Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]([CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:17][CH2:16][CH:15]([OH:18])[CH2:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]=2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: OCC(O)Cc1cccc(Cc2ccccc2)c1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)Cc2cccc(Cc3ccccc3)c2OCc2ccccc2)cc1
Yield: 70.2 %

Procedure:
Treatment of (±)-3-[3-benzyl-2-(benzyloxy)phenyl]propane-1,2-diol (9.76 g, 0.028 mol) with p-toluenesulfonyl chloride (5.87 g, 0.031 mol) in pyridine (250 mL) generally according to the procedure described for Intermediate 3 gave 9.88 g (70%) of (±)-3-[3-benzyl-2-(benzyloxy)phenyl]-2-hydroxypropyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C30H30O5S: C, 71.69; H, 6.02. Found: C, 70.41; H, 6.14.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:19]=[N:20][C:21]([N+:24]([O-])=O)=[CH:22][CH:23]=3)[CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:4]1.[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([N:5]3[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:27])[CH3:1])[CH2:4]3)=[O:9])[CH:16]=2)=[CH:23][CH:22]=1
Reactant: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(N)nc3)ccn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
A solution of (R)-3-(dimethylamino)-N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide (0.720 g, 1.934 mmol) in MeOH (10 mL) and THF (10 mL) was treated with NH4Cl (3.10 g, 58.0 mmol) followed by zinc dust (1.264 g, 19.34 mmol) and the mixture stirred at RT for 0.5 h. The mixture was diluted with EtOAc, the solids removed via filtration and washed with EtOAc. The filtrate was re-filtered and concentrated to dryness to afford (R)—N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide (600 mg, 91%). MS (ESI) m/z: 343.2 (M+H+).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[C:34]3[C:33]4[C:28](=[CH:29][C:30]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:32]=4)[NH:27][C:26]=3[N:25]=[C:24]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[N:51][OH:52])[C:47]([F:50])([F:49])[F:48])[CH:41]=3)[N:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[C:34]3[C:33]4[C:28](=[CH:29][C:30]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:32]=4)[NH:27][C:26]=3[N:25]=[C:24]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[N:51][O:52][S:1]([C:4]4[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=4)(=[O:3])=[O:2])[C:47]([F:50])([F:48])[F:49])[CH:41]=3)[N:23]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NO)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NOS(=O)(=O)c4ccc(C)cc4)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Reaction time: 1 h
Yield: 113.6 %

Procedure:
Tosyl chloride (0.048 g, 0.251 mmol) was added portionwise to a cold mixture of methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (0.130 g, 0.229 mmol), 4-dimethylaminopyridine (2.79 mg, 0.023 mmol) and triethylamine (0.038 mL, 0.274 mmol) in DCM (10.00 mL) to give a white suspension. After one hour at room temperature, the amber solution was diluted with DCM (10 mL) and washed with water (3×10 mL). The organic layer was dried over anh. MgSO4, filtered and concentrated to dryness to give methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (188 mg, 99% yield) as a tan foam: MS m/z 723.2 (M+H)+; HPLC >89%, RT=2.09 minutes.
Reaction SMILES: [CH2:1]([O:6][C:7](Cl)=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:10]1([C@H:16]2[NH:19][C:18](=[O:20])[C@@H:17]2[O:21][Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([O:6][C:7]([N:19]1[C@H:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:17]([O:21][Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[C:18]1=[O:20])=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)COC(=O)Cl
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@@H]1c1ccccc1
Product: CC[Si](CC)(CC)O[C@H]1C(=O)N(C(=O)OCC(C)(C)C)[C@@H]1c1ccccc1

Procedure:
By following the above procedure and using neopentylchloroformate, (3R,4R)-4-phenyl-3-triethylsilyloxy-azetidin-2-one was converted to the title product: 1H NMR (CDCl3) δ 0.39-0.97 (m, 24H), 3.73 (d, 1H, J=10.2 Hz), 3.90 (d, 1H, J=10.2 Hz), 5.10 (m, 2H), 7.31 (m, 5H).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([OH:3])=O.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([C:1]([N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20]3)=[O:3])[CH2:5][CH2:6]2)=[N:11][CH:12]=1)#[N:17]
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Reactant: COC(=O)CC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)CC1

Procedure:
2.3 g of 4-carboxy-1-(5-cyanopyrid-2-yl)-piperidine, 2.0 g of methyl 4-piperidylacetate hydrochloride, 4.8 g of 2-[(1H)-benzotriazol-1-yl]-1,1,3,3-tetramethyl-uronium tetrafluoroborate and 5 ml of triethylamine in 75 ml of dimethylformamide is stirred at ambient temperature for 16 hours. The solvent is removed under reduced pressure. The residue is diluted with water and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and saturated saline solution and dried over sodium sulphate. The solvent is removed under reduced pressure and the residue is chromatographed over silica gel. Yield: 2.75 g (74% of theory), Melting point: 112°-115° C. Rf value: 0.40 (silica gel; methylene chloride/methanol=15:1)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.C(OC(=O)[NH:36][CH2:37][CH2:38][NH2:39])(C)(C)C.Cl>>[NH2:36][CH2:37][CH2:38][NH:39][C:12](=[O:13])[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH2:21][CH2:22]2)=[O:16])=[CH:7]1
Reactant: O=C(O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Product: NCCNC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure I, the coupling of {6-chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetic acid (preparation described herein), with (commercially available) (2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatment with HCl and neutralisation, the title compound.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:28]([P:32](Cl)(Cl)=[O:33])([CH3:31])([CH3:30])[CH3:29]>CCCCCC.C1CCCCC1>[C:28]([P:32]1(=[O:33])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][N:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)P(=O)(Cl)Cl
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CC(C)(C)P1(=O)c2ccccc2CN1c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 8.2 %

Procedure:
Under a static nitrogen atmosphere at 26° C., a solution of n-butyllithium (3.93 g, 7.13 mol) in hexane was added to a solution of tetramethylethylenediamine (1.8 g, 0.0155 mol) in 30 ml. of anhydrous cyclohexane with constant stirring. The reaction mixture was cooled to 0° C. and then a solution of N-benzylaniline (5.5 g, 0.03 mol) in 30 ml. of anhydrous cyclohexane was added to the mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2.5 hours at 26° C. and then cooled to 0° C. A solution of t-butylphosphonic dichloride (5.6 g, 0.032 mol) in 30 ml. of anhydrous cyclohexane was added dropwise to the suspension and the resulting mixture was stirred for 1.5 hours at 26° C. The reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 10 ml. of a saturated solution of ammonium chloride. The resulting mixture was concentrated in vacuo and the residue was partitioned in methylene chloride and water. The layers were separated and the methylene chloride layer was washed with 5% hydrochloric acid, then with water, dried over sodium sulfate and concentrated in vacuo to yield a red oil. The red oil was separated on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was triturated with isopropyl ether and petroleum ether to yield a white solid. The white solid was recrystallized from isopropyl ether to yield 1-(t-butyl)-2-pheny-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.7 g, 8% yield) as colorless needles having a melting point of 171°-172° C. and the following analysis:
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH:14]=O)=[N:3]1.[OH-:16].[Na+].Cl.[NH2:19]O>C(O)C.O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH:14]=[N:19][OH:16])=[N:3]1
Reactant: NO
Reactant: Cn1cc2c([C@@H]3C[C@H]3C=O)cccc2n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1cc2c([C@@H]3C[C@H]3C=NO)cccc2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
Trans-2-(2-methyl-2H-indazol-4-yl)cyclopropanecarbaldehyde (330 mg, 1.65 mmol), 8 M aqueous sodium hydroxide solution (824 μL, 6.59 mmol) and hydroxylamine hydrochloride (378 mg, 5.44 mmol) were dissolved in ethanol/water (15 mL/3 mL), and the mixture was stirred at 60° C. for 3 hr. The reaction solution was concentrated, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (349 mg, yield 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=[CH:21][CH:20]=3)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)[CH:7]=1.C(N(CC)CC)C.[CH:36]1([NH2:39])[CH2:38][CH2:37]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[C:24]([C:25]([NH:39][CH:36]4[CH2:38][CH2:37]4)=[O:27])=[CH:23][N:22]=[CH:21][CH:20]=3)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)[CH:7]=1
Reactant: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Reactant: NC1CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.3 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-ylamino]-nicotinic acid (40 mg, 0.10 mmol, 1 eq) in dry DMF (1 ml) was added triethylamine (15 μl, 0.11 mmol, 1.1 eq) followed by cyclopropylamine (70μl, 0.10 mmol, 10 eq). To the suspension was added a solution of PyBrOP (56 mg, 0.21 mmol, 1.2 eq) in DMF (500 μl ) dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and the residue was triturated with ether (2×20 ml). The crude residue was purified by flash column chromatography (0-5% MeOH in CHCl3) to give 4-[2-(5-Chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-ylamino]-N-cyclopropyl nicotinamide, 45 (15 mg, 34%) as a white solid.
Reaction SMILES: C(OC(=O)C([N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)=O)C.[Li+].[OH-]>C1COCC1.O>[C:16]([O:15][C:13](=[O:14])[NH:7][CH:8]1[CH2:9][CH:10]=[CH:11][CH2:12]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C(=O)N(C(=O)OC(C)(C)C)C1CC=CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC=CC1
Temperature: 0 °C
Yield: 53 %

Procedure:
To a stirred solution cooled in an ice-water bath of the above crude product, (tert-butoxycarbonyl-cyclopent-3-enyl-amino)-oxo-acetic acid ethyl ester, (3.80 g) in THF (35 mL) was added a solution of LiOH (0.0765 mol) in water (35 mL). The mixture was stirred in the ice-water bath for 3 h. The organic material was extracted with CH2Cl2 (30 mL×3), the organic layers were combined and washed with brine (30 mL×2), and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, 100% dichloromethane) to obtain white crystals of pure product (53%).
Reaction SMILES: BrCC(N1C[CH2:9][N:8]([C:11](=O)[C:12]2[CH:17]=[C:16](C)[CH:15]=[C:14](C)[CH:13]=2)[CH2:7][CH:6]1[C:21]1[CH:26]=[CH:25]C(Cl)=C(Cl)C=1)=O.Cl.[O:30]1CCOCC1.[OH-].[Na+]>C(Cl)Cl.O>[CH2:11]([N:8]1[CH2:7][CH2:6][C:21](=[O:30])[CH:26]([CH3:25])[CH2:9]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CBr)C(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 3 (Ar2 =3,4-dichlorophenyl) (16 g, 28.49 mmol) in CH2Cl2 (142.5 mL) at 0° C. was added 4N HCl-dioxane solution (71.24 mL, 284.9 mmol) through a dropping funnel. The reaction was gradually warmed up to RT and stirred for 4 h. After completion the solvents were evaporated to give a light yellow solid which was dissolved in H2O (400 mL) and brought to pH 10 with 1N NaOH. The product was extracted from basic aqueous solution with CH2Cl2 (200 mL, 4×), dried over MgSO4, filtered and concentrated to give compound 4 (Ar2 =3,4-dichlorophenyl) as a light yellow solid (12.5 g, 27.09 mmol, 95%). FAB MS [M+1]+ 35 Cl 461.1 Compound 4 was the key intermediate which was used to couple with various aromatic acid for the synthesis of many compounds.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[Br:23][C:24]1[C:29]([F:30])=[CH:28][C:27](O)=[C:26]([F:32])[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[Br:23][C:24]1[C:29]([F:30])=[CH:28][C:27]([O:1][CH2:2][CH2:3][C@@H:4]2[CH2:6][C@@H:5]2[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9][CH2:8]2)=[C:26]([F:32])[CH:25]=1
Reactant: Oc1cc(F)c(Br)cc1F
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCOc2cc(F)c(Br)cc2F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (2.24 g, 7.38 mmol) in DCM (35 ml) was added 4-bromo-2,5-difluorophenol (1.62 g, 7.75 mmol), 3.93 g of triphenylphosphine (polymer-bound, 3.0 mmol/g) and di-tert-butyl diazene-1,2-dicarboxylate (2.21 g, 9.60 mmol). The reaction mixture was stirred at RT for 4 hours. The solid was removed by filtration through celite and the filtrate concentrated. The residue was purified by column chromatography on silica gel (Biotage column, 50 g SNAP) using a gradient 0-20% then 20% EtOAc in hexanes to afford the title compound. LC/MS (m/z): 496.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.C[Si]([O:29][Si](C)(C)C)(C)C.[K].[Si](O[K])(C)(C)C>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[C:5]3[N:6]([C:8](=[O:11])[NH:9][N:10]=3)[NH:7][C:2](=[O:29])[C:3]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)O[Si](C)(C)C
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccncc3)c(Cl)nn12
Agent: C[Si](C)(C)O[K]
Agent: [K]
Solvent: C1CCOC1
Product: O=c1[nH]n2c(=O)[nH]nc2c(-c2ccc(Cl)cc2)c1-c1ccncc1
Temperature: 25 °C
Yield: 32 %

Procedure:
To the solution of 6-Chloro-8-(4-chlorophenyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (29 mg, 0.081 mmol), prepared as described in Example 9, in THF (3 ml) was added potassium trimethylsilyloxide, TMSOK, (36 mg, 0.28 mmol). The solution was heated to refluxed for 15 min. After this time, the solution was cooled to RT. The reaction mixture was concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound, 8-(4-chlorophenyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione, (12 mg, 32%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[O:11]=[C:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:24]=[CH:23]4)[CH:3]=[CH:4][CH:5]=2)[NH:9]1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: O=C1Cc2cccc(Br)c2N1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Cc2cccc(-c3ccc4cc(NC(=O)c5ccsc5)ccc4c3)c2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 24.3 %

Procedure:
7-bromoindolin-2-one (25.4 mg, 0.120 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (89.5 mg, 0.236 mmol), Fibercat palladium catalyst (Johnson-Matthey, 35.4 mg), and K2CO3 (2 M in water, 0.34 ml, 0.68 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.2 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C, first for 10 minutes, and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (20 ml, 5 ml, 2×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA). The fractions with product were purified on silica gel (3:2 hexanes/EtOAc->EtOAc->4:1 EtOAc/MeOH) to afford title compound (11.2 mg, 24%). MS (ESI pos. ion) m/z: 385 (M+H). Calc'd Exact Mass for C23H16N2O2S: 384.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:10]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C@@H:10]([O:13][Si:14]([CH:15]([CH3:16])[CH3:17])([CH:18]([CH3:19])[CH3:20])[CH:21]([CH3:22])[CH3:23])[CH2:11][OH:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[Si](O[C@@H](CO)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Solvent: CO
Product: CC(C)[Si](O[C@@H](CO)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Yield: 67 %

Procedure:
The monosilylated diol of Step 2 was hydrogenated with 5% Rh-C at 60 psi and 60° C. in MeOH (135 mL). The mixture was filtered and the filtrate evaporated. The residue was purified by chromatography, eluting with (15% EtOAc in hexane) to give the title alcohol (8.70 g, 67% yield, mp 61°-63° C.). The 1H, 13C, and APT NMR spectral data were consistent with the proposed product.
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[F:14][C:15]([F:23])([F:22])[CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>C1COCC1>[NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([N:18]2[CH2:19][CH2:20][CH2:21][CH:16]([C:15]([F:23])([F:22])[F:14])[CH2:17]2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1N
Reactant: FC(F)(F)C1CCCNC1
Solvent: C1CCOC1
Product: N#Cc1c(N2CCCC(C(F)(F)F)C2)ccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-amino-6-fluoro-3-nitrobenzonitrile (3.1 g, 17 mmol), 3-trifluoromethylpiperidine (2.5 g, 19 mmol), TEA (3.4 g, 34 mmol) and THF (110 mL) was stirred under Ar at rt for 3 h. The mixture was concentrated and poured into H2O and thereafter extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. Crystallization from EtOAc gave the sub-title compound.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].O.[NH2:16][NH2:17].CCCCCC>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5](=[N:16][NH2:17])[CH3:6]
Reactant: NN
Reactant: CON=C(C(C)=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Solvent: CCCCCC
Product: CON=C(C(C)=NN)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 6.12 g of 1-(4-chlorophenyl)-propane-1,2-dione-1-(O-methyloxime) in 20 ml of ethanol is mixed with 4 ml of hydrazine hydrate. After stirring for 21 hours at room temperature, 80 ml of hexane are added. The precipitated crystals are filtered off, washed with a little hexane and dried. In this way, 4.5 g of 1-(4-chlorophenyl)-2-hydrazono-propan-1-one O-methyloxime are obtained as white crystals having a melting point of 118-119° C. A solution of 3.06 g of the above substance and 3.0 g of (2-formylphenyl)-methoxyimino-acetic acid methyl ester (EP 621277) in 30 ml of pyridine is stirred for 18 hours at 90° C. After cooling, the reaction solution is poured onto ice water and the precipitated oil is extracted with ethyl acetate. Purification takes place with ethyl acetate/hexane (1:9) on silica gel, and the title compound is obtained as a viscous, yellow oil, which crystallises after some time. (melting point 104-105° C.).