Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:10]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)([CH3:9])[CH3:8])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.C1COCC1.CO.Br[CH2:45][C:46]1[N:47]([CH3:71])[C:48]2[C:53]([N:54]=1)=[C:52]([N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)[N:51]=[C:50]([N:61]1[C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=3[N:63]=[C:62]1[CH3:70])[N:49]=2>>[CH3:71][N:47]1[C:46]([CH2:45][N:1]2[CH2:2][CH2:3][CH:4]([C:7]([NH2:10])([CH3:8])[CH3:9])[CH2:5][CH2:6]2)=[N:54][C:53]2[C:48]1=[N:49][C:50]([N:61]1[C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=3[N:63]=[C:62]1[CH3:70])=[N:51][C:52]=2[N:55]1[CH2:56][CH2:57][O:58][CH2:59][CH2:60]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)N)CC3)n(C)c2n1
Reaction time: 8 h
Yield: 35.7 %

Procedure:
According to General Procedure E, [(9H-fluoren-9-yl)methyl 2-(piperidin-4-yl)propan-2-ylcarbamate (0.0923 g, 0.253 mmol) and N,N-diisopropylethylamine (0.265 mL, 0.00152 mol) were mixed in THF (0.7 mL, 0.008 mol) and Methanol (0.7 mL, 0.02 mol) at room temperature, and 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (0.112 g, 0.253 mmol) was added. The reaction was stirred overnight. The reaction mixture was concentrated to dryness. The crude residue was dissolved in N,N-Dimethylformamide (2.0 mL) and Piperidine (0.200 mL) was added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated. The crude was purified by reverse phase HPLC to give 383 (45.5 mg, 35.7%). [M+H]+=504.3.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH3:10])[CH2:3][O:4][N:5]=C(C)C.OCC(ON=C(C)C)CC.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:1]([CH:2]([CH2:9][CH3:10])[CH2:3][O:4][NH2:5])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCC(O)CON=C(C)C
Reactant: Oc1ccccc1
Agent: CCC(CO)ON=C(C)C
Product: CCC(CON)Oc1ccccc1
Yield: 50 %

Procedure:
The starting material was a mixture of 2-propanone O-(2-hydroxybutyl)oxime and 2-propanone O-(2-hydroxy-1-ethylethyl)oxime in the ratio 96.7:3.3. Phenol was used in place of 4-chlorophenol, otherwise the procedure was as in Example 1. This resulted in O-(2-phenoxybutyl)hydroxylamine (yield: 50%) and O-(2-phenoxy-1-ethylethyl)hydroxylamine in the ratio 99.8:0.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.[Br-:31].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][Br:31])[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)COC2)C1c1ccc(F)c(Br)c1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(CBr)NC2=C(C(=O)COC2)C1c1ccc(F)c(Br)c1
Reaction time: 1 h
Yield: 65.1 %

Procedure:
A solution of the product from Example 25A (0.87 g, 2.2 mmol) in chloroform (10 mL) was cooled to −10° C., treated with pyridine (0.21 mL, 2.6 mmol), then treated with pyridinium tribromide (0.84 g, 2.6 mmol), stirred for 1 hour, diluted with methylene chloride (150 mL) and washed with 1N HCl (25 mL). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography over silica gel (1% and then 2% methanol/methylene chloride) to provide the title compound (0.68 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[C:7]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:13]#[C:14][CH2:15][CH3:16])=[O:4].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC.CC(C)=O>[C:20]([O:19][C:17]([C:7]1([CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16])[CH:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][CH:8]1[OH:11])=[O:18])([CH3:21])([CH3:23])[CH3:22]
Reactant: [H][H]
Reactant: CCC#CCC1(C(=O)OC(C)(C)C)C(O)CCC1CC(=O)OC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC/C=C\CC1(C(=O)OC(C)(C)C)C(O)CCC1CC(=O)OC

Procedure:
A 1.4 g quantity of 3-methoxycarbonylmethyl-2-methoxycarbonyl-2-(2-pentynyl)-cyclopentanol (compound (1-a)) and 2.2 g of Lindlar catalyst are dissolved in a mixture of 50 ml of n-hexane and 5 ml of acetone. The starting compound is thus reduced at room temperature and atmospheric pressure with use of hydrogen gas. The reaction is completed when the solution has absorbed the theoretical amount of the gas, whereupon the catalyst is filtered off. The filtrate is concentrated in vacuo, and the residue dissolved in benzene-ethyl acetate and purified with a silica gel column. The product is distilled in a vacuum, giving 2-methoxycarbonyl-3-methoxycarbonylmethyl-2-(cis-2-pentenyl)-cyclopentanol (compound (1-b), R1 =R2 =CH3) in a yield of 87%, b.p. 74°-78° C./0.01 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1([CH2:9][CH2:10][CH:11]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)[C:12](O)=[O:13])[CH2:8][CH2:7]1)[CH3:2].[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1([CH2:9][CH2:10][CH:11]([CH2:12][OH:13])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1(CCC(CCc2ccc(C(=O)OC)cc2)C(=O)O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(CCC(CO)CCc2ccc(C(=O)OC)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At −10° C., 2.13 ml of a 1 M borane/THF complex solution (2.13 mmol) are added dropwise to a solution of 400 mg (1.06 mmol) of 4-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]-2-{2-[4-(methoxy-carbonyl)phenyl]ethyl}butanoic acid in 10 ml of THF. After warming to 0° C., the mixture is stirred at this temperature for another 2 hours. After complete conversion, saturated ammonium chloride solution is added, and the reaction mixture is extracted three times with 20 ml of ethyl acetate. The combined organic phases are then dried over sodium sulfate, and the solvent is evaporated to dryness. This gives 330 mg (85% of theory) of a colorless oil.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[C:13]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)Cl>[C:13]1([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1CCCCCCC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C2=CCCCCCC2)cc1
Temperature: 15 °C
Reaction time: 5 h

Procedure:
To a vigorously stirred suspension of 19.5 g of magnesium chips (which have been washed with chloroform and activated with iodine) in 800 ml of absolute tetrahydrofuran is added in increments a solution of 131 g of p-bromanisol in 200 ml of absolute tetrahydrofuran in such a way that it is possible to maintain gently the Crignard reaction. The reaction mixture is allowed to continue to react for 1 hour, cooled to 15° C and treated dropwise with 88 g of cyclooctanone. After the reaction mixture has been stirred for a further 5 hours, it is treated with ice and with saturated ammonium chloride solution. The whole mixture is extracted with ether, the ether layers are washed with water, dried over sodium sulphate and evaporated in vacuo. During distillation under a high vacuum, water is split off from the oily residue to thus yield the p-(1-cyclooctenyl)-anisol, which boils at 115°-118° C (0.05mm Hg).
Reaction SMILES: OC(C(F)(F)F)=O.NC1C(C2C=CC(C(O)=O)=C(F)C=2)=NC(C2CCOCC2)=CN=1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:50]([CH2:53][C@@H:54]([NH:63]C(=O)OC(C)(C)C)[C:55]1[CH:60]=[C:59]([I:61])[CH:58]=[C:57]([F:62])[CH:56]=1)=[N+:51]=[N-:52].[ClH:71]>CN(C=O)C.O1CCOCC1>[ClH:71].[N:50]([CH2:53][C@H:54]([C:55]1[CH:60]=[C:59]([I:61])[CH:58]=[C:57]([F:62])[CH:56]=1)[NH2:63])=[N+:51]=[N-:52]
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])c1cc(F)cc(I)c1
Agent: Cl
Agent: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NC[C@@H](N)c1cc(F)cc(I)c1

Procedure:
4-(3-Amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoic acid TFA adduct (126 mg, 0.292 mmol) and HOAt (0.060 g, 0.438 mmol) was dissolved in DMF (1 mL) and DIEA (0.156 mL, 0.876 mmol). (S)-2-azido-1-(3-fluoro-5-iodophenyl)ethanamine hydrochloride salt (100 mg, 292 mmol), obtained from the reaction of (S)-tert-butyl (2-azido-1-(3-fluoro-5-iodophenyl)ethyl)carbamate with 4M HCl in dioxane (Step 9 in Scheme 76), was added, followed by EDC (0.090 g, 0.467 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and water, and the organic layer was washed with water twice and then with saturated Na2CO3. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo providing crude (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(2-azido-1-(3-fluoro-5-iodophenyl)ethyl)-2-fluorobenzamide without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.Cl.[NH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:21][O:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:30][CH:31]3[S:35][C:34](=[O:36])[NH:33][C:32]3=[O:37])=[CH:38][CH:39]=2)[CH3:18])=[CH:13][CH:12]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: COc1ccc(OC)c(-c2ccc(C(C)=O)cc2)c1
Agent: Cl
Product: COc1ccc(OC)c(-c2ccc(C(C)=NOCCOc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Yield: 92.7 %

Procedure:
Following a procedure similar to that described in Example 40(f), 256 mg of 4'-(2,5-dimethoxyphenyl)acetophenone were reacted with 382 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 482 mg of the title compound as an amorphous solid, melting at 47-52° C. (softening point).
Reaction SMILES: [C:1]([C:3]1([CH2:13][O:14][C:15]2[C:27]([CH:28]3[CH2:30][CH2:29]3)=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([F:31])[CH:16]=2)[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)#[N:2]>ClCCl>[C:1]([C:3]1([CH2:13][O:14][C:15]2[C:27]([CH:28]3[CH2:30][CH2:29]3)=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:31])[CH:16]=2)[CH:4]2[CH2:5][CH:6]3[CH2:7][CH:8]([CH2:9][CH:10]1[CH2:11]3)[CH2:12]2)#[N:2]
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Solvent: ClCCl
Product: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.5 %

Procedure:
To a solution of tert-butyl 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate (0.38 g, 0.88 mmol) in dichloromethane (30 mL) trifluoroacetic acid (10 mL) was added. The solution was stirred at ambient temperature for 16 hours and concentrated in vacuo to give the title compound as a pale yellow solid (0.33 g, quant.): 1H NMR (300 MHz, DMSO-d6) δ 12.86 (br s, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.09 (d, J=13.0 Hz, 1H), 4.45 (s, 2H), 2.16-1.78 (m, 11H), 1.70-1.60 (m, 4H), 0.90-0.84 (m, 2H), 0.60-0.55 (m, 2H); MS (ES−) m/z 468.2 (M−1).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:31][NH2:32]>CO>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:32][CH3:31])=[CH:6][CH:7]=2)=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:13][CH3:14])=[CH:25][CH:26]=1
Reactant: CN
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)c(OC)c1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc(O)c(OC)c1
Temperature: 85 °C
Yield: 48 %

Procedure:
To a stirred solution of 4-(1-(4-(2-Chloroethoxy)phenyl)-1-(4-hydroxyphenyl)-but-1-en-2-yl)-2-methoxyphenol (88 mg, impure) in 10 mL MeOH was added 2 mL CH3NH2 (aq). After the mixture was heated at 85° C. for 24 h., the solvent was removed in vacuo, EtOAc was added, the mixture was washed with water and brine, dried over Na2SO4, filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography (CH2Cl2/MeOH(NH3 gas)=10/1) to give the desired product (42 mg, 48% yield, Z/E=1/1) as a white solid. m/z=420[M+1]+.
Reaction SMILES: ClCl.[Cl:3]C(=C)C#N.[Cl:8][C:9]([Cl:14])([CH2:12][Cl:13])[C:10]#[N:11].OS(O)(=O)=O.O=S(Cl)Cl.CN([CH:27]=[O:28])C>>[Cl:8][C:9]([Cl:14])([CH2:12][Cl:13])[C:10]#[N:11].[Cl:8][C:9]([Cl:14])([CH2:12][Cl:13])[C:27]([Cl:3])=[O:28]
Reactant: C=C(Cl)C#N
Reactant: CN(C)C=O
Agent: ClCl
Agent: N#CC(Cl)(Cl)CCl
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: O=C(Cl)C(Cl)(Cl)CCl
Reaction time: 1 h

Procedure:
Firstly 2,2,3-trichloropropionitrile is prepared by adding chlorine to α-chloroacrylonitrile, as descibed by H. Brintzinger et al in Angew. Chemie, 1948, 60,p.311 and then the 2,2,3-trichloropropionitrile undergoes acid hydrolysis with 60% H2SO4 at 125° C. and for 5 hours in order to obtain the corresponding acid, as described by H. Laato in Suomen Kemistilehti, 1968, 41B, p.266. The acid is then treated by SOCl2 in the presence of a catalytic quantity of DMF at 40° to 50° C.and for 1 hour, which gives 2,2,3-trichloropropanoyl chloride, which is distilled at 50° C. under 2700 Pa (20 mm of Hg),the yield being 66%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[Cl-].[CH:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1>C(Cl)Cl.C(OCC)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][N:12]([C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: O=C(O)C1CC1
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 9.1 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and of 4.04 g of triethylamine in 40 ml of methylene chloride cooled to 0° C., a solution of 4.2 g of chloride of cyclopropanecarboxylic acid in 20 ml of methylene chloride is added dropwise, while ensuring that the temperature does not exceed 5° C. The reaction mixture is left for 30 minutes at 0°-5° C., then for one hour at room temperature. 200 ml of diethyl ether are added, the mixture is filtered, the organic phase is washed three times with water, dried and evaporated to dryness under reduced pressure. Thus 11.5 g of 4-(3-trifluoromethylphenyl)-1-cyclopropylcarbonyl-1,2,3,6-tetrahydropyridine are obtained: yellow/brown oil containing traces of impurities.
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[C@H:2]([C:7]([O:9]C1C(F)=C(F)C(F)=C(F)C=1F)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]>C1COCC1>[NH:1]([C:21]([O:23][CH2:24][CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:22])[C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Yield: 29.2 %

Procedure:
A solution of AE (50 mg; 0.185 mmol) in THF (5 ml) was added with Fmoc-L-Ile-OPfp (211 mg; 0.407 mmol). The solution was refluxed for 48 hrs, the solvent was evaporated, and the residue was purified by chromatography (petroleum ether/ethyl acetate 3:1). 42 mg (37%) of Fmoc-L-Ile-Aloe was isolated as an an orange-coloured powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:12][CH:11]=[C:10]([NH:18][CH2:19][CH2:20][NH:21]C(OC(C)(C)C)=O)[N:9]=1)(C)(C)C.[ClH:30]>O1CCOCC1.C(OCC)C>[ClH:30].[NH2:7][C:8]1[C:13]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:12][CH:11]=[C:10]([NH:18][CH2:19][CH2:20][NH2:21])[N:9]=1
Reactant: CCC(=O)c1ccc(NCCNC(=O)OC(C)(C)C)nc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCC(=O)c1ccc(NCCN)nc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
530 mg (1.30 mmol) of tert-butyl[6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-3-propanoylpyridin-2-yl]carbamate (Example 24A) were dissolved in 15 ml of a solution of hydrochloric acid in dioxane (4 M), and the mixture was stirred at RT for 20 h. After the reaction had gone to completion, the reaction mixture was diluted with diethyl ether (100 ml), and the precipitate was filtered off, washed with diethyl ether (100 ml) and dried. This gave 290 mg (91% of theory) of the product as a solid.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([F:14])[CH:3]=1.Cl[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>CN(C)C=O.FC(F)(F)C(O)=O.[Mn]>[F:14][C:4]1[CH:3]=[C:2]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:12][C:5]=1[CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)NCc1ccc(Br)cc1F
Reactant: CCOC(=O)C(C)Cl
Agent: [Mn]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1ccc(CNS(C)(=O)=O)c(F)c1
Temperature: 60 °C
Reaction time: 36 h

Procedure:
To a stirred solution of N-(4-bromo-2-fluorobenzyl)methanesulfonamide (2.94 g, 10.421 mmol) in dimethylformamide were added ethyl 2-chloropropionate (1.725 mL), manganese (1.145 g) and (2,2′-bipyridine)nickel(II)-dibromide (273 mg, mmol). Trifluoroacetic acid (2 drops) was added. The reaction mixture was stirred for 36 h at 60° C. After cooling down to room temperature, the mixture was hydrolysed by 1N HCl and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo. The crude was purified by column chromatography to obtain ethyl 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoate (218 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:32])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:45].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl.O>[NH2:45][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][C:19]3([OH:32])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
To a solution of tert-butyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate (96%, 10.0 g, 22.7 mmol) in dichloromethane (150 mL) at rt was added m-CPBA (55%, 7.12 g, 22.7 mmol). After 1.5 h, the mixture was cooled to 0° C. and concentrated ammonium hydroxide (150 mL) was added, followed by TsCl (4.54 g, 23.8 mmol). The reaction was stirred rapidly overnight. More TsCl (1.00 g and 0.47 g) was added as the mixture was stirred an additional 6 h. Water (200 mL) was added and the mixture was extracted with dichloromethane (3×200 mL). The combined organic phases were washed with brine (3×250 mL) and dried over MgSO4, filtered, and concentrated to a foam, which was crystallized from acetonitrile twice. The fine yellow crystals were dried under vacuum to yield 1.60 g (15%) of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate, mp 195-197° C. 1H NMR (CDCl3, 300 MHz) δ 8.04 (dm, J=8.3 Hz, 1H), 7.82 (dm, J=8.3 Hz, 1H), 7.53 (m, 1H), 7.31 (m, 1H), 5.40 (br s, 2H), 4.85 (s, 2H), 4.75 (br s, 2H), 3.93 (br s, 3H), 3.72 (q, J=7.0 Hz, 2H), 3.03 (m, 2H), 1.76 (m, 2H), 1.49-1.40 (m, 2H), 1.42 (s, 9H), 1.27 (t, J=7.0 Hz, 3H); MS (APCI) m/z 456 (M+H+); Anal. calcd for C24H33N5O4: C, 63.28; H, 7.30; N, 15.37. Found: C, 63.32; H, 7.53; N, 15.39.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=O)[CH2:30][C:31]([CH3:36])([CH3:35])[O:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CCOCC>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)=[CH:30][C:31]([CH3:36])([CH3:35])[O:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC1(C)CC(=O)c2ccc(OCc3ccccc3)cc2O1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC1(C)C=C(c2ccc(C(F)(F)F)cc2)c2ccc(OCc3ccccc3)cc2O1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
n-Butyl-lithium (142 ml of a 2.4 M solution) was added under dry nitrogen to a solution of 4-bromobenzotrifluoride (76.5 g) in dry ether at -50° C. The mixture was left to stir for 2 hours. 7-Benzyloxy-2,2dimethylchroman-4-one (64 g) in dry ether was added dropwise. Water was added and the ether layer washed with 5N.HCl (2×100 ml), and dried (MgSO4). Removal of the solvent under reduced pressure gave an oil (84 g) which was chromatographed on alumina. Elution with petrolether (1:1) gave the title compound (52 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:16]=[C:15]([C:17]([NH2:19])=O)[CH:14]=[CH:13][CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:26]>>[ClH:26].[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:16]=[C:15]([CH2:17][NH2:19])[CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1cccc(N2CCc3ccccc3C2)n1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: NCc1cccc(N2CCc3ccccc3C2)n1

Procedure:
Following the general method described in example 9, 6-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridine-2-carboxylic acid amide (example 22a) was reacted with lithium aluminum hydride. After workup and chromatography the free base of the title compound was treated with hydrogen chloride and crystallized as the off white salt. Mp. 192-195° C. (iPr2O), MS: m/e=239 (M+).
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][C@@H:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])(C)C)[CH3:12])(C)(C)C.C1(CN)CC1.[CH:36]([O:39][C:40]1[CH:41]=[C:42]([CH:61]=[C:62]([N:64]2[CH2:68][CH2:67][CH2:66][C:65]2=[O:69])[CH:63]=1)C(N[C@H]([C@@H]1C[C@@H](C)C(=O)O1)CC1C=CC=CC=1)=O)([CH3:38])[CH3:37]>>[CH2:23]([C@H:8]([NH:7][C:6](=[O:30])[C:42]1[CH:61]=[C:62]([N:64]2[CH2:68][CH2:67][CH2:66][C:65]2=[O:69])[CH:63]=[C:40]([O:39][CH:36]([CH3:38])[CH3:37])[CH:41]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH:16]1[CH2:17][CH2:20]1)[CH3:12])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H]2C[C@@H](C)C(=O)O2)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Agent: NCC1CC1
Product: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCC2CC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D1 from cyclopropylmethylamine and 3-isopropoxy-N-[(S)-1-((2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl)-2-phenylethyl]-5-(2-oxopyrrolidin-1-yl)benzamide (D49).