Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN(C=O)C.CCN(C(C)C)C(C)C>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:10]([CH2:11][C:12](=[O:14])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCC(CC(=O)O)c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(CC(=O)Nc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56021.9 %

Procedure:
To a solution of 33 (0.206 g, 0.657 mmol, 1.2 eq) and aniline (0.051 g, 0.548 mmol) in dry DMF (5 ml) HATU (0.315 g, 0.9087 mmol, 1.5 eq) and DIPEA (0.340 g, 2.63 mmol, 4 eq) was added at room temperature under Ar. After stirring overnight at room temperature, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2×15 ml). The organic extracts were collected, dried over Na2SO4 and the solvent was distilled off under reduced pressure. The crude compound was purified by chromatography on silica gel (3:7 ethyl acetate/hexane, v/v, Rf 0.30) to give 34 as a white solid (0.120 g, 0.307 mol, 47%), mp 165-167° C. 1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 2.55 (1H, dd, J 5.0, 13.8 Hz), 2.75 (1H, dd, J 8.4, 13.6 Hz), 3.16-3.39 (2H, m), 3.52-3.57 (1H, m), 4.60 (1H, bs), 7.07-7.13 (3H, m), 7.29-7.32 (4H, m), 7.54 (2H, d, J 8.4 Hz), 8.61 (1H, bs).
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[CH2:17][CH2:18][CH2:19][CH:20]1[O:24][C:23](=[O:25])[N:22]([CH3:26])[CH2:21]1.C(=O)(O)[O-].[Na+].[I-].[K+]>C(O)CCC>[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][CH:20]2[O:24][C:23](=[O:25])[N:22]([CH3:26])[CH2:21]2)[CH2:12][CH2:11]1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: CN1CC(CCCCl)OC1=O
Agent: Br
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCCCO
Product: CN1CC(CCCN2CCN(c3ccccc3O)CC2)OC1=O
Yield: 20 %

Procedure:
Following the procedure of Example 5, a mixture of 1-(2-hydroxyphenyl)piperazine dihydrobromide (9.6 g, 0.0282 mol), 5-(3-chloropropyl)-3-methyl-2-oxazolidinone (5.0 g, 0.0282 mol), sodium bicarbonate (9.5 g, 0.113 mol), and potassium iodide in 1-butanol (100 ml) gave an oil. The oil was triturated several times with light pet ether (decanting each time) and dissolved in ethyl acetate/isopropyl ether. Cooling the solution gave a solid which was collected by filtration and dried under high vacuum to give 1.80 g (20% yield), mp 112°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:11][N:12]([CH3:14])[CH:13]=[N:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1]
Reactant: COC(OC)N(C)C
Reactant: Nc1ccccc1Cl
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1ccccc1Cl

Procedure:
98% 2-chloroaniline (195 g; 1.5 mol) and 98% dimethylformamide dimethyl acetal (228.2 g; 1.8 mol) were dissolved in toluene (300 g), and the solution was heated under reflux for 4 h. During this time, the internal temperature fell from 96 to 77° C. Thereafter, 15 g of distillate were removed, and the internal temperature rose again during this time to 84° C. Finally, the reaction solution was concentrated on a rotary evaporator at 90° C. and 5 mbar and the resulting brown oil (270.5 g) was fractionated by means of column distillation. The main fraction distilled over at 120° C. and 1.4 mbar and comprised the product in a purity of >99% (determined using area percentages of the GC spectrum).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([N:17]2[CH2:22][CH:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[C@@H:4]([C:29]([O:31][CH3:32])=[O:30])[CH2:3]1.O1CCCC1.[N:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:23]1([C:20]2[CH2:21][CH2:22][N:17]([C:15]([C@@H:5]3[C@@H:4]([C:29]([O:31][CH3:32])=[O:30])[CH2:3][C@H:2]([O:1][C:41]4[CH:42]=[CH:43][N:38]=[CH:39][CH:40]=4)[CH2:7][N:6]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:16])[CH2:18][CH:19]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccncc1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Oc2ccncc2)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Temperature: 70 °C

Procedure:
To a solution of 1-tert-butyl 3-methyl (2S,3S,5R)-5-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-1,3-dicarboxylate (100 mg, 0.0002 mol) in tetrahydrofuran (0.912 mL, 0.0112 mol) was added 4-pyridinol (25.7 mg, 0.000270 mol), triphenylphosphine (70.8 mg, 0.000270 mol), followed by diisopropyl azodicarboxylate (0.0532 mL, 0.000270 mol). The mixture was heated at 70 Celsius overnight. After concentrated to dry, the mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to afford the desired ether compound (56 mg, 50%). MS (ESI): (M+H)+=522.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:5][NH:6][CH:7]([CH3:9])[CH3:8].Cl.[CH3:15][C:16]1([CH3:26])[O:20][C:19](=[CH:21][C:22](Cl)=[O:23])[C:18](=[O:25])[O:17]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:5][N:6]([CH:7]([CH3:9])[CH3:8])[C:22](=[O:23])[CH:21]=[C:19]1[C:18](=[O:25])[O:17][C:16]([CH3:15])([CH3:26])[O:20]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CC(C)NCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)N(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a stirred mixture of (3,4-dichloro-benzyl)-isopropyl-amine; compound hydrochloride (260 mg, 1.024 mmol) and (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (190 mg, 1.0 mmol) in CH2Cl2 (20 mL) at room temperature was added diisopropylethylamine (350 μL, 2.0 mmol). After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL), washed with dilute aqueous HCl (1×5 mL), water (1×10 mL), and saturated aq. NaCl (1×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give viscous yellow oil. Purification on a silica gel column using hexanes/ethyl acetate (3:2) gave pure product as a viscous yellow oil (372 mg, 93% yield). 1H NMR (500 MHz, CDCl3) δ: 7.41–7.30 (2H, m), 7.11 (0.67H, d, J=10.1 Hz), 7.10 (0.33H, d, J=10.1 Hz), 6.22 (0.67H, s), 5.87 (0.33H, s), 4.87–4.81 (0.33H, m), 4.51 (1.34H, s), 4.47 (0.66H, s), 4.30–4.24 (0.67H, m), 1.73 (4H, s), 1.71 (2H, s), 1.21 (4H, d, J=6.2 Hz), 1.11 (2H, d, J=6.7 Hz). MS calcd for C17H20Cl2NO4 (M+H): 372.24. found: 372.18.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:19][C@H:20]([C:28]([NH2:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([NH:19][C@H:20]([C:28]([NH2:30])=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:14])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(N)=O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline was reacted with L-phenylalanine amide using the procedure described in Method 12 to yield N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide. To a solution of NaH (60% mineral oil—prewashed with THF) in THF at 0° C. was added N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide and the reaction was stirred at 0° C. for 45 minutes. Toluene-4-sulfonyl chloride was added and the reaction was stirred for 16 hours at room temperature. The reaction mixture was extracted with EtOAc (3×50 mL) and 0.2 N HCl (50 mL), and the combined organic layers were washed successively with sat. NaHCO (50 mL), and sat. NaCl (2×50 mL), dried over MgSO4, filtered, and concentrated to yield the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([CH:19]=[O:20])=[CH:17][CH:18]=2)[CH:12]=1.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([C:19]([CH:26]3[CH2:28][CH2:27]3)=[O:20])=[CH:17][CH:18]=2)[CH:12]=1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1
Product: O=C(Nc1cnn(Cc2ccc(C(=O)C3CC3)o2)c1)OCc1ccccc1Cl

Procedure:
Following general procedures G and H, starting from [1-(5-formyl-furan-2-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester and cyclopropylmagnesium bromide.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:8]([C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[CH2:7][CH:6]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:4].[N:32]([C:35]1[CH:36]=[C:37]([CH:43]=[CH:44][CH:45]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:33]=[O:34]>O1CCCC1>[CH2:41]([O:40][C:38]([C:37]1[CH:36]=[C:35]([NH:32][C:33](=[O:34])[NH:1][CH2:2][C:3]([N:5]2[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[CH:8]([C:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[O:18])[CH2:7][CH:6]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:4])[CH:45]=[CH:44][CH:43]=1)=[O:39])[CH3:42]
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)C1CC(C(=O)N2CCOCC2)C(c2ccccc2F)N1C(=O)CN
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)N3CCOCC3)C2c2ccccc2F)c1
Yield: 61.3 %

Procedure:
B tert-Butyl (2RS,4SR,5SR)-1-{2-[3-(3-(ethoxycarbomyl)phenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-(morpholinocarbonyl)pyrrolidine-2-carboxylate can be prepared as described in Example 17B, but from 1.7 g of tert-butyl (2RS,4SR,5SR)-1-(2-aminoacetyl)-5-(2-fluorophenyl)-4-(morpholinocarbonyl)pyrrolidine-2-carboxylate and 0.75 g of ethyl 3-isocyanatobenzoate in 80 cm3 of tetrahydrofuran. After treatment, there are obtained 1.5 g of tert-butyl (2RS,4SR,5SR)-1-{2-[3-(3-(ethoxycarbonyl)phenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-(morpholinocarbonyl)pyrrolidine-2-carboxylate in the form of a foam used as is in the subsequent syntheses.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=2)=[N:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39]>O1CCCC1>[CH3:39][O:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][CH2:30][CH:15]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:16](=[O:18])[CH:17]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:8]=[C:9]12
Reactant: O=c1cc(-c2ccncn2)nc2n1CCCCC2
Reactant: COc1ccccc1CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1CCC1CCCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.2 %

Procedure:
To a solution of 0.500 g (2.06 mmol) of 2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one in dry tetrahydrofuran (20 mL) under argon at −30° C. was added 3.10 mL (3.10 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at room temperature for 10 min and 1.31 mL of 1-(2-bromo-ethyl)-2-methoxy-benzene (8.25 mmol) was added. The reaction was stirred at 70° C. for 6 hours. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane with 3% of methanol and 0.3% of ammonia) to afford 0.087 g of a solid (11%).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 92 %

Procedure:
As described for example 272, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (97.6 mg, 0.3 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (97 mg, 92%) which was obtained as a white solid. MS: m/e=353.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:11]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:44][C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1[C:47](O)=[O:48].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:44][C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1[C:47]([O:17][CH2:16][C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:18]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[C:11]2[CH:12]=1)=[O:48]
Reactant: OCc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Reactant: Cc1ccccc1C(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)OCc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Temperature: 25 °C

Procedure:
2-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (Example 6. 50 mg, 0.157 mmol), triphenyl phosphine (82 mg, 0.314 mmol) and 2-methylbenzoic acid (0.314 mmol) are dissolved in dry THF (3 mL). To the stirred solution is added diethyl azodicarboxylate (55 mg, 0.314 mmol) dropwise. The resulting solution is stirred at room temperature until reaction is complete as determined by TLC and then diluted with hexane/ethyl acetate (30 mL of a 1:1 mixture) and washed with water (×3). The organic phase is then shaken with dilute hydrochloric acid. In cases were the hydrochloride salt of the product deposits at this stage it is filtered off, washed with water and then hexane and dried. If no deposit is observed, the acidic phase is separated, washed once with hexane/ethyl acetate (15 mL of a 1:1 mixture) and basified with saturated sodium bicarbonate solution. This is then extracted with dichloromethane (15 mL) five times and the dichloromethane solution dried (MgSO4), filtered and concentrated to give the title compound. 1H NMR (d6-DMSO) δ 2.50 (s, 3H), 5.41 (s, 2H), 7.25–7.33 (m, 5H), 7.48 (t, J=7.4 Hz, 1H), 7.56 (dd, J=5.6, 8.5 Hz, 2H), 7.73 (d, J=5.8 Hz, 2H), 7.88 (d, J=7.9 Hz, 1H), 8.06 (s, 1H), 8.71 (d, J=6.2 Hz, 2H), 8.92 (d, J=7.1 Hz, 1H). APESI-MS m/z 438 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[C:3]#[CH:4].C([Li])CCC.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[CH2:22]([O:21][C:19](=[O:20])[C:4]#[C:3][C:2]([CH3:12])([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH3:1])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: C#CC(C)(C)OC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(C)(C)OC1CCCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a solution of 2-(1,1-dimethyl-prop-2-ynyloxy)-tetrahydropyran (10.0 g, 59.4 mmol) in THF (100 mL), cooled to −78° C. was added n-butyl lithium (26 mL, 65 mmol) as a solution in hexanes. The mixture was stirred at −78° C. for 1 h then a solution of ethyl chloroformate (7.0 mL, 108.5 mmol) in THF (100 mL) was added dropwise. The mixture was stirred at −78° C. for 1 h then quenched by addition of a saturated aqueous solution of ammonium chloride. This mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and concentrated to provide 7.5 g (53%) of 4-methyl-4-(tetrahydro-pyran-2-yloxy)-pent-2-ynoic acid ethyl ester as a clear oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:12]
Reactant: NCCCCO
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCCO)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
2-Benzofurancarboxylic acid (5.0 g, 30.8 mmol) and 4-amino-1-butanol (3.4 ml, 37 mmol) were dissolved in DMF (45 ml). 1-hydroxybenzotriazole (5.0 g, 37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.7 g, 40 mmol), and diisopropylethylamine (10.7 ml, 61.7 mmol) were added sequentially to the solution and allowed to stir at room temperature overnight. After removing excess solvent in vacuo, the residue was taken up in water and the product was extracted into dichloromethane. The organics were combined, washed with brine, dried over Na2SO4, and solvent removed in vacuo to give a solid which was purified by column chromatography (100% ethyl acetate) to give 3.5 g (50% yield) of a white solid. 1H NMR (DMSO-d6): δ 1.35-1.62 (m, CH2, CH2), 3.29 (q, CH2), 3.41 (q, CH2), 4.3 (t, NH), 7.78 (d, 1 Ar H), 7.63 (d, 1 Ar H), 7.51 (s, 1 Ar H), 7.46 (t, 1 Ar H), 7.35 (t, 1 Ar H), 8.71 (t, NH) Electrospray Mass Spec: m/z 234.2 (M+H)+.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:19].O1CCOCC1>CO>[ClH:19].[ClH:19].[NH:9]1[CH2:10][CH2:11][C@@H:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2CCCCC2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C1CCN([C@@H]2CCNC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred, room temperature solution of (R)-tert-butyl 3-(piperidin-1-yl)pyrrolidine-1-carboxylate (Reference Example 5b, 6.87 g, 27.0 mmol) in methanol (100 mL) was treated with 4 N HCl in dioxane (67.5 mL, 0.2700 mole). The reaction mixture was stirred at room temperature overnight, then volatiles were removed under reduced pressure. The resulting solid was crystallized from methanol/ether to provide (R)-1-(pyrrolidin-3-yl)piperidine dihydrochloride. 1H NMR (300 MHz, CD3OD) δ ppm 1.46-2.03 (m, 6H), 2.32-2.46 (m, 1H), 2.53-2.63 (m, 1H), 2.95-3.20 (m, 2H), 3.33-3.43 (m, 1H), 3.47-3.72 (m, 4H), 3.78-3.85 (m, 1H), 4.09 (pentet, J=8 Hz, 1H); MS (ESI) m/z 155 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH:7]1([C:10]2[C:11]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([C:27]4[CH:28]=[N:29][C:30](F)=[CH:31][C:32]=4[CH3:33])=[O:26])[CH2:21][CH2:20]3)=[N:12][CH:13]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[CH2:9][CH2:8]1>>[CH:7]1([C:10]2[C:11]([N:19]3[CH2:20][CH2:21][N:22]([C:25]([C:27]4[C:32]([CH3:33])=[CH:31][C:30]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[N:29][CH:28]=4)=[O:26])[CH2:23][CH2:24]3)=[N:12][CH:13]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[CH2:8][CH2:9]1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1CCCN1
Product: Cc1cc(N2CCCC2=O)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1

Procedure:
Using pyrrolidin-2-one (326 μL) and [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (400 mg) described in Preparation Example 174 and by the reaction and treatment in the same manner as in Example 323, the title compound (187 mg) was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C=O)C>[CH:20]1([CH2:19][O:1][CH2:2][C:3]2[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)C(=O)Nc1cccc(CO)n1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1cccc(COCC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(6-Hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (1.04 g, Papadopoulou,; J. Heterocycl. Chem., 32, 1995, 675) in DMF (25 mL) was treated with sodium hydride (0.64 g, 60% suspension in oil), the mixture was then stirred for 1 h at RT, bromomethyl cyclopropane (0.688 g) was added dropwise and stirring was continued for further 1.75 h. The reaction mixture was partitioned between 2 M aqueous KHCO3 and AcOEt, the layers were separated, the aqueous layer extracted twice with AcOEt. The combined organic layers were washed with saturated aqueous NaCl and water, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/AcOEt 100% to 50%) to N-(6-cyclopropylmethoxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.884 g) as a yellow oil. MS (ESI): 263.2 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:34])([CH3:33])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
Compound 1 (150 mg, 0.32 mmol) was dissolved in DCM and TFA (0.25 mL, 3.20 mmol) was added. The resulting mixture was stirred overnight. The mixture was concentrated, diluted with DCM and washed with saturated NaHCO3 solution. The filtrate was dried anhydrous Na2SO4, filtered and concentrated. The residue was purified by normal phase chromatography, eluting with 0-30% 1M methanolic ammonia/dichloromethane to give desired product, Compound 2 as a white solid (0.10 g, 85%). MS: m/z 370.2 [M+H]+. 1H-NMR (400 MHz, CD3OD) δ: 1.05 (s, 9H), 2.76 (s, 3H), 3.16 (m, 2H), 4.11 (m, 2H), 4.37 (m, 3H), 7.53 (m, 3H), 7.71 (m, 2H).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([O:20]C)=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Br>[CH2:1]([NH:8][CH:9]1[CH2:10][C:11]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:12]=2[CH2:13][CH2:14][CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Agent: Br
Product: Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 66.7 %

Procedure:
A mixture of N-benzyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (3.0 g) and 47% hydrobromic acid (106 ml) was stirred at 130° C. for 1.5 hours. After cooling, the reaction mixture was concentrated in vacuo. To the residue was added 28% ammonium hydroxide, and the whole was extracted once with ethyl acetate. The extract was washed twice with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; chloroform-methanol; 25:1 to 15:1) to give 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (1.9 g) as an oil, which solidified on standing.