Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[CH3:5][NH:6][C@@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[O:22][C:18]=2[C:17](F)=[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]=1[CH3:35])#[N:13].C(N(CC)CC)C>[Cl-].[Na+].O>[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[O:22][C:18]=2[C:17]([N:9]2[CH2:10][CH2:11][C@@H:7]([NH:6][CH3:5])[CH2:8]2)=[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]=1[CH3:35])#[N:13]
Reactant: CN[C@@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CN[C@@H]1CCN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (3 ml) solution of (3R)-3-methylaminopyrrolidine (95 μl, 0.88 mmol) was added at 150° C. to a dimethyl sulfoxide (17 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (271 mg, 0.838 mmol) and triethylamine (156 μl, 1.09 mmol), followed by stirring at the same temperature for 30 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with chloroform.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:18][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)OC(C)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (0.7 g., 80% w/w suspension in mineral oil) was added gradually to a stirred solution of 1-[4-(4-chlorophenyl)phenyl]ethanol (4.7 g.) in dry dimethylformamide (20 ml.), keeping the temperature below 40° C. After 30 minutes stirring ethyl 2-bromopropionate (2.6 ml.) was then added, keeping the temperature below 30° C. After stirring for 16 hours at room temperature, the mixture was poured into water (150 ml.), and the subsequent mixture was extracted with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated to give ethyl 2-{1-[4-(4-chlorophenyl)phenyl]ethoxy}propionate, as an oil (3.0 g.).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].C([O:8][C@@H:9]1[C@H:13]([O:14]C(=O)C)[C@@H:12]([CH2:18][O:19]C(=O)C)[O:11][C@H:10]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][C:26]([NH2:33])=[N:27][C:28]=2Cl)(=O)C.N>>[NH2:33][C:26]1[N:27]=[C:28]([NH:3][N:2]([CH3:4])[CH3:1])[C:29]2[N:30]=[CH:31][N:23]([C:24]=2[N:25]=1)[C@@H:10]1[O:11][C@H:12]([CH2:18][OH:19])[C@@H:13]([OH:14])[C@H:9]1[OH:8]
Reactant: CN(C)N
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Product: CN(C)Nc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 18.4 %

Procedure:
The title compound was prepared according to method A as described in example 4 by reacting 1,1-dimethylhydrazine (0.79 g, 13.1 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloro-9H-purine (4.0 g, 9.35 mmol) and debenzoylating the purified product using methanolic ammonia to provide the title 2-amino-N-(dimethylamino)adenosine (after column chromatography) as an amorphous foam (0.56 g, 45%), 1H NMR (DMSO-d6)γ 2.54 (6H, s, 2×--CH3), 3.50-3.57 (1H, m, H-5'b), 3.61-3.68 (1H, m, H-5'b), 3.93 (1H, q, H-4'), 4.12 (1H, q, H-3'), 4.51 (1H, q, H-2'), 5.12, 5.38 (2H, 2d, 2'- and 3'-OH), 5.42 (1H, t, 5'-OH), 5.76 (1H, d, H-1'), 5.95 (2H, s, --NH2), 7.93 (1H, s, H-8), 8.20 (1H, s, N-H).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=5)=[CH:26][C:25]=4F)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(C1C=CC(C2C=CN=CC=2)=C([F:51])C=1)#C>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]5[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=5)=[C:28]([F:51])[CH:29]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:16])([F:17])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(n2cc(-c3ccc(-c4ccncc4)cc3F)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Reactant: C#Cc1ccc(-c2ccncc2)c(F)c1
Product: O=C1C(n2cc(-c3ccc(-c4ccncc4)c(F)c3)nn2)CCc2c(F)cccc2N1CC(F)(F)F

Procedure:
The title compound was prepared by the same route as 6-fluoro-3-{4-[2-fluoro-4-(pyridin-4-yl)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one using 4-(4-ethynyl-2-fluorophenyl)pyridine as the alkyne.
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[C:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:4]([O:6]C)=[O:5].[OH-].[K+]>CO>[Cl:15][C:2]([Cl:1])=[C:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(=C(Cl)Cl)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=C(Cl)Cl)c1ccc(Cl)cc1
Temperature: 22.5 °C
Reaction time: 20 h

Procedure:
A solution of 17.1 g (64 mmol) of the ester of Example 3 in 50 ml of methanol was treated with 193 ml of 1 N KOH solution and then stirred for 20 hours at 20 to 25° C. After the solvent had been distilled off, the residue was acidified with 20% strength H2SO4 to pH 1 and extracted with ethyl acetate. The organic phases were dried and stripped from the solvent, whereupon 15 g of the title compound were isolated.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([O:18]C)=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:8]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:8]2)=[CH:26][CH:27]=1
Reactant: COCCOCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)O)cc12
Temperature: 40 °C

Procedure:
To a solution of methyl 1-(4-fluorobenzyl)-3-[(2-methoxyethoxy)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (542 mg 1.4645 mmol) in THF (10 mL) was added lithium hydroxide monohydrate (123 mg 2.929 mmol, 2 eq.) and water (5 mL) and the clear solution was warmed to 40° C. for 3 hours. THF was removed under vacuum and 1 M HCl added (2.93 mL 2.93 mmol, 2 eq.) the crude product was extracted into EtOAc (3×30 mL) then DCM:MeOH 100:5 (3×30 mL). The organics were dried (Na2SO4) volatiles were removed in vacuo to give the title product as a cream colored powder 400 mg (76%). LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, ESI, +mode): RT—1.753 min, m/e=359.1 (M+H+, base). 1H-NMR (300 MHz, CD3OD): δ=3.68 (s, 3H), 3.60 (m, 2H), 3.73 (m, 2H), 4.86 (s, 2H), 5.64 (s, 2H), 7.12 (m, 2H), 7.36 (m, 2H), 8.06 (s, 1H), 8.3 (s, 1H), 8.86 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:74]1[CH:79]=[CH:78][C:77](B2OC(C)(C)C(C)(C)O2)=[C:76]([CH3:89])[CH:75]=1)([C:55]1[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:63]([CH2:71][CH3:72])([O:66][Si:67]([CH3:70])([CH3:69])[CH3:68])[CH2:64][CH3:65])=[C:57]([CH3:73])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:77]2[CH:78]=[CH:79][C:74]([C:52]([CH2:53][CH3:54])([C:55]3[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:63]([CH2:71][CH3:72])([O:66][Si:67]([CH3:68])([CH3:69])[CH3:70])[CH2:64][CH3:65])=[C:57]([CH3:73])[CH:56]=3)[CH2:50][CH3:51])=[CH:75][C:76]=2[CH3:89])[CH:10]=1
Reactant: CCC(C#Cc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)(CC)O[Si](C)(C)C
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C#Cc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)c(C)c2)cc1C)(CC)O[Si](C)(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
(5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 27 mg, 0.118 mmol), palladium acetate (1.8 mg, 0.008 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (6.6 mg, 0.016 mmol), potassium phosphate (50 mg, 0.234 mmol) and water (0.2 mL) were added to a solution of 2-(4-{1-ethyl-1-[4-(3-ethyl-3-trimethylsilanyloxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 124-(3); 44 mg, 0.078 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for one hour. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (36.9 mg, 81%).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: COCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CCOC)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(O)ccc2C1
Yield: 36.3 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.5 mg) was obtained.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14](O)(=[O:17])[CH2:15][OH:16].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[OH:17][CH2:14][C:15]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:16]
Reactant: O=C(O)CO
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)CO)C(=O)OCC
Yield: 62.7 %

Procedure:
To a solution of diethyl 2-aminomalonate hydrochloride (4.2 g) and glycolic acid (1.6 g) in dimethylformamide is added triethylamine (2.12 g), and to the mixture are added 1-hydroxybenzotriazole (2.7 g) and N,N'-dicyclohexylcarbodiimide (4.33 g) with stirring under ice cooling. The mixture is reacted at 0° to 5° C. for 2 hours and further reacted at room temperature for 15 hours. The reaction mixture is concentrated under reduced pressure, and to the residue is added ethyl acetate, and the undissolved substance is filtered off. The filtrate is washed with aqueous sodium carbonate solution, dried and then the solvent is distilled off. The residue is purified by silica gel column chromatography [solvent: chloroform-ethyl acetate (2:1)] to give diethyl 2-[(hydroxyacetyl)amino]malonate (2.9 g), m.p. 74°-74.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].[OH-].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>CO>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH:16]=[CH2:15])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: Cc1ccc(O)c2c1CCC2=O
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCOc1ccc(C)c2c1C(=O)CC2

Procedure:
Into a solution of 36 g of 4-methyl-7-hydroxy-1-indanone and 17.6 g of potassium hydroxide in 650 ml of methanol was added 25 ml of allyl bromide, and the mixture was refluxed by heating for 6 hours. The insoluble matters in the reaction mixture were removed by filtration, then the solvent was removed by evaporation. The residue obtained was extracted with chloroform-water, and the chloroform layer was collected by separation, then the solvent was removed by evaporation. The residue thus obtained was washed with ether and purified by means of a column chromatography to obtain 32 g of 4-methyl-7-allyloxy-1-indanone.
Reaction SMILES: COC1C=C2C(CCC(=O)C2)=CC=1.C([O-])=O.[Na+].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.N[C@H](C(O)=O)C.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.[CH3:84][O:85][C:86]1[CH:95]=[C:94]2[C:89]([CH2:90][CH2:91][CH:92]([NH2:96])[CH2:93]2)=[CH:88][CH:87]=1>C(O)=O>[CH3:84][O:85][C:86]1[CH:95]=[C:94]2[C:89]([CH2:90][CH2:91][C@H:92]([NH2:96])[CH2:93]2)=[CH:88][CH:87]=1
Reactant: COc1ccc2c(c1)CC(N)CC2
Agent: COc1ccc2c(c1)CC(=O)CC2
Agent: C[C@H](N)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Solvent: O=CO
Product: COc1ccc2c(c1)C[C@@H](N)CC2

Procedure:
Into a flask containing 520 mg of a substrate 7-methoxy-2-tetralone, 10 mg of sodium formate, 3 mg of NAD+, 1.57 mg of L-alanine, and 20 mg of pyridoxal phosphate, a culture fluid of the recombinant E. coli HB101 (pNMTAPAF), obtained in Example 29, which expresses MTA, PALDH, and FDH was added so that total volume was 30 ml. The resultant product was stirred at 35° C. for 28 hours while being adjusted to a pH of 6.3 by drippage of 5 N aqueous solution of formic acid. The rate of conversion into 7-methoxy-2-aminotetraline after the reaction was 92.6%. The absolute configuration of 7-methoxy-2-aminotetraline was (S), and the optical purity was 98.1% e.e.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:19]([O-])=O)=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:6].[H][H]>CO.[C].[Pd]>[NH2:19][C:3]1[C:2]([OH:1])=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[O:6]
Reactant: [H][H]
Reactant: COc1ccc(NC(=O)c2cccc(O)c2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(NC(=O)c2cccc(O)c2N)cc1
Yield: 93.8 %

Procedure:
3-Hydroxy-4′-methoxy-2-nitrobenzanilide (1.15 g) was suspended in 50 ml of methanol, 300 mg of 10% palladium-carbon powder were added and the mixture was stirred in a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered through Celite and washed with methanol and the filtrate was concentrated in vacuo to give 966 mg of 2-amino-3-hydroxy-4′-methoxybenzanilide.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:12]1[CH:17]=[C:16]([I:18])[C:15]([CH3:19])=[CH:14][N:13]=1)[C:7]([CH:9]1[CH2:11][CH2:10]1)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:18][C:16]1[C:15]([CH3:19])=[CH:14][N:13]=[C:12]([NH:6][C:7]([CH:9]2[CH2:11][CH2:10]2)=[O:8])[CH:17]=1
Reactant: COc1ccc(CN(C(=O)C2CC2)c2cc(I)c(C)cn2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(NC(=O)C2CC2)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-N-(4-iodo-5-methylpyridin-2-yl)cyclopropanecarboxamide (1.8 g, 3.95 mmol) in DCM (23 mL) was added TFA. The reaction mixture was allowed to stir at rt overnight and then concentrated. The residue was diluted with DCM and aqueous saturated NaHCO3 and the mixture was extracted with DCM. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give N-(4-iodo-5-methylpyridin-2-yl)cyclopropanecarboxamide (1.0 g, 75%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:18][CH:16]1[CH2:15][N:14]([C:12]([N:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:6][CH2:7]2)=[O:13])[CH2:17]1)(=[O:22])=[O:21]
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a stirred solution of 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (100 mg, 0.395 mmol) in DCM (5 ml) at 0° C. was added TEA (120 mg, 1.2 mmol) and methansulphonyl chloride (110 mg, 0.94 mmol). The mixture was stirred for 2 h at RT, then diluted with DCM (15 ml) and washed with saturated NaHCO3 (10 ml). The organic layer was separated, dried (Na2SO4), filtered and concentrated providing the title compound as pale yellow solid (130 mg, 92%).
Reaction SMILES: Cl.[Sn](Cl)Cl.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:8]([N+:18]([O-])=O)[CH:7]=1.C(=O)(O)[O-].[Na+]>CO>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:8]([CH:7]=1)[NH2:18]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1N1CCCCC1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1cc(Cl)ccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
Concentrated hydrochloric acid (2.00 ml, 24.0 mmol) and anhydrous tin dichloride (1.84 g, 9.70 mmol) were sequentially added at 0° C. to a methanol (10 ml) solution of 1-(4-chloro-2-nitrophenyl)piperidine (471 mg, 1.95 mmol), obtained as described in Referential Example 15-1. The resulting mixture was warmed to room temperature and stirred for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture. The mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=9/1). Thus, 5-chloro-2-(1-piperidinyl)aniline (388 mg, 94.3%) was yielded as a colorless oily material.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.CCCCCC.CN([CH:23]=[O:24])C.[BH4-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.[NH4+].[Cl-]>[OH:24][CH2:23][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OCc1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 7 h
Yield: 67.1 %

Procedure:
Dissolve 2,5-dibromopyridine (10 g, 42 mmol) in toluene (500 mL) and cool to −78° C. Add 2.5M n-butyllithium in hexane (20.3 mL, 50.6 mmol) and stir the mixture for 7 h at the same temperature. Add DMF (4.2 mL, 54.87 mmol) and stir for 1 h. Warm the solution to 0° C. and add sodium borohydride (3.2 g, 84.42 mmol). Stir the mixture at ambient temperature for 3 h. Dilute with EtOAc and saturated aqueous NH4Cl. Separate the layers and extract the aqueous layer three times with EtOAc. Dry over anhydrous Na2SO4, filter and concentrate in vacuo. Recrystallization from hexane/EtOAc (9:1) gives the desired intermediate as a white solid (5.3 g, 66%).
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([NH:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])[CH2:10][O:9][C:8]([CH3:23])([CH3:22])[CH2:7]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+].C([O-])(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:24]([C@@H:6]1[CH2:7][C:8]([CH3:23])([CH3:22])[O:9][CH2:10][C@@H:11]1[NH:12][C:13](=[O:14])[O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[N+:25]=[N-:26]
Reactant: CC1(C)C[C@H](OS(C)(=O)=O)[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)C[C@@H](N=[N+]=[N-])[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Temperature: 25 °C
Yield: 118.1 %

Procedure:
To a solution of (4S,5S)-2,2-dimethyl-5-((2-(trimethylsilyl)ethoxy)carbonylamino)-tetrahydro-2H-pyran-4-yl methanesulfonate (1.6 g, 3.5 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (2.3 g, 35 mmol) and sodium acetate (2.8 g, 35 mmol) at room temperature. The resultant mixture was stirred at 95° C. for 2 days. After that, the mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed by water (100 mL×8) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (1.3 g, crude) as a yellow oil, which was directly used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[BH4-].[Na+].Cl>CO.C(O)(=O)C>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[CH:10][CH:9]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NCCCO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNCCCO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a solution of 3-amino-propan-1-ol (15.0 g, 200 mmol) in methanol (300 ml) was added para-methoxybenzaldehyde (28.6 g, 210 mmol) and a few drops of acetic acid at room temperature. The mixture was stirred at room temperature for 2 hours and cooled to 0° C. After the addition of sodium borohydride (11.4 g, 300 mmol), the mixture was stirred at room temperature for another 2 hours and acidified with 3N hydrochloric acid. The biphasic mixture was stirred at room temperature for 10 minutes. The organic solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous phase was washed with ethyl acetate and basified with 6N sodium hydroxide. Extraction with chloroform was performed and the organic phase was dried over sodium sulfate followed by concentration in vacuo to afford 3-(4-methoxy-benzylamino)-propan-1-ol as pale yellow oil (16.4 g, 42%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH2:6][CH:7]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH:21]3[CH2:23][CH2:22]3)[N:19]=2)[N:14](COCC[Si](C)(C)C)[CH:13]=1)=[O:11])[CH3:8])=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4]([CH2:6][CH:7]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH:21]3[CH2:22][CH2:23]3)[N:19]=2)[NH:14][CH:13]=1)=[O:11])[CH3:8])=[O:5])[CH3:2]
Reactant: CCNC(=O)CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)CC(C)NC(=O)c1c[nH]c2ncc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-ethylcarbamoyl-1-methyl-ethyl)-amide (0.114 g, 0.25 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was dissolved in MeOH (7 mL) and H2O (0.5 mL) and Et3N (1 mL) were added. The reaction mixture was stirred at room temperature overnight then concentrated. The residue was purified by SiO2 chromatography (4% MeOH/CH2Cl2) to afford 0.012 g (16%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-ethylcarbamoyl-1-methyl-ethyl)-amide as a white solid. MS: (M+H)+=316; mp=182.0-184.0.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29]1)[CH3:27]>>[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: CCN1CC[C@H](N)C1
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Product: CCN1CC[C@H](Nc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1

Procedure:
Prepared by proceeding in a similar manner to Example 77, starting from (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67) and (S)-1-ethylpyrrolidin-3-ylamine (Intermediate 194).