Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12].F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25].[OH-].[Li+].O>CS(C)=O.ClCCl>[N+:24]([C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12])([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: N#Cc1c(N)sc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: N#Cc1c(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])sc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
Combine 2-amino-benzo[b]thiophene-3-carbonitrile (3.48 g, 20.0 mmol), 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (4.31 g, 20.0 mmol), and lithium hydroxide (0.958 g, 40.0 mmol) in anhydrous dimethylsulfoxide (50 mL), and heat at 55° C. for 2 hours. Cool to ambient temperature, pour into a beaker filled with ice/deionized water (50 mL), and stir for 30 minutes. Add deionized water and dichloromethane and then separate the organic layer. Extract the aqueous layer with dichloromethane many times. Then wash the organics with deionized water (3×). Combine the washes and back extract them with dichloromethane. Wash the organics with a saturated solution of sodium chloride, and back extract the combined washes with dichloromethane. Dry (sodium sulfate), filter, and concentrate the organics under reduced pressure to a residue. After triturating the residue with methanol, isolate the resulting solid by suction filtration, wash with methanol, and dry at ambient temperature under reduced pressure to give the title compound (4.61 g). Concentrate the filtrate under reduced pressure and purify by flash chromatography, eluting with a gradient of ethyl acetate: dichloromethane: hexane (0.25:5:5, 0-100% in hexane) to give the title compound (0.53 g). Total solid: 5.14 g (70.8%). NMR (1H, 300 MHz, CDCl3), δ (ppm): 10.26 (s, 1H), 8.63-8.56 (m, 1H), 7.93-7.85 (m, 1H), 7.84-7.75 (m, 2H), 7.64-7.45 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15]([F:18])[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([O:23]CC)=[O:22])=[CH:9]1.O.Cl>C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15]([F:18])[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1
Reactant: CCOC(=O)c1cn(-c2ccncc2F)c2cc(F)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn(-c2ccncc2F)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
5 g of ethyl 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate is added with 20 ml of water, 30 ml of ethanol and 15 ml of conc. hydrochloric acid and refluxed for 8 hours. After cooling to room temperature and standing for 2 hours, filtering and drying are carried out to obtain 4.2 g of the desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH2:13][C:12](=O)[NH:11][C:10]3[N:16]([CH3:20])[N:17]=[C:18]([CH3:19])[C:9]2=3)=[C:4]([CH3:21])[CH:3]=1.BrC1C=CC(C=O)=C(C)C=1.CN1C(N)=CC(C)=N1.[Li]CCCC.[C:45](=[O:47])=[O:46]>C1COCC1>[CH3:20][N:16]1[C:10]2[NH:11][CH2:12][CH2:13][CH2:14][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:45]([OH:47])=[O:46])=[CH:3][C:4]=3[CH3:21])[C:9]=2[C:18]([CH3:19])=[N:17]1
Reactant: O=C=O
Reactant: Cc1cc(Br)ccc1C1CCC(=O)Nc2c1c(C)nn2C
Agent: Cc1cc(Br)ccc1C=O
Agent: Cc1cc(N)n(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1C1CCCNc2c1c(C)nn2C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-(4-bromo-2-methylphenyl)-1,3-dimethyl-4,5,6,8-tetrahydropyrazolo[3,4-b]azepin-7(1H)-one (0.143 g, 0.41 mmol, prepared using W from 4-bromo-2-methylbenzaldehyde (Ark Pharm, Inc), X from 1,3-dimethyl-1H-pyrazol-5-amine, Y, Z, then AA) in dry THF (20 mL) was cooled to about −78° C. under nitrogen. A solution of n-BuLi (0.66 mL, 1.64 mmol) (2.5M in THF) was added dropwise maintaining the reaction temperature below about −70° C. The mixture was stirred for about an additional 10 min at about −78° C. and then a stream of CO2 generated from dry ice was bubbled through the solution for about 15 min. Cooling was removed and the reaction was allowed to warm to rt. The reaction was concentrated to solids and then acidified with 2N HCl (2 mL) and extracted with EtOAc (2×10 mL). The EtOAc extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica gel using a gradient of 0-10% MeOH in DCM. Product fractions were combined and concentrated in vacuo and dried on vacuum pump to yield 4-(1,3-dimethyl-1,4,5,6,7,8-hexahydropyrazolo[3,4-b]azepin-4-yl)-3-methylbenzoic acid as an off white solid (0.055 g, 0.18 mmol, 53%); LC-MS (Table 1, Method g) Rt=1.37 min, m/z 312 (M−H)−. The carboxylate was used in the next step without further manipulation.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[S:28][C:27]([CH:29]=[O:30])=[N:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:31][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[S:28][C:27]([CH:29]([OH:30])[CH3:31])=[N:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: C[Mg]Br
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(C=O)s3)[nH]2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)[nH]2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of 5-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazole-2-carbaldehyde (700 mg) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (1M tetrahydrofuran solution) (3.46 mL) and the mixture was stirred at room temperature for 10 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (460 mg, yield 63%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). MS: 462 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]23[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]3=O)[N:3]=[CH:2]1.O.NN.[OH-].[K+]>O>[CH:9]1[C:8]2[CH2:7][C:6]3([C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1c2ccccc2C2CCCCC12c1c[nH]cn1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)CC1(c3c[nH]cn3)CCCCC21
Temperature: 190 °C

Procedure:
9a-(1H-Imidazol-4-yl)-1,2,3,4,4a,9a-hexahydrofluoren-9-one (2.5 g) was mixed with di(ethylene glycol) (50 ml), hydrazine hydrate (7.2 ml) and KOH (9.5 g). The mixture was heated at 150° C. for 30 minutes and at 190° C. for 4 hours. After cooling to the ambient temperature the reaction mixture was diluted with water (150 ml) and extracted with CH2Cl2 (4×50 ml). The organic phase was washed with water (30 ml). The organic phase was mixed with water (200 ml) and the pH was adjusted to 1 with concentrated HCl solution. The layers were separated and the aqueous phase was washed with CH2Cl2 (2×30 ml). The aqueous phase was mixed with CH2Cl2 (150 ml) and the pH was adjusted to 11.5-13.5 with 48% NaOH solution. The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×30 ml). The combined organic phases were washed with water (50 ml), dried over Na2SO4 and evaporated. The yield was 1.4 g.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31](N(C(NC)=O)CCCC3CCCCC3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[O-2:48].[Al+3].[O-2:50].[O-2].[Al+3]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([O:48][C:5]([NH:6][CH:7]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:8]3)=[O:50])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(CCCC3CCCCC3)C(=O)NC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [O-2]
Agent: [Al+3]
Product: CCCCc1nc2ccc(OC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-6-(N-methylaminocarbonyl-N-(3-cyclohexyl-n-propyl)-amino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.15 (aluminium oxide: petroleum ether/ethyl acetate=2:3)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([N:15]([CH3:17])[CH3:16])=[N:13][N:14]=[C:7]1[NH:6][C:5]2=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[CH:33][CH2:34]Cl)[CH:27]=1>COCCOC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([N:15]([CH3:16])[CH3:17])=[N:13][N:14]=[C:7]1[N:6]([CH2:34][CH:33]=[CH:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)[C:5]2=[O:18]
Reactant: ClCC=Cc1cccnc1
Reactant: CN(C)c1nnc2[nH]c(=O)c3cc(Br)ccc3n12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CN(C)c1nnc2n(CC=Cc3cccnc3)c(=O)c3cc(Br)ccc3n12
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
In a reactor equipped with magnetic shaker and refrigeration, we resuspend 7.4 g (0.024 mol) of 7-bromo-1-(N,N-dimethylamino)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one in 200 ml de 1,2-dimethoxyethane then we shake. We add 17.0 g (0.052 mol) of cesium carbonate then shake at ambient temperature for 15 minutes. 4.5 g (0.024 mol) of 3-(3-pyridyl)-allyl chloride hydrochloride are then added by fraction, then the mixture is heated to 70° C., under shaking, for 3 hours. The solvent is evaporated under vacuum then the residue is then put in suspension in 300 ml of iced water. After repeated extractions with ethyl acetate, the joined organic phases are washed with aqueous solution saturated with sodium chloride, dried on sodium sulfate then the solvent is evaporated under vacuum.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1>C1(C)C=CC=CC=1>[C:1]([O:9][CH2:1][CH2:2][CH2:7][CH3:6])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1cccnc1
Temperature: 116 °C
Reaction time: 6 h
Yield: 192.3 %

Procedure:
N-butanol (133.2 g, 1.8 mol), nicotinic acid (73.8 g, 0.6 mol) and toluene (45.0 g) were charged to a 450 mL pressure reactor kettle equipped with mechanical stir, a pressure take-out trap, and a thermocouple. The reactor was sparged with nitrogen and heated to 116° C., sealed, then heated to 220° C. and held for 6 hours. The mixture was then removed from the reaction kettle and volatiles removed under vacuum on a rotary evaporator at 60° C. The product was then filtered through celite on a Buchner funnel. 103.4 g product was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@H:20]([C:24](O)=[O:25])[CH2:21][CH2:22][CH2:23][N:16]2[C:15](=[O:27])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:53][CH2:54][C:55]([C:57]1[CH:62]=[CH:61][C:60]([Br:63])=[CH:59][CH:58]=1)=[O:56].CCN(C(C)C)C(C)C>[Cl-].[Na+].O.O.CN(C=O)C>[Br:63][C:60]1[CH:61]=[CH:62][C:57]([C:55](=[O:56])[CH2:54][NH:53][C:24]([C@H:20]2[N:17]3[C:18](=[O:19])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:13][CH2:14][C:15](=[O:27])[N:16]3[CH2:23][CH2:22][CH2:21]2)=[O:25])=[CH:58][CH:59]=1
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)NCC(=O)c3ccc(Br)cc3)N2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.9 %

Procedure:
In a 50 ml, round-bottomed flask, (1S,9S)-9-(benzyloxycarbonylamino)-6,10-dioxo octahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid (1 g, 2.66 mmol) was combined with DMF (15 ml) to give a colorless solution. HATU (1.01 g, 2.66 mmol) was added and stirred at room temperature for 10 min. 2-Amino-1-(4-bromophenyl)ethanone HCl (666 mg, 2.66 mmol, Eq: 1.00) and DIPEA (1.03 g, 1.4 ml, 7.99 mmol) were added and stirred at room temperature overnight. The reaction mixture was diluted with brine and H2O and extracted with EtOAc (2×60 ml). The organic layers were combined, washed with brine (2×20 mL), H2O (2×50 mL), dried with MgSO4 and concentrated in vacuo. The crude product was purified on a silica gel column (CH2Cl2, 2%, 3%, 5%, 6%, 8% MeOH/CH2Cl2) to afford benzyl (4S,7S)-4-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate as a light yellow solid (1.2 g, 78.8%). ESI-LRMS m/e calcd for C26H27BrN4O6 [M+] 571. found 572 [M+H+].
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]/[I:17])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>O1CCCC1>[I:17]/[CH:16]=[CH:15]/[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CCCOc1ccccc1/C=C/I
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCCCOc1ccccc1/C=C/I
Temperature: 0 °C
Yield: 54.3 %

Procedure:
A solution of 250 mg of 4-[2-[(E)-2-iodovinyl]-phenoxy]butyric acid ethyl ester in 5 ml of tetrahydrofuran is instilled into a suspension of 80 mg of lithium aluminum hydride at 0° C. with stirring and under argon atmosphere. Then, it is stirred for an hour with ice cooling, the mixture is decomposed under argon atmosphere with ice water, shaken out with diethyl ether, dried (Na2SO4) and concentrated by evaporation. 120 mg of 4-[2-[(E)-2-iodovinyl]-phenoxy]-butan-1-ol is obtained as a yellow oil, which is further reacted as a crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH3:24])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH2:27][CH2:26]1>>[CH2:23]([O:22][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:34]([CH2:33][CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)(=[O:36])=[O:35])=[CH:7][C:6]=1[C:8]1[NH:9][C:10](=[O:21])[C:11]2[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=2[N:13]=1)[CH3:24]
Reactant: O=S(=O)(Cl)CCCN1CCOCC1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(N)ccc3OCC)nc12
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(NS(=O)(=O)CCCN4CCOCC4)ccc3OCC)nc12

Procedure:
The title compound was prepared form 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one and 3-morpholinopropylsulphonyl chloride, following the procedure of Example 41, and was obtained as brown crystals (14%), m.p. 157°-159° C. Found: C,55.42; H,6.53; N,16.01. C24H34N6O5S requires C,55.58; H,6.61; N,16.21%.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH2:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:31])=[N:13][N:12]=1>CN(C=O)C>[Cl:31][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:30])[C:24]=1[CH2:23][C:14]1[C:15]2[C:20](=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][N:13]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Oc3ccccc3)c2c1
Temperature: 25 °C
Yield: 43 %

Procedure:
A suspension of DMF (15 ml), phenol (0.53 g, 5.64 mmoles) and NaH (4.23 mmoles) was stirred under dry N2 at room temperature. After 15 minutes 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.5 g, 1.41 mmoles), prepared as described in example 45, was dropped and the temperature brought to 100° C. After 20 hours the mixture was partitioned between water and CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give a residue which was triturated in ethyl ether. The insoluble was flash chromatographed (eluent: hexane/ethyl acetate 7:3) to give a solid which was crystallised from isopropyl ether (15 ml) and yielded 0.25 g of the title compound (yield: 49%). m.p.: 130-132° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:36]([NH:40][NH2:41])(=[O:39])[CH2:37][CH3:38]>O1CCCC1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:41][NH:40][C:36](=[O:39])[CH2:37][CH3:38])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
To a solution of the carboxylic acid of Example 9 or 16 (6b, 354 mg, 1.28 mmol) in tetrahydrofuran (10 mL) were added triethylamine (0.216 mL) and isobutyl chloroformate (208 μl) under ice-cooling, followed by agitating at 0° C. for 15 minutes. To the reaction solution were added a solution of propionohydrazide (161 mg, prepared following a procedure analogous to Reference Example 3 and Reference Example 6) in tetrahydrofuran (3 mL) at 0° C., followed by stirring at room temperature for 1 hour, and then concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-0/1) to afford 425 mg of the title compound (yield 96%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[O:30]CC1C=CC=CC=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].O1CCCC1>[C:1]([O:5][C:6](=[O:38])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[OH:30])(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1O
Yield: 98.3 %

Procedure:
11.4 g (20.7 mmol) (S)-3-(4-Acetylamino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester, 1 g 20% Pd/C, and 100 mL tetrahydrofuran was shaken under a 50 psi hydrogen atmosphere for 19 h. TLC analysis indicated incomplete reaction, so an additional 1 g 20% Pd/C was added and the reaction shaken an additional 20 h under a 50 psig hydrogen atmosphere. TLC showed complete reaction. The catalyst was filtered and the resulting solution was concentrated to give an oil. The product was purified over silica eluting with ethyl acetate to yield 9.37 g (20.34 mmol, 98.3%) of (S)-3-(4-acetylamino-2-hydroxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester as an ivory-yellow solid. MS (APCI) m/z 459.1 (M−1).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:25])[C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[C:12](Br)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:45]=[C:44]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[C:43](B4OC(C)(C)C(C)(C)O4)=[CH:42][C:36]=3[C:37]=2[C:38]([NH:40][CH3:41])=[O:39])=[CH:29][CH:28]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([NH:8][C:9](=[O:25])[C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[C:12]([C:43]2[C:44]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])=[CH:45][C:35]3[O:34][C:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[C:37]([C:38](=[O:39])[NH:40][CH3:41])[C:36]=3[CH:42]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1nc(Br)ccc1OCc1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)NCc4ccccc4)n3)cc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a solution of N-benzyl-3-(benzyloxy)-6-bromopicolinamide (107 mg, 0.27 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (prepared according to previous patents, 117 mg, 0.23 mmol) and K3PO4.3H2O (187 mg, 0.70 mmol) in dioxane/H2O (3 mL) were added Pd2(dba)3 (11 mg, 0.01 mmol) and X-Phos (11 mg, 0.03 mmol) under N2. The mixture was stirred at 110° C. for 1 hour. Then it was filtered and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (DCM:MeOH=50:1) to afford the product of N-benzyl-3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinamide (100 mg, yield: 61.7%). 1H-NMR (CD3OD, 400 MHz) δ 7.91˜7.94 (m, 2H), 7.83 (s, 1H), 7.77 (s, 1H), 7.67˜7.72 (m, 2H), 7.43˜7.45 (m, 2H), 7.29˜7.33 (m, 5H), 7.20˜7.24 (m, 5H), 5.23 (s, 2H), 4.54 (s, 2H), 3.15 (s, 3H), 2.89 (s, 3H), 2.87 (s, 3H). MS (M+H)+: 693.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[NH:37]1[CH:41]=[N:40][C:39]([NH2:42])=[N:38]1.C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:42][C:39]3[N:40]=[CH:41][NH:37][N:38]=3)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Reactant: Nc1nc[nH]n1
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)Nc4nc[nH]n4)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and 1H-1,2,4-triazol-3-amine using diethyl cyanophosphonate as a coupling reagent. Mass: 575.13 (M+H).