Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[CH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[CH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(C=C4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)C1CCC(=Cc2ccc3cc(CN4CCC(C(=O)O)CC4)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
To a solution of ethyl 1-((6-((4-tert-butylcyclohexylidene)methyl)naphthalen-2-yl)methyl)piperidine-4-carboxylate (50 mg, 0.11 mmol) in MeOH (3 mL) was added NaOH (22 mg, 0.55 mmol, 5.0 eq) and H2O (0.5 mL). The reaction mixture was stirred at 80° C. for 4 h. The pH of the solution was adjusted to 6 with 3 N HCl. The mixture was filtered and the yellow solid was the desired product 1-((6-((4-tert-butylcyclohexylidene)methyl)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid (35 mg, yield: 81%). ESI-MS (M+1)+: 420.1. 1HNMR (400 MHz, CD3OD) δ: 7.86 (s, 1H), 7.83˜7.80 (m, 1H), 7.77-7.74 (m, 1H), 7.60 (br, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.35˜7.32 (m, 1H), 6.30 (s, 1H), 4.29 (s, 2H), 3.33 (br, 2H), 2.97-2.94 (m, 3H), 2.42-2.38 (m, 2H), 2.20-2.03 (m, 1H), 2.03-2.00 (m, 2H), 1.89-1.80 (m, 5H), 1.22-1.12 (m, 3H), 0.80 (s, 9H). HPLC: 100%.
Reaction SMILES: [CH2:1]1[C:3]2([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[C:4]([NH:6][C:7](=O)[CH:2]12)=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1C=CC=CC=1>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([C:3]23[CH2:1][CH:2]2[CH2:7][NH:6][CH2:4]3)=[CH:14][CH:13]=1
Reactant: O=C1NC(=O)C2(c3ccc(Cl)cc3)CC12
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Clc1ccc(C23CNCC2C3)cc1

Procedure:
Following the procedure described in Example 1 the compound 1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide (U.S. Pat. No. 3,344,026--Example 1) is reduced with sodium bis(2-methoxyethoxy)aluminum hydride 70% solution in benzene to produce the compound 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane.
Reaction SMILES: [C:1]([O:4][CH:5]([C:30]1[S:31][CH:32]=[C:33]([C:35]([NH:37][CH:38]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:39][CH:40]([CH3:44])[C:41]([OH:43])=[O:42])=[O:36])[N:34]=1)[CH2:6][CH:7]([N:11]([C:20](=[O:29])[CH:21]([N:26]=[N+]=[N-])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH2:12][O:13][C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2].FC1C([O:59][C:60](=O)[CH2:61][N:62]([CH3:64])[CH3:63])=C(F)C(F)=C(F)C=1F>CCOC(C)=O.[Pd]>[C:1]([O:4][CH:5]([C:30]1[S:31][CH:32]=[C:33]([C:35]([NH:37][CH:38]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:39][CH:40]([CH3:44])[C:41]([OH:43])=[O:42])=[O:36])[N:34]=1)[CH2:6][CH:7]([N:11]([C:20](=[O:29])[CH:21]([NH:26][C:60](=[O:59])[CH2:61][N:62]([CH3:64])[CH3:63])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH2:12][O:13][C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CCC(C)C(N=[N+]=[N-])C(=O)N(COC(=O)CC(C)C)C(CC(OC(C)=O)c1nc(C(=O)NC(Cc2ccccc2)CC(C)C(=O)O)cs1)C(C)C
Reactant: CN(C)CC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(C)C(NC(=O)CN(C)C)C(=O)N(COC(=O)CC(C)C)C(CC(OC(C)=O)c1nc(C(=O)NC(Cc2ccccc2)CC(C)C(=O)O)cs1)C(C)C
Reaction time: 26 h
Yield: 47.8 %

Procedure:
Pd/C (10 wt %, 8.7 μg) and azide 8 (18.0 mg, 0.0247 mmol) were added to a 0.20 M solution of 18 (0.0988 mmol) in 0.40 mL of EtOAc (filtered through activated alumina). The reaction mixture was stirred under a hydrogen atmosphere for 26 h and then filtered through a plug of Celite with washing of the filter pad with EtOAc. The filtrate was concentrated, and a 1:1 mixture of deoxygenated H2O/dioxane (4.0 mL) was added. The mixture was stirred for 20 h at rt and concentrated. Reverse-phase HPFC (20:80 to 100:0 MeCN:H2O) followed by lyophilization afforded 9.3 mg (48%) of 6 as an amorphous solid. [α]D23=−2.0 (c=0.6, MeOH). IR: 1226, 1496, 1542, 1741, 2964 cm−1. 1H NMR (500 MHz, MeOD): δ 0.81 (d, 3H, J=6.5 Hz), 0.87 (d, 3H, J=6.5 Hz), 0.89 (d, 3H, J=7.0 Hz), 0.92 (t, 3H, J=7.5 Hz), 0.98 (d, 3H, J=6.5 Hz), 1.06 (d, 3H, J=6.5 Hz), 1.12-1.21 (m, 1H), 1.17 (d, 3H, J=7.0 Hz), 1.58-1.70 (m, 2H), 1.77-1.91 (m, 2H), 1.92-2.05 (m, 3H), 2.06-2.17 (m, 2H), 2.16 (s, 3H), 2.35 (s, 6H), 2.46-2.57 (m, 2H), 2.92 (d, 2H, J=5.5 Hz), 3.11 (q, 2H, J=16.2 Hz), 4.28-4.50 (br s, 1H), 4.32-4.38 (m, 1H), 4.70 (d, 1H, J=8.5 Hz), 5.46 (d, 1H, J=12.0 Hz), 5.87 (d, 1H, J=11.0 Hz), 6.05 (d, 1H, J=12.0 Hz), 7.12-7.18 (m, 1H), 7.19-7.26 (m, 4H), 8.09 (s, 1H). 13C NMR (125 MHz, MeOD) δ 11.1, 16.6, 19.0, 20.3, 20.8, 20.9, 22.9, 25.5, 26.2, 26.9, 32.4, 35.9, 37.6, 39.1, 39.7, 42.1, 44.5, 45.8, 51.2, 55.2, 62.7, 70.8, 125.6, 127.5, 129.4, 130.6, 139.7, 150.9, 162.7, 170.8, 171.7, 172.0, 173.3, 176.5, 181.8. HRMS (FAB) calcd for C40H62N5O9S (M+H): 788.4268. Found: 788.4256.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.[H-].[Na+]>CN(C)C=O>[N:23]1([CH2:22][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:12]4[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=4[S:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc2c(-c3ccc(O)cc3)csc2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccc(OCCN4CCCC4)cc3)csc2c1
Temperature: 0 °C

Procedure:
To 80 ml. of N,N-dimethylformamide (DMF) were added 10.0 grams (0.039 mole) of 3-(4-hydroxyphenyl)-6-methoxybenzothiophene. The mixture was cooled to 0° C., and 6.6 grams (0.039 mole) of N-(2-chloroethyl)pyrrolidine hydrochloride were added followed by 2.81 grams (0.117 mole) of sodium hydride added in small portions. Effervescence developed, and, when the effervescence had ceased, the mixture was heated at 95° C. for 14 hours. To the mixture then were added 10 ml. of ethanol, and the solvents of the resulting mixture then were evaporated. The resulting residue was dissolved in a mixture of water and ethyl acetate. The ethyl acetate layer was separated from the aqueous layer and was washed with 25 ml. of sodium chloride solution. The ethyl acetate solution then was extracted twice with 40 ml. of 1N hydrochloric acid. The acid layer was separated and rendered alkaline by addition of 50 ml. of 2N sodium hydroxide. The alkaline mixture then was extracted with 250 ml. of ethyl acetate. The ethyl acetate layer was separated, dried over magnesium sulfate, and evaporated to give 3-[4-(2-pyrrolidinoethoxy)phenyl]-6-methoxybenzothiophene as an oil. The oil was dissolved in methanol and treated with excess methanolic hydrochloric acid. The mixture was evaporated, and the solid residue was recrystallized from methanol to give 11.6 grams (76 percent) of the hydrochloride salt of 3-[4-(2-pyrrolidinoethoxy)phenyl]-6-methoxybenzothiophene, m.p. 200°-202° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22](Cl)=[O:23]>>[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([NH:12][C:10]1[S:11][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[C:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]=1)=[O:23]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Product: Cc1nc(-c2sc(NC(=O)CC(C)(C)C)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and 3,3-dimethyl-butyryl chloride.
Reaction SMILES: [C:1](CC(N)=O)#[N:2].[OH:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][N:9]=1>>[OH:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:1]#[N:2])[CH:21]=2)[S:10][N:9]=1
Reactant: N#Cc1c(O)nsc1Nc1ccccc1
Reactant: N#CCC(N)=O
Product: N#Cc1cccc(Nc2snc(O)c2C#N)c1

Procedure:
The title compound was prepared from 1-isothiacyanato-3-cyano-benzene and 2-cyanoacetamide by the procedure analogous to Method 2 for 3-Hydroxy-5-phenylamino-isothiazol-4-carbonitrile. 1H NMR (CD3OD) δ: 7.5–7.7 (m, 4H) ppm; MS (ES, m/z): 242.9, [M-H]+, 241.1 [M-H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].[B]>>[CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C@@H:4]1[OH:9]
Reactant: COC1(OC)CCOCC1=O
Agent: [B]
Product: COC1(OC)CCOC[C@@H]1O

Procedure:
reacting 4,4-dimethoxydihydro-2H-pyran-3(4H)-one with a boron reducing agent and R-(+)-2-methyl-CBS-oxazaborolidine, over a period of at least six hours to provide the (S)-4,4-dimethoxytetrahydro-2H-pyran-3-ol in at least 90% enantiomeric excess.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]([O:14][CH2:15][CH2:16][O:17][C:18](ON1C(=O)CCC1=O)=[O:19])(=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]>>[OH:4][CH2:3][C@@H:2]([NH:1][C:18]([O:17][CH2:16][CH2:15][O:14][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:19])[C:5]([OH:7])=[O:6]
Reactant: CCCCC(=O)OCCOC(=O)ON1C(=O)CCC1=O
Reactant: N[C@H](CO)C(=O)O
Product: CCCCC(=O)OCCOC(=O)N[C@H](CO)C(=O)O
Yield: 72.9 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (504 mg, 4.8 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl pentanoate (1.1 g, 4.0 mmol) were reacted to provide 809 mg (73% yield) of the title compound (31) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.80 (m, 1H), 6.26 (br s, 1H), 5.50 (br s, 1H), 4.40 (m, 1H), 4.02 (m, 1H), 3.85 (m, 1H), 2.36 (m, 2H), 1.60 (m, 2H), 1.47 (d, 3H), 1.37 (m, 2H), 0.91 (t, 3H). MS (ESI) m/z 295.19 (M+NH4)+; 300.08 (M+Na)+; 272.12 (M−H)−.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:15]([Cl:16])=[C:14]([O:17][CH2:18][C:19]#[N:20])[CH:13]=[C:12]2[C:4]=1[C:5]1[C:10]([CH2:21][CH2:22][CH3:23])([CH2:11]2)[CH2:9][CH2:8][C:7](=[O:24])[CH:6]=1.Cl.Cl.[CH2:27](N)[CH2:28][NH2:29].Cl>CO>[Cl:2][C:3]1[C:15]([Cl:16])=[C:14]([O:17][CH2:18][C:19]2[NH:29][CH2:28][CH2:27][N:20]=2)[CH:13]=[C:12]2[C:4]=1[C:5]1[C:10]([CH2:21][CH2:22][CH3:23])([CH2:11]2)[CH2:9][CH2:8][C:7](=[O:24])[CH:6]=1
Reactant: NCCN
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC#N)c(Cl)c1Cl)C2
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC3=NCCN3)c(Cl)c1Cl)C2
Reaction time: 4 h

Procedure:
To a solution of sodium metal (20 mg) in methanol (30 ml) was added (+) [(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propy-1H-fluoren-7-yl)oxy]-acetonitrile (1.05 g, 3.0 mMole). The reaction mixture was stirred for 11/4 hours in a nitrogen atmosphere then treated with ethylenediamine dihydrochloride (410 mg, 3.1 mMole) and stirring was continued for 2 hours. Ethanolic hydrogen chloride was added until the reaction mixture was just acidic. After 1/2 hour, the methanol was distilled at reduced pressure, the residue dissolved in water, treated with 10N sodium hydroxide (1 ml), extracted with ether containing 5% tetrahydrofuran, washed with water, brine, dried over potassium carbonate and evaporated to dryness to give the (+)-enantiomer of 2-[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren-7-yl)-oxymethl]imidazoline which melts at 152°-154° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1[C:24]([NH2:32])=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[CH:26]2.C1(C)C(C)=CC=CC=1.[Cl-].[Na+]>C(OCC)(=O)C>[F:16][C:13]([F:14])([F:15])[C:10]([CH:11]=[N:32][C:24]1[C:23]([CH3:22])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][NH:28]2)([OH:17])[CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:20][CH3:21])([CH3:19])[CH3:18]
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Cc1ccc2[nH]ncc2c1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: COc1c(F)cccc1C(C)(C)CC(O)(C=Nc1c(C)ccc2[nH]ncc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal (308 mg, 1.0 mmol) and 5-methyl-1H-indazol-4-ylamine (148 mg, 1.0 mmol) are introduced into 15.0 ml of xylene and mixed with titanium(IV)ethylate (0.42 ml, 2.0 mmol). After 3 hours under reflux, the reaction mixture is allowed to cool to room temperature. After ethyl acetate and saturated sodium chloride solution are added, it is stirred vigorously for 30 minutes at room temperature. The deposited precipitate is suctioned off, the aqueous phase is separated, and the organic phase is dried on sodium sulfate. The purification is carried out by means of chromatography on silica gel with hexane/ethyl acetate (30-40% ethyl acetate). 345 mg (79% of theory) of 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-[(5-methyl-1H-indazol-4-ylimino)methyl]-pentan-2-ol is obtained.
Reaction SMILES: C[O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:13][CH2:14]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 51.3 %

Procedure:
1-[1-(4-Methoxyphenethyl)piperidin-4-yl]indoline (0.23 g) was dissolved in a 47% aqueous solution (5 ml) of hydrobromic acid and the resultant solution was heated under reflux for 90 min. After allowing to cool, the resultant mixture was poured into a saturated aqueous solution of sodium bicarbonate (pH 9-10), extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (0.113 g) as colorless crystals (yield: 75.7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:52]1([C:58]2([CH2:61][NH2:62])[CH2:60][CH2:59]2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCl.CN(C)C=O>[CH3:20][O:19][C@@H:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:14]([CH3:18])[C:15](=[O:17])[NH:62][CH2:61][C:58]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:60][CH2:59]1
Reactant: NCC1(c2ccccc2)CC1
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H]([C@@H](C)C(=O)NCC1(c2ccccc2)CC1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 68 %

Procedure:
According to general procedure D, from #11 (2.15 g, 7.48 mmol, 1.1 eq.) in dichloromethane (20 mL, 0.3 M) and N,N-dimethylformamide (4 mL), 1-(1-phenylcyclopropyl)methanamine #@1 (1.001 g, 6.799 mmol, 1 eq.), HATU (3.10 g, 8.16 mmol, 1.2 eq.) and triethylamine (2.84 mL, 20.4 mmol, 3 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane), producing #57 (1.93 g, 68%) as a solid. HPLC (Protocol A at 45° C.): m/z 417.3 [M+H+], retention time=10.575 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers: δ 7.75-7.81 (m, 1H), 7.20-7.27 (m, 4H), 7.12-7.19 (m, 1H), 3.33-3.62 and 3.71-3.80 (br multiplets, total 4H), 3.28 (s, 3H), 2.97-3.17 (br m, 2H), 2.14-2.24 (m, 1H), 1.67-1.80 (br m, 2H), 1.45-1.65 (m, 2H), 1.41 (s, 9H), 1.00 (d, J=6.6 Hz, 3H), 0.67-0.93 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([C:28]([NH:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]2)=[O:29])[CH:25]=[CH:24][CH:23]=1>>[NH2:9][C:7]([C:6]1[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=2[F:20])[S:3][C:2]=1[NH:1][C:22]1[N:27]=[C:26]([C:28]([NH:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]2)=[O:29])[CH:25]=[CH:24][CH:23]=1)=[O:8]
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)c1cccc(Br)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(=O)N[C@H]4CC[C@H](O)CC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 with 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.11 g, 0.39 mmol) and 6-bromo-N-(trans-4-hydroxycyclohexyl)pyridine-2-carboxamide (0.11 g, 0.38 mmol) as the starting materials.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=2)=[N:17][C:16]=1[C:30]1[N:34](COCC[Si](C)(C)C)[CH:33]=[N:32][N:31]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:19][C:18]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:25]=2)=[N:17][C:16]=1[C:30]1[N:34]=[CH:33][NH:32][N:31]=1
Reactant: CC(=O)Nc1ccc(-c2nc(-c3nncn3COCC[Si](C)(C)C)c(-c3ccccc3Cl)o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2nc(-c3nc[nH]n3)c(-c3ccccc3Cl)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
TFA (0.6 mL) was added to a solution of N-{4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]phenyl}acetamide (0.10 g, 0.20 mmol) in DCM (3 mL). The reaction mixture was allowed to stir at rt overnight and then concentrated. The residue was purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(1H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]phenyl}acetamide (Compound I-8) (0.026 g, 32%). LCMS (FA): m/z=380 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14][C:15]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH3:28])[CH:19]=2)=[O:16])[CH2:8][CH2:7]1.Cl>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][NH:14][C:15]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH3:28])[CH:19]=2)=[O:16])[CH2:10][CH2:11]1
Reactant: Cc1cccc(C=C2CCN(CCNC(=O)Nc3cc(C)nc4ccccc34)CC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cccc(CC2CCN(CCNC(=O)Nc3cc(C)nc4ccccc34)CC2)c1
Reaction time: 6 h

Procedure:
A suspension of 1-{2-[4-(3-methyl-benzylidene)-piperidin-1-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea (21 mg, 0.05 mmol), 2M aqueous HCl (0.5 mL, 1 mmol) and Pd—C (10%, 5 mg) in MeOH (2 mL) is stirred under hydrogen atmosphere for 6 h. The catalyst is filtered off and the filtrate evaporated to provide the title compound as hydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4]([CH3:10])[CH2:5][NH:6][CH2:7][CH:8]=[CH2:9].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:11])[CH:4]([CH3:10])[CH2:5][N:6]([CH2:7][CH:8]=[CH2:9])[C:17]1[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=[C:13]([Cl:12])[N:18]=1
Reactant: C=CCNCC(C)C(=O)OC
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCN(CC(C)C(=O)OC)c1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 81 %

Procedure:
To a mixture of 1.71 g (0.010 mole) of (rac)-2-methyl-3-(2-propenylamino)-propanoic acid methyl ester, 1.94 g (0.010 mole) of 2,4-dichloro-5-nitro-pyrimidine, 50 mL of ethyl acetate and 25 mL of water was added 3.0 g (0.030 mole) of potassium bicarbonate. The mixture was stirred for 3 hours, and then diluted with 50 mL of ethyl acetate and 50 mL of water. The aqueous layer was extracted with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate (100:0-97.5:2.5) to give 2.55 g of (rac)-3-[allyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-2-methyl-propanoic acid methyl ester (IV-65) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[C:15](O)(=O)[C:16]([CH3:19])([CH3:18])[CH3:17].N>O>[CH3:15][C:16]([C:19]1[NH:11][C:10]2[CH:9]=[C:8]3[NH:7][C:6](=[O:12])[C:5]([CH3:14])([CH3:13])[C:4]3=[CH:3][C:2]=2[N:1]=1)([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=O)O
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Agent: N
Solvent: O
Product: CC(C)(C)c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Temperature: 200 °C

Procedure:
Analogously to Example 11, 0.286 g. 5,6-diamino-3,3-dimethylindolin-2-one and 0.18 g. pivalic acid are heated with 3 g. polyphosphoric acid in a pre-heated bath for 30 minutes at 200° C. A further 0.18 g. pivalic acid are then added thereto and further heated for 30 minutes at 200° C. This procedure is repeated three times so that, in all, 0.9 g. pivalic acid are used with a total reaction time of 2.5 hours. After cooling, the mixture is dissolved in about 9 ml. water and adjusted to about pH 7 to 8 with concentrated aqueous ammonia solution. The precipitate obtained is filtered off with suction and washed with water to give 0.28 g. of the title compound; m.p. >300° C. For further purification, it is dissolved in a little hot ethanol, the turbid solution is treated with charcoal, the hot clear filtrate is evaporated in a vacuum and the evaporation residue is triturated with diethyl ether. One mole of the title compound thus obtained contains 1 mole of water; m.p. >300° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:22][O:23][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14][C:13]3=[O:21].[NH:24]1[C:32]2[C:27](=CC=C[CH:31]=2)[C:26]2(COC3C=C4C(=[CH:43][C:33]2=3)CCO4)C1=O.Br.BrCC1C=CC=CN=1.ClCC1C=NC(OC)=NC=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:22][O:23][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[N:14]([CH2:31][C:32]1[CH:27]=[CH:26][CH:33]=[CH:43][N:24]=1)[C:13]3=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: COCCOc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Agent: Br
Agent: BrCc1ccccn1
Agent: COc1ncc(CCl)cn1
Product: COCCOc1ccc2c(c1)OCC21C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using 6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 5-(chloromethyl)-2-methoxypyrimidine, 6-(2-methoxyethoxy)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (72%): mp 94-95° C.; 1H NMR (300 MHz, CDCl3) δ8.56 (d, J=4.7 Hz, 1H), 7.69-7.59 (m, 1H), 7.25-7.09 (m, 4H), 7.05-6.95 (m, 1H), 6.92-6.82 (m, 2H), 6.81-6.73 (m, 1H), 6.37 (s, 1H), 5.08 (ABq, 2H), 4.83 (ABq, 2H), 3.93 (t, J=4.7 Hz, 2H), 3.62 (t, J=4.7 Hz, 2H), 3.36 (s, 3H); 13C NMR (75 MHz, CDCl3 δ 177.2, 155.5, 155.1, 153.7, 149.5, 142.1, 137.1, 132.0, 129.6, 128.9, 123.8, 123.5, 122.8, 121.6, 115.8, 110.5, 110.4, 109.5, 79.8, 71.0, 68.1, 59.1, 58.5, 46.1; MS (ES+) m/z 403.0 (M+1).