Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)=[CH2:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CO>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C1COCCN1
Reactant: C=Cc1ccc(CCl)cc1
Solvent: CO
Product: C=Cc1ccc(CN2CCOCC2)cc1
Yield: 86.4 %

Procedure:
20 ml (0.14 mol) of 4-vinylbenzylchloride and 25 ml (0.28 mol) of morpholine were refluxed in 150 ml of methanol for 3 h. The mixture was then concentrated in vacuo, and the resulting residue was partitioned between 1M hydrochloric acid and water [sic]. The acidic phase was washed with ether and then made alkaline with 2M sodium hydroxide solution. This aqueous phase was extracted with ether. This organic phase was dried and concentrated in vacuo, resulting in 24.6 g of the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.[CH2:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]1([CH:27]=[CH:26][C:2]2[CH:7]=[CH:6][C:5]3[CH2:8][C:9]4[C:21]5[NH:20][C:19]6[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=6)[C:13]=5[C:12]5[C:22](=[O:25])[NH:23][CH2:24][C:11]=5[C:10]=4[C:4]=3[CH:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Reactant: C=Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(C=Cc2ccccc2)cc1-3
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a solution of 3-bromo-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-9) (100 mg, 0.26 mmol), styrene (30 mg, 0.29 mmol) and triethylamine (0.5 mL) in DMF (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (25 mg). The solution was heated in a sealed reaction tube at 100°-110° C. for 48 hours. The mixture was cooled to ambient temperature, filtered through a pad of Celite®, then the solvent was concentrated at reduced pressure. The product was triturated with MeOH to give 85 mg (80%) of a brown solid. Recrystallization from DMF-Et2O gave the product, Compound I-24, as a tan solid. The melting point was greater than 300° C. The following NMR data were obtained: 1H NMR (DMSO-d6, 300 MHz): δ4.2 (s, 2H), 5.02 (s, 2H), 7.25-7.5 (m, 7H), 7.6-7.75 (m,4H), 7.8 (d, 1H, J=8Hz), 8.2 (s, 1H), 8.6 (s, 1H), 9.4 (d, 1H, J=9 Hz), 12.8 (s, 1H). MS(FAB): m/e 413 (m+1)+.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][C:16]1[N:21]=[C:20]([CH2:22]O)[CH:19]=[CH:18][N:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:22][C:20]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:15])[N:21]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Reactant: Nc1nccc(CO)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nccc(COc2ccc([N+](=O)[O-])c3ccccc23)n1
Temperature: -50 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
A mixture of 4-nitronaphthol (741 mg, 3.92 mmol), (2-aminopyrimidin-4-yl)methanol (31) (700 mg, 3.92 mmol) and PPh3 (1233 mg, 4.70 mmol) in THF (20 mL) was cooled to −50° C. under nitrogen and was treated dropwise over 5 min with DIAD (996 μl, 4.70 mmol). After completion of the addition, the mixture was allowed to warm to RT and stirred for 1 hr. A yellow precipitate forms during this time. After stirring overnight, the volatiles were evaporated and the residue triturated from MeOH (50 mL). The pale yellow solid collected by filtration and washed with diethyl ether (50 mL) to give 4-((4-nitronaphthalen-1-yloxy)methyl)pyrimidin-2-amine (32) (1.1 g, 93%): m/z 297 (M+H)+ (ES+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:36]([CH3:35])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1
Reactant: CNc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(N(C)c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-{4′-[4-(3-bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and N-methylaniline.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O>CO>[CH3:3][C:4]1[CH:5]=[C:6]([CH2:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:17]=[C:18]([C:21]([CH3:24])([CH3:22])[CH3:23])[C:19]=1[OH:20]
Reactant: Cc1cc(C(=O)CCCCCC(=O)O)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CCCCCCC(=O)O)cc(C(C)(C)C)c1O

Procedure:
To a cooled (-5° C.) solution of 103 parts of ethyl 6-chloroformyl hexanoate in 100 parts by volume of ethylene chloride is rapidly added with stirring 133 parts of granular anhydrous aluminum chloride. To this mixture is next added a solution of 88 parts of 2-methyl-6-t-butylphenol in 500 parts by volume of ethylene chloride. The reaction mixture is stirred at -5° C. for 5 hours and then allowed to slowly attain room temperature overnight. At the end of this time the material is poured over ice, rendered acidic with 6N hydrochloric acid and extracted with ether. The combined extracts are successively washed with water, dilute aqueous sodium bicarbonate solution and saturated aqueous sodium bicarbonate solution. After drying over sodium sulfate, the solvent is removed under reduced pressure to yield ethyl 6-(3-methyl-5-t-butyl-4-hydroxybenzoyl)hexanoate, which is saponified with excess potassium hydroxide in methanol. After acidification of the reaction mixture, the solid, comprising 6-(3-methyl-5-t-butyl-4-hydroxybenzoyl)hexanoic acid, is subjected to a Clemmenson reduction as modified by Martin [J.A.C.S. 58, 1438 (1936)] to yield 7-(3-methyl-5-t-butyl-4-hydroxyphenyl)heptanoic acid which is esterified with ethanol and p-toluenesulfonic acid to yield the corresponding ethyl ester.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[NH:13][C@@H:12]1[C@@H:16]([CH3:26])[C:17](=[O:25])[CH2:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S([N:43]=[N+:44]=[N-])(=O)=O)=CC=1>C(#N)C>[N+:43](=[C:18]([C:17](=[O:25])[C@@H:16]([C@@H:12]1[C@@H:11]([C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH3:10])[C:14](=[O:15])[NH:13]1)[CH3:26])[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[N-:44]
Reactant: C=CCOC(=O)CC(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCOC(=O)C(=[N+]=[N-])C(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of allyl (4R)-4-[(2R,3S)-3-{(1R)-1-t-butyldimethylsilyloxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (6.52 g) and triethylamine (6.8 ml) in acetonitrile (50 ml) was added a lM solution (17 ml) of p-toluenesulfonyl azide in acetonitrile at 0°-5° C. and the mixture was stirred at the same temprature for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was triturated with hexane. The precipitates were filtered off. The filtrate was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (80 g) and eluted with a mixture of ethyl acetate and hexane (1:9 V/V) to give allyl (4R)-2-diazo-4-[(2R,3S)-3{(1R)-1-t-butyldimetylsilyloxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (3.78 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH:22]=O>>[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1/[CH:22]=[C:7]1/[C:8](=[O:14])[C:9]2[C:5]([CH2:6]/1)=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2
Reactant: O=Cc1ccncc1Br
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Product: COc1cc2c(cc1OC)C(=O)/C(=C/c1ccncc1Br)C2

Procedure:
The title compound 89 is prepared according to the procedure reported in Example 34.1 with 5,6-dimethoxy-1-indanone (1.92 g, 10 mmol) and 3-bromo-4-pyridinecarboxaldehyde (2.3 g, 10 mmol) as reactants. White solid. (Yield 2.34 g, 65%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[O:11]1CCO[CH:12]1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=1>>[CH:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=2)=[C:18]([O:23][CH3:24])[CH:17]=1)=[O:11]
Reactant: COc1cc(C2OCCO2)ccc1O
Reactant: NC(=O)c1ccc(F)cn1
Product: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)nc1
Yield: 16.2 %

Procedure:
Using a method similar to Example 388 Part D, using 5-fluoropyridine-2-carboxamide (Example 388 Part C) (0.400 g, 2.85 mmol) and 4-[1,3]dioxolan-2-yl-2-methoxyphenol (Example 386, Part C2) (0.560 g, 2.85 mmol) gives the title compound (0.126 g, 16%): MS ES+ 272.9 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 min, S-5 microm). 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min. 5-95% over 19 min], tR=11.1 min. 97.2% purity.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:19][CH3:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][C:32]#[N:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25](/[C:31](=[CH:13]/[C:12]2[CH:15]=[C:16]([O:17][CH3:18])[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:10]([O:19][CH3:20])[CH:11]=2)/[C:32]#[N:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COc1cc(C=O)cc(OC)c1OCCCCCCO
Product: COc1ccc(/C(C#N)=C/c2cc(OC)c(OCCCCCCO)c(OC)c2)cc1OC
Yield: 97 %

Procedure:
(2Z)-2-(3,4-dimethoxyphenyl)-3-{4-[(6-hydroxyhexyl)oxy]-3,5-dimethoxyphenyl}prop-2-enenitrile is prepared starting from 4-[(6-hydroxyhexyl)oxy]-3,5-dimethoxybenzaldehyde and (3,4-dimethoxyphenyl)acetonitrile according the same procedure following for example 10 in 97% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C@@H:45]([CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[CH2:46][C:47]([OH:49])=O)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:65]([O:69][C:70](=[O:77])[NH:71][CH2:72][CH:73]([OH:76])[CH2:74][NH2:75])([CH3:68])([CH3:67])[CH3:66]>CN(C=O)C>[CH2:34]([O:41][C:42](=[O:43])[NH:44][C@H:45]([CH2:46][C:47]([NH:75][CH2:74][CH:73]([OH:76])[CH2:72][NH:71][C:70]([O:69][C:65]([CH3:67])([CH3:66])[CH3:68])=[O:77])=[O:49])[CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)NCC(O)CN
Reactant: O=C(O)C[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(O)CNC(=O)C[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
418.2 mg (1.1 mmol) of HATU and 258.7 mg (2 mmol) of N,N-diisopropylethylamine are added to a solution of 428.5 mg (1 mmol) of (3S)-3,7-bis{[(benzyloxy)carbonyl]amino}heptanoic acid in 30 ml of anhydrous DMF. After stirring at RT for 15 min, 209.2 mg (1.1 mmol) of tert-butyl(3-amino-2-hydroxypropyl)carbamate are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: C1(S(CC[O:12][C:13](=[O:66])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]3[S:34]([CH2:36][C:37]3[C:42]([CH3:43])=[C:41]([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])[CH:40]=[CH:39][N:38]=3)=[O:35])(=[O:24])=[O:23])=[CH:18][C:17]=2[O:50][CH2:51][C:52]([O:54]CCS(C2C=CC=CC=2)(=O)=O)=[O:53])(=O)=O)C=CC=CC=1.C([O-])(O)=O.[Na+:71]>C1COCC1.O>[Na+:71].[Na+:71].[C:52]([CH2:51][O:50][C:17]1[CH:18]=[C:19]([S:22]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]=[C:26]2[S:34]([CH2:36][C:37]2[C:42]([CH3:43])=[C:41]([O:44][CH2:45][C:46]([F:47])([F:48])[F:49])[CH:40]=[CH:39][N:38]=2)=[O:35])(=[O:23])=[O:24])[CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:13]([O-:66])=[O:12])([OH:54])=[O:53].[C:52]([CH2:51][O:50][C:17]1[CH:18]=[C:19]([S:22]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]=[C:26]2[S:34]([CH2:36][C:37]2[C:42]([CH3:43])=[C:41]([O:44][CH2:45][C:46]([F:47])([F:48])[F:49])[CH:40]=[CH:39][N:38]=2)=[O:35])(=[O:23])=[O:24])[CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:13]([O-:66])=[O:12])([OH:54])=[O:53]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)OCCS(=O)(=O)c2ccccc2)c(OCC(=O)OCCS(=O)(=O)c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)[O-])c(OCC(=O)O)c1
Yield: 88.3 %

Procedure:
A solution of (2-(2-benzenesulfonyl-ethoxycarbonylmethoxy)-4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}phenoxy)acetic acid 2-benzenesulfonyl-ethyl ester (Intermediate 30, 500 mg, 0.50 mmol) and NaHCO3 (90 mg, 1.10 mmol, 2.2 eq) in THF-H2O (6 mL-3 mL) was heated to 70° C. for 2 h. Thereafter volatile materials were removed by evaporation under reduced pressure and the residual semi-solid was briefly treated with MeOH-CH2Cl2 (1:1). The resulting solid was collected by filtration to give Compound 12 (300 mg, 74%) as an off-white solid.
Reaction SMILES: [N:1]1([NH:7][C:8](=[O:31])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]=2[CH3:30])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:32]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH:32]1([N:4]2[CH2:5][CH2:6][N:1]([NH:7][C:8](=[O:31])[CH2:9][C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]([C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[C:11]=3[CH3:30])[CH2:2][CH2:3]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COc1ccc2c(c1)c(CC(=O)NN1CCNCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(=O)NN1CCN(C3CCCCC3)CC1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.112 g (0.26 mmol) of N-(piperazin-1-yl)-1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetamide and 0.03 mL (0.25 mmol) of cyclohexanone in 2 mL of anhydrous tetrahydrofuran was added 0.02 mL (0.32 mmol) of acetic acid then 0.078 g (0.37 mmol) of sodium triacetoxyborohydride. The reaction was stirred at room temperature for 20 hr then partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate (20 mL). The organic phase was washed with more bicarbonate (2×20 mL) then dried (MgSO4), filtered and evaporated. Preparative HPLC was used to isolate the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:33][CH:23]2[CH2:22][CH2:21][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[CH:18]=3)[CH2:25][CH2:24]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCCC1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(NC4CCCCC4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-pieridone (400 mg) and cyclohexylamine (134 mg) were react ed in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: [OH2:1].[CH3:2][C:3]([OH:5])=[O:4]>>[C:3]([OH:5])(=[O:4])[CH2:2][C:2]([CH2:2][C:3]([OH:5])=[O:4])([C:3]([OH:5])=[O:4])[OH:1]
Reactant: O
Reactant: CC(=O)O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
A first mixture of water, mustard, vinegar and citric acid was produced as well as a second mixture of the remaining ingredients except for the oil. The two mixtures were then mixed in a heatable “Stephan Cutter UMC 5 electronic” at 600 rpm for approximately 3 minutes (the mayonnaise at a temperature of 60° C. and the dressing at 25° C.). The oil was then added and mixed in for a further minute in the same conditions.
Reaction SMILES: C([NH:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[C:13]=2[C:12]([CH3:21])=[C:11]([CH3:22])[C:10]=1[CH3:23])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[NH2:8][C:9]1[C:17]2[O:16][C:15]([CH3:18])([CH3:19])[C:14](=[O:20])[C:13]=2[C:12]([CH3:21])=[C:11]([CH3:22])[C:10]=1[CH3:23]
Reactant: Cc1c(C)c(NCc2ccccc2)c2c(c1C)C(=O)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c(N)c2c(c1C)C(=O)C(C)(C)O2

Procedure:
Using 7-(benzylamino)-2,2,4,5,6-pentamethyl-1-benzofuran-3 (2H)-one obtained in Reference Example 53, the title compound was synthesized in the same manner as in Reference Example 30. Yield: quantitative. Melting point: 141-142° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3C)ncc1Cl
Yield: 28.8 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (35 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (50 mgs) gave the title compound as an off-white solid (22 mgs). 1H-NMR (CDCl3, 400 MHz): 9.65 (s, 1H), 8.55 (d, J=8.3 Hz, 1H); 8.19 (s, 2H), 7.94 (d, J=8.1 Hz, 1H), 7.65-7.58 (m, 2H), 7.37 (s, 1H), 7.30-7.26 (m, 1H); 7.14-7.10 (m, 2H); 3.31 (s, 3H); 3.28-3.23 (m, 1H), 2.33-2.30 (m, 2H), 2.03 (broad s, 2H), 1.34 (d, J=7.1 Hz, 6H), 1.27 (s, 6H). LC/MS: found 528.15 (M+H)+; MP: 195-197° C.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:10]=[CH:11]2)=[CH:6][CH:5]=1.C(OCC)(=O)C.C(O)C>[Pd]>[CH2:3]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:10]=[CH:11]2)=[CH:6][CH:5]=1)[CH:2]([CH3:20])[CH3:1]
Reactant: CC(C)=Cc1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
To a solution of N-(7-(2-methylprop-1-enyl)isoquinolin-3-yl)cyclopropanecarboxamide (100.0 mg, 0.2891 mmol) in ethyl acetate (10.0 mL, 102 mmol) was added palladium (30.6 mg, 0.0288 mmol) (10 wt % on carbon). The reaction vessel was purged first with nitrogen and then with hydrogen, and stirred at room temperature under a hydrogen balloon for 2 hours. Ethanol (5.0 mL, 86 mmol) and palladium (41.9 mg, 0.0394 mmol) were added, and the reaction maintained at room temperature for 19 hours. The reaction mixture was then filtered through celite and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 54.4 mg (70%) of N-(7-isobutylisoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT=5.079, M+H=269.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.06 (s, 1H), 8.41 (s, 1H), 7.86-7.70 (m, 2H), 7.54 (dd, J=8.6, 1.3 Hz, 1H), 2.62 (d, J=7.1 Hz, 2H), 2.13-2.01 (m, 1H), 1.94 (dp, J=13.4, 6.7 Hz, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.86-0.75 (m, 4H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[CH3:34][NH:35][CH3:36]>>[CH3:34][N:35]([CH3:36])[C:29](=[O:30])[C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: CNC
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N(C)C
Yield: 58 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with dimethylamine to give the title compound as a solid (120 mg, 58%); NMR Spectrum 1.59 (d, 3H), 2.93 (s, 3H), 3.14 (s, 3H), 5.79 (s, 2H), 5.85 (q, 1H), 7.29 (d, 1H), 7.34 (d, 1H), 7.51 (s, 1H), 7.77-7.72 (m, 2H), 7.83 (m, 1H), 8.11 (s, 1H), 8.52 (m, 2H), 9.04 (s, 1H), 11.12 (br s, 1H); Mass spectrum MH+ 474.
Reaction SMILES: [F:1][C:2]1([F:12])[CH2:7][CH2:6][CH:5]([C:8](NC)=[O:9])[CH2:4][CH2:3]1.[CH3:13][Mg+].[Br-].O>C1COCC1>[F:1][C:2]1([F:12])[CH2:7][CH2:6][CH:5]([C:8](=[O:9])[CH3:13])[CH2:4][CH2:3]1
Reactant: CNC(=O)C1CCC(F)(F)CC1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C1CCC(F)(F)CC1
Temperature: -78 °C
Reaction time: 5 h
Yield: 63.8 %

Procedure:
To a solution of 4,4-difluoro-N-methyl cyclohexanecarboxamide (3 g, 14.5 mmol) in THF (20 mL) were added CH3MgBr (5.19 g, 43.5 mmol) in −78° C. The mixture was stirred at −78° C. for 5 hr. Water (10 mL) was added and the mixture was concentrated and extracted by CH2Cl2 (40 mL*3). The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated to give 1-(4,4-difluorocyclohexyl)ethanone (1.5 g, crude) for next step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Cl.[P:11](OCC)([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4][P:11](=[O:12])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: CCOP(=O)(OCC)OCC
Reactant: ClCc1c(Cl)cccc1Cl
Product: CCOP(=O)(Cc1c(Cl)cccc1Cl)OCC

Procedure:
2,6-Dichlorobenzyl chloride (1200 grams) and triethyl phosphate (1115 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated for a period of 60 minutes until the temperature reached 195° C. After this time the mixture was cooled and thereafter distilled under reduced pressure to yield the desired product O,O-diethyl 2,6-dichlorobenzylphosphonate having a boiling point of 158° to 168° C. at 0.4-0.6 mm of Hg pressure.