Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[NH:12][C:11]2=[O:24])=[CH:6][CH:5]=1.[Br:27]Br>C(O)(=O)C>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([Br:27])=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[NH:12][C:11]2=[O:24])=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: O=c1cc(-c2ccccc2Cl)[nH]c(=O)n1-c1ccc(OC(F)(F)F)cc1
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2Cl)c(Br)c(=O)n1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
3.8 g of 3-(4-trifluoromethoxyphenyl)-6-(2-chlorophenyl)-2,4(1H,3H)-pyrimidinedione was added to 75 ml of acetic acid, followed by dropwise addition of 1.7 g of bromine to the solution with stirring at room temperature. The reaction mixture was further stirred for 2 hours and then the solvent was distilled away under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate, washed with an aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous sodium sulfate. Then the solvent was distilled away to obtain 4.5 g of a crude product. This crude crystal product was washed with heated diisopropyl ether and dried to obtain 4.1 g of the objective compound.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[CH2:14][N:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:21][CH:20]=2)[C:16](=[O:18])[CH3:17])[CH:9]=[CH:10][CH:11]=1)(=[NH:5])[NH2:4].Cl.[C:33](=[NH:38])(OCC)[CH3:34].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[C:33]([N:29]1[CH2:28][CH2:27][CH:26]([O:25][C:22]2[CH:21]=[CH:20][C:19]([N:15]([CH2:14]/[CH:13]=[CH:12]/[C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:3](=[NH:4])[NH2:5])[CH:7]=3)[C:16](=[O:18])[CH3:17])=[CH:24][CH:23]=2)[CH2:31][CH2:30]1)(=[NH:38])[CH3:34]
Reactant: CC(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CO
Product: CC(=N)N1CCC(Oc2ccc(N(C/C=C/c3cccc(C(=N)N)c3)C(C)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 157.1 %

Procedure:
To a solution of N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]acetamide dihydrochloride (400 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (320 mg) and triethylamine (0.60 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 15% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (342 mg, yield 79%) as a colorless amorphous solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.CCN(C(C)C)C(C)C.[Br:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[C:21]([CH:36]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([Cl:35])([F:34])[F:33])=[CH:27][CH:26]=1)=[O:23].CCOC(C)=O>CC(O)C>[Br:16][C:17]1[C:18]([N:1]2[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]2)=[N:19][CH:20]=[C:21]([CH:36]=1)[C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([Cl:35])([F:33])[F:34])=[CH:29][CH:30]=1)=[O:23]
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
(R)-Pyrrolidin-3-ol (9.55 g, 109.6 mmol) and DIPEA (35.1 ml, 201.3 mmol) were added to a suspension of 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 9.3, 37.7 g, 91.5 mmol) in iPrOH (65 mL) and stirred at 140° C. for 1 h. EtOAc (700 mL) was added and the solution was washed 1N HCl (2×200 mL), sat. NaHCO3 (200 mL) and brine (2×200 mL), dried over Na2SO4, and the solution was concentrated under reduced pressure until crystallization commenced. n-Heptane (1 L) were added and the mixture was stirred at RT for 30 min, filtered and washed with iPr2O (500 mL) to afford the title compound as a white crystalline solid. HPLC (Condition 5) tR=6.68 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=462.2/464.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.78-2.01 (m, 2H) 3.55 (d, J=11.34 Hz, 1H) 3.66-3.75 (m, 1H) 3.79-3.93 (m, 2H) 4.34 (br. s, 1H) 4.98 (d, =3.13 Hz, 1H) 7.32 (d, J=8.99 Hz, 2H) 7.84 (d, J=8.99 Hz, 2H) 8.33 (d, J=1.96 Hz, 1H) 8.66 (d, J=1.96 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCCCC5)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (15.0 mg, 0.034 mmol) in DCM (2 mL) was added piperidine (4.0 ul, 0.04 mmol). The reaction solution was stirred at ambient temperature for 1 hr prior to addition of NaBH(OAc)3 (23.0 mg, 0.109 mmol). The resulting mixture was stirred overnight at ambient temperature after which time the solvent was removed under reduced pressure. The resulting residue was dissolved in 1.2 mL DMSO and all undissolved solid was filtered off. This DMSO solution of crude product was purified by reverse phase HPLC(H2O/CH3CN, 0.1% TFA 10-90%) to give the title compound (8.8 mg, 50.5%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:13]O>O1CCOCC1>[CH3:13][O:10][C:9]([C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][N:4]=1)=[O:11]
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ncc(F)cc1F
Temperature: 60 °C
Yield: 86 %

Procedure:
3,5-Difluoropicolinic acid (1.40 g, 8.78 mmol) was dissolved in 30 mL MeOH and 0.5 mL 4.0 M HCl in 1,4-dioxane. The mixture was heated at 60° C. for 1.5 h and concentrated. Saturated aqueous NaHCO3 was added. The mixture was extracted with EtOAc, dried over Na2SO4, and concentrated to give a yellow solid (1.30 g, 86% yield). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=2.27 Hz, 1 H) 7.28-7.47 (m, 1 H) 4.03 (s, 3 H); LCMS for C7H5F2NO2 m/z 174.00 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH:23]([CH3:25])[CH3:24]>>[CH:23]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)([CH3:25])[CH3:24]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CC(C)Br
Product: CC(C)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 152 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-bromopropane and conditions outlined in procedure V. M.p.=197-198° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.92-7.88 (m, 1H), 7.82-7.74 (m, 2H), 7.6-7.52 (m, 1H), 3.06 (s, 2H), 2.8-2.63 (m, 3H), 2.6-2.48 (m, 2H), 2.1-1.94 (m, 2H), 1.85-1.7 (m, 2H), 1.01 (d, J=3.1 Hz, 6H); LCMS: 344 [M+H].
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2
Reactant: Fc1cccc(F)c1
Reactant: Brc1ccc2ncccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Fc1cccc(F)c1-c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
A 1.55 M solution of n-butyllithium (40 ml) in hexanes was added dropwise to a stirred solution of 1,3-difluorobenzene (5.7 g) in 150 ml of dry tetrahydrofuran at -78° C. After one hour at -78° C. a solution of anhydrous zinc chloride (10.22 g) in 40 ml of tetrahydrofuran was added. After a further 10 minutes at -78° C., 9.36 g (45 mmoles) 6-bromoquinoline was added neat followed by tetrakistriphenylphosphine palladium (2.5 g, 2.16 mmoles). The solution was then allowed to warm slowly to room temperature and heated to 40° C. for 12 hours. The mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The pH was adjusted to 9 and the product was extracted with ethyl acetate, dried over MgSO4 ; filtered and concentrated in vacuo to give a white solid (9.5 g, 88%) of m.p. 112°-113° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.N1C=CC=CC=1.[N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[NH:41][C:40]=1[S:48](Cl)(=[O:50])=[O:49]>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:48]([C:40]3[NH:39][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)(=[O:49])=[O:50])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: O=S(=O)(Cl)c1nc2ccccc2[nH]1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4nc5ccccc5[nH]4)ccc3N2)=C(O)c2ccccc21
Yield: 45 %

Procedure:
A mixture of Example 39H (47.6 mg, 0.10 mmol), pyridine (64 mg, 0.80 mmol), and 2-benzimidazole sulfonyl chloride (87 mg, 0.40 mmol, prepared according to the procedure reported by S. M. Deshpande et al, J. Med. Chem. 1970,13, 143-144) in acetone (2 mL) was stirred at rt for 16 h. The reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with 99:1 dichloromethane/methanol to provide the title compound (28.0 mg, 45% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.39 (m, 1H) 0.67 (d, J=6.62 Hz, 3H) 0.70 (d, J=6.62 Hz, 3H) 0.77 (m, 1H) 1.29 (m, 1H) 1.54 (s, 3H) 2.04 (m, 1H) 2.19 (m, 1H) 7.35 (dd, J=6.25, 2.94 Hz, 2H) 7.51 (m, 1H) 7.64 (m, 8H) 8.13 (d, J=7.72 Hz, 1H) 11.51 (s, 1H) 13.77 (s, 1H). MS (ESI+) m/z 620.0 (M+H)+, 641.9 (M+H−Na)+, (ESI−) m/z 618.0 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[C:7]([C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:32][CH:31]=1>CN1CCCC1=O>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][N:38]2[CH2:39][CH2:40][N:41]([C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[NH:5][CH:4]=[C:3]4[C:1]#[N:2])=[O:14])[CH2:42][CH2:43]2)=[CH:32][CH:31]=1
Reactant: N#Cc1c[nH]c2c(C(=O)O)cccc12
Reactant: Fc1ccc(CCN2CCNCC2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: N#Cc1c[nH]c2c(C(=O)N3CCN(CCc4ccc(F)cc4)CC3)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 g (0.027 mol) of 3-cyanoindole-7-carboxylic acid are dissolved in 40 ml of hot N-methylpyrrolidone, the solution is cooled to 40°, and 7.6 g (0.027 mol) of N,N-carbonyldiimidazole are added. The mixture is stirred at room temperature for a further one hour. A suspension of 1-(2-(4-fluorophenyl)ethyl)piperazine dihydrochloride in 40 ml of N-methylpyrrolidone is subsequently poured in. After 5 minutes, a clear solution is formed and just afterwards white crystals deposit. The mixture is stirred overnight at room temperature. The crystals are filtered off with suction, washed and dried, giving 5 g of 7-{4-[2-(4-fluorophenyl)ethyl]piperazin-1-carbonyl}-1H-indole-3-carbonitrile as the free base having a melting point (m.p.) of 192.0-193.5°.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[CH2:15][OH:16].F[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=1.[Cl-].[Na+]>C1COCC1>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:16][CH2:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH3:3])[N:19]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Cc1cccc(F)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(OCc2c(-c3ccccc3)noc2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 48 mg, 1.1 mmol) in THF (1.5 mL) was added a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (189 mg, 1.0 mmol) in THF (3 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of 2-fluoro-6-methylpyridine (122 mg, 1.1 mmol) in THF (3 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title compound (135 mg, 48%) which was obtained as a yellow oil. MS: m/e=281.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[C:11]([Cu])#[N:12]>CN1C(=O)CCC1.[Cu]I>[NH2:7][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([F:10])=[C:2]([CH:8]=1)[C:11]#[N:12]
Reactant: N#C[Cu]
Reactant: Cc1cc(F)c(Br)cc1N
Agent: [Cu]I
Solvent: CN1CCCC1=O
Product: Cc1cc(F)c(C#N)cc1N
Temperature: 195 °C
Yield: 36 %

Procedure:
A mixture of 5-bromo-4-fluoro-2-methylaniline (2.04 g, 10.0 mmol), CuCN (889 mg, 10.0 mmol) and CuI (1.9 g, 10.0 mmol) in NMP was purged with N2 for 5 minutes and then sealed and heated at 195° C. for 30 minutes under microwave condition. The mixture was subjected to standard aqueous workup to give a residue which was purified by silica chromatography to yield 5-amino-2-fluoro-4-methylbenzonitrile (51) (540 mg, 36% yield). MS m/z 151.0 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:29][CH2:26][CH2:27][CH3:28])[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: CCCN
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Solvent: COCCOC
Product: CCCNc1nc(N)nc(-c2cc(OC)c(OC)c(OC)c2)c1C#N

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile and propylamine in DME. ES-MS m/e (%): 382 (M+K+, 10), 366 (M+Na+, 20), 344 (M+H+, 100).
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:29][C:30]#[N:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[CH2:29][C:30]#[N:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCl
Reactant: COc1ccc(N2CCNC(Cc3ccccc3)C2)cc1OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(CC#N)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 60 °C
Yield: 57.2 %

Procedure:
Into a 25 mL screw-cap vial were added 3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (104 mg, 0.28 mmol), chloroacetonitrile (25 μL, 0.39 mmol), K2CO3 (88 mg, 0.64 mmol), and DMF (2 mL). The reaction mixture was heated at 60° C. for 8 h then cooled to room temperature. The reaction mixture was concentrated and adsorbed onto silica gel then purified by silica gel flash chromatography with a 0-10% MeOH/CH2Cl2 gradient to afford product as a light green solid (65 mg, 57%). LC/MS (Method B) 3.84 min, [M+1]+ 406.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@@H:31]([C:38]([NH2:40])=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][C:25](=[O:27])[OH:26])=[O:21])[CH2:17][CH2:18][CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[ClH:48].SC(O)C>O1CCOCC1>[NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@@H:31]([C:38]([NH2:40])=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][C:25](=[O:26])[OH:27])=[O:21])[CH2:17][CH2:18][CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[ClH:48]
Reactant: CCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Agent: CC(O)S
Agent: Cl
Solvent: C1COCCO1
Product: CCC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Yield: 99 %

Procedure:
1.50 g (2.30 mmoles) of BOC-Trp-Nva-Asp-D-Phg-NH2 are treated with 20 ml of 4 n hydrochloric acid in dioxane in the presence of 0.77 ml (11 moles) of mercaptoethanol. After 30 minutes the suspension is evaporated in vacuo, the solid residue is admixed with ether, and the suspension is filtered. 1.34 g (99.0 %) of H-Trp-Nva-Asp-D-Phg-NH2.HCl are obtained; m.p.: 216° C. (decomposition), Rf7 :0.30, [α]D :-53.3° (c: 1.0, in dimethyl formamide).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)=[O:21])([CH2:14][CH2:13]1)[CH2:18][CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: CN1CCN(C(=O)C23CCC(N(CC(=O)N4C[C@@H](F)C[C@H]4C#N)C(=O)OCc4ccccc4)(CC2)CC3)CC1

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-methylpiperazine (14.5 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(4-methylpiperazin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (36.0 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.CCN(CC)CC.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Cl:38])[C:32](Cl)=[O:33]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Cl:38])[C:32]([N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1)=[O:33]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)c(Cl)c1)N1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cold solution of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (10.4 g; 0.04 mole in 150 ml CH2Cl2) and 6.7 ml Et3N (0.048 mole) was slowly added a solution of 3,4-dichlorobenzoyl chloride (10.05 g; 0.048 mole in 60 ml CH2Cl2). This was stirred at room temperature for 15 minutes.
Reaction SMILES: Cl.[N+:2]([CH2:5][CH2:6][C:7]([OH:9])=O)([O-:4])=[O:3].[NH2:10][C@@H:11]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:13]>>[CH2:31]([O:30][CH2:29][C@H:11]([NH:10][C:7](=[O:9])[CH2:6][CH2:5][N+:2]([O-:4])=[O:3])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CC[N+](=O)[O-]
Agent: Cl
Product: O=C(CC[N+](=O)[O-])N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 46.2 %

Procedure:
Proceeding as in Example 1, but substituting 3-nitropropanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 245, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(3-nitropropanamido)propanamide (3 mg, 46.2%). MS (EI) for C25H24FN3O6. found 482.5 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[O:8][CH:9]=1)=O.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>ClCCl>[C:15]([O:14][C:12](=[O:13])[NH:11][CH2:10][C:7]1[O:8][CH:9]=[C:5]([CH2:3][OH:2])[N:6]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1coc(CNC(=O)OC(C)(C)C)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1nc(CO)co1
Temperature: 0 °C
Reaction time: 2 h
Yield: 28.4 %

Procedure:
The ester (178 mg, 0.695 mmol) in 0° C. dichloromethane (8 mL) was treated with DIBAL-H (1 M in dichloromethane, 2.08 mL, 2.08 mmol). The mixture was then stirred at 0° C. for 2 hours before being treated with aqueous 5% sodium potassium tartrate (8 mL). The mixture was stirred rapidly for 30 minutes (until the aqueous and organic layers clarified), and the layers were then separated. The aqueous layer was extracted twice with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate and concentrated. Purification by chromatography on silica gel (5% methanol in dichloromethane) gave (4-hydroxymethyl-oxazol-2-ylmethyl)-carbamic acid tert-butyl ester as an oil (45 mg, 28%). 1H NMR (CDCl3) δ 1.40 (s, 9H), 4.43 (d, 2H, J=5.6 Hz), 4.56 (s, 2H), 5.37 (s, 1H), 7.54 (s, 1H).
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[CH2:24][C:23]2=[O:38]>>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:25]1[CH2:24][CH:23]([OH:38])[C:22]2[C:27](=[CH:28][CH:29]=[C:20]([OH:19])[CH:21]=2)[O:26]1
Reactant: COc1ccccc1C1CC(=O)c2cc(O)ccc2O1
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: COc1ccccc1C1CC(O)c2cc(O)ccc2O1

Procedure:
2-(2-Methoxyphenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 6-hydroxy-2-(2-methoxyphenyl)-chroman-4-one. 1H NMR (300 MHz, d6-DMSO) δ: 8.79 (s, 1H), 7.45 (dd, 1H, J 7.6, 1.6 Hz), 7.31 (dt, 1H, J 8.5, 7.3, 1.6 Hz), 7.04 (d, 1H, J 8.5 Hz), 6.99 (d, 1H, J 7.3 Hz), 6.88 (d, 1H, J 2.7 Hz), 6.59 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7, 2.7 Hz), 5.38 (s, 1H), 5.34 (d, 1H, J 11.4 Hz), 4.80-4.88 (m, 1H), 3.81 (s, 3H), 2.24-2.28 (m, 1H), 1.74-1.86 (m, 1H).