Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:28](O)=[O:29])[CH3:27])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C>[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:28]([N:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@@H:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:29])[CH3:27])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1CC2CCCCC2N1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC2CCCCC2N1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 10.0 g of ethyl octahydroindole-2-carboxylate (prepared in as shown in paragraph A of this example) in 400 ml of ethyl acetate add 17.0 g of N-benzyloxycarbonyl-(S)-alanine, N-hydroxysuccinimide ester. Stir the reaction mixture at room temperature for 20 hours and concentrate it in vacuo. Place the residue on a column of silica gel (3000 g, 60-200 mesh) and elute with chloroform:ethyl acetate 10:1 to give 1-[N-benzyloxycarbonyl-(S)-alanyl]octahydroindole-2(R)-carboxylic acid, ethyl ester, a colorless oil [α]D26 +22.0° (ethanol) and 1-[N-benzyloxycarbonyl-(S)alanyl]octahydroindole-2(S)-carboxylic acid, ethyl ester, a colorless oil [α]D26 -96.4° (ethanol).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH2:9][C:10]#[N:11])=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.Cl[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1>C1COCC1>[C:7](=[N:8][CH:9]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1)[C:10]#[N:11])([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccnc2ccccc12
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC(Cc1ccnc2ccccc12)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
To N-(Diphenylmethylene) aminoacetonitrile (0.360 g, 1.633 mmol) in 10 ml of anhydrous THF and HMPA (hexamethyl phosphoramidite) (0.38 ml, 2.12 mmol), at −78° C., LDA (2.0 M, 1.06 ml, 2.12 mmol) was added dropwise over a period of 5 minutes. The color of solution turns from colorless to yellow to dark brown. It was then stirred at −78° C. for one hour. 4-Chloromethylquinoline (0.29 g, 1.63 mmol) was added dropwise over a period of 5 minutes and the reaction mixture was slowly brought to room temperature over a period of five minutes. The reaction mixture was quenched by addition of ice and partitioned between EtOAc (20 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered concentrated and column purified (hexanes:EtOAc; 3.5:1.5) to give 0.155 g (26%) of the product as a syrup, which was used as such for the subsequent step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[C:16](=[N:18][OH:19])[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][NH:22][C:23]([NH2:25])=[S:24].Cl>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[N:21][NH:22][C:23]([NH2:25])=[S:24])[C:16](=[N:18][OH:19])[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=NO)C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Product: CC(=NO)C(=NNC(N)=S)c1ccc(OCc2ccccc2)cc1
Yield: 66.7 %

Procedure:
A mixture of 4'-benzyloxy-2-hydroxyiminopropiophenone (21.1 g), thiosemicarbazide (7.15 g), methanol (107 ml) and a saturated solution of hydrogen chloride in methanol (2 ml) was refluxed for 65 minutes with stirring. After cooling, the resultant precipitates were collected by filtration, washed successively with methanol, water and methanol, and then dried to give 17.9 g of 4'-benzyloxy-2-hydroxyiminopropiophenone thiosemicarbazone.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[C:14]([Cl:31])[CH:13]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[K+].O>C(O)C>[Cl:31][C:14]1[CH:13]=[C:12]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:17]=[CH:16][C:15]=1[CH2:18][CH:19]1[CH2:23][CH2:22][N:21]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[C:20]1=[O:30]
Reactant: CCOC(=O)c1ccccc1-c1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccccc1-c1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.2 %

Procedure:
Dissolve 3′-chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-2-carboxylic acid ethyl ester (Preparation 81) (287 mg, 0.65 mmol) in ethanol (10 mL) and add KOH (370 mg, 6.5 mmol). Stir at room temperature for 3 days. Pour into water and extract with ether. Acidify the aqueous layer to pH 1. Extract with ether. Dry over sodium sulfate, filter and concentrate to yield 220 mg (82%) of the title compound as a pale yellow solid: Mass spectrum (apci) m/z=410.3 (M−H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:20]1[CH2:22][O:21]1)[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:23].[Na+].C[Si](C)(C)Cl>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH:20]([OH:21])[CH2:22][I:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: O=C(N[C@@H](CC1CCCCC1)C1CO1)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CC#N
Product: O=C(N[C@@H](CC1CCCCC1)C(O)CI)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
42.3 g of (1(S)-benzyloxycarbonylamino-2-cyclohexyl-ethyl)-oxirane are taken up in 200 ml of acetonitrile and the resulting solution is cooled to 0°. After the addition of 20.9 g of sodium iodide, there are added dropwise at 0°, over a period of 30 minutes, 17.7 ml of trimethylchlorosilane. The mixture is stirred at 0°-3° for 40 minutes and then poured onto 700 ml of ice-cold water. The aqueous mixture is extracted with ether, and the organic phase is washed with 750 ml of 5% aqueous sodium thiosulphate solution and 750 ml of saturated, aqueous sodium chloride solution. After drying over sodium sulphate and concentrating by evaporation, an oily mixture of the title compound is obtained which is further processed directly.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.S1C(CN)=CC2C=CC=CC1=2.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][N:31]([C:34]2[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=2)[C:30](=[O:43])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][N:31]([C:34]2[S:35][C:36]([C:40]([NH:8][CH2:7][C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:41])=[C:37]([CH3:39])[N:38]=2)[C:30](=[O:43])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: Cc1ccc(CN)s1
Agent: NCc1cc2ccccc2s1
Product: Cc1ccc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)s1
Yield: 43 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (5-methylthiophen-2-yl)methanamine in replace of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 43% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.82 (t, J=5.8 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 7.45-7.30 (m, 5H), 6.73 (d, J=3.3 Hz, 1H), 7.59-6.57 (m, 1H), 6.38 (dd, J=8.1, 2.7 Hz, 1H), 6.22 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.43 (d, J=5.8 Hz, 2H), 2.53 (s, 3H), 2.34 (s, 3H); MS (ES+) m/z 452.1 (M+1).
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:15]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([CH:13]=[O:14])=[C:4]1[CH:1]([CH3:3])[CH3:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1[nH]c2ccccc2c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1c(C=O)c2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-isopropyl-1H-indole-3-carbaldehyde (Compound 39, 1.19 g, 6.4 mmol) in DMF (6.0 ml) was added benzyl bromide (1.5 ml, 12.8 mmol) and K2CO3 (2.65 g, 19.2 mmol). The mixture was stirred at room temperature for 24 h and was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 0-30% EtOAc-hexanes to yield 1-benzyl-2-isopropyl-1H-indole-3-carbaldehyde (Compound 40) as a light brown solid.
Reaction SMILES: [C:1]([C:4]1[S:12][C:11]2[CH:10]=[N:9][C:8]([NH:13][C:14]3[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[CH:15]=3)=[N:7][C:6]=2[C:5]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][C:42]([F:45])([F:44])[F:43])(=[O:3])[NH2:2].[ClH:46]>C(OCC)(=O)C>[ClH:46].[NH:25]1[CH2:24][CH2:23][CH:22]([C:16]2[CH:15]=[C:14]([NH:13][C:8]3[N:9]=[CH:10][C:11]4[S:12][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[O:41][C:42]([F:43])([F:44])[F:45])[C:6]=4[N:7]=3)[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=2)[CH2:27][CH2:26]1
Reactant: CC(C)n1nc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Nc1ncc2sc(C(N)=O)c(-c3ccccc3OC(F)(F)F)c2n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)n1nc(C2CCNCC2)cc1Nc1ncc2sc(C(N)=O)c(-c3ccccc3OC(F)(F)F)c2n1
Reaction time: 0.5 h

Procedure:
220 mg of 2-methylpropan-2-yl 4-[5-({6-carbamoyl-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidin-2-yl}amino)-1-(propan-2-yl)-1H-pyrazol-3-yl]piperidine-1-carboxylate are added to 5 ml of a 1N solution of hydrochloric acid in ethyl acetate at a temperature of about 20° C. and the mixture is left to stir for 30 minutes. A further addition of 3 ml of the 1N acid solution is carried out and the mixture is left to stir for 15 h. After concentration of the mixture under reduced pressure, a solid is obtained which is washed successively with dichloromethane and then with ether. The solid is dried under reduced pressure, so as to obtain 139 mg of 2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:15][CH:16]=[O:17])[CH:5](O)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:7].S(Br)(Br)=O.[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:15][CH:16]=[O:17])/[CH:5]=[C:6](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[CH2:7][P:23]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:30]
Reactant: CCOP(OCC)OCC
Reactant: C=C(c1ccccc1)C(O)C(NC=O)C(=O)OC
Agent: O=S(Br)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOP(=O)(C/C(=C/C(NC=O)C(=O)OC)c1ccccc1)OCC

Procedure:
By reaction of the 2-formylamino-3-hydroxy-4-phenyl-4-pentenoic acid methyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1, and after chromatography (silica gel; ethyl acetate/hexane 4:1), E-2-formylamino-4-phenyl-5-diethylphosphono-3-pentenoic acid methyl ester is obtained in the form of a colourless oil. 1H-NMR (CDCl3): 2.98 (d, 2H,C(5)-H); 5.03 (dd, 1H, C(2)-H); 5.77 (dd, 1H, C(3)-H).
Reaction SMILES: [OH:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][NH:12][C:11]1=[O:16])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:17][C:18]([F:27])([F:26])[C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N>O1CCCCO1.[Cu]I>[OH:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:27])([F:26])[F:17])=[CH:20][CH:21]=2)[C:11]1=[O:16])[C:3]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4]
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCNC1=O
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: [Cu]I
Agent: C1CCOOC1
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Product: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCN(c2ccc(C(F)(F)F)cc2)C1=O
Temperature: 115 °C
Yield: 58.8 %

Procedure:
(R)-tert-butyl 2-hydroxy-2-((R)-3-oxomorpholin-2-yl)acetate (0.5 g, 0.002162 mol) and 4-trifluoromethylphenyl iodide (0.882 g, 1.5 eq) were dissolved in 1,2-dioxane (14 ml), to this mixture were added CuI (82 mg, 0.2 eq), K2CO3 (598 mg, 2 eq), and trans-N,N-dimethylcyclohexane-1,2-diamine (0.1 ml, 0.3 eq). The resulting solution was degassed and heated at 115° C. for 5 hours. The mixture was cooled to rt, the solid removed by filtration, solution washed with water, dried (MgSO4), and concentrated. The resulting residue was then purified by silica gel chromatography (0-20% EtOAc in hexane) to give 477 mg of compound 93-1.
Reaction SMILES: [CH3:1][NH2:2].Br[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]>C(O)C.O>[CH3:1][NH:2][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNc1cncc(C(=O)O)c1

Procedure:
The intermediate methyl 5-methylamino-nicotinate has been obtained as follows: reaction of methylamine (40% in water) with 5-bromo-nicotinic acid in autoclave at 140° C. for seven hours gives 5-methylamino-nicotinic acid, m.p. 239°-242° C. from ethanol/water; this acid reacts with SOCl in methanol under reflux for seven hours to afford the ester (methyl 5-methylaminonicotinate; m.p. 113°-115° C., from petroleum ether.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[NH:4][N:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>N1C=CC=CC=1>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[NH:1][C:25](=[O:27])[CH3:26])(=[O:13])=[O:14])(=[O:23])=[O:22]
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(N)c2c1
Solvent: c1ccncc1
Product: CC(=O)Nc1n[nH]c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12

Procedure:
N-[5-(2-Methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl)-acetamide can be obtained as described in Example 28 from 0.5 g of N-(3-amino-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide, 3 ml of pyridine and 98 μl of acetyl chloride. 338 mg of N-[5-(2-methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl)-acetamide are thus obtained in the form of a white solid which decomposes at approximately 145° C. (analysis C16H16N4O5S2 % calculated C, 47.05; H, 3.95; N, 13.72; O, 19.59; S, 15.7. % found C, 46.96; H, 4.27; N, 13.23; S, 14.91).
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[C:13](=O)([O-])O.[Na+]>CO.O>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(N)c1N

Procedure:
A solution of 2,3-diaminobenzoic acid (0.2 g, 1.32 mmol) in methanol (40 ml) was saturated with hydrogen chloride as described above, and the mixture was subsequently heated under reflux for 2 hours. The solid residue obtained on evaporation of the solvent was dissolved in water, and the solution was adjusted to pH 7.0 with sodium hydrogen carbonate. After extraction with ethyl acetate (2×30 ml), the combined organic layers were dried (MgSO4), and the solvent was removed to give methyl 2,3-diaminobenzoate as a brown oil which solidified on trituration with petrol (40/60) (121.6 mg, 56%), m.p. 62-63° C. Found: C, 58.35; H, 5.80; N, 16.69. C8H10N2O2 requires C, 57.83; H, 6.02; N, 16.87%; δH (d6 -DMSO), 200 MHz) 3.87 (3H, s, OCH3). 4.90 (2H, br s, Ar-2-NH2), 6.32 (2H, br s, Ar-3-NH2), 6.46-6.54 (1H, t, Ar-5H), 6.80-6.84 (1H, dd, Ar-4H), 7.18-7.23 (1H, dd, Ar-6H); m/z (EI) 166 (M+), 134, 106, 79.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[CH2:16][C@H:17]([NH:19]C(=O)OC(C)(C)C)[CH3:18]>>[NH2:19][C@H:17]([CH3:18])[CH2:16][N:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:14]1
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1Cl
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Product: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Yield: 17 %

Procedure:
The title compound was prepared with the Mitsunobu reaction using the method of Example 3(c) starting from 2-chloro-4-(1H-pyrazol-5-yl)-benzonitrile (2.00 g, 9.82 mmol) and (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (1.893 g, 10.80 mmol). After Boc removal and workups 0.434 g (17%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 0.97 (d, 3H), 2.96 (m, 2H), 4.15 (m, 2H), 6.98 (d, 1H), 7.86 (d, 1H), 7.92-8.00 (m, 2H), 8.11 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[P:14]([O-:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOP([O-])OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Product: CCOP(=O)(OCC)C1(O)CCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
A mixture of 1.9 g (10.3 mmol) of 1-tert-butoxycarbonyl-3-oxopyrrolidine (from Step B), 1.3 mL (10.3 mmol) of diethyl phosphite and 1.4 mL (10.3 mmol) of TEA was stirred at 100° C. for 1.5 h. Volatiles were removed under reduced pressure. The residue was purified on a 40M Biotage column using 13:7 v/v hexane/acetone as the eluant to afford 1.78 g (53%) of the title compound as a yellow oil: RF: 0.16 (7:3 v/v hexane/acetone); 1H-NMR (500 MHz) δ 1.33 (t, J=7.0, 6H), 1.45 (s, 9H), 2.08 (m, 1H), 2.18 (m, 1H), 3.47-3.64 (m, 4H), 4.13-4.22 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]=1[O:8]CC1C=CC=CC=1.Cl>[Pd].C(O)C>[CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]=1[OH:8]
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1[nH]ccc(=O)c1O
Reaction time: 4 h
Yield: 67.2 %

Procedure:
1.00 g (2.68 mmol) of 2-methyl-3-benzyloxypyridine-4(1H)-one of dimethylene xylitol compound is put into a mixture of 10 mL ethanol—2 mL H2O; then 0.08 g of Pd/C at 10% is added, and the pH of the solution is adjusted to pH=1 with a solution of concentrated HCl. The reaction medium is then subjected to catalytic hydrogenolysis under agitation at room temperature for 4 hours. At the end of this hydrogenolysis, the reaction medium is filtered. Then, 25 mL of water is added to the residue, and the solution is neutralized by addition of an aqueous solution of soda. The reaction medium is extracted with 2×20 mL of dichloromethane; the organic phases are collected, dried on sodium sulphate, filtered, and evaporated under reduced pressure; 509 mg (1.80 mmol) of 2-methyl-3-hydroxypyridine-4(1H)-one of dimethylene xylitol is isolated, which is pure at chromatographic and NMR analyses. Yield: 67%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C1(C)C(C)=CC=CC=1>O>[C:13]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH:6]([CH3:12])[C:7]1=[O:11])(=[O:15])[CH3:14]
Reactant: CC1C(=O)Nc2cc(Br)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(=O)N1C(=O)C(C)c2ccc(Br)cc21

Procedure:
To 6-bromo-3-methyl-1,3-dihydro-2H-indol-2-one (11.2 g) were added acetic anhydride (12 ml) and xylene (120 ml), and the mixture was refluxed for 5 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate solution was washed successively with water, a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (9.5 g) as a red solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([S:10]([OH:13])(=[O:12])=[O:11])[CH:9]=1)(=[NH:3])[NH2:2].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([S:10]([OH:13])(=[O:11])=[O:12])[CH:9]=1)(=[NH:2])[NH2:3]
Reactant: N=C(N)c1ccc(O)c(S(=O)(=O)O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: N=C(N)c1ccc(OC(=O)c2ccccc2)c(S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 30 ml of dried pyridine, was added 3.0 g of 5-amidino-2-hydroxybenzenesulfonic acid. To the mixture, while being cooled in ice, was slowly added dropwise 2.0 g of benzoyl chloride. After the addition, the mixture was stirred overnight at room temperature. The insolubles deposited from the reaction mixture were separated by filtration, washed with pyridine, then with water, finally with acetone, and suspended in methanol. The insolubles were removed by filtration, and ethyl ether was added to the filtrate to precipitate a colorless solid. The solid was collected by filtration and recrystallized from a methanol-ethyl ether mixture to obtain 5-amidino-2-benzoyloxybenzenesulfonic acid in colorless solid form.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]1[C:16]([CH:17]=[CH2:18])=[CH:15][N:14]=[C:13]([C:19]3[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]4[O:26][C:25]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=4[CH:38]=3)[N:12]=1)[NH:6]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:11]4[N:12]=[C:13]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[N:14]=[CH:15][C:16]=4[CH2:17][CH2:18][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: C=Cc1cnc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1-c1cc2c(F)cccc2[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ncc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of 5-(4-(4-fluoro-1H-indol-2-yl)-5-vinylpyrimidin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.08 mmol) in DMAc (1 mL), K3PO4 (100 mg, 0.37 mmol) was added under N2 protection. The reaction mixture was stirred at 90° C. overnight. Then the mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by prep-HPLC to give the product of 5-(11-fluoro-5,6-dihydropyrimido[4′,5′:3,4]pyrido[1,2-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (10 mg, yield: 20.0%). 1H-NMR (CDCl3, 400 MHz) δ 8.75 (s, 1H), 8.36 (s, 1H), 8.00˜8.10 (m, 2H), 7.75 (s, 1H), 7.53 (s, 1H), 7.15˜7.25 (m, 4H), 6.84 (t, J=8.8 Hz, 1H), 6.01 (br s, 1H), 4.41 (t, J=6.4 Hz, 2H), 3.50 (s, 3H), 3.34 (t, J=6.4 Hz, 2H), 3.05 (d, J=4.8 Hz, 3H), 2.83 (s, 3H). MS (M+H)+: 614