Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:27]2[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=2)=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
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: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)OC(C)(C)C

Procedure:
Suzuki Coupling. To a solution of (S)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester in toluene (250 mL) was added 4-cyanobenzeneboronic acid, Pd(PPh3)4, and 1N Na2CO3 solution (105 mL). The mixture was heated at reflux for 7 h. After completion of the reaction, the aqueous layer was drained. The organic layer was washed with 10% Na2CO3 and 1 N HCl. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The residue was then purified by column chromatography (hexanes-EtOAc) to provide (S)-2-tert-Butoxycarbonylamino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (18.2 g). LCMS (m/z) 382.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[S:12]([NH:15][CH:16]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:17]([F:20])([F:19])[F:18])(=[O:14])=[O:13].Cl.C(=O)(O)[O-].[Na+]>CO.[Zn]>[NH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[S:12]([NH:15][CH:16]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:17]([F:20])([F:18])[F:19])(=[O:14])=[O:13]
Reactant: Cc1cc(C)c(S(=O)(=O)NC(Cc2c[nH]c3ccccc23)C(F)(F)F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(S(=O)(=O)NC(Cc2c[nH]c3ccccc23)C(F)(F)F)c(N)c1
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of 125 mg (0.28 mmol) of 2,4-dimethyl-6-nitro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide in 5 mL of methanol was added 220 mg (3.36 (mmol) of zinc powder followed by 3 mL of 1 N aqueous HCl. After 3 hours, the mixture was made basic with saturated aqueous sodium bicarbonate solution and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with two 5 mL portions of saturated aqueous sodium bicarbonate solution and three 5 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The oil residue was chromatographed on silica gel eluting first with dichloromethane-hexanes (1:1) and then ethyl acetate-hexanes (5-20% gradient). The material from the column was solidified from ether-hexanes with a few drops of ethanol to afford 100 mg (85%) of 2-amino-4,6-dimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide. MS: m/z 412.48 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[Cl:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[Cl:26])[CH:13]=[N:12]2)[C:8]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(Cl)c2Cl)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4cccc(Cl)c4Cl)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2,3-dichloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 70) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-2-[4-(2,3-dichloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as a light brown solid as a mixture of diastereomers (1.28 g, 88%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4](OC)=[O:5].[BH4-].[Li+]>C1COCC1.O>[CH2:11]([O:10][CH2:9][CH2:8][CH:2]([OH:1])[CH2:3][CH2:4][OH:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C[C@@H](O)CCOCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCC(O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-(S)-hydroxy-5-benzyloxypentanoate (38, Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R., J. Am. Chem. Soc. 1988, 110 629-631) (183 mmol) in anhydrous THF (1 l) is added lithium borohydride (7.7 g, excess) at 0° C. over 15 min. The reaction mixture is stirred at RT for 30 minutes, and then refluxed for 6 hours. The mixture is then cooled to 0° C., diluted with water (60 ml), and stirred overnight at RT. A white precipitate is removed by filtration, the solvent removed in vacuum, and the residue distilled under vacuum to yield 5-benzyloxy-1,3-pentanediol 39.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH2:30][NH:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:39](=O)[CH3:40].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[CH2:30][N:31]([CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH2:39][CH3:40])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1CNC1CCC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCN(Cc1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)C1CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[(cyclobutylamino)methyl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (3.6 mg, 6.50×10−3 mmol) in dichloroethane (300 μL) was added acetaldehyde (40 μL, 0.709 mmol) and NaBH(OAc)3 (excess). The reaction was stirred at room temperature for 2 hours and then diluted with EtOAc (10 mL) and washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-{[cyclobutyl(ethyl)amino]methyl}-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.69 (25% EtOAc/hexanes). LCMS=583.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.90 (s, 1H), 7.80 (s, 2H), 7.54-7.52 (m, 3H), 5.74 (d, J=8.0 Hz, 1H), 4.99 (d, J=16.1 Hz, 1H), 4.65 (d, J=16.2 Hz, 1H), 4.04-3.98 (m, 1H), 3.64 (d, J=13.9 Hz, 1H), 3.47 (d, J=13.9 Hz, 1H), 3.18-3.12 (m, 1H), 2.48-2.39 (m, 2H), 1.98-1.92 (m, 2H), 1.87-1.74 (m, 2H), 1.67-1.58 (m, 2H), 0.90 (t, J=7.2 Hz, 3H), 0.80 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[Cl:8][C:9]1[C:18]([NH2:19])=[C:17]([NH:20][CH2:21][C:22]#[CH:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[C:18]([NH:19][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:17]([NH:20][CH2:21][C:22]#[CH:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CCOCC(=O)Cl
Reactant: C#CCNc1c(N)c(Cl)nc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNc1c(NC(=O)COCC)c(Cl)nc2ccccc12
Reaction time: 2 h
Yield: 79 %

Procedure:
Ethoxyacetyl chloride (89%, 28 g, 0.20 mol) was added dropwise to a solution of 2-chloro-N4-prop-2-ynylquinoline-3,4-diamine (43.5 g, 0.188 mol) and triethylamine (39 mL, 0.28 mol) in dichloromethane (600 mL) at 6° C. After two hours, the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The aqueous layer was back-extracted with dichloromethane three times. The organic layers were combined and washed twice with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting brown solid was triturated with toluene with heating. A fine tan solid was isolated by filtration, rinsed with diethyl ether, and dried to yield N-[2-chloro-4-(prop-2-ynylamino)quinolin-3-yl]-2-ethoxyacetamide (47.2 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][O:7][CH3:8])=[O:3].[CH:9]1[C:15]([NH2:16])=[N:14][C:12](=[O:13])[N:11]([C@@H:17]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C:18]2([F:26])[F:25])[CH:10]=1.Cl>>[F:26][C:18]1([F:25])[C@H:19]([OH:24])[C@@H:20]([CH2:22][OH:23])[O:21][C@H:17]1[N:11]1[CH:10]=[CH:9][C:15]([NH:16][C:2]([O:4][CH2:5][CH2:6][O:7][CH3:8])=[O:3])=[N:14][C:12]1=[O:13]
Reactant: COCCOC(=O)Cl
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Agent: Cl
Product: COCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 60 %

Procedure:
Using Method A and 2-methoxyethyl chloroformate, gemcitabine hydrochloride was converted to 50 (white solid, 60% yield): 1H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.25-8.27 (d, 1H), 7.11-7.13 (d, 1H), 6.30-6.32 (t, 1H), 6.18-6.22 (t, 1H), 5.32-5.35 (t, 1H), 4.23-4.26 (m, 2H), 4.13-4.22 (m, 1H), 3.86-3.90 (m, 1H), 3.78-3.81 (m, 1H), 3.62-3.66 (m, 1H), 3.54-3.57 (m, 2H), 3.32 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[O:11])[CH:7]=[N:8][CH:9]=1>CO.CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[N:8][CH:9]=1
Reactant: O=Cc1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Sodium borohydride (2.2 g, 59.1 mmol) was added to a suspension of 5-bromo-pyridine-3-carbaldehyde (10.0 g, 53.7 mmol) in MeOH (100 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour before it was quenched by the addition of water (5.0 mL). Evaporation of solvents afforded a light yellowish oil which was re-dissolved in EtOAc and washed with water. The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the title compound (9.6 g, 95%) as colorless oil. MS: 188.0 & 190.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1([C:14]2[S:15][C:16]([C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([NH:26][C:27]4[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[N:20]=3)=[CH:17][N:18]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]1=2.[N-:37]=[N+:38]=[N-:39].[Na+]>[Br-].[Zn+2].[Br-].CN(C=O)C>[CH3:25][C:23]1[CH:22]=[C:21]([NH:26][C:27]2[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][N:28]=2)[N:20]=[C:19]([C:16]2[S:15][C:14]([C:2]3([OH:1])[C:3]4[C:8](=[CH:7][C:6]([C:12]5[N:37]=[N:38][NH:39][N:13]=5)=[CH:5][CH:4]=4)[CH2:9][CH2:10][CH2:11]3)=[N:18][CH:17]=2)[CH:24]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(O)CCCc4cc(C#N)ccc43)s2)c1
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(O)CCCc4cc(-c5nn[nH]n5)ccc43)s2)c1
Temperature: 125 °C
Yield: 12.9 %

Procedure:
To a microwave vial was added 5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (250 mg, 0.493 mmol), sodium azide (32.0 mg, 0.493 mmol), zinc bromide (111 mg, 0.493 mmol) and DMF (2463 μl). The tube was sealed and heated to 125° C. for 16 h. The reaction was cooled to rt and filtered, then purified by reverse phase HPLC using a C18 column with a solvent system containing MeCN and H2O modified with 0.1% TFA. Product containing fractions were lyophilyzed to give 1-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-6-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydronaphthalen-1-ol (35 mg, 13%) as a white powder. MS ESI calcd for C26H21F3N8OS [M+H]+ 551, found 551. 1H NMR (600 MHz, dmso) δ 10.17 (s, 1H), 8.63 (s, 1H), 8.46 (d, J=4.8, 1H), 8.22 (s, 1H), 7.81 (s, 1H), 7.75 (d, J=7.8, 1H), 7.41 (d, J=8.1, 1H), 7.34 (s, 1H), 7.18 (d, J=4.0, 1H), 7.07 (s, 1H), 6.62 (s, 1H), 2.90 (d, J=4.3, 2H), 2.42-2.33 (m, 1H), 2.28 (s, 3H), 2.19-2.07 (m, 1H), 2.07-1.90 (m, 2H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:25](Cl)[C:26]([O:28]C)=[O:27].Cl>CN(C)C=O.O>[C:10]1([C:7]2[C:6]3[CH:16]=[C:2]4[O:1][CH:25]([C:26]([OH:28])=[O:27])[O:17][C:3]4=[CH:4][C:5]=3[O:9][N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cc2onc(-c3ccccc3)c2cc1O
Reactant: COC(=O)C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C1Oc2cc3onc(-c4ccccc4)c3cc2O1
Reaction time: 2.5 h
Yield: 55.3 %

Procedure:
A mixture of 5,6-dihydroxy-3-phenyl-1,2-benzisoxazole (2.9 g), potassium carbonate (10.7 g) and methyl dichloroacetate (3.7 g) in 50 ml of N,N-dimethylformamide was stirred at 90°-100° C. for 2.5 hours. After cooling, water (50 ml) was added to the mixture followed by stirring it at 90°-100° C. for 40 minutes. After cooling and acidifying the mixture with hydrochloric acid, the mixture was extracted with ether. The ether layer was washed with water, dried and evaporated to remove the solvent. The residue was washed with methylene chloride, recrystallized from acetone/water to give 2.0 g of 3-phenyl-1,3-dioxolo[4,5-f]-1,2-benzisoxazole-6-carboxylic acid. m.p.: 202.5°-203.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12])[C:5]([CH3:14])=[CH:4][N:3]=1.[CH2:15]([O:17][C:18](=[O:30])[CH2:19][C@H:20]1[C:28]2[C:23](=[CH:24][C:25](O)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH3:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][O:12][C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[C@H:20]([CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:30])[CH2:21][CH2:22]3)[C:5]([CH3:14])=[CH:4][N:3]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: Cc1cnc(Cl)nc1N(C)CCCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)ncc3C)ccc21
Reaction time: 24 h
Yield: 77 %

Procedure:
To a solution of 3-[(2-chloro-5-methyl-4-pyrimidinyl)(methyl)amino]-1-propanol (Example 341, 785 mg, 3.64 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 401 mg, 1.82 mmol) in THF (17 mL) were added PPh3 (954 mg, 3.64 mmol) and ADDP (918 mg, 3.64 mmol). The reaction mixture was vigorously stirred at rt for 24 h after which additional PPh3 (954 mg, 3.64 mmol) and ADDP (918 mg, 3.64 mmol) were added. After an additional 24 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (3:1 hexanes/EtOAc) to give the product (586 mg, 77%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.26 (t, 3H), 1.71-1.76 (m, 1H), 2.06-2.11 (m, 2H), 2.26 (s, 3H), 2.34-2.42 (m, 2H), 2.67-2.88 (m, 3H), 3.15 (s, 3H), 3.49-3.50 (m, 1H), 3.70 (t, 2H), 3.94 (t, 2H), 4.13 (q, 2H), 6.64 (d, 1 H), 6.70 (s, 1H), 7.02 (d, 1H), 7.75 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([NH:13][C:14](=[O:35])[CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)(=[O:24])=[O:23])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C)C(=O)C>[N:36]1([CH2:1][C:3]2[CH:12]=[C:11]3[C:6]([C@H:7]([NH:13][C:14](=[O:35])[CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][N:17]4[S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=4)(=[O:24])=[O:23])[CH2:8][CH2:9][O:10]3)=[CH:5][CH:4]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc2c(c1)OCC[C@H]2NC(=O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCOc2cc(CN3CCCCC3)ccc21
Reaction time: 14 h

Procedure:
N-(7-Formyl-chroman-4-(R)-yl)-2-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-2-yl]-acetamide (135 mg, 0.26 mmol) and piperidine (28 mg, 0.33 mmol) were added to N,N-dimethyl-acetamide (1.5 mL) solution, followed by NaBH(OAc)3 (115 mg, 0.52 mmol) and the reaction was stirred overnight (14 h). The reaction was quenched with dilute NaHCO3—H2O (10 mL), and the mixture was extracted with CH2Cl2 (2×10 mL), and the organic phase was washed with dilute NaHCO3—H2O and H2O, and dried over MgSO4. After filtration and concentration in vacuo, the crude was purified by precipitation and crystallization as the HCl salt in Et2O to provide a white solid (of the title compound as a mixture of diastereomers (ca. 1:1 by 1H NMR). MS (ESI) 580 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[CH3:16][C:17]([CH2:21][OH:22])([CH2:19][NH2:20])[CH3:18]>>[CH3:16][C:17]([CH3:18])([CH2:21][OH:22])[CH2:19][N:20]=[C:14]([CH:5]1[CH:6]([C:11]([OH:13])=[O:12])[CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)[OH:15]
Reactant: CC(C)(CN)CO
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCC(C)(C)CO

Procedure:
204 g of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (isomeric mixture) are reacted with 103 g of neopentanolamine at 120° C. for 4 hours, and the product is distilled. There is obtained between 169° and 172° C. at 2.53 Pa 268 g (92.7% of theory) of a yellow oil having a refractive index n25D of 1.5190 and a viscosity of 6.21 Pa.s.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@@H:4](/[CH:5]=[CH:6]/[CH3:7])[C@@H:3]1[C:8]([OH:10])=[O:9].Br[CH2:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[C:17]([CH3:22])=[C:16]([F:23])[C:15]=1[F:24].CN(C)C=O.C(N(CC)CC)C>O>[CH3:11][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]/[CH3:7])[C@@H:3]1[C:8]([O:10][CH2:13][C:14]1[C:15]([F:24])=[C:16]([F:23])[C:17]([CH3:22])=[C:18]([F:21])[C:19]=1[F:20])=[O:9]
Reactant: C/C=C/[C@H]1[C@H](C(=O)O)C1(C)C
Reactant: Cc1c(F)c(F)c(CBr)c(F)c1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C/C=C/[C@H]1[C@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a mixture solution of 0.50 g of (1RS)-trans-2,2-dimethyl-3-((E)-1-propenyl)cyclopropanecarboxylic acid, 0.72 g of 1-bromomethyl-2,3,5,6-tetrafluoro-4-methylbenzene and 8 ml of dimethylformamide, 1.0 g of triethylamine was added and the mixture was stirred at 80° C. for 4 hours. After the mixture was cooled to room temperature, water was poured into the mixture and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give 0.83 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl(1RS)-trans-2,2-dimethyl-3-((E)-1-propenyl)cyclopropanecarboxylate
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].[H-].[Na+].Cl[CH2:23][C:24]1[CH:29]=[C:28]([CH:30](C)C)[CH:27]=[CH:26][C:25]=1[CH3:33].O>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([CH2:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:33])[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: Cc1ccc(C(C)C)cc1CCl
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1-c1cc2ccn(Cc3cc(C)ccc3C)c2cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (15 mg, 0.06 mmol) in DMF (0.5 mL) is added NaH (95%, 4 mg). The reaction mixture is stirred at room temperature for 30 minutes, and 2-chloromethyl-4-isopropyl-1-methyl-benzene (33 mg, 0.18 mmol) is then added. The mixture is heated at 60° C. for three hours and cooled. To the mixture, water (2 mL) and EtOAc (2 mL) are added. The organic layer is separated, washed with water once and concentrated under reduced pressure. The residue is purified by PTLC (Hexane/EtOAc 4:1) to give the titled compound. 1H NMR: (CDCl3) 8.81 (s, 1H), 7.47 (s, 1H), 7.28 (t, 1H), 7.13-7.19 (m, 5H), 6.77 (s, 1H), 6.52 (d, 1H), 5.39 (s, 2H), 2.80 (m, 1H), 2.27-2.40 (m, 7H), 1.14 (d, 2H), 1.01 (t, 6).
Reaction SMILES: [O:1]=[C:2]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10]([C@H:12]([NH:22][C:23](=[O:35])[C:24]([NH:27]C(OC(C)(C)C)=O)([CH3:26])[CH3:25])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[O:1]=[C:2]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:4]2([CH2:5][CH2:6][N:7]([C:10]([C@H:12]([NH:22][C:23](=[O:35])[C:24]([NH2:27])([CH3:26])[CH3:25])[CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:11])[CH2:8][CH2:9]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](CCCc1ccccc1)C(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)C(=O)N[C@H](CCCc1ccccc1)C(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product obtained from Step A in 2 mL of dichloromethane was added 2 mL of trifluoroacetic acid and stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to yield the title compound as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[CH3:34][O:33][C:31]([C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:22]([C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:6][N:7]=1)[CH:23]=[CH:24]2)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Product: COC(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and methyl 1H-indole-5-carboxylate (0.615 g, 21%).