Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:21]2[CH2:22][CH2:23][CH:18]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:19][CH2:20]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCC(N3CCCC3)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 17 h

Procedure:
200 mg (1.170 mmol) 4-fluoro-2-methoxy-1-nitro-benzene are dissolvedjin 1 ml NMP, combined with 198 mg (1.284 mmol) 4-pyrrolidin-1-yl-piperidine and 300 μl diisopropylethylamine and stirred for 17 h at 80° C. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is C18-RP gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point.
Reaction SMILES: [NH2:1][C:2]1[N:35]=[C:5]2[N:6]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[C:7]([CH3:24])=[C:8]([C:22]#[N:23])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=3[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.C1COCC1.Cl[C:42]([O:44][CH3:45])=[O:43]>N1C=CC=CC=1>[CH3:45][O:44][C:42](=[O:43])[NH:1][C:2]1[N:35]=[C:5]2[N:6]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)[C:7]([CH3:24])=[C:8]([C:22]#[N:23])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=3[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1
Reactant: COC(=O)Cl
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2S(C)(=O)=O)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)Nc1nc2n(n1)C(c1ccc(C#N)cc1S(C)(=O)=O)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Under an atmosphere of argon protective gas, 2-amino-7-[4-cyano-2-(methylsulfonyl)phenyl]-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (7 mg, 13.6 μmol) was dissolved in a mixture of abs. THF (0.6 ml) and abs. pyridine (11 μl). At room temperature, abs. pyridine (5×11 μl) and methyl chloroformate (5×6.4 mg, 5×68.1 μmol; 25 eq.) were added in a plurality of portions. The mixture was then heated as 80° C. for 12 h. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (5.4 mg, 69% of theory).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12](OC)=[O:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[CH3:18][NH2:19].C[O-].[Na+].S(=O)(=O)(O)O>CN(C=O)C>[CH3:1][CH:2]([O:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([NH:19][CH3:18])=[O:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Oc1ccc(OCC(=O)OC)cc1
Reactant: CN
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCC(=O)NC)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 4-(1-methylpropoxy)phenoxyacetate (7.94 g, 33.3 mmol) in 65 ml of dry DMF at 0° and with stirring is added methylamine gas to saturation (ca. 25 min.). A trace of sodium methoxide (ca. 10 mg) is added and the mixture is allowed to warm to RT. After 20 hours at RT, the reaction mixture is poured into ice water and 10 ml of 3N sulfuric acid and extracted with ether. The combined organic phases are washed with water, with 10% sodium bicarbonate, with water and with brine, dried, filtered and the filtrate evaporated in vacuo to give 4-(1-methylpropoxy)phenoxy-N-methylacetamide.
Reaction SMILES: [C:1]1([C:7]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)([OH:12])[CH2:8][CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:19]>O1CCCC1.CCOCC>[ClH:19].[NH:11]=[C:10]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:12]1
Reactant: N#CCCC(O)(c1ccccc1)C1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: N=C1CCC(c2ccccc2)(C2CCCCC2)O1
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 1-phenyl-1-cyclohexyl-3-cyano-1-propanol (1.4 g) in anhydrous tetrahydrofuran (THF), a solution of HCl 10% w/v in ether (2.5 ml) was added dropwise. The mixture was stirred and cooled for 48 hours. The solvent was removed and the residue triturated with diethyl ether/THF to afford 0.8 g of 2-imino-5-phenyl-5-cyclohexyltetrahydrofuran hydrochloride. M.p. 100°-102° C.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]1[CH:29]=[CH:28][C:17]2[C@:18]3([CH3:27])[C@@H:23]([CH2:24][CH2:25][C:16]=2[CH:15]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3.[C:30](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:22]1[C@H:23]2[C@@:18]([CH3:27])([C:17]3[CH:28]=[CH:29][C:14]([C:2]4[CH:3]=[CH:4][C:5]5[C:6]6[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=6)[CH2:12][C:13]=5[CH:1]=4)=[CH:15][C:16]=3[CH2:25][CH2:24]2)[CH2:19][CH2:20][C:21]1=[O:26]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc4c(c3)Cc3ccccc3-4)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)Cc4ccccc4-5)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-fluorenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (31 mg, 0.08 mmol), 0.2 mL of t-butanol, and potassium t-butoxide (27 mg, 0.24 mmol). Methyl iodide (0.015 mL, 0.24 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 26 mg (82%) of the title compound as an off-white solid. mp 175° (decomp). FDMS: m/e=393.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[S:13]1[CH2:16][CH:15]([OH:17])[CH2:14]1.O[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[S:13]1[CH2:16][CH:15]([O:17][N:19]2[C:20](=[O:29])[C:21]3=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]3[C:23]2=[O:24])[CH2:14]1
Reactant: OC1CSC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CSC1
Temperature: 40 °C
Reaction time: 12 h
Yield: 38.5 %

Procedure:
Diethyl azodicarboxylate (4.3 g) was added all at once to a stirred mixture of 3-thietanol (2.0 g), N-hydroxyphthalimide (3.6 g) and triphenylphosphine (5.8 g) in dry tetrahydrofuran (100 ml) at room temperature. The temperature of the reaction mixture was raised to 40° C. The mixture became clear solution and was stirred for 12 hours at room temperature. Tetrahydrofuran was evaporated in vacuo and the residue was dissolved in ethyl acetate (50 ml). The insoluble substance was filtered off. The filtrate was washed three times with a saturated aqueous solution of sodium bicarbonate (50 ml) and with a saturated aqueous solution of sodium chloride (50 ml), dried over magnesium sulfate and evaporated. The residue was dissolved in methylene chloride (50 ml), subjected to column chromatography on silica gel and eluted with methylene chloride. The fractions containing the object compound were collected and evaporated in vacuo to give N-(3-thietanyloxy)phthalimide (2.0 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH:22]([OH:25])[CH:21]([NH2:26])[CH2:20][CH:19]1CC1C=CC=CC=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH:22]([OH:25])[CH:21]([NH:26][C:1](=[O:3])[CH3:2])[CH2:20][CH2:19]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC1CC(Cc2ccccc2)N(C(=O)OCc2ccccc2)CCC1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NC1CCN(C(=O)OCc2ccccc2)CCC1O
Reaction time: 1 h

Procedure:
3 mL acetic anhydride was added to 8.4 g benzyl 4-amino-5-hydroxy-azepane-1-carboxylic acid benzyl ester in 115 ml dichloromethane at 0° C. After 1 h at RT, saturated sodium bicarbonate was added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried over sodium sulphate, filtered and concentrated. The residue was purified by chromatographie on silica gel (ethyl acetate/hexane 2:1) to yield 4.5 g of the desired product. (M+H)+: 307
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
To a mixture of 4-methyl-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (10 mmol) and sodium bicarbonate (20 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (20 mmol) is added. After heating the reaction mixture at 70°-75° C. for 20 hours, the solvent is removed. The residue is redissolved in methylene chloride and washed with water. The organic fractions are combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture is chromatographed (silica gel, toluene/ethyl acetate, 7/3) to give 2-(4-methylphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17])([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([S:2][CH3:1])[CH:4]=1)=[O:17])([O-:12])=[O:11]
Reactant: CSc1cccc(N)c1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Product: CSc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1
Yield: 94.6 %

Procedure:
Using 3-methylthioaniline (2.1 ml, 16.5 mmol) and 3-nitrobenzoic acid (2.64 g, 15.0 mmol), the procedure of Reference Example 16 was repeated to obtain 4.09 g (94.6%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[NH:9][CH3:10].CCN=C=NCCCN(C)C.Cl.[NH2:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:33]=1.O>C(Cl)Cl>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([NH:31][C:14]([C:13]([NH:12][C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:9][CH3:10])=[O:11])=[C:2]([F:1])[CH:3]=2)([CH3:18])[CH3:17])=[O:16])=[CH:33][C:34]=1[C:40]([F:41])([F:42])[F:43])#[N:37]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CNC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1ccc(NC(C)(C)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.8 %

Procedure:
The title compound was made in accordance with General Method 1. 2-(3-Fluoro-4-methylcarbamoyl-phenylamino)-2-methyl-propionic acid (1.27 g) was dissolved in DCM. EDCI-HCl (1.91 g) was added to it and the reaction mixture was stirred for 5 min at RT. 4-Amino-2-(trifluoromethyl)benzonitrile (1.00 g) was added portionwise and stirring was continued for 5 h at RT. Water was added to the reaction mixture, and the product was extracted with DCM. The combined organic layer was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh silica gel) eluting with 5% MeOH-DCM to obtain 650 mg of 4-[1-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-1-methyl-ethylamino]-2-fluoro-N-methyl-benzamide, HPLC, Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase A:0.05% TFA, Mobile Phase B:ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min, 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 11.174 min, M+1: 423.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[C:16]2[CH:22]=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[I:25]I>CN(C=O)C>[I:25][C:22]1[C:16]2[C:17](=[N:18][CH:19]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:15]=2)[NH:20][CH:21]=1
Reactant: II
Reactant: c1ccc(Oc2ccccc2-c2cnc3[nH]ccc3c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1c[nH]c2ncc(-c3ccccc3Oc3ccccc3)cc12
Reaction time: 0.5 h

Procedure:
To a solution of the azaindole 25 (18.30 g, 63.9 mmol) in DMF (100 mL) was added KOH (13.27 g, 236.5 mmol) in a single portion. After 0.5 h, iodine (16.18 g, 63.9 mmol) was added in portions over a 3 min. period. After a further 1 h the reaction was quenched by the addition of a solution of sodium thiosulfate (70 g) in H2O (400 mL). The semisolid was filtered off, dissolved in dichloromethane. The solution and washed with saturated brine (1×), dried (MgSO4), and concentrated to afford the iodide 26, which was used directly in the next step without further purification. 1H NMR (400 MHz; CDCl3) δ6.92-6.95 (m, 2H), 7.01 (tt, J=7.3, 1.0 Hz, 1H), 7.08 (dd, J=8.1, 1.3 Hz, 1H), 7.23-7.30 (m, 3H), 7.36 (dt, J=7.3, 1.8 Hz, 1H), 7.40 (s, H), 7.54 (dd, J=7.6, 1.8 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H) and 11.06 (bs, 1H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:22])[F:21])[N:15]([CH3:23])[N:14]=2)[CH:9]=[CH:10][C:11]=1[Cl:12]>CO>[Cl:18][C:17]1[C:13]([C:8]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([CH2:5][O:2][CH3:1])[CH:7]=2)=[N:14][N:15]([CH3:23])[C:16]=1[O:19][CH:20]([F:22])[F:21]
Reactant: C[O-]
Reactant: Cn1nc(-c2ccc(Cl)c(CBr)c2)c(Cl)c1OC(F)F
Agent: [Na+]
Solvent: CO
Product: COCc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Temperature: 40 °C
Reaction time: 3 h

Procedure:
1.6 g (9.0 mmol) of a 30% strength by weight solution of sodium methylate in methanol was added dropwise to a solution of 2.3 g (6.0 mmol) of 3-(3-bromomethyl-4-chlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole in 60 ml of methanol. The reaction mixture was stirred at 40° C. for 3 hours and then concentrated. The residue was taken up in water and dichloromethane, after which concentrated hydrochloric acid was added until the acid reaction took place. Product remaining in the aqueous phase was extracted with dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and concentrated. Yield: 1.8 g.
Reaction SMILES: [OH-:1].[K+].CN(C)[C:5](=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21]>C(O)C>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:5]([OH:22])=[O:1]
Reactant: CN(C)C(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Yield: 92.9 %

Procedure:
To 40 ml of a 15% ethanol solution of potassium hydroxide was added 1.7 g of N,N-dimethyl-o-(2,6-dichloroanilino)phenylacetamide, and the mixture was agitated under reflux for 4 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and 30 ml of water was added to the residue and the mixture was made acidic by hydrochloric acid at a temperature lower than 5° C. The precipitated crystal was recovered by filtration under suction, washed with water and dried. Recrystallization from a mixed solvent of ether and petroleum ether gave 1.45 g of a colorless crystal having a melting point of 158° to 160° C. The yield was 92.9%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][C@H:17]([CH3:23])[C:18]([CH3:22])([CH3:21])[C:19]#[N:20].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][C@@H:17]([C:18]([C:19]#[N:20])([CH3:22])[CH3:21])[CH3:23])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: C[C@@H](N)C(C)(C)C#N
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C(C)(C)C#N
Temperature: 100 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (250 mg, 0.911 mmol) and (R)-3-amino-2,2-dimethylbutanenitrile hydrochloride (165 mg, 0.408 mmol) in DMF (10 mL) taken in a pressure tube (25 mL) was added DIPEA (0.477 mL, 2.73 mmol) at rt. The resulting reaction mixture was heated 100° C. and stirred for overnight. Reaction was monitored by LCMS. Reaction mass was quenched with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was dried and concentrated under reduced pressure to get crude as brown colored oil. The crude was purified by combiflash using 24 g silicycle column eluted with 50% EA in hexane. The fractions were concentrated under reduced pressure to get (R)-6-bromo-4-((3-cyano-3-methylbutan-2-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (165 mg, 0.408 mmol, 44.7% yield) as pale brown solid. 1HNMR (400 MHz, DMSO-d6) δ ppm: 11.16-11.13 (d, J=9.6 Hz, 1H), 8.32 (s, 1H), 7.96-7.93 (d, J=13.2 Hz, 2H), 7.92 (bs, 2H), 7.22-7.21 (d, J=1.6 Hz, 2H), 4.43-4.39 (q, J=6.4, 3.6 and 6.4 Hz, 1H), 1.43-1.35 (m, 9H). HPLC purity: Column: Sunfire C18 (4.6×150 mm, 3.5μ, Buffer: 0.05% TFA in H2O pH 2.5, Solvent A: Buffer: CH3CN (95:5). Solvent B: Buffer: CH3CN (5:95). Time: 0-10, 12-100, 15-100 min, Flow: 1.0 mL/min Retention Time: 9.68: Purity: 91.94%. LCMS Purity: Column: Purospher@star RP-18 (4×55) mm, 3 μm. Buffer: 20 mM NH4OAc in water Mobile Phase A: Buffer: CH3CN (90:10). Solvent B: Buffer: CH3CN (10:90).Flow: 2.5 mL/min, Time: 0-0, 2-100, 2.5-100, 3.0-0 min. Retention Time: 1.688 min. Purity: 91.5% (m/z=348.2 M-2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:12])[CH:3]=1.N1C=CC=CC=1.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>ClCCl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[C:4]([Cl:12])[CH:3]=1)=[O:22]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1ccc(C(F)(F)F)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)c(Cl)c1)C(Cl)(Cl)Cl
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solution of 4-amino-2-chlorobenzotrifluoride (300 mg) and pyridine (243 mg) in dichloromethane (10 mL) was added a solution of trichloroacetyl chloride (279 mg) in dichloromethane (5 mL) dropwise. The solution was stirred for 2 hrs and then concentrated at reduced pressure. The residue was purified by silica gel chromatography eluting with 0-10% ethyl acetate in hexane to give the title compound as a white solid (360 mg, 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([OH:15])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[NH:29][C:28]1=[O:36].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>C(C(C)=O)C(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:15])[CH:9]2[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][N:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[NH:29][C:28]3=[O:36])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: O=c1[nH]c2ccccc2n1CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
2.1 g (0.007 mole) of 4-[bis(4-fluorophenyl)hydroxymethyl]piperidine, 1.8 g (0.007 mole) of 1-(1-bromo-3-propyl)-1,3-dihydro-2(2H)-benzimidazolone, 0.85 g (0.008 mole) of Na2CO3 and a few crystals of NaI are heated for 5 h at reflux temperature in 60 ml of methyl isobutyl ketone. The solvent is evaporated off, the residue is taken up with a mixture of water and CH2Cl2, and the organic phase is dried and evaporated down. A solid residue is obtained which is chromatographed on a column of silica (eluent: CH2Cl2/MeOH 97/3, 96/4 and then 94/6). The pure fractions are evaporated down, the evaporation residue is taken up with ether and a white product is filtered off and crystallized from 90 ml of ethyl acetate. M.p.=141°-143° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH:16]=O)=[C:11]([Cl:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[C:23]([CH:37]=[CH:38][C:39]=1[NH2:40])[C:24]([NH:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:25].OOS([O-])=O.[K+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([C:16]2[NH:20][C:21]3[CH:22]=[C:23]([C:24](=[O:25])[NH:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[CH:37]=[CH:38][C:39]=3[N:40]=2)=[C:11]([Cl:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(C=O)c(Cl)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1
Reaction time: 1 h

Procedure:
A mixture of 3-(3,5-dichloro-4-formylphenyl)-propionic acid tert butyl ester (440 mg, 0.8 mmol), 3,4-diamino-N-quinolin-2-yl-benzamide (403 mg, 1 eq) and oxone (600 mg, 0.67 eq) in DMF (10 mL)/H2O (1 mL) was stirred vigorously open to air for 1 h. The mixture was partitioned between water and ethyl acetate. The ethyl acetate fractions were dried over magnesium sulphate and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give 3-{3,5-dichloro-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl}-propionic acid tert-butyl ester as an orange foam. 1H-NMR (CDCl3, 400 MHz): δ 8.60 (d, J=8.97 Hz, 1H), 8.38 (s, 1H), 8.21-8.29 (m, 1H), 7.95 (dd, J=8.34, 1.26 Hz, 1H), 7.82-7.91 (m, 2H), 7.71 (ddd, J=8.37, 6.98, 1.33 Hz, 2H), 7.47-7.56 (m, 1H), 7.17-7.24 (m, 2H), 2.85 (t, J=7.33 Hz, 2H), 2.50-2.57 (m, 2H), 1.42-1.48 (m, 10H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.C([C@H]1C[O:17][C:16]([CH3:20])([CH3:19])[N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:19][C:16]1([CH3:20])[N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:2]([CH:3]=[CH2:4])[CH2:1][O:17]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a suspension of methyl triphenylphosphonium bromide (5.63 g, 15.8 mmol) in tetrahydrofuran (140 mL) was added 2.5 M n-butyllithium in hexane (7.35 mL, 18.4 mmol). The deep red solution was stirred at 0° C. for 1 h. Then a solution of tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (from Aldrich, 3.01 g, 13.1 mmol) in tetrahydrofuran (7.3 mL) was added drop wise at 0° C. The red solution was warmed to room temperature and stirred for 12 h. Hexanes was added to the reaction mixture in 4:1 (v/v) ratio. The suspension was filtered through Celite and the filtrate concentrated. The resultant residue was purified by flash chromatography (eluting with 10% ethyl acetate in hexanes) to give the desired compound as colorless oil (1.92 g, 64%).