Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][O:18][CH2:19][CH2:20][C:21]1[C:26]([CH2:27]O)=[CH:25][N:24]=[C:23]([C:29]2[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=2)[N:22]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:27][C:26]3[C:21]([CH2:20][CH2:19][O:18][CH3:17])=[N:22][C:23]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)=[N:24][CH:25]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cnc(-c4ccc(C(F)(F)F)nc4)nc3CCOC)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with [4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield the title compound as yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:20](=[O:27])[NH:19][C:18]2=[O:28])=[CH:13][CH:12]=1)[CH3:8].Cl[CH2:31][C:32]([NH:34][C:35]1[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:38]=[CH:37][C:36]=1[CH:44]([CH3:46])[CH3:45])=[O:33].O>CN(C)C=O>[CH2:7]([O:9][C:10](=[O:29])[C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:20](=[O:27])[N:19]([CH2:31][C:32](=[O:33])[NH:34][C:35]3[C:36]([CH:44]([CH3:46])[CH3:45])=[CH:37][CH:38]=[CH:39][C:40]=3[CH:41]([CH3:43])[CH3:42])[C:18]2=[O:28])=[CH:15][CH:16]=1)[CH3:8]
Reactant: CCOC(=O)c1ccc(N2C(=O)NC(=O)C23CCCCC3)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2C(=O)N(CC(=O)Nc3c(C(C)C)cccc3C(C)C)C(=O)C23CCCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
87 mg (0.63 mmol, 1 eq.) of potassium carbonate are added to a solution of 200 mg (0.63 mmol, 1 eq.) of 4-(2,4-dioxo-1,3-diazaspiro[4.5]dec-1-yl)benzoic acid ethyl ester and 160 mg (0.63 mmol, 1 eq.) of 2-chloro-N-(2,6-diisopropylphenyl)acetamide in 30 ml of dimethylformamide. The reaction medium is stirred at room temperature overnight. It is then poured into water and extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated off. The residue is precipitated from dichloromethane and heptane. The product 4-{3-[(2,6-diisopropyl-phenylcarbamoyl)methyl]-2,4-dioxo-1,3-diaza-spiro[4.5]dec-1-yl}benzoic acid ethyl ester is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:3]([Cl:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2
Reactant: Nc1ccc2c(=O)[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Nc1ccc2c(=O)[nH]ccc2c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.3 %

Procedure:
To a solution of 0.500 g (3.12 mmol) of 6-amino-2H-isoquinolin-1-one in DMF (30 mL) was added 0.45 g (3.4 mol) of N-chlorosuccinimide. The mixture was stirred at room temperature for 15 h then poured over ice and stirred until all the ice was melted during which time a solid precipitated from solution. The tan solid was collected by filtration, washed with water and dried on the filter pad to provide 0.50 g (82% yield) of the title compound. MS calc. for C9H8ClN2O [M+H]+: 195.63. Found: 195.23.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[CH2:22]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([F:21])[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:24])[CH3:23]
Reactant: [H][H]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Yield: 77.4 %

Procedure:
Twenty percent Pd/C was added to a solution of 3-benzyloxy-1-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example C, 0.055 g, 0.16 mmol) in 25 mL of THF and 25 mL of methanol. This was shaken under 50 PSI of hydrogen for 12.5 hours. The mixture was filtered and concentrated to afford 0.03 g of the title compound as a solid, mp 172-174° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH:6](O)[C:7]([OH:9])=[O:8])=[O:4].S(=O)(=O)(O)O.C(O)(=O)C.[S:20]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]1=2>O>[Cl:1][CH2:2][C:3]([NH:5][CH:6]([C:26]1[CH:27]=[CH:28][C:21]2[S:20][CH2:24][CH2:23][C:22]=2[CH:25]=1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: O=C(CCl)NC(O)C(=O)O
Reactant: c1ccc2c(c1)CCS2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCl)NC(C(=O)O)c1ccc2c(c1)CCS2
Yield: 65.3 %

Procedure:
N-Chloroacetyl-α-hydroxyglycine (6.5 g., 0.038 mole) was added to a cold, stirred mixture of concentrated sulphuric acid (1.5 ml.) and glacial acetic acid (15 ml.) followed, after five minutes, by the dropwise addition of 2,3-dihydrobenzo(b)thiophen (98%, 4.1 g., 0.03 mole). The reaction mixture was stirred at ambient temperature for five hours, then water (75 ml.) was added to the resulting suspension and the mixture thoroughly stirred. Filtration gave a solid which was washed successively with water, diethyl ether and hexane, then dried, to afford DL-α-chloroacetamido-2,3-dihydro-5-benzo(b)thienylacetic acid (5.6 g.), m.p. 173°-175° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=1.O>CN(C=O)C>[CH3:20][N:19]([CH3:21])[C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[CH:18][N:17]=1
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: CN(C)c1ccc(N)cn1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc(N(C)C)nc1

Procedure:
A mixture of 8.1 g (35 mM) of the phenyl carbamate 8 and 2.5 g (23 mM) of 5-amino-2-dimethylaminopyridine in 50 ml of anhydrous DMF was heated at 55° for 3.5 hrs. and then cooled and poured into 200 ml of water. The resulting mixture was extracted with three 100 ml portions of ethyl acetate and the combined extracts were dried (MgSO4), filtered and concentrated to a volume of 50 ml. The precipitate which formed was collected and recrystallized from acetone to give 0.84 of the above urea as tan crystals, m.p. 212°-213° C.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6]1)=[O:4].O.[OH-].[Li+:14]>CO.O>[CH3:10][C:7]1([CH3:11])[O:6][C@@H:5]([C:3]([O-:4])=[O:2])[CH2:9][O:8]1.[Li+:14]
Reactant: COC(=O)[C@H]1COC(C)(C)O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)OC[C@H](C(=O)[O-])O1
Yield: 96.6 %

Procedure:
To a solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid methyl ester (5.0 g, 31.25 mmol) in MeOH (32.0 mL) at room temperature was added a solution of lithium hydroxide monohydrate (1.31 g, 31.25 mmol) in water (10.0 mL). The resulting mixture was stirred for thirty min before it was concentrated. The resulting white solid was further dried under vacuum to give the title compound (4.59 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.[H-].[Na+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C)C=O>[C:31]([O:30][C:29]([NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:4]4[N:3]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:2](=[O:1])[CH2:7][O:6][C:5]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)=[O:35])([CH3:32])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
In a 15 mL reaction tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.106 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give a red solution, then cooled to 0° C. under a nitrogen atmosphere. Sodium hydride, 60% in oil (6.4 mg, 0.159 mmol) was added and the mixture stirred at 0° C. for 15 minutes. Ethyl 2-bromoacetate (0.035 mL, 0.318 mmol) was added and the mixture stirred at 0° C. for 30 minutes, allowed to warm to room temperature then stirred for one hour. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (5 mL) and extracted into ethyl acetate (3×3 mL). The organic phase was washed with 50:50 water:brine (2×5 mL) then brine (5 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 88:12 to 0:100) to give the desired product as an off-white solid (22 mg, 39% yield). 1H-NMR (500 MHz, CDCl3) δ 7.13-7.28 (8H, m), 7.37-7.43 (2H, m), 5.24 (1H, br s), 5.18 (2H, s), 4.89 (2H, s), 4.49 (2H, q), 2.40-2.90 (4H, m), 2.21-2.35 (1H, m), 1.90-2.10 (1H, m), 1.20-1.75 (9H, br m), 1.53 (3H, t). LCMS (Method A) RT=7.20 min, M+H+=558.13.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: N#Cc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To 10 mL of a chloroform solution containing 58 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-cyanoquinoxalin-2(1H)-one and 35 mg of 2,3-dihydro-1,4-dioxino[2,3-c]pyridine-7-carbaldehyde, 11 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 67 mg of sodium triacetoxyborohydride was added, and stirred for 2 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=5:1] to give 43 mg of 1-(2-(4-((2,3-dihydro-1,4-dioxino[2,3-c]pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-cyanoquinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [ClH:1].[C:2]1([CH:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14](O)[CH3:15]>>[ClH:1].[CH3:8][CH:9]1[NH:13][C:15](=[N:13][CH:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:10]1
Reactant: CCO
Reactant: NC1CCCC1c1ccccc1
Agent: Cl
Product: CC1CCC(=NC2CCCC2c2ccccc2)N1
Temperature: -20 °C
Reaction time: 144 h

Procedure:
A slurry of 3.0 g (0.0152 mole) of powdered 2-phenylcyclopentylamine hydrochloride and 3 ml of 5,O-dimethylbutyrolactim is allowed to stand at room temperature for 6 days with occasional stirring during which time sufficient ethanol is added to maintain the slurry. The slurry is then cooled to -20° C., and after about 4 hours a precipitate forms. The precipitate is collected and recrystallized several times from acetone-methanol to give 5-methyl-2-[(2-phenylcyclopentyl)imino]pyrrolidine hydrochloride, M.P. 175°-178° C.
Reaction SMILES: [NH2:1][C:2]([O:4][C@@H:5]([C@@H:48]([CH3:53])/[CH:49]=[CH:50]\[CH:51]=[CH2:52])[C@@H:6]([CH3:47])[C@H:7]([O:39][Si](C(C)(C)C)(C)C)[C@@H:8]([CH3:38])[CH2:9]/[C:10](/[CH3:37])=[CH:11]\[C@H:12]([CH3:36])[C@@H:13]([O:28][Si](C(C)(C)C)(C)C)[C@@H:14]([CH3:27])/[CH:15]=[CH:16]\[C:17]([N:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])=[O:3].Cl.C([O-])(O)=O.[Na+]>CO>[NH2:1][C:2]([O:4][C@@H:5]([C@@H:48]([CH3:53])/[CH:49]=[CH:50]\[CH:51]=[CH2:52])[C@@H:6]([CH3:47])[C@H:7]([OH:39])[C@@H:8]([CH3:38])[CH2:9]/[C:10](/[CH3:37])=[CH:11]\[CH:12]([CH3:36])[CH:13]([OH:28])[CH:14]([CH3:27])/[CH:15]=[CH:16]\[C:17]([N:19]([CH3:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:18])=[O:3]
Reactant: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)N(C)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C/C(C)=C\C(C)C(O)C(C)/C=C\C(=O)N(C)c1ccccc1
Temperature: 23 °C
Reaction time: 36 h
Yield: 31.5 %

Procedure:
To a solution of (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-13-[(aminocarbonyl)oxy]-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-N,4,6,8,10,12,14-heptamethyl-N-phenyl-2,7,15,17-octadecatetraenamide (70 mg, 0.091 mmol, 1 eq) in MeOH (10 mL) is added a MeOH solution of HCl (15.5 mL, 15 mL MeOH+0.5 mL 12N HCl). The resulting solution is stirred at 23° C. (36 hours). The pH is adjusted to 8 by the addition of solid NaHCO3 at 0° C. The solution was dried in vacuo, the residue was dissolved in CH2Cl2 (10 mL) and filter through Celite. HPLC purification provided the desired compound (15.5 mg, 32%) as a white solid: [α]25D=+225.738° (c 0.25, CH2Cl2); HRMS ESI m/z 541.3588 (M+H+, C32H50O5N2 requires 541.3641).
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[NH2:13][C:14]([CH3:25])([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])[CH3:15]>C(O)C>[CH3:25][C:14]([NH:13][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])([CH3:15])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24]
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: CC(C)(N)CCc1ccccc1O
Solvent: CCO
Product: CC(C)(CCc1ccccc1O)NC[C@H](O)c1ccc2nnnn2c1

Procedure:
A solution of 156 mg (1.46 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 170 ml of 2-amino-2-methyl-4-(2-hydroxyphenyl)butane in 15 ml of absolute ethanol is heated at reflux for 6 hours. The reaction mixture is concentrated and the residue chromatographed on silica gel to give the desired product.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([CH:23]1[CH2:25][CH2:24]1)[C:20]([NH2:22])=[O:21].CO>CCCCCCC>[C:20]([CH:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH:23]1[CH2:25][CH2:24]1)(=[O:21])[NH2:22]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)C(N)C1CC1
Solvent: CO
Solvent: CCCCCCC
Product: NC(=O)C(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-amino-cyclopropaneacetamide (CAN 1100749-41-4) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/20% 2-propanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 97.7%, 330.1804 (M+H)+, αD20 (MeOH)=+43.3°.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][S:8]([NH:11][C:12](OC(C)(C)C)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.OC[CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][S:8]([NH:11][CH2:12][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:9])=[O:10])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1ccc(Cl)cc1
Reactant: OCCN1CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(NCCN1CCCC1)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
To an ice-cooled solution of of the product from Example 109 step b (321 mg, 1.00 mmol), 1-(2-hydroxyethyl)pyrrolidine (0.152 ml, 1.30 mmol) and triphenylphosphine (393 mg, 1.50 mmol) in THF (2 ml) was added in a single portion diethylazodicarboxylate (0.257 ml, 1.50 mmol). The coolant was removed and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with ethyl acetate (25 ml) and washed sequentially with water (20 ml), twice with aqueous hydrochloric acid (2M, 25 ml) and brine (25 ml). The organic phase was dried over anhydrous sodium sulfate and the filtrate was evaporated at reduced pressure. The residue was dissolved in 1,4-dioxan (5 ml) and treated with aqueous hydrochloric acid (2M, 5 ml). The resultant mixture was heated at reflux for 1 h and then diluted with further aqueous hydrochloric acid (30 ml). The aqueous was washed twice with diethyl ether (30 ml) and then the pH was adjusted to 11 with ammonia (880). The now basic phase was extracted twice with chloroform (50 ml) and then dried over anhydrous sodium sulfate. The filtrate was evaporated at reduced pressure and the residue was purified by flash column chromatography (200:10:1 DCM:methanol:ammonia) to afford the title compound as a white solid (95 mg, 30%). 1H NMR 7.35-7.28 (4H, m), 6.04.5 (2H, br s), 4.20 (2H, s), 3.19 (2H, t, 5.7), 2.59 (2H, t, 5.7), 2.50-2.46 (4H, m), 1.73-1.67 (4H, m). Microanalysis found C 49.05 H 6.36 N 13.09 C13H20ClN3O2S requires C 49.13 H 6.34 N 13.22.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[ClH:33].[CH3:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[CH2:41][CH2:42][CH2:43][C:44](O)=[O:45].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(OCC)C>[ClH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]3[CH3:34])=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Reactant: CC1CCCCN1CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCCCC3C)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, γ-(2-methylpiperidino)butyric acid hydrochloride and dicyclohexylcarbodiimide in methylene chloride are stirred at room temperature for 16 hours. The reaction mixture is cooled and the solid removed by suction filtration. The methylene chloride is evaporated to give a residue which is dissolved in methylene chloride and diethyl ether. After removing the resulting crude product, the solvents are evaporated and the gummy resin is dried, triturated with diethyl ether, and dried to yield the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[N:5][N:4]=1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K].[I-].[Na+].O>CN(C)C=O>[CH3:8][N:7]1[C:3]([CH2:2][N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])=[N:4][N:5]=[N:6]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cn1nnnc1CCl
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnnc1CN1C(=O)c2ccccc2C1=O
Yield: 4 %

Procedure:
5-(Chloromethyl)-1-methyl-1H-tetrazole (a crude product 6.9 g prepared in accordance with Chemical & Pharmaceutical Bulletin, 37(2), 322-6:1989), was dissolved in 50 mL of dimethylformamide and stirred with potassium phthalimide (5.00 g, 27.0 mmol) and sodium iodide (391 mg, 2.60 mmol) at room temperature for 17 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the desired product (550 mg, 4% yield, two steps).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:5]([F:20])=[CH:4][C:3]=1[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23].C(N(CC)CC)C.[CH3:34][C:35]1([O:38][C:39](ON2C(=O)CCC2=O)=[O:40])[CH2:37][CH2:36]1>ClCCl>[CH3:25][N:24]([CH3:26])[C:22](=[O:23])[CH2:21][C:3]1[C:2]([F:1])=[CH:7][C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:39]([O:38][C:35]3([CH3:34])[CH2:37][CH2:36]3)=[O:40])[CH2:18][CH2:19]2)=[C:5]([F:20])[CH:4]=1
Reactant: CC1(OC(=O)ON2C(=O)CCC2=O)CC1
Reactant: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OC3(C)CC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2,5-difluoro-4-{2-[(1S,2R)-2-piperidin-4 ylcyclopropyl]ethoxy}phenyl-)-N,N-dimethylacetamide (40.0 mg, 0.109 mmol) in 1 ml anhydrous dichloromethane at 0° C. was added triethylamine (0.0300 ml, 0.218 mmol) and 1-({[(1-methylcyclopropyl)oxy]carbonyl}oxy)pyrrolidine-2,5-dione (27.9 mg, 0.131 mmol). The reaction was stirred at RT for 2 hours. The solvent was evaporated, and the residue was purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 25-85% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 465.4 (M+H)+. Human EC50: 2.2 nM
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH2:20])=[N:17][CH:18]=3)[N:13]([CH3:21])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[O:8]C>Br.O>[NH2:20][C:16]1[N:15]=[C:14]2[N:13]([CH3:21])[N:12]=[C:11]([C:4]3[CH:5]=[C:6]([F:10])[C:7]([OH:8])=[C:2]([F:1])[CH:3]=3)[C:19]2=[CH:18][N:17]=1
Reactant: COc1c(F)cc(-c2nn(C)c3nc(N)ncc23)cc1F
Agent: Br
Solvent: O
Product: Cn1nc(-c2cc(F)c(O)c(F)c2)c2cnc(N)nc21

Procedure:
3-(3,5-Difluoro-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 98) (0.1 g, 0.342 mmol) is dissolved in 48% HBr in water (5 ml) and heated using microwave radiation at 120° C. for 30 minutes. Purification of the reaction mixture by preparative HPLC (water/acetonitrile, 0.1% TFA) affords the title compound as a white solid.