Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCc1ccc([N+](=O)[O-])cc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](OCCc1ccc(N)cc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A solution of 6.5 g (16 mmol) 4-[2-(tert-butyldiphenylsilyloxy)ethyl]nitrobenzene in methanol (30 ml) containing 750 mg of 10% palladium on carbon was hydrogenated at room temperature and atmospheric pressure for 2 hours. The catalyst was removed by filtration and the solvent evaporated to give 5.7 g of 4-[2-(tert-butyldiphenylsilyloxy)ethyl]phenylamine as a colorless liquid. [Mass spectrum (ESI) MH+ =376].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@@H:23]1[O:25][CH2:24]1)(=O)=O>>[CH2:22]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[C:1]#[N:2])[C@@H:23]1[O:25][CH2:24]1
Reactant: CCOC(=O)CCCc1ccc(O)c(C#N)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Product: CCOC(=O)CCCc1ccc(OC[C@H]2CO2)c(C#N)c1
Yield: 66.3 %

Procedure:
Using the method of example 30(b), supra, ethyl 4-(3-cyano-4-hydroxyphenyl)butanoate (0.93 g, 4 mmol) and (R)-glycidyl nosylate (1.00 g, 3.86 mmol) were used to prepare 0.74 g (66%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21]>>[CH2:37]([O:36][CH:35]([O:39][CH2:40][CH3:41])[C@@H:34]([N:22]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:13])[CH3:43])[CH3:42])[CH3:38]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 99 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16](=[CH2:30])[C:17]([NH:19][C:20]2[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:21]=2[OH:29])=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].CC(C1C=C(C(=C)C(NC2C=CC(O)=C([N+]([O-])=O)C=2)=O)C=C(C(C)(C)C)C=1O)(C)C>>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([C:16](=[CH2:30])[C:17]([NH:19][C:20]2[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:21]=2[OH:29])=[O:18])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: C=C(C(=O)Nc1cc([N+](=O)[O-])ccc1O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C=C(C(=O)Nc1ccc(O)c([N+](=O)[O-])c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: C=C(C(=O)Nc1cc(N)ccc1O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 74 %

Procedure:
The experimental protocol used is the same as that described for intermediate 18.2, with 3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-nitrophenyl)-2-propenamide replacing the 3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide . A yellow powder is obtained with a yield of 74%. The product is used without additional purification in the following stage.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[C:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.C([O-])(=O)C.[Na+].[I:22]Cl>C(Cl)(Cl)Cl.CO.O=[Pt]=O>[I:22][C:5]1[CH:6]=[C:7]([CH2:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:15]=[CH:16][C:4]=1[NH2:1]
Reactant: ClI
Reactant: O=[N+]([O-])c1ccc(C=C2CCOCC2)cc1
Agent: O=[Pt]=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1ccc(CC2CCOCC2)cc1I
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 34 %

Procedure:
A mixture of 4-(4-nitrobenzylidene)tetrahydro-2H-pyran (2.0 g) and PtO2 (0.2 g) is hydrogenated at 40 p.s.i. H2 for 3.5 h. The mixture is filtered through celite and the filtrate condensed. The crude residue is dissolved in a mixture of 40 mL CHCl3 and 4 mL MeOH. To this is added sodium acetate (2.24 g), followed by the dropwise addition of a solution of ICl (0.69 mL) in MeOH (10 mL). The reaction is stirred at room temperature for 1 h then quenched by pouring into an iced saturated solution of aqueous sodium bisulfite (200 mL). The mixture is stirred for 30 minutes then concentrated until all of the organics are gone. The aqueous solution is extracted with CH2Cl2 (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed (Biotage flash 40M, eluent CH2Cl2) to yield 1.0 g (34%) of the desired product as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)=[O:9]>C(Cl)Cl>[I:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[CH2:7][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:16][CH:15]=1
Reactant: C1CCNC1
Reactant: O=C(CCl)Nc1ccc(I)cc1
Solvent: ClCCl
Product: O=C(CN1CCCC1)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.53 mL (18.6 mmol) pyrrolidine are added to a solution of 2.20 g (7.45 mmol) 2-chloro-N-(4-iodo-phenyl)-acetamide in 50 mL DCM. The reaction solution is stirred overnight at RT. The mixture is filtered, the filtrate dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([O:10][C:11]([CH2:13][S+](C)C)=[O:12])[CH3:9]>C(Cl)(Cl)Cl>[CH2:8]([O:10][C:11]([C@@H:13]1[CH2:3][C@H:2]1[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:12])[CH3:9]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C[S+](C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)OCC
Temperature: 22 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
Ethyl acrylate (99%, 270 g, 1.4 eq.) was added to a solution of 2 (282 g, 1.91 mol) in CHCl3 (1500 mL) at 5° C. Cooling was removed and the reaction was stirred at 22° C. for 12 h. Evaporation of the solvent and excess acrylate left an orange oil, which was vacuum distilled (bp 70-75° C./1 mm) to produce 3 (286 g, 80.6%) as a clear thick oil. 1H NMR (250 MHz, CDCl3) δ4.15 (q, J=7.1, 4H); 2.16 (dd, J=7.5, 5.7, 2H); 1.41 (dd, J=7.5, 5.7, 2H); 0.88 (t, J=7.1, 6H). 13C NMR (62.5 MHz, CDCl3) δ171.69; 60.96; 22.26; 15.18; 14.08.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(C)(C)C#N)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(O)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
Add anhydrous dichloromethane (400 mL) to 2-(4-methoxy-phenyl)-2-methyl-propionitrile (11.93 g, 68.1 mmol) and cool to −78° C. under nitrogen. Then add boron tribromide (33.0 mL, 349 mmol) and stir at −78° C. for 30 minutes. Remove the dry ice/acetone bath and allow the reaction to warm to room temperature. Stir for 3 h and then pour the reaction onto ice. Extract with ethyl acetate (2×150 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 35% ethyl acetate/hexanes to yield 9.79 g (89%) of 2-(4-hydroxy-phenyl)-2-methyl-propionitrile: TLC: Rf in 40% ethyl acetate/hexanes: 0.38; 1H NMR (CDCl3): 7.34-7.32 (m, 2H), 6.86-6.83 (m, 2H), 5.23 (s, 1H), 1.70 (s, 6H).
Reaction SMILES: [C:1]1([C:14]([OH:16])=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH:22]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:24]=[C:25]([NH:26][C:14]([C:1]3[C:13]4[NH:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:16])[CH:27]=[CH:28][CH:29]=2)[CH:22]=1
Reactant: Cc1cn(-c2cccc(N)c2)cn1
Reactant: O=C(O)c1cccc2c1[nH]c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cn(-c2cccc(NC(=O)c3cccc4c3[nH]c3ccccc34)c2)cn1
Reaction time: 40 h
Yield: 37 %

Procedure:
To a suspension of 9H-carbazole-1-carboxylic acid (106 mg) and 3-(4-methylimidazol-1-yl)aniline (87 mg) in dichloromethane (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg) and 4-dimethylaminopyridine (31 mg), and the mixture was stirred for 40 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with methanol, and the insoluble material was collected by filtration and dried to give N-[3-(4-methylimidazol-1-yl)-phenyl]-9H-carbazole-1-carboxamide (68 mg, 37.0%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])SC)#[N:5].CC1N=CNC=1CSCCN>C(O)C>[C:4]([NH:6][C:7]([NH:3][CH2:1][CH3:2])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])#[N:5]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CCN
Agent: Cc1nc[nH]c1CSCCN
Solvent: CCO
Product: CCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
Anhydrous ethylamine (9.0 g) was added to a solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (5.0 g), prepared from 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole by the procedure of Example 97, in ethanol. The solution was heated under reflux for 8 hours and concentrated under reduced pressure. The residue was dissolved in isopropyl alcohol, filtered, and diluted with water. The white solid obtained was recrystallised from isopropyl alcohol-ether to yield N-cyano-N'-ethyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, m.p. 118°-120°.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br.[NH:12]1[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]1=2>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]1=2
Reactant: BrCc1cccc(Br)c1
Reactant: O=C1CCCc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCc2ccccc2N1Cc1cccc(Br)c1
Reaction time: 1 h

Procedure:
To a stirred mixture of 0.1 g (4 mmole) sodium hydride and 0.75 g (3.0 mmole) 3-bromobenzyl bromide in 5 mL dimethylformamide was added 0.438 g (2.72 mmole) solid 1,3,4,5-tetrahydro-benzo[b]azepin-2-one. The mixture was cooled in a water bath, then it was stirred at 23° for 1 hr. The solvent was removed under reduced pressure and the residue was partitioned between 30 mL ethyl acetate and 5 mL water. The organic phase was washed with 5 mL water, 5 mL saturated sodium chloride, dried (mgSO4) and concentrated under reduced pressure. The residue was recrystallized from hexane to provide the title compound, 0.658 g, m.p. 81-82°.
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28](S(C)(=O)=O)[N:27]=1.O>CN(C)C=O.C(O)(=O)C>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([O:1][CH:2]([C:7]([O:20][CH3:21])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][CH3:6])=[O:4])[N:27]=1
Reactant: COC(=O)C(O)C(OC)(c1ccccc1)c1ccccc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(OC)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
2.86 g (10 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride was added. The mixture was stirred for 1 h and then 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine were added. After stirring at room temperature for 24 h, cautious hydrolysis was carried out with 10 ml of water, the pH was adjusted to 5 with acetic acid, and the solvent was removed by distillation under high vacuum. The residue was taken up in 100 ml of ethyl acetate, washed with water and dried over magnesium sulfate, and the solvent was distilled out. The residue was mixed with 10 ml of ether, and the resulting precipitate was filtered off with suction. After drying, 3.48 g (82%) of a white powder remained. Melting point 81° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(O)(=O)C>CO.[Zn]>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cc(F)c(Cl)nc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1cc(F)cnc1Cl
Reaction time: 24 h

Procedure:
A suspension of 21.9 g (335.35 mmol) of zinc in methanol (207 ml) was admixed at RT with 44 g (210.58 mmol) of 2,6-dichloro-5-fluoronicotinamide. Acetic acid (18.5 ml) was then added, and the mixture was heated to reflux while stirring for 24 h. The contents of the flask were then decanted off from the zinc, and ethyl acetate (414 ml) and saturated aqueous sodium hydrogencarbonate solution (414 ml) were added, followed by vigorous stirring. Subsequently, the reaction mixture was filtered with suction through kieselguhr and washed through three times with ethyl acetate (517 ml each time). The organic phase was removed and the aqueous phase was washed with ethyl acetate (258 ml). The combined organic phases were washed once with saturated aqueous sodium hydrogencarbonate solution (414 ml), dried and concentrated under reduced pressure. Dichloromethane (388 ml) was added to the crystals thus obtained, and the mixture was stirred for 20 min. The mixture was once more filtered with suction, washed through with diethyl ether and sucked dry.
Reaction SMILES: CC([N:5]([C:9]([CH3:33])([CH3:32])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[C:21]3[CH:22]4[CH2:30][C:23]4([CH3:31])[CH2:24][O:25][C:26]=3[CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:33][C:9]([C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[C:21]3[CH:22]4[CH2:30][C:23]4([CH3:31])[CH2:24][O:25][C:26]=3[CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:18]=1)=[O:11])([CH3:32])[NH2:5]
Reactant: CC12COc3cccc(Oc4ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn4)c3C1C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2CC2(C)CO3)nc1
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl[1,1-dimethyl-2-({6-[(1a-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-yl)oxy]-3-pyridinyl}amino)-2-oxoethyl]carbamate (Intermediate 128, 135 mg, 0.298 mmol) in dry dichloromethane (10 ml) at 0° C. TFA (5 ml, 64.9 mmol) was slowly added and the reaction mixture was stirred for 2 hours at the same temperature. The solvent and the excess of TFA were evaporated and the residue was dissolved in dichloromethane and a saturated solution of NaHCO3 was slowly added while the pH was allowed to reach 8. Two phases were separated and the organic layer was dried over sodium sulphate, filtered and evaporated affording the title compound as a colourless oil used as it was without any further purification (105 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][N:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=45)[CH:21]=[CH:20][N:19]=3)=[C:10]([O:33][CH3:34])[CH:9]=2)[CH2:4]1.[NH4+].[Cl-].C(O)C>[Fe].O>[CH3:35][N:2]([CH3:1])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([O:33][CH3:34])[C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][N:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=45)[CH:21]=[CH:20][N:19]=3)=[CH:12][C:13]=2[NH2:14])[CH2:4]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Yield: 82 %

Procedure:
A mixture of N-[4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 154, 440 mg, 0.93 mmol), iron (311 mg, 5.56 mmol), NH4Cl (37.2 mg, 0.70 mmol), ethanol (15 mL) and water (5 mL) was heated at reflux for 1.5 h. After cooling the mixture was concentrated in vacuo. The resulting residue was triturated in 10% CH3OH in CH2Cl2 (20 mL) for 15 minutes and then filtered. The residues were triturated again with 10% CH3OH in CH2Cl2 (10 mL) and then filtered. The combined filtrates were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (339 mg, 82%) as a yellow solid after trituration with diethyl ether; 1H NMR: 1.73-1.83 (1H, m), 2.00-2.10 (1H, m), 2.20 (6H, s), 2.81-2.90 (1H, m), 2.92-3.00 (2H, m), 3.11-3.16 (1H, m), 3.17-3.24 (1H, m), 3.73 (3H, s), 4.28 (2H, br s), 6.71 (1H, s), 7.07 (1H, td), 7.20 (1H, d), 7.27 (1H, s), 7.37-7.42 (1H, m), 7.97 (1H, s), 8.30 (1H, d), 8.53 (1H, d), 8.76 (1H, s), 8.79 (1H, d); m/z: ES+ MH+ 445.33.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][CH:15]=[CH2:16])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][CH:15]=[CH2:16])[CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A solution of compound 18f (9.5 g, 41.5 mmol) in THF (50 mL) was cooled in an ice bath under argon. To this mixture was added LAH (3.9 g, 104 mmol) portionwise, and then the ice bath was removed and the reaction mixture was allowed to stir at rt for 2 h and then quenched with water (30 mL). The aqueous layer was extracted with EA (3×50 mL). The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC to give compound 18g (6.2 g, 75% yield) as yellow oil.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[N:17][CH:16]=2)=[CH:11][CH:10]=1.[F:26][C:27]([F:43])([F:42])[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=2)[C:36](O)=[O:37])[N:29]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:36]([C:35]4[CH:39]=[CH:40][CH:41]=[C:33]([C:30]5[N:29]=[C:28]([C:27]([F:42])([F:26])[F:43])[O:32][N:31]=5)[CH:34]=4)=[O:37])[CH2:21]3)=[N:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: Fc1ccc(-c2cnc(C3CCCNC3)o2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCCC(c2ncc(-c3ccc(F)cc3)o2)C1
Yield: 9 %

Procedure:
This compound was synthesized from 5-(4-fluorophenyl)-2-(piperidin-3-yl)oxazole TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (25 mg, yield 9%). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ 8.11-8.09 (m, 1H), 7.97 (s, 1H), 7.69-7.61 (m, 4H), 7.45 (s, 1H), 7.24-7.20 (t, J=8.8 Hz, 2H), 4.16 (m, 1H), 3.71-3.67 (m, 1H), 3.62-3.56 (dd, J=12.9 Hz, 8.4 Hz, 1H), 3.47-3.41 (m, 1H), 3.24-3.18 (m, 1H), 2.22-2.17 (m, 1H), 2.03-1.94 (m, 1H), 1.89-1.84 (m, 1H), 1.69-1.59 (m, 1H). MS (ESI) m/z: Calculated for C24H18F4N4O3: 486.13. found: 487.3 (M+H)+
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([S:21][C:22]4[CH:23]=[CH:24][C:25]([N+:29]([O-])=O)=[C:26]([CH:28]=4)[NH2:27])=[N:19][N:20]=3)[N:17]=2)=[CH:8][CH:7]=1.[OH-].[Na+].O>CO.C(OCC)C.[Fe]>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([S:21][C:22]4[CH:28]=[C:26]([NH2:27])[C:25]([NH2:29])=[CH:24][CH:23]=4)=[N:19][N:20]=3)[N:17]=2)=[CH:8][CH:7]=1
Reactant: Nc1cc(Sc2nnc3ccc(-c4ccc(F)cc4)nn23)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(Sc2nnc3ccc(-c4ccc(F)cc4)nn23)cc1N
Yield: 52.8 %

Procedure:
0.6 cm3 of acetic acid and 145 mg of iron(0) are added to a mixture of 146 mg of 5-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-2-nitroaniline in 7 cm3 of methanol. The reaction mixture is then stirred at reflux for 5 h 15 and then overnight at 20° C. before the addition of 10 cm3 of a 5N aqueous solution of sodium hydroxide and 10 cm3 of demineralized water. The mixture obtained is extracted with 2×30 cm3 of ethyl acetate. The combined organic phases are washed with 20 cm3 of water and then dried over magnesium sulphate and concentrated to dryness. The beige solid obtained is taken up in diethyl ether, spin-filter-dried, and then dried under vacuum. 71 mg of 4-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}benzene-1,2-diamine are thus obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:7]=2.[H-].[Na+].[CH3:34]I>CN(C=O)C>[CH3:34][N:15]([C@H:11]1[CH2:10][C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[C:6]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:7]=3)[N:2]([CH3:1])[C:14]=2[CH2:13][CH2:12]1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)C[C@H](NC(=O)OC(C)(C)C)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCc2c(c3cc(S(=O)(=O)c4ccccc4)ccc3n2C)C1
Temperature: 25 °C
Reaction time: 1.1 h
Yield: 75.7 %

Procedure:
A solution of tert-butyl (3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamate (1.74 g, 3.95 mmol) in DMF (13.0 mL) was added to a 0° C. suspension of 60% sodium hydride (0.38 g, 9.62 mmol) in DMF (3.0 mL) and stirred at room temperature for 1.1 hours. Methyl iodide (0.30 mL, 4.81 mmol) was added, and the reaction was stirred at room temperature for 2.0 hours. The reaction was cooled to 0° C., quenched with water and filtered. The filtrate was concentrated in vacuo, combined with the previously filtered solid and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to dryness, the residue was recrystallized from EtOAc/hexane to give 1.36 g (76%) of tert-butyl methyl[(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]carbamate as a colorless solid: mp 181.4-183.2° C.; [α]D=+103° (c 1.02, DMSO); 1H NMR (400 MHz, DMSO-d6) δ 8.06, 7.93-7.91, 7.62-7.53, 4.22, 3.64, 2.96-2.92, 2.84-2.79, 1.99-1.94, 1.42; 13C NMR (100 MHz, DMSO-d6) δ 155.6, 142.8, 138.7, 138.0, 132.7, 130.5, 129.3, 126.7, 125.9, 119.1, 118.0, 110.0, 108.6, 78.5, 29.3, 28.5, 28.0, 26.4, 23.5, 21.2; IR (diffuse reflectance) 1684, 1481, 1448, 1398, 1378, 1364, 1357, 1304, 1184, 1149 (s), 1103, 732, 690, 622, 612 cm−1; HRMS (FAB) calcd for C25H30N2O4S+H 455.2004, found 455.2027; Anal. Calcd for C25H30N2O4S: C, 66.05; H, 6.65; N, 6.16. Found: C, 65.99; H, 6.66; N, 6.19.