Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][CH:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:14][CH2:13]1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)CN1CCC(Cc2ccccc2)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCC(Cc2ccccc2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 44.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-benzylpiperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 220, (S)-3-(benzyloxy)-2-(2-(4-benzylpiperidin-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (21.4 mg, 44.9%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.93 (d, 1H), 7.60 (d, 2H), 7.26-7.34 (m, 7H), 7.14-7.24 (m, 5H), 6.98-7.04 (m, 4H), 4.67-4.71 (m, 1H), 4.52 (s, 2H), 3.68-3.80 (m, 2H), 2.92 (d, 2H), 2.78-2.87 (m, 2H), 2.47-2.50 (m, 2H), 1.94-2.02 (m, 2H), 1.43-1.55 (m, 3H), 1.17-1.24 (m, 2H). MS (EI) for C36H38FN3O4. found 596.7 (MH+).
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[C:28]([O:37][CH3:38])[C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1>>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][N:18]([C:23]3[C:32]4[C:27](=[C:28]([O:37][CH3:38])[C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][N:24]=3)[CH2:17][CH2:16]2)[C:4]1=[O:21]
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Reactant: COc1cc2c(Cl)ncnc2c(OC)c1OC
Agent: Br
Product: COc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2c(OC)c1OC
Yield: 25 %

Procedure:
The procedure similar to that described in Example 57 was repeated, except that 1.06 g (3.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-6,7,8-trimethoxyquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 365.1 mg (yield: 25%) of Compound 86 was obtained as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[CH2:7][C@H:8]([NH:11]C(OCC1C2CC3C(=CC=CC=3)C=2C=CC=1)=O)[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].C(NCC)C>CN(C=O)C>[C:1]([O:5][C:6](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[CH2:7][C@H:8]([NH2:11])[CH:9]=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(C[C@@H](C=O)NC(=O)OCc1cccc2c1Cc1ccccc1-2)=NNC(N)=O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)(C)OC(C[C@H](N)C=O)=NNC(N)=O

Procedure:
(3S)-3-(1-Fluorenylmethyloxycarbonylamino)-4-oxobutyric acid tert-butyl ester semicarbazone (210 mg, 0.45 mol, Prepared in a similar manner to the benzyloxycarbonyl analog in Graybill et al., Int. J. Protein Res., 44, pp. 173-82 (1994).) was dissolved in 10 ml of DMF and 2 ml of diethylamine and stirred for 2 h. The reaction was concentrated in vacuo to give (3S)-3-amino-4-oxobutyric acid tert-butyl ester semicarbazone. The 0° C. solution of the above residue and 603a (200 mg, 0.42 mmol) in 5 ml of DMF and 5 ml of CH2Cl2 was treated with 1-hydroxybenzotriazole (57 mg, 0.42 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg, 0.51 mmol). The reaction was stirred at RT for 18 h, poured onto EtOAc (75 ml) and washed with aq. 0.3 N KHSO4, sat. aq. NaHCO3 and sat. aq. NaCl, dried over NaSO4 and concentrated in vacuo. Chromatography (flash, SiO2, 0% to 4% MeOH/0.1% NH4OH/CH2Cl2) to give 240 mg (83%) of 604a.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.C(N(CC)CC)C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>O1CCCC1>[C:30]([O:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1)(=[O:33])[CH:31]=[CH2:32]
Reactant: C=CC(=O)Cl
Reactant: O=C1NCC(CO)O1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OCC1CNC(=O)O1

Procedure:
105 g (0.90 mol.) of 5-hydroxymethyl-oxazolidin-2-one were placed into a one liter, three necked, round bottomed flask equipped with a paddle stirrer and thermometer. This was followed by 500 ml of tetrahydrofuran, 101 g (1.0 mol.) of triethylamine and 0.5 g of phenothiazine. Stirring was started as 90 g (1.0 mol.) of acryloyl chloride were added dropwise in such a way that the contents of the flask were maintained at 30° C. or less. When the addition was complete, the contents were stirred overnight at room temperature. The triethylamine hydrochloride was filtered and the solution was allowed to stand over NaHCO3 and Na2SO4. The solution was filtered, transferred to a one liter, round bottomed flask and placed on a rotoevaporator. The solution was concentrated by purging with a stream of air while rotating the flask. The resulting liquid was confirmed by 13C NMR to contain a mixture of the desired product and unreacted starting material.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCS(=O)(=O)Cl
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CC)c1
Reaction time: 48 h
Yield: 52.3 %

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 200 mg, 0.735 mmol) in dichloromethane (5 ml) at room temperature was added pyridine (0.15 ml, 1.84 mmol) then dropwise over 5 minutes ethanesulfonylchloride (0.131 ml, 177 mg, 1.38 mmol). The mixture was stirred for 48 hours, concentrated in vacuo and the residue was purified by silica (10 g) column chromatography eluting with ethyl acetate then 90:10:1 ethyl acetate:methanol:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (140 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][C:12]=1[CH3:13].[NH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.O>C(O)(=O)C>[CH3:13][C:12]1[CH:11]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:9](=[O:10])[N:14]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:6]2=[O:8]
Reactant: Cc1cc2c(cc1C)C(=O)OC2=O
Reactant: Nc1cccnc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1C)C(=O)N(c1cccnc1)C2=O
Yield: 82.9 %

Procedure:
4,5-dimethylphthalic anhydride (2.0 g, 11 mmol) and 3-aminopyridine (1.0 g, 11 mmol) were heated under reflux in acetic acid (30 ml) for 1.5 hrs. After standing to cool, water was added thereto, the precipitated crystals were collected by filtration, washed with water, followed by drying to give 2.3 g of 5,6-dimethyl-2-(3-pyridyl)isoindolin-1,3-dione.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH:15]2[CH2:27][OH:28])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29].O1CCOCC1>>[ClH:29].[CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[CH2:27][OH:28])=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Cc3ccccc3)cn2)C(CO)C1
Agent: Cl
Solvent: C1COCCO1
Product: OCC1CNCCN1c1ncc(Cc2ccccc2)cn1
Yield: 100 %

Procedure:
A solution of tert-butyl 4-(5-benzylpyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (400 mg, 1.042 mmol) in 4 M HCl/dioxane (20 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to afford (1-(5-benzylpyrimidin-2-yl)piperazin-2-yl)methanol HCl salt (294 mg, 100%). MS (ES+) C16H20N4O requires: 284, found: 285 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].[CH2:12](Br)[CH2:13]Br.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:10]#[N:11])[CH2:13][CH2:12]1
Reactant: BrCCBr
Reactant: COc1ccccc1CC#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1C1(C#N)CC1
Reaction time: 20 h

Procedure:
A mixture of (2-methoxyphenyl)acetonitrile (147 g and 1,2-dibromomethane (168 ml) in dimethylsulphoxide (250 ml) was added over 1 hour to a stirred suspension of powdered potassium hydroxide (250 g) and 18-Crown-6 (5 g) in dimethylsulphoxide (1200 ml) at 25° C. Stirring was continued for 20 hours. Water (1200 ml) was added and the mixture extracted with ether to give a crude oil which was purified by distillation (b.p. 102°/0.25) to give 1-(2-methoxyphenyl)cyclopropane carbonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].B(F)(F)F.CCOCC.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)([CH3:22])[CH2:6][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccc(Cl)cc1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4-Benzyloxyphenyl)-3-hydroxy-2-(4-chlorophenoxy)-2-methylpropionic acid ethyl ester (9.5 mmol) in anhydrous CH2Cl2 (30 mL) was cooled to 0° C. and treated with BF3-Et2O (1.16 mL, 9.5 mmol) and triethylsilane (1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and gradually warmed to ambient temperature. Saturated aqueous Na2CO3 (15 mL) was added and the mixture was stirred vigorously. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to produce 3-(4-benzyloxyphenyl)-2-(4-chlorophenoxy)-2-methylpropionic acid ethyl ester as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:29])[CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[N:27][OH:28])[CH:21]=1)=[O:17])(C)(C)C>ClCCl>[OH:28][N:27]=[CH:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][NH:18][C:16](=[O:17])[CH2:15][CH2:14][C:13]([OH:29])=[O:12]
Reactant: CC(C)(C)OC(=O)CCC(=O)NCc1cccc(C=NO)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC(=O)NCc1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 145 %

Procedure:
Trifluoroacetic acid (7 ml) was added to a solution of crude N-[3-((hydroxyimino)methyl)benzyl]succinamic acid tert-butyl ester (249 mg, 0.81 mmol) in dichloromethane (7 ml). The reaction mixture was stirred for 55 min at room temperature. The solvent was removed in vacuo. The residue was redissolved in dichloromethane (50 ml). The solvent was removed in vacuo. The latter procedure was repeated twice to give 294 mg of crude N-[3-(hydroxyiminomethyl)benzyl]succinamic acid, which was used in the next step without further purification.
Reaction SMILES: O.NN.[NH2:4][C:5]1[C:6]([C:23]2[O:27][C:26]([NH:28][C:29](=[O:42])[CH2:30][N:31]3C(=O)C4C(=CC=CC=4)C3=O)=[N:25][N:24]=2)=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:9][N:10]=1.C(Cl)Cl>CO>[NH2:31][CH2:30][C:29]([NH:28][C:26]1[O:27][C:23]([C:6]2[C:5]([NH2:4])=[N:10][CH:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:18])=[O:19])=[CH:15][CH:16]=3)[N:7]=2)=[N:24][N:25]=1)=[O:42]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(NC(=O)CN4C(=O)c5ccccc5C4=O)o3)n2)cc1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(NC(=O)CN)o3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
Hydrazine hydrate (8.065 mg, 7.838 μL, 0.1611 mmol) was added to a stirred suspension of N-(5-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)-2-(1,3-dioxoisoindolin-2-yl)acetamide (147 mg, 0.1611 mmol) in MeOH (5 mL)/CH2Cl2 (5 mL) and the reaction mixture was allowed to stir at ambient temperature for 2 hours. A further portion of hydrazine hydrate (16.13 mg, 15.68 μL, 0.3222 mmol) was added and the reaction stirred for a further 16 hours. The solvent was removed in vacuo and residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (10 mg, 11%); 1H NMR (400.0 MHz, DMSO) d 1.18 (d, 6H), 3.50-3.53 (m, 1H), 4.11 (s, 1.4H), 4.33 (s, 0.6H), 7.81 (s, 2H), 7.91 (d, 2H), 8.53 (d, 2H), 9.07 (s, 1H), 10.99 (s, 0.7H) and 11.16 (s, 0.3H) ppm; MS (ES+) 418.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][O:36][CH2:35]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][O:36][CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OCC1CCCOC1)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CC2CCCOC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
450 mg (purity 94%, 1.13 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.24 ml (1.24 mmol, 1.1 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 467 mg (1.69 mmol, 1.5 eq.) of tetrahydro-2H-pyran-3-ylmethyl trifluoromethanesulphonate (racemate) were reacted according to General Method 7B. Yield: 451 mg (purity 82%, 69% of theory)
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([CH2:17][OH:18])([CH2:12][O:13][CH2:14][CH:15]=[CH2:16])[CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[CH:2]=[CH2:3].[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>C1COCC1>[CH2:9]([O:8][CH2:7][C:6]([CH2:17][O:18][CH2:23][CH:22]=[CH2:21])([CH2:12][O:13][CH2:14][CH:15]=[CH2:16])[CH2:5][O:4][CH2:1][CH:2]=[CH2:3])[CH:10]=[CH2:11]
Reactant: C=CCBr
Reactant: C=CCOCC(CO)(COCC=C)COCC=C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCC(COCC=C)(COCC=C)COCC=C
Yield: 99.2 %

Procedure:
30.7 g (0.12 mol) of pentaerythritol triallylether was dissolved in 100 ml of dry THF and 4.4 g (0.18 mol) of NaH was added in small portions while stirring. After gas evolution had ceased, 16 ml (0.18 mol) of allyl bromide was added and the reaction mixture was stirred overnight at room temperature. In order to drive the reaction to completion, it was subsequently brought to reflux and stirred for 1 hr. The precipitated salts were removed by filtration over ca. 1 cm of Celite 545 and the solvent and excess allyl bromide were evaporated, yielding 35.3 g (99.5%) of a pale yellow oil. The raw product was dissolved in 100 ml of diethyl ether and washed subsequently with 50 ml of 0.1 M aqueous KHSO4 and 50 ml of saturated aqueous NaHCO3 solution. Drying the organic layer with MgSO4 and evaporation of the solvent yielded 34.4 g (97%) of the pure product.
Reaction SMILES: [F:1][C:2]([F:19])([O:7][C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].O.[NH2:21][NH2:22]>CCO>[F:1][C:2]([F:19])([O:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([NH:21][NH2:22])=[O:13])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CCOC(=O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Temperature: 85 °C
Yield: 73 %

Procedure:
To a solution of ethyl 4-(perfluoroethoxy)benzoate (4.58 g, 16.1 mmol) in EtOH (16 mL) was added hydrazine monohydrate (1.96 mL, 40.3 mmol) and the reaction was heated at 85° C. for 36 hours. The reaction was cooled and poured into ice water (100 mL). A white gel-solid formed and was filtered through a Büchner funnel under vacuum. The solid was dried in a vacuum oven at 45° C. overnight to provide 4-(perfluoroethoxy)benzohydrazide as an off-white solid (3.177 g, 73%): mp 117-119.5° C.; 1H NMR (400 MHz, CDCl3) δ 7.83-7.76 (m, 2H), 7.36 (s, 1H), 7.31 (d, J=8.8 Hz, 2H), 4.13 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −86.01, −87.83; ESIMS m/z 269 [(M−H]−).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[N:27]1[CH2:32][C@H:31]([CH3:33])[N:30]([CH3:34])[C@H:29]([CH3:35])[CH2:28]1)[NH:23][CH2:22][CH2:21]2>>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([N:23]1[C:24]2[C:20](=[CH:19][C:18]([O:17][CH3:16])=[C:26]([N:27]3[CH2:32][C@H:31]([CH3:33])[N:30]([CH3:34])[C@H:29]([CH3:35])[CH2:28]3)[CH:25]=2)[CH2:21][CH2:22]1)=[O:15]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1F
Reactant: COc1cc2c(cc1N1C[C@@H](C)N(C)[C@@H](C)C1)NCC2
Product: COc1cc2c(cc1N1C[C@@H](C)N(C)[C@@H](C)C1)N(C(=O)Cc1cccc(C(F)(F)F)c1F)CC2

Procedure:
The title compound was prepared from 2-fluoro-3-trifluoromethylphenylacetic acid (155 mg, 0.70 mmole) and D3 (150 mg, 0.54 mmole) using a similar procedure to Example 8. The product was obtained as a pale yellow oil (210 mg, 81%), which was converted to its hydrochloride salt as a beige solid.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:10]2[N:11]([CH:18]=[C:19]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=3)[CH:20]=2)[N:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])[CH3:2].[C:34]([C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38])#[N:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:34]([C:36]([CH3:41])([CH3:40])[C:37]([N:6]1[CH2:7][C@H:3]([CH2:1][CH3:2])[C@H:4]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH2:5]1)=[O:38])#[N:35]
Reactant: CC(C)(C#N)C(=O)O
Reactant: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H]1CN(C(=O)C(C)(C)C#N)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A mixture of 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, 2hydroiodide (30 mg, 0.042 mmol), 2-cyano-2-methylpropanoic acid (14.39 mg, 0.127 mmol), BOP (56.3 mg, 0.127 mmol) and Hunig's Base (0.052 mL, 0.297 mmol) in DMF (0.25 mL) was stirred at rt for 2 hr. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (6 mg, 0.011 mmol, 26% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.79 (dd, J=9.4, 2.0 Hz, 1H), 8.14 (d, J=5.0 Hz, 1H), 8.06-7.93 (m, 2H), 7.38 (dd, J=8.2, 3.2 Hz, 1H), 7.20-7.10 (m, 1H), 5.07-4.87 (m, 1H), 4.57 (s, 2H), 4.36-4.14 (m, 2H), 3.97 (s, 2H), 3.95-3.68 (m, 2H), 3.46 (s, 3H), 2.68-2.44 (m, 1H), 1.83-1.39 (m, 8H), 1.07-0.95 (m, 3H). MS (ES+) m/z: 547.1 (M+H); LC retention time: 1.19 min (analytical LCMS Method H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:11](=[O:13])[CH3:12]>>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([CH2:8][CH:11]([OH:13])[CH3:12])[CH:7]=1
Reactant: Cc1cnc(C#N)c(Br)c1
Reactant: CC=O
Product: CC(O)Cc1cnc(C#N)c(Br)c1

Procedure:
3-Bromo-5-(2-hydroxypropyl)picolinonitrile was prepared from 3-bromo-5-methylpicolinonitrile (from the previous step) and acetaldehyde following the procedures described for Example 53/Step 3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[S:9][C:10]([C:27](=[O:29])[CH3:28])=[CH:11][C:12]=1[S:13](=[O:26])(=[O:25])[N:14]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:15])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Si:38](OS(C(F)(F)F)(=O)=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[S:9][C:10]([C:27]([O:29][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[CH2:28])=[CH:11][C:12]=1[S:13](=[O:25])(=[O:26])[N:14]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)c(NC(=O)OC(C)(C)C)s1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)c(NC(=O)OC(C)(C)C)s1
Reaction time: 0.5 h

Procedure:
To a solution of (5-acetyl-3-{[2-(4-fluorophenyl)ethyl]methylsulfamoyl}thiophene-2-yl)-carbamic acid t-butyl ester (the compound of Preparation Example 111) (946 mg) in dichloromethane (8 mL) was added triethylamine (0.58 mL) and 0.71 mL of t-butyldimethylsilyltrifluoromethane sulfonate (0.71 mL) on an ice bath. After stirring for 30 minutes, an aqueous solution of saturated sodium bicarbonate was added, and the solution was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the residue that was obtained upon removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate) and, the title compound (985 mg) was obtained as a colorless oily matter.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([OH:19])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:14]([CH:18]=1)[C:15]([O:17][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:16]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
(Bromomethyl)benzene (34.2 ml, 288 mmol) was added over 5 minutes to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (28.4 g, 131 mmol) and potassium carbonate (45.2 g, 327 mmol) in acetone (300 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. After filtering, the filtrate was evaporated to give a light yellow oil, dried in a vacuum to give yellow solid, which was washed by petroleum ether (300 ml×2), filtered and dried in vacuum to yield the title compound as a white solid. 48.2 g.