Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([Cl:32])[C:16]=2[N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19]2)[NH:11][CH:10]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1.O[Li].O>CN1C(=O)CCC1.C(Cl)Cl.CO.CCOC(C)=O>[Cl:32][C:15]1[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:19]2)=[C:17]2[C:9]([NH:8][C:36]([CH:33]3[CH2:35][CH2:34]3)=[O:37])=[CH:10][NH:11][C:12]2=[N:13][CH:14]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Agent: [Li]O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (1018 μL, 7.462 mmol) was added to an aliquot of (R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (390 mg, 1.066 mmol; Example 91, Step A) in NMP (3 mL) at 0° C. under N2 atmosphere. The mixture was treated dropwise with cyclopropanecarbonyl chloride (580.4 μL, 6.396 mmol) and stirred at 0° C. for 1 hour. The reaction mixture was then diluted with CH2Cl2 (4 mL). 2M LiOH.H2O (9 mL) was added, and the mixture was allowed to stir for 24 hours. The mixture was then diluted with 2% MeOH/EtOAc (100 mL) and washed with water (4×20 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by reverse phase chromatography (Biotage SP4, C-18 40M+, 15-85% CH3CN/water, 38 CV) to provide (R)-tert-butyl 1-(5-chloro-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate as a solid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[C:13](I)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][N:9]=1.[C:21]([N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1B(O)O)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>O.C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:7][C:8]1[C:13]([C:29]2[N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:36]3[C:31]([CH:30]=2)=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: Fc1ncc(-c2ccccc2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1c(-c2cc(-c3ccccc3)cnc2F)cc2ccccc21
Temperature: 25 °C
Yield: 76.3 %

Procedure:
Na2CO3 (279 mg, 2.63 mmol, 6.9 Eq.) in water (2 mL) was added to a mixture of 2-fluoro-3-iodo-5-phenyl-pyridine (114 mg, 0.38 mmol, 1.0 Eq.), Pd(PPh3)4 (44 mg, 0.04 mmol, 10 mol %) and 1-boc-indole-2-boronic acid (116 mg, 0.57 mmol, 1.5 Eq.) in toluene (5 mL) and EtOH (1 mL). The reaction was heated at reflux under nitrogen overnight. After cooling to ambient temperature the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by column chromatography on SiO2, eluting with 10% Et2O/petroleum ether to give the desired compound as a white foam (113 mg, 0.29 mmol, 76%).
Reaction SMILES: ClC1[CH:41]=[CH:40][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.[N:42]1C=CC(B(O)O)=CC=1>>[CH:27]1([N:26]2[C:25]3[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=3[N:23]=[C:22]2[C:17]2[CH:16]=[C:15]3[C:14](=[CH:19][CH:18]=2)[N:13]=[C:12]([C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:4]=[CH:3][N:42]=[CH:41][CH:40]=2)[CH:21]=[CH:20]3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Reactant: OB(O)c1ccncc1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4-c4ccncc4)ccc3c1)n2C1CCCCC1

Procedure:
The title compound was synthesized as described for Compound 387 except pyridine-4-boronic acid was used instead of 4-chlorophenyl-boronic acid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]3[N:12]=[C:13]([CH:15]([OH:17])[CH3:16])[NH:14][C:8]3=[CH:7][C:6]=2[C:5]([CH3:19])([CH3:18])[C:4]1=[O:20])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:15]([C:13]1[NH:14][C:8]2=[CH:7][C:6]3[C:5]([CH3:19])([CH3:18])[C:4](=[O:20])[N:3]([CH2:1][CH3:2])[C:11]=3[CH:10]=[C:9]2[N:12]=1)(=[O:17])[CH3:16]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(C(C)O)nc3cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(C(C)=O)nc3cc21
Temperature: 65 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
5-Ethyl-2-(1-hydroxy-ethyl)-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (13 g, 47.6 mmol) and manganese(IV)dioxide (16.54 g, 190 mmol) were suspended in chloroform (400 mL) and stirred at 65° C. for 16 h. The mixture was cooled, filtered over Celite and the filtrate concentrated in vacuo yielding 11.6 g (90%) of a beige solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])=[O:6].[CH:13](I)([CH3:15])[CH3:14].Cl>CN(C)C=O>[CH:13]([C:7]1([C:5]([O:4][CH3:3])=[O:6])[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])([CH3:15])[CH3:14]
Reactant: COC(=O)C1CCCC1=O
Reactant: CC(C)I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C(C)C)CCCC1=O
Reaction time: 3.5 h

Procedure:
7.7 g of sodium hydride (free of oil) was added to 80 ml of dimethylformamide. 25 g of 2-methoxycarbonylcylopentanone was slowly added dropwise while cooling with ice. The reaction mixture was allowed to come to room temperature, whereupon 45 g of isopropyl iodide was added, followed by stirring for a further 3.5 hours at 70°-80° C. The reaction mixture thus obtained was poured into 400 ml of 10% hydrochloric acid solution and extracted with 100 ml of ethyl acetate. The organic layer was washed with water, dried, and concentrated to obtain 25.5 g (yield, 78.7%) of the title compound.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:35]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:35][C:34]3[CH:37]=[CH:38][C:39]([CH3:40])=[C:32]([F:31])[CH:33]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Cc1ccc(CBr)cc1F
Product: Cc1ccc(Cn2ccc3c(-c4ccc5c(c4)CCCO5)c(C(OC(C)(C)C)C(=O)O)c(C)nc32)cc1F

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 3-fluoro-4-methylbenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.42 (m, 1 H), 7.21 (dd, J=1.9, 10.8 Hz, 1 H), 7.14 (t, J=7.7 Hz, 1 H), 7.05 (t, J=3.4 Hz, 1 H), 6.99-6.89 (m, 3 H), 6.28 (dd, J=3.5, 11.5 Hz, 1 H), 5.60-5.56 (m, 1 H), 5.56-5.39 (m, 2 H), 4.28 (t, J=4.5 Hz, 2 H), 2.95-2.80 (m, 2 H), 2.76 (s, 3 H), 2.25 (s, 3 H), 2.09 (d, 2 H), 1.03-0.88 (s, 9 H); LC/MS (m/z) ES+=517.38 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].CCOCC.C1([Li])C=CC=CC=1.[CH2:20]([N:23]=[C:24]=[S:25])[CH:21]=[CH2:22]>C1C=CC=CC=1.CCOCC>[CH2:20]([NH:23][C:24](=[S:25])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH:21]=[CH2:22]
Reactant: Cc1ccccn1
Reactant: C=CCN=C=S
Agent: [Li]c1ccccc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=CCNC(=S)Cc1ccccn1
Reaction time: 1 h

Procedure:
A solution of 9.3 g. (0.1 mole) of 2-picoline in 50 ml. of anhydrous ether is added dropwise at 15°C. to 50 ml. of a 2.1M solution of phenyl lithium in benzene/ether under nitrogen. The resulting mixture is stirred for 1 hour, then added dropwise to a stirred solution of 9.9 g. (0.1 mole) of allyl isothiocyanate in 200 ml. of anhydrous ether at -50°C. under nitrogen. The mixture is stirred for 15 minutes after the addition is complete and then poured into 150 ml. of dilute hydrochloric acid/ice and stirred. The layers are separated and the aqueous phase is basified with 5% aqueous sodium carbonate solution and then extracted with ethyl acetate. The extracts are dried and concentrated and the residue is recrystallized from benzene/petroleum ether to give N-allyl-2-(2-pyridyl)thioacetamide, m.p. 67°-68°C.
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:19][S-:20].[Na+]>O1CCOCC1>[CH3:19][S:20][CH:2]([O:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)C(Br)Oc1cc(Cl)cc(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSC(Oc1cc(Cl)cc(Cl)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.1 %

Procedure:
t-Butyl 2-bromo-2-(3,5-dichlorophenoxy)acetate (1.0 g) was dissolved in 1,4-dioxane (3 ml), and sodium thiomethoxide (0.218 g) was added to the mixture. The resulting pale yellow suspension was stirred at ambient temperature for 5 hours and then stored for 18 hours. The solvent was evaporated, water was added and the aqueous layer was extracted twice with ethyl acetate (100 ml). The organic layers were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated to give t-butyl 2-methylthio-2-(3,5-dichlorophenoxy)acetate as a pale yellow solid (0.80 g) which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1([NH2:18])[CH2:17][CH2:16]1.[BH4-].[Na+].O>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:15]1([NH:18][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: NC1CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
3.78 mL (13 mmol) of titanium isopropoxide and 2 g (10 mmol) of (S)-1-tert-butoxycarbonyl-pyrrolidine-2-carbaldehyde are added to a solution of 1.7 mL (30 mmol) of cyclopropylamine in 10 mL of anhydrous methanol. The solution is stirred for 5 hours at room temperature then 378 mg (10 mmol) of sodium borohydride is added. Stirring is continued for a further 2 hours then 2 mL of water is added. The reaction mixture is filtered then the solvents are evaporated. Water is added and the compound is extracted with diethyl ether. The organic phases are dried over magnesium sulfate, filtered and evaporated to give 2.34 g (97%) of (S)—N-cyclopropyl-1-tert-butoxycarbonyl-pyrrolidin-2-ylmethyl-amine in the form of a colourless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]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.[Cl:53][C:54]1[CH:55]=[C:56]([CH2:61][C:62](O)=[O:63])[CH:57]=[C:58]([F:60])[CH:59]=1>CN(C=O)C.CO.C(Cl)Cl>[Cl:53][C:54]1[CH:55]=[C:56]([CH2:61][C:62]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:18]5[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=5[O:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:63])[CH:57]=[C:58]([F:60])[CH:59]=1
Reactant: Nc1ncnc2occ(-c3ccc4c(c3)CCN4)c12
Reactant: O=C(O)Cc1cc(F)cc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ncnc2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)cc(Cl)c3)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred dark greenish solution of 5-(2,3-dihydro-1H-indol-5-yl)furo[2,3-d]pyrimidin-4-amine (500 mg, 1.98 mmol) and HATU (829 mg, 2.18 mmol, 1.1 equiv) in 5 mL of DMF was added DIEA (381 uL, 2.18 mmol, 1.1 equiv). To this mixture was added (3-chloro-5-fluorophenyl)acetic acid portionwise (374 mg total, 1.98 mmol, 1 equiv), about 130 mg at 30 min intervals. After 2 h, LCMS showed conversion complete. The mixture was poured into 50 mL of ice cold water to give a suspension, which was filtered. The cake was washed with water (2×10 mL) and dried under house vacuum for 18 h to afford crude product (1.0 g), which was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an SF25-60 g silica gel cartridge using gradient elution of 1% A in DCM to 50% A in DCM (A was a mixture of 3200/800/80 DCM/MeOH/NH4OH). The desired product eluted impure from 24-30% A. The fractions containing product were combined and concentrated in vacuo and reabsorbed onto a dryload cartridge. Purification was done on an SF25-80 g silica gel cartridge using gradient elution of 1% A to 75% A in EtOAc. (B was a 2.5% MeOH in EtOAc). Two fractions were collected. The first fraction eluted from 15-35% B as a sharp peak, which was conc in vacuo. The residue was taken up in CHCl3 (2 mL) and MTBE (6 mL) as a suspension, which was filtered. The solids were washed with MTBE (2×3 mL) and hexane (2×3 mL). The second fraction eluted from 63-100% B as a broad. The large eluted solvent volume was concentrated in vacuo. This residue was taken up in CHCl3 (2 mL) and MTBE (8 mL) as a suspension, which was filtered. The cake was washed with MTBE (2×3 mL) and hexane (3×4 mL). The solids were combined with the solids above from the first fraction and dried under vacuum at 65° C. for 18 h to afford 5-{1-[(3-chloro-5-fluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[2,3-d]pyrimidin-4-amine (492 mg) as off-white solids. LC-MS (ES) m/z=423 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d ppm 3.26 (t, J=8.3 Hz, 2H), 3.97 (s, 2H), 4.25 (t, J=8.5 Hz, 2H), 7.18 (d, J=9.9 Hz, 1H), 7.27 (s, 1H), 7.29-7.38 (m, 2H), 7.39 (s, 1H), 7.93 (s, 1H), 8.15 (d, J=8.1 Hz, 1H), 8.25 (s, 1H), NH2 protons not visible.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[CH3:18][C:19]([CH3:34])([C:23]([NH:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[O:24])[C:20](O)=[O:21]>>[CH3:18][C:19]([CH3:34])([C:23]([NH:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:29])([F:31])[F:30])=[O:24])[C:20]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:21]
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Product: CC(C)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21

Procedure:
(S)-7-Amino-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in examples 65 and 66 to yield 2,2-dimethyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][F:10].C([Li])CCC.CN([CH:19]=[O:20])C.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:19]=[O:20])=[C:3]([CH2:9][F:10])[CH:4]=1
Reactant: CN(C)C=O
Reactant: FCc1cc(Cl)ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ccc(Cl)cc1CF
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
To a solution of 1-bromo-4-chloro-2-(fluoromethyl)benzene (0.5 g, 2.2 mmol) in anhydrous THF (20 mL) was added a solution of n-butyl lithium (1.0 mL, 2.5 M in hexanes, 2.5 mmol) in anhydrous THF (10 mL), at about −75° C. The resulting mixture was stirred for about 30 min at about −75° C. and then DMF (0.34 mL, 4.5 mmol) was added slowly. Over about 1 h the mixture was warmed to about −55° C. and then saturated aqueous ammonium chloride (10 mL) was added followed by diethyl ether (50 mL). The layers were separated and the organic layer was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:3) to give 4-chloro-2-(fluoromethyl)benzaldehyde (0.15 g, 0.87 mmol, 39%) as a white solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 5.85 (2 H, d, J=47.8 Hz) 7.52 (1 H, dd, J=8.2, 2.0 Hz) 7.72 (1 H, br s) 7.80 (1 H, dd, J=8.2, 1.4 Hz) 10.04 (1 H, d, J=1.4 Hz).
Reaction SMILES: [NH3:1].C(O)C.[O:5]1[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6]1>O>[OH:5][CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][NH2:1]
Reactant: CCCCCCC1CO1
Reactant: N
Solvent: CCO
Solvent: O
Product: CCCCCCC(O)CN
Reaction time: 1.17 h
Yield: 76.6 %

Procedure:
One-thousand one-hundred grams of ammonia gas was introduced into a mixture of 6 liters of ethanol and 1 liter of water and within 30 minutes there were dropped in at room temperature 320 grams of 1,2-epoxyoctane. The mixture was left at room temperature for 70 minutes under gentle stirring, then the solvent and excess ammonia drawn off and the residue rectified in a vacuum. There were obtained 277.6 grams (77.1% of theory) of 2-hydroxyoctyl amine having a boiling point (0.4 mm Hg) of 80° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]3[CH2:16][O:15]3)[CH:5]=[CH:4][C:3]1=2.[NH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][CH2:16][CH:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)[OH:15])=[CH:29][CH:28]=1)([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C3CO3)ccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(NCC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 30.9 %

Procedure:
26 g (110 millimoles) of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-oxirane, 15 g (90 millimoles) of ethyl 4-aminobenzoate, 135 g of basic alumina and 450 ml of toluene were refluxed for 2 hours. The solid was then filtered off and the filtrate was evaporated down. After recrystallization from n-heptane with a little ethyl acetate, the residue gave 11.0 g of N-(4-carbethoxyphenyl)-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-aminoethanol. The structure was determined by H-NMR spectroscopy.
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(C4C=CSC=4)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[S:31]1[CH:35]=[CH:34][C:33]([C:36]2[C:44]3[O:43][CH:42]([CH2:45][N:46]=[N+]=[N-])[CH2:41][C:40]=3[CH:39]=[CH:38][CH:37]=2)=[CH:32]1.[N-]=[N+]=[N-]>[Pd]>[S:31]1[CH:35]=[CH:34][C:33]([C:36]2[C:44]3[O:43][CH:42]([CH2:45][NH2:46])[CH2:41][C:40]=3[CH:39]=[CH:38][CH:37]=2)=[CH:32]1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3ccsc3)c2O1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccsc4)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: NCC1Cc2cccc(-c3ccsc3)c2O1
Yield: 55 %

Procedure:
Treatment of (±)-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.2 g, 5.64 mmol) with sodium azide (1.48 g, 22.77 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl azide. Treatment of the azide with palladium on carbon (0.130 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.838 g (55%) of (±)-1-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp >200° C.; Anal. calcd. for C13H13FNOSHCl: C, 58.31; H, 5.27; N, 5.23. Found: C, 56.4; H, 5.23; N, 4.95.
Reaction SMILES: [C:1]1([C@@:7]2([CH3:35])[C:11](=[O:12])[N:10]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=O)[C:9](=[O:21])[N:8]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC([C@@]2(C)C(=O)N([C@@H](CC(C)C)C(OC(C)(C)C)=O)C(=O)N2)=CC=1.C1(C2C=CC(CBr)=CC=2)C=CC=CC=1.C1([C@@]2(C)C(=O)N([C@@H](CC(C)C)C([O-])=O)C(=O)N2CC2C=CC=CC=2)C=CC=CC=1.[NH2:106][C@H:107]([C:116]1[CH:121]=[CH:120][C:119]2[O:122][CH2:123][O:124][C:118]=2[CH:117]=1)[CH2:108][C:109]([O:111]C(C)(C)C)=[O:110].FC(F)(F)C(O)=O>>[C:1]1([C@@:7]2([CH3:35])[C:11](=[O:12])[N:10]([C@@H:13]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:14]([NH:106][C@H:107]([C:116]3[CH:121]=[CH:120][C:119]4[O:122][CH2:123][O:124][C:118]=4[CH:117]=3)[CH2:108][C:109]([OH:111])=[O:110])=[O:16])[C:9](=[O:21])[N:8]2[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@@H](C(=O)O)N1C(=O)N(Cc2ccc(-c3ccccc3)cc2)[C@@](C)(c2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1ccc2c(c1)OCO2
Agent: BrCc1ccc(-c2ccccc2)cc1
Agent: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1C(=O)N[C@@](C)(c2ccc(Br)cc2)C1=O
Agent: CC(C)C[C@@H](C(=O)[O-])N1C(=O)N(Cc2ccccc2)[C@@](C)(c2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)c1ccc2c(c1)OCO2)N1C(=O)N(Cc2ccc(-c3ccccc3)cc2)[C@@](C)(c2ccccc2)C1=O

Procedure:
(by reaction of (S)-2-((S)-4-phenyl-3-((4-biphenylyl)methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetic acid (obtainable by reaction of 169.2 with 4-phenylbenzyl bromide analogously to the synthesis of 169.3 and subsequent reactions analogously to the preparation of 169.5) with tert-butyl (S)-3-amino-3-(3,4-methylenedioxyphenyl)propionate and subsequent cleavage of the tert-butyl ester with trifluoroacetic acid)
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH:21]1(CO)C[CH2:22]1>C[O-].[Na+].C1C=CC=CC=1>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21]3)=[O:14])=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1CC1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=C(OCC1CC1)c1ccc(OCc2ccccc2)cc1
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 12.8 parts of ethyl 4-(phenylmethoxy)benzoate, 180 parts of benzene and 5 drops of a sodium methoxide solution 30% was stirred and refluxed using a water separator. 10.8 Parts of cyclopropanemethanol in 90 parts of benzene was added dropwise during a period of 1 hour. Upon complete addition, stirring was continued for 4 hours at reflux. After cooling, the whole was washed with water, the organic layer was dried, filtered and evaporated, yielding 14 parts (100%) of (cyclopropylmethyl) 4-(phenylmethoxy)benzoate as a residue (int. 3).
Reaction SMILES: COC1C=C(C=C(OC)C=1OC)C(N(C(C)(C)C)CCCCCC(O)=O)=O.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][CH2:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[CH:32][CH:31]=1.[OH-].[K+]>C(O)C>[CH3:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:34][CH:35]=1
Reactant: CCOC(=O)CCCNc1ccc(OC)cc1
Agent: COc1cc(C(=O)N(CCCCCC(=O)O)C(C)(C)C)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(NCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(3,4,5-trimethoxybenzoyl)-6-(tert.-butylamino)caproic acid and ethyl γ-(p-anisidino)butyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(3,4,5-trimethoxybenzoyl)-6-tert.-butylamino)hexanoyl]-4-(p-anisidino)butyric acid.