Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH3:7][C:8]1[C:9]([CH:15]=O)=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=1.[BH4-].[Na+]>CO>[CH3:7][C:8]1[C:9]([CH2:15][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: NCCCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(CNCCCCO)c(C)c1

Procedure:
Using General Procedure B, 4-amino-butan-1-ol and 3,5-dimethyl-pyridine-2-carbaldehyde in MeOH were reacted with NaBH4 to give 4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butan-1-ol as a pale yellow oil.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>C1COCC1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(Cl)nc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of cyanuric chloride (1.5 g, 8.13 mmol) in THF (50 mL) Diisopropyethylamine (1.56 mL, 8.94 mmol) was added. The solution was placed in an ice-water bath (0° C.). Using a syringe, 4-methoxy-benzyl amine (1.16 mL, 8.94 mmol) dissolved in THF (150 mL) was slowly dripped into the reaction mixture. The reaction stirred at 0° C. for 3 hours. The crude compound was purified by column chromatography initially eluting with EA:Hexane (1:6). Compound was obtained as a white solid.
Reaction SMILES: [CH2:1]([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:19][CH2:18]1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][CH:17]([C:15]([C:7]3[S:6][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=3)=[CH2:1])[CH2:18][CH2:19]2)=[CH:26][CH:27]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(CCN2CCC(C(=O)c3nc4ccccc4s3)CC2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1nc2ccccc2s1)C1CCN(CCc2ccc(OC)cc2)CC1
Reaction time: 2 h

Procedure:
Dissolve methyltriphenylphosphonium bromide (2.50 g, 6.99 mmol) in anhydrous tetrahydrofuran (50 mL). Add n-butyllithium (2.8 mL of a 2.5M solution in hexane, 6.99 mmol) and cool to -10° C. Add, by dropwise addition, a solution of [2-benzothiazolyl][1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methanone (2.66 g, 6. 99 mmol) in anhydrous tetrahydrofuran (50 mL). Stir for 2 hours then quench with water. Separate the organic phase and extract the aqueous phase with ethyl ether. Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (50% ethyl ether/hexane) to give the title compound as a white powder; mp 84°-85° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][OH:8])[N:3]=1.[CH3:9][C:10](=O)[CH2:11][C:12](=O)[CH3:13]>C(O)(=O)C>[CH3:9][C:10]1[CH:11]=[C:12]([CH3:13])[N:6]2[N:5]=[C:4]([CH2:7][OH:8])[N:3]=[C:2]2[N:1]=1
Reactant: Nc1nc(CO)n[nH]1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(CO)nc2n1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (9.5 g, 50 mmol) from step 6 above in acetic acid (200 mL) was added 2,4-pentanedione (5.13 mL, 50 mmol). The mixture was heated to reflux for 4 hours, and then cooled to room temperature. The product was isolated by removing the solvent by rotary evaporation (8.5 g, 95% yield). MS (ESI): 179 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[NH:29][CH:30]=[N:31][C:27]=3[CH:26]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][CH3:23])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:34].C(Cl)(=O)C.[O:39]1[CH2:44][CH2:43]OCC1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Cl:34])=[CH:4][C:5]([S:9]([NH:12][CH:13]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[NH:29][CH:30]=[N:31][C:27]=3[CH:26]=2)[C:14]([N:16]2[CH2:17][CH2:18][CH:19]([N:22]([CH3:23])[C:44](=[O:39])[CH3:43])[CH2:20][CH2:21]2)=[O:15])(=[O:10])=[O:11])=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Reactant: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)N(C)C1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1

Procedure:
Prepared from 4-amino-N-[1-(1H-benzimidazol-5-yl-methyl)-2-(4-methylamino-piperidin-1-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide and acetylchloride in dioxane and triethylamine analogously to Example 2.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.N1C2C(=CC=C([C@H]3[C@@]4(C5C(=CC=CC=5)N([CH2:43][CH2:44][O:45][CH3:46])C4=O)C3)C=2)C=N1>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:43][CH2:44][O:45][CH3:46])[C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Reactant: COCCN1C(=O)[C@@]2(C[C@H]2c2ccc3cn[nH]c3c2)c2ccccc21
Product: COCCN1C(=O)[C@@]2(C[C@H]2c2ccc3c(I)n[nH]c3c2)c2ccccc21
Yield: 66 %

Procedure:
The title compound was prepared in a manner similar to the method of (1R,2S)-2-(3-iodo-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (1R,2S)-2-(1H-indazol-6-yl)-1′-(2-methoxyethyl)spiro[cyclopropane-1,3′-indolin]-2′-one (260 mg, 0.779 mmol). Purification using 0-30% EtOAc in hexane on Biotage Isolera with SNAP 25 g column yielded the title compound as a white solid (235 mg, 66%; 98% e.e.) with the major (1R,2S) enantiomer eluting at 2.6 min (Phenomenex Lux 5μ Amylose-2 150×4.6 mm, 2.5 mL/min with isocratic at 20% EtOH in hexane for 0.5 min, then gradient 20-50% EtOH in hexane over 2.5 min, then isocratic at 50% for 1 min). From the racemic reference standard, the retention time of the (1S,2R) enantiomer was 3.2 min using this method. 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.34 (s, 1H), 7.14 (t, J=7.6 Hz, 1H), 7.06-7.01 (m, 2H), 6.63 (t, J=7.2 Hz, 1H), 5.87 (d, J=7.6 Hz, 1H), 4.14-3.97 (bm, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.46 (t, J=7.6 Hz, 1H), 3.39 (s, 3H), 2.28-2.26 (m, 1H), 2.05-2.01 (m, 1H); MS ESI 460.1 [M+H]+, calcd for [C20H18IN3O2+H]+ 460.0. Optical Rotation: [α]22D=−239° (c 0.243, MeOH).
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]2[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=2[OH:20])=[O:19])=[CH:16][CH:15]=1)#[N:18]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(C#N)cc1)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(C#N)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 46 %

Procedure:
3-[(4-Cyanobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 62-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (46% yield); mp 161° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.17 (2H, s, NCH2), 4.93 (2H, s, NCH2), 7.44 (2H, d, J=8.2 Hz, aromatics), 7.65 (2H, d, J=8.2 Hz, aromatics). Anal. calcd for C15H15N3O4: C, 59.79; H, 5.01; N, 13.94. Found: C, 59.51; H, 4.90; N, 13.69.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[C:21]1(=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:28])=[O:3])=[CH:8][CH:9]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)COc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)COc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
Ethyl({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)acetate (190) (0.20 g, 0.53 mmol) was dissolved in THF and EtOH (1:1, 6 mL). To the above solution was added 1 N NaOH (2.5 mL) at room temperature. The reaction was heated at 70° C. with stirring for 0.5 h and then cooled at RT. Reaction mixture was acidified with 20% aqueous HCl, and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by flash column chromatography with chloroform and methanol (9:1 to 4:1) as an eluent to give 0.182 g of compound 191 as an off-white solid. mp 170-171° C. 1H NMR (300 MHz, DMSO-d6): δ 12.92 (s, 1H), 9.25 (s, 1H), 7.00 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 6.66 (d, J=8.4 Hz, 2H), 4.62 (s, 2H), 2.22 (br s, 4H), 1.5 (br s, 8H). LCMS (ESI): m/z 375.08 (M+Na)+. Anal. Calcd for C22H24O4: C, 74.98; H, 6.86. Found: C, 73.05, H, 6.74.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:26](Cl)=[O:27])[CH:20]=[CH:19]2>C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:26]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])=[O:27])[CH:20]=[CH:19]2
Reactant: CC(C)NC(C)C
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc2cc(Br)ccc2c1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (800 mL) of diisopropylamine (112 mL) and triethylamine (112 mL) in THF was added dropwise a solution (400 mL) of 6-bromo-2-naphthoyl chloride in THF under ice-cooling. The mixture was stirred at room temperature for 1 hr. A half amount of the solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, washed successively with water, 1N aqueous sodium hydroxide solution, water and saturated brine and dried over magnesium sulfate. The solvent was evaporated and the obtained solid was washed with isopropyl ether to give the title compound (117 g) as colorless flakes.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:35])[NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH:27]=4)[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:25]1[CH2:26][CH:27]=[C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[NH:11][C:10]([NH:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:36])([F:37])[F:1])[N:8]=2)=[O:35])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3nccc(NC(=O)Nc4cccc(C(F)(F)F)n4)c3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(C(F)(F)F)n1)Nc1ccnc2ccc(C3=CCNCC3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
0.2 g of tert-butyl 4-{4-[3-(6-trifluoromethyl-pyridin-2-yl)-ureido]-quinolin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylate (0.389 mmol) were dissolved in 0.6 ml DCM (yellow solution). 0.300 ml of TFA (3.89 mmol) were added and the reaction mixture was stirred for 2 h at RT. After evaporation of the solvent and excess TFA in vacuum, water was added to the residue, the acidic mixture extracted with ethyl acetate, the water phase adjusted to pH 9 with 1M NaOH and subsequently extracted three times with DCM. The combined DCM solutions were washed with a small amount of brine, dried over sodium sulphate and the solvent was removed in vacuum. 130 mg of the desired product were obtained as light yellow powder (yield: 81%).
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].CCOC(/N=N/C(OCC)=O)=O.O[C:44]1[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)C>[CH3:51][O:50][C:48]([C:47]1[CH:52]=[CH:53][C:44]([O:1][CH:2]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:45][CH:46]=1)=[O:49]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: COC(=O)CCCCC(O)CCc1ccccc1OCCCCCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CCCCC(CCc1ccccc1OCCCCc1ccccc1)Oc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Over a period of 2 h, a solution of 100.0 mg (0.24 mmol) of methyl 6-hydroxy-8-{2-[(5-phenylpentyl)oxy]phenyl}octanoate from Ex. XXXIa and 63.32 mg (0.36 mmol) of DEAD in 2.5 ml of THF was added dropwise to a solution of 55.32 mg (0.36 mmol) of methyl 4-hydroxybenzoate and 95.36 mg (0.36 mmol) of triphenylphosphine in 2.5 ml of THF. The mixture was stirred at RT for 18 h, 40 ml of diethyl ether were added, the mixture was filtered and the solvent was removed. The product was purified chromatographically (silica gel, cyclohexane/EA 10:1). This gave 63.0 mg (47.5%) of a colorless oil.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1.O>C(O)(=O)C>[NH2:3][C:4]1[C:9]([Br:1])=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1
Reactant: BrBr
Reactant: Nc1ccc(Cl)cn1
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncc(Cl)cc1Br
Temperature: 25 °C
Yield: 63.8 %

Procedure:
A solution of 257 g (1.61 mol) of bromine in 380 ml of acetic acid was added dropwise over a period of one hour to a solution of 187 g (1.45 mol) of 2-amino-5-chloropyridine in 1.5 l of acetic acid. The reaction mixture was refluxed for 3 h and then allowed to cool to ambient temperature. 1.9 l of demineralized water were added and the mixture was concentrated in vacuo. The residue was partitioned between 4 l of ethyl acetate and 1.8 l of water. The mixture was basified with 3 l of a 10% by weight aqueous sodium hydroxide solution. The organic layer was separated and washed with brine (2×1.5 l), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was filtered, washed with hexane (2×100 ml) and dried in vacuo to give 192 g of 2-amino-3-bromo-5-chloropyridine. The mother liquor was concentrated in vacuo, filtered, washed with hexane and dried to give further 75 g of the same product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[C:22]([O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH:34]([CH3:38])[C:35](Cl)=[O:36])=[CH:31][CH:30]=2)=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=1>C1(C)C=CC=CC=1>[Cl:20][C:21]1[C:22]([O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH:34]([CH3:38])[C:35]([O:12][CH:10]([CH3:11])[CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:36])=[CH:31][CH:30]=2)=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: CC(O)COCc1ccccc1
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(COCc1ccccc1)OC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Temperature: 0 °C

Procedure:
16.6 g of 1-benzyloxy-2-propanol and 10.6 g of triethylamine were dissolved in 200 ml of toluene, then cooled to 0° C. To this solution was dropwise added a solution of 34.7 g of 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]-propionyl chloride in 80 ml of toluene at 0° to 5° C. with stirring. After the dropwise addition, the mixture was gradually heated and, at 40° to 50° C., it was stirred for one hour to complete the reaction. After cooling to room temperature, it was washed successively with 1% strength by weight sodium hydroxide aqueous solution and water, followed by drying. Upon distilling off toluene under reduced pressure, there were obtained 43.3 g of pale yellow, viscous, oily 1-methyl-2-benzyloxyethyl 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionate. nD20 1.5710
Reaction SMILES: [C:1]([C:9]12OC1[O:13][C:12]([C:16]([O:18]CC)=[O:17])=[CH:11][C:10]2=[O:21])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:22]>O1CCOCC1>[Cl:22][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([C:16]([OH:18])=[O:17])[O:13][C:1]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl
Reactant: CCOC(=O)C1=CC(=O)C2(C(=O)c3ccccc3)OC2O1
Solvent: C1COCCO1
Product: O=C(O)c1cc(=O)c(Cl)c(-c2ccccc2)o1

Procedure:
A solution of ethyl 6-benzoyl-5-oxo-2,7-dioxabicyclo[4.1.0]-hept-3-ene-3-carboxylate (2.9 g) prepared as in Example 44, in dioxan (30 ml) and concentrated hydrochloric acid (10 mol) was heated under reflux for 2 hours. The solution was evaporated under vacuum and the solid residue was crystallised from ethyl acetate-petroleum ether 60°-80° C. and then from dioxan-water to give the title product (mp 216°-218° C. with decomposition).
Reaction SMILES: S1C=CC(C(Cl)=[O:7])=C1.C([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][C:25](C4SC=CC=4C([O-])=O)=[CH:26][CH:27]=3)[O:22][C:21]=2[C:39]2[CH:43]=[CH:42][S:41][CH:40]=2)=[CH:16][CH:15]=1)=[O:13])C>>[OH:7][C:25]1[CH:24]=[C:23]2[C:28]([C:29](=[O:30])[C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:12]([OH:11])=[O:13])=[CH:15][CH:16]=3)=[C:21]([C:39]3[CH:43]=[CH:42][S:41][CH:40]=3)[O:22]2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1ccc(-c2c(-c3ccsc3)oc3cc(-c4sccc4C(=O)[O-])ccc3c2=O)cc1
Reactant: O=C(Cl)c1ccsc1
Product: O=C(O)c1ccc(-c2c(-c3ccsc3)oc3cc(O)ccc3c2=O)cc1

Procedure:
Prepared following General Scheme 1, starting from Intermediate A-1a and thiophene-3-carbonyl chloride in step 1 using condition b) to 3-(4-(ethoxycarbonyl)phenyl)-4-oxo-2-(thiophen-3-yl)-4H-chromen-7-ylthiophene-3-carboxylate. Step 2 followed d) conditions. See Example 3 for detailed example.
Reaction SMILES: O[C:2]1([OH:9])[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(Cl)Cl.CN(C=O)C.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:30]1([N:34]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[CH:30]1([N:34]2[CH2:40][CH2:39][CH2:38][N:37]([C:6]([CH:4]3[CH2:3][C:2](=[O:9])[CH2:5]3)=[O:8])[CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31]1
Reactant: C1CC(N2CCCNCC2)C1
Reactant: O=C(O)C1CC(O)(O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
To a stirred solution of 3,3-dihydroxycyclobutanecarboxylic acid (80 mg, 0.61 mmol) in 4:1 DCM/DMF (2.5 ml) was added CDI (103 mg, 0.64 mmol) at RT. The mixture was stirred for 1.5 h at RT and 1-cyclobutyl-1,4-diazepane (98 mg, 0.64 mmol) was added. The resulting solution was stirred at RT for 3 H, diluted with DCM (20 ml) and washed with 1:1 H2O/brine (20 ml). The organic layer was dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by silica gel FCC (eluting with DCM/MeOH/NH3 90:10:1) provided the title compound as colourless oil (84 mg, 56%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH2:11])[CH2:8]2.[CH2:12]1[CH2:19][O:18][S:15](=[O:17])(=[O:16])[CH2:14][CH2:13]1>O1CCOCC1>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][CH2:19][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16])[CH2:8]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: O=S1(=O)CCCCO1
Solvent: C1COCCO1
Product: O=S(=O)(O)CCCCNC1C2CC3CC(C2)CC1C3
Temperature: 25 °C

Procedure:
To a solution of 2-adamantanamine (1.06 g, 7.0 mmol) in 1,4-dioxane (6 mL) was added 1,4-butane sultone (955 mg, 6.7 mmol). The solution was stirred at reflux for 5 hours. The reaction was cooled to room temperature. The solid was collected by filtration. It was suspended in EtOH (25 mL) and the mixture was heated to reflux for 1 minute before the solid was filtered. It was washed with EtOH (1×15 mL) and dried in vacuo. Yield: 55%. 1H NMR (D2O, 500 MHz) δ ppm 3.29 (m, 1H), 2.97 (m, 2H), 2.83 (m, 2H), 2.02 (m, 2H), 1.83 (m, 2H), 1.68 (m, 14H). 13C NMR (D2O, 125 MHz) δ ppm 63.07, 50.25, 45.03, 36.55, 36.31, 29.85, 29.05, 26.68, 26.41, 24.47, 21.61. ES-MS 286 (M−1).
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].Cl.[NH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1>N1C=CC=CC=1>[CH2:3]([O:2][C:1]([NH:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)=[O:5])[CH3:4]
Reactant: Cn1ccnc1N
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nccn1C
Temperature: 100 °C

Procedure:
Ethyl chlorocarbonate (0.6 g) was added to a solution of 2-amino-1-methylimidazole hydrochloride (0.3 g) in pyridine (5 ml), and the mixture was stirred under heating at 100° C. for 2 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in water, and sodium carbonate was added until the solution became alkaline. The solvent was evaporated under reduced pressure, and then the residue was purified by column chromatography on silica gel (eluent: chloroform) to give 2-ethoxycarbonylamino-1-methylimidazole. This compound was dissolved in dichloromethane, and 4N hydrochloric acid-ethyl acetate (2 ml) was added to form its hydrochloric acid salt. The resulting crude crystals were washed with ether to give 2-ethoxycarbonylamino-1-methylimidazole hydrochloride (0.29 g, Yield: 56%) as colorless prisms.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][O:26][CH2:27][CH3:28].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][CH2:25][O:26][CH2:27][CH3:28])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1cc(C2CCN(C(=O)OCC)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
Under inert atmosphere, a solution of 12.5 g (0.045 mol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester in 50 ml of anhydrous DMF was added dropwise to a suspension containing 2.75 g (0.068 mol) of sodium hydride (60% in mineral oil) in 200 ml of anhydrous DMF. After stirring at room temperature for 1 hour, 6.6 ml (0.06 mol) of 1-bromo-2-ethoxyethane were added. The reaction mixture was heated at 60° C. for 3 hours. The crude mixture was poured into water and extracted with ethyl acetate. After drying, the solvent was removed under reduced pressure and 16 g of a crude oil were obtained and used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1cncc(F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: C[C@H](NC(=O)c1cc(Cl)ccc1COc1cncc(F)c1)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-{[(5-fluoropyridin-3-yl)oxy]methyl}benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):