Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:10]([NH:12][C@@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:14]([NH:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([C@@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])=[O:15])=[O:11].[O:49]1[CH2:54][CH2:53][N:52]([CH2:55][C:56](O)=[O:57])[CH2:51][CH2:50]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:42]([O:41][CH2:40][C@H:9]([NH:8][C:56](=[O:57])[CH2:55][N:52]1[CH2:53][CH2:54][O:49][CH2:50][CH2:51]1)[C:10]([NH:12][C@@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:14]([NH:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([C@@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])=[O:15])=[O:11])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COc1ccc(C[C@H](NC(=O)[C@@H](N)COCc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Reactant: O=C(O)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C[C@H](NC(=O)[C@H](COCc2ccccc2)NC(=O)CN2CCOCC2)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
To (S)-2-amino-3-(benzyloxy)-N-((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)propanamide TFA salt (2.94 mmol assumed) was added 2-morpholinoacetic acid (647 mg, 4.46 mmol), HATU (1.86 g, 4.91 mmol), and DMF (5 mL). The mixture was cooled to 0° C. and DIEA (3.10 mL, 17.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate+0-10% methanol) provided (S)-3-(benzyloxy)-N-((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)-2-(2-morpholinoacetamido)propanamide (660 mg, 28% over 5 steps) as an amorphous colorless solid. MS (EI) for C38H46N4O8, found 687.4 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:24][CH2:25][CH3:26])[C:13]([C:15]1[CH:16]=[C:17]2[CH:23]=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1)=[O:14])=O)(C)(C)C>Cl>[CH2:24]([C:9]1([C:13]([C:15]2[CH:16]=[C:17]3[CH:23]=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12][NH:8]1)[CH2:25][CH3:26]
Reactant: CCCC1(C(=O)c2cnc3[nH]ccc3c2)CCCN1C(=O)OC(C)(C)C
Agent: Cl
Product: CCCC1(C(=O)c2cnc3[nH]ccc3c2)CCCN1
Yield: 97 %

Procedure:
A solution of 2-propyl-2-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.240 g, 0.672 mmol) in 1N methanolic HCl (10.1 mL) was stirred at 20° C. under nitrogen for 18 hours. The reaction mixture was concentrated in vacuo then triturated with DCM (5 mL) and concentrated in vacuo to yield (2-propyl-pyrrolidin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-5-yl)-methanone (0.215 g, 0.652 mmol, 97%) as a white powder and as a monohydrochloride salt, MS=258 [M+H]+.
Reaction SMILES: CON(C)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH2:14][CH3:15].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(P(=[CH:43][C:44]([O:46][CH3:47])=[O:45])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:47][O:46][C:44](=[O:45])[CH:43]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCNc1cc(F)ccc1C(=O)N(C)OC
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCNc1cc(F)ccc1C=CC(=O)OC
Temperature: -35 °C
Reaction time: 0.67 h
Yield: 70.8 %

Procedure:
To a solution of N-methoxy-N-methyl-4-fluoro-2-propylamino-benzamide (0.33 g, 1.37 mmol) in THF (4 mL) was added dropwise LiAlH4 (1 M in THF, 0.7 mL) at −45° C. The mixture was stirred for 40 minutes at −35° C. and then quenched by adding saturated aqueous KHSO4 solution. The mixture was diluted with EtOAc, washed with 3 N HCl, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was reacted with methyl (triphenylphosphoranylidene)acetate (0.5 g, 1.5 mmol) in toluene (4 mL) overnight at 100° C. The mixture was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.23 g, 69%) after purification by column chromatography (EtOAc:hexane=1:10).
Reaction SMILES: ClC1C=CC(O[C:7]([C:17]([F:20])([F:19])[F:18])([C:13]([F:16])([F:15])[F:14])[C:8]([O:10]CC)=[O:9])=CC=1.[OH-].[K+].CO>O>[F:14][C:13]([F:15])([F:16])[CH:7]([C:17]([F:18])([F:20])[F:19])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 2-(4-chlorophenoxy)-3,3,3-trifluoro2-trifluoromethylpropionate (14.6 g.), 4.5 N-aqueous potassium hydroxide (19.2 ml.) and methanol (35 ml.) is stirred at ambient temperature for 21/4 hours. The resulting solution is diluted with water and washed with ether. The aqueous phase is acidified with concentrated hydrochloric acid, and extracted with ether. The extract is washed with water, dried with sodium sulphate and evaporated. The residue is sublimed twice at 100° C. and 0.3 mm. pressure, and the sublimate is washed with light petroleum (b.p. 30°-40° C.) to give 2-(4-chloropheonxy)- 3,3,3-trifluoro-2-trifluoromethylpropionic acid, m.p. 81°-83° C. (5.1 g.). The acid may be further purified by crystallisation (prisms) from light petroleum (b.p. 60°-80° C.) followed by sublimation, which yields material of m.p. 82°-83° C.
Reaction SMILES: [C:1]12([NH:6][C:7]3[N:12]=[C:11]([NH:13][C@@H:14]4[CH2:19][CH2:18][C@@H:17]([CH3:20])[C@H:16]([OH:21])[CH2:15]4)[C:10]([C:22]#[N:23])=[CH:9][N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[OH-:24].[Na+].OO>CS(C)=O>[C:1]12([NH:6][C:7]3[N:12]=[C:11]([NH:13][C@@H:14]4[CH2:19][CH2:18][C@@H:17]([CH3:20])[C@H:16]([OH:21])[CH2:15]4)[C:10]([C:22]([NH2:23])=[O:24])=[CH:9][N:8]=3)[CH2:2][CH:3]([CH2:4]1)[CH2:5]2
Reactant: [OH-]
Reactant: C[C@@H]1CC[C@@H](Nc2nc(NC34CC(C3)C4)ncc2C#N)C[C@H]1O
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H]1CC[C@@H](Nc2nc(NC34CC(C3)C4)ncc2C(N)=O)C[C@H]1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
2-(Bicyclo[1.1.1]pentan-1-ylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)pyrimidine-5-carbonitrile (0.38 g, 1.213 mmol) was dissolved in DMSO (26.9 mL) and to this solution was added a 50% aqueous sodium hydroxide solution (0.097 ml, 1.213 mmol) and a 30% aqueous hydrogen peroxide solution 0.137 mL, 1.213 mmol) at room temperature. Then the reaction mixture was stirred at 50° C. for 1 h. The reaction was cooled to room temperature and it was poured into 50 mL of ice water. The white precipitate was collected on filter paper and was washed twice with water. The precipitate was dried to give 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide (0.269 g, 0.812 mmol, 67% yield). 1H NMR (DMSO-d6, 400 MHz): δ ppm 0.94 (d, J=6.25 Hz, 3H) 1.10-1.26 (m, 3H) 1.68 (d, J=10.54 Hz, 1H) 1.92 (d, J=10.93 Hz, 1H) 2.06 (s, 6H) 2.17 (d, J=9.76 Hz, 1H) 2.46 (s, 1H) 2.98 (br. s., 1H) 3.82-3.95 (m, 1H) 4.63 (br. s., 1H) 7.16 (br. s., 1H) 7.77 (br. s., 1H) 8.11 (br. s., 1H) 8.33 (s, 1H) 9.24 (br. s., 1H); MS (ESI): m/z 332.3 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:35][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[CH:15]=[CH:14]2)[N:21]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:20]=[CH:19]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1>[Pd].C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:35][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[CH2:15][CH2:14]2)[N:21]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:20]=[CH:19]4)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc4c(ccn4S(=O)(=O)c4ccc(C)cc4)c3O2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc4c(ccn4S(=O)(=O)c4ccc(C)cc4)c3O2)cc1

Procedure:
Treatment of {(2R)-7-[(4-methylphenyl)sulfonyl]-2,7-dihydropyrano[2,3-e]indol-2-yl}methyl 4-methylbenzenesulfonate with palladium on carbon (10 wt. %) in ethanol following the procedure described for Example 1c gives {(2R)-7-[(4-methylphenyl)sulfonyl]-2,3,4,7-tetrahydropyrano[2,3-e]indol-2-yl}methyl 4-methylbenzenesulfonate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19])[CH:6]=[CH:5]2.C([Li])CCC.[F:25][C:26]1[CH:27]=[C:28]([CH:35]=[CH:36][CH:37]=1)[C:29](N(OC)C)=[O:30]>C1COCC1>[F:25][C:26]1[CH:27]=[C:28]([C:29]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH3:19])[CH:6]=[CH:5]3)=[O:30])[CH:35]=[CH:36][CH:37]=1
Reactant: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Reactant: CON(C)C(=O)c1cccc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1ccc2cc(C(=O)c3cccc(F)c3)ccc2n1
Temperature: 25 °C

Procedure:
The product from Example 42D (320 mg, 1.0 mmol) in THF (10 mL) was treated with 2.5M n-butyllithium (0.5 mL, 1.25 mmol) at −78° C. The solution was mixed for 15 min, and treated with a solution of 3-fluoro-N-methoxy-N-methylbenzamide (2.0 mmol) in THF (5.0 mL) at −78° C. The mixture was allowed to warm to room temperature overnight, quenched by 1 mL ethanol, concentrated, and diluted with ethyl acetate. The mixture was washed with 5% NaHCO3 (25 mL×3), 25% brine (25 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (heptane:acetone:CH2Cl2:TEA (60:40:5:1) to provide the title compound. The title compound was treated with HCl in IPA:ethyl acetate to give the dihydrochloride salt. mp 162-164° C. (dec.); MS (ESI) 363 (M+H)+; 1H NMR (DMSO-d6) δ 8.79 (1H, d), 8.53 (1H, d), 8.30 (1H, d), 8.21 (1H, dd), 7.82 (1H, d), 7.6 (4H, m), 3.9 (1H, br, m), 3.63 (2H, br, m), 3.50 (2H, br, m), 3.21 (1H, br, m), 2.2 (1H, m), 1.98 (2H, br, m), 1.7 (1H, br, m), 1.46 (1H, m), 1.30 (3H, d).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:3][OH:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[CH3:1][CH:2]([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH:3]=[O:4]
Reactant: CC(CO)COC1CCCCO1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C=O)COC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A solution of 2-methyl-3-tetrahydropyranyloxy-1-propanol (250 mg; 1.4 mmol) in dichloromethane (4 ml) was added to a suspension of pyridinium chlorochromate (500 mg; 2.32 mmol) and celite (2.5 g) in dichloromethane (10 ml), and stirred at room temperature for 3 hours. Ether (100 ml) was added thereto. The resultant mixture was filtered, and the filtrate was distilled under reduced pressure to give the solvent. The residue was purified by silica gel chromatography using a mixture of ethyl acetate and benzene (1:4) to give 2-methyl-3-tetrahydropyranyloxypropanal (178 mg; yield, 73%).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].[I:17][CH2:18][CH2:19][CH2:20]O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[I:17][CH2:18][CH2:19][CH2:20][O:3][C:2](=[O:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH:16]2[NH:15][C:13](=[O:14])[NH:12][CH:11]2[CH2:10][S:9]1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: OCCCI
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1NC2CSC(CCCCC(=O)OCCCI)C2N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.4 %

Procedure:
A solution of biotin (125 mg, 0.5 mmol), 3-iodo-1-propanol (150 μL, 1.6 mmol) and TsOH (10 mg, 0.05 mmol) in PhMe (50 mL)) was heated under reflux and Ar for 3 d in a Dean-Stark apparatus. After cooling down to ambient temperature, the mixture was filtered and the solvent distilled off under reduced pressure. The residue was dissolved in CH2Cl2 (30 mL) and washed with H2O (5 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to yield 4 (75 mg, 36%) as a white solid. FABMS: m/z=413 [M+H]+; 1H-NMR (400 MHz, CDCl3): δ=1.40-1.45 (2H, m), 1.61-1.75 (4H, m), 2.10-2.16 (2H, m), 2.30 (2H, t, 7 Hz), 2.79 (1H, d, 13 Hz), 2.88 (1H, dd, 5 and 13 Hz), 3.15-3.18 (1H, m), 3.22 (2H, t, 7 Hz), 4.13 (2H, t, 6 Hz), 4.42-4.45 (1H, m), 4.61-4.65 (1H, m), 7.22 (1H, d, 8 Hz); 7.72 (1H, d, 8 Hz); 13C-NMR (100 MHz, CDCl3): δ=25.0, 28.4, 28.8, 32.6, 34.2, 40.5, 55.8, 61.8, 63.6, 64.4, 164.5, 173.9.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:29][CH2:30][CH3:31])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([OH:10])=[O:9])[CH3:2].[C:32](Cl)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.Cl>C(Cl)Cl.O>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:29][CH2:30][CH3:31])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:25]([C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[N:26]=[N:27][N:28]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([OH:10])=[O:9])[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCc1nc(CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCc1nc(CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A mixture of 7.5 g of 4-ethyl-2-propyl-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylic acid, 5.17 g trityl chloride and 1.92 g triethylamine in 50 mL CH2Cl2 is stirred overnight. After water addition and acidification with 1N HCl to pH 3, the mixture was separated and the organic phase was extracted with CH2Cl2/ ethyl acetate (1:1). The mixture was dried with Na2SO4, suction filtered and the solvent evaporated. 6.46 g of product was obtained after flash chromatography with ethyl acetate.
Reaction SMILES: Cl.[CH:2]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([C:17](=[O:28])[CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>CCOC(C)=O.C(OCC)C>[NH2:20][CH2:19][CH2:18][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH:2]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:12]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)NCCC(=O)c1cccc(OCC2CCCCCC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: NCCC(=O)c1cccc(OCC2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HCl gas was bubbled for 1-2 min through an ice-cold solution of tert-butyl 3-(3-(cycloheptylmethoxy)phenyl)-3-oxopropylcarbamate (0.495 g, 1.318 mmol) in EtOAc (ca. 20 mL). The reaction mixture was warmed to room temperature. After stirring overnight, the mixture was diluted with diethyl ether (ca. 30 mL). The white solid was collected by filtration, washed with diethyl ether and hexanes and dried under vacuum for 4 h. Example 16 was isolated as a white solid. Yield (0.285 g, 69%): 1H NMR (400 MHz, DMSO-d6) δ 8.05 (br s, 3H), 7.52 (dt, J=8.0, 1.2 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.40 (t, J=2.4 Hz, 1H), 7.23 (ddd, J=8.4, 2.8, 1.2 Hz, 1H), 3.81 (d, J=6.4 Hz, 2H), 3.41 (t, J=6.4 Hz, 2H), 3.10 (q, J=5.6 Hz, 2H), 1.88-1.95 (m, 1H), 1.76-1.83 (m, 2H), 1.61-1.69 (m, 2H), 1.38-1.59 (m, 6H), 1.22-1.31 (m, 2H).*
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:3]=1
Reactant: CCCCCN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: CCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(pentylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, pentylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([S:32][CH2:33][CH2:34][CH2:35]Cl)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:35][CH2:34][CH2:33][S:32][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Reactant: COc1ccc(SCCCCl)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(SCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5- tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 3-(3,4-dimethoxyphenylthio)-propylchloride with the addition of pyridine analogously to Example 3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH:16]2[C:19]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH2:21][CH2:20]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][CH2:39][CH2:40]Br>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([CH2:40][CH2:39][O:38][CH3:37])[CH:16]2[C:19]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH2:20][CH2:21]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3Cl)CC1)NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCN1CCc2cc(OC)c(OCc3ccccc3)cc2C1C1(c2ccccc2Cl)CC1
Reaction time: 16 h

Procedure:
A mixture of 7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline (2.1 g, free base liberated from the hydrobromide salt prepared in a similar manner to that described in Example RC14), acetone (30 ml), anhydrous potassium carbonate (1.6 g) and 2-methoxyethyl bromide (2.1 g) was heated under reflux for 6 hours. After a further 16 hours at ambient temperature, potassium carbonate (3 g) and 2-methoxyethyl bromide (2.22 g) were added, and heating continued for 6 hours. The mixture was filtered, the residue washed with acetone, and solvent removed from the filtrate in vacuo to yield 7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:33]([Cl:42])[CH:32]=5)[O:28][N:27]=4)=[CH:23][CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:7][C:8]([CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:33]([Cl:42])[CH:32]=4)[O:28][N:27]=3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CCCCOc1ccc(-c2nc(-c3ccc4c(c3)CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1Cl
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CCCCOc1ccc(-c2nc(-c3ccc4c(c3)CCN4CC(N)(CO)CO)no2)cc1Cl
Yield: 52 %

Procedure:
When the product of Step E was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 52% yield. 1H-NMR (DMSO-d6) 0.92 (tr, 3H, J=7.47 Hz); 1.07-1.48 (m, 2H); 1.71-1.76 (m, 2H); 2.98 (s, 2H); 3.22-3.56 (m, 8H); 4.17 (tr, 2H, J=6.36 Hz); 4.62 (m, 2H); 6.76 (d, 1H, J=7.74 Hz); 7.13 (tr, 1H, J=7.83 Hz); 7.24 (d, 1H, J=7.17 Hz); 7.37 (d, 1H, J=8.79 Hz); 8.07 (dd, 1H, J=2.13, 8.64 Hz); 8.12 (d, 1H, J=2.13 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:28]([O:30]CC)=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:26][CH2:27]3)=[CH:16][C:15]=2[F:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(OC3CCN(C(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 92.1 %

Procedure:
A mixture of 1.28 g of ethyl 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 3.5 ml of 1N aq. sodium hydroxide solution and 30 ml of tetrahydrofuran was heated under reflux for 1.5 hours. The mixture was concentrated under reduced pressure. To the residue was added 10% aq. citric acid to acidify the same, followed by extraction with chloroform. The chloroform layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated to dryness. The residue was recrystallized from chloroform-diisopropyl ether, whereby 1.11 g of the title compound was obtained as colorless powder.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@:3]1([CH2:16][F:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25].[OH-].[Na+]>O>[F:18][C:2]1([F:1])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@:3]1([CH2:16][F:17])[C:9]1[CH:14]=[C:13]([N+:24]([O-:26])=[O:25])[CH:12]=[CH:11][C:10]=1[F:15]
Reactant: NC1=N[C@](CF)(c2ccccc2F)C(F)(F)CO1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC1=N[C@](CF)(c2cc([N+](=O)[O-])ccc2F)C(F)(F)CO1
Reaction time: 2 h
Yield: 102.4 %

Procedure:
A dispersion of (S)-5,5-difluoro-4-fluoromethyl-4-(2-fluoro-phenyl)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate F6.1) (32.5 mg, 124 μmol) in sulfuric acid (1.01 g, 554 μl, 9.92 mmol) was cooled to 0° C. and stirring was continued until a complete solution was obtained. At 0° C. fuming nitric acid (12.1 mg, 8.68 μl, 174 μmol) was added in one portion and stifling continued for 2 hours. For the workup, the solution was added dropwise to a mixture of crushed ice and water. With an aqueous solution of sodium hydroxide (6 M) the pH was adjusted to 7-8. The aqueous layer was extracted three times with ethyl acetate, thereafter the combined organic layers were washed with brine, then dried over sodium sulphate and evaporated at reduced pressure. The (S)-5,5-difluoro-4-fluoromethyl-4-(2-fluoro-5-nitro-phenyl)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (39 mg, quantitative yield) was obtained as a light yellow solid and was engaged in the following step without further purification. MS (ISP): m/z=308.3 [M+H]+.