Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([OH:16])[CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH3:2].Cl[CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH2:1]([N:3]([CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:4][CH:5]([OH:16])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1)[CH3:2]
Reactant: CCNCC(O)COc1ccc(C#N)cc1
Reactant: ClCCCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCCSc1ccccc1)CC(O)COc1ccc(C#N)cc1

Procedure:
5.0 g of 4-[3-(ethylamino)-2-hydroxypropoxy]-benzonitrile and 4.0 g of 1-chloro-3-(phenylthio) propane was dissolved in 70 ml of acetonitrile and mixed with 6.4 g potassium carbonate and 8.0 g of sodium iodide. The mixture was refluxed over night, filtrated, evaporated and the residue was dissolved in 2 M hydrochloric acid. This acidic waterlayer was washed with two portions of diethylether, alkalized with 10 M sodium hydroxide and extracted with three portions of dichlorometane. The combined layers of dichloromethane were dried over sodium sulphate and evaporated. The oily residue was purified by column chromatography on silica gel. Yield: 2.1 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=2)[NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C1(N=C=NC2CCCCC2)CCCCC1>CC(C)=O.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([CH:30]([CH2:29][CH2:28][NH2:27])[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[O:26])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=2)[NH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C(CCN)C(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)OCc1ccccc1
Yield: 95 %

Procedure:
85 mmol of N-benzyloxycarbonyl-5-hydroxy-L-tryptophan and 85 mmol of tert.-butyl γ-aminobutyrate are dissolved in 170 ml of acetone and 300 ml of pure chloroform. A solution of 17.7 g (86 mmol) of dicyclohexylcarbodiimide in 80 ml of chloroform is then added and the mixture is stirred at ordinary temperature until the condensation has ended. After evaporation, taking up with ethyl acetate and the customary treatment, 40 g of a crude product are obtained, which are purified by chromatography on a silica column, elution being carried out with a methylene chloride/acetone mixture. This gives 48% of a pure product showing a single spot in TLC on Kieselgel in the system chloroform 20/acetone 6, of Rf=0.45. The NMR spectrum is recorded in solution in CDCl3 : 8.4 ppm (s) (1H) --OH; 7.3 ppm (s) (5H) benzyl; 7.2 to 6.6 ppm (m) (4H) arom; 6.4 ppm (m) (1H) and 5.9 ppm (d) (1H) --NH; 5 ppm (s) (2H) CH2 --Ph; 4.4 ppm (m) (1H) CH(NH)--CO; 3.1 ppm (m) (4H) CH2 --CH(--NH)CO and NH CH2 ; 2.1 to 1.8 ppm (m) 4H: CH2 --CH2 ; 1.4 ppm (s) (9H) tert.-butyl.
Reaction SMILES: ClC1C=C(S([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)(=O)=O)C=C(Cl)C=1.CO[C:35]([C:37]1C=C2C(C=CN2)=CC=1)=O.COC(C1C=C2C(CCN2)=CC=1)=O.COC(C1C=C2C(CCN2C(OC(C)(C)C)=O)=CC=1)=O.C(OC(N1C2C(=CC=C(C(O)=O)C=2)CC1)=O)(C)(C)C.C(OC(=O)C1C=CC(N)=CC=1)C>>[CH2:35]([O:30][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][NH:12]3)=[CH:16][CH:17]=2)=[O:22])=[CH:32][CH:31]=1)[CH3:37]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)cc(Cl)c2)CC3)cc1
Agent: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc21
Agent: CCOC(=O)c1ccc(N)cc1
Agent: COC(=O)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CC2
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1

Procedure:
4-{[1-(3,5-Dichloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=488.9 (M−H), was prepared in analogy to example 14, steps 1 to 6. Step 1 was performed starting from 1H-indole-6-carboxylic acid methyl ester, which was reduced to 2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (see also example 34). This was protected in step 2 to 2,3-dihydro-indole-1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester, which was then hydrolyzed to 2,3-dihydro-indole-1,6-dicarboxylic acid 1-tert-butyl ester in step 3. Step 4 was performed using 4-amino-benzoic acid ethyl ester, yielding 4-[(2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid ethyl ester. This was reacted with 3,5-dichloro-benzenesulfonyl chloride in step 5, yielding 4-{[1-(3,5-dichloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, which was hydrolyzed in step 6.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C(=O)([O-])[O-].[K+].[K+].[CH:11]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1)=[CH2:12]>C(Cl)(Cl)Cl>[CH:11]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:3][CH2:2][CH2:1][NH:4][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([CH:11]=[CH2:12])=[CH:14][CH:15]=2)=[CH:15][CH:14]=1)=[CH2:12]
Reactant: NCCN
Reactant: C=Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc(CNCCNCc2ccc(C=C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.6 %

Procedure:
In a 500 mL, 3-necked round-bottomed flask were taken 5.31 grams of 1,2-ethylenediamine and 32.48 g of anhydrous potassium carbonate, and 300 mL of chloroform. To this suspension was added 30 g of 4-vinylbenzyl chloride. The resulting reaction mixture was stirred at 25° C. for 18 hr. Subsequently the reaction mixture was filtered. The solvent was moved under reduced pressure. To the residue was added 300 mL of deionized water followed by 37% aqueous HCl until the pH of the solution was 2.0. The resulting aqueous solution was extracted with tert-butyl methyl ether (2×250 mL). The aqueous layer was collected and was treated with 40% (w/w) NaOH until the pH of the solution was 11.4. The resulting aqueous solution was extracted with tert-butyl methyl ether (2×250 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure yielding 3 g of the product as a light yellow oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:18][CH:17]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH2:29]([O:33][C:34](=[O:40])[CH2:35][CH2:36][C:37](O)=[O:38])[CH2:30][CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:29]([O:33][C:34](=[O:40])[CH2:35][CH2:36][C:37]([NH:2][C@H:3]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:20][CH:21]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])=[O:38])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOC(=O)CCC(=O)O
Reactant: N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCOC(=O)CCC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A mixture of (R)-benzyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (150 mg, 0.360 mmol), 4-butoxy-4-oxobutanoic acid (107 mg, 0.540 mmol, 88% purity), EDCl (104 mg, 0.540 mmol), DIPEA (0.094 ml, 0.540 mmol) and HOAt (73.6 mg, 0.540 mmol) in DMF (2 ml) is allowed to stir at room temperature for 1 hour. The reaction mixture is diluted with water, and then the precipitated solid is collected on a funnel, washed with H2O, and dried under reduced pressure to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100) to give (R)-benzyl 3-(4-butoxy-4-oxobutanamido)-4-(3′-chlorobiphenyl-4-yl)butanoate (178.9 mg); HPLC retention time=1.47 minutes (condition B); MS (m+1)=536.42; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90-0.94 (m, 3H) 1.31-1.40 (m, 2H) 1.56-1.63 (m, 2H) 2.39-2.42 (m, 2H) 2.48-2.62 (m, 4H) 2.84 (A of ABX, Jab=13.6 Hz, Jax=8.1 Hz, 1H) 2.97 (B of ABX, Jab=13.6 Hz, Jbx=6.6 Hz, 1H) 4.07 (t, J=6.7 Hz, 2H) 4.48-4.56 (m, 1H) 5.12 (A of AB, J=12.1 Hz, 1H) 5.18 (B of AB, J=12.1 Hz, 1H) 6.27 (br d, J=7.7 Hz, 1H) 7.20 (d, J=8.3 Hz, 1H) 7.29-7.39 (m, 7H) 7.42-7.47 (m, 3H) 7.54-7.55 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([OH:10])[CH2:4][C:5]([O:7]CC)=[O:6].[Na].C(O)(=O)CCC.C[C@H](N)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C@H:3]([OH:10])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CC(O)C(F)(F)F
Agent: C[C@H](N)c1ccccc1
Agent: [Na]
Solvent: CCCC(=O)O
Product: O=C(O)C[C@@H](O)C(F)(F)F

Procedure:
According to this process, ethyl (±)-4,4,4-trifluoro-3-hydroxybutanoate is converted to the sodium salt of the corresponding butanoic acid which is hydrolysed to give (±)-4,4,4-trifluoro-3-hydroxbutanoic acid, this acid is reacted with (S)-α-methylbenzylamine, the (S)-α-methylbenzylamine salt of 4,4,4-trifluoro-3(R)-hydroxybutanoic acid is separated from the mixture of diastereoisomers formed by crystallization from ethanol and this salt is then hydrolysed in acid medium to produce 4,4,4-trifluoro-3(R)-hydroxybutanoic acid. 4,4,4-Trifluoro-1,3(R)-butanediol is then obtained by reduction of 4,4,4-trifluoro-3(R)-hydroxybutanoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[OH:33])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]([F:51])([F:52])[F:53])=[CH:46][CH:45]=2)=[CH:40][CH:41]=1)[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccc(CCc2ccc(CCl)cc2)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1cc(F)ccc1O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1cc(F)ccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
2 g (4.36 mmol) of rac-ethyl 5-{(tert-butoxycarbonyl)[2-(5-fluoro-2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 106A), 1433 mg (4.80 mmol) of 1-(chloromethyl)-4-{2-[4-(trifluoromethyl)phenyl]ethyl}benzene and 1507 mg (10.90 mmol) of potassium carbonate in 50 ml of acetonitrile were heated to 110° C. and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed repeatedly with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1→10:1). This gave 2490 mg (3.29 mmol, 95% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.Br[CH2:19][CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]4[C:30](=[O:31])[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]4=[O:32])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenol and 2-(3-bromopropyl)-1H-isoindole-1,3 (2H)-dione using the method described in Example 41.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C@@H:8]2[NH:13][C:12](=O)[CH2:11][NH:10][C:9]2=O)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][C@H:8]2[CH2:9][NH:10][CH2:11][CH2:12][NH:13]2)[CH2:5][CH2:6]1
Reactant: O=C1CNC(=O)[C@H](CC2CCOCC2)N1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: C1CN[C@@H](CC2CCOCC2)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A 250-mL round-bottomed flask was charged with (3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,5-piperazinedione (1.44 g, 6.78 mmol), 50 mL of THF, and LAH (1M in THF, 27.1 mL, 27.1 mmol, Sigma-Aldrich, St. Louis, Mo.). After heating at reflux for 2 h, the mixture was allowed to cool to room temperature. Sodium sulfate decahydrate (10 g) was then added and the mixture was stirred at temperature for 1 h. The mixture was filtered and the filtrate was concentrated to give (2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)piperazine (0.950 g, 5.16 mmol) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[NH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[N:11]([C:28](=[O:29])[NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cccc(-c2n[nH]c(-c3ccccc3C)n2)c1
Solvent: CC#N
Product: COc1cccc(-c2nc(-c3ccccc3C)n(C(=O)Nc3ccccc3)n2)c1
Reaction time: 8 h

Procedure:
A solution of 0.53 g (0.002 mole) of 3-(3-methoxyphenyl)-5-(2-methylphenyl)-1H-1,2,4-triazole and 0.22 ml. (0.002 mole) of phenylisocyanate in 5 ml of acetonitrile was strred for 7 hours at room temperature and, subsequently, it was left standing overnight. The solvent was evaporated off and the obtained residue was first taken up with hexane, then, after separating the liquid and the solid phase by decantation, it was recrystallized from acetonitrile. Yield: 0.25 g of the title compound. M.p. 123°-125° C. Δδ=-0.18.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH:11]1[C:21]2[CH2:20][CH:19]([CH2:22][NH2:23])[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O>[CH:1]([NH:23][CH2:22][CH:19]1[C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=2[CH2:16][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:21]=2[CH2:20]1)=[O:3]
Reactant: NCC1Cc2ccccc2Cc2ccccc21
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=CNCC1Cc2ccccc2Cc2ccccc21
Reaction time: 1 h

Procedure:
A mixture of formic acid and acetic anhydride (1:1, 20 ml) is prepared at 0° to 10° C and added to 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10-methylamine (15.0 g). The mixture is stirred for 1 hr. and then allowed to stand for 18 hr. Water (100 ml) and ice chips are are added. After stirring for 15 min., the mixture is rendered alkaline with dilute NaOH solution and extracted with ether. The extract is washed with water, dried (MgSO4) and concentrated to afford N-formyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10-methylamine, m.p. 109° - 111° C, δmaxCHCl3 3445, 3350, 1685 cm-1, after recrystallization from ether.
Reaction SMILES: [CH2:1](OP(CC(C)=CC(OCC)=O)(OCC)=O)C.C([Li])CCC.CCCCCC.[CH2:29]([N:31]1[C:40]2[C:35](=[CH:36][C:37]([CH:47]([CH3:49])[CH3:48])=[CH:38][C:39]=2/[C:41](/[CH3:46])=[C:42](/[F:45])\[CH:43]=[O:44])[C:34]([CH3:51])([CH3:50])[CH2:33][CH2:32]1)[CH3:30]>C1COCC1.CN1CCCN(C)C1=O>[F:45]/[C:42](=[C:41](/[C:39]1[CH:38]=[C:37]([CH:47]([CH3:48])[CH3:49])[CH:36]=[C:35]2[C:40]=1[N:31]([CH2:29][CH2:30][CH3:1])[CH2:32][CH2:33][C:34]2([CH3:50])[CH3:51])\[CH3:46])/[CH:43]=[O:44]
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)C=O)c21
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)C=O)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2-enoate (210 mg, 0.80 mmol), 10 ml of anhydrous THF, and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.12 ml) under argon at −78° C. was slowly added a 1.6 M solution of n-butyl lithium and hexane (0.52 ml, 0.84 mmol). The resulting mixture was stirred at −78° C. for 30 minutes before a solution of (E)-3-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-2-fluoro-but-2-enal (Intermediate 21, 87 mg, 0.27 mmol) and 3 ml THF was added by cannula. The resulting mixture was stirred at 0° C. for 1 h. The reaction was quenched with saturated NH4Cl, and the product was extracted with ethyl ether. The extract was washed with water, and brine, and dried over Na2SO4. The solution was filtered and concentrated in vacuo. The residue was purified by column chromatography using 5% ethyl acetate in hexane to yield the title compound as a bright yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:10]([CH2:20][CH2:21][OH:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl.O>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:22][CH2:21][CH2:20][N:10]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=[C:9]2[CH3:8])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(-c2ccccc2)cn1CCO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCn2cc(-c3ccccc3)cc2C)cc1
Reaction time: 16 h
Yield: 44.4 %

Procedure:
Triethylamine (2.1 mL, 15.22 mmol) was added to a solution of 2-(2-methyl-4-phenylpyrrol-1-yl)ethanol (1.53 g, 7.61 mmol) in dry dichloromethane (20 mL) at room temperature followed by the addition of p-toluene sulfonyl chloride (1.88 g, 9.89 mmol). The resulting reaction mixture was stirred for 16 h and then diluted with water (30 mL) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (2×25 mL), brine (2×25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to yield the crude compound. Purification by column chromatography over silica gel (100-200 mesh) with gradient elution with 10-12% ethyl acetate in petroleum ether as eluent afforded 2-(2-methyl-4-phenyl-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate (1.2 g, 44%) as a brownish white crystalline solid.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][C@H:5]1[C:10]([O:12]C)=O)#[N:2]>[Ni].CO>[OH:9][C@H:7]1[CH2:8][N:4]2[CH2:3][CH2:1][NH:2][C:10](=[O:12])[C@@H:5]2[CH2:6]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1CC#N
Agent: [Ni]
Solvent: CO
Product: O=C1NCCN2C[C@H](O)C[C@@H]12
Temperature: 80 °C
Reaction time: 9 h
Yield: 48.1 %

Procedure:
(2S,4R)-Methyl 1-(cyanomethyl)-4-hydroxypyrrolidine-2-carboxylate (0.5 g, 2.71 mmol) from Step 1 and methanol (20 mL) were added to Raney®-nickel 2800 water slurry (1.000 g, 17.04 mmol) in a 50 mL pressure bottle. The reaction mixture was stirred for 9 hours under hydrogen (30 psi) at 80° C. The mixture was filtered though a nylon membrane, and the solvent was evaporated in vacuo. The resulting crude oil was purified on a 4 g silica gel cartridge eluted with 20% methanol/dichloromethane over 10 minutes to provide the crude solid product. Further purification on a 4 g cartridge with 20% methanol (2 N ammonia)/dichloromethane afforded (7R,8aS)-7-hydroxy-hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (0.204 g, 1.303 mmol, 48% yield) as a white solid. 1H NMR (500 MHz, pyridine-d5) δ ppm 8.44 (bs, 1H), 6.57 (d, J=4.0 Hz, 1H), 4.68 (d, J=3.2 Hz, 1H), 3.86 (t, J=8.2 Hz, 1H), 3.54-3.45 (m, 1H), 3.30 (dd, J=10.0, 5.8 Hz, 1H), 3.28-3.23 (m, 1H), 2.95 (dd, J=9.9, 3.6 Hz, 1H), 2.88 (dt, J=12.0, 4.2 Hz, 1H), 2.79 (ddd, J=12.1, 9.4, 4.2 Hz, 1H), 2.61-2.55 (m, 2H); MS (ESI+) m/z 157 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]=[C:27]=[O:28]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]([F:17])([F:29])[F:30])=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1ccccc1OC(F)(F)F
Product: COc1ccc(NC(=O)Nc2ccccc2OC(F)(F)F)cc1-c1c(Cl)cnn1C
Yield: 3 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2-trifluoromethoxyphenyl isocyanate in a similar manner as described in Example 1.53, providing 1.5 mg (3%) of Compound 34: LCMS m/z (%)=440 (M+H37Cl, 14), 438 (M+H35Cl, 14). 1H NMR (400 MHz, acetone-d6) δ: 8.19 (s, 1H), 7.90 (s, 1H), 7.43 (d, J=4 Hz, 1H), 7.25 (s, 1H), 7.04 (t, J=12 Hz, 2H), 6.99 (dd, J1=8 Hz, J2=2 Hz, 1H), 6.75 (d, J=4 Hz, 1H), 6.72 (d, J=4 Hz, 1H), 6.66 (d, J=2 Hz, 1H), 3.63 (s, 3H), 3.45 (s, 3H).
Reaction SMILES: C(C1C=C([CH2+]=NC2C=C[C:15]([O:16]C3C=CN=C(C(NC)=O)C=3)=[CH:14]C=2F)N(C2C=CC=C(CO)C=2)N=1)(C)(C)C.[C:38]([C:42]1[CH:46]=[C:45]([NH:47][C:48]([NH:50][C:51]2[CH:67]=[CH:66][C:54]([O:55][C:56]3[CH:61]=[CH:60][N:59]=[C:58]([C:62]([NH:64][CH3:65])=[O:63])[CH:57]=3)=[CH:53][C:52]=2[F:68])=[O:49])[N:44]([C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][OH:76])[CH:70]=2)[N:43]=1)([CH3:41])([CH3:40])[CH3:39].C(Cl)(=O)C>ClCCl>[C:15]([O:76][CH2:75][C:71]1[CH:72]=[CH:73][CH:74]=[C:69]([N:44]2[C:45]([NH:47][C:48](=[O:49])[NH:50][C:51]3[CH:67]=[CH:66][C:54]([O:55][C:56]4[CH:61]=[CH:60][N:59]=[C:58]([C:62](=[O:63])[NH:64][CH3:65])[CH:57]=4)=[CH:53][C:52]=3[F:68])=[CH:46][C:42]([C:38]([CH3:41])([CH3:39])[CH3:40])=[N:43]2)[CH:70]=1)(=[O:16])[CH3:14]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Reactant: CNC(=O)c1cc(Oc2ccc(N=[CH2+]c3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(COC(C)=O)c3)c(F)c2)ccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a 0° C. solution of example 1, (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, (1.00 g, 1.88 mmol) in dichloromethane (15 mL) was added dropwise acetyl chloride (0.15 mL, 2.07 mmol). The reaction mixture was allowed to stir at 0° C. for 1 h. The reaction mixture was quenched with water and extracted with CH2Cl2. The combined organic layer was dried and concentrated. The crude material was purified via column chromatography (CH2Cl2:2M NH3 in MeOH, 97:3) to afford 0.32 g (30%) of the desired product as a white powder. MS m/z 575.1 (M+H)+; Retention time (LC-MS): 3.55 min.