Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]1[S:15][CH2:16][CH2:17][N:18]=1.Cl.N>C(#N)C.CO>[S:15]1[CH2:16][CH2:17][N:18]2[C:3]([C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=3)=[CH:2][N:13]=[C:14]12
Reactant: NC1=NCCS1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CC#N
Product: N#Cc1ccc(-c2cnc3n2CCS3)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
3.00 g (12.72 mmol) of 4-bromoacetylbenzonitrile is dissolved in 40 mL acetonitrile, and combined with 2.65 g (25.42 mmol) of 2-amino-4,5-dihydrothiazole and 2.00 g of molecular sieve 4 Å. Then the mixture is stirred for 2.5 days at ambient temperature. Then the solvent is eliminated in vacuo, and the residue is taken up with 100 mL of 1 molar hydrochloric acid solution and the insoluble matter is taken up with a little methanol and concentrated ammonia solution. After filtration, the filtrate is concentrated in vacuo and purified by chromatography on silica gel (gradient: initially ethyl acetate/ethanol=100:0 □40:60+0.5% ammonia, then dichloromethane/methanol=6:4+2% triethylamine). Yield: 2.4 g; Rf value: 0.65 (silica gel; ethyl acetate/ethanol=8:2+1% ammonia); C12H9N3S (227.29); mass spectrum: (M+H)+=228
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]([OH:21])[CH2:22][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:7]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OC[C@H]1CO1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)c2cc1C#N
Temperature: 50 °C
Reaction time: 2 h

Procedure:
After adding tetrahydrofuran (4 ml) and diethylamine (0.2 ml) to N-(4-(6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N′-(thiazol-2-yl)urea (200 mg), the mixture was stirred at 50° C. for 2 hours. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (60 mg) as light yellow crystals.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[ClH:21].N([O-])=O.[Na+].[S:26](=[O:28])=[O:27]>C(O)(=O)C.O>[Cl:21][S:26]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:28])=[O:27]
Reactant: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: O=S=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl 3-amino-5-[(dipropylamino)carbonyl]benzoate (XXXI, PREPARATION 10, 1.11 g, 4 mmol) is added to a mixture of water (5 mL) and concentrated hydrochloric acid (1 mL). Sodium nitrite (0.276 g, 4 mmol) is added to the mixture slowly at 0 degrees C. The mixture is then added to an acetic acid solution (5 mL) of CuCl2.2H2O saturated with sulfur dioxide. The mixture is stirred for 0.5 hours and poured into ice water. The mixture is extracted with ethyl acetate. The organic phase is separated and washed with saturated sodium bicarbonate, water, and saline and dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound, NMR (300 MHz, CDCl3) delta 8.69, 8.38, 8.20, 4.01, 3.49, 3.14, 1.72, 1.59, 1.01 and 0.79; MS (ESI+) for C15H20ClNO5S m/z (M+H)+=362.2
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH2:15][NH2:16])[CH:10]=[N:11][CH:12]=1.[C:17]1(=[S:22])[O:21][CH2:20][CH2:19][CH2:18]1.CO>O>[SH:22][CH2:17][CH2:18][CH2:19][C:20]([NH:16][CH2:15][CH2:14][O:13][C:9]1[CH:10]=[N:11][CH:12]=[C:7]([C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])[CH:8]=1)=[O:21]
Reactant: S=C1CCCO1
Reactant: CN1CCC[C@H]1c1cncc(OCCN)c1
Solvent: CO
Solvent: O
Product: CN1CCC[C@H]1c1cncc(OCCNC(=O)CCCS)c1
Temperature: 60 °C
Yield: 43 %

Procedure:
A solution of 2-({5-[(2S)-1-methylpyrrolidin-2-yl]pyridin-3-yl}oxy)ethanamine (preparation 12) (1100 mg, 4.971 mmol), in water (10 ml), was treated with γ-thiobutyrolactone (861 ul, 9.94 mmol) and the reaction mixture was heated to 60° C. overnight. It was then evaporated in vacuo to leave a colourless gum, which was pre-adsorbed onto silica from MeOH. This was then chromatographed on a 40 g ISCO column, eluting with EtOAc to EtOAc:MeOH:NH3 80:20:1. The appropriate fractions were evaporated in vacuo to give the title compound as a colourless gum, 690 mg. Yield=43%.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]2>C(Cl)Cl>[C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:8]=[O:7])[CH:18]=[CH:17]2)([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc2cc(CO)ccc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2cc(C=O)ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A mixture of 5 mL (61.8 mmol) of pyridine and 70 mL of CH2Cl2 was cooled to 0° C. Then 3.0 g (30 mmol) of CrO3 was added in several portions. The mixture was stirred at 0° C. for 15 min before a solution of 0.69 g (3.19 mmol) of methyl 6-hydroxymethyl-2-naphthoate in 10 mL of CH2Cl2 was added. The mixture was stirred at room temperature for 2 hr and then filtered through Florisil (500 mL CH2Cl2 rinse). The filtrate and washings were concentrated and filtered through 50 g of silica gel with 50% EtOAc/hexane to give 0.66 g (96% yield) of the pure aldehyde as a white solid. The analytical sample was recrystallized from EtOAc/hexane: mp 132°-134° C.; IR (mull) 1740, 1700, 1350, 1310, 1270, 1220, 1180, 1140, 1110, 990, 920, 830, 780, 760 cm- 1 ; 1H NMR (CDCl3) δ4.00 (s, 3, CO2CH3), 8.0-8.7 (m, 6, ArH), 10.23 (s, 1, CHO); MS calcd for C13H10O3 214.0630, found 214.0627.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[CH2:15]([SH:19])[CH2:16][CH2:17][CH3:18].CCN(C(C)C)C(C)C>>[CH2:15]([S:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCS
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCSc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 39a was used, starting from 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c), butane-1-thiol and DIEA to give 4-butylsulfanyl-6-iodo-quinoline-3-carbonitrile. LC-MS m/e 369 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:5]([OH:12])[C:4]([CH3:13])=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35]>CN(C)C=O>[CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:5]([O:12][C:21]2[CH:26]=[C:25]([O:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[F:28])[N:24]=[CH:23][N:22]=2)[C:4]([CH3:13])=[N:3]1
Reactant: Clc1cc(Cl)ncn1
Reactant: Oc1ccccc1F
Reactant: COC(=O)Cc1c(O)c(C)nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Oc2cc(Oc3ccccc3F)ncn2)c(C)nn1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.0 g (16.3 mmol) of methyl (1,3-dimethyl-4-hydroxypyrazol-5-yl)acetate in 80 ml of dimethyl formamide are added 6.9 g (50.0 mmol) of potassium carbonate and 2.7 g (18.0 mmol) of 4,6-dichloropyrimidine. After stirring for 3 hours at room temperature, 2.2 g (20.0 mmol) of 2-fluorophenol are added and stirring is continued for 3 hours at 80°-85° C. Then 300 ml of ice-water are added, followed by extraction with 400 ml of diethyl ether. The organic phase is washed with 2M sodium hydroxide solution, water and sodium chloride solution, dried and concentrated under vacuum. The resultant brown oil is chromatographed over silica gel with tetrahydrofuran/n-hexane (1:1) as eluant, giving methyl {1,3-dimethyl-4-[6-(2-fluorophenoxy)pyrimidin-4-yloxy]pyrazol-5-yl}acetate as a yellow resin: MS: 372 (M+, 80%), 312 (100).
Reaction SMILES: [CH3:1][CH:2]1[NH:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:12][C:5]=2[O:4][CH2:3]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:30](C)=O.[Na+].O>C(O)(=O)C.C(Cl)Cl>[CH3:1][CH:2]1[N:8]([CH3:30])[CH2:7][C:6]2[CH:9]=[CH:10][C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14]3)=[N:12][C:5]=2[O:4][CH2:3]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC1COc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2CN1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC1COc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2CN1C
Temperature: 25 °C
Reaction time: 25 h
Yield: 39.1 %

Procedure:
To a solution of the compound (0.30 g) obtained in Example 22 and paraformaldehyde (0.052 g) in a mixture of acetic acid (0.20 mL) and CH2Cl2 (4 mL) was added NaBH(OAc)3 (0.274 g), and the mixture was stirred at room temperature for 25 hr. Paraformaldehyde (0.052 g) and NaBH(OAc)3 (0.274 g) were further added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the resultant product was extracted with CH2Cl2. The organic layer was washed with water and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 30→60% ethyl acetate/hexane) to give the title compound (0.122 g, 39%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33])=[CH:21]1>>[F:11][C:12]1[CH:13]=[C:14]([CH:15]([C:3]2[C:4](=[O:10])[NH:5][CH:6]([CH:7]([CH3:9])[CH3:8])[C:2]=2[OH:1])[C:21]2[NH:20][C:28]3[C:23]([C:22]=2[CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33])=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: O=Cc1cccc(F)c1
Reactant: CC(C)C1NC(=O)C=C1O
Product: CC(=O)NCCc1c(C(C2=C(O)C(C(C)C)NC2=O)c2cccc(F)c2)[nH]c2ccccc12

Procedure:
Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) was reacted with 3-fluoro-benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as a yellow solid. MS: 450.1 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:5]=1)(=O)[CH3:2].COC(OC)[N:22]([CH3:24])C.[C:27](#[N:29])C>>[CH3:12][O:11][C:8]1[C:9](=[O:10])[C:4]([C:1]2[N:22]([CH3:24])[N:29]=[CH:27][CH:2]=2)=[N:5][N:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CC#N
Reactant: COc1cn(-c2cccnc2)nc(C(C)=O)c1=O
Product: COc1cn(-c2cccnc2)nc(-c2ccnn2C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An acetonitrile suspension (7.5 mL) of 3-acetyl-5-methoxy-1-(pyridin-3-yl)pyridazin-4(1H)-one (0.5 g) was stirred at 70° C. for 10 min, and allowed to be cooled to room temperature. Then, N,N-dimethylformamide dimethyl acetal (2.5 mL) was added thereto, and the mixture was stirred at 80° C. for 2 hr. The insoluble material was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in ethanol (5.4 mL). To the reaction mixture was added dropwise a 10%-TFA containing ethanol solution (5.4 mL) of methylhydrazine (139 mg) under ice-cooling with stirring, and the mixture was stirred at the same temperature for 10 min, allowed to be warmed to room temperature, and stirred for 16 hr. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (NH, ethyl acetate/methanol). The eluted product was crystallized from ethyl acetate to give the title compound (47 mg) as pale-yellow crystals.
Reaction SMILES: C(OC(=O)C)C.[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][O:17][C:18](=[O:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[CH:23][CH:22]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.I.[NH2:41][C:42]1[C:43]([C:50]([NH:52][C:53](=[NH:56])SC)=[O:51])=[N:44][C:45]([Cl:49])=[C:46]([NH2:48])[N:47]=1>C1COCC1>[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][O:17][C:18](=[O:32])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:53]([NH2:56])=[N:52][C:50]([C:43]2[C:42]([NH2:41])=[N:47][C:46]([NH2:48])=[C:45]([Cl:49])[N:44]=2)=[O:51])=[CH:25][CH:26]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCOC(=O)COc1ccc(CCCCN)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCOC(=O)COc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
A solution of [4-(4-aminobutyl)phenoxy]acetic acid 2-tert-butoxycarbonylaminoethyl ester ethyl acetate 45a (50 mg, 0.27 mmol) and triethylamine (0.27 mL, 1.53 mmol) in anhydrous THF (4 mL) was stirred at 55° C. (oil bath) for 15 min. To the solution was added 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (130 mg, 0.34 mmol) in two portions during a period of 15 min. The reaction mixture was stirred at 55° C. for 1 h and cooled to room temperature. The mixture was concentrated by rotary evaporation. The crude residue was purified by flash silica gel column chromatography eluting with dichloromethane/methanol/concentrated ammonium hydroxide (200:10:0, 200:10:1, and 150:10:1, v/v) to give (4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)acetic acid 2-tert-butoxycarbonylaminoethyl ester 46a (PSA 25309) as a yellow solid (60 mg, 76% yield). An analytical pure sample was obtained by semi-preparative HPLC purification (acetonitrile/water). mp 80-82° C. 1H NMR (300 MHz, CD3OD) δ 1.45 (s, 9H), 1.60-1.78 (m, 4H), 2.56-2.66 (m, 2H), 3.30-3.38 (m, 4H), 4.15-4.21 (m, 2H), 4.64 (s, 2H), 6.81 (d, 2H), 7.10 (d, 2H). m/z (ESI) 579 [C25H35ClN8O6+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.CI.[C:15](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:15])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)C=Cc1ccc(F)cc1
Reaction time: 72 h
Yield: 93.1 %

Procedure:
To a solution of 3-(4-fluorophenyl)-2-propenoic acid (24.2 g, 146 mmol) in DMF (120 ml) were added methyl iodide (31.1 g, 219 mmol) and potassium carbonate (40.4 g, 292 mmol) at room temperature and the mixture was stirred for 72 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain 24.5 g (yield 93%) of the title compound. mp. 43–46° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][C:17]([NH:21]C(OCC3C=CC=CC=3)=O)([CH3:20])[CH2:16][CH2:15]2)=[N:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)(C)C.CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][C:17]([NH2:21])([CH3:20])[CH2:16][CH2:15]2)=[N:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(C(=O)OC(C)(C)C)cn2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC1(N)CCN(c2ccc(C(=O)OC(C)(C)C)cn2)CC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-benzyloxycarbonylamino-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-5′-carboxylic acid tert-butyl ester (0.29 g, 0.68 mmol) in isopropanol, methanol and ethyl acetate (1:1:1, 5.0 mL) at room temperature was added ammonium formate (0.25 g, 1.07 mmol) and 10% Pd/C (25 mg) under nitrogen. The reaction mixture was stirred at 80° C. for 30 minutes, cooled, filtered through Celite, and concentrated under reduced pressure to provide the titled compound. MS (CI) m/z 292 (M+1)+; 1H NMR (300 MHz, methanol-d4) δ ppm 8.61 (d, 1H), 7.95 (d,d 1H), 6.79 (d, 1H), 4.80 (s, 2H), 3.85-3.79 (m, 2H), 3.66-3.60 (m, 2H), 1.67-1.59 (m, 4H), 1.58 (s, 9H), 1.23 (s, 3H).
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][N+:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:20]=[N:21][NH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[Cl:18][C:19]1[CH:20]=[N:21][N:22]([CH2:6][CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][C:2]([OH:1])([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:11][CH2:10]2)[CH:23]=1
Reactant: Clc1cn[nH]c1
Reactant: OC1(c2ccccc2)CC[N+]2(CCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OC1(c2ccccc2)CCN(CCCCn2cc(Cl)cn2)CC1
Yield: 77.3 %

Procedure:
A mixture of 15.0 g (48 mmol) of 8-hydroxy-8-phenyl-5-azoniaspiro[4,5]decane, 5.4 g (53 mmol) of 4-chloropyrazole and 13.2 g of potassium carbonate in 200 ml of dimethylformamide is heated at reflux for 20 hours. Evaporation to dryness is then carried out at reduced pressure, the residue is redissolved in chloroform and washing is carried out repeatedly with water. The organic phase is dried with anhydrous sodium sulfate and evaporation is carried out at reduced pressure, a crude product being obtained which is suspended in ethyl ether, which is filtered while cold and which is washed with ethyl ether. 12.4 g (37.1 mmol) of 4-chloro-1-[4-(4-hydroxy-4-phenyl-1-piperidyl)butyl]-1H-pyrazole are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([CH:20]=O)=[CH:16][CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH2:9][CH2:10]1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1cccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)c1

Procedure:
153.8 mg of the target compound (0.45 mmol, 54.9%) was obtained using 1-(3-methylphenyl)piperazine (289 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:21]([OH:23])=[O:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][Cl:20])=[CH:13][CH:12]=1)=O)(C)(C)C>O1CCOCC1>[ClH:20].[Cl:20][CH2:19][CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C@@H:9]([C:21]([OH:23])=[O:22])[NH2:8])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCCCl)cc1)C(=O)O
Solvent: C1COCCO1
Product: Cl
Product: N[C@@H](Cc1ccc(OCCCl)cc1)C(=O)O
Reaction time: 28 h
Yield: 77.6 %

Procedure:
5 g of (S)-N-tert-butoxycarbonyl-4-O-(2-chloroethyl)tyrosine, dissolved in 50 ml of hydrochloric dioxane, are placed in a round-bottomed flask. After having been stirred for 28 h, the mixture is concentrated to dryness under reduced pressure. The resulting residue is taken up in 50 ml of ether and this solution is then stirred and filtered. The resulting solid is washed with 2 times 25 ml of ether and then dried under reduced pressure in order to yield 1.58 g of (S)-4-O-(2-chloroethyl)tyrosine hydrochloride in the form of a white solid which melts at 260° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][OH:6].O1CCCC1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([O:6][CH2:5][C:4]3[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=3)[N:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: OCc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(OCc3cc(F)cc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
3,5-Difluorobenzyl alcohol (227.5 μL, 2.01 mmol) was dissolved into 15 mL of anhydrous tetrahydrofuran and treated with sodium hydride (80.3 mg, 60% dispersion in mineral oil, 2.01 mmol). This was stirred under nitrogen for 15 minutes at ambient temperature, then the reaction was treated with 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (I-1a) (500 mg, 1.67 mmol) in one portion. The resultant mixture was refluxed under nitrogen for 4 hours. After cooling to room temperature, the reaction was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (20 mL), then dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 1:1 ethyl acetate:hexanes) to afford 605.2 mg of the title product (I-1b).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)([OH:25])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:18]1([O:17][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]([OH:25])=[O:14])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A rapidly stirred solution of 4-benzyloxy-3-cyclopentyloxybenzaldehyde (10.5 g; that is prepared as described in Reference Example 37) in glacial acetic acid (100 mL) is treated with sulfamic acid (4.85 g) and stirred at room temperature for 10 minutes. The solution is then cooled in an ice bath and treated with a solution of sodium chlorite (4.2 g) in water (100 mL) during 15 minutes at 13-15° C. During the addition a white precipitate forms and, because stirring becomes difficult, a further quantity of glacial acetic acid (60 mL) is added. After warning to room temperature, the solution is stirred for a further 6 hours and further quantities of sodium chlorite (1.6 g) and sulfamic acid (1.7 g) are added. The mixture is poured onto water and the resulting solid is filtered off and dried, to give 3-cyclopentyloxy-4-benzyloxybenzoic acid (10 g).
Reaction SMILES: C(O)C.C(O[Na])C.[O:8]=[CH:9][C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1.Br[C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH:9]([C:10]1[CH:18]=[CH:17][C:15]([O:16][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:12]([O:13][CH3:14])[CH:11]=1)=[O:8]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: CCO[Na]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1OC
Temperature: 80 °C
Yield: 36 %

Procedure:
In a co-solvent including ethanol (3 mL) and DMF (3 mL), IN ethoxy sodium (NaOEt) (2.96 mL, 2.96 mmol) was added dropwise to a solution including vanillin (300 mg, 1.97 mmol) and ethyl α-bromoisobutyrate (0.43 mL, 2.93 mmol), and then, the reaction mixture was heated at a temperature of 80° C. overnight. Ethanol was evaporated, and the residual was distributed between ether and water, and an organic layer was dried, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (EtOAc) (4:1) to obtain Compound 122a (188.7 mg, 36%).