-dimethylformamide provided the known antiviral agent 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[C:16](=[O:17])[CH:15]3[CH2:18][CH2:19][CH:12]2[CH2:13][CH2:14]3)=[CH:5][CH:4]=1)#[CH:2].C([Li])CCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[O:17]=[C:16]1[CH:15]2[CH2:18][CH2:19][CH:12]([CH2:13][CH2:14]2)[N:11]1[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:21][CH:20]=1
Reactant: C#Cc1ccc(OCCCN2C(=O)C3CCC2CC3)cc1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Product: CCOC(=O)C#Cc1ccc(OCCCN2C(=O)C3CCC2CC3)cc1

Procedure:
In the a) route at scheme 2,2-azabicyclo[2.2.2]octan-3-one(isoquinuclidine-3-one) (4) is treated with sodium hydride (NaH) in DMF, then it is reacted with the intermediate as above (3) in the presence of potassium iodide to yield 2-[3-(4-ethynylphenoxy)propane-1-yl]-2-azabicyclo[2.2.2]octane-3-one (compound 5). Further, compound 5 is treated with n-butyl lithium (n-BuLi), then it is reacted with ethyl chloroformate to obtain ethyl 4-[3-(3-oxo-2-azabicyclo[2.2.2]octan-2-yl)propoxy]phenylpropiolate (compound 6). Then 4-[3-(3-oxo-2-azabicyclo[2.2.2]octan-2-yl)propoxy]phenylpropiolic acid (compound 7) is provided by the hydrolysis of compound 6 using 10% sodium hydroxide in water solution (10% NaOHaq).
Reaction SMILES: [CH3:1][CH:2]([C:12]1[C:20]2([CH3:21])[CH:15]([CH:16]([O:22][Si](C)(C)C)[CH2:17][CH2:18][CH2:19]2)[CH2:14][CH:13]=1)[CH2:3][C:4]#[C:5][C:6]([CH2:10][CH3:11])([OH:9])[CH2:7][CH3:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O.[Cl-].[Na+].O>[CH3:1][CH:2]([C:12]1[C:20]2([CH3:21])[CH:15]([CH:16]([OH:22])[CH2:17][CH2:18][CH2:19]2)[CH2:14][CH:13]=1)[CH2:3][C:4]#[C:5][C:6]([CH2:10][CH3:11])([OH:9])[CH2:7][CH3:8]
Reactant: CCC(O)(C#CCC(C)C1=CCC2C(O[Si](C)(C)C)CCCC12C)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)(C#CCC(C)C1=CCC2C(O)CCCC12C)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a stirred solution of 1.178 g (3.12 mmole) of [1(R*),3aR* (3aα,4β,7aβ)]-3a,4,5,6,7,7a-hexahydro-1-[1-methyl-5-ethyl-5-hydroxy-3-heptynyl)-7a-methyl-4-[(trimethylsilyl)oxy]-3H-indene in 15 ml anhydrous tetrahydrofuran was added 6 ml (6 mmole) of 1M tetrabutyl ammonium fluoride. The reaction mixture was stirred at room temperature overnight in an argon atmosphere. It was then diluted with 150 ml of water-brine 1:1 and extracted thoroughly with ethyl acetate. The combined extracts were washed with 2×30 ml water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH chromatography to give 900 mg (94.5%) of the title compound, as a white crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]=2[NH:6][CH2:5][C:4]2=[CH:13][CH:14]=[CH:15][N:3]12.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([N:6]1[C:7]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[N:3]2[CH:15]=[CH:14][CH:13]=[C:4]2[CH2:5]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CN1c2ccncc2NCc2cccn21
Product: CC(=O)N1Cc2cccn2N(C)c2ccncc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 20 ml of acetic anhydride and 4.0 g of 10,11-dihydro-5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine was stirred at room temperature for two hours. The mixture was then evaporated, the residue dissolved in water, and the aqueous layer extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrate was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate) to afford 2.3 g of 11-acetyl-10,11-dihydro-5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine as an oil which solidified upon standing (mp 125°-130° C.). The solid was dissolved in ethanol and acidified with an ethanol solution of maleic acid. Dilution with diethyl ether precipitated 2.25 g (31.4%) of the corresponding maleate, mp 139°-141° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[CH3:25][C:26]1([CH3:36])[O:31][CH2:30][C:29]([C:33](O)=[O:34])([CH3:32])[CH2:28][O:27]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][N:8]([C:33]([C:29]3([CH3:32])[CH2:28][O:27][C:26]([CH3:36])([CH3:25])[O:31][CH2:30]3)=[O:34])[CH2:7][CH2:6]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)[C:22]#[C:23][CH3:24]
Reactant: CC1(C)OCC(C)(C(=O)O)CO1
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1

Procedure:
Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylate was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in dimethylformamide (10 ml), (2,2,5-trimethyl-1,3-dioxan-5-yl)carboxylic acid (224 mg, 1.29 mmol), 1-hydroxybenzotriazole (209 mg, 1.56 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (346 mg, 1.81 mmol), and N-methylmorpholine (0.212 ml, 1.94 mmol), to obtain 385 mg (59%) of the product as a solid. HR-MS: m/z Calculated for C25H33NO8S 508.2000; Found 508.1998.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)C.CN(C=O)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:18](=[O:20])[NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
A reaction mixture of BOC-L-4-iodophenylalanine (10 g, 25.6 mmol), tert-butylamine (2.19 g, 30 mmol), DMF (25 mL), HBTU (9.7 g, 25.6 mmol), and diisopropylethylamine (6.6 g, 51 mmol) was stirred for 2 hours. The mixture was diluted with 40 mL of diethylether, washed with 1N HCl (2×25 mL), saturated NaHCO3 (2×25 mL), and saturated solution of brine (2×25 mL). The organic layer was separated, dried with Na2SO4, and evaporated to dryness. The crude was purified by column chromatography (silica gel, 25% EtOAc/hexanes) to yield the title compound (10.2 g).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[N:22]1([CH2:21][CH2:20][N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[NH2:6])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Nc1ncc[nH]1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: Nc1nccn1CCN1CCCCC1
Temperature: 100 °C
Yield: 22.6 %

Procedure:
2-Aminoimidazole monosulfate (500 mg, 1.89 mmol) and potassium carbonate (580 mg, 4.16 mmol) were suspended in DMF (2 mL) and chloroethyl piperidine mono hydrochloride (766 mg, 4.16 mmol) was added. The reaction was heated at 100° C. for 2.5 hours before being cooled to room temperature and filtered. The filtrate was concentrated and purified by column chromatography (95:4.5:0.5 dichloromethane:methanol:aqueous ammonia) and the product was isolated as a brown oil (83 mg, 11%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH:18](=[C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH:18](=[C:22]1[CH2:27][CH2:26][N:25]([CH2:14][C@@H:13]([CH3:16])[CH2:12][N:7]2[C:6]3[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Reactant: CCCC=C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)COc3ccc(F)cc32)CC1
Yield: 54 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF04)_(0.718 g, 2.06 mmol) and 4-Butylidenepiperidine (0.301 g, 2.16 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF06) (0.40 g, 54%). 1HNMR(CDCl3) δ 7.01 (dd, J=3.0 Hz, J=10.2 Hz, 1H), 6.90 (dd, J=5.4 Hz, J=8.6 Hz, 1H), 6.89-6.63 (m, 1H), 5.12 (t, J=7.4 Hz, 1H), 4.63-4.51 (m, 2H), 4.02-3.89 (m, 1H), 2.51-2.44 (m, 2H), 2.32-2.23 (m, 5H), 2.21-2.15 (m, 5H), 2.11-2.03 (m, 1H), 1.98-1.93 (m, 2H), 1.39-1.29 (m, 2H), 0.91-0.86 (m, 6H); 13C NMR (CDCl3) δ 164.8, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.7 Hz), 136.2, 130.0 (d, J=10.8 Hz), 122.7, 117.6 (d, J=9.3 Hz), 109.5 (d, J=23.1 Hz), 103.4 (d, J=29.1 Hz), 67.8, 63.7, 56.6, 55.8, 45.7, 36.2, 29.4, 29.3, 28.4, 23.3, 17.0, 13.9.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]2[C:12]3[C:17]([C:18]([CH2:19][C:20]#[N:21])=[C:4]2[NH:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.CO.N>CN(C=O)C.C(O)C.[Ni]>[NH2:21][CH2:20][CH2:19][C:18]1[C:17]2[C:12]([N:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2](=[O:1])[NH:3][C:4]=13)=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: N#CCc1c2ccccc2n2c1[nH]c(=O)c1ccccc12
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CO
Product: NCCc1c2ccccc2n2c1[nH]c(=O)c1ccccc12

Procedure:
(5-Oxo-5,6-dihydro-indolo[1,2-a]quinazoline-7-yl)-acetonitrile (0.5 g, 1.83 mmol) (example 15) is dissolved in DMF (25 ml) and MeOH with 10% NH3 (25 ml) and catalytically hydrogenolized with Raney-Nickel (0.2 g) in ethanol at 50° C. for 9 h. The catalyst is removed by filtration. The product spontaneously crystallizes from the filtrate giving 0.23 mg (46%) slightly greenish crystals. m.p.: >300° C. ES-MS(+): 278 (M+1).
Reaction SMILES: Cl.[NH:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][N:5]=1)[NH2:3].[CH3:14]C(C)=O>>[CH3:14][C:7](=[N:6][NH2:5])[CH3:8].[NH:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][N:5]=1)[NH2:3]
Reactant: CC(C)=O
Agent: Cl
Agent: NNc1nncc2ccccc12
Product: CC(C)=NN

Procedure:
1-hydrazinophthalazine HCL (395 mg; 2 mmoles) is dissolved in 2.5 ml of acetone and allowed to react for 1 hour. The solvent is evaporated and the slightly yellow material is dried in vacuo to yield 411 mg of 1-hydrazinophthalazine acetone hydrazone. (99% of theoretical yield). [British Journal of Pharmacology 61: 345-349 (1977)].
Reaction SMILES: C(N[C:4]([NH:9][CH2:10][C:11]#C)=[N:5][CH2:6][CH2:7]S)#N.[C:13]([NH:15][C:16]([NH:21][CH:22]([C:24]#[CH:25])[CH3:23])=[N:17][CH2:18][CH2:19][SH:20])#[N:14]>>[C:13]([NH:15][C:16]([NH:17][CH2:18][CH2:19][S:20][CH2:11][C:10]1[NH:9][CH:4]=[N:5][C:6]=1[CH3:7])=[N:21][CH:22]([C:24]#[CH:25])[CH3:23])#[N:14]
Reactant: C#CC(C)NC(=NCCS)NC#N
Reactant: C#CCNC(=NCCS)NC#N
Product: C#CC(C)N=C(NC#N)NCCSCc1[nH]cnc1C

Procedure:
The general procedure of Example 1C is repeated except that the N-cyano-N'-propargyl-N"-(2-mercaptoethyl)guanidine utilized therein is replaced by an equimolar amount of N-cyano-N'-(3-butyn-2-yl)-N"-(2-mercaptoethyl)guanidine, and the title product is thereby produced.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:21]([CH3:23])[CH3:22])[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[S-:24][C:25]#[N:26].[Na+].Cl>C(O)(=O)C>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[NH:26][C:25](=[S:24])[NH:2][C:3]=2[CH:21]([CH3:23])[CH3:22])[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]=1[OH:16])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)C(N)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: N#C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1[nH]c(=S)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 23.2 %

Procedure:
By following the same procedure as in Example 8 using 3.4 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-1-butanone hydrochloride, 1.6 g of sodium thiocyanate, 1 ml of concentrated hydrochloric acid, and 31 ml of acetic acid and recrystallizing the reaction product from water-containing isopropanol, 0.8 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2-thioxo-4-imidazoline was obtained.