Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[CH:8][C:9]([N-:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:10])=[CH:5][CH:4]=1.[C:21]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:22][C:23]([O:25]CC)=O.[O-]CC.[Na+]>COCCOCCOC>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([CH:7]2[CH2:8][C:9](=[O:10])[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:23](=[O:25])[CH:22]2[C:21]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][CH:18]=1
Reactant: CCCCC[N-]C(=O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCCCCN1C(=O)CC(c2ccc(C(F)(F)F)cc2)C(C(=O)OCC)C1=O
Yield: 54.8 %

Procedure:
105 mmol 4-trifluoromethylcinnamoyl-N-pentylamide, 116 mmol diethyl malonate, and 285 mmol sodium ethoxide were refluxed in a 1:1 touene/diglyme mixture for 7 h, cooled and washed with dilute HCl and water. Evaporation at 2 torr gave a dark red oil, which was purified by column chromatography on silica to give 23 g 4-(4-trifluoromethyl-phenyl)-3-ethoxycarbonyl-1-pentylpiperidine-2,6-dione as a reddish oil. 57 mmol 4-(4-trifluoromethylphenyl)-3-ethoxycarbonyl-1-pentylpiperidine-2,6-dione in 100 ml THF was slowly added with stirring to a suspension of 260 mmol LiAlH4 in 100 ml THF maintaining the temperature at 10° C., followed by stirring at room temperature overnight. Excess hydride was destroyed by addition of water, followed by 500 ml 4 N HCl. The THF was removed by evaporation, the aqueous phase was extracted by methylene chloride, and the organic phase was washed with 4 N NaOH, dried, and evaporated. Column chromatography on silica yielded the pure compound, which was crystallized from EtOAc. Compound (93). Yield 3.7 g. M.p. 112°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH:38]1(Br)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: BrC1CCCCC1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(OC4CCCCC4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with cyclohexyl bromide
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:28])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:18]=[C:19]([CH:22]=O)[S:20][CH:21]=3)[CH:15]=2)[N:10]([C:24](=[O:26])[CH3:25])[C@@H:9]([CH3:27])[CH2:8]1)[CH3:3].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:18]=[C:19]([CH2:22][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[S:20][CH:21]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:28])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:27])(=[O:26])[CH3:25]
Reactant: CC(=O)N1c2ccc(-c3csc(C=O)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3csc(CN4CCCCC4)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 0.5 h

Procedure:
1-Methylethyl[(cis)-1-acetyl-6-(2-formyl-1,3-thiazol-4-yl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 39) (21 mg, 0.052 mmol) was dissolved in dichloromethane (DCM) (1 mL), mixed with piperidine (7.77 μL, 0.078 mmol) and acetic acid (7.49 μL, 0.131 mmol) and stirred under nitrogen for 30 minutes. Sodium triacetoxyborohydride (16.63 mg, 0.078 mmol) was added and the mixture was allowed to stir under nitrogen. The mixture was loaded onto a 2 g SCX-column, eluting with MeOH (25 mL) followed by 2M MeOH/NH3 (25 mL). Product-containing fractions were evaporated to dryness to give a solid (18 mg). This was purified on a 12+M Biotage silica column, eluting with 0 to 4% 2N methanolic ammonia in DCM. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (16 mg).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[N:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:21]=2)[CH:11]=1
Reactant: CS(=O)(=O)Nc1cncc(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CS(=O)(=O)Nc1cncc(C#Cc2cc(Cl)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 35, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and N-(5-bromopyridin-3-yl)methanesulfonamide (prepared according to the method described in WO2008141065), the title compound was obtained as a beige solid after purification.
Reaction SMILES: CON(C)[C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:7][N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:11][C:9]1[C:8]([O:12][CH2:13][C:14]([F:17])([F:15])[F:16])=[CH:7][N:6]=[C:5]([CH:4]=[O:18])[CH:10]=1
Reactant: CON(C)C(=O)c1cc(C)c(OCC(F)(F)F)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(C=O)ncc1OCC(F)(F)F
Yield: 95 %

Procedure:
The title compound is prepared in 95% yield (1.2 g, a pale brown solid) from N-methoxy-N,4-dimethyl-5-(2,2,2-trifluoroethoxy)picolinamide (1.6 g, 5.8 mmol, Step-2) and lithium aluminum hydride (80 mg, 2.9 mmol) in a similar manner to Step-2 of Amine-3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([OH:8])=[O:7].CCOCC.C(=O)(O)[O-].[Na+].[N+:19]([C:22]1[CH:32]=[CH:31][C:25]([CH2:26][O:27][C:28](Cl)=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20]>O>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]([NH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([OH:8])=[O:7])=[O:29])=[CH:31][CH:32]=1)([O-:21])=[O:20]
Reactant: NCCOCC(=O)O
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)COCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.2 %

Procedure:
With cooling on an ice bath, to 596 mg of 2-(2-aminoethoxy)acetic acid dissolved in 10 ml of water was added an ether solution of 883 mg sodium bicarbonate and 1.29 g p-nitrobenzyloxycarbonyl chloride in dropwise manner. After stirring the reaction solution for 17 hours at room temperature, the resulting aqueous layer was collected, adjusted to acidic with concentrated hydrochloric acid and extracted with ethyl acetate, and the resulting organic layer was washed with water and dried over sodium sulfate, followed by evaporation of the solvent under a reduced pressure to yield 1.48 g of 2-(2-(p-nitrobenzyloxycarbonylamino)ethoxy)acetic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:19]([C:17]1[CH:16]=[C:15]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)[CH:14]=[C:13]([NH:12][C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH:18]=1)([O-:21])=[O:20]
Reactant: Nc1cc(-c2cnc(C3(O)CCC3)s2)cc([N+](=O)[O-])c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 100 °C
Yield: 60.1 %

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyrimidine (2.04 mL, 16.9 mmol), Intermediate 22 (4.69 g, 16.1 mmol), cesium carbonate (10.5 g, 32.2 mmol), XantPhos (1.40 g, 2.41 mmol) and Pd(OAc)2 (0.361 g, 1.61 mmol) in dixoane (100 mL) was heated to 100° C. overnight. Upon completion the reaction was cooled to room temperature and was diluted with ethyl acetate (100 mL) and filtered through Celite. After in vacuo concentration, purification by chromatography on silica gel (70:30 to 20:80 hexanes:ethyl acetate) provided 4.23 g (9.67 mmol, 60%) of 1-[5-(3-nitro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanol as a bright yellow solid. MS APCI: [M+H]+ m/z 438.0. 1H NMR (400 MHz, Acetone): δ 9.74 (s, 1H); 8.96 (s, 1H); 8.85 (s, 1H); 8.60 (s, 1H); 8.24 (s, 1H); 8.15 (s, 1H); 7.40 (s, 1H); 5.64 (s, 1H); 2.86 (s, 2H); 2.72 (s, 2H); 2.47 (d, J=11.2 Hz, 2H). rhSYK=++.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[F:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[CH2:16][Zn+].Cl>C1COCC1.CC(OC)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[CH2:16][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Fc1ccc(C[Zn+])c(F)c1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccc(F)cc2F)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
Methyl 2-chloroisonicotinate (5.2 g, 30.31 mmol) and Pd(PPh3)4 (0.700 g, 0.61 mmol) were dissolved in THF (100 mL) under nitrogen and (2,4-difluorobenzyl)zinc(II) chloride (0.5 M in THF, 90 mL, 45.00 mmol) was added and the brown solution was stirred at 60° C. overnight (18 h). The reaction was quenched by addition of methanol (50.0 mL). The solution was diluted with EtOAc and washed with NH4Cl (aq) and brine and dried over Na2SO4 to give a red oil. The crude was redissolved in MTBE (200 mL) and solids were filtered off. Hydrogen chloride (4 M in dioxane, 7.58 mL, 30.31 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 15 min. The solid was collected by filtration and washed with MTBE. The solid was dissolved in MTBE/satd NaHCO3. The phases were separated, the organic phase dried over Na2SO4, filtered and evaporated to yield methyl 2-(2,4-difluorobenzyl)isonicotinate (7.011 g, 88%) as a red oil. 1H NMR (400 MHz, cdcl3) δ 3.93 (s, 3H), 4.20 (s, 2H), 6.77-6.88 (m, 2H), 7.18-7.25 (m, 1H), 7.62-7.73 (m, 2H), 8.69 (dd, 1H). MS m/z 264 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]2[CH:20]=[CH:19][S:18][C:12]=2[NH:13][C:14](=S)[CH2:15][N:16]=1)([O-:3])=[O:2].[C:21]([NH:24][NH2:25])(=O)[CH3:22]>C(O)CCC>[CH3:22][C:21]1[N:13]2[C:12]3[S:18][CH:19]=[CH:20][C:11]=3[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])=[N:16][CH2:15][C:14]2=[N:25][N:24]=1
Reactant: CC(=O)NN
Reactant: O=[N+]([O-])c1ccccc1C1=NCC(=S)Nc2sccc21
Solvent: CCCCO
Product: Cc1nnc2n1-c1sccc1C(c1ccccc1[N+](=O)[O-])=NC2
Reaction time: 2 h

Procedure:
9.1 g (0.03 mol) of 1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepine-2-thione are refluxed with 500 ml of absolute butanol and 9 g of acetic hydrazide, a stream of nitrogen being conducted through the solution. After 2 hours, the solvent is evaporated and the residue taken up in 300 ml of methylene chloride and washed three times with 100 ml of water each time. After drying and evaporation of the organic phase and trituration with ethyl acetate, there is obtained crystalline 9-methyl-4-(o-nitrophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine which, after recrystallization from ethanol and treatment with active carbon, melts at 260°-262° C.
Reaction SMILES: [C:1]([C:3]1[NH:4][CH:5]=[N+:6]([C@@H:9]2[O:21][C@H:20]([CH2:22][O:23]C(=O)C)[C@@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[C:7]=1[O-:8])#[N:2].CO.C[O-].[Na+]>CO>[C:1]([C:3]1[NH:4][CH:5]=[N+:6]([C@@H:9]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:15]([OH:16])[C@H:10]2[OH:11])[C:7]=1[O-:8])#[N:2]
Reactant: CC(=O)OC[C@H]1O[C@@H]([n+]2c[nH]c(C#N)c2[O-])[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1[nH]c[n+]([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1[O-]
Yield: 92.6 %

Procedure:
To a mixture of 6.921 g of 4-cyano-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazolium-5-olate and 50 ml of dry methanol was added 20.37 g of 25% (W/W) sodium methoxide methanol solution under ice-cooling. The reaction mixture was stirred for ten minutes at the same temperature and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography on reversed phase silica gel [Merck RP-8 eluted with 1% acetic acid solution] to give 4.21 g of 4-cyano-1-β-D-ribofuranosylimidazolium-5-olate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[H-].[Na+].[CH2:13]([O:15][CH2:16]Cl)[CH3:14].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][O:15][CH2:13][CH3:14])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCOc1ccc(Br)cc1CC
Reaction time: 0.5 h

Procedure:
24.5 g (121 mmol) of 4-bromo-2-ethylphenol are dissolved in 150 ml of DMF, and this solution is slowly added to a suspension of 5.3 g (133 mmol) of sodium hydride in 50 ml of DMF. The medium is stirred for 30 minutes, and then 12.4 ml (133 mmol) of ethoxymethyl chloride are added. The reaction medium is stirred for 4 hours at room temperature, and then poured into water and extracted with ethyl acetate. The organic phases are washed with water, and the residue obtained after drying and concentration is purified by chromatography on a silica column (eluent ethyl acetate 10/heptane 90). A yellow oil is obtained (m=25 g, y=80%)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.CN1CCCC1.[CH:17](Cl)([Cl:19])[Cl:18].[OH-].[Na+]>>[Cl:8][C:7]1[C:2]([CH:17]([Cl:19])[Cl:18])=[N:3][C:4]([Cl:10])=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Reactant: ClC(Cl)Cl
Agent: CN1CCCC1
Agent: [Na+]
Agent: [OH-]
Product: Clc1cc(Cl)c(C(Cl)Cl)nc1Cl

Procedure:
2,3,5,6-Tetrachloropyridine (1.1 g, 0.005 mole) was combined with 5 ml of N-methylpyrrolidine and 5 ml (about 0.062 mole) of chloroform in a reaction vessel and to the resulting solution 6 g of 50 percent aqueous sodium hydroxide (0.075 mole) was added with stirring. After 30 minutes the title compound was shown to be present in the reaction mixture by gas chromatography at approximately 15 percent conversion.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][C:6]#[N:7].Br[CH2:12][CH2:13]Cl.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2([C:6]#[N:7])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: ClCCBr
Reactant: N#CCc1cccc(Br)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2cccc(Br)c2)CC1

Procedure:
25 g (0.13 mol) of 3-bromo-benzylcyanide are taken up in 32 ml (0.38 mol) of 1-bromo-2-chloro-ethane and combined with 0.6 g (2.6 mmol) of benzyltriethylammonium chloride. Then a solution of 105.8 g (2.65 mol) of sodium hydroxide in 106 ml of water is added dropwise at 10 to 25° C. After 20 hours at 55° C. the reaction solution is poured onto ice water and extracted with ethyl acetate. The organic extracts are dried and evaporated down. The residue is triturated with petroleum ether, suction filtered and dried.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[I:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[I:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc(I)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(I)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Iodo-benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1F
Reactant: N#Cc1ccc(F)cc1
Product: Cc1cc(Oc2ccc(C#N)cc2)ccc1F

Procedure:
4-Fluoro-3-methylphenol and 4-fluorobenzonitrile were coupled following the procedure outlined in example 28 to give 4-(4-fluoro-3-methylphenoxy)benzonitrile. A mixture of 4-(4-fluoro-3-methylphenoxy)benzonitrile (1.1 g, 4.8 mmol), N-bromosuccinimide (NBS, 1.0 g, 5.6 mmol), dibenzoyl peroxide (90 mg, 0.37 mmol), and CCl4 (20 mL) was heated at reflux under N2. After 1 h, a second aliquot of dibenzoyl peroxide was added. After an additional 3 h, a second aliquot of NBS and a third aliquot of dibenzoyl peroxide were added. After an additional 4 h, a fourth aliquot of dibenzoyl peroxide was added. After an additional 15 h, the reaction was allowed to cool to rt and purified by silica gel chromatography (hexanes:ethyl acetate—1:0→4:1) to give an off-white solid. MS (ESI): 306/308 (M+H). A similar reaction sequence as outlined in example 1 was followed using the above bromide and 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol. 1H NMR (500 MHz, DMSO) δ 8.01 (d, 2H), 7.33 (t, 1H), 7.30-7.24 (m, 2H), 7.21 (d, 1H), 7.21-7.13 (m, 3H), 6.98 (d, 1H), 6.37 (d, 1H), 5.12 (s, 2H), 3.90 (s, 2H), 2.71 (t, 2H), 1.53-1.43 (m, 2H), 0.91 (s, 9H), 0.78 (t, 3H). MS (ESI): 514.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:36]=[CH:35][C:22]([O:23][C:24]4[CH:25]=[CH:26][N:27]=[C:28]5[C:33]=4[NH:32][C:31](=[O:34])[CH:30]=[CH:29]5)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:40]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N:18]([CH3:40])[C:19]3[CH:20]=[CH:21][C:22]([O:23][C:24]4[CH:25]=[CH:26][N:27]=[C:28]5[C:33]=4[NH:32][C:31](=[O:34])[CH:30]=[CH:29]5)=[CH:35][CH:36]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1ccc2nccc(Oc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccc(Oc2ccnc3ccc(=O)[nH]c23)cc1)c1nnc(-c2ccc(Cl)cc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 20 mL sealed tube, was dissolved 8-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenoxy)-1,5-naphthyridin-2(1H)-one (0.25 g, 0.508 mmol) in THF (2.2 mL), and the mixture was cooled to 0° C. Sodium Hydride, 60% in mineral oil (0.045 g, 1.12 mmol), was added and the mixture was stirred at 0° C. for 1 hour. Iodomethane (0.070 mL, 1. 12 mmol), was added and the mixture was warmed to 60° C., and stirred for 3 hours. A mixture of products was revealed by LC/MS. The mixture was cooled to RT, quenched with water, extracted into ethyl acetate, washed 1× water, 1× NaCl, dried with Na2SO4, filtered through fritted funnel, and filtrate was concentrated. The crude concentrate was purified by reverse phase chromatography. The product containing fractions were extracted into DCM, washed 1× sodium carbonate, 1×H2O, dried with Na2SO4, filtered through fritted funnel, and the filtrate was concentrated down to a light yellow solid containing two methylated products. The solids were suspended in methanol, filtered, rinsed with methanol, and air dried to yield 8-(4-((4-(4-chlorophenyl)phthalazin-1-yl)(methyl)amino)phenoxy)-1,5-naphthyridin-2(1H)-one. MS: [M+H]=506.0; Calc'd 505.9 for C29H20ClN5O2.
Reaction SMILES: [F:1][C:2]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:17])=[C:12]([CH2:15][OH:16])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[F:1][C:2]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:17])=[C:12]([CH:15]=[O:16])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1
Reactant: Cc1nc2c(ccn2Cc2cccc(F)c2F)c(I)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1nc2c(ccn2Cc2cccc(F)c2F)c(I)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of (1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (8.75 g, 21.13 mmol) in dichloromethane (DCM) (200 mL) at 0° C. was added PCC (9.11 g, 42.3 mmol) and silica gel (6.4 g, 70% wt. of the amount of PCC) and the mixture was stirred at ambient temperature for 3 h. The mixture was filtered through silica gel washing with dichloromethane (1 L). The filtrate was concentrated to provide 1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (9.44 g, 19.93 mmol, 94% yield) as a brownish solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.90 (s, 3H), 5.56 (s, 2 H), 6.54 (d, J=3.71 Hz, 1 H), 6.88-7.05 (m, 2 H), 7.05-7.19 (m, 1 H), 7.30 (d, J=3.51 Hz, 1 H), 10.38 (s, 1 H); LCMS (m/z) ES+=412 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:12])[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.[BH4-].[Na+].O>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:12])[CH2:10][NH:16][CH:13]1[CH2:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: C[C@@H](CNC1CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.3 %

Procedure:
4.3 mL (14.3 mmol) of titanium isopropoxide and 1.9 g (5 mmol) of (S)-2-(tert-butoxycarbonylamino)-propionaldehyde (prepared according to the method described by Itaya, Taisuke et al., Tetrahedron Lett., 1986, 52(27), 6349-52) are added to a solution of 1.88 g (33 mmol) of cyclopropylamine in 10 mL of anhydrous methanol. The solution is stirred for 5 hours at room temperature then 227 mg (6 mmol) of sodium borohydride is added. Stirring is continued for a further 2 hours then 2 mL of water is added. The reaction mixture is filtered then the solvents are evaporated. The residue is purified by chromatography on silica (eluent dichloromethane/methanol 98/2) to give 400 mg (17%) of (S)—N′-tert-butoxycarbonyl-N-cyclopropyl-propane-1,2-diamine in the form of a colourless oil.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][O:2]1.[CH2:7]([NH2:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:7]([NH:13][C:1](=[O:6])[O:2][CH2:3][CH2:4][OH:5])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C1OCCO1
Reactant: CCCCCCN
Product: CCCCCCNC(=O)OCCO
Temperature: 50 °C

Procedure:
90.7 grams (1.03 moles) of ethylene carbonate were placed in a flask, melted and stirred at about 50° C. 104.2 grams (1.03 moles) of n-hexylamine were then added drop wise over a 11/2 hour period to the flask at a rate sufficient to maintain the flask contents at 60° to 70° C. The flask contents were held at 80° C. for an additional 51/2 hours and then allowed to cool overnight. Infrared and NMR analyses of the resultant product were consistent with the proposed structure.