Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(CN)O.O>COCC(O)CO>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: COCC(O)CO
Solvent: NCCO
Solvent: O
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 20 °C
Reaction time: 1.25 h
Yield: 80.6 %

Procedure:
Thebaine (4.0 g dry basis, 12.9 mmol) is placed in a mixture of 3-methoxy-1,2-propanediol (13.0 g) and ethanolamine (1.3 g, 21.3 mmol, 1.65 equiv) and is heated at 110 to 114° C. p-Toluenesulfonylhydrazide (4.8 g, 25.8 mmol, 2.0 equiv) is dissolved at 15 to 25° C. in a mixture of ethanolamine (9.6 g, 157.2 mol, 12.2 equiv) and 3-methoxy-1,2-propanediol (0.8 g) and the solution is added in portions to the thebaine mixture over 1.25 hours. The reaction mixture is held at 110 to 114° C. for 1.25 hours then cooled to 15 to 25° C. and water (24 g) added while maintaining the batch temperature at ≦30° C. The resulting slurry (pH 10.9) is stirred, further cooled to 0 to 5° C. and then filtered. The product is washed with water (3×8 g) and dried at 40° C. to a constant weight to give 8,14-dihydrothebaine (3.26 g, 81.0% yield; 97.0 area % purity by HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][Br:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(Br)c1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
AIBN (79 mg) was added to a stirred suspension of methyl 3-bromo-4-methylbenzoate (11.0 g, 48.0 mmol) and NBS (10.3 g, 57.6 mmol) in CCl4 (400 mL), and the resultant mixture was heated to reflux for 2 h. After cooling to room temperature, the mixture was diluted with hexanes (200 mL) before it was filtered and concentrated to give 14.7 g (crude yield 100%) of methyl 3-bromo-4-(bromomethyl)benzoate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])=[CH:2]1.[NH2:17][OH:18].Cl>C(N(CC)CC)C>[OH:18][NH:17][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:7]
Reactant: NO
Reactant: O=C(O)CCCCCCC(=O)c1ccoc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC(=O)c1ccoc1)NO
Yield: 33 %

Procedure:
Following the procedure described in Example 14, step 3, but substituting carboxylic acid 50j for 37 and using 1.1 equivalent of NH2OH.HCl and triethylamine each, the title compound was obtained as light yellow solid in 33% yield: 1H NMR (300 MHz, CD3OD/CDCl3=5/1) δ 8.09 (br s, 1H), 7.46 (m, 1H), 6.75 (m, 1H), 2.76 (t, J=7.5 Hz, 2H), 2.10 (t, J=7.5 Hz, 2H), 1.60-1.72 (m, 4H), 1.36 (m, 4H); 13C NMR (75.4 MHz, CD3OD/CDCl3=5/1) δ 23.90, 24.99, 28.45(2), 32.48, 39.98, 108.19, 127.37, 144.15, 147.43, 171.08, 196.21.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].O.[NH2:14][NH2:15]>C(O)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:7])[NH:14][NH:15][C:5]2=[O:6]
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c(Cl)cccc12
Temperature: 125 °C

Procedure:
3-Chloro-phthalic anhydride (5a, purchased from TCI) (10 g, 54.95 mmol) was dissolved in glacial acetic acid (100 mL), and hydrazine hydrate (20 mL) was added dropwise at 0° C., and then refluxed for two hours at 125° C. When the reaction was completed, the solution was cooled down to room temperature, filtrated, and washed with water until the filtrate pH 6.0, and then dried to give 5-chloro-2,3-dihydrophthalazin-1,4-dione (5b), 10.08 g white solid (yield 93%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: CCCCCCN(CCC#N)CCC#N
Reactant: [H][H]
Solvent: C1COCCO1
Product: CCCCCCN(CCCN)CCCN
Yield: 100.6 %

Procedure:
31.0 g of N,N-bis(2-cyanoethyl)hexylamine, 4.65 g of RaneyCo, 150 ml of 1,4-dioxane was charged to an autoclave, and hydrogen addition reaction was carried out by supplying hydrogen at an initial pressure of 9.1 MPa at 110° C. for 2 hours. After removing a catalyst by filtration, the obtained filtrate was concentrated and dried to obtain 32.4 g of a target compound as a pale red oily product.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)#[CH:18]>>[C:19]1([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1cccc2ccccc12
Product: O=c1[nH]c2nccc(C#Cc3cccc4ccccc34)c2c2ccccc12
Yield: 66.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 1-ethynylnaphthalene (0.09 mL, 0.65 mmol) to provide 253 (99 mg, 66% yield) as a tan solid. LC-MS (M+H=347 obsd.=347). 1H NMR (400 MHz, d6-DMSO): δ 12.25 (s, 1H), 9.89 (d, 1H), 8.55 (d, 1H), 8.46 (d, 2H), 8.16 (d, 1H), 8.10 (m, 2H), 8.01 (m, 1H), 7.75 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:23](=O)[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([NH:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)(=[O:10])=[O:11])=[CH:3][C:2]=1[NH:1][CH2:23][CH3:24]
Reactant: CC=O
Reactant: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Cl)c(N)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCNc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)OC)CC2)ccc1Cl
Reaction time: 8 h

Procedure:
A round bottom flask was charged with methyl trans-4-(3-amino-4-chlorophenylsulfonamido)cyclohexamecarboxylate (Intermediate 10, 333 mg, 0.922 mmol) and acetaldehyde (52.1 μl, 0.922 mmol) followed by sodium triacetoxyborohydride (293 mg, 1.383 mmol) in DCE (9217 μl) and the reaction was stirred overnight. The reaction was diluted with DCM/sat'd NaHCO3, and the organic layer was separated and dried over MgSO4, then filtered and chromatographed on a Biotage 25S column to yield the title compound (224 mg, 0.598 mmol, 64.8% yield). Rf (50% EtOAc/heptane): sm=0.43; product=0.58. MS MH+=375.2
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[NH2:19].[C:25]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH:25]1([NH:19][C:18]2[CH:17]=[C:16]([F:15])[C:22]([F:23])=[C:21]([F:24])[CH:20]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1CCCC1
Reactant: Nc1cc(F)c(F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1cc(NC2CCCC2)cc(F)c1F
Reaction time: 3.5 h

Procedure:
Under ice-cooling, 11.5 g of sodium triacetoxyborohydride was added in small portions to a solution of 4.0 g of 3,4,5-trifluoroaniline and 3.6 ml cyclopentanone in 150 ml dichloroethane and 3.1 ml acetic acid, and, after rising to room temperature, stirred for 3.5 hours. Aqueous saturated sodium hydrogen carbonate was added thereto, followed by extraction with chloroform and subsequent drying over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 5.4 g of N-cyclopentyl-3,4,5-trifluoroaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](Cl)=[O:6].C(N(CC)C(C)C)(C)C.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CN1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
3-chloro-4-nitro-benzoyl chloride (Intermediate 54; 2.2 g, 10.00 mmol) was dissolved in DCM (20 mL) and N,N-diisopropylethylamine (2.095 mL, 12.00 mmol) added. The mixture was cooled in an ice/water bath and 4-amino-1-methylpiperidine (Fluorochem; 1.14 g, 10.00 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hr. A white precipitate resulted. The reaction mixture was washed with 2N NaOH, filtered and the filter cake washed with water and dried on a sinter over the weekend to give the title compound as a white solid (1.80 g, 60%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]([F:37])([C:33]([F:36])([F:35])[F:34])[CH2:4][C:5]([F:32])([F:31])[CH2:6][C:7]([F:30])([F:29])[CH2:8][CH:9]([C:25]([F:28])([F:27])[F:26])[CH2:10][CH:11]([C:21]([F:24])([F:23])[F:22])[CH2:12][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:14][CH2:15]I.C(O)C.[S-:43][C:44]#[N:45].[K+]>C(O)(=O)C>[F:1][C:2]([F:39])([F:38])[C:3]([F:37])([C:33]([F:36])([F:35])[F:34])[CH2:4][C:5]([F:32])([F:31])[CH2:6][C:7]([F:30])([F:29])[CH2:8][CH:9]([C:25]([F:28])([F:27])[F:26])[CH2:10][CH:11]([C:21]([F:24])([F:23])[F:22])[CH2:12][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:14][CH2:15][S:43][C:44]#[N:45]
Reactant: N#C[S-]
Reactant: FC(F)(CC(CC(CC(CCI)C(F)(F)F)C(F)(F)F)C(F)(F)F)CC(F)(F)CC(F)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CSCCC(CC(CC(CC(F)(F)CC(F)(F)CC(F)(C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 94.4 %

Procedure:
According to scheme (27) above, in a flask that can be equipped with an agitator, thermocouple and a reflux condenser, 20 grams (27 mmol) of 1,1,1,2,4,4,6,6-octafluoro-2,8,10,12-tetrakis(trifluoromethyl)-14-iodotetradecane (see, e.g. Published Patent Applications), 20 ml of absolute ethanol, 3.9 grams (40.5 mmol) of potassium thiocyanate (KSCN) and 0.5 ml of glacial acetic acid (HOAc) can be placed to form a mixture. The mixture can be heated to reflux (84.7 C) and maintained stirring for overnight. The mixture can be concentrated in vacuo to afford what can be observed as a thick yellow slurry. The slurry can be extracted with 300 ml of diethyl ether and decanted twice and filtered to afford a wet cake and a filtrate. The wet cake can be washed with three 100 ml portions of diethyl ether and the filtrates combined. The combined filtrates can be concentrated in vacuo to afford 17.12 grams (94.6% yield) of the 1,1,1,2,4,4,6,6-octafluoro-2,8,10,12-tetrakis(trifluoromethyl)-14-thiocyanatotetradecane product that can be observed as a light yellow oil. The product structure can be confirmed by NMR and/or chromatographic analysis.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH:11][NH2:12])=[O:10])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH3:16])[CH3:2].[N:17]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH3:29])[CH:24]=[CH:23]2)=[C:18]=[S:19]>C(O)C>[CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH:11][NH:12][C:18]([NH:17][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([CH3:29])[CH:24]=[CH:23]3)=[S:19])=[O:10])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH3:16])[CH3:2]
Reactant: CCc1nc(C(=O)NN)c(OC)cc1OC
Reactant: Cn1ccc2cc(N=C=S)ccc21
Solvent: CCO
Product: CCc1nc(C(=O)NNC(=S)Nc2ccc3c(ccn3C)c2)c(OC)cc1OC
Yield: 73.3 %

Procedure:
A flask was charged with 6-ethyl-3,5-dimethoxy-pyridine-2-carboxylic acid hydrazide (34 mg; 0.15 mmol), 5-isothiocyanato-1-methyl-1H-indole (28 mg; 0.15 mmol) and ethanol (2 mL) and the mixture was heated at reflux for three hours. The reaction was then cooled, and the precipitate was filtered and dried to give N-[6-Ethyl-3,5-dimethoxy-pyridine-2-carboxamidyl]-N′-(1-Methyl-1H-indol-5-yl)-thiourea (44 mg; 0.11 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH:14]3[CH2:16][CH:11]2[C:12](=O)[CH2:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O-]S([O-])(=O)=O.[Na+].[Na+].[C@@H:25]1([NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[NH2:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH:14]3[CH2:16][CH:11]2[C@@H:12]([NH:31][C@@H:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]2[NH2:32])[CH2:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CC2CC1N(c1ccc([N+](=O)[O-])cc1)C2
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N[C@@H]1CCCC[C@H]1N[C@H]1CC2CC1N(c1ccc([N+](=O)[O-])cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a round bottom flask was added 2-(4-nitrophenyl)-2-azabicyclo[2.2.1]heptan-6-one (120 mg, 0.517 mmol), CH2Cl2 (3 mL) and Na2SO4 (5 gms). The reaction was purged with argon. Then (1R,2R)-cyclohexane-1,2-diamine (118 mg, 1.033 mmol) and acetic acid (0.592 mL, 10.33 mmol) were added to the reaction. The reaction was stirred at rt for 1 hr. After this time, sodium triacetoxyborohydride (548 mg, 2.58 mmol) was added to the reaction and the reaction was stirred at rt overnight. The reaction was diluted with CH2Cl2 (50 ml) and filtered. The organic layer was washed with 0.5N NaOH (30 ml), water (30 ml) and saturated aqueous NaCl (30 ml). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC. Two isomers were separated from RP prep-HPLC. The fractions with the desired product, which eluted later than the undesired isomer, were concentrated to give (1R,2R)—N1-((6S)-2-(4-nitrophenyl)-2-azabicyclo[2.2.1]heptan-6-yl)cyclohexane-1,2-diamine (80 mg, 0.242 mmol, 46% yield) as a yellow solid. Anal. Calcd. for C18H26N4O2 m/z 330.4, found: 331.3 (M+H)+.
Reaction SMILES: [CH2:1](O)[CH3:2].S(=O)(=O)(O)O.[C:9]([NH:17][C@H:18]([C:22]([OH:24])=[O:23])[CH:19]([CH3:21])[CH3:20])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:9]([NH:17][C@H:18]([C:22]([O:24][CH2:1][CH3:2])=[O:23])[CH:19]([CH3:21])[CH3:20])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCO
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Yield: 71 %

Procedure:
Dissolve in 100 ml of ethanol 0.045 mol (10 g) of N-benzoylvaline obtained in the preceding Step, add 5 ml of concentrated sulphuric acid, then heat at reflux for 24 hours. Evaporate to dryness, take up in ether, wash with water then with a 10% potassium bicarbonate solution, dry, filter and evaporate to dryness. Ethyl N-benzoylvalinate is obtained.
Reaction SMILES: [OH-].[Na+].[Si]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:38]([F:41])([F:40])[F:39])=[C:21]([CH:37]=2)[C:22]([NH:24][C:25]2[C:34]([CH3:35])=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][C:26]=2[CH3:36])=[O:23])[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.CO>C1COCC1>[OH:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:38]([F:41])([F:39])[F:40])=[C:21]([CH:37]=2)[C:22]([NH:24][C:25]2[C:26]([CH3:36])=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][C:34]=2[CH3:35])=[O:23])[CH2:15][CH2:16]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)ccc2C(F)(F)F)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc(C)c1NC(=O)c1cc(N2CCC(O)CC2)ccc1C(F)(F)F
Reaction time: 12 h
Yield: 0.1 %

Procedure:
A solution of aqueous 2N NaOH (1.5.00 ml) is added to a stirred solution of methyl 4-[[5-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]-2-(trifluoromethyl)benzoyl]amino]-3,5-dimethyl-benzoate (60.0 mg, 133.20 mmoles) in THF:MeOH (5 ml:0.5 ml). After 12 h at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH4 with aqueous citric acid, and extracted with ethyl acetate (2×20 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with pentane and diethyl ether and filtered to afford the title compound as an off-white solid (0.04 g, 60%). Mass spectrum (m/z): 437.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH3:21][N:22]([CH3:33])[CH2:23][C:24]([N:27]1[CH:31]=[C:30]([NH2:32])[N:29]=[CH:28]1)([CH3:26])[CH3:25]>>[CH3:33][N:22]([CH3:21])[CH2:23][C:24]([N:27]1[CH:31]=[C:30]([NH:32][C:15](=[O:17])[CH:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])[N:29]=[CH:28]1)([CH3:26])[CH3:25]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CN(C)CC(C)(C)n1cnc(N)c1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN(C)C)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 2) was reacted with 1-(2-Dimethylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-ylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.5, 26.2, 28.2, 28.8, 28.9, 29.8, 36.6, 48.0, 52.8, 59.0, 60.9, 70.0, 100.8, 101.1, 101.3, 104.6, 110.7, 110.8, 131.3, 137.4, 172.3; MS m/z 448.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1>>[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH:34][C:14]2[N:13]=[C:12]3[N:11]([CH3:23])[C:10](=[O:24])[N:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[CH2:18][C:17]3=[CH:16][N:15]=2)=[CH:28][CH:27]=1
Reactant: NCCc1ccc(N)cc1
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Product: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(NCCc3ccc(N)cc3)nc21
Temperature: 70 °C
Yield: 2.6 %

Procedure:
A mixture of 100 mg (0.26 mmol) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-methanesulfonyl-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 140 mg (1 mmol) of 2-(4-aminophenyl)ethylamine was heated at 70° C. for 20 minutes. The product was purified by flash column chromatography using 5% methanol in dichloromethane for the elution. Product-containing fractions were combined and evaporated. The residue was recrystallized from ethyl acetate and 3 mg (3%) of 7-[2-(4-aminophenyl)ethylamino]-3-(2,6-dichlorophenyl)-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one were isolated as a yellow solid of melting point 174-175° C.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]([F:24])([F:23])[C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[C:13]([OH:15])=[O:14]>C1(C)C=CC=CC=1.CO>[CH3:1][O:14][C:13](=[O:15])[C:12]1[CH:11]=[C:10]([C:9]([F:23])([F:24])[F:8])[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trimethylsilyldiazomethane (11.5 mL) was added drop-wise to a solution of 3,5-bis-(trifluoromethyl)-benzoic acid (2 g) in dry toluene (20 mL) and methanol (0.5 mL) previously cooled to 0° C. under a nitrogen atmosphere. The solution was stirred at r.t. for 1 hr, then concentrated in vacuo to give 3,5-bis-(trifluoromethyl)-benzoic acid methyl ester (2 g) as a colourless oil.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[CH3:56][S:57](Cl)(=[O:59])=[O:58].S(Cl)(Cl)(=O)=O>>[Cl:54][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][C:50]=1[Cl:53])[CH2:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([C@H:37]2[CH2:36][O:35][C:31]3=[CH:32][C:33]4[CH2:34][C@@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]5[CH:13]=[CH:12][C:11]([C:14]6[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=6[CH3:21])=[CH:10][CH:9]=5)[C:5]([OH:4])=[O:55])=[O:24])[N:26]([S:57]([CH3:56])(=[O:59])=[O:58])[CH2:27][C:28]=4[CH:29]=[C:30]3[O:38]2)=[CH:40][CH:41]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3S(C)(=O)=O)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (25 mg) was reacted with methanesulfonyl chloride according to General Procedure E (with excess of sulfonyl chloride). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (14 mg) LCMS (m/z): 819.
Reaction SMILES: CN1CCOCC1.[N:8]1([C:14]2[N:19]=[CH:18][C:17]([C:20]3([C:23]([N:25]4[CH2:29][CH2:28][C@@:27]5([C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=6[C:31](=[O:38])[O:30]5)[CH2:26]4)=[O:24])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH:39]1([C:42](O)=[O:43])[CH2:41][CH2:40]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(#N)C>>[CH:39]1([C:42]([N:11]2[CH2:12][CH2:13][N:8]([C:14]3[N:19]=[CH:18][C:17]([C:20]4([C:23]([N:25]5[CH2:29][CH2:28][C@@:27]6([C:33]7[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=7[C:31](=[O:38])[O:30]6)[CH2:26]5)=[O:24])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH2:9][CH2:10]2)=[O:43])[CH2:41][CH2:40]1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCNCC5)nc4)CC3)C2)c2ccccc21
Reactant: O=C(O)C1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCN(C(=O)C6CC6)CC5)nc4)CC3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methylmorpholine (2.0×10−1 μL, 0.00018 mol) was added to a mixture of (1R)-1′-{[1-(6-piperazin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (15 mg, 0.000036 mol, this compound was prepared in a way similar to that described in example 163), cyclopropanecarboxylic acid (3.4 μL, 0.000043 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (19 mg, 0.000043 mol) in acetonitrile (0.7 mL, 0.01 mol). The reaction mixture was stirred at room temperature overnight. The crude product was purified by prep-LCMS. LC/MS: 487.3 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](C2C=CC=CC=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([S:28]([C:2]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1cccc(C(N)=O)c1Br
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)cc1
Product: Cc1cccc(C(N)=O)c1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1

Procedure:
Prepared from 2-bromo-3-methylbenzamide by the procedure of Example 135 using Intermediate 2 in Step 2. m/z (ES+) 397 [(M-NH2)+].