Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(N(CC)CC)C>C(#N)C.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.[Cu]I>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[C:8]1[CH:7]=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:1]#[CH:2]
Reactant: C#Cc1ccc(OC)cc1
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#Cc1ccc(OC)cc1-c1nccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
The alkyne of the current example, 2-(2-thiazolyl)-4-methoxyphenylacetylene was prepared by adding to a degassed solution of 4 mmol of 4-ethynylanisole, 4 mmol of 2-bromothiazole, and 1 ml of triethylamine in 10 ml of acetonitrile, 140 mg (0.2 mmol) of PdCl2(PPh3)2 and 19 mg(0.1 mmol) of CuI. The mixture was degassed and stirred for 5 minutes at RT and heated to 90° C. for 12 hours. The reaction mixture was concentrated in vacuo and purified by silica column to afford 0.61 g of brown liquid in a 70% yield.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[C:21](Cl)([Cl:23])=[S:22].[Cl-].[Ca+2].[Cl-]>O.C(Cl)(Cl)Cl>[Cl:23][C:21]([O:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)=[S:22]
Reactant: N#Cc1ccc(SC(=O)c2ccc(O)cc2)cc1
Reactant: S=C(Cl)Cl
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccc(SC(=O)c2ccc(OC(=S)Cl)cc2)cc1
Reaction time: 2 h

Procedure:
A solution of 566 mg of sodium hydroxide in 5 ml of water was added dropwise with vigorous stirring to a solution of 3.00 g of S-(4-cyanophenyl) 4-(hydroxy)thiobenzoate and 1.35 ml of thiophosgene in 60 ml of chloroform. Stirring was continued for 2 hours when the filtered solution was treated with calcium chloride and stirred for a further 30 minutes. Evaporation of the filtered solution gave 3.66 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:25])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([O:20][CH2:21][C:22](O)=[O:23])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].N12CCCN=C1CCCCC2>CN(C)C=O.O>[CH3:38][S:39]([NH:42][C:22](=[O:23])[CH2:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:25])(=[O:41])=[O:40]
Reactant: CS(N)(=O)=O
Reactant: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)NS(C)(=O)=O)cccc12)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 4 h
Yield: 38.3 %

Procedure:
A solution of (R)-[3-(2-(tert-butoxycarbonylamino)propyl)-1H-indol-7-yloxy]acetic acid (0.30 g, 0.86 mmol) and carbonyldiimidazole (0.21 g, 1.3 mmol) in dimethylformamide (10 mL) is stirred at room temperature for 3 days. To the mixture are added methanesulfonamide (0.16 g, 1.7 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (0.26 mL, 1.7 mmol), and the mixture is stirred at 50° C. for 4 hours. After cooling, to the mixture is added water (0.1 mL), and the mixture is concentrated. The residue is purified by silica gel column chromatography (methanol/chloroform=1/10→1/3), and the resultant is dissolved in ethyl acetate, washed with a 0.05N hydrochloric acid (×2) and saturated brine, and further dried over magnesium sulfate and concentrated to give the desired tert-butyl (R)-{2-[7-(2-methanesulfonylamino-2-oxo-ethoxy)-1H-indol-3-yl]-1-methylethyl}carbamate (0.14 g, yield: 38%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1>>[Cl:37][C:38]1[CH:43]=[C:42]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH:41]=[CH:40][CH:39]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)N5CCCCC5)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(C(=O)N4CCCCC4)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 5, from {4-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-piperazin-1-yl}-piperidin-1-yl-methanone (example 14) and 3-chlorophenylboronic acid to afford the desired product as a light-brown foam (49%). MS (ISP): 605.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1.[CH3:25][CH2:26][O:27]CC.C(Cl)(=O)C>O>[C:26]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:27])[CH3:25]
Reactant: CCOCC
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCCC2
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)Nc1sc2c(c1C(=O)c1ccccc1)CCCC2

Procedure:
To a mixture of 35 g of 2-amino-3-benzoyl-4,5,6,7-tetrahydrobenzo[b]thiophene, 35 g of pyridine and 1950 ml of anhydrous ether is added dropwise 35 g of acetyl chloride. Then the reaction mixture is stirred under reflux for 3 hours. After cooling, the reaction mixture is poured into water. The ether layer is separated and washed with water, and dried over sodium sulfate. The solvent is removed under reduced pressure to give an oily residure, which is crystallized from ether to give 2-acetylamino-3-benzoyl-4,5,6,7-tetrahydrobenzo[b]thiophene having a melting point of 116° - 119°C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=CC(C(O)=O)=[C:4](C)[CH:3]=1.B.[CH2:13]1[CH2:17][O:16][CH2:15][CH2:14]1.CO>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:13]([CH2:17][OH:16])[CH:14]=[CH:15][C:3]=1[CH3:4]
Reactant: C1CCOC1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: B
Solvent: CO
Product: Cc1ccc(CO)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 4-chloro-2-methylbenzoic acid (800 mg, 4.69 mmol) in THF (8 mL) that was cooled at 0° C., BH3THF (14 mL, 1M in THF) was added into the solution drop wise. The mixture was then stirred at r.t. overnight. Add methanol to the system at 0° C. slowly until no gas released. Remove the solvent and the residue was extracted with ethylacetate, concentrated the organic phase to give 894 mg of the title compound (85%). 1H NMR (400 MHz, CDCl3): δ 2.36 (3H, s), 4.63 (2H, s), 7.13-7.22 (2H, m), 7.35 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH3:14]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH2:10][C:11]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(Cl)nc2)O1
Reactant: N
Product: NC(=O)CCC(O)c1ccc(Cl)nc1
Temperature: 45 °C

Procedure:
3.6 g of 5-(6-chloropyridin-3-yl)tetrahydrofuran-2-one (prepared as described in Example 15) was dissolved in 30 ml of 25 percent aqueous ammonia solution and the mixture was heated at 45° C. for 1.5 hours. The solution was evaporated in vacuo. The oily residue (4.65 g) was dried in vacuo over phosphorus pentoxide. The product yield was 3.9 g (approximately 100%) of rubber-like product. Other data concerning the product was:
Reaction SMILES: Cl.[N:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]3)[C:6]=12.[C:17]1([N:23]2[CH:27]=[N:26][C:25]([C:28](O)=[O:29])=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][C:28]([C:25]4[N:26]=[CH:27][N:23]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:24]=4)=[O:29])[CH2:12]3)[C:6]=12
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CCN(c2nccn3ccnc23)C1)c1ncn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a suspension of the above (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine hydrochloride salt (84 mg, 0.3 mmol) and 1-phenyl-1H-1,2,4-triazole-3-carboxylic acid (57 mg, 0.3 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (120 mg, 0.31 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solutions of KH2PO4 and NaHCO3, followed by brine. The organic layer was concentrated in vacuo and the residue purified by silica gel flash chromatography (2 to 5% MeOH in CH2Cl2 as eluent) followed by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) to give 60 mg of the title compound (54% yield) as white solid. MS: (ES) m/z calculated for C19H18N8O [M+H]+ 375.2, found 375.2.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[O:24][CH3:25])[C:6]2[C:11](=[O:12])[NH:10][N:9]=[CH:8][C:7]=2[NH:13][C:14]=1[CH3:15])(=[O:3])[CH3:2].ClCCl.F[B-](F)(F)F.[CH2:34]([O+](CC)CC)[CH3:35].CO>O>[C:1]([C:4]1[CH:5]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[O:24][CH3:25])[C:6]2[C:7]([NH:13][C:14]=1[CH3:15])=[CH:8][N:9]=[N:10][C:11]=2[O:12][CH2:34][CH3:35])(=[O:3])[CH3:2]
Reactant: CC[O+](CC)CC
Reactant: COc1cc(C#N)ccc1C1C(C(C)=O)=C(C)Nc2cn[nH]c(=O)c21
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCOc1nncc2c1C(c1ccc(C#N)cc1OC)C(C(C)=O)=C(C)N2
Reaction time: 2 h

Procedure:
65 mg (0.193 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydropyrido[2,3-d]pyridazin-4-yl)-3-methoxybenzonitrile are mixed under an argon atmosphere with 4 ml of abs. dichloromethane and 73.4 mg (0.386 mmol) of triethyloxonium tetrafluoroborate. After a reaction time of 2 hours at room temperature (reaction check by HPLC), conversion remains incomplete. Two further equivalents of triethyloxonium tetrafluoroborate are added. After a further reaction time of 3 h, the mixture is mixed with 5 ml of methanol and 0.5 ml of water and again stirred for 2 h. It is then diluted with 20 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 8 mg (11.3% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:42])(=[O:41])/[CH:30]=[CH:31]/[C:32]1[CH:40]=[CH:39][C:37]([OH:38])=[C:34]([O:35][CH3:36])[CH:33]=1.C(OC(C)C)(C)C>CO>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:42])(=[O:41])/[CH:30]=[CH:31]/[C:32]1[CH:40]=[CH:39][C:37]([OH:38])=[C:34]([O:35][CH3:36])[CH:33]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CO
Solvent: CC(C)OC(C)C
Product: COc1cc(/C=C/C(=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sitagliptin free base (0.5 gms) and ferulic acid (0.25 gms) were dissolved in methanol (3 ml) at 60° C. to 65° C. and the solution was cooled to room temperature. Isopropyl ether (25 ml) was added to the clear solution and stirred for 2 hours. Filtered the precipitated solids and allowed for suck dry for 30 minutes to obtain the title compound. Yield: 0.42 gms.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24](O)=[O:25])=[C:12]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].Cl>O1CCCC1.CN(C)C=O.COCCOC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([CH2:24][OH:25])=[C:12]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cn1c(C(=O)O)c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: C1CCOC1
Product: CC(C)Cn1c(CO)c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of 6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (4.90 g, 11 mmol) in tetrahydrofuran (50 mL) were added oxalyl chloride (1.1 mL, 13.2 mmol) and N,N-dimethylformamide (3 drops), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (30 mL). The obtained solution was added dropwise to a suspension of sodium tetrahydroborate (1.46 g, 38.5 mmol) in 1,2-dimethoxyethane (30 mL) at 0° C. The obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 6-benzyloxy-4-(2-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone (4.38 g, 92.4%) as crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C:22]1[N:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CCNC(=O)OC(C)(C)C)N1CCC(=O)CC1
Reactant: N#Cc1cccc(CN)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(CCNC(=O)OC(C)(C)C)N1CCC(NCc2cccc(C#N)n2)CC1
Yield: 77 %

Procedure:
Using general procedure A, [3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (0.361 g, 1.34 mmol), 6-aminomethyl-pyridine-2-carbonitrile (0.178 g, 1.34 mmol), sodium triacetoxyborohydride (0.425 g, 2.01 mmol) and acetic acid (0.2 ml, cat.) in CH2Cl2 (15 ml) at rt for 16 h gave the crude product as a pale yellow oil. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 86:12:2, v/v/v) afforded (3-{4-[(6-cyano-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.400 g, 77%) as a colorless oil. 1H NMR (CDCl3) δ 0.93 (d, 3H, J=6.0 Hz), 1.40 (s+m, 13H), 1.65 (m, 1H), 1.92 (m, 2H), 2.13 (br t, 1H, J=9.0 Hz), 2.45 (m, 2H), 2.69-2.81 (m, 3H), 3.07 (m, 1H), 3.30 (m, 1H), 3.97 (s, 2H), 5.95 (br s, 1H), 7.56 (d, 1H, J=9.0 Hz), 7.59 (d, 1H, J=9.0 Hz), 7.77 (t, 1H, J=7.5 Hz).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C@@H:4]([C:7]2[C:8]([N+:21]([O-:23])=[O:22])=[CH:9][C:10]([Cl:20])=[C:11]([NH:13]C(=O)C(F)(F)F)[CH:12]=2)[CH2:3]1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C.O>[NH2:13][C:11]1[CH:12]=[C:7]([C@@H:4]2[CH2:5][NH:6][C:2](=[O:1])[CH2:3]2)[C:8]([N+:21]([O-:23])=[O:22])=[CH:9][C:10]=1[Cl:20]
Reactant: O=C1C[C@H](c2cc(NC(=O)C(F)(F)F)c(Cl)cc2[N+](=O)[O-])CN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc([C@@H]2CNC(=O)C2)c([N+](=O)[O-])cc1Cl
Temperature: 50 °C
Yield: 55.4 %

Procedure:
To a solution of N-(5-((3R)-5-oxopyrrolidin-3-yl)-2-chloro-4-nitrophenyl)-2,2,2-trifluoroacetamide (8.7 g, 24.7 mmol) in 48 mL of ethanol was added 9 mL of 4N NaOH aqueous solution. The mixture was then heated to 50° C. for 3 h. The reaction mixture was diluted with ethyl acetate (100 mL) and water (50 mL). The layers were separated. The organic layer was dried over Na2SO4 and concentrated in vacuo to provide the title compound (3.5 g, 57% yield). MS (ESI) m/z 256.03 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][N:20]=2)[C:14]([O:16]C)=O)[C:7]1=[O:21].[C-:26]#[N:27].[Na+]>N1C=CC=CC=1CN>[CH2:26]([NH:27][C:14](=[O:16])[C:13]1[CH:18]=[CH:19][N:20]=[C:11]([N:8]2[CH2:9][CH2:10][N:6]([CH2:5][C:4]3[CH:22]=[CH:23][C:24]([F:25])=[CH:2][CH:3]=3)[C:7]2=[O:21])[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)c(F)c3)C2=O)c1
Reactant: [C-]#N
Agent: NCc1ccccn1
Agent: [Na+]
Product: O=C(NCc1ccccc1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 116.8 %

Procedure:
A solution of methyl 2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate (0.25 g, 0.72 mmol) and sodium cyanide (0.10 g, 2.04 mmol) in pyridin-2-ylmethanamine (3.0 mL) was stirred at 95° C. for 16 hours and concentrated in vacuo. The residue was purified by column chromatography eluted with 0 to 90% of ethyl acetate in dichloromethane to give N-benzyl-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-isonicotinamide as a colorless solid (0.17 g, yield 54%): mp 99-101° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.74 (t, J=6.0 Hz, 1H), 8.62 (s, 1H), 8.49-8.47 (m, 1H), 8.39 (d, J=5.1 Hz, 1H), 7.76-7.70 (m, 1H), 7.44-7.22 (m, 5H), 7.19-7.15 (m, 1H), 4.54 (d, J=6.0 Hz, 2H), 4.39 (s, 2H), 3.96 (t, J=8.1 Hz, 2H), 3.38 (t, J=8.1 Hz, 2H); MS (ES+) m/z 423.8 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:12]=[C:11]([S:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>C(O)CC>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[S:13][C:11]1[N:12]=[C:5]2[NH:2][N:3]=[C:7]([NH2:8])[C:6]2=[CH:9][CH:10]=1
Reactant: NN
Reactant: N#Cc1ccc(Sc2ccc(F)cc2F)nc1Cl
Solvent: CCCO
Solvent: O
Product: Nc1n[nH]c2nc(Sc3ccc(F)cc3F)ccc12
Temperature: 80 °C
Yield: 39.1 %

Procedure:
0.561 mL (11.57 mmol) of hydrazine monohydrate is added under nitrogen to a stirring solution of 1.09 g (3.86 mmol) of 2-chloro-6-(2,4-difluorophenylthio)nicotinonitrile in 15 mL of propanol. The reaction medium is heated at 80° C. for 4 hours. A precipitate is obtained when the reaction medium is returned to room temperature. This precipitate is filtered and rinced with ethanol. The solid is dissolved in an ethyl acetate fraction and washed with a 1N HCl solution. The organic phase is dried on magnesium sulfate and dry evaporated to yield 420 mg (39%) of 6-(2,4-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-amine in the form of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11](OC([O-])=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1ccccc1CN
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: C1CCOC1
Product: COc1ccccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
2-Methoxybenzylamine (13.0 g) was dissolved in 80 ml of tetrahydrofuran, and then a solution of 16 g of t-butyl dicarbonate in tetrahydrofuran (20 ml) was added thereto. The mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated. The residue was dissolved in ethyl acetate and successively washed with 1N hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated to give 19.0 g of the title compound.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[C:4]1=2.[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27]Br)([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C.C(Cl)(Cl)Cl.CC(O)C>[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:4]2[S:3][CH:7]=[CH:6][C:5]=2[CH:8]=[CH:9][CH:10]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Oc1ccccc1-c1cccc2ccsc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCOc1ccccc1-c1cccc2ccsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
Add sodium hydride (424 mg, 18 mmol) to a solution of 2-benzo[b]thiophen-7-yl-phenol (1 g, 4.4 mmol) in 10 mL of DMF. Stir the mixture at RT for 1 h and add (2-bromo-ethyl)-carbamic acid tert-butyl ester (2 g, 8.9 mmol). Continue to stir the reaction mixture for another 4 h at RT. Dilute the mixture with chloroform-IPA (3:1, 100 mL). Wash the organic phase with aqueous saturated sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo. Purify the residue by column chromatography (20% ethyl acetate in hexane) to give the title compound as a pale yellow solid (1.4 g, 86%). MS (ES) m/z 392 [M+Na]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[NH2:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[N:20][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[NH2:15][C:16]1[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[N:18][CH:19]=[N:20][CH:21]=1
Reactant: Nc1cncnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ncncc2N)C1
Temperature: 150 °C
Yield: 39.3 %

Procedure:
tert-butyl ((3S)-1-(5-amino-4-pyrimidinyl)-3-piperidinyl) carbamate. A mixture of (S)-tert-butyl piperidin-3-ylcarbamate (486 mg, 2.42 mmol), 5-amino -4-chloropyrimidine (262 mg, 2.02 mmol, Magical Scientific, Atchison, Kans.) and Cs2CO3 (988 mg, 3.03 mmol) in 2 mL of DMF was heated in a microwave at 150° C. for 45 min. The mixture was diluted with 50 mL of EtOAc and filtered through a pad of Celite. The filtrate was washed with 5 mL saturated NH4Cl (aq.) followed by 5 mL of brine. The organic solution was concentrated and purified by silica gel chromatography (60-100% EtOAc in hexanes) to give tert-butyl ((3S)-1-(5-amino-4-pyrimidinyl)-3-piperidinyl)carbamate (233 mg, 39% yield, 90% purity). This material used without further purification. MS (ESI, pos. ion) m/z: 294.2 (M+1).