Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1S([O-])(=O)=O.[Na+].[NH2-:16].[Na+].N>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:16]
Reactant: O=S(=O)([O-])c1ccc2ccccc2c1
Reactant: [NH2-]
Agent: N
Agent: [Na+]
Product: Nc1ccc2ccccc2c1
Yield: 85.7 %

Procedure:
In a 200-ml autoclave were placed 27.4 grams (0.119 mole) of anhydrous sodium 2-naphthalene sulfonate, 10 grams (0.25 mole) of sodium amide and 80 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 120° C for 10 hours. The reaction pressure in the autoclave was 90 atm. during the reaction. After the ammonia was removed, 15 ml of water was added to the reaction mixture for hydrolysis. The product was extracted with ether and the ether was distilled off to produce crude 2-naphthylamine. Recrystallization from methanol gave 14.6 grams of 2-naphthylamine having a melting point of 111° to 112° C. Yield was 85.7%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH2:23][NH:22][CH2:21][CH2:20]3)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH2:23][N:22]([CH3:30])[CH2:21][CH2:20]3)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1CCc1ccc2c(c1)CCNC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCc2cc(CCn3ccc(OCc4ccccc4)cc3=O)ccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 170 mg (0.47 mmol) 4-benzyloxy-1-[2-(1,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1H-pyridin-2-one (example 27.2) in 5.0 mL THF is added 57 μL (0.71 mmol) aqueous 37% formaldehyde solution. The mixture is acidified with 3 drops of acetic acid and then 150 mg (0.71 mmol) sodium triacetoxy-borohydride is added. The reaction mixture is stirred 2 h at RT, poured into aqueous 10% Na2CO3-solution and the layers are separated. The aqueous phase is extracted with tert-butylmethylether, the combined organic phase is washed a few times with water, dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:18](=[O:44])[N:19]([CH3:43])[CH:20]=[C:21]([C:23]3[C:24]([CH3:42])=[C:25]([NH:29][C:30]([C:32]4[S:36][C:35]5[C:37](=[O:41])[CH2:38][CH2:39][CH2:40][C:34]=5[CH:33]=4)=[O:31])[CH:26]=[CH:27][CH:28]=3)[N:22]=2)=[CH:12][CH:11]=1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:18](=[O:44])[N:19]([CH3:43])[CH:20]=[C:21]([C:23]3[C:24]([CH3:42])=[C:25]([NH:29][C:30]([C:32]4[S:36][C:35]5[CH:37]([OH:41])[CH2:38][CH2:39][CH2:40][C:34]=5[CH:33]=4)=[O:31])[CH:26]=[CH:27][CH:28]=3)[N:22]=2)=[CH:12][CH:11]=1
Reactant: Cc1c(NC(=O)c2cc3c(s2)C(=O)CCC3)cccc1-c1cn(C)c(=O)c(Nc2ccc(C3C(=O)N(C)CCN3C)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(NC(=O)c2cc3c(s2)C(O)CCC3)cccc1-c1cn(C)c(=O)c(Nc2ccc(C3C(=O)N(C)CCN3C)cc2)n1
Temperature: 0 °C
Yield: 88 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 17 (250 mg, 0.409 mmol) and methanol (10 mL). The resulting solution was cooled to 0° C., and sodium borohydride (31 mg, 0.819 mmol) was added. After stirring the reaction at room temperature for 2 h, the solvent was evaporated under reduced pressure. The resulting residue was purified by flash chromatography to afford 18 in 88% yield (220 mg) as a white solid: mp 165-166° C.; 1H NMR (500 MHz, CD2Cl2) δ 8.38 (s, 1H), 7.90 (d, 1H, J=7.5 Hz), 7.81 (d, 2H, J=8.5 Hz), 7.71 (s, 1H), 7.39 (s, 1H), 7.34-7.27 (m, 4H), 6.80 (s, 1H), 4.94 (m, 1H), 3.72 (td, 1H, J=11.5, 4.5 Hz), 3.65 (s, 1H), 3.62 (s, 3H), 3.21 (m, 1H), 3.01 (m, 1H), 2.95 (s, 3H), 2.76-2.62 (m, 3H), 2.43 (s, 3H), 2.22-2.13 (m, 5H), 2.02 (m, 1H), 1.83 (m, 2H); MS (ESI+) m/z 595.2 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([C:29]([F:32])([F:31])[F:30])=[C:21]3[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][C:22]=23)=[O:17])=[CH:9][C:8]=1[CH2:33][CH3:34])C>C1COCC1.CO.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:28][C:25]1([CH3:27])[CH2:24][CH2:23][C:22]2=[C:18]([C:16](=[O:17])[CH2:15][CH2:14][C:10]3[CH:11]=[C:12]([CH3:13])[C:7]([CH2:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([CH2:33][CH3:34])[CH:9]=3)[S:19][C:20]([C:29]([F:32])([F:30])[F:31])=[C:21]2[CH2:26]1
Reactant: CCOC(=O)CCc1c(C)cc(CCC(=O)c2sc(C(F)(F)F)c3c2CCC(C)(C)C3)cc1CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(CCC(=O)c2sc(C(F)(F)F)c3c2CCC(C)(C)C3)cc(C)c1CCC(=O)O
Yield: 64.2 %

Procedure:
A solution of 3-{4-[3-(5,5-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2-ethyl-6-methyl-phenyl}-propionic acid ethyl ester (340 mg, 0.668 mmol) in THF (5 mL), methanol (4 mL) and 2 N aq. LiOH (2 mL) is stirred at rt for 2 h before it is diluted with 10% aq. citric acid solution and extracted with DCM (3×75 mL). The combined organic extracts are dried over MgSO4, filtered and the solvent of the filtrate is evaporated. The crude product is purified on prep. TLC plates with heptane:EA 3:4 to give 3-{4-[3-(5,5-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2-ethyl-6-methyl-phenyl}-propionic acid (206 mg) as a colourless glass; LC-MS: tR=1.17 min, [M+1]=481.36.
Reaction SMILES: O[C:2]1[C:11](O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.BrCCBr>>[CH:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cc2ccccc2cc1O
Solvent: BrCCBr
Product: c1ccc2ccccc2c1

Procedure:
contacting 2,3-dihydroxy naphthalene with 1,2-dibromoethane in the presence of base under conditions suitable to produce an ethylenedioxy derivative of naphthalene,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([SH:10])=[N:9][C:5]=2[CH:4]=1.Cl.Cl[CH2:15][C:16]1[C:21]([CH3:22])=[C:20]([S:23][CH2:24][CH2:25][C:26]2[S:30][CH:29]=[N:28][C:27]=2[CH3:31])[CH:19]=[CH:18][N:17]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([S:10][CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([S:23][CH2:24][CH2:25][C:26]4[S:30][CH:29]=[N:28][C:27]=4[CH3:31])[CH:19]=[CH:18][N:17]=3)=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c(S)nc2c1
Reactant: Cc1ncsc1CCSc1ccnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2[nH]c(SCc3nccc(SCCc4scnc4C)c3C)nc2c1

Procedure:
Following the procedure described in Example 1, the reaction of 5-methoxy-2-mercapto-1H-benzimidazole with 2-chloromethyl-3-methyl-4-[2-(4-methyl-5-thiazolyl)ethylthio]pyridine hydrochloride and aqueous sodium hydroxide solution gives the title compound as a yellow oil, from which a hydrochloride salt of the title compound is obtained as a colorless powder of m.p. 165° C (decomp.) by following the procedure described in Example 4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]#[C:8][CH2:9][CH2:10][OH:11])=[CH:3][CH:2]=1>CO.[Pt](=O)=O>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:3][CH:2]=1
Reactant: OCCC#Cc1ccncc1
Agent: O=[Pt]=O
Solvent: CO
Product: OCCCCc1ccncc1
Reaction time: 2.5 h
Yield: 83.4 %

Procedure:
4-(4-Pyridyl)-3-butyn-1-ol (3.5 g) was dissolved in methanol (100 mL) in a Parr hydrogenation bottle and platinum (IV) oxide [Adams' Catalyst] (0.3 g) was added. The Parr bottle was placed on a Parr hydrogenation apparatus and the solution hydrogenated at 40 psi for 2.5 h after which time the starting material had been judged to be consumed by TLC. The spent catalyst was removed by filtration through a Celite pad and the pad carefully washed with more methanol. The combined filtrates were evaporated under reduced pressure on a rotary evaporator and the oily residues then subjected to column chromatography on a short silica column using neat ethyl acetate as the eluant to provide the title compound (3.0 g).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[SH:16][C:17]1[S:21][C:20]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:19][N:18]=1>>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:16][C:17]2[S:21][C:20]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:19][N:18]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCCCCSc1nnc(S)s1
Product: CCCc1c(CSc2nnc(SCCCCCC(=O)OCC)s2)ccc(C(C)=O)c1O
Yield: 92.4 %

Procedure:
Using as starting materials 0.30 g of 4-acetyl-3- hydroxy-2-propylbenzyl chloride and 0.46 g of ethyl 6-[(5- mercapto-1,3,4-thiadiazol-2-yl]thio]hexanoate, 0.59 g of oily ethyl 6-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4- thiadiazol-2-yl]thio]hexanate was obtained in a manner similar to Example 9.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>>[CH3:24][C:10]1[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:13]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)[CH:3]=2)[N:9]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccnc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.21) (0.392 g, 1.00 mmol) and commercially available 3-pyridineboronic acid (0.122 g, 0.99 mmol) according to the general procedure VI. Obtained as a white solid (0.080 g, 27%). MS (ISP) 391.1 [(M+H)+]; mp 89-106° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH:18]=C)=[CH:17][C:12]=3[C:11]3=[N:20][CH:21]=[N:22][N:10]3[C:9]2=[O:23])=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:27].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O.C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH:18]=[O:27])=[CH:17][C:12]=3[C:11]3=[N:20][CH:21]=[N:22][N:10]3[C:9]2=[O:23])=[CH:24][CH:25]=1
Reactant: C=Cc1cnc2c(c1)c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C=O)cnc32)cc1
Reaction time: 4 h
Yield: 103.5 %

Procedure:
6-(4-Methoxybenzyl)-9-vinylpyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 30, 3.96 g, 11.9 mmol) was suspended in THF (80 mL) and heated with a heat gun to effect dissolution. Similarly, sodium periodate (5.84 g, 27.3 mmol) was heated in water (40 mL) to effect dissolution. The above solutions were combined with vigorous stirring. While the stirred mixture was still at 40° C., osmium(VIII) oxide in ten-butanol (2.90 mL, 2.5%, 0.30 mmol) was added and the mixture was stirred vigorously for 4 h. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (3×150 mL) and DCM (3×150 mL). The combined organic layers were dried (MgSO4) and concentrated to afford the title compound (4.13 g, 99%) as a black solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.77 (s, 3H), 5.80 (s, 2H), 6.83 (d, J=8.66 Hz, 2H), 7.61 (d, J=8.66 Hz, 2H), 8.41 (s, 1H), 9.10 (d, J=2.13 Hz, 1H), 9.26 (d, J=2.13 Hz, 1H), 10.21 (s, 1H). [M+H]=336.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(N(CC)CC)C.C(N=C=NC(C)C)(C)C>C1COCC1.CN(C=O)C>[CH:15]1([N:18]2[C:11](=[O:12])[C:6]3=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[C:7]3[C:8]2=[O:10])[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1C1CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
4-Nitrophthalic anhydride (5.60 g, 28.9 mmol) was dissolved in THF (50 mL), and cyclopropylamine (2.10 mL, 30 mmol) was added slowly while stirring under an inert atmosphere. After 30 min, a suspension was obtained. Triethylamine (8.2 mL, 60 mmol) and diisopropylcarbodiimide (5.50 mL, 35 mmol) were added followed by DMF (100 mL). The reaction mixture was then heated to 70° C. for 48 hours. The mixture was cooled to room temperature and the reaction volume was reduced to one-tenth of the original volume by rotary evaporation in vacuo. The precipitated N,N′-diisopropylurea was removed by filtration, and water (40 mL) was added to the mother liquor resulting in formation of a precipitate. The precipitate was collected by filtration and dried overnight in a vacuum oven to give 6.02 g (90%) of N-cyclopropyl-4-nitrophthalimide.
Reaction SMILES: [C:1]([NH:4][C:5](=[C:11]([NH2:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].C([BH3-])#N.[Na+].Cl>CO.CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2>[C:1]([NH:4][CH:5]([CH:11]([NH2:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)=C(C)N
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCOC(=O)C(NC(C)=O)C(C)N
Reaction time: 2 h

Procedure:
After dispersing 0.043 mol of ethyl 2-acetamido-3-aminobut-2-enoate in 25 ml of methanol together with 0.043 mol of sodium cyanoborohydride and a few drops of 0.04% bromcresol green indicator, the reaction mixture was cooled in ice, and 2M methanolic hydrochloric acid was added until the yellow color stabilized. The ice bath was removed, and the reaction was stirred for two hours, after which the solvent was removed and the reaction mixture worked up to provide ethyl 2-acetamido-3-aminobutyrate as a slightly greenish oil containing a 2.5/1 molar ratio of threo and erythro diastereomers.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:8][O:9][CH3:10])[NH:5][C:6]=1I.[O-]S([O-])=O.[Na+].[Na+]>C(O)C.O>[I:1][C:2]1[NH:3][C:4]([CH2:8][O:9][CH3:10])=[N:5][CH:6]=1
Reactant: COCc1nc(I)c(I)[nH]1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCc1ncc(I)[nH]1
Temperature: 90 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 4,5-diiodo-2-(methoxymethyl)-1H-imidazole (compound 230.3, 2 g, 5.50 mmol) in ethanol (40 mL). A solution of Na2SO3 (5.9 g, 46.83 mmol) in water (80 mL) was added to the reaction. The reaction mixture was stirred overnight at 90° C. The resulting mixture was concentrated under reduced pressure. The residue was extracted with 3×20 mL of dichloromethane and the organic layers combined and concentrated under reduced pressure. This resulted in 1 g (76%) of the title compounds as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=1.[NH2:31][C:32]1[C:33]([C:39](O)=[O:40])=[N:34][C:35]([Br:38])=[CH:36][CH:37]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:31][C:32]1[C:33]([C:39]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[CH:9]=[C:10]([N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[N:11]=[C:12]([S:14][CH3:15])[N:13]=2)=[O:40])=[N:34][C:35]([Br:38])=[CH:36][CH:37]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: CSc1nc(-c2ccncc2N)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CSc1nc(-c2ccncc2NC(=O)c2nc(Br)ccc2N)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 30 %

Procedure:
Method 27 was followed using 6-(3-aminopyridin-4-yl)-N,N-di-BOC-2-(methylthio)pyrimidin-4-amine (1.0 equiv.), 3-amino-6-bromopicolinic acid (1.0 equiv), EDC (1.0 equiv.), and HOAt (1.0 equiv.) in DMF yielding 3-amino-6-bromo-N-(4-(6-(di-BOC-amino)-2-(methylthio)pyrimidin-4-yl)pyridin-3-yl)picolinamide in 30% yield. LCMS (m/z): 632.1/634.0 (MH+); LC Rt=4.55 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27]>N1C=CC=CC=1.C(Cl)Cl>[C:26]([NH:30][C:31]([N:21]1[CH2:22][CH2:23][CH2:24][C@@H:19]([CH2:18][NH:17][C:15]2[C:14]([F:25])=[CH:13][N:12]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[NH:8][CH:9]=3)[N:16]=2)[CH2:20]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N=C=O
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NC[C@@H]1CCCNC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)NC(=O)N1CCC[C@@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)pyrimidin-4-amine, 12a, (0.013 g, 0.036 mmol) in mixture of pyridine/CH2Cl2 (1 mL of 1:1 mixture was added tert-butyl isocyanate (0.005 mL, 0.046 mmol). The reaction mixture was stirred at 40° C. for 12 h. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 20.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[O:37][N:36]=[C:35]([CH2:38][O:39][CH3:40])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:40][O:39][CH2:38][C:35]1[N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[O:37][N:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: COCc1noc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (6.41 g; compound B50) is reacted with 5-(chloromethyl)-3-(methoxymethyl)-1,2,4-oxadiazole (2.44 g; compound D14) in the presence of potassium carbonate (2.07 g) in DMF (45 ml). Using WU1 a solid is obtained which is dissolved in EtOAc (400 ml) at 65° C. The solvent is removed in vacuo to a volume of 40 ml at 40° C. To this solution 20 ml of diethyl ether is added at RT and the resulting suspension is filtered off and the filter cake is washed with little amounts of EtOAc and diethyl ether. The solid is dried in vacuo at 60° C. for 1 h to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=O)[CH2:5][CH2:4][N:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:14]([NH:21]CC1C=CC=CC=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl.CO>ClC(Cl)C.CO>[CH2:14]([NH:21][CH:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]([CH3:1])[CH2:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCOC(=O)N1CCC(NCc2ccccc2)CC1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of ethyl 2-methyl-4-oxopiperidine-1-carboxylate (2.20 grams, 11.9 mmol) and benzyl benzylamine in dichloroethane/methanol (4:1, 50 mL) was heated over 3 Å molecular sieves at 90° C. for 16 hours. The reaction mixture was cooled to 0° C., and sodium triacetoxy borohydride (5.03 g, 23.8 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes and then was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. The residue was taken up in aqueous 1N HCl solution and washed with ether (2×50 mL). The pH of the aqueous phase was adjusted to a pH of approximately 7 with 1M aqueous sodium bicarbonate solution. The aqueous phase was back extracted twice with ether (4×50 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (94:6) gave 1.57 g (47% yield) of a yellow oil.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7])=[N-].O.[C:10]1([S:16]([OH:19])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[O:8]=[C:4]([CH2:5][CH2:6][CH3:7])[CH2:3][O:19][S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(O)c1ccccc1
Reactant: CCCC(=O)C=[N+]=[N-]
Solvent: O
Solvent: CCOCC
Product: CCCC(=O)COS(=O)(=O)c1ccccc1
Yield: 77.2 %

Procedure:
A 1.2 g quantity of 1-diazo-2-pentanone is dissolved in 50 ml of ether, and 2.3 g of benzenesulfonic acid monohydrate is slowly added to the solution at room temperature. The same procedure as in Example 1 is thereafter followed to give 2.0 g of 2-oxopentylbenzene sulfonate in the form of a colorless transparent oil (Compound 6). Yield 77.2%.
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].ClC1C=CC=C(C(OO)=[O:22])C=1>CO.C(OCC)(=O)C>[S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][N+:9]([O-:22])=[CH:8][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NS(=O)(=O)c1cc2cnccc2o1
Solvent: CO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cc2c[n+]([O-])ccc2o1
Reaction time: 18 h
Yield: 83 %

Procedure:
To a warm (40° C.) solution of 2-sulfamoylfuro[3,2-c]pyridine (2.68 g, 13.5 mmol) in methanol (30 ml) and ethyl acetate (10 ml) was added dropwise a solution of m-chloroperbenzoic acid (3.22 g, 15 mmol) in ethyl acetate (13 ml). The reaction mixture was stirred for 18 hours as product precipitated. The pure product was collected by filtration and crystallized from hot dimethyl sulfoxide by dilution with ethanol to give 2.4 g (83% yield), m.p. 247°-248° C.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34](Cl)[O:35][CH:36]=2)=[O:31])[CH3:28])[CH:18]=[C:19]([F:26])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:19]1[CH:18]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[O:35][CH:36]=2)=[O:31])[CH3:28])[CH:16]=[C:15]([F:14])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cccc3ccccc23)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 29.4 %

Procedure:
1-Naphthaleneboronic acid (44.7 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (18 mg, 29%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).